Broad Efficacy of Scavenging Free Radicals: *Cordyceps* sp.

*Loknath Deshmukh, Rajendra Singh and Sardul Singh Sandhu*

## **Abstract**

Scavenging free radical potency of cordycepin is the major bioactive segment extricated from *Cordyceps* species. In some new years, *Cordyceps* has gotten growing thought inferable from its distinctive restorative/pharmacological tests. This assessment reviews continuous explores on the counter oxidant impacts and the associated analyses of *Cordyceps* species. The results from our review show that *Cordyceps* of the cordycepin applies protective effects against hostile to oxidant injury for certain, afflictions including constant obstructive pneumonic infection (COPD), hepatitis, asthma, cerebral paralysis, Parkinson's illness (PD), coronary course sickness (CAD), Alzheimer illness, respiratory failure, malignancy infection, maturing, waterfalls, and mind brokenness. *Cordyceps* coordinates the NF-κB, RIP2/ Caspase-1, Akt/GSK-3β/p70S6K, TGF-β/Smads, and Nrf2/HO-1 hailing pathways among others of cordycepin. A couple of assessments focusing in on *Cordyceps* auxiliaries were surveyed and found to down metabolic speed of *Cordyceps* and augmentation its bioavailability. In addition, cordycepin further developed opposition, prevented the duplication of viral RNA, and covered cytokine storms, therefore proposing its capacity to treat COVID-19 and other viral defilements. From the accumulated and assessed information, this article gives the speculative reason to the clinical usages of cordycepin and inspects the way for future assessments focusing in on expanding the restorative use of *Cordyceps* species. Cordycepin and its analogs show unfathomable potential as the accompanying new class of against oxidant specialists.

**Keywords:** *Cordyceps* species, anti-oxidant, cordycepin, oxidant diseases, fruiting body and secondary metabolite, pharmacodynamics

## **1. Introduction**

*Cordyceps* species (Ascomycetes *genus*) is a bug parasitizing development; they are thusly entomopathogenic life forms. The name *Cordyceps* begins from the Latin words line and ceps, meaning 'club' and 'head', independently. From a genuine perspective "summer grass, winter worm", Chinese caterpillar development, is the Chinese name given to the complex of hatchlings and parasites [1–3] which this helpful mushroom has been found ordinarily at high heights of around 14,000 ft. in the Himalayan territories including Nepal, China, Bhutan, Thailand, Tibet, and India [4]. The *Cordyceps* as*genus*ment consolidates more than 400 species, among which *Cordyceps* species have been used generally for millennia in China as a food, tonic, and natural drug for various prosperity related issues, for instance, kidney and lung brokenness, weakness, and exhaustion [5, 6]. This development lives in

a general sense on the highest point of the hatchling of one explicit *genus* of moth, Hepialus armoricanus, and yet is unexpectedly found creating on other moth species [7]. It is generally called 'Dong Chong Xia Cao' in Chinese and 'Tockukaso' in Japanese, implying 'winter-frightening little animal and summer-plant' because of the creating cycle: the development at first parasitizes the hatchling of specific species Hepiaidae, outlining a parasitic complex that includes the leftover pieces of the caterpillar and the stroma of the creature [8]. *Cordyceps* are a stunning cordycepin wellspring of bioactive metabolites that show various clinically asserted advantages for human prosperity. Since people have an inclination towards trademark/ home grown medicines, the usage of *Cordyceps* as a trademark remedial mushroom is unpreventable [9]. The bio metabolite cordycepin was first isolates from the matured supply of the therapeutic mushroom *Cordyceps* militaris [10]. Which is an entomopathogen creature that grows parasitically on lepidopteron hatchlings and bug pupae. The family *Cordyceps* is prominent in standard Chinese medicine and shows a variety of clinical prosperity impacts including hostile to diabetic, immunomodulatory, against oxidant, against oxidant, anticancer, cardiovascular effects, against fibrotic, and against microbial exercises [11–13]. *Cordyceps* sp. has been represented to have a various extent of pharmacological effects of which, its antitumor, against angiogenic, and antagonistic to oxidative properties are for the most part examined [14, 15]. Growing considers showing that it applies solid malignant growth counteraction specialist exercises in different cell types including macrophages, chondrocytes, glial, and lung epithelial cells [16]. Then, at that point, against oxidant impacts are furthermore found in liver, and LPS-impelled exceptional lung injury, alcohol started Hyperlipidemia, ominously vulnerable asthma, doxorubicin-instigated, cardiotoxicity, irritation actuated osteoporosis, and cerebral ischemia–reperfusion injury when various animal mice models are used [17–19]. With a rising income in cordycepin, the usage of assistant changes to block the metabolic speed and augmentation efficiency has been explored [20]. There are as of now a gigantic number of studies zeroing in on its enemy of oxidant impacts; regardless, an aggregate and productive overview of composing is inadequate. In this review, we surveyed the late enemy of oxidant focuses on cordycepin to choose its future perspective as an enemy of oxidant drug and to clarify its critical enemy of oxidant systems of activity.

## **2. Oxidative stress and damage to nucleic acid, protein and lipids**

Oxidative mischief to nucleic acid (DNA), proteins, and various macromolecules gathers with age and has been conjectured to be a major, yet by all record not the sole, sort of endogenous damage inciting developing [6, 21, 22]. Superoxide (0₂), hydrogen peroxide (H₂0₂), and hydroxyl progressive (− OH), which are mutagens conveyed by radiation, are also results of normal processing [12, 23]. Endogenous oxidants similarly hurt proteins and lipids [24] have demonstrated that the activity of proteolytic mixtures that hydrolyze oxidized proteins isn't fit thwart an age-related augmentation of oxidized proteins. In two human diseases related with inauspicious developing, Werner issue, and progeria, oxidized proteins increase at tons higher rate than is common [25]. Lipid peroxidation offers to rise to mutagenic lipid epoxides, lipid hydro-peroxides, lipid alkoxyl and peroxyl fanatics, and enals (a,4-unsaturated aldehydes) [26]. Singlet oxygen, a high-energy and mutagenic sort of oxygen, are frequently conveyed by the move of energy from light, the respiratory burst from neutrophils, or lipid peroxidation [27]. Animals have different malignancy avoidance specialist securities, yet since these watchmen aren't incredible, some DNA is oxidized. Oxidatively hurt DNA is fixed

**325**

*Broad Efficacy of Scavenging Free Radicals:* Cordyceps *sp.*

by intensifies that remove the wounds, which are then released inside the pee. Strategies are made to take a gander several of those separated hurt bases inside the pee of model rodents and others [28], basically all of which show up on the grounds that the free base from a fix by glycosylases. We check that the quantity of oxidative hits to DNA per cell daily is around 100,000 inside the model rodents and around 10,000 inside the human. DNA-fix synthetics capably dispense with most, yet not all, of the wounds outlined [6, 29–31] for instance, the significant change repeat in human lymphocytes, of which the responsibility of oxidative DNA bruises is dark, is around numerous occasions more vital in elderly people than in youths [32]. Mitochondrial DNA (mtDNA) from rat liver has in more than numerous occasions the level of oxidative DNA hurt than does nuclear DNA from an indistinguishable tissue [16, 33]. This extension could be because of a shortfall of mtDNA fix proteins, a shortfall of histones getting mtDNA, and subsequently the closeness of mtDNA to oxidants delivered during natural cycle. The cell shields itself against this high speed of mischief by a uniform turnover of mitochondria, thusly presumably killing those hurt mitochondria that produce extended oxidants. Notwithstanding this turnover, oxidative wounds appear to gather with age in mtDNA at a preferable rate over in nuclear DNA [34, 35]. Fluorescent tones, which are accepted to be relied upon somewhat to crosslinks among protein and lipid peroxidation things, moreover increase with age [36]. The significance of oxidative DNA wounds in illness and developing is highlighted by the presence of express fix glycosylases that separate these injuries from DNA. Because of 8-oxo-2′- deoxy-guanosine, a physical issue molded from oxidative mischief to guanine stores in DNA, loss of a particular glycosylase development prompts a reasonable extension inside the unconstrained change rate [12, 20, 37, 38], exhibiting the trademark mutagenic ability of this DNA sore. Various other oxidative DNA injuries are probably going to be huge too [39].

*Cordyceps* sp. cordycepin (3′-deoxyadenosine) prominent as purine or pyrimidine nucleobase adenosine, cytidine, and guanosine straightforward that have particular sort of bioactivities [40]. The cordycepin will be changed over into 5′-mono, di, and triphosphates and thusly obstruct the advancement of ribose-phosphate pyrophospho kinase and 5-phosphoribosyl-1-pyrophosphate amido-transferase in the again purines biosynthesis, just as the nucleic acids, mix causing the counter metastatic, antitumor and antimicrobial results [12, 41, 42]. Similarly, cordycepin with its enemy of leukemic limit normally get along with adenosine deaminase inhibitor and this will cause the inhibitory effect on happen which serves to analogs of 2′, 5′-oligoadenylate towards the human immunodeficiency contamination illness [43]. Immense degree refined of mycelial through designed can be used as another wellspring of cordycepin on account of its limited total in a typical source. Tow stage control of deteriorated oxygen or development of NH4+ to the brought down medium can help with working on the formation of cordycepin [44]. Despite creation using development advancement, cordycepin could be in like manner conveyed misleadingly. In any case, the manufactured blend has some hindrance, for instance, the trouble of the cycle and the utilization of gigantic volume of normal solvents which decrease the allure of this cycle [18, 45]. Exploration that the lifestyle created on xylose showed high creation yield of cordycepin on dry biomass. Standing out xylose from other carbon sources, a lot of essentially up-coordinated characteristics in xylose were progressed in pentose and glucoronate interconversion, and cordycepin biosynthesis [46]. The place of the current examination was to choose if cordycepin controls duplication, development, and angiogenesis in a

*DOI: http://dx.doi.org/10.5772/intechopen.99405*

**3. Sources and effects of cordycepin**

*Broad Efficacy of Scavenging Free Radicals:* Cordyceps *sp. DOI: http://dx.doi.org/10.5772/intechopen.99405*

*Antioxidants - Benefits, Sources, Mechanisms of Action*

a general sense on the highest point of the hatchling of one explicit *genus* of moth, Hepialus armoricanus, and yet is unexpectedly found creating on other moth species [7]. It is generally called 'Dong Chong Xia Cao' in Chinese and 'Tockukaso' in Japanese, implying 'winter-frightening little animal and summer-plant' because of the creating cycle: the development at first parasitizes the hatchling of specific species Hepiaidae, outlining a parasitic complex that includes the leftover pieces of the caterpillar and the stroma of the creature [8]. *Cordyceps* are a stunning cordycepin wellspring of bioactive metabolites that show various clinically asserted advantages for human prosperity. Since people have an inclination towards trademark/ home grown medicines, the usage of *Cordyceps* as a trademark remedial mushroom is unpreventable [9]. The bio metabolite cordycepin was first isolates from the matured supply of the therapeutic mushroom *Cordyceps* militaris [10]. Which is an entomopathogen creature that grows parasitically on lepidopteron hatchlings and bug pupae. The family *Cordyceps* is prominent in standard Chinese medicine and shows a variety of clinical prosperity impacts including hostile to diabetic, immunomodulatory, against oxidant, against oxidant, anticancer, cardiovascular effects, against fibrotic, and against microbial exercises [11–13]. *Cordyceps* sp. has been represented to have a various extent of pharmacological effects of which, its antitumor, against angiogenic, and antagonistic to oxidative properties are for the most part examined [14, 15]. Growing considers showing that it applies solid malignant growth counteraction specialist exercises in different cell types including macrophages, chondrocytes, glial, and lung epithelial cells [16]. Then, at that point, against oxidant impacts are furthermore found in liver, and LPS-impelled exceptional lung injury, alcohol started Hyperlipidemia, ominously vulnerable asthma, doxorubicin-instigated, cardiotoxicity, irritation actuated osteoporosis, and cerebral ischemia–reperfusion injury when various animal mice models are used [17–19]. With a rising income in cordycepin, the usage of assistant changes to block the metabolic speed and augmentation efficiency has been explored [20]. There are as of now a gigantic number of studies zeroing in on its enemy of oxidant impacts; regardless, an aggregate and productive overview of composing is inadequate. In this review, we surveyed the late enemy of oxidant focuses on cordycepin to choose its future perspective as an enemy of oxidant drug and to clarify its critical enemy

**2. Oxidative stress and damage to nucleic acid, protein and lipids**

Oxidative mischief to nucleic acid (DNA), proteins, and various macromolecules gathers with age and has been conjectured to be a major, yet by all record not the sole, sort of endogenous damage inciting developing [6, 21, 22]. Superoxide (0₂), hydrogen peroxide (H₂0₂), and hydroxyl progressive (− OH), which are mutagens conveyed by radiation, are also results of normal processing [12, 23]. Endogenous oxidants similarly hurt proteins and lipids [24] have demonstrated that the activity of proteolytic mixtures that hydrolyze oxidized proteins isn't fit thwart an age-related augmentation of oxidized proteins. In two human diseases related with inauspicious developing, Werner issue, and progeria, oxidized proteins increase at tons higher rate than is common [25]. Lipid peroxidation offers to rise to mutagenic lipid epoxides, lipid hydro-peroxides, lipid alkoxyl and peroxyl fanatics, and enals (a,4-unsaturated aldehydes) [26]. Singlet oxygen, a high-energy and mutagenic sort of oxygen, are frequently conveyed by the move of energy from light, the respiratory burst from neutrophils, or lipid peroxidation [27]. Animals have different malignancy avoidance specialist securities, yet since these watchmen aren't incredible, some DNA is oxidized. Oxidatively hurt DNA is fixed

**324**

of oxidant systems of activity.

by intensifies that remove the wounds, which are then released inside the pee. Strategies are made to take a gander several of those separated hurt bases inside the pee of model rodents and others [28], basically all of which show up on the grounds that the free base from a fix by glycosylases. We check that the quantity of oxidative hits to DNA per cell daily is around 100,000 inside the model rodents and around 10,000 inside the human. DNA-fix synthetics capably dispense with most, yet not all, of the wounds outlined [6, 29–31] for instance, the significant change repeat in human lymphocytes, of which the responsibility of oxidative DNA bruises is dark, is around numerous occasions more vital in elderly people than in youths [32]. Mitochondrial DNA (mtDNA) from rat liver has in more than numerous occasions the level of oxidative DNA hurt than does nuclear DNA from an indistinguishable tissue [16, 33]. This extension could be because of a shortfall of mtDNA fix proteins, a shortfall of histones getting mtDNA, and subsequently the closeness of mtDNA to oxidants delivered during natural cycle. The cell shields itself against this high speed of mischief by a uniform turnover of mitochondria, thusly presumably killing those hurt mitochondria that produce extended oxidants. Notwithstanding this turnover, oxidative wounds appear to gather with age in mtDNA at a preferable rate over in nuclear DNA [34, 35]. Fluorescent tones, which are accepted to be relied upon somewhat to crosslinks among protein and lipid peroxidation things, moreover increase with age [36]. The significance of oxidative DNA wounds in illness and developing is highlighted by the presence of express fix glycosylases that separate these injuries from DNA. Because of 8-oxo-2′- deoxy-guanosine, a physical issue molded from oxidative mischief to guanine stores in DNA, loss of a particular glycosylase development prompts a reasonable extension inside the unconstrained change rate [12, 20, 37, 38], exhibiting the trademark mutagenic ability of this DNA sore. Various other oxidative DNA injuries are probably going to be huge too [39].

## **3. Sources and effects of cordycepin**

*Cordyceps* sp. cordycepin (3′-deoxyadenosine) prominent as purine or pyrimidine nucleobase adenosine, cytidine, and guanosine straightforward that have particular sort of bioactivities [40]. The cordycepin will be changed over into 5′-mono, di, and triphosphates and thusly obstruct the advancement of ribose-phosphate pyrophospho kinase and 5-phosphoribosyl-1-pyrophosphate amido-transferase in the again purines biosynthesis, just as the nucleic acids, mix causing the counter metastatic, antitumor and antimicrobial results [12, 41, 42]. Similarly, cordycepin with its enemy of leukemic limit normally get along with adenosine deaminase inhibitor and this will cause the inhibitory effect on happen which serves to analogs of 2′, 5′-oligoadenylate towards the human immunodeficiency contamination illness [43]. Immense degree refined of mycelial through designed can be used as another wellspring of cordycepin on account of its limited total in a typical source. Tow stage control of deteriorated oxygen or development of NH4+ to the brought down medium can help with working on the formation of cordycepin [44]. Despite creation using development advancement, cordycepin could be in like manner conveyed misleadingly. In any case, the manufactured blend has some hindrance, for instance, the trouble of the cycle and the utilization of gigantic volume of normal solvents which decrease the allure of this cycle [18, 45]. Exploration that the lifestyle created on xylose showed high creation yield of cordycepin on dry biomass. Standing out xylose from other carbon sources, a lot of essentially up-coordinated characteristics in xylose were progressed in pentose and glucoronate interconversion, and cordycepin biosynthesis [46]. The place of the current examination was to choose if cordycepin controls duplication, development, and angiogenesis in a

**Figure 1.** *Chemical structure of Cordycepin and Adenosine [40].*

human umbilical vein endothelial (huve) cell line and in a hepatocellular carcinoma (hcc) cell line [47–49]. MTT was used to study cell development. Apoptosis was poor somewhere near stream cytometry (propidium iodide recoloring). Transwell and wound repairing measures were used to research the movement and interruption of hcc cell line and huve cells. Angiogenesis in huve cells was studied using a chamber advancement test. Cordycepin immovably smothered hcc cell line and huve cell increase in a dose- and time-dependent way. Cordycepin activated huve cell apoptosis in a dose-dependent way (2,000 μg/ml, 50.20 ± 1.55% versus 0 μg/ ml, 2.62 ± 0.19%, P < 0.01) [50–53]. The genome-wide transcriptome assessment showed 8747 imparted characteristics in the glucose and sucrose social orders created under light-programming and faint conditions. Cordycepin curbed cell improvement and set off apoptosis in U87MG cells with wild-type p53, yet not in T98G cells with freak type p53 [54, 55] (**Figure 1**).

## **4. Fruiting body and secondary metabolites action**

The entomopathogenic development *Cordyceps* species is a consumable mushroom with numerous drug/therapeutic properties. Numerous past research analyzed the cell reinforcement exercises that of the refined where refined fruiting collection of *Cordyceps sinensis* and *Cordyceps militaries* class [56, 57]. Methanolic concentrate of *Cordyceps* sp. was tasted when exercises for its antibacterial, cancer prevention agent, antifungal, and antiproliferative properties in different human cell lines. The methanolic concentrate of *Cordyceps* showed to thwart lipid peroxidation, have reducing force and search free radicals [58]. The assessment was coordinated under research facilities produce *Cordyceps* sp. improvement, with five Selenium (Se) different centers (μg g−1) and three sorts of Selenium components like selenate. *Cordyceps* can hold inorganic component from the compound and overhaul it to normal Selenium blends in fruiting bodies [59–62]. As per Yamaguchi and partners the concentrates investigated, the high temperature water discrete (70°C for 5 min) demonstrated the best without oxygen extremist searching activity. Moreover, when low-thickness lipoprotein (LTL) was incubated with macrophages inside seeing copper dichloride (1 mM), the high temperature water eliminate demonstrated a strong inhibitory effect against lipid peroxidation in

**327**

*Broad Efficacy of Scavenging Free Radicals:* Cordyceps *sp.*

medium and resulting assortment of cholesteryl ester in macrophages [63–66]. As per the as of late examinations, the fruiting body tests were set up in four particular model plans, which were flawless fruiting bodies, cut fruiting bodies, dried powder, and dried unpleasant concentrate [67, 68]. The real proportion of the adenosine and cordycepin obsessions in fresh fruiting bodies was inspected by world class liquid chromatography [69]. These optimal models gave a coefficient of confirmation of assumption, standard botch of figure, inclination, and waiting farsighted deviation, which were independently 0.95, 16.60 mg kg−1, −8.57 mg kg−1, and 5.04 for adenosine conjecture, and 0.98, 181.56 mg kg−1, −1.05 mg kg−1, and 8.9 for cordycepin

There is uncommon potential for the creation of metabolites from *Cordyceps* species, this is one phase towards finding and depicting with the bounty of nuclear essential assortment in this genera. Presented here is the essential chromosome level social affair of a genome from the *Cordyceps* genera. This get-together and assessment has revealed that *Cordyceps* militaris has seven chromosomes containing a wealth of value bunches for optional metabolite creation that entomopathogenic sort. With this genome, further assessment and depiction of the discretionary metabolites conveyed by *Cordyceps* militaris might benefit from outside input through genome based procedures including heterologous explanation of value gatherings. Of the 36 quality gatherings recognized using the antiSMASH and SMURF computations, three gatherings are found to have a genuine degree of equivalence with bunches from various life frames that produce a known molecule

Different affirmation parts inside the living being have advanced to restrict the degrees of open oxidants and the underhandedness they cause to the human body [73]. Among the protections are compounds, for example, glutathione peroxidase, catalase, and superoxide dismutase. The glutathione S-transferases inactivate responsive electrophilic mutagens, including the aldehyde delayed consequences of lipid peroxidation. There are also different partner guards, for example, sequestration of H202-production engineered substances in peroxisomes and chelation of any free iron or copper salts in transferrin and ferritin or ceruloplasmin to keep away from Fenton science. O2, in any case, can pass on iron from ferritin [65, 74]. Oxidized DNA is fixed by a development of glycosylases that are unequivocal for express oxidized bases and perhaps by questionable extraction fix compounds. Without cell division, these oxidative wounds are discarded from DNA sensibly and the change rate is kept to a base [20, 75]. Oxidized proteins are destroyed by proteases. Lipid hydroperoxides are crushed by glutathione peroxidase. Basically these safeguards show up, clearly, to be inducible, as are most different sorts of watchmen i.e., the sums increment because of hurt. There is enormous making exhibiting that cells react to low degrees of radiation, and oxidative mutagen, by beginning infection aversion expert shields that help to promise them against change by gigantic levels of radiation [44, 68, 71]. In spite of the defensive impacts of endogenous enzymatic harm evasion expert safeguards, utilization of dietary cell fortresses shows up, evidently, to be fundamental. Food sources created all along, fundamental wellspring of cell fortresses in the eating schedule, are associated with a cut down hazard of degenerative issues [76]. Square and her associates have really inspected various numbers amasses in the epidemiological forming that relate, with

*DOI: http://dx.doi.org/10.5772/intechopen.99405*

gauge by Singpoonga and partners [70].

[58, 62, 71, 72].

**5. Anti-oxidant potency**

**5.1 Antioxidants secure against disease**

*Broad Efficacy of Scavenging Free Radicals:* Cordyceps *sp. DOI: http://dx.doi.org/10.5772/intechopen.99405*

*Antioxidants - Benefits, Sources, Mechanisms of Action*

T98G cells with freak type p53 [54, 55] (**Figure 1**).

*Chemical structure of Cordycepin and Adenosine [40].*

**4. Fruiting body and secondary metabolites action**

The entomopathogenic development *Cordyceps* species is a consumable mushroom with numerous drug/therapeutic properties. Numerous past research analyzed the cell reinforcement exercises that of the refined where refined fruiting collection of *Cordyceps sinensis* and *Cordyceps militaries* class [56, 57]. Methanolic concentrate of *Cordyceps* sp. was tasted when exercises for its antibacterial, cancer prevention agent, antifungal, and antiproliferative properties in different human cell lines. The methanolic concentrate of *Cordyceps* showed to thwart lipid peroxidation, have reducing force and search free radicals [58]. The assessment was coordinated under research facilities produce *Cordyceps* sp. improvement, with five Selenium (Se) different centers (μg g−1) and three sorts of Selenium components like selenate. *Cordyceps* can hold inorganic component from the compound and overhaul it to normal Selenium blends in fruiting bodies [59–62]. As per Yamaguchi and partners the concentrates investigated, the high temperature water discrete (70°C for 5 min) demonstrated the best without oxygen extremist searching activity. Moreover, when low-thickness lipoprotein (LTL) was incubated with macrophages inside seeing copper dichloride (1 mM), the high temperature water eliminate demonstrated a strong inhibitory effect against lipid peroxidation in

human umbilical vein endothelial (huve) cell line and in a hepatocellular carcinoma (hcc) cell line [47–49]. MTT was used to study cell development. Apoptosis was poor somewhere near stream cytometry (propidium iodide recoloring). Transwell and wound repairing measures were used to research the movement and interruption of hcc cell line and huve cells. Angiogenesis in huve cells was studied using a chamber advancement test. Cordycepin immovably smothered hcc cell line and huve cell increase in a dose- and time-dependent way. Cordycepin activated huve cell apoptosis in a dose-dependent way (2,000 μg/ml, 50.20 ± 1.55% versus 0 μg/ ml, 2.62 ± 0.19%, P < 0.01) [50–53]. The genome-wide transcriptome assessment showed 8747 imparted characteristics in the glucose and sucrose social orders created under light-programming and faint conditions. Cordycepin curbed cell improvement and set off apoptosis in U87MG cells with wild-type p53, yet not in

**326**

**Figure 1.**

medium and resulting assortment of cholesteryl ester in macrophages [63–66]. As per the as of late examinations, the fruiting body tests were set up in four particular model plans, which were flawless fruiting bodies, cut fruiting bodies, dried powder, and dried unpleasant concentrate [67, 68]. The real proportion of the adenosine and cordycepin obsessions in fresh fruiting bodies was inspected by world class liquid chromatography [69]. These optimal models gave a coefficient of confirmation of assumption, standard botch of figure, inclination, and waiting farsighted deviation, which were independently 0.95, 16.60 mg kg−1, −8.57 mg kg−1, and 5.04 for adenosine conjecture, and 0.98, 181.56 mg kg−1, −1.05 mg kg−1, and 8.9 for cordycepin gauge by Singpoonga and partners [70].

There is uncommon potential for the creation of metabolites from *Cordyceps* species, this is one phase towards finding and depicting with the bounty of nuclear essential assortment in this genera. Presented here is the essential chromosome level social affair of a genome from the *Cordyceps* genera. This get-together and assessment has revealed that *Cordyceps* militaris has seven chromosomes containing a wealth of value bunches for optional metabolite creation that entomopathogenic sort. With this genome, further assessment and depiction of the discretionary metabolites conveyed by *Cordyceps* militaris might benefit from outside input through genome based procedures including heterologous explanation of value gatherings. Of the 36 quality gatherings recognized using the antiSMASH and SMURF computations, three gatherings are found to have a genuine degree of equivalence with bunches from various life frames that produce a known molecule [58, 62, 71, 72].

## **5. Anti-oxidant potency**

#### **5.1 Antioxidants secure against disease**

Different affirmation parts inside the living being have advanced to restrict the degrees of open oxidants and the underhandedness they cause to the human body [73]. Among the protections are compounds, for example, glutathione peroxidase, catalase, and superoxide dismutase. The glutathione S-transferases inactivate responsive electrophilic mutagens, including the aldehyde delayed consequences of lipid peroxidation. There are also different partner guards, for example, sequestration of H202-production engineered substances in peroxisomes and chelation of any free iron or copper salts in transferrin and ferritin or ceruloplasmin to keep away from Fenton science. O2, in any case, can pass on iron from ferritin [65, 74]. Oxidized DNA is fixed by a development of glycosylases that are unequivocal for express oxidized bases and perhaps by questionable extraction fix compounds. Without cell division, these oxidative wounds are discarded from DNA sensibly and the change rate is kept to a base [20, 75]. Oxidized proteins are destroyed by proteases. Lipid hydroperoxides are crushed by glutathione peroxidase. Basically these safeguards show up, clearly, to be inducible, as are most different sorts of watchmen i.e., the sums increment because of hurt. There is enormous making exhibiting that cells react to low degrees of radiation, and oxidative mutagen, by beginning infection aversion expert shields that help to promise them against change by gigantic levels of radiation [44, 68, 71]. In spite of the defensive impacts of endogenous enzymatic harm evasion expert safeguards, utilization of dietary cell fortresses shows up, evidently, to be fundamental. Food sources created all along, fundamental wellspring of cell fortresses in the eating schedule, are associated with a cut down hazard of degenerative issues [76]. Square and her associates have really inspected various numbers amasses in the epidemiological forming that relate, with

unimaginable consistency, the deficit of good use of verdant food assortments to destructive advancement rate. The quarter of everybody with low dietary affirmation of food assortments created beginning from the soonest stage twofold the infection rate for most kinds of hurtful turn of events (lung, larynx, oral melancholy, throat, stomach, colon and rectum, bladder, pancreas, cervix, and ovary) when stuck out and the quarter from high attestation [14, 40, 77]. Information on the genus of perilous improvement known to be associated with compound levels are not as reliable and show less affirmation by food sources created beginning from the most punctual stage: chest disease the defensive impact was about 30% [78]. The expense of after effects of the soil is an immense factor in agitating use. Less fortunate individuals spend a more raised level of their remuneration on food, eat less consequences of the soil, and have more confined future than all the more wealthy individuals [79]. A basic partner of thriving in this century was made pesticides, which very diminished the expense of food creation and guaranteed that by a wide margin the vast majority of the harvests planted would be eaten by people as opposed to bugs [80]. Planned pesticide stores don't show up in everybody to be a huge defense compromising turn of events.

### **5.2 Birth defects, childhood tumour and oxidation**

Oxidative stresses in sperm DNA are extended products number when levels of dietary ascorbate are insufficient to keep unique fluid ascorbate at an adequate level [81]. A sizable level of the few country people ingests lacking levels of dietary ascorbate, particularly single folks, destitute individuals, and smokers [82]. The oxidants in tobacco smoke channel the cell fortifications in plasma. Smokers should eat 2–3 times more ascorbate than non-smokers to achieve a comparable level of ascorbate in the blood [83], nonetheless, they only sometimes do. In assessments of sperm from smokers and non-smokers [84] the amount of sperm and the degree of motile sperm decay basically in smokers, and this reducing was dependent upon the part and term of smoking. Paternal smoking, explicitly, appears to in-wrinkle the peril of birth distortions and youth threatening development in successors [85, 86]. One expects, and discovers, much greater obligation to the germ-line change rate from the father than from the mother, with the age of the father being a huge peril factor [87, 88]. As such, inadequate eating regimens (and smoking) of fathers appear to achieve hurt not only to their own DNA yet moreover to the DNA of their sperm, an effect that may resonate down individuals later on and new age [81, 89, 90].

#### **5.3 Cardiovascular system diseases**

Coronary vein illness (CAD) is a condition reliant upon various factors or causes diligent vascular provocative bruises that lead to the start of cardiovascular framework infections [91]. Atherosclerotic coronary illness related irritation is mediated by great for combustible cytokines, provocative hailing pathways, bioactive lipids, and bond particles [92]. Extended extension and development of cardio vascular smooth muscle cells also intercede in the beginning and development of CAD [93]. *Cordyceps* controls the duplication of aortic smooth muscle cells (RatAOSMCs) in the carotid stock course of inflatable hurt Sprague–Dawley rodent model. In addition, in collagen type I-incited RatAOSMCs, Cordycepin (3′- deoxyadenosine) famously controls the inception of MMP-2 and - 9 and the surge of particles [94]. Myocardial ischemia–reperfusion (I/R) injury is a cardiovascular sickness caused in view of an outrageous prevention in coronary blood adaptability. It can provoke tissue hypoxia, cell decay, organ brokenness, and even apoptosis in outrageous conditions [95]. 3′- deoxyadenosine applies cardio-defensive effects against I/R-started

**329**

*Broad Efficacy of Scavenging Free Radicals:* Cordyceps *sp.*

hot cytokines, and overseeing safe cell limits [97].

**5.4 Central nervous system diseases**

rat heart injury; its arrangement of action can be credited to the obstacle of Bax, isolated caspase-3 enunciation, the ascent of Bcl-2 verbalization, and activation of the Akt/GSK-3β/p70S6K hailing pathways. Plus, *Cordyceps* sp. in like manner grows the affirmation of the disease anticipation specialist protein HO-1 [93, 96]. In a mouse cardiovascular exchange model, *Cordyceps* 3′- deoxyadenosine got together with ECDI-SPs has an immense effect in lessening the production of good for combustible cytokines including IL-1β, IL-6, IL-17, and TNF-α, growing the release of quieting cytokines IL-10 and TGF-β, and upsetting Th17 and progressing Tregs, then, at that point ECDI-SPs monotherapy alone [92]. All things considered, *Cordyceps* could ease up disturbance activated by CAD through impeding the extension and development of smooth muscle cells similarly as tweaking diverse related cytokines and chemokines and the assertion of record factors. Additionally, *Cordyceps* applies therapeutic ramifications for myocardial ischemia–reperfusion (I/R) injury by obstructing cell apoptosis, lessening the making of positive for red

Parkinson's affliction is a neurodegenerative disease that shows as an improve-

ment issue, in which degeneration and loss of dopaminergic neurons of the substantia nigra are the brand name features. Oxidative pressing factor and neuroaggravation accept critical parts in the pathogenic frameworks of Parkinson's disorder [98–100]. In a continuous report, cordycepin is found to direct the motor issues in MPTP-treated Parkinsonism rodents and seemed to apply neuroprotective effects through easing up bothering and oxidative pressing factor response. Likewise, such neuroprotective effects may be connected with the limitation of the TLR/NF-κB hailing pathway in MPTP-started Parkinson's disorder rodents and LPS-incited BV2 cells [101]. Stroke is perhaps the most notable ailments in cerebrovascular affliction and can be clinically isolated into two genuss: ischemic and hemorrhagic. Extreme ischemic stroke is responsible for 80%, in light of everything, and the fundamental wellspring of failure and end from one side of the planet to the other. Recovery of circulation system (reperfusion) and contravention of cell injury (neuroprotection) are two potential treatment frameworks got in the organization of strokes [102, 103]. Extending evidence suggests that a blazing response is related with stroke and contributes by and large to mind injury [104]. In a MCAO-started preliminary frontal cortex injury model with pathogenesis taking after that of human ischemic stroke, cordycepin applies neuroprotective effects by preventing the outpouring of MMP-3, lessening glutamate and aspartate levels, working on the development of SOD, and reducing MDA levels [105]. The standardized *Cordyceps* in improved concentrate of *C. militaris*, which contains 8.2% (w/w) cordycepin, on a very basic level reduces the attack of ED-1-and MPO-positive searing cells into ischemic wounds, diminishes infarct volume, and debilitates cerebral edema and blood–mind limit hurts in MCAO rodents [102, 105, 106]. Likewise, cordycepin quite eases up frontal cortex edema, neurological lacks, and perihematomal tissue hurt after ICH, joined by an immense decline in the statement of HMGB1. Foolishly, cordycepin applies a neuroprotective effect in ICH models possibly through the prevention of NLRP3 inflammasome commencement [107]. Another assessment shows that cordycepin can enough get BBB genuineness by recovery of tight crossing point proteins, relief

of close by exacerbation, and restriction of NOX activity [108].

Different sclerosis is a provocative demyelinating disease of the central tangible framework depicted by motor brokenness, neuro-aggravation, glial-cell institution, loss of foster oligodendrocytes, and axonal injury [109]. The CPZ-prompted demyelination model has been by and large used to assessment MS, especially in

*DOI: http://dx.doi.org/10.5772/intechopen.99405*

*Broad Efficacy of Scavenging Free Radicals:* Cordyceps *sp. DOI: http://dx.doi.org/10.5772/intechopen.99405*

*Antioxidants - Benefits, Sources, Mechanisms of Action*

huge defense compromising turn of events.

**5.3 Cardiovascular system diseases**

**5.2 Birth defects, childhood tumour and oxidation**

unimaginable consistency, the deficit of good use of verdant food assortments to destructive advancement rate. The quarter of everybody with low dietary affirmation of food assortments created beginning from the soonest stage twofold the infection rate for most kinds of hurtful turn of events (lung, larynx, oral melancholy, throat, stomach, colon and rectum, bladder, pancreas, cervix, and ovary) when stuck out and the quarter from high attestation [14, 40, 77]. Information on the genus of perilous improvement known to be associated with compound levels are not as reliable and show less affirmation by food sources created beginning from the most punctual stage: chest disease the defensive impact was about 30% [78]. The expense of after effects of the soil is an immense factor in agitating use. Less fortunate individuals spend a more raised level of their remuneration on food, eat less consequences of the soil, and have more confined future than all the more wealthy individuals [79]. A basic partner of thriving in this century was made pesticides, which very diminished the expense of food creation and guaranteed that by a wide margin the vast majority of the harvests planted would be eaten by people as opposed to bugs [80]. Planned pesticide stores don't show up in everybody to be a

Oxidative stresses in sperm DNA are extended products number when levels of dietary ascorbate are insufficient to keep unique fluid ascorbate at an adequate level [81]. A sizable level of the few country people ingests lacking levels of dietary ascorbate, particularly single folks, destitute individuals, and smokers [82]. The oxidants in tobacco smoke channel the cell fortifications in plasma. Smokers should eat 2–3 times more ascorbate than non-smokers to achieve a comparable level of ascorbate in the blood [83], nonetheless, they only sometimes do. In assessments of sperm from smokers and non-smokers [84] the amount of sperm and the degree of motile sperm decay basically in smokers, and this reducing was dependent upon the part and term of smoking. Paternal smoking, explicitly, appears to in-wrinkle the peril of birth distortions and youth threatening development in successors [85, 86]. One expects, and discovers, much greater obligation to the germ-line change rate from the father than from the mother, with the age of the father being a huge peril factor [87, 88]. As such, inadequate eating regimens (and smoking) of fathers appear to achieve hurt not only to their own DNA yet moreover to the DNA of their sperm, an

effect that may resonate down individuals later on and new age [81, 89, 90].

Coronary vein illness (CAD) is a condition reliant upon various factors or causes diligent vascular provocative bruises that lead to the start of cardiovascular framework infections [91]. Atherosclerotic coronary illness related irritation is mediated by great for combustible cytokines, provocative hailing pathways, bioactive lipids, and bond particles [92]. Extended extension and development of cardio vascular smooth muscle cells also intercede in the beginning and development of CAD [93]. *Cordyceps* controls the duplication of aortic smooth muscle cells (RatAOSMCs) in the carotid stock course of inflatable hurt Sprague–Dawley rodent model. In addition, in collagen type I-incited RatAOSMCs, Cordycepin (3′- deoxyadenosine) famously controls the inception of MMP-2 and - 9 and the surge of particles [94]. Myocardial ischemia–reperfusion (I/R) injury is a cardiovascular sickness caused in view of an outrageous prevention in coronary blood adaptability. It can provoke tissue hypoxia, cell decay, organ brokenness, and even apoptosis in outrageous conditions [95]. 3′- deoxyadenosine applies cardio-defensive effects against I/R-started

**328**

rat heart injury; its arrangement of action can be credited to the obstacle of Bax, isolated caspase-3 enunciation, the ascent of Bcl-2 verbalization, and activation of the Akt/GSK-3β/p70S6K hailing pathways. Plus, *Cordyceps* sp. in like manner grows the affirmation of the disease anticipation specialist protein HO-1 [93, 96]. In a mouse cardiovascular exchange model, *Cordyceps* 3′- deoxyadenosine got together with ECDI-SPs has an immense effect in lessening the production of good for combustible cytokines including IL-1β, IL-6, IL-17, and TNF-α, growing the release of quieting cytokines IL-10 and TGF-β, and upsetting Th17 and progressing Tregs, then, at that point ECDI-SPs monotherapy alone [92]. All things considered, *Cordyceps* could ease up disturbance activated by CAD through impeding the extension and development of smooth muscle cells similarly as tweaking diverse related cytokines and chemokines and the assertion of record factors. Additionally, *Cordyceps* applies therapeutic ramifications for myocardial ischemia–reperfusion (I/R) injury by obstructing cell apoptosis, lessening the making of positive for red hot cytokines, and overseeing safe cell limits [97].

### **5.4 Central nervous system diseases**

Parkinson's affliction is a neurodegenerative disease that shows as an improvement issue, in which degeneration and loss of dopaminergic neurons of the substantia nigra are the brand name features. Oxidative pressing factor and neuroaggravation accept critical parts in the pathogenic frameworks of Parkinson's disorder [98–100]. In a continuous report, cordycepin is found to direct the motor issues in MPTP-treated Parkinsonism rodents and seemed to apply neuroprotective effects through easing up bothering and oxidative pressing factor response. Likewise, such neuroprotective effects may be connected with the limitation of the TLR/NF-κB hailing pathway in MPTP-started Parkinson's disorder rodents and LPS-incited BV2 cells [101]. Stroke is perhaps the most notable ailments in cerebrovascular affliction and can be clinically isolated into two genuss: ischemic and hemorrhagic. Extreme ischemic stroke is responsible for 80%, in light of everything, and the fundamental wellspring of failure and end from one side of the planet to the other. Recovery of circulation system (reperfusion) and contravention of cell injury (neuroprotection) are two potential treatment frameworks got in the organization of strokes [102, 103]. Extending evidence suggests that a blazing response is related with stroke and contributes by and large to mind injury [104]. In a MCAO-started preliminary frontal cortex injury model with pathogenesis taking after that of human ischemic stroke, cordycepin applies neuroprotective effects by preventing the outpouring of MMP-3, lessening glutamate and aspartate levels, working on the development of SOD, and reducing MDA levels [105]. The standardized *Cordyceps* in improved concentrate of *C. militaris*, which contains 8.2% (w/w) cordycepin, on a very basic level reduces the attack of ED-1-and MPO-positive searing cells into ischemic wounds, diminishes infarct volume, and debilitates cerebral edema and blood–mind limit hurts in MCAO rodents [102, 105, 106]. Likewise, cordycepin quite eases up frontal cortex edema, neurological lacks, and perihematomal tissue hurt after ICH, joined by an immense decline in the statement of HMGB1. Foolishly, cordycepin applies a neuroprotective effect in ICH models possibly through the prevention of NLRP3 inflammasome commencement [107]. Another assessment shows that cordycepin can enough get BBB genuineness by recovery of tight crossing point proteins, relief of close by exacerbation, and restriction of NOX activity [108].

Different sclerosis is a provocative demyelinating disease of the central tangible framework depicted by motor brokenness, neuro-aggravation, glial-cell institution, loss of foster oligodendrocytes, and axonal injury [109]. The CPZ-prompted demyelination model has been by and large used to assessment MS, especially in

investigating de-and re-myelination in the corpus callosum. Cordycepin mitigates CPZ-prompted incidental effects in mice by protecting motor brokenness, propelling re-myelination, stifling glial-cell incitation, lessening the outpouring of the steady of combustible cytokines, IL-1β and IL-6, and growing the levels of the quieting cytokine IL-4 [101, 106, 110]. All around, cordycepin is useful in Parkinson's infection and applies its possessions generally by reducing oxidative pressing factor and against oxidant bothering through the TLR/NF-κB hailing pathway. Besides, cordycepin could further develop stroke by diminishing the infarct volume, reducing cerebral edema, controlling the levels of the connected cytokines, and obstructing the commencement of the NLRP3 inflammasome. Additionally, cordycepin applies impacts on MS through protecting motor brokenness, propelling re-myelination, stifling glialcell incitation, and dealing with the steady of and against oxidant cytokines [111].

## **5.5 Dietary antioxidants**

The effect of dietary affirmation of the malignant growth anticipation specialist's ascorbate, tocopherol, and carotenoids is difficult to disentangle by epidemiological assessments from other critical supplements and trimmings in verdant food sources [112, 113]. Taking everything into account, a couple of conflicts suggest that the disease avoidance specialist content of results of the dirt is a critical ally of their protective effect. Biochemical data, discussed above, show that oxidative damage is gigantic and is likely going to be the major endogenous mischief to DNA, proteins, and lipids [114]. Oxidative damage to sperm DNA is extended when dietary ascorbate is inadequate. Epidemiological assessments and intervention fundamentals on neutralization of harmful development and cardiovascular disease in people taking malignancy counteraction specialist supplements are interesting, notwithstanding, greater examinations ought to be done [115]. Clinical starters using disease anticipation specialists will be the essential test for an enormous number of considerations inspected here [116]. Studies on oxidative instruments and the investigation of infection transmission on malignant growth anticipation specialist protection for individual degenerative ailments are discussed underneath. Little particle dietary disease counteraction specialists [112, 117], for instance, supplement C (ascorbate), supplement E (tocopherol), and carotenoids have made explicit interest as adversaries of malignancy causing specialists and as shields against degenerative sicknesses [118]. Most carotenoids have cell support development, particularly against singlet oxygen, and many, including/ - carotene, can be utilized to supplement A (retinal) [119]. Earlier papers have called attention to different as of late dismissed physiological cell fortifications, including urate, bilirubin, carnosine, and ubiquinol [120]. Ubiquinone (CoQ1o), for example, is the fundamental little molecule for delivery electrons in mitochondria for the period of energy [121]. Its reduced construction, ubiquinol, is an amazing disease counteraction specialist in films [122]. Optimal levels of dietary ubiquinone/ubiquinol could be of importance in an enormous number of degenerative contaminations.

## **5.6 Respiratory system diseases**

*Cordyceps* has been seemed to apply against oxidant impacts in exploratory models of avionics course provocative contaminations including extremely touchy asthma and intense lung injury [123]. Ominously vulnerable asthma is a continuous provocative sickness of the flight course divider that is depicted by means of aeronautics course aggravation, flying course divider overhauling, organic liquid hypersecretion, and avionics course hyper-responsiveness [12, 124]. It is credited to the infiltration of leukocytes including lymphocytes, eosinophils and neutrophils into the lungs. Also, the tallness of Th2 cytokines, for instance, IL-4, IL-5, and

**331**

enemy of oxidant component activity.

*Broad Efficacy of Scavenging Free Radicals:* Cordyceps *sp.*

IL-13, and extended levels of IgE are watched [38, 123, 125]. T accomplice type 2 (Th2) cells and the cytokines conveyed by them are clinically associated with the presentation of a wide range of asthma and are the fundamental drivers of extremely touchy asthma. The Th2 cytokine pathway is one of the rule centers in developing new prescriptions for asthma [126]. *Cordyceps* sp. has been all around archived by different assessment social affairs and is known to have expected therapeutic properties for the treatment of ominously defenseless asthma [127]. Cordycepin concedes the release of allergen-unequivocal IgE, eotaxin, and ICAM-1, decreases the BAL fluid Th2 cytokines IL-4, IL-5, and IL-13 levels, and tightens ovalbumin-driven cup cell hyperplasia, organic liquid hypersecretion, and AHR in a bit subordinate way in the ovalbumin-incited mouse exploratory easily affected asthma model [128]. Carelessly, cordycepin has against asthmatic properties including the deterrent of Th2-type responses, no doubt through interfering with the MAPKs and NF-κB hailing course pathways. In another assessment, cordycepin is appeared to basically subdue an ovalbumin-affected augmentation in eosinophil check; it smothers IL-17A and fabricates IL-10 cytokine levels in the BALF, and supports [129]. Treg responses and covers Th17 responses in ovalbuminhoned mice [130]. In an ovalbumin-started rat model of steady asthma, cordycepin tightens immunoglobulin IgE, eases up the avionics course divider thickness, and reduces eosinophils and neutrophils in the BALF. Noticeably, cordycepin decreases the upregulation of IL-5, IL-13, and TNF-α in the BALF, and controls the development of A2AAR mRNA and the decay of TGF-β1 explanation. Besides, *Cordyceps* when co-controlled with glucocorticoids shows synergistically huge feasibility in quelling avionics course remodeling [123, 131]. From these results it might be derived that cordycepin applies medicinal effects in negatively powerless asthma by upsetting eotaxin verbalization, conveying cytokines, and dealing with the Th1/Th2 balance. The ideal for combustible cytokines TNF-α, IL–1β, IL-6, IL-8, and IL-18 are among the most reassuring biomarkers for predicting bleakness and mortality [132]. LPS-impelled ALI models resemble certain features of human ALI; *Cordyceps* is found to exceptionally decrease neutrophil gathering and MPO activity in lung tissues, decay the production of provocative cytokines including TNF-α, IL-6, and IL-1β, and debilitate lung disturbance in this model apparently by the sanctioning of Nrf2 and upregulation of HO-1 verbalization [133]. The inhibitory effect of cordycepin on TNF-α and IL-6 emanation is debilitated by before association of SnPP, an amazing HO-1 inhibitor, including that cordycepin gives protection against ALI through inception of HO-1. Extraordinarily, cordycepin treatment constructs the combination of IL-10, which insistently oversees disturbance [126, 130, 132]. These examinations suggest that cordycepin can ease up ALI by lessening the social affair of neutrophils and the production of strong of red hot cytokines. SARS-CoV-2, the causative microorganism of Coronavirus Disease 2019 (COVID-19), has caused a pandemic of respiratory infirmity all throughout the planet. The quick famous replication is fundamentally associated with gigantic provocative cell entrance and raised strong of combustible cytokine/chemokine responses. Raised levels of the cytokines GCSF, IP10, MCP1, MIP1A, and TNF-α, are perceived in the plasma of patients who test positive for COVID-19, showing the cytokine storm that is connected with contamination earnestness [134]. Adenosine is an amazing regulator of disturbance, which intervenes its effects on cells by interfacing with four particular receptor subtypes, explicitly, A1, A2A, A2B, and A3 [135]. In particular, the impelling of adenosine receptors A2A and A3 could cause quieting impacts, which are intervened by the covering of steady of combustible cytokines [136]. These revelations showed the capacity of cordycepin in the treatment of COVID-19, hence, it was invaluable to moreover research its

*DOI: http://dx.doi.org/10.5772/intechopen.99405*

*Broad Efficacy of Scavenging Free Radicals:* Cordyceps *sp. DOI: http://dx.doi.org/10.5772/intechopen.99405*

*Antioxidants - Benefits, Sources, Mechanisms of Action*

**5.5 Dietary antioxidants**

investigating de-and re-myelination in the corpus callosum. Cordycepin mitigates CPZ-prompted incidental effects in mice by protecting motor brokenness, propelling re-myelination, stifling glial-cell incitation, lessening the outpouring of the steady of combustible cytokines, IL-1β and IL-6, and growing the levels of the quieting cytokine IL-4 [101, 106, 110]. All around, cordycepin is useful in Parkinson's infection and applies its possessions generally by reducing oxidative pressing factor and against oxidant bothering through the TLR/NF-κB hailing pathway. Besides, cordycepin could further develop stroke by diminishing the infarct volume, reducing cerebral edema, controlling the levels of the connected cytokines, and obstructing the commencement of the NLRP3 inflammasome. Additionally, cordycepin applies impacts on MS through protecting motor brokenness, propelling re-myelination, stifling glialcell incitation, and dealing with the steady of and against oxidant cytokines [111].

The effect of dietary affirmation of the malignant growth anticipation specialist's ascorbate, tocopherol, and carotenoids is difficult to disentangle by epidemiological assessments from other critical supplements and trimmings in verdant food sources [112, 113]. Taking everything into account, a couple of conflicts suggest that the disease avoidance specialist content of results of the dirt is a critical ally of their protective effect. Biochemical data, discussed above, show that oxidative damage is gigantic and is likely going to be the major endogenous mischief to DNA, proteins, and lipids [114]. Oxidative damage to sperm DNA is extended when dietary ascorbate is inadequate. Epidemiological assessments and intervention fundamentals on neutralization of harmful development and cardiovascular disease in people taking malignancy counteraction specialist supplements are interesting, notwithstanding, greater examinations ought to be done [115]. Clinical starters using disease anticipation specialists will be the essential test for an enormous number of considerations inspected here [116]. Studies on oxidative instruments and the investigation of infection transmission on malignant growth anticipation specialist protection for individual degenerative ailments are discussed underneath. Little particle dietary disease counteraction specialists [112, 117], for instance, supplement C (ascorbate), supplement E (tocopherol), and carotenoids have made explicit interest as adversaries of malignancy causing specialists and as shields against degenerative sicknesses [118]. Most carotenoids have cell support development, particularly against singlet oxygen, and many, including/ - carotene, can be utilized to supplement A (retinal) [119]. Earlier papers have called attention to different as of late dismissed physiological cell fortifications, including urate, bilirubin, carnosine, and ubiquinol [120]. Ubiquinone (CoQ1o), for example, is the fundamental little molecule for delivery electrons in mitochondria for the period of energy [121]. Its reduced construction, ubiquinol, is an amazing disease counteraction specialist in films [122]. Optimal levels of dietary ubiquinone/ubiquinol could be of

importance in an enormous number of degenerative contaminations.

*Cordyceps* has been seemed to apply against oxidant impacts in exploratory models of avionics course provocative contaminations including extremely touchy asthma and intense lung injury [123]. Ominously vulnerable asthma is a continuous provocative sickness of the flight course divider that is depicted by means of aeronautics course aggravation, flying course divider overhauling, organic liquid hypersecretion, and avionics course hyper-responsiveness [12, 124]. It is credited to the infiltration of leukocytes including lymphocytes, eosinophils and neutrophils into the lungs. Also, the tallness of Th2 cytokines, for instance, IL-4, IL-5, and

**5.6 Respiratory system diseases**

**330**

IL-13, and extended levels of IgE are watched [38, 123, 125]. T accomplice type 2 (Th2) cells and the cytokines conveyed by them are clinically associated with the presentation of a wide range of asthma and are the fundamental drivers of extremely touchy asthma. The Th2 cytokine pathway is one of the rule centers in developing new prescriptions for asthma [126]. *Cordyceps* sp. has been all around archived by different assessment social affairs and is known to have expected therapeutic properties for the treatment of ominously defenseless asthma [127].

Cordycepin concedes the release of allergen-unequivocal IgE, eotaxin, and ICAM-1, decreases the BAL fluid Th2 cytokines IL-4, IL-5, and IL-13 levels, and tightens ovalbumin-driven cup cell hyperplasia, organic liquid hypersecretion, and AHR in a bit subordinate way in the ovalbumin-incited mouse exploratory easily affected asthma model [128]. Carelessly, cordycepin has against asthmatic properties including the deterrent of Th2-type responses, no doubt through interfering with the MAPKs and NF-κB hailing course pathways. In another assessment, cordycepin is appeared to basically subdue an ovalbumin-affected augmentation in eosinophil check; it smothers IL-17A and fabricates IL-10 cytokine levels in the BALF, and supports [129]. Treg responses and covers Th17 responses in ovalbuminhoned mice [130]. In an ovalbumin-started rat model of steady asthma, cordycepin tightens immunoglobulin IgE, eases up the avionics course divider thickness, and reduces eosinophils and neutrophils in the BALF. Noticeably, cordycepin decreases the upregulation of IL-5, IL-13, and TNF-α in the BALF, and controls the development of A2AAR mRNA and the decay of TGF-β1 explanation. Besides, *Cordyceps* when co-controlled with glucocorticoids shows synergistically huge feasibility in quelling avionics course remodeling [123, 131]. From these results it might be derived that cordycepin applies medicinal effects in negatively powerless asthma by upsetting eotaxin verbalization, conveying cytokines, and dealing with the Th1/Th2 balance. The ideal for combustible cytokines TNF-α, IL–1β, IL-6, IL-8, and IL-18 are among the most reassuring biomarkers for predicting bleakness and mortality [132]. LPS-impelled ALI models resemble certain features of human ALI; *Cordyceps* is found to exceptionally decrease neutrophil gathering and MPO activity in lung tissues, decay the production of provocative cytokines including TNF-α, IL-6, and IL-1β, and debilitate lung disturbance in this model apparently by the sanctioning of Nrf2 and upregulation of HO-1 verbalization [133]. The inhibitory effect of cordycepin on TNF-α and IL-6 emanation is debilitated by before association of SnPP, an amazing HO-1 inhibitor, including that cordycepin gives protection against ALI through inception of HO-1. Extraordinarily, cordycepin treatment constructs the combination of IL-10, which insistently oversees disturbance [126, 130, 132]. These examinations suggest that cordycepin can ease up ALI by lessening the social affair of neutrophils and the production of strong of red hot cytokines. SARS-CoV-2, the causative microorganism of Coronavirus Disease 2019 (COVID-19), has caused a pandemic of respiratory infirmity all throughout the planet. The quick famous replication is fundamentally associated with gigantic provocative cell entrance and raised strong of combustible cytokine/chemokine responses. Raised levels of the cytokines GCSF, IP10, MCP1, MIP1A, and TNF-α, are perceived in the plasma of patients who test positive for COVID-19, showing the cytokine storm that is connected with contamination earnestness [134]. Adenosine is an amazing regulator of disturbance, which intervenes its effects on cells by interfacing with four particular receptor subtypes, explicitly, A1, A2A, A2B, and A3 [135]. In particular, the impelling of adenosine receptors A2A and A3 could cause quieting impacts, which are intervened by the covering of steady of combustible cytokines [136]. These revelations showed the capacity of cordycepin in the treatment of COVID-19, hence, it was invaluable to moreover research its enemy of oxidant component activity.

## **5.7 Cataracts and antioxidants**

Cararacts departure is the most generally perceived action in the overall around (65.5 million consistently) with expenses of more than 98.45 billion dollars [137, 138], has actually investigated the imperative confirmation that Cataract have an oxidative etiology and that dietary cell fortifications can prevent their game plan in individuals [139]. Five epidemiological examinations that have investigated the effect of dietary cell fortifications on Cataract show strong insurance effects of ascorbate, tocopherol, and carotenoids [140, 141]. Those individuals taking regular upgrades of ascorbate or tocopherol had around 33% the risk of making Cataract. Smoking, a genuine oxidative pressing factor, is a huge peril factor for Cataract, and radiation, an oxidative mutagen, is striking to cause Cataract [142]. Eye proteins show an extended level of methionine sulfoxide with age, and proteins in human Cataract have >60% of their methionine stores oxidized [143]. Pregnant mice depleted of glutathione, the essential sulfhydryl disease avoidance specialist in cells, produce any kind of future family with Cataract [144]. The most reassuring hindrance framework against Cataract radiates an impression of being to extend dietary malignancy anticipation specialists (cell reinforcement specialists) and to lessen smoking [145].

### **5.8 Brain dysfunction and antioxidants**

Biochemical assessments recommend that oxidation may be huge in different brain pathologies [146]. A few epidemiological assessments are dependable with a guarded effect of verdant food varieties or cell fortifications [147] in different neurological pathologies, including mind ischemia, Parkinson disease, and familial amyotrophic level sclerosis (Lou Gehrig's disorder), a degenerative issue of motor neurons [148, 149]. Ischemic scenes free iron, a critical stimulus in reactions forming oxygen progressives; iron chelators diminish neuron incident after this injury [150]. In individuals encountering Parkinson's ailment, oxidative DNA hurt is raised inside mind districts rich in dopaminergic neurons (E. Overvik, J. Sanchez-Ramos, and B.N.A., unpublished work) [151]. The most convincing confirmation so far for an association between neurological issues and oxygen progressive improvement is the strong alliance found between familial amyotrophic sidelong sclerosis and changes in the Cu/Zn superoxide dismutase quality, suggesting that oxygen progressives might be obligated for the specific degeneration of motor neurons occurring in this deadly sickness [152–155]. The cautious piece of superoxide dismutase against frontal cortex injury due to ischemia is maintained by the finding that its overproduction is guarded in a transgenic mouse model [156]. Considering the similar cautious effects against ischemia-activated brain injury by limitation of NO turn of events, and the continuous evidence involving these two radical species in cytotoxicity of neuronal cells [157, 158], without a doubt peroxynitrite, a historic oxidant molded from the mix of Oj and NO (1%), expects a huge capacity in neuronal injury following ischemia and reperfusion [159].

## **6. Lack of side effects**

*Cordyceps* containing bioactive compounds with lower health risk. A month after oral association of *Cordyceps* (5 mg/kg), the hematology, blood science, and hypochondriac changes of the rodents show no basic changes are comparable to those of the conventional rodents. Furthermore, the Ames test exhibits that *Cordyceps* is a non-mutagenic compound [160, 161]. Another report in mice shows that *Cordyceps* shows slight destructiveness when controlled at oral doses of 20 mg/kg for 21 days

**333**

*Broad Efficacy of Scavenging Free Radicals:* Cordyceps *sp.*

[162]. *Cordyceps* is found to apply unsafe effects when controlled at a part of 8 mg/ kg for 3 days. Signs of toxicity, for instance, wasting and detachment of the guts are not seen when *Cordyceps* is overseen at a bit of 2 mg/kg or lower [163]. What's more, following 3 days of intravenous imbuements association of *Cordyceps* (20 mg/kg) in beagle canines, *Cordyceps* shows no prescription related toxic substance levels, displaying the security profile of *Cordyceps* [164]. *Cordyceps* is noxious just to hurtful threat cells and doesn't show cytotoxicity toward strong cells, subsequently showing it's anything but a foe of infection expert [165, 166]. In any case, a previous report communicates that *Cordyceps* shows toxicity toward sound erythrocytes and maybe starts feebleness in patients with harm when used in chemotherapy [167]. Despite these promising prosperity profiles, comprehensive preclinical toxicological assessments on *Cordyceps* ought to be coordinated and further checked for their effects.

Being a *Cordyceps* species simple, physiologic and biochemical impacts of medications (specifically, drug tranquilizes), the metabolic and pharmacodynamics profiles of *Cordyceps* cordycepin resemble those of adenosine. In vivo breaks down recommend that *Cordyceps* can be utilized to 30-deoxyinosine coming about in light of the fast deamination by Adenosine deaminase, or may go through phosphorylation by adenosine kinase to be changed over into 30-deoxyadenosine mono-, di-, and triphosphate [168]. It has been suggested ahead of time that 30-deoxyinosine is an inactive metabolite, while 30-deoxyadenosine triphosphate is the powerful moiety at risk for the accommodating effects of *Cordyceps* [169]. A continuous report shows that 30-deoxyinosine can be changed over to the unique moiety, 30-deoxyadenosine triphosphate, in mammalian cells [170]. In addition, the pharmacokinetics and bioavailability examinations of *Cordyceps* show that it is held and released rapidly in rodents. *Cordyceps* has a short removal half-life (t1/2) of 1.6 min at a bit of 10 mg/ kg when overseen intravenously. In the meantime, the region under the curve, most noteworthy obsession, and the opportunity of *Cordyceps* have been made plans to be 38.5 ± 10.3 min μg/ml, 3.1 ± 0.9 μg/l and 2.1 ± 1.2 L/min/kg, independently [171]. In a biopharmaceutical assessment study, *Cordyceps* is seemed to have low protein official, high plasma breathing space, low vulnerability, and high hepatic first-pass sway in vitro, which can explain the shortfall of its oral bioavailability [172].

As a working fragment of customary Chinese drug, *Cordyceps* species has been seen to have expansive enemy of oxidant and safe managerial effects of cordycepin. The sensitive rule of provocative safe response is another course for the improvement of imaginative meds for the treatment of resistant framework ailments. *Cordyceps* species has shown its probable accommodating motivating force in various red hot contamination models, for instance, asthma, Parkinson's, rheumatoid joint torment, atherosclerosis, pneumonia, hepatitis, and atopic dermatitis. Many hailing pathways including MAPKs, TGF-β/Smads, and NF-κB, Nrf2/HO-1, and Akt/GSK-3β/p70S6K check out the disturbance cycle in various afflictions/infections [173]. As of late investigations, RNA-seq demonstrated 1088 differentially imparted characteristics among CMsA and CMsB social events. Furthermore, oxidative phosphorylation-related Gene reasoning terms were up-overseen in CMsB social affairs. Additionally, the eventual outcomes of fundamental examination (FTIR range, monosaccharide sythesis, periodate oxidation) and bioactivity

*DOI: http://dx.doi.org/10.5772/intechopen.99405*

**7. Pharmacodynamics**

**8. Conclusion and future perspectives**

*Broad Efficacy of Scavenging Free Radicals:* Cordyceps *sp. DOI: http://dx.doi.org/10.5772/intechopen.99405*

[162]. *Cordyceps* is found to apply unsafe effects when controlled at a part of 8 mg/ kg for 3 days. Signs of toxicity, for instance, wasting and detachment of the guts are not seen when *Cordyceps* is overseen at a bit of 2 mg/kg or lower [163]. What's more, following 3 days of intravenous imbuements association of *Cordyceps* (20 mg/kg) in beagle canines, *Cordyceps* shows no prescription related toxic substance levels, displaying the security profile of *Cordyceps* [164]. *Cordyceps* is noxious just to hurtful threat cells and doesn't show cytotoxicity toward strong cells, subsequently showing it's anything but a foe of infection expert [165, 166]. In any case, a previous report communicates that *Cordyceps* shows toxicity toward sound erythrocytes and maybe starts feebleness in patients with harm when used in chemotherapy [167]. Despite these promising prosperity profiles, comprehensive preclinical toxicological assessments on *Cordyceps* ought to be coordinated and further checked for their effects.

## **7. Pharmacodynamics**

*Antioxidants - Benefits, Sources, Mechanisms of Action*

(cell reinforcement specialists) and to lessen smoking [145].

in neuronal injury following ischemia and reperfusion [159].

**5.8 Brain dysfunction and antioxidants**

Cararacts departure is the most generally perceived action in the overall around (65.5 million consistently) with expenses of more than 98.45 billion dollars [137, 138], has actually investigated the imperative confirmation that Cataract have an oxidative etiology and that dietary cell fortifications can prevent their game plan in individuals [139]. Five epidemiological examinations that have investigated the effect of dietary cell fortifications on Cataract show strong insurance effects of ascorbate, tocopherol, and carotenoids [140, 141]. Those individuals taking regular upgrades of ascorbate or tocopherol had around 33% the risk of making Cataract. Smoking, a genuine oxidative pressing factor, is a huge peril factor for Cataract, and radiation, an oxidative mutagen, is striking to cause Cataract [142]. Eye proteins show an extended level of methionine sulfoxide with age, and proteins in human Cataract have >60% of their methionine stores oxidized [143]. Pregnant mice depleted of glutathione, the essential sulfhydryl disease avoidance specialist in cells, produce any kind of future family with Cataract [144]. The most reassuring hindrance framework against Cataract radiates an impression of being to extend dietary malignancy anticipation specialists

Biochemical assessments recommend that oxidation may be huge in different brain pathologies [146]. A few epidemiological assessments are dependable with a guarded effect of verdant food varieties or cell fortifications [147] in different neurological pathologies, including mind ischemia, Parkinson disease, and familial amyotrophic level sclerosis (Lou Gehrig's disorder), a degenerative issue of motor neurons [148, 149]. Ischemic scenes free iron, a critical stimulus in reactions forming oxygen progressives; iron chelators diminish neuron incident after this injury [150]. In individuals encountering Parkinson's ailment, oxidative DNA hurt is raised inside mind districts rich in dopaminergic neurons (E. Overvik, J. Sanchez-Ramos, and B.N.A., unpublished work) [151]. The most convincing confirmation so far for an association between neurological issues and oxygen progressive improvement is the strong alliance found between familial amyotrophic sidelong sclerosis and changes in the Cu/Zn superoxide dismutase quality, suggesting that oxygen progressives might be obligated for the specific degeneration of motor neurons occurring in this deadly sickness [152–155]. The cautious piece of superoxide dismutase against frontal cortex injury due to ischemia is maintained by the finding that its overproduction is guarded in a transgenic mouse model [156]. Considering the similar cautious effects against ischemia-activated brain injury by limitation of NO turn of events, and the continuous evidence involving these two radical species in cytotoxicity of neuronal cells [157, 158], without a doubt peroxynitrite, a historic oxidant molded from the mix of Oj and NO (1%), expects a huge capacity

*Cordyceps* containing bioactive compounds with lower health risk. A month after oral association of *Cordyceps* (5 mg/kg), the hematology, blood science, and hypochondriac changes of the rodents show no basic changes are comparable to those of the conventional rodents. Furthermore, the Ames test exhibits that *Cordyceps* is a non-mutagenic compound [160, 161]. Another report in mice shows that *Cordyceps* shows slight destructiveness when controlled at oral doses of 20 mg/kg for 21 days

**5.7 Cataracts and antioxidants**

**332**

**6. Lack of side effects**

Being a *Cordyceps* species simple, physiologic and biochemical impacts of medications (specifically, drug tranquilizes), the metabolic and pharmacodynamics profiles of *Cordyceps* cordycepin resemble those of adenosine. In vivo breaks down recommend that *Cordyceps* can be utilized to 30-deoxyinosine coming about in light of the fast deamination by Adenosine deaminase, or may go through phosphorylation by adenosine kinase to be changed over into 30-deoxyadenosine mono-, di-, and triphosphate [168]. It has been suggested ahead of time that 30-deoxyinosine is an inactive metabolite, while 30-deoxyadenosine triphosphate is the powerful moiety at risk for the accommodating effects of *Cordyceps* [169]. A continuous report shows that 30-deoxyinosine can be changed over to the unique moiety, 30-deoxyadenosine triphosphate, in mammalian cells [170]. In addition, the pharmacokinetics and bioavailability examinations of *Cordyceps* show that it is held and released rapidly in rodents. *Cordyceps* has a short removal half-life (t1/2) of 1.6 min at a bit of 10 mg/ kg when overseen intravenously. In the meantime, the region under the curve, most noteworthy obsession, and the opportunity of *Cordyceps* have been made plans to be 38.5 ± 10.3 min μg/ml, 3.1 ± 0.9 μg/l and 2.1 ± 1.2 L/min/kg, independently [171]. In a biopharmaceutical assessment study, *Cordyceps* is seemed to have low protein official, high plasma breathing space, low vulnerability, and high hepatic first-pass sway in vitro, which can explain the shortfall of its oral bioavailability [172].

## **8. Conclusion and future perspectives**

As a working fragment of customary Chinese drug, *Cordyceps* species has been seen to have expansive enemy of oxidant and safe managerial effects of cordycepin. The sensitive rule of provocative safe response is another course for the improvement of imaginative meds for the treatment of resistant framework ailments. *Cordyceps* species has shown its probable accommodating motivating force in various red hot contamination models, for instance, asthma, Parkinson's, rheumatoid joint torment, atherosclerosis, pneumonia, hepatitis, and atopic dermatitis. Many hailing pathways including MAPKs, TGF-β/Smads, and NF-κB, Nrf2/HO-1, and Akt/GSK-3β/p70S6K check out the disturbance cycle in various afflictions/infections [173]. As of late investigations, RNA-seq demonstrated 1088 differentially imparted characteristics among CMsA and CMsB social events. Furthermore, oxidative phosphorylation-related Gene reasoning terms were up-overseen in CMsB social affairs. Additionally, the eventual outcomes of fundamental examination (FTIR range, monosaccharide sythesis, periodate oxidation) and bioactivity

appraisal guessed that *C. militaris* polysaccharides had higher β-(1 → 6)- glucan substance and malignancy counteraction specialist practices in CMsB social occasions [174]. Similarly, the water remove (CW) contained the on a very basic level most significant substance of cordycepin, phenolics, and flavonoids, which were at risk for cell support activity. CW was the most grounded disease avoidance specialist. CW had for all intents and purposes indistinguishable 2,2′-diphenyl-1-picrylhydrazyl progressive looking through activity and lipid peroxidation restriction to l-ascorbic corrosive (96.9 ± 3.1%) and alpha-tocopherol (87.2 ± 1.0%). worked on the adequacy of CW, had no cytotoxicity sway and no skin irritation, conveyed the most CW (0.9 ± 0.0% w/w after 24 h), and passed on the most raised CW into the skin layer (33.5 ± 0.7% w/w) by Marsup and colleagus [175].

As indicated by zhu and associates examined the cell support activity related with the polysaccharides from *Cordyceps* cicadae (CP). To moreover research which of the division of CP had the best strength, in here, the in vitro cell support and in vivo against developing activities of the parts CP30–CP80 of CP were evaluated. The in vitro malignancy avoidance specialist development results revealed that every one of the divisions (for instance CP30–CP80) were incredible with CP70 as the most grounded. Conspicuously, CP70 postponed the future of Drosophila (P < 0.05), extended the activities of catalase (CAT) and glutathione peroxidase (GSH-Px) (P < 0.01), and subdued the plan of malondialdehyde (MDA) (P < 0.01). Also, CP70 upregulated the enunciation level of cell support related characteristics CAT, SOD1 and MTH in Drosophila (P < 0.05). These results showed that CP70 may draw out the future of Drosophila through the up-rule of the verbalization level of cell support related characteristics CAT, SOD1 and MTH in Drosophila. Thusly, polysaccharides from *Cordyceps* cicadae have gigantic malignant growth anticipation specialist and threatening to developing activities, and could be examined as another dietary upgrade to ruin the developing cycle [176].

In this assessment, the NBW-liquid maturing system was first settled to evaluate the effects of NBW on mycelia of *Cordyceps* militaris. The most raised mycelium center (3.90 mg/mL) and crude polysaccharides extraction yield (12.76%) were obtained in 25%-NBW (v/v) gathering. The malignancy counteraction specialist activities of mycelia were on a very basic level progressed after supplementation with NBW. The polysaccharides from 25%-NBW, 75%-NBW, and half NBW bundles showed the most grounded DPPH progressive, ABTS radical scrounging works out, and diminishing power, independently, achieving the most raised progressive looking through rate (practically 100% at 1.2 mg/mL), the least IC50 regard (1.09 mg/mL) and the most raised OD regard (2.13 at 2.0 mg/mL) [177].

In any case, there are still some data openings and limitations in energy research. First thing, most assessments revolve around the cell level; accordingly, more in vivo assessments in various animal models that appear as though human fanatical conditions and clinical applications are expected to support the sufficiency of *Cordyceps* in treating diverse blazing diseases and clarifying its nuclear parts. Second, a couple of examinations show that *Cordyceps* has staggering enemy of oxidant and safe authoritative contacts with less outcomes. Regardless, broad preclinical toxicological screens and clinical security research on *Cordyceps* are at this point inadequate. Accordingly, construct more productive assessments to survey the effects of its estimations on pharmacological activity and choose destructiveness so it will in general be used safely. Likewise, pharmacodynamics and active analyzes show that *Cordyceps* has a short half-life and vulnerable oral bioavailability generally in view of the quick deamination by adenosine deaminase (ADA), which confines its applications in affliction countering and treatment. Along these lines, the impediment of cordycepin to ADA addresses a basic issue which ought to be tended to in future assessment. Lately, this issue has been tended to through the mix of cordycepin and

**335**

**Acknowledgements**

*improved strains (P#01, P#02, F02).*

**Figure 2.**

**Conflict of interest**

The authors declare no conflict of interest.

*Broad Efficacy of Scavenging Free Radicals:* Cordyceps *sp.*

ADA inhibitors to design ADA-safe cordycepin subordinates using nanotechnology or scaled down atom movement systems to fight ADA-resistance. These systems may be important for growing the oral bioavailability of cordycepin. Essential change is a promising system for procuring cordycepin auxiliaries with a respectable accommodating effect and high bioavailability. Appropriately, the insightful arrangement of new *Cordyceps* auxiliaries is of unfathomable vitality for the headway of new meds later on. With everything taken into account, more assessments are relied upon to progress cordycepin bioavailability and accomplish an amicability between its toxicological security and remedial practicality. This review intends to plot the medicinal potential and possible frameworks of *Cordyceps* in various provocative ailments and to give the reason to its use in the incredible treatment of searing issues (**Figure 2**).

*Showing research output: Cordyceps militaris have broad spectrum free radical scavenging activity with their* 

The authors are obliged to Vice Chancellor, R.D. University, Jabalpur and interminable thankfulness to Director, Bio-Design Innovation Centre, R.D. University, Jabalpur (M.P.), for finishing this review & to avail in words for publication.

*DOI: http://dx.doi.org/10.5772/intechopen.99405*

*Broad Efficacy of Scavenging Free Radicals:* Cordyceps *sp. DOI: http://dx.doi.org/10.5772/intechopen.99405*

#### **Figure 2.**

*Antioxidants - Benefits, Sources, Mechanisms of Action*

skin layer (33.5 ± 0.7% w/w) by Marsup and colleagus [175].

ined as another dietary upgrade to ruin the developing cycle [176].

appraisal guessed that *C. militaris* polysaccharides had higher β-(1 → 6)- glucan substance and malignancy counteraction specialist practices in CMsB social occasions [174]. Similarly, the water remove (CW) contained the on a very basic level most significant substance of cordycepin, phenolics, and flavonoids, which were at risk for cell support activity. CW was the most grounded disease avoidance specialist. CW had for all intents and purposes indistinguishable 2,2′-diphenyl-1-picrylhydrazyl progressive looking through activity and lipid peroxidation restriction to l-ascorbic corrosive (96.9 ± 3.1%) and alpha-tocopherol (87.2 ± 1.0%). worked on the adequacy of CW, had no cytotoxicity sway and no skin irritation, conveyed the most CW (0.9 ± 0.0% w/w after 24 h), and passed on the most raised CW into the

As indicated by zhu and associates examined the cell support activity related with the polysaccharides from *Cordyceps* cicadae (CP). To moreover research which of the division of CP had the best strength, in here, the in vitro cell support and in vivo against developing activities of the parts CP30–CP80 of CP were evaluated. The in vitro malignancy avoidance specialist development results revealed that every one of the divisions (for instance CP30–CP80) were incredible with CP70 as the most grounded. Conspicuously, CP70 postponed the future of Drosophila (P < 0.05), extended the activities of catalase (CAT) and glutathione peroxidase (GSH-Px) (P < 0.01), and subdued the plan of malondialdehyde (MDA) (P < 0.01). Also, CP70 upregulated the enunciation level of cell support related characteristics CAT, SOD1 and MTH in Drosophila (P < 0.05). These results showed that CP70 may draw out the future of Drosophila through the up-rule of the verbalization level of cell support related characteristics CAT, SOD1 and MTH in Drosophila. Thusly, polysaccharides from *Cordyceps* cicadae have gigantic malignant growth anticipation specialist and threatening to developing activities, and could be exam-

In this assessment, the NBW-liquid maturing system was first settled to evaluate the effects of NBW on mycelia of *Cordyceps* militaris. The most raised mycelium center (3.90 mg/mL) and crude polysaccharides extraction yield (12.76%) were obtained in 25%-NBW (v/v) gathering. The malignancy counteraction specialist activities of mycelia were on a very basic level progressed after supplementation with NBW. The polysaccharides from 25%-NBW, 75%-NBW, and half NBW bundles showed the most grounded DPPH progressive, ABTS radical scrounging works out, and diminishing power, independently, achieving the most raised progressive looking through rate (practically 100% at 1.2 mg/mL), the least IC50 regard (1.09 mg/mL) and the most raised OD regard (2.13 at 2.0 mg/mL) [177]. In any case, there are still some data openings and limitations in energy research. First thing, most assessments revolve around the cell level; accordingly, more in vivo assessments in various animal models that appear as though human fanatical conditions and clinical applications are expected to support the sufficiency of *Cordyceps* in treating diverse blazing diseases and clarifying its nuclear parts. Second, a couple of examinations show that *Cordyceps* has staggering enemy of oxidant and safe authoritative contacts with less outcomes. Regardless, broad preclinical toxicological screens and clinical security research on *Cordyceps* are at this point inadequate. Accordingly, construct more productive assessments to survey the effects of its estimations on pharmacological activity and choose destructiveness so it will in general be used safely. Likewise, pharmacodynamics and active analyzes show that *Cordyceps* has a short half-life and vulnerable oral bioavailability generally in view of the quick deamination by adenosine deaminase (ADA), which confines its applications in affliction countering and treatment. Along these lines, the impediment of cordycepin to ADA addresses a basic issue which ought to be tended to in future assessment. Lately, this issue has been tended to through the mix of cordycepin and

**334**

*Showing research output: Cordyceps militaris have broad spectrum free radical scavenging activity with their improved strains (P#01, P#02, F02).*

ADA inhibitors to design ADA-safe cordycepin subordinates using nanotechnology or scaled down atom movement systems to fight ADA-resistance. These systems may be important for growing the oral bioavailability of cordycepin. Essential change is a promising system for procuring cordycepin auxiliaries with a respectable accommodating effect and high bioavailability. Appropriately, the insightful arrangement of new *Cordyceps* auxiliaries is of unfathomable vitality for the headway of new meds later on. With everything taken into account, more assessments are relied upon to progress cordycepin bioavailability and accomplish an amicability between its toxicological security and remedial practicality. This review intends to plot the medicinal potential and possible frameworks of *Cordyceps* in various provocative ailments and to give the reason to its use in the incredible treatment of searing issues (**Figure 2**).

#### **Acknowledgements**

The authors are obliged to Vice Chancellor, R.D. University, Jabalpur and interminable thankfulness to Director, Bio-Design Innovation Centre, R.D. University, Jabalpur (M.P.), for finishing this review & to avail in words for publication.

## **Conflict of interest**

The authors declare no conflict of interest.

*Antioxidants - Benefits, Sources, Mechanisms of Action*

## **Author details**

Loknath Deshmukh1 \*, Rajendra Singh<sup>2</sup> and Sardul Singh Sandhu1

1 Department of Biological Science, Bio-Design Innovation Centre, R.D. University, Jabalpur, M.P., India

2 Department of Biological Science, Fungal Biotechnology and Invertebrate Pathology Laboratory, R.D. University, Jabalpur, M.P., India

\*Address all correspondence to: loknath.deshmukh3108@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**337**

*Broad Efficacy of Scavenging Free Radicals:* Cordyceps *sp.*

between *Cordyceps militaris* and *Cordycpes sinensis*. Journal of Jilin Agriculture University. 1995; 17: 80-83.

[10] Hur H. Chemical ingredients of *Cordyceps militaris*. Mycobiology. 2008;

[11] Liu Y, Wang J, Wang W, Zhang H, Zhang X, Han C. The chemical constituents and pharmacological actions of *Cordyceps sinensis*. Evid Based

[12] Tuli HS, Sandhu SS, Sharma AK. Pharmacological and therapeutic potential of *Cordyceps* with special reference to cordycepin. Biotechnology. 2013;3. http://dx.doi.org/10.1007/

[13] Lu H, Li X, Zhang J, Shi H, Zhu X, He X. Effects of cordycepin on HepG2

[14] Kodama EN, McCaffrey RP, Yusa K and Mitsuya H: Antileukemic activity and mechanism of action of cordycepin against terminal deoxynucleotidyl transferasepositive (TdT+) leukemic cells. Biochem Pharmacol. 2000;

[15] Rong Wu, Jian-Ping Gao, Hui-Lin Wang, Yan Gao, Qian Wu, Xiao-Hua Cui. Effects of fermented *Cordyceps sinensis* on oxidative stress in

doxorubicin treated rats. 2015; 11, 44:

[16] Shengli Yanga, Xi Yanga and Hui Zhangb. Extracellular polysaccharide biosynthesis in *Cordyceps*. 2020. https:// doi.org/10.1080/1040841X.2020.

and EA. hy926 cells: potential antiproliferative, antimetastatic and anti-angiogenic effects on hepatocellular

carcinoma. Oncol Lett. 2014; 7:

Complement Alternat Med

2015;2015: 575063.

s13205-013-0121-9.

1556-1562.

59:273-281.

724-731.

1794788.

(in Chinese).

36:233-5.

*DOI: http://dx.doi.org/10.5772/intechopen.99405*

rediscovery of an ancient Chinese herbal medicine: *Cordyceps sinensis*: part I. J Altern Complement Med. 1998; 4:

[2] Meena H, Mohsin M, Pandey HK, Negi PS, Ahmed Z. Estimation of cordycepin by improved HPLC method in the natural and cultured mycelia of high medicinal value Himalayan

entomogenous fungus *Cordyceps sinensis*.

[3] Deshmukh, L., Agrawal, D., Sandhu, S.S., 2019. Development of Marker in the Soft Gold Mushroom *Cordyceps* spp. for Strain Improvement. In: Kundu R, Narila R. Advance in plant & microbial biotechnology. Springer Nature,

[4] Pegler DN. The Chinese 'caterpillar fungus'. Mycologist. 1994; 8: 3-5.

[5] Mizuno T. Medicinal effects and utilization of *Cordyceps* (Fr.) Link (Ascomycetes) and Isaria Fr.

Mushrooms. 1999; 1: 251-261.

Luangsa-ard JJ, Shrestha B,

[8] Cunningham KG, Manson W, Spring FS, Hutchinson SA. Cordycepin, a metabolic product isolated from cultures of *Cordyceps militaris* (Linn.) link. Nature. 1950; 166:949-54.

(Mitosporic Fungi) Chinese caterpillar fungi, 'Tochukaso' (review). Int J Med

[6] Hardeep S. Tuli, Anil K. Sharma, Sardul S. Sandhu, and Dharambir Kashyap. Cordycepin: A bioactive metabolite with therapeutic potential Life Sciences. 2013; 93:863-869.

[7] Sung GH, Hywel-Jones NL, Sung JM,

Spatafora JW. Phylogenetic classification of *Cordyceps* and the clavicipitaceous fungi. Stud Mycol. 2007; 57:5-59.

[9] Li, N., Song, J.G., Liu, J.Y. and Zhang, H. Compared chemical composition

EJEAF Che. 2010;9: 1598-603.

Singapore; 2019.p.33-39.

[1] Zhu JS et al. The scientific

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*Broad Efficacy of Scavenging Free Radicals:* Cordyceps *sp. DOI: http://dx.doi.org/10.5772/intechopen.99405*

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*Antioxidants - Benefits, Sources, Mechanisms of Action*

**336**

**Author details**

Loknath Deshmukh1

Jabalpur, M.P., India

\*, Rajendra Singh<sup>2</sup>

Pathology Laboratory, R.D. University, Jabalpur, M.P., India

provided the original work is properly cited.

\*Address all correspondence to: loknath.deshmukh3108@gmail.com

and Sardul Singh Sandhu1

1 Department of Biological Science, Bio-Design Innovation Centre, R.D. University,

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 Department of Biological Science, Fungal Biotechnology and Invertebrate

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[3] Deshmukh, L., Agrawal, D., Sandhu, S.S., 2019. Development of Marker in the Soft Gold Mushroom *Cordyceps* spp. for Strain Improvement. In: Kundu R, Narila R. Advance in plant & microbial biotechnology. Springer Nature, Singapore; 2019.p.33-39.

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[5] Mizuno T. Medicinal effects and utilization of *Cordyceps* (Fr.) Link (Ascomycetes) and Isaria Fr. (Mitosporic Fungi) Chinese caterpillar fungi, 'Tochukaso' (review). Int J Med Mushrooms. 1999; 1: 251-261.

[6] Hardeep S. Tuli, Anil K. Sharma, Sardul S. Sandhu, and Dharambir Kashyap. Cordycepin: A bioactive metabolite with therapeutic potential Life Sciences. 2013; 93:863-869.

[7] Sung GH, Hywel-Jones NL, Sung JM, Luangsa-ard JJ, Shrestha B, Spatafora JW. Phylogenetic classification of *Cordyceps* and the clavicipitaceous fungi. Stud Mycol. 2007; 57:5-59.

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[11] Liu Y, Wang J, Wang W, Zhang H, Zhang X, Han C. The chemical constituents and pharmacological actions of *Cordyceps sinensis*. Evid Based Complement Alternat Med 2015;2015: 575063.

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*Broad Efficacy of Scavenging Free Radicals:* Cordyceps *sp.*

Durán-Sequeda, D., Cruz, L. J., Serrano, J. D., Sierra, R. Effect of bioactive compounds extracted from *Cordyceps nidus* ANDES-F1080 on laccase activity of Pleurotus ostreatus ANDES-F515. Biotechnology Reports. 2020; 26, e00466. doi:10.1016/j.btre.2020.e00466.

[166] Rottenberg, M. E., Masocha, W., Ferella, M., Petitto-Assis, F., Goto, H.,

Treatment of African trypanosomiasis with cordycepin and adenosine

deaminase inhibitors in a mouse model. Journal of Infectious Diseases. 2005;

[167] Lui, J.C.K., Wong, J.W.Y., Suen, Y.K. *et al.* Cordycepin induced eryptosis in mouse erythrocytes through a Ca2+ dependent pathway without caspase-3 activation. Arch Toxicol. 2007; 81, 859-865. https://doi.org/10.1007/

[169] Tsai, Y.-S., Hsu, J.-H., Lin, D. P.-C., Chang, H.-H., Chang, W.-J., Chen, Y.-L., & Chen, C.-C. Safety Assessment of HEA-Enriched *Cordyceps cicadae*

Mycelium: A Randomized Clinical Trial. Journal of the American College of Nutrition. 2020; 1-6. doi:10.1080/073157

[170] Chen, B.; Sun, Y.; Luo, F.; Wang, C. Bioactive Metabolites and Potential Mycotoxins Produced by *Cordyceps* Fungi: A Review of Safety. *Toxins*

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Kristensson, K., … Wigzell, H.

192(9), 1658-1665.

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*DOI: http://dx.doi.org/10.5772/intechopen.99405*

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[163] Cai, Z. L., Wang, C. Y., Jiang, Z. J., Li, H. H., Liu, W. X., Gong, L. W., Li, C. H. Effects of cordycepin on Y-maze learning task in mice. European Journal of Pharmacology. 2013; 714(1-3), 249-253. https://doi.org/10.1016/j.

[164] Ren, Y., Sun, P., Li, H., & Zhu, Z.

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migration. Journal of

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[159] Bai, X., Tan, T.-Y., Li, Y.-X., Li, Y., Chen, Y.-F., Ma, R., … Liu, Z.-Q. The protective effect of *Cordyceps sinensis* extract on cerebral ischemic injury via modulating the mitochondrial respiratory chain and inhibiting the mitochondrial apoptotic pathway. Biomedicine & Pharmacotherapy. 2020; 124, 109834. doi:10.1016/j. biopha.2020.109834.

[160] Hayden, M., West, A. & Ghosh, S. NF-*κ*B and the immune response. Oncogene. 2006; 25, 6758-6780. https:// doi.org/10.1038/sj.onc.1209943.

[161] Qin, P.; Li, X.; Yang, H.; Wang, Z.-Y.; Lu, D. Therapeutic Potential and Biological Applications of Cordycepin and Metabolic Mechanisms in Cordycepin-Producing Fungi. *Molecules*. 2019; *24*, 2231.

[162] Chen, B., Sun, Y., Luo, F., & Wang, C. Bioactive Metabolites and Potential Mycotoxins Produced by *Cordyceps* Fungi: A Review of Safety. Toxins. 2020; 12(6), 410. doi:10.3390/toxins12060410.

[163] Cai, Z. L., Wang, C. Y., Jiang, Z. J., Li, H. H., Liu, W. X., Gong, L. W., Li, C. H. Effects of cordycepin on Y-maze learning task in mice. European Journal of Pharmacology. 2013; 714(1-3), 249-253. https://doi.org/10.1016/j. ejphar.2013.05.049.

[164] Ren, Y., Sun, P., Li, H., & Zhu, Z. Effects of Na2SeO3 on growth, metabolism, antioxidase and enzymes involved in polysaccharide synthesis of *Cordyceps militaris*. Process Biochemistry. 2020. doi:10.1016/j. procbio.2020.06.018.

[165] Durán-Aranguren, D., Chiriví-Salomón, J. S., Anaya, L.,

Durán-Sequeda, D., Cruz, L. J., Serrano, J. D., Sierra, R. Effect of bioactive compounds extracted from *Cordyceps nidus* ANDES-F1080 on laccase activity of Pleurotus ostreatus ANDES-F515. Biotechnology Reports. 2020; 26, e00466. doi:10.1016/j.btre.2020.e00466.

[166] Rottenberg, M. E., Masocha, W., Ferella, M., Petitto-Assis, F., Goto, H., Kristensson, K., … Wigzell, H. Treatment of African trypanosomiasis with cordycepin and adenosine deaminase inhibitors in a mouse model. Journal of Infectious Diseases. 2005; 192(9), 1658-1665.

[167] Lui, J.C.K., Wong, J.W.Y., Suen, Y.K. *et al.* Cordycepin induced eryptosis in mouse erythrocytes through a Ca2+ dependent pathway without caspase-3 activation. Arch Toxicol. 2007; 81, 859-865. https://doi.org/10.1007/ s00204-007-0214-5.

[168] Sornchaithawatwong, C., Kunthakudee, N., Sunsandee, N., & Ramakul, P. Selective extraction of cordycepin from *Cordyceps militaris* – optimisation, kinetics and equilibrium studies. Indian Chemical Engineer. 2020; 1-13. doi:10.1080/00194506.202 0.1776163.

[169] Tsai, Y.-S., Hsu, J.-H., Lin, D. P.-C., Chang, H.-H., Chang, W.-J., Chen, Y.-L., & Chen, C.-C. Safety Assessment of HEA-Enriched *Cordyceps cicadae* Mycelium: A Randomized Clinical Trial. Journal of the American College of Nutrition. 2020; 1-6. doi:10.1080/073157 24.2020.1743211.

[170] Chen, B.; Sun, Y.; Luo, F.; Wang, C. Bioactive Metabolites and Potential Mycotoxins Produced by *Cordyceps* Fungi: A Review of Safety. *Toxins* 2020; *12*:410.

[171] Zheng, P., Xia, Y., Zhang, S. *et al.* Genetics of *Cordyceps* and related fungi. Appl Microbiol Biotechnol. 2013; 97, 2797-2804. https://doi.org/10.1007/ s00253-013-4771-7.

[172] Li, B., Hou, Y., Zhu, M., Bao, H., Nie, J., Zhang, G. Y., … Du, J. 3'-Deoxyadenosine (Cordycepin) Produces a Rapid and Robust Antidepressant Effect via Enhancing Prefrontal AMPA Receptor Signaling Pathway. International Journal of Neuropsycho pharmacology. 2015; 19(4), pyv112. doi:10.1093/ijnp/pyv112.

[173] Tan, L., Song, X., Ren, Y., Wang, M., Guo, C., Guo, D., Deng, Y. Antiinflammatory effects of cordycepin: A review. Phytotherapy Research. 2020. doi:10.1002/ptr.6890.

[174] Liu, Y., Li, Y., Zhang, H., Li, C., Zhang, Z., Liu, A., … Wu, W. Polysaccharides from *Cordyceps miltaris* cultured at different pH: Sugar composition and antioxidant activity. International Journal of Biological Macromolecules. 2020. doi:10.1016/j. ijbiomac.2020.06.182.

[175] Marsup, P. Yeerong, K. Neimkhum, W. Sirithunyalug, J. Anuchapreeda, S. To-anun, C. Chaiyana, W. Enhancement of Chemical Stability and Dermal Delivery of *Cordyceps militaris* Extracts by Nanoemulsion. N*anomaterials.* 2020; *10*:1565.

[176] Zhu, Y., Yu, X., Ge, Q., Li, J., Wang, D., Wei, Y., & Ouyang, Z. Antioxidant and anti-aging activities of polysaccharides from *Cordyceps cicadae*. International Journal of Biological Macromolecules. 2020. doi:10.1016/j. ijbiomac.2020.04.163.

[177] Xiao, L., Sun, S., Li, K., Lei, Z., Shimizu, K., Zhang, Z., & Adachi, Y. Effects of nanobubble water supplementation on biomass accumulation during mycelium cultivation of *Cordyceps militaris* and the antioxidant activities of extracted polysaccharides. Bioresource Technology Reports. 2020; 12, 100600. doi:10.1016/j.biteb.2020.100600.

**351**

**1. Introduction**

**Chapter 17**

**Abstract**

One Health and the Positive

*Vincent F. Lembo and Cheryl A. Frye*

Effects of Alaskan Blueberries

One Health is a principle that takes into account the interactions of humans, animals, the surrounding environment, and how they affect each other. In order to examine this concept in an experimental paradigm, the effects and benefits of wild Alaskan blueberries were compared to those from the continental United States (Lower-48 states) in human and animal studies. Blueberries have been hailed as a superfood for years now due to their high antioxidant levels and the positive effects they have on cardiovascular health and overall health and well-being. We hypothesize that although they are both beneficial, wild Alaskan blueberries have a greater positive effect on health and well-being than those from the lower 48. First, teachers and staff at the Anne Wien Elementary School in Fairbanks Alaska were provided with Alaskan and Lower-48 blueberries and asked to log the effects each coded sample had on their mental and physical health compared to a 5-day control period without blueberries. There was a significant stepwise positive effect of respondents reporting higher self-ratings of well-being overall. Alaskan blueberries significantly improved self-ratings of well-being compared to those from Lower-48 blueberries, albeit those blueberries did improve well-being compared to no blueberries. This experiment was replicated at a control site contemporaneously. The following year it was also replicated by participating teachers and staff at William S. Hackett Middle School in Albany, New York, as well as a control site. Further, lab rats, whose diets were supplemented with with Alaskan blueberries, performed better in exploratory and cognitive tests than did rats whose diets were supplemented with Lower-48 blueberries (who, similar to the previous trials, performed better than rats whose diets had not been supplemented at all). These findings suggest that blueberries have an overall positive effect on self-rated wellness in people and cognitive performance in lab rats and that Alaskan blueberries have a particularly greater and more beneficial effect. Whether this is due to greater antioxidant effects associated with higher altitude or fewer endocrine-disrupting contaminants in Alaska compared to

the Lower-48 States is unknown and subject to ongoing investigation.

**Keywords:** antioxidants, cholesterol, triglycerides, low density liposaccharides, high blood pressure, hypercholesterolemia, cognitive decline, neurosteroids

Consumption of fruits and vegetables is often correlated with brain and heart health and cancer prevention. One way that fruits and vegetables have beneficial effects on health is through their antioxidant actions. Not all fruits and vegetables are the same in terms of their antioxidant actions. When scientists tested 143

## **Chapter 17**

*Antioxidants - Benefits, Sources, Mechanisms of Action*

[172] Li, B., Hou, Y., Zhu, M., Bao, H.,

Antidepressant Effect via Enhancing Prefrontal AMPA Receptor Signaling Pathway. International Journal of Neuropsycho pharmacology. 2015; 19(4), pyv112. doi:10.1093/ijnp/pyv112.

[173] Tan, L., Song, X., Ren, Y., Wang, M., Guo, C., Guo, D., Deng, Y. Antiinflammatory effects of cordycepin: A review. Phytotherapy Research. 2020.

[174] Liu, Y., Li, Y., Zhang, H., Li, C., Zhang, Z., Liu, A., … Wu, W.

cultured at different pH: Sugar composition and antioxidant activity. International Journal of Biological Macromolecules. 2020. doi:10.1016/j.

Polysaccharides from *Cordyceps miltaris*

[175] Marsup, P. Yeerong, K. Neimkhum, W. Sirithunyalug, J. Anuchapreeda, S. To-anun, C. Chaiyana, W. Enhancement of Chemical Stability and Dermal Delivery of *Cordyceps militaris* Extracts by Nanoemulsion. N*anomaterials.* 2020;

[176] Zhu, Y., Yu, X., Ge, Q., Li, J., Wang, D., Wei, Y., & Ouyang, Z. Antioxidant

polysaccharides from *Cordyceps cicadae*. International Journal of Biological Macromolecules. 2020. doi:10.1016/j.

[177] Xiao, L., Sun, S., Li, K., Lei, Z., Shimizu, K., Zhang, Z., & Adachi, Y.

cultivation of *Cordyceps militaris* and the antioxidant activities of extracted polysaccharides. Bioresource

Technology Reports. 2020; 12, 100600. doi:10.1016/j.biteb.2020.100600.

Effects of nanobubble water supplementation on biomass accumulation during mycelium

and anti-aging activities of

ijbiomac.2020.04.163.

doi:10.1002/ptr.6890.

ijbiomac.2020.06.182.

*10*:1565.

Nie, J., Zhang, G. Y., … Du, J. 3'-Deoxyadenosine (Cordycepin) Produces a Rapid and Robust

**350**

## One Health and the Positive Effects of Alaskan Blueberries

*Vincent F. Lembo and Cheryl A. Frye*

## **Abstract**

One Health is a principle that takes into account the interactions of humans, animals, the surrounding environment, and how they affect each other. In order to examine this concept in an experimental paradigm, the effects and benefits of wild Alaskan blueberries were compared to those from the continental United States (Lower-48 states) in human and animal studies. Blueberries have been hailed as a superfood for years now due to their high antioxidant levels and the positive effects they have on cardiovascular health and overall health and well-being. We hypothesize that although they are both beneficial, wild Alaskan blueberries have a greater positive effect on health and well-being than those from the lower 48. First, teachers and staff at the Anne Wien Elementary School in Fairbanks Alaska were provided with Alaskan and Lower-48 blueberries and asked to log the effects each coded sample had on their mental and physical health compared to a 5-day control period without blueberries. There was a significant stepwise positive effect of respondents reporting higher self-ratings of well-being overall. Alaskan blueberries significantly improved self-ratings of well-being compared to those from Lower-48 blueberries, albeit those blueberries did improve well-being compared to no blueberries. This experiment was replicated at a control site contemporaneously. The following year it was also replicated by participating teachers and staff at William S. Hackett Middle School in Albany, New York, as well as a control site. Further, lab rats, whose diets were supplemented with with Alaskan blueberries, performed better in exploratory and cognitive tests than did rats whose diets were supplemented with Lower-48 blueberries (who, similar to the previous trials, performed better than rats whose diets had not been supplemented at all). These findings suggest that blueberries have an overall positive effect on self-rated wellness in people and cognitive performance in lab rats and that Alaskan blueberries have a particularly greater and more beneficial effect. Whether this is due to greater antioxidant effects associated with higher altitude or fewer endocrine-disrupting contaminants in Alaska compared to the Lower-48 States is unknown and subject to ongoing investigation.

**Keywords:** antioxidants, cholesterol, triglycerides, low density liposaccharides, high blood pressure, hypercholesterolemia, cognitive decline, neurosteroids

## **1. Introduction**

Consumption of fruits and vegetables is often correlated with brain and heart health and cancer prevention. One way that fruits and vegetables have beneficial effects on health is through their antioxidant actions. Not all fruits and vegetables are the same in terms of their antioxidant actions. When scientists tested 143

different plants for their antioxidant power: blueberries scored 4669 > cherries were 3747 and prune juice came in at 2036; avocado was at 1922; grapefruit had a power score of 1640, spinach was 1513 and raw broccoli was 1510 and pineapple was a low 385. These results on an ORAC scale compare items among food groups that show relative antioxidant activity. ORAC is a measure of water-soluble antioxidant levels and does not distinguish among those antioxidants that have benefits to humans and those that do not. It is simply an overall estimate of antioxidant activity in a particular experiment. Due to the limited utility of this index, the USDA's Nutrient Data Laboratory (NDL) removed the ORAC database from the NDL website [1].

Wild berries contain an impressive array of bioactive phytochemical compounds, which collectively present a range of biological activities targeting key mechanisms involved in healthy tissue development and aging [2, 3]. The human health-relevant bioactive properties of wild berries can be primarily attributed to their considerable diversity of polyphenolic constituents, typically exhibiting antioxidant, anti-inflammatory, and antimicrobial capabilities [4, 5]. The Nurses' Health Study evaluated 16,000 participants regarding cognitive decline and consumption of berries over a 20-year period. Greater intakes of flavonoids particularly from strawberries and blueberries were associated with slower cognitive decline in older adults [6]. This again supports the beneficial effects of blueberries.

Wild blueberries (*Vaccinium angustifolium*) are rich sources of polyphenols (e.g. flavonols, phenolic acids, anthocyanins) and decrease the risk of cardiovascular and degenerative diseases [7]. Memory function and mood in older adults with memory decline was improved by regular consumption of wild blueberries [8].

Various wild berry species endemic to Alaska and the circumpolar North that exhibit unique medicinal properties have long been appreciated by indigenous Arctic communities. Berry picking is a cherished tradition among all Alaskans that provides important physical and recreational activities for young and old alike. It has been an integral part of subsistence activities for thousands of years. Alaska is rich in wild edible berries that provide essential nutrients, especially vitamin C, and antioxidants for northern climates.

Interspecific differences, as well as environmental factors, such as geographic location and climatic variation, substantially influence the accumulation of berry phytochemicals and thus likely alter their profile of health-related bioactivities [9–11].

These experiments were designed to test the hypotheses that (1) wild blueberries would have beneficial short-term effects effect on healthy individuals (2) blueberries from Alaska would be more effective than those from the lower 48 (3) these effects would be seen across groups and species.

## **2. Methods**

*The protocol for Experiment 1 was approved by the Principal of Anne Wien Elementary School. All participants were volunteers and signed an informed consent indicating that they would comply with the guidelines of the experiment. At any time, volunteers could drop out as non-participants and their data would not be included.*

## **2.1 Comparing effects of wild Alaskan blueberries to those from the lower 48 for effects on stress, mood, and affective function in people in Fairbanks, Alaska**

The Native Alaskan blueberries used in this experiment were hand-picked by the authors, and their associates, the summer before the experiment began, and frozen

**353**

New York.

**2.2 Rats**

*2.2.1 Husbandry*

a year after experiment 1.

ance number 497513).

*One Health and the Positive Effects of Alaskan Blueberries*

*2.1.1 Procedures for examining effects of blueberries*

at −20 degrees Fahrenheit. These were low bush blueberries of large size, which are known to have high antioxidant value. The store-bought blueberries were purchased fresh from the local grocery store (Fred Meyers, Fairbanks, Alaska) around the same time. Half cup portions were prepackaged and labeled (A or B) and then placed in a refrigerator in the faculty lounge in the experimental locations.

**Experiment 1:** In the first experiment, teachers and staff members at Anne Wien Elementary School (https://www.k12northstar.org/annewien) were provided with two samples of blueberries: hand-picked Alaskan blueberries, labeled A, and store-bought blueberries, labeled B, and surveys (see **Figure 1**) for them to answer after consuming the blueberries for 5 days or no blueberries control. This experiment was three weeks long. Participants consumed ½ a cup of one type of blueberries every day for one work week, repeated that process the next week with the other type of blueberries, and completed another survey after a third control week where no blueberries were consumed. Participants were allowed to use any sample any given week, so long as they only used that sample (or no sample) for the full work week and completed the other two sample weeks in the remaining time.

Custom surveys were created to enable participants to fully document the effects, positive, negative, or lack thereof, of the blueberries on their mental and physical health and well-being. Datasheets were turned in to the research supervisor at each site each week. There were 7 participants from Anne Wien Elementary (Fairbanks, AK) and 6 from an alternate site in Fairbanks (https://www.uafarc.com/overview), as well as 7 more from Hackett Middle School (Albany, NY) and 5 more from an alternate site

*The protocol for Experiment 2 was approved by the principal of Hackett Middle School, all participants were volunteers and signed an informed consent indicating that they would comply with the guidelines of the experiment. At any time, volunteers could* 

Experiment 2 was identical in procedure to experiment 1, the difference was the population that was tested. Experiment 2 took place at Hackett Middle School (https://www.albanyschools.org/schools/hackett/index) in Albany, New York about

**Experiment 2:** Comparing Effects of Wild Alaskan Blueberries to those from the Lower 48 for effects on Stress, Mood, and Affective Function in People in Albany,

**Experiment 3:** Comparing Effects of Wild Alaskan Blueberries to those from the Lower 48 for effects on Stress, Mood, and Affective Function in Long-Evans Rats. The University of Alaska Fairbanks Institutional Animal Care and Use Committee approved the animal care and experimental procedures (IACUC assur-

Long-Evans rats were housed in polypropylene cages with wood shavings in a temperature (22 ± 1°C) and humidity (60–80%) controlled room of the Biological Research and Diagnostics (BiRD) Facility vivarium on a reversed 12:12 h dark-light cycle. Pups were weaned at 19–21 days of age and housed with same-sex littermates until the end of all experiments. Food (Purina Mills, Rat Diet, St. Louis, MO) and water were available *ad libitum*. Rats were also provided ½ cup blueberries from

in Albany later on for replication in the lower 48 States. (Experiment 2).

*drop out as non-participants and their data would not be included.*

*DOI: http://dx.doi.org/10.5772/intechopen.94738*

*Antioxidants - Benefits, Sources, Mechanisms of Action*

different plants for their antioxidant power: blueberries scored 4669 > cherries were 3747 and prune juice came in at 2036; avocado was at 1922; grapefruit had a power score of 1640, spinach was 1513 and raw broccoli was 1510 and pineapple was a low 385. These results on an ORAC scale compare items among food groups that show relative antioxidant activity. ORAC is a measure of water-soluble antioxidant levels and does not distinguish among those antioxidants that have benefits to humans and those that do not. It is simply an overall estimate of antioxidant activity in a particular experiment. Due to the limited utility of this index, the USDA's Nutrient Data Laboratory (NDL) removed the ORAC database from the NDL website [1]. Wild berries contain an impressive array of bioactive phytochemical compounds, which collectively present a range of biological activities targeting key mechanisms involved in healthy tissue development and aging [2, 3]. The human health-relevant bioactive properties of wild berries can be primarily attributed to their considerable diversity of polyphenolic constituents, typically exhibiting antioxidant, anti-inflammatory, and antimicrobial capabilities [4, 5]. The Nurses' Health Study evaluated 16,000 participants regarding cognitive decline and consumption of berries over a 20-year period. Greater intakes of flavonoids particularly from strawberries and blueberries were associated with slower cognitive decline in

older adults [6]. This again supports the beneficial effects of blueberries.

decline was improved by regular consumption of wild blueberries [8].

antioxidants for northern climates.

effects would be seen across groups and species.

tivities [9–11].

**2. Methods**

**Alaska**

Wild blueberries (*Vaccinium angustifolium*) are rich sources of polyphenols (e.g. flavonols, phenolic acids, anthocyanins) and decrease the risk of cardiovascular and degenerative diseases [7]. Memory function and mood in older adults with memory

Various wild berry species endemic to Alaska and the circumpolar North that exhibit unique medicinal properties have long been appreciated by indigenous Arctic communities. Berry picking is a cherished tradition among all Alaskans that provides important physical and recreational activities for young and old alike. It has been an integral part of subsistence activities for thousands of years. Alaska is rich in wild edible berries that provide essential nutrients, especially vitamin C, and

Interspecific differences, as well as environmental factors, such as geographic

These experiments were designed to test the hypotheses that (1) wild blueberries would have beneficial short-term effects effect on healthy individuals (2) blueberries from Alaska would be more effective than those from the lower 48 (3) these

location and climatic variation, substantially influence the accumulation of berry phytochemicals and thus likely alter their profile of health-related bioac-

*The protocol for Experiment 1 was approved by the Principal of Anne Wien Elementary School. All participants were volunteers and signed an informed consent indicating that they would comply with the guidelines of the experiment. At any time, volunteers could drop out as non-participants and their data would not be included.*

**2.1 Comparing effects of wild Alaskan blueberries to those from the lower 48 for effects on stress, mood, and affective function in people in Fairbanks,** 

The Native Alaskan blueberries used in this experiment were hand-picked by the authors, and their associates, the summer before the experiment began, and frozen

**352**

at −20 degrees Fahrenheit. These were low bush blueberries of large size, which are known to have high antioxidant value. The store-bought blueberries were purchased fresh from the local grocery store (Fred Meyers, Fairbanks, Alaska) around the same time. Half cup portions were prepackaged and labeled (A or B) and then placed in a refrigerator in the faculty lounge in the experimental locations.

### *2.1.1 Procedures for examining effects of blueberries*

**Experiment 1:** In the first experiment, teachers and staff members at Anne Wien Elementary School (https://www.k12northstar.org/annewien) were provided with two samples of blueberries: hand-picked Alaskan blueberries, labeled A, and store-bought blueberries, labeled B, and surveys (see **Figure 1**) for them to answer after consuming the blueberries for 5 days or no blueberries control. This experiment was three weeks long. Participants consumed ½ a cup of one type of blueberries every day for one work week, repeated that process the next week with the other type of blueberries, and completed another survey after a third control week where no blueberries were consumed. Participants were allowed to use any sample any given week, so long as they only used that sample (or no sample) for the full work week and completed the other two sample weeks in the remaining time.

Custom surveys were created to enable participants to fully document the effects, positive, negative, or lack thereof, of the blueberries on their mental and physical health and well-being. Datasheets were turned in to the research supervisor at each site each week. There were 7 participants from Anne Wien Elementary (Fairbanks, AK) and 6 from an alternate site in Fairbanks (https://www.uafarc.com/overview), as well as 7 more from Hackett Middle School (Albany, NY) and 5 more from an alternate site in Albany later on for replication in the lower 48 States. (Experiment 2).

*The protocol for Experiment 2 was approved by the principal of Hackett Middle School, all participants were volunteers and signed an informed consent indicating that they would comply with the guidelines of the experiment. At any time, volunteers could drop out as non-participants and their data would not be included.*

**Experiment 2:** Comparing Effects of Wild Alaskan Blueberries to those from the Lower 48 for effects on Stress, Mood, and Affective Function in People in Albany, New York.

Experiment 2 was identical in procedure to experiment 1, the difference was the population that was tested. Experiment 2 took place at Hackett Middle School (https://www.albanyschools.org/schools/hackett/index) in Albany, New York about a year after experiment 1.

**Experiment 3:** Comparing Effects of Wild Alaskan Blueberries to those from the Lower 48 for effects on Stress, Mood, and Affective Function in Long-Evans Rats.

The University of Alaska Fairbanks Institutional Animal Care and Use Committee approved the animal care and experimental procedures (IACUC assurance number 497513).

#### **2.2 Rats**

#### *2.2.1 Husbandry*

Long-Evans rats were housed in polypropylene cages with wood shavings in a temperature (22 ± 1°C) and humidity (60–80%) controlled room of the Biological Research and Diagnostics (BiRD) Facility vivarium on a reversed 12:12 h dark-light cycle. Pups were weaned at 19–21 days of age and housed with same-sex littermates until the end of all experiments. Food (Purina Mills, Rat Diet, St. Louis, MO) and water were available *ad libitum*. Rats were also provided ½ cup blueberries from


#### **Figure 1.**

*This figure depicts the survey used by the participants of each trial to record the effects (or lack of effects) that each sample of blueberries, as well as no blueberries, has had on them. This survey was completed at the end of each trial week by each participant and is completely anonymous. Several measures were provided for the user to describe and show how they felt after each trial week including a list of pronouns that the participant could choose best reflects them that week and survey questions that would help identify if blueberries were having a positive or negative effect on the participant. Demographic information was also collected for each participant.*

Alaska or the lower 48 or none (as a control) each day for 4–5 days leading up to their anticipated 5th day of proestrus when they were tested.

#### *2.2.2 Estrous cycle*

Female rats in proestrus were used for the study. The proestrus stage was determined daily by both visual and vaginal cytology methods. Vaginal cytology was performed on those females that showed visual signs of proestrus. The females for which proestrus was confirmed through cytology were subjected to behavioral testing the same day. This procedure was conducted daily until the desired sample

**355**

*One Health and the Positive Effects of Alaskan Blueberries*

hypothesized outcome of the study collected all data.

which occurs in the same box on the following days.

sizes were achieved for a specific test. When the females cycled to their next proestrus, which was typically on the 4th or the 5th day, they were subjected to the next behavioral test in the schedule and this cycle was continued until all behavioral tests were completed. Typically, the no blueberry control week was the interval washout period between tests 1 and 3, which were randomized to blueberry condition.

All female rats were at least 60 days old at the start of the experiment. All behavioral tests were done in the dark phase of the light–dark cycle. For females, behavioral tests were conducted every 4–5 days depending on their cycle stage. All females underwent behavioral tests once every 5–10 days: open field (on day 5 or 10) and novel object recognition (on day 15 or 20). A minimum gap of 5 days for females between the two behavioral tests minimized the behaviors interfering with each other. An observer blind to the conditions of experimental animals and the

Behavior in the open field is used as a measure of exploration, anxiety, and locomotor behavior [12, 13]. The open field (76 cm x 57 cm x 35 cm) has a 48-square grid floor (6 x 8 squares, 9.5 cm/side): there is an overhead light illuminating the central squares (all but the 24 perimeter squares were considered central). Behavior was recorded by the ANYMaze video-tracking program (Stoelting Co., IL, USA). The apparatus was cleaned before and after each test. Per previous methods, rats were placed in the open field and the path of their exploration was recorded for five minutes. The number of squares entered by rats in the center or periphery of the grid was calculated and these data were added together to yield the total number of squares entered. Prior reports indicate that total square entries in this task are robustly modulated by the hormonal status of female rats and by steroid-sensitive manipulations [14–16]. Because the current study utilized a sample of female rats that were all matched on the phase of estrous cycle, motor differences were expected to be minimized. Thus, central square entries were utilized as an index of anti-anxiety, and total square entries as an index of thigmotaxis, and motor behavior. Additionally, engaging in this task provides habituation for object recognition,

The object recognition task is a working memory task that primarily relies on cortical functioning and, to a lesser extent, hippocampal functioning [17–19]. This task was used as modified from previously published methods [20–22]. During training, rats are placed in a white open field (76 cm x 57 cm x 35 cm) in a brightly-lit testing room. Rats are allowed 3 min to explore the open field, which contains two identical objects in adjacent corners. These objects were colored spherical shapes (plastic toys in the shape of oranges). The time spent investigating the two identical objects (plastic toys) within a 5 cm distance in the open field arena was recorded for 3 min with the ANYMaze video tracking program (Stoelting.co, Chicago, IL). Rats were then taken out of the arena and returned to their holding cages for 4 hrs. After 4 hrs., one of the objects was replaced with a novel object of different shape and size, and animals were then reintroduced into the arena and allowed to explore the objects for 3 min. Time spent exploring the familiar and novel objects were recorded. The preference of one object over another was assessed through the Recognition

*DOI: http://dx.doi.org/10.5772/intechopen.94738*

*2.2.3 Experimental design*

*2.2.4 Open field*

*2.2.5 Object recognition*

sizes were achieved for a specific test. When the females cycled to their next proestrus, which was typically on the 4th or the 5th day, they were subjected to the next behavioral test in the schedule and this cycle was continued until all behavioral tests were completed. Typically, the no blueberry control week was the interval washout period between tests 1 and 3, which were randomized to blueberry condition.

## *2.2.3 Experimental design*

*Antioxidants - Benefits, Sources, Mechanisms of Action*

Alaska or the lower 48 or none (as a control) each day for 4–5 days leading up to

*This figure depicts the survey used by the participants of each trial to record the effects (or lack of effects) that each sample of blueberries, as well as no blueberries, has had on them. This survey was completed at the end of each trial week by each participant and is completely anonymous. Several measures were provided for the user to describe and show how they felt after each trial week including a list of pronouns that the participant could choose best reflects them that week and survey questions that would help identify if blueberries were having a positive or negative effect on the participant. Demographic information was also collected for each participant.*

Female rats in proestrus were used for the study. The proestrus stage was determined daily by both visual and vaginal cytology methods. Vaginal cytology was performed on those females that showed visual signs of proestrus. The females for which proestrus was confirmed through cytology were subjected to behavioral testing the same day. This procedure was conducted daily until the desired sample

their anticipated 5th day of proestrus when they were tested.

**354**

*2.2.2 Estrous cycle*

**Figure 1.**

All female rats were at least 60 days old at the start of the experiment. All behavioral tests were done in the dark phase of the light–dark cycle. For females, behavioral tests were conducted every 4–5 days depending on their cycle stage. All females underwent behavioral tests once every 5–10 days: open field (on day 5 or 10) and novel object recognition (on day 15 or 20). A minimum gap of 5 days for females between the two behavioral tests minimized the behaviors interfering with each other. An observer blind to the conditions of experimental animals and the hypothesized outcome of the study collected all data.

## *2.2.4 Open field*

Behavior in the open field is used as a measure of exploration, anxiety, and locomotor behavior [12, 13]. The open field (76 cm x 57 cm x 35 cm) has a 48-square grid floor (6 x 8 squares, 9.5 cm/side): there is an overhead light illuminating the central squares (all but the 24 perimeter squares were considered central). Behavior was recorded by the ANYMaze video-tracking program (Stoelting Co., IL, USA). The apparatus was cleaned before and after each test. Per previous methods, rats were placed in the open field and the path of their exploration was recorded for five minutes. The number of squares entered by rats in the center or periphery of the grid was calculated and these data were added together to yield the total number of squares entered. Prior reports indicate that total square entries in this task are robustly modulated by the hormonal status of female rats and by steroid-sensitive manipulations [14–16]. Because the current study utilized a sample of female rats that were all matched on the phase of estrous cycle, motor differences were expected to be minimized. Thus, central square entries were utilized as an index of anti-anxiety, and total square entries as an index of thigmotaxis, and motor behavior. Additionally, engaging in this task provides habituation for object recognition, which occurs in the same box on the following days.

## *2.2.5 Object recognition*

The object recognition task is a working memory task that primarily relies on cortical functioning and, to a lesser extent, hippocampal functioning [17–19]. This task was used as modified from previously published methods [20–22]. During training, rats are placed in a white open field (76 cm x 57 cm x 35 cm) in a brightly-lit testing room. Rats are allowed 3 min to explore the open field, which contains two identical objects in adjacent corners. These objects were colored spherical shapes (plastic toys in the shape of oranges). The time spent investigating the two identical objects (plastic toys) within a 5 cm distance in the open field arena was recorded for 3 min with the ANYMaze video tracking program (Stoelting.co, Chicago, IL). Rats were then taken out of the arena and returned to their holding cages for 4 hrs. After 4 hrs., one of the objects was replaced with a novel object of different shape and size, and animals were then reintroduced into the arena and allowed to explore the objects for 3 min. Time spent exploring the familiar and novel objects were recorded. The preference of one object over another was assessed through the Recognition

Percentage, which is the time spent on the novel object relative to the time spent on both novel and familiar objects: [RI = TN/(TN + TF) x 100] where TN is time spent on the novel object and TF is time spent on the familiar object). A greater percentage of time spent exploring the novel object as a function of the total amount of time spent exploring both objects during testing (duration spent with novel object/ (duration spent with novel object + duration spent with familiar object) Å x 100) is considered an index of enhanced cognitive performance in these tasks.

*2.2.6 Statistical analyses: one-way repeated measure analyses of variance was utilized to examine the effects of the condition (Blueberries) on self ratings*

*Post hoc* analyses to determine group differences consisted of repeated t-tests with Bonferroni-corrections. Results are only reported for effects where the overall ANOVAs were significant, at the alpha level of 0.05, which was the case for each experiment. Overall effects and specific group differences are described below and in the tables and figures and their legends.

## **3. Results**

**Experiment 1a:** Self-reports of health and wellness of middle-aged elementary school teachers in Fairbanks, Alaska were significantly greater following 5 days of consumption of Alaskan blueberries compared to blueberries from the Lower-48, which still had a beneficial effect compared to no blueberry consumption.

Self-reports of beneficial effects on stress, anxiety, and cognition are reported among women participants in Fairbanks, Alaska (demographics in **Table 1** left side, far) after 5 days of consumption of Alaskan blueberries > Lower-48 blueberries > no blueberries. Repeated measures analysis of variance revealed that there was an overall interaction between the type of blueberries and effects on self-ratings. *Post hoc* analyses revealed consumption of Alaskan berries resulted in higher ratings overall than did berries from the Lower-48 or no consumption of berries. This effect was seen for ratings of calmness, feelings of being well-balanced, and ability to maintain control and stay on top of things. Notably, self-reports of cognitive benefits of blueberries from Alaska, as well as the Lower-48, were not different but were significantly higher than the consumption of no berries among the participants at Anne Wien Elementary School. See **Figure 2**.

**Experiment 1b:** Demographics are described in **Table 1** (left center). Selfreports of health and wellness of young adult lab workers in Fairbanks, Alaska were significantly greater following 5 days of consumption of Alaskan blueberries compared to blueberries from the Lower-48, which still had a beneficial effect compared to no blueberry consumption.

To confirm and extend these findings, the experiment was replicated at an alternative site in Fairbanks (see **Table 1**, left middle, for demographics). There were even greater statistically significant interactions between types of blueberries and effects on self-reports at this alternative site than at Anne Wien Elementary School. Ratings for weeks following consumption of Alaskan blueberries > Lower-48 blueberries >no blueberries for self-reports of feelings of calmness, being well-balanced, in control, on top of things, cognitive benefits. Thus, women in Alaska who consumed blueberries for 5 days experienced beneficial effects as per their self-ratings. The magnitude of these effects was greater at the alternative site. See **Figure 3**.

**357**

*One Health and the Positive Effects of Alaskan Blueberries*

**Eiementary School**

2 Native Alaskan

n = of participants 7 8 6 5 Age (avg. years) 42.3 33.6 40.0 48.7

*The mean average demographics obtained from the Anne-Wien elementary school and the alternative site in Fairbanks (Byrd animal facility staff at U Alaska Fairbanks) on the left side. On the right side are the demographics for the Hackett middle School in Albany and the alternative site in Albany, NY (Comprehensive* 

3 Caucasian 2 Native Alaskan 2 Biracial 1 African American

**Fairbanks, AK Albany, NY**

**Alternate site Hackett** 

15.3 14.7 16.0 15.4

**Middle School Albany, NY**

> 2 Caucasian 2 African American 2 Latina

**Alternate site**

3 Caucasian 1 African American 1 Native Alaskan 1 Native American

**Experiment 2a:** Self-reports of health and wellness of middle-aged middle school teachers in Albany, New York were significantly greater following 5 days of consumption of Alaskan blueberries compared to blueberries from the Lower-48,

*This figure represents the mean + standard error of the mean of self-ratings in several categories by each participant in Fairbanks, Alaska at Anne-Wien Elementary School. This figure shows a significant overall effect of treatment (blueberries) to increase ratings of calm, a sense of well-balanced and ability to control surroundings and stay on top of things, except for self-ratings of cognitive benefit compared to consumption of no blueberries. Furthermore, consumption of wild Alaskan blueberries (orange) increased the participant's rating in each of the aforementioned categories compared to Lower-48 berries (gray) or no berries (blue).*

Self-reports of beneficial effects on stress, anxiety, and cognition are reported among women participants in Albany, New York after 5 days of consumption of Alaskan blueberries > Lower-48 blueberries > no blueberries. One-way, repeated analysis of variance revealed that there were overall interactions between the type of blueberries and effects on self-ratings. Some of the same patterns were observed among the participants at Hackett Middle School (Albany, NY) that were previously seen at Anne Wien Elementary (Fairbanks, AK). In particular, self-reports of feeling well-balanced, as well as in control and on top of things were higher in participants when they consumed Alaskan blueberries for a week compared to when they consumed Lower-48 blueberries or no blueberries. Demographics are reported

which still had a beneficial effect compared to no blueberry consumption.

in **Table 1** center-right. See **Figure 3** for results.

*DOI: http://dx.doi.org/10.5772/intechopen.94738*

**Location Anne-Wien** 

Ethnicity 5 Caucasian

Education (avg. years)

*Neuropsychological Services).*

**Table 1.**

**Figure 2.**

*One Health and the Positive Effects of Alaskan Blueberries DOI: http://dx.doi.org/10.5772/intechopen.94738*


#### **Table 1.**

*Antioxidants - Benefits, Sources, Mechanisms of Action*

in the tables and figures and their legends.

pants at Anne Wien Elementary School. See **Figure 2**.

compared to no blueberry consumption.

*self ratings*

**3. Results**

Percentage, which is the time spent on the novel object relative to the time spent on both novel and familiar objects: [RI = TN/(TN + TF) x 100] where TN is time spent on the novel object and TF is time spent on the familiar object). A greater percentage of time spent exploring the novel object as a function of the total amount of time spent exploring both objects during testing (duration spent with novel object/ (duration spent with novel object + duration spent with familiar object) Å x 100) is

*Post hoc* analyses to determine group differences consisted of repeated t-tests with Bonferroni-corrections. Results are only reported for effects where the overall ANOVAs were significant, at the alpha level of 0.05, which was the case for each experiment. Overall effects and specific group differences are described below and

**Experiment 1a:** Self-reports of health and wellness of middle-aged elementary school teachers in Fairbanks, Alaska were significantly greater following 5 days of consumption of Alaskan blueberries compared to blueberries from the Lower-48,

Self-reports of beneficial effects on stress, anxiety, and cognition are reported among women participants in Fairbanks, Alaska (demographics in **Table 1** left side, far) after 5 days of consumption of Alaskan blueberries > Lower-48 blueberries > no blueberries. Repeated measures analysis of variance revealed that there was an overall interaction between the type of blueberries and effects on self-ratings. *Post hoc* analyses revealed consumption of Alaskan berries resulted in higher ratings overall than did berries from the Lower-48 or no consumption of berries. This effect was seen for ratings of calmness, feelings of being well-balanced, and ability to maintain control and stay on top of things. Notably, self-reports of cognitive benefits of blueberries from Alaska, as well as the Lower-48, were not different but were significantly higher than the consumption of no berries among the partici-

**Experiment 1b:** Demographics are described in **Table 1** (left center). Selfreports of health and wellness of young adult lab workers in Fairbanks, Alaska were significantly greater following 5 days of consumption of Alaskan blueberries compared to blueberries from the Lower-48, which still had a beneficial effect

To confirm and extend these findings, the experiment was replicated at an alternative site in Fairbanks (see **Table 1**, left middle, for demographics). There were even greater statistically significant interactions between types of blueberries and effects on self-reports at this alternative site than at Anne Wien Elementary School. Ratings for weeks following consumption of Alaskan blueberries > Lower-48 blueberries >no blueberries for self-reports of feelings of calmness, being well-balanced, in control, on top of things, cognitive benefits. Thus, women in Alaska who consumed blueberries for 5 days experienced beneficial effects as per their self-ratings. The magnitude of these effects was greater at the alternative site.

which still had a beneficial effect compared to no blueberry consumption.

considered an index of enhanced cognitive performance in these tasks.

*2.2.6 Statistical analyses: one-way repeated measure analyses of variance was utilized to examine the effects of the condition (Blueberries) on* 

**356**

See **Figure 3**.

*The mean average demographics obtained from the Anne-Wien elementary school and the alternative site in Fairbanks (Byrd animal facility staff at U Alaska Fairbanks) on the left side. On the right side are the demographics for the Hackett middle School in Albany and the alternative site in Albany, NY (Comprehensive Neuropsychological Services).*

#### **Figure 2.**

*This figure represents the mean + standard error of the mean of self-ratings in several categories by each participant in Fairbanks, Alaska at Anne-Wien Elementary School. This figure shows a significant overall effect of treatment (blueberries) to increase ratings of calm, a sense of well-balanced and ability to control surroundings and stay on top of things, except for self-ratings of cognitive benefit compared to consumption of no blueberries. Furthermore, consumption of wild Alaskan blueberries (orange) increased the participant's rating in each of the aforementioned categories compared to Lower-48 berries (gray) or no berries (blue).*

**Experiment 2a:** Self-reports of health and wellness of middle-aged middle school teachers in Albany, New York were significantly greater following 5 days of consumption of Alaskan blueberries compared to blueberries from the Lower-48, which still had a beneficial effect compared to no blueberry consumption.

Self-reports of beneficial effects on stress, anxiety, and cognition are reported among women participants in Albany, New York after 5 days of consumption of Alaskan blueberries > Lower-48 blueberries > no blueberries. One-way, repeated analysis of variance revealed that there were overall interactions between the type of blueberries and effects on self-ratings. Some of the same patterns were observed among the participants at Hackett Middle School (Albany, NY) that were previously seen at Anne Wien Elementary (Fairbanks, AK). In particular, self-reports of feeling well-balanced, as well as in control and on top of things were higher in participants when they consumed Alaskan blueberries for a week compared to when they consumed Lower-48 blueberries or no blueberries. Demographics are reported in **Table 1** center-right. See **Figure 3** for results.

**Experiment 2b:** Self-reports of health and wellness of middle-aged office workers in Albany, New York were significantly greater following 5 days of consumption of Alaskan blueberries, compared to blueberries from the Lower-48.

There were even greater statistically significant interactions between types of blueberries and effects on self-reports at this alternative site than at Hackett Middle School in Albany, NY. Ratings for weeks following consumption of Alaskan blueberries > Lower-48 blueberries ≥ no blueberries for self-ratings of feelings of calmness, well-balanced. See demographics in **Table 1** and ratings in **Table 2**.

**Experiment 3:** Female Long-Evans rats whose diets were supplemented by Alaskan blueberries > Lower-48 blueberries > no supplement (control) were significantly more active, less anxious, and performed better in a novel object recognition task.

There were 8 female Long-Evans rats in each of the 3 trial groups. Those who had 5 days of access to Alaskan blueberries made more total entries (245 entries) into the brightly lit open field than did those with access to blueberries from the Lower-48 (223 entries), as well as those with no blueberry supplementation (196 entries) in a

#### **Figure 3.**

*This figure represents the mean + standard error of the mean of self-ratings in several categories by each participant in Albany, New York at Hackett Middle School. This figure shows a significant overall effect of treatment (blueberries) to increase ratings wild Alaskan blueberries (orange) to overall increase participant's rating in each of the aforementioned categories compared to Lower-48 berries (gray) or no berries (blue).*


#### **Table 2.**

*The mean average self-ratings obtained from the Fairbanks (n = 8) and Albany sites alternative site (n = 5) after 5 days of no consumption blueberries, lower 48 or Alaskan blueberries.*

**359**

*One Health and the Positive Effects of Alaskan Blueberries*

5-minute period. The number of central entries (all but peripheral squares) during this 5-minute task was also greater for rats with access to Alaskan blueberries (120 entries) than rats whose diets were supplemented with blueberries from the Lower-48 (113 entries) as well as rats whose diets were not supplemented (93 entries). The number of inner 8 entries (central squares of open field) during this 5-minute task was greater for rats with access to Alaskan blueberries (25 entries) compared to rats whose diets were supplemented with blueberries from the Lower-48 (19 entries), as well as rats whose diets were not supplemented (13 entries). When rats were tested in the novel object recognition task, those consuming Alaskan berries spent 70% of their time than the novel object, whereas rats consuming Lower-48 berries spent only 61% of their time with the object. Rats whose diets were not supplemented spent the least amount of time, 51% (no greater than chance levels), with the novel

*This figure represents the scores in several tasks by Long-Evans laboratory rats at the BiRD Animal Research and Development facility at UAF as their diets were supplemented with Lower-48 or Alaskan blueberries, or no berries at all similar to human participants in the first trials. This figure shows that blueberries increase the number of total entries as well as central entries, Inner8 entries, and time spent with a novel object compared to consumption of no blueberries. Furthermore, consumption of wild Alaskan blueberries (orange) increased the rat's scores in each of the aforementioned categories compared to Lower-48 berries (gray) or no berries (blue).*

The results of these experiments were consistent with the proposed hypotheses. First, blueberry consumption had beneficial short-term effects on healthy individuals. Blueberries had positive effects on the Alaskan participants' health and well-being after 5 days of consumption. This was also observed in the Albany cohorts. Participants consuming blueberries rated their levels of calm, well-balanced, ability to control themselves, and stay on top of things, and cognitive benefit, higher than when they consumed no berries. Second, this effect was seen more obviously when participants consumed Alaskan blueberries. They rated themselves even higher in the aforementioned categories than when they consumed Lower-48 blueberries. This effect was not identical; however, in New York, data from participants show an effect of blueberries but not a statistically significant difference between Alaskan blueberries and berries from the Lower-48. Third, blueberries had similar patterns of effects in rats. Notably, in more global tasks, such as total entries and central entries in an open field, there was an effect of blueberries, irrespective of their source, to improve performance among rats. However, in more challenging tasks, such as the Inner 8 entries and the percent of time with novel object, consumption of Alaskan blueberries had a greater effect than did those from the lower-48. In summary, short term consumption of blueberries can have

*DOI: http://dx.doi.org/10.5772/intechopen.94738*

object during testing (See **Figure 4**).

**4. Discussion**

**Figure 4.**

*One Health and the Positive Effects of Alaskan Blueberries DOI: http://dx.doi.org/10.5772/intechopen.94738*

#### **Figure 4.**

*Antioxidants - Benefits, Sources, Mechanisms of Action*

recognition task.

**Self-ratings-alternative sites**

Blueberry Source

**Figure 3.**

**Self-Ratings**

On Top of Things

Cognitive Benefit

**Fairbanks-bird animal facility UAlaska**

**Albany-comprehensive neuropsychological services**

**None Lower 48 Alaskan none Lower 48 Alaskan**

2.5 3.5 4.5 1.9 2.7 3.5

2.9 4.2 5.4 2.4 3.2 3.9

Calmness 2.1 3.3 4.2 1.5 2.3 3.6 Well Balanced 1.6 2.5 3.6 1.8 2.9 4.3 Able to Control 1.5 2.3 3.8 1.3 2.4 2.7

*This figure represents the mean + standard error of the mean of self-ratings in several categories by each participant in Albany, New York at Hackett Middle School. This figure shows a significant overall effect of treatment (blueberries) to increase ratings wild Alaskan blueberries (orange) to overall increase participant's rating in each of the aforementioned categories compared to Lower-48 berries (gray) or no berries (blue).*

*The mean average self-ratings obtained from the Fairbanks (n = 8) and Albany sites alternative site (n = 5)* 

*after 5 days of no consumption blueberries, lower 48 or Alaskan blueberries.*

**Experiment 2b:** Self-reports of health and wellness of middle-aged office workers in Albany, New York were significantly greater following 5 days of consumption of Alaskan blueberries, compared to blueberries from the Lower-48. There were even greater statistically significant interactions between types of blueberries and effects on self-reports at this alternative site than at Hackett Middle School in Albany, NY. Ratings for weeks following consumption of Alaskan blueberries > Lower-48 blueberries ≥ no blueberries for self-ratings of feelings of calmness, well-balanced. See demographics in **Table 1** and ratings in **Table 2**. **Experiment 3:** Female Long-Evans rats whose diets were supplemented by Alaskan blueberries > Lower-48 blueberries > no supplement (control) were significantly more active, less anxious, and performed better in a novel object

There were 8 female Long-Evans rats in each of the 3 trial groups. Those who had 5 days of access to Alaskan blueberries made more total entries (245 entries) into the brightly lit open field than did those with access to blueberries from the Lower-48 (223 entries), as well as those with no blueberry supplementation (196 entries) in a

**358**

**Table 2.**

*This figure represents the scores in several tasks by Long-Evans laboratory rats at the BiRD Animal Research and Development facility at UAF as their diets were supplemented with Lower-48 or Alaskan blueberries, or no berries at all similar to human participants in the first trials. This figure shows that blueberries increase the number of total entries as well as central entries, Inner8 entries, and time spent with a novel object compared to consumption of no blueberries. Furthermore, consumption of wild Alaskan blueberries (orange) increased the rat's scores in each of the aforementioned categories compared to Lower-48 berries (gray) or no berries (blue).*

5-minute period. The number of central entries (all but peripheral squares) during this 5-minute task was also greater for rats with access to Alaskan blueberries (120 entries) than rats whose diets were supplemented with blueberries from the Lower-48 (113 entries) as well as rats whose diets were not supplemented (93 entries). The number of inner 8 entries (central squares of open field) during this 5-minute task was greater for rats with access to Alaskan blueberries (25 entries) compared to rats whose diets were supplemented with blueberries from the Lower-48 (19 entries), as well as rats whose diets were not supplemented (13 entries). When rats were tested in the novel object recognition task, those consuming Alaskan berries spent 70% of their time than the novel object, whereas rats consuming Lower-48 berries spent only 61% of their time with the object. Rats whose diets were not supplemented spent the least amount of time, 51% (no greater than chance levels), with the novel object during testing (See **Figure 4**).

#### **4. Discussion**

The results of these experiments were consistent with the proposed hypotheses. First, blueberry consumption had beneficial short-term effects on healthy individuals. Blueberries had positive effects on the Alaskan participants' health and well-being after 5 days of consumption. This was also observed in the Albany cohorts. Participants consuming blueberries rated their levels of calm, well-balanced, ability to control themselves, and stay on top of things, and cognitive benefit, higher than when they consumed no berries. Second, this effect was seen more obviously when participants consumed Alaskan blueberries. They rated themselves even higher in the aforementioned categories than when they consumed Lower-48 blueberries. This effect was not identical; however, in New York, data from participants show an effect of blueberries but not a statistically significant difference between Alaskan blueberries and berries from the Lower-48. Third, blueberries had similar patterns of effects in rats. Notably, in more global tasks, such as total entries and central entries in an open field, there was an effect of blueberries, irrespective of their source, to improve performance among rats. However, in more challenging tasks, such as the Inner 8 entries and the percent of time with novel object, consumption of Alaskan blueberries had a greater effect than did those from the lower-48. In summary, short term consumption of blueberries can have

beneficial effects among some individuals. Further, the consumption of blueberries from Alaska had a more amplified effect than did berries from the Lower-48. Among Long Evans laboratory rats, Lower-48 or Alaskan blueberries increased motor activity and central entries (all non-peripheral squares) compared to control rats that did not consume any blueberries. However, rats consuming Alaskan blueberries made more Inner-8 entries, indicating that they were significantly bolder than rats that consumed Lower-48 blueberries or none at all. They also showed greater recollection and memory skills in the object recognition task than did those that consumed Lower-48 blueberries or none.

As mentioned in previous studies, blueberries as well as other fruits and vegetables have been linked to improving memory function as well as mood in older adults [23–25]. Our findings confirm and extend previous findings that blueberries can be beneficial to staving off cardiovascular disease, cognitive decline, and other age-related deleterious effects when consumed as part of a lifestyle. Here we show that short-term consumption of blueberries, 5 days of consumption, has perceived cognitive benefit among women age 30–55. Our participants' self-ratings of their perceived cognitive benefit from short term consumption of blueberries, as well as high ratings in other categories, such as their ability to remain calm and well-balanced, show that short term consumption of blueberries has the ability to improve mood and mental well-being among women age 30–55. Further, in our third experiment, healthy adult rats' performances benefited from blueberry consumption to have enhanced motor function, exploratory behavior, anti-anxiety effects, and learning. These latter findings are clearly objective, as they are not self-ratings and they demonstrate cross-species performance effects. Together, these findings confirm and extend the previous literature that older individuals can benefit from blueberry consumption as part of their lifestyle to indicate that short-term consumption of blueberries improves self-ratings of neurotypical women age 30–55 as well as objective effects on performance in rats. Another explanation may be that people in Alaska have greater access and exposure to foods with higher antioxidant levels than do people from the Lower 48 [26].

Consumption of Alaskan blueberries seemed to have a greater effect among participants in Alaska compared to participants in New York. An important question to ask is, what underlies this effect? One explanation could be that experiment 1 was conducted in Fairbanks, Alaska at the end of the winter season. This time of year in Alaska is also known as breakup and is associated with higher rates of suicide. There is tension in communities throughout Alaska caused by long harsh winters, and fresh blueberries may have had a greater effect on the moods and mental well-being of consumers during this sensitive time. Experiment 2 was conducted almost a full year later in Albany, New York, where the winters are much less harsh and dark. There may be some confounding variables due to these time frames. For example, the wild Alaskan blueberries had to be frozen for a longer period of time between experiments, 8 months for Experiment 1, versus 20 months, which may have caused a depletion in the potency of the Alaskan berries.

Another interesting finding relating to group differences was that the Alaskan blueberries had a greater effect among the office workers controls compared to the teachers in both control cohorts in Fairbanks and Albany. A likely explanation for this is that the office workers had a much calmer work environment than did the schoolteachers. They had greater control over their scope of work and when they engaged in their work activities, compared to being on a rigorous schedule with a limited break time that was preset and absolute. Further, office workers were not responsible for or surrounded by 20–30 children each day. They had a much quieter work environment. As such, the blueberries may have had a greater effect on individuals who were in a position to feel greater effects of the blueberries because

**361**

*One Health and the Positive Effects of Alaskan Blueberries*

they could engage in other behaviors to enhance their wellbeing (such as listening to music, while at work engaging in brief meditation activities, having time for

All experiments have limitations, one possible limitation of this experiment was that the pool of participants was small, only 6–8 participants in each experiment. However, the fact that significant results were observed and replicated across multiple domains indicates the power and consistency of the effects shown in all 5 experiments. This limitation was out of our control because all participants were volunteers, and some participant's data were excluded because they did not participate in all 3 trial weeks. Another limitation is that a large majority of the participants in both trials were women, and mostly fell into the 30–55-year-old age range. A more diverse population next time might verify the results and show that the consumption of blueberries, especially wild Alaskan berries, are beneficial to everyone, and not just these populations. The notion that beneficial effects were seen in male rats suggests that this is a highly conserved effect and could be replicated on other populations. Another factor considered in this study is that living in Alaska is much closer to the earth and people in Alaska are much more affected by their environment. Experiences such as having 20 hours of sunlight each day in the summer and 20 hours of darkness in the winter have significant effects on mental and cognitive health and well-being. Also, the food that they eat is more likely to directly affect them; many Alaskans do not eat a strictly market diet but consume

Blueberries are known to have a number of phytochemicals that contain several bioactive compounds that cause different physiological effects. One phytochemical are flavanols that contain the bioactive compounds *Epicatechin-gallates, Procyanidins,* and *Catechin* [27–30]. The physiological and pharmacological effects of these compounds include activities of antioxidants that increase free-radical scavenging, decrease the hypothalamic inflammation of microglia overactivation in the brain, and improve cognition. Further, other phytochemical effects include activities at phenolic acids, including the bioactive compounds phenolic acid and ferulic acid, which can have antioxidant and anti-inflammatory properties, as well as improve cognition and stave off neurodegeneration [31]. Blueberries are considered a functional food, which is defined as one that has clinically proven health benefits. Bioactive compounds such as flavonoids can suppress the release of cytokines such as IL-1beta and TNF-alpha from activated microglia. Flavonoids also affect nitric oxide synthase, inhibit activation of NADPH-oxidase, and downregulate pro-inflammatory transcription factors including NF-kappa B which plays a role in intestinal responses through caffeic acid. NF-kappa B influences intestinal inflammatory responses through flavonoids' actions in part involving caffeic acid which inhibits the expression of TNF-alpha, IL-beta, CO-2, INOS, and other

An important question is how do blueberries have beneficial effects through the mechanisms described above? Particularly relevant to this study are Vitamins D, A, E, and K (fat-soluble vitamins). Vitamin D is considered a (neuro) steroid that has effects on calcium, metabolism, and absorption of calcium and phosphorus from the intestine. Vitamin D exerts many other biological effects including processes involved in brain development and neuronal activity [35]. Deficiency in Vitamin D is considered a risk factor for neuropsychiatric disorders, including post partum depression, major depression and schizophrenia [36–39]. It causes alterations in brain structure and in dopamine and glutamate signaling, which are hallmarks of depression, anxiety, drug abuse and schizoaffective disorders. Functional foods rich in micronutrients that have the ability to stimulate PPAR, in addition to exert important anti-inflammatory actions may also induce significant mood- elevating

*DOI: http://dx.doi.org/10.5772/intechopen.94738*

self-care).

fish, game, and berries.

inflammatory factors [32–34].

*Antioxidants - Benefits, Sources, Mechanisms of Action*

levels than do people from the Lower 48 [26].

a depletion in the potency of the Alaskan berries.

or none.

beneficial effects among some individuals. Further, the consumption of blueberries from Alaska had a more amplified effect than did berries from the Lower-48. Among Long Evans laboratory rats, Lower-48 or Alaskan blueberries increased motor activity and central entries (all non-peripheral squares) compared to control rats that did not consume any blueberries. However, rats consuming Alaskan blueberries made more Inner-8 entries, indicating that they were significantly bolder than rats that consumed Lower-48 blueberries or none at all. They also showed greater recollection and memory skills in the object recognition task than did those that consumed Lower-48 blueberries

As mentioned in previous studies, blueberries as well as other fruits and vegetables have been linked to improving memory function as well as mood in older adults [23–25]. Our findings confirm and extend previous findings that blueberries can be beneficial to staving off cardiovascular disease, cognitive decline, and other age-related deleterious effects when consumed as part of a lifestyle. Here we show that short-term consumption of blueberries, 5 days of consumption, has perceived cognitive benefit among women age 30–55. Our participants' self-ratings of their perceived cognitive benefit from short term consumption of blueberries, as well as high ratings in other categories, such as their ability to remain calm and well-balanced, show that short term consumption of blueberries has the ability to improve mood and mental well-being among women age 30–55. Further, in our third experiment, healthy adult rats' performances benefited from blueberry consumption to have enhanced motor function, exploratory behavior, anti-anxiety effects, and learning. These latter findings are clearly objective, as they are not self-ratings and they demonstrate cross-species performance effects. Together, these findings confirm and extend the previous literature that older individuals can benefit from blueberry consumption as part of their lifestyle to indicate that short-term consumption of blueberries improves self-ratings of neurotypical women age 30–55 as well as objective effects on performance in rats. Another explanation may be that people in Alaska have greater access and exposure to foods with higher antioxidant

Consumption of Alaskan blueberries seemed to have a greater effect among participants in Alaska compared to participants in New York. An important question to ask is, what underlies this effect? One explanation could be that experiment 1 was conducted in Fairbanks, Alaska at the end of the winter season. This time of year in Alaska is also known as breakup and is associated with higher rates of suicide. There is tension in communities throughout Alaska caused by long harsh winters, and fresh blueberries may have had a greater effect on the moods and mental well-being of consumers during this sensitive time. Experiment 2 was conducted almost a full year later in Albany, New York, where the winters are much less harsh and dark. There may be some confounding variables due to these time frames. For example, the wild Alaskan blueberries had to be frozen for a longer period of time between experiments, 8 months for Experiment 1, versus 20 months, which may have caused

Another interesting finding relating to group differences was that the Alaskan blueberries had a greater effect among the office workers controls compared to the teachers in both control cohorts in Fairbanks and Albany. A likely explanation for this is that the office workers had a much calmer work environment than did the schoolteachers. They had greater control over their scope of work and when they engaged in their work activities, compared to being on a rigorous schedule with a limited break time that was preset and absolute. Further, office workers were not responsible for or surrounded by 20–30 children each day. They had a much quieter work environment. As such, the blueberries may have had a greater effect on individuals who were in a position to feel greater effects of the blueberries because

**360**

they could engage in other behaviors to enhance their wellbeing (such as listening to music, while at work engaging in brief meditation activities, having time for self-care).

All experiments have limitations, one possible limitation of this experiment was that the pool of participants was small, only 6–8 participants in each experiment. However, the fact that significant results were observed and replicated across multiple domains indicates the power and consistency of the effects shown in all 5 experiments. This limitation was out of our control because all participants were volunteers, and some participant's data were excluded because they did not participate in all 3 trial weeks. Another limitation is that a large majority of the participants in both trials were women, and mostly fell into the 30–55-year-old age range. A more diverse population next time might verify the results and show that the consumption of blueberries, especially wild Alaskan berries, are beneficial to everyone, and not just these populations. The notion that beneficial effects were seen in male rats suggests that this is a highly conserved effect and could be replicated on other populations. Another factor considered in this study is that living in Alaska is much closer to the earth and people in Alaska are much more affected by their environment. Experiences such as having 20 hours of sunlight each day in the summer and 20 hours of darkness in the winter have significant effects on mental and cognitive health and well-being. Also, the food that they eat is more likely to directly affect them; many Alaskans do not eat a strictly market diet but consume fish, game, and berries.

Blueberries are known to have a number of phytochemicals that contain several bioactive compounds that cause different physiological effects. One phytochemical are flavanols that contain the bioactive compounds *Epicatechin-gallates, Procyanidins,* and *Catechin* [27–30]. The physiological and pharmacological effects of these compounds include activities of antioxidants that increase free-radical scavenging, decrease the hypothalamic inflammation of microglia overactivation in the brain, and improve cognition. Further, other phytochemical effects include activities at phenolic acids, including the bioactive compounds phenolic acid and ferulic acid, which can have antioxidant and anti-inflammatory properties, as well as improve cognition and stave off neurodegeneration [31]. Blueberries are considered a functional food, which is defined as one that has clinically proven health benefits. Bioactive compounds such as flavonoids can suppress the release of cytokines such as IL-1beta and TNF-alpha from activated microglia. Flavonoids also affect nitric oxide synthase, inhibit activation of NADPH-oxidase, and downregulate pro-inflammatory transcription factors including NF-kappa B which plays a role in intestinal responses through caffeic acid. NF-kappa B influences intestinal inflammatory responses through flavonoids' actions in part involving caffeic acid which inhibits the expression of TNF-alpha, IL-beta, CO-2, INOS, and other inflammatory factors [32–34].

An important question is how do blueberries have beneficial effects through the mechanisms described above? Particularly relevant to this study are Vitamins D, A, E, and K (fat-soluble vitamins). Vitamin D is considered a (neuro) steroid that has effects on calcium, metabolism, and absorption of calcium and phosphorus from the intestine. Vitamin D exerts many other biological effects including processes involved in brain development and neuronal activity [35]. Deficiency in Vitamin D is considered a risk factor for neuropsychiatric disorders, including post partum depression, major depression and schizophrenia [36–39]. It causes alterations in brain structure and in dopamine and glutamate signaling, which are hallmarks of depression, anxiety, drug abuse and schizoaffective disorders. Functional foods rich in micronutrients that have the ability to stimulate PPAR, in addition to exert important anti-inflammatory actions may also induce significant mood- elevating

properties, although the underlying mechanisms are not fully understood. PPAR might work in synergism with stimulation of neurosteroid biosynthesis to exert their beneficial effects by decreasing inflammation and relieving mood symptoms.

In summary, these experiments revealed that five days of blueberry consumption has beneficial effects on middle-aged women in Fairbanks, Alaska, as well as Albany, New York. The initial study in Fairbanks, Alaska (during "breakup season"), revealed a greater sensitivity and responsiveness to Alaskan blueberries than those from the Lower-48. Albeit, the second experiment, conducted in Albany, New York, showed a beneficial effect of blueberry consumption but not a differential effect between wild Alaskan and store-bought berries from the Lower-48. This may be due to the decomposition of antioxidants, flavonoids, and other important health factors caused by freezer storage for a full year. Our third experiment, using an animal model, conducted over the summer between the two human experiments, revealed beneficial effects of both Alaskan and Lower-48 blueberries when given as a supplement to male Long Evans rats. The rats that consumed blueberries had improved motor skills and exploratory behavior, irrespective of the source of blueberries. However, in more challenging tasks, such as entries into the Inner 8 squares in an open field (an anti-anxiety measure) and performance on the object recognition task, Alaskan blueberries had a greater effect on performance than did berries from the Lower-48 or no berries. To address the mechanism underlying these effects, we will be extracting the bioactive compounds and creating an Alaskan elixir to reassess their relative efficacy of Alaskan blueberries versus those from the Lower-48 on people as well as animal subjects.

## **5. Conclusion**

In conclusion, it seems that blueberries can have short term effects as functional foods when consumed by individuals over a 5-day period. The precise mechanisms underlying these effects are unclear, however, differences between Fairbanks and Albany suggest that blueberries from a higher altitude may be more effective because they contain more flavonoids and more antioxidant effects. The beneficial effects of flavonoids may be mediated in part through actions of neurosteroids, such as Vitamin-D, allopregnanolone, 3α diol, which can inhibit deleterious effects of activation of PPAR and other physiological and pharmacological effects [34].

## **Acknowledgements**

Research herein was supported in part by grants National Institute of Mental Health (MH06769801, RMH067698B) and the National Institute of General Medical Sciences of the National Institutes of Health (P20GM103395). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Assistance in the studies described herein provided by members of the laboratory, past, and present, is greatly appreciated.

**363**

**Author details**

Vincent F. Lembo and Cheryl A. Frye\*

provided the original work is properly cited.

\*Address all correspondence to: cherylafrye@gmail.com

Alaska INBRE Program, University of Alaska Fairbanks, Fairbanks, AK, USA

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*One Health and the Positive Effects of Alaskan Blueberries*

*DOI: http://dx.doi.org/10.5772/intechopen.94738*

*One Health and the Positive Effects of Alaskan Blueberries DOI: http://dx.doi.org/10.5772/intechopen.94738*

*Antioxidants - Benefits, Sources, Mechanisms of Action*

from the Lower-48 on people as well as animal subjects.

**5. Conclusion**

**Acknowledgements**

greatly appreciated.

properties, although the underlying mechanisms are not fully understood. PPAR might work in synergism with stimulation of neurosteroid biosynthesis to exert their beneficial effects by decreasing inflammation and relieving mood symptoms. In summary, these experiments revealed that five days of blueberry consumption has beneficial effects on middle-aged women in Fairbanks, Alaska, as well as Albany, New York. The initial study in Fairbanks, Alaska (during "breakup season"), revealed a greater sensitivity and responsiveness to Alaskan blueberries than those from the Lower-48. Albeit, the second experiment, conducted in Albany, New York, showed a beneficial effect of blueberry consumption but not a differential effect between wild Alaskan and store-bought berries from the Lower-48. This may be due to the decomposition of antioxidants, flavonoids, and other important health factors caused by freezer storage for a full year. Our third experiment, using an animal model, conducted over the summer between the two human experiments, revealed beneficial effects of both Alaskan and Lower-48 blueberries when given as a supplement to male Long Evans rats. The rats that consumed blueberries had improved motor skills and exploratory behavior, irrespective of the source of blueberries. However, in more challenging tasks, such as entries into the Inner 8 squares in an open field (an anti-anxiety measure) and performance on the object recognition task, Alaskan blueberries had a greater effect on performance than did berries from the Lower-48 or no berries. To address the mechanism underlying these effects, we will be extracting the bioactive compounds and creating an Alaskan elixir to reassess their relative efficacy of Alaskan blueberries versus those

In conclusion, it seems that blueberries can have short term effects as functional foods when consumed by individuals over a 5-day period. The precise mechanisms underlying these effects are unclear, however, differences between Fairbanks and Albany suggest that blueberries from a higher altitude may be more effective because they contain more flavonoids and more antioxidant effects. The beneficial effects of flavonoids may be mediated in part through actions of neurosteroids, such as Vitamin-D, allopregnanolone, 3α diol, which can inhibit deleterious effects of activation of PPAR and other physiological and pharmacological effects [34].

Research herein was supported in part by grants National Institute of Mental Health (MH06769801, RMH067698B) and the National Institute of General Medical Sciences of the National Institutes of Health (P20GM103395). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Assistance in the studies described herein provided by members of the laboratory, past, and present, is

**362**

## **Author details**

Vincent F. Lembo and Cheryl A. Frye\* Alaska INBRE Program, University of Alaska Fairbanks, Fairbanks, AK, USA

\*Address all correspondence to: cherylafrye@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[17] Ennaceur A, Neave N, Aggleton JP. Spontaneous object recognition and object location memory in rats: the effects of lesions in the cingulate cortices, the medial prefrontal cortex, the cingulum bundle and the fornix. Exp Brain Res. 1997;113(3):509-519. doi:10.1007/pl00005603

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[22] Luine VN, Jacome LF, Maclusky NJ. Rapid enhancement of visual and

place memory by estrogens in rats. *Endocrinology*. 2003;144(7):2836-2844. doi:10.1210/en.2003-0004

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ijms17081258

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[31] Mallik S.B., Mudgal J., Nampoothiri M., Hall S., Anoopkumar-Dukie S., Grant G. Caffeic acid attenuates lipopolysaccharideinduced sickness behaviour and neuroinflammation in mice. Neurosci. Lett. 2016;632:218-223.

[32] Ward et al., 2018 A.B. Ward, H. Mir, N. Kapur, D.N. Gales, P.P. Carriere, S. Singh Quercetin inhibits prostate cancer by attenuating cell survival and inhibiting anti-apoptotic pathwaysWorld J. Surg. Oncol., 16 (1) (2018),

[33] Wang et al., 2018J. Wang, P. Um, B.A. Dickerman, J. Liu Zinc, magnesium, selenium and depression: a review of the evidence, potential mechanisms and implications Nutrients, 10 (5) (2018)

[34] Matrisciano F, Pinna G. PPAR and functional foods: Rationale for natural neurosteroid-based interventions for postpartum depression. Neurobiol Stress. 2020 Apr 19;12:100222. doi: 10.1016/j.ynstr.2020.100222. PMID: 32426424; PMCID: PMC7226878.

[35] D. Eyles, T. Burne, J. McGrath Vitamin D in fetal brain development. Semin. Cell Dev. Biol., 22 (6) (2011), pp. 629-636

[36] S. Amini, R. Amani, S. Jafarirad, B.Cheraghian, M. Sayyah, A.A. HemmatiThe effect of vitamin D and calcium supplementation on inflammatory biomarkers, estradiol levels and severity of symptoms in women with postpartum depression: a randomized double-blind clinical trial Nutr. Neurosci., 3 (2020), pp. 1-11

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[38] D.M. Zhu, W. Zhao, B. Zhang, Y. Zhang, Y. Yang, C. Zhang, et al.The relationship between serum concentration of vitamin D, total intracranial volume, and severity of depressive symptoms in patients with major depressive disorder Front. Psychiatr., 10 (2019), p. 322

[39] J.J. McGrath, D.W. Eyles, C.B.Pedersen, C. Anderson, P. Ko, T.H.Burne, et al.Neonatal vitamin D status and risk of schizophrenia: a population-based case-control study Arch. Gen. Psychiatr., 67 (2010), pp. 889-894

**367**

**Chapter 18**

Plant

**Abstract**

Antioxidant Properties of Alpine

Alpines are the exceptional regions of the world's biomes. They have unique climatic and topographic conditions; they are the habitat of some of the highly specialized flora and fauna. The harsh environmental conditions and extreme fluctuations in them on a seasonal and diurnal basis created extremely stressful situations for the alpine plants. Such stress causes damage to biochemical structures and compounds of the plant cells leads to the production of free radicals, *i.e.* reactive oxygen species (ROS), which can further damage the plant cells or tissues. Alpine plants protect themselves from those ROS efficiently by their highly competent enzymatic and non-enzymatic antioxidant system. In general, this protection increases in alpine plants with altitudes; however, some exceptions are also reported. Antioxidant compounds *viz.* ascorbic acid, tocopherol, glutathione, carotenoids found in alpine flora in higher concentrations as compared to low land plants. Phenolic compounds protected the alpine plants from UV induced ROS by screening the UV radiations and blocking their entries in the cell's mesophyll. This higher antioxidant potential of the alpine plants is highly beneficial for the human

*Vijay Laxmi Trivedi and Mohan Chandra Nautiyal*

being as most alpine plants are the sources of some life-saving drugs.

freeze–thaw cycles, flavonoids

estimated their extent to 3.56Mkm2

**1. Introduction**

2.59Mkm2

0.32Mkm2

**Keywords:** enzymes, non-enzymatic compounds, UV radiation, medicinal plants,

Alpine biomes of the world are characterized by their unique features and usually lie between an altitude of about 10,000 feet (3,000 meters) and where the snow line of a mountain begins. The Alpine and Arctic biomes cover 16% of the earth's surface area. Testolin *et al*. [1], based on regional tree line models,

outside Antarctica. Asia hosts almost three-fourths of the global alpine area with

contribute to only 1% of the global alpine area. The climate of the alpine regions is dynamic and changes as you move above the lower to higher elevations. The most prominent environmental factor, *i.e.* the temperature normally drops by about 10 °C for every 1000 meters as we go up a mountain. The alpine regions experience a long and cold winter season that lasts about nine months in some alpine areas of the world from around October to May. Temperatures in summer normally ranges from 40 to 60 °F and may last from June to September. Temperature shows very high fluctuations and can normally drop from warm to freezing within a day. The

, followed by South America (15%; 0.55Mkm2

), and Europe (2%; 0.08Mkm2

, corresponding to 2.64% of the total land area

), while Oceania and Africa together

), North America (9%;

## **Chapter 18**

*Antioxidants - Benefits, Sources, Mechanisms of Action*

[37] M.J. SzpunarAssociation of antepartum vitamin D deficiency with postpartum depression: a clinical perspective Publ. Health Nutr. (2019),

[38] D.M. Zhu, W. Zhao, B. Zhang, Y. Zhang, Y. Yang, C. Zhang, et al.The relationship between serum concentration of vitamin D, total intracranial volume, and severity of depressive symptoms in patients with major depressive disorder Front.

Psychiatr., 10 (2019), p. 322

[39] J.J. McGrath, D.W. Eyles, C.B.Pedersen, C. Anderson, P. Ko, T.H.Burne, et al.Neonatal vitamin D status and risk of schizophrenia: a population-based case-control study Arch. Gen. Psychiatr., 67 (2010), pp.

pp. 1-6

889-894

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[31] Mallik S.B., Mudgal J.,

Lett. 2016;632:218-223.

Dukie S., Grant G. Caffeic acid attenuates lipopolysaccharideinduced sickness behaviour and neuroinflammation in mice. Neurosci.

[32] Ward et al., 2018 A.B. Ward, H. Mir, N. Kapur, D.N. Gales, P.P. Carriere, S. Singh Quercetin inhibits prostate cancer by attenuating cell survival and inhibiting anti-apoptotic pathwaysWorld J. Surg. Oncol., 16 (1)

[33] Wang et al., 2018J. Wang, P. Um, B.A. Dickerman, J. Liu Zinc, magnesium, selenium and depression: a review of the evidence, potential mechanisms and implications Nutrients,

[34] Matrisciano F, Pinna G. PPAR and functional foods: Rationale for natural neurosteroid-based interventions for postpartum depression. Neurobiol Stress. 2020 Apr 19;12:100222. doi: 10.1016/j.ynstr.2020.100222. PMID: 32426424; PMCID: PMC7226878.

[35] D. Eyles, T. Burne, J. McGrath Vitamin D in fetal brain development. Semin. Cell Dev. Biol., 22 (6) (2011),

[36] S. Amini, R. Amani, S. Jafarirad, B.Cheraghian, M. Sayyah, A.A. HemmatiThe effect of vitamin D and calcium supplementation on inflammatory biomarkers, estradiol levels and severity of symptoms in women with postpartum depression: a randomized double-blind clinical trial Nutr. Neurosci., 3 (2020), pp. 1-11

Nampoothiri M., Hall S., Anoopkumar-

108

(2018),

10 (5) (2018)

pp. 629-636

**366**
