**Abstract**

Lipid peroxidation is an end process of cellular injury driven by oxidative stress (OS) and inflammation through several molecular changes. Metabolismgenerated reactive oxygen species avidly attack the polyunsaturated fatty acids in lipid cell membranes, initiating a self-propagating chain-reaction. Cell membrane destruction, lipids and the end-products of lipid peroxidation reactions are hostile to the viability of cells, even tissues causing and exacerbating Diabetes Mellitus (DM), neurodegenerative disorders (NDDs), cardiovascular diseases (CVDs) and Rheumatoid Arthritis (RA). Current treatment regimens have untoward side effects in the long-term necessitating phytochemical use as these are part of natural food sources. Enzymatic and non-enzymatic antioxidant defense mechanisms may be over run causing lipid peroxidation to take place. In disease states, oxidative stress may increase with subsequent production of increased free radicals which may over run the antioxidant capacity of the body with resultant oxidative damage on polyunsaturated fatty acids in the cell fluid membranes with cellular and tissue damage. Phytochemicals, have been shown to ameliorate diseases through attenuation of oxidative stress, inflammation, lipid peroxidation, causing tissue regeneration by regulating signaling systems and neuroprotective processes. Involvement of polyphenolic and non-phenolic phytochemical in the attenuation of OS, inflammation and lipid peroxidation remain areas of critical importance in combating DM, CVDA, NDD and RA.

**Keywords:** phytotherapeutics, oxidative stress, inflammation, lipid peroxidation, severe and chronic diseases, phytochemicals

#### **1. Introduction**

There is a significant contributory role the Fenton and Haber Weiss reaction makes in oxidative stress (OS) building up to several progressive diseases such as Alzheimer's disease (AD). Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are manufactured by these reactions causing OS in AD. Iron, copper and aluminum influences creation of free radicals such as hydroxyl radicals with impairment to DNA, proteins, lipids and carbohydrates.

Beta amyloid (Aβ42) toxicity is created by hydroxyl (OH<sup>−</sup> ) radicals from the Fenton reaction [1, 2] in AD. Soluble human fibrinogen is converted into an insoluble fibrin-like aggregate seen in neurodegenerative diseases such as AD when it reacts with hydroxyl radical [3]. The Fenton gated OS attenuates DNA base substitutions of guanine to cytosine when catalyzed by iron and guanine to thymine and cytosine to thymine when catalyzed by copper and Nickel [4].

Phosphoinositide 3- kinase (PI3K), c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1 and 2 (ERK1/2), p38 and transcription factors such as activator protein-1(AP-1), and p53 are signal transduction molecules that are stimulated by ROS [5]. Hastening of AD development are OH<sup>−</sup> radicals that impair DNA through p53 pathway. When tumor suppressor gene (TP53) has a mutation, there is increased potential for AD pathogenesis development [6].

The Fenton reaction triggers OS through subtraction of one electron from the molecular oxygen (O2) resulting in the formation of superoxide (O2 **−** ) which often produces other ROS species such as H2O2 and peroxynitrite (ONOO)− and hydroxyl radicals (OH− ) [7]. This may imply that phytotherapeutics which are able to quench the electron abstraction may alleviate oxidative stress. Moreover, under normal conditions, O2**−** has emerged as an important signaling molecule, which regulates precise biochemical reactions and metabolic progressions [8].

The linkage between O2 − production and H2O2 may involve a reduced flavin enzyme by transferring an electron to activate molecular oxygen into superoxide which is either released or enzymatically converted into H2O2 [9, 10] or drugs like statins may modify the process [11, 12].

Extreme challenges in the field of ROS-gated diseases is to bridge the knowledge gap between atomic, cellular level and how natural phytochemicals may be used to attenuate OS in certain diseases [13, 14].

The understanding of the Fenton and Haber Weiss reaction and how it may be modified or detoxified or neutralized by phytotherapeutics or nutraceuticals may assist to bridging the knowledge and practice of treating chronic diseases of old age. When phytochemicals stop the subtraction of one electron in Fenton reaction, creation of OS may be averted.

#### **2. Lipid peroxidation products**

Characteristics of various lipid peroxidation products as biomarkers have been reviewed on the basis of mechanisms and dynamics of their formation and metabolism and also on the methods of measurement, with an emphasis on the advantages and limitations [15].

Lipid peroxidation or unsaturated lipid reaction with molecular or ROS produces a wide variety of oxidation products with the main primary products being lipid hydroperoxides (LOOH). Many different aldehydes which can be formed as subsequent products during lipid peroxidation include malondialdehyde (MDA), propanal, hexanal, and 4-hydroxynonenal (4-HNE) (**Figure 1**) [16–20].

MDA gives the impression to be the most mutagenic product of lipid peroxidation, whereas 4-HNE is the most toxic [21]. MDA has been extensively used for many years as an expedient biomarker for lipid peroxidation of omega-3 and omega-6 fatty acids because of its simplistic reaction with thiobarbituric acid (TBA) [22]. The TBA test is predicated on the reactivity of TBA toward MDA to yield an intensely colored chromogen fluorescent red adducts. Food chemists used this test initially to evaluate autoxidative degradation of fats and oils [23].

*Phytotherapeutics Attenuation of Oxidative Stress, Inflammation and Lipid Peroxidation… DOI: http://dx.doi.org/10.5772/intechopen.99832*

**Figure 1.**

*(a): Structure of 4-hydroxymalondialdehyde and malondialdehyde at equilibrium and (b) 4-hydroxynonenal.*

MDA is one of the most popular and reliable biomarkers that determine OS in clinical situations and due to MDA's high reactivity and the toxicity underlying the molecular effect, this molecule is very relevant to biomedical research community [24].

First to be discovered in the 1960s was 4-HNE [25]. Later, in 1980s 4-HNE was described as a cytotoxic product originating from the peroxidation of liver microsomal lipids [26]. The genotoxic effects exerted on human beings results from the subsequently produced 4-HNE from progression of bio membranes lipids peroxidation elicited by free radicals or chemicals [27]. Comparatively large amounts of 4-HNE are produced and they are very reactive aldehydes that act as second messengers of free radicals making them of high significance in disease of old age [28]. Therefore, 4-HNE the most likely easier target for phytotherapeutics as antioxidant in lipid peroxidation.

Also, 4-HNE is a major bioactive marker of lipid peroxidation and a signaling molecule elaborate in regulation of several transcription mediators that are sensitive to stress such as nuclear factor erythroid 2-related factor 2 (Nrf2), activating protein-1 (AP-1), NF-B, and peroxisome-proliferator-activated receptors (PPAR). These play a critical role in cell proliferation and/or differentiation, cell survival, autophagy, senescence, apoptosis, and necrosis [29]. 4-HNE may stimulate intrinsic and extrinsic apoptotic pathways and interact with typical actors such as tumor protein 53, JNK, Fas or mitochondrial regulators, due to its oxidant status. Simultaneous 4-HNE induces cellular defense mechanisms against OS, thus being involved in its own detoxification and in turn limiting its apoptotic potential [30]. These dualities can imbalance cell fate, either toward cell death or toward survival, depending on the cell type, the metabolic state and the ability to detoxify [31]. The pleiotropism displayed by phytotherapeutics like Asiatic acid [13, 32–36], maslinic acid [37, 38] and oleanolic acid [36] and their involvement in redox reactions may influence 4-HNE activity thus modulating the its function in stress induces pathology of old age.

#### **3. Phytotherapeutics and lipid peroxidation products**

Phytotherapeutics which may restore or facilitate the restoration of 4-HNE's apoptotic inhibition potential as well as catalyze its oxidant signaling pathways through direct redox reactions or attenuation of enzymatic antioxidant systems, have a great capacity in modulating lipid peroxidation related diseases [13, 14, 35]. Triterpenes with pleiotropic activities have been shown to possess antioxidant properties as well oxidative functions in certain parasitic infections ameliorating disease outcomes and outputs [33, 39].

#### *Accenting Lipid Peroxidation*

Other phytochemicals also follow in this narrative in their use as antioxidants in lipid peroxidation agents and their use to fight against associated diseases using various mechanism. By inhibiting formation of both primary and secondary products of the lipid peroxidation process, plant phytochemicals may exert their effect on hydroperoxide groups from attaching to free fatty acids, triacylglycerols, phospholipids, and sterols [40].

While, hydroperoxides may decompose *in vivo* through two-electron reduction, which may inhibit the peroxidative damage, phytochemicals may also facilitate this process of antioxidant lipid peroxidation through enhancing activity of enzymes for two-electron reduction of hydroperoxides such as selenium-dependent glutathione peroxidases (GPx) and selenoprotein P (SeP) [41, 42].

### **4. Phytochemical and Antioxidative activity in lipid peroxidation**

#### **4.1** *Salix aegyptiaca* **and lipid peroxidation**

*Salix aegyptiaca* is a deciduous plant belonging to S*alicaceae* family and is popularly known as Musk Willow from the Middle-East [43]. As part of a traditional medicine from ancient times, *S. aegyptiaca* is used as a confectionary, flavourful syrup and fragrance additive. The extract from bark and leaves have shown to exert beneficial effects, as laxative, cardioprotective, nervonic, sedative, hypnotic, somnolent, aphrodisiac, orexoiogenic, carnative, gastroprotector, anthelmintic and vermifuge [44]. Important findings associated with *salicaceae* family is that they contain salicylate composites such as salicylic acid which subsequently led to the finding of acetylsalicylic acid identified as aspirin, a worldwide analgesic, antipyretic, anti-inflammatory drug [45].

Later, the presence of other polyphenols such as gallic acid, caffeic acid, vanillin, p-coumaric acid, myricetin, catechin, epigallocatechin gallate, rutin and quercetin were confirmed to contribute as to the beneficial effects of *S. aegyptiaca* [46].

With the body generating OS through the Fenton and Haber Weiss leading to the initiation and development of several health complications such as diabetes, Alzheimer's disease, atherosclerosis, cardiovascular problems and various kinds of cancers [47–49] and considering the wide range of medicinal applications of *S. aegyptiaca*, the interesting and essential component in delineation of the bioactivity of its flavonoid and phenolic phytochemicals other than salicylates, is astounding.

Invariably, plant natural compounds with antioxidant activity are likely to preserve redox homeostasis disturbed during the natural cellular mechanism or the consequences of exposure to detrimental chemical agents. By rummaging for the free radicals, influencing the antioxidant non-enzymatic and enzymatic defense systems as well as drug metabolizing enzyme systems, *S. aegyptiaca* proves influential in the attenuation of OS and lipid peroxidation. These phytochemicals are expectable to modify the diverse biological activities such as inflammation, necrosis and carcinogenesis leading to cytoprotecting of cellular environment [50].

The interdependency of redox-potential, antioxidant activity and anti-inflammatory activity of gallic acid, quercetin, rutin and vanillin as well as acetylsalicylic acid has been examined [50]. Finding the relevance of the biological systems, the influence of gallic acid and acetylsalicylic acid have been studied on the drug metabolizing phase I and phase II enzymes as well as on endogenous antioxidant enzymes and peroxidative damage in the liver of C57BL/6 mice.

Oxidation–reduction potential of gallic acid, acetylsalicylic acid, rutin, quercetin and vanillin have been tested with the agents exhibiting reduction potential in

#### *Phytotherapeutics Attenuation of Oxidative Stress, Inflammation and Lipid Peroxidation… DOI: http://dx.doi.org/10.5772/intechopen.99832*

a dose dependent manner of 5–50 μg/ml [50]. The reduction potential was in the order of gallic acid > quercetin > rutin > vanillin > acetylsalicylic acid.

In red and yellow onion [51] and in *S. aegyptiaca,* the antioxidant activity of gallic acid, acetylsalicylic acid, rutin, quercetin and vanillin have been examined for their scavenging of 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals and displayed inhibition of DPPH radicals, an indicator of antioxidant activity, in concentration dependent manner. In the *S. aegyptiaca* experiments, DPPH radical scavenging activity was shown by gallic acid to be greater than that of quercetin which was greater than of rutin which was greater than that of vanillin which was greater than that of acetylsalicylic acid [50].

### *4.1.1* Salix aegyptiaca *anti-inflammatory and antioxidant activity*

To determine the anti-inflammatory activity of the *S. aegyptiaca* phytochemicals (62.5–1000 μg/ml) inhibition of protein denaturation was used. The phytochemicals' concentration-dependent inhibitory effect displayed a relative repressive effect in the ensuing order of acetylsalicylic acid > gallic acid > rutin > quercetin > vanillin [50]. Also, cumulative therapeutic effects of phytochemicals in *Arnica montana* flower extract has been reported to alleviate collagen-induced arthritis while inhibition of both pro-inflammatory mediators and OS [52].

#### *4.1.2* Salix aegyptiaca *and protein carbonyl estimation and oxidative stress*

Protein carbonyl measurements provide a sensitive index of OS damage occurring early in severe sepsis and major trauma patients. Elevated protein carbonyl concentrations in plasma and in bronchial aspirates indicates wide spread of oxidation though out the body beyond the lungs. The correlation between oxidative biomarkers and myeloperoxidase concentrations correlations in the lung may indicate that neutrophil oxidants could be responsible for the lung injury [53, 54] and also, protein carbonyl as a marker of OS is associated with overhydration, sarcopenia and mortality in hemodialysis patients [55]**.** Moreover, plasma protein carbonyls have been shown to be a predictive biomarker of oxidative stress in chronic kidney disease, dialysis, and transplantation [56]. However, Mkhwanazi *et al*. have reported that a maslinic acid triterpene derivative improved the renal function of streptozotocin-induced diabetic rats [37]. Furthermore, Mavondo et al. chronologies how malarial inflammation-driven pathophysiology and were reduced by triterpene application in various *in vivo* and *ex vivo* experiments of Asiatic acid [34].

Phytotherapeutics *S. aegyptiaca* obtained gallic acid, acetylsalicylic acid, rutin and quercetin (62.5–1000 μg/ml) showed a dose-dependent protection against protein carbonyl damage caused by the Fenton reagent with higher protection percentage as compared to the control, being maximum for gallic acid > quercetin > rutin > acetylsalicylic acid [50].

#### *4.1.3* Salix aegyptiaca *and peroxidative damage and its inhibition*

Some water extractable phytochemicals inhibited Fe2+-induced *in vitro* lipid peroxidation in a rat's brain [57] while Solanum *xanthocarpum* root extract protective efficacy was demonstrated against free radical damage and its phytochemical analysis was carried out and antioxidant effect determined [58]. Over more, microsomes were used *in vitro* to study the peroxidative damage and its inhibition by phytochemicals (62.5–1000 μg/ml) [50]. In these experiments, the Fenton reagent

#### *Accenting Lipid Peroxidation*

initiated by peroxidation and determined in terms of TBARS formation. Ultimately, all the phytochemicals showed inhibitory effect against peroxidative damage, in a dose dependent manner showing inhibition order: gallic acid > quercetin > rutin > acetylsalicylic acid.

Treatment with 50 μg/kg of acetylsalicylic acid and with 100 μg/kg of gallic acid increased cytochrome P450 reductase activity (1.26-fold, p < 0.01) and cytochrome b5 reductase (1.45-fold, p < 0.01) as equated to control [50]. Treatment using a reversed concentration combination of the two phytochemicals further enhanced the enzymatic activity (cytochrome P450 reductase vs. cytochrome b5 reductase) by a 1.58-fold and 1.66-fold when a larger dose (50 μg/kg body weight) and a lower dose (25 μg/kg body weight) of acetylsalicylic acid was used, respectively, showing their antioxidant capacity [50].

#### *4.1.4 Glutathione S-transferase and DT-diaphorase*

Precise activity of glutathione S-transferase (GST) tend to be amplified by 1.92 fold (p < 0.01) and 2.11-fold (p < 0.001) when animals were treated with 50 μg/kg of acetylsalicylic acid (group III) and 100 μg/kg weight of gallic acid as compared to controls, an observation seen with. The activity of DT-diaphorase (DTD) was also observed to be significantly elevated by 1.79-fold (p < 0.001) and 2.36-fold (p < 0.001) when animals were treated with 50 μg/kg 100 μg/kg gallic acid, respectively, as compared to control group.

For both phytochemicals, a reversed concentration combination of acetylsalicylic acid and gallic acid treatment increased the activity of both enzymes showing improved anti-inflammatory [50]. Similar observation were demonstrated with thymoquinone on antioxidant enzyme activities, lipid peroxidation and DT-diaphorase in different tissues of mice with possible mechanism of action demonstrated [59]. Also, in early cancer studies similar antioxidant and anti-peroxidation effects of dietary curcumin have been shown on glutathione *S*-Transferase and the attenuation of malondialdehyde-DNA adducts in rat liver and colon mucosa [60].

#### *4.1.5 Superoxide dismutase (SOD), catalase, glutathione reductase and glutathione peroxidase*

Superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) plays an important and indispensable role in the entire defense strategy of antioxidants as fundamental first line defense antioxidants. This is more so with reference to super oxide anion radical (\*O2) which is ceaselessly generated in normal body metabolism, particularly through the mitochondrial energy production pathway (MEPP) [61] and is attenuated when phytotherapeutics are administered.

Significantly increases in activities of SOD, CAT, GPX and glutathione reductase have been shown to be triggered by treating animals with gallic acid and acetylsalicylic acid. Animals treated with 100 μg/kg gallic experience enhanced SOD activity (1.47-fold). Variable concentrations of acetylsalicylic acid addition raises of these enzymatic antioxidants activity even higher [50] testimony to the efficacies of these phytochemicals in fighting lipid peroxidation.

#### **4.2 Phytochemicals neuroprotection against oxidative stress**

The foremost causes of dementia include neurodegenerative diseases and ischemic stroke and all have OS as an important player in their pathophysiology [62]. By modifying the expressions of antioxidant molecules and enzymes, the

#### *Phytotherapeutics Attenuation of Oxidative Stress, Inflammation and Lipid Peroxidation… DOI: http://dx.doi.org/10.5772/intechopen.99832*

Nrf2-ARE (nuclear factor erythroid 2-related factor 2/antioxidant responsive element antioxidant) system plays an essential role in neuroprotection as the primary cellular defense against OS. However, concurrent events of overproduction of ROS and dysregulation of the Nrf2-ARE system causes harm to indispensable cell components resulting in loss of neuron structural and functional integrity. On the other hand, TrkB (tropomyosin-related kinase B) signaling which is a classical neurotrophin signaling pathway, regulates neuronal endurance and synaptic plasticity important for fundamental functions in memory and cognition. The TrkB signaling, especially the TrkB/PI3K/Akt (TrkB/phosphatidylinositol 3 kinase/protein kinase B) pathway promotes the initiation and nuclear translocation of Nrf2, and brings in neuroprotection against OS. Essentially, the TrkB signaling pathway is also known to be downregulated in brain disorders due to lack of neurotrophin support. Therefore, activations of TrkB and the Nrf2-ARE signaling system suggests a potential approach to the design of novel phytochemical therapeutic agents for brain disorders.

The association between OS and the pathogenesis of neurodegenerative diseases, brain injury and the neuroprotective effects of phytochemicals that can co-activate the neuronal defense systems orchestrates important facets of the cellular antioxidant defense and TrkB signaling-mediated cell survival systems as possible pharmacological targets for the treatment of neurodegenerative diseases.

Factors contributive to OS in the brain include excitotoxicity, cellular antioxidant system exhaustion, lipid-rich membranes, susceptibility to lipid peroxidation, and brain high oxygen demand [63]. Excess ROS causes structural and functional modifications of cellular biomolecules, including proteins, DNA, and lipids, potentially limiting neuronal function and survival. The mechanisms rudimentary to the pathobiology of neurodegenerative diseases (NDDs) remain elusive. However, indications strongly advocates a noteworthy relationship between OS and NDDs, encompassing AD and Parkinson's disease (PD) [64]. Moreover, OS contributes to the pathogeneses of secondary damage after cerebral ischemia and other brain injuries [65, 66].

The deposition of misfolded proteins, seen in major NDDs, induce inflammatory responses, promoting ROS generation and resulting in OS [67]. Furthermore, OS causes and is caused by mitochondrial dysfunction [68]. Agreed, the central role the mitochondria play in energy metabolism and the regulation of redox homeostasis, mitochondrial malfunction contributes to the pathobiology of brain disorders. Howsoever caused, when encountered, cells compensate for the OS detrimental effect by triggering intracellular antioxidant defense system, unfortunately, contextually compromised in NDD. Therefore, activating the endogenous defense system by actuating Nrf2 using phytotherapeutics might provide a means of suppressing OS mediated cellular damage [62]. However, while OS may harm neuronal cytoarchitecture and restraining the detrimental effect of ROS alone may not suffice to prevent/reverse OS-mediated cellular damage. Approaches that support regeneration of damaged neuronal structures are necessary such that phytochemical interventions may be used for this purpose with outstanding results.

Physiologically, neuronal growth and survival are preserved via the neurotrophic signaling pathway, but modification in the regulation of specific neurotrophic factors and their receptors supervenes in the degenerating and aging brains [69]. Particularly, the brain-derived neurotrophic factor (BDNF)-dependent TrkB pathway, which is a critical signaling.

pathway for the survival and normal functioning of mature neurons, is compromised due to lack of BDNF [70, 71]. Put together, the TrkB pathway and the Nrf2 signaling system seem to suggest potential targets for encouraging neuronal survival and initiating the regeneration of injured neuronal structures and synaptic

#### *Accenting Lipid Peroxidation*

connectivity. Therefore, phytochemicals and other natural products can directly scavenge oxygen free radicals and boost the expressions of cellular antioxidant enzymes and molecules [36, 72]. This way, protection against OS-mediated cellular injury by these molecules may be possible [73, 74]. The neuritogenic potentials of the phytochemical therapeutics agents have been demonstrated [75, 76] to support the reconstruction of synaptic connectivity by renewing damaged neuronal processes [77, 78].

Different varieties of natural pharmacological modulate co-activate antioxidant defense and neurotrophin signaling-mediated cell survival systems [79–81] signifying that these compounds have therapeutic potential for the treatment of OS-mediated brain disorders. Targeting both of these signaling systems with a single compound offers benefits over combinations through possible the bypass of drug–drug interactions that could be either synergistic or antagonistic [62]. Furthermore, a single compound which can activate both the signaling and defense systems, would be more convenient to establish a therapeutic agent regarding pharmacokinetics and drug delivery.

#### *4.2.1 Oxidative stress in case of neurodegenerative disease or brain injury*

Disorders of dementia, to include NDDs, ischemic stroke or traumatic brain injury (TBI, complications are foremost public health concerns intimately linked to OS. Significantly higher concentrations of OS biomarkers and lower amounts of antioxidant biomarkers have been observed in the brain, peripheral tissues and body fluids of patients with brain disorders during preclinical and clinical studies [82, 83]. In these cases, high lipid peroxidation biomarkers are displayed as well.

#### *4.2.1.1 Alzheimer's disease and lipid peroxidation effects*

The major cause of dementia and most common progressive NDD is Alzheimer's disease [84, 85]. The main pathological hallmarks of AD, include extracellular β amyloid (βA) plaque deposits, intraneuronal aggregation of neurofibrillary tangles (NFTs), and brain atrophy [86]. Furthermore, OS has been shown to provoke βA deposition (plaque formation), tau hyperphosphorylation (NFT formation), and the ensuing degenerations of synaptic connectivity and neurons by damaging the protein degradation system [85].

Wojsiat et al., and Youssef, P., (2018) have reported raised levels of ROSmediated vagaries in AD brains, supporting the notion that OS is caught up in the pathobiology of AD [87, 88], as shown by elevated concentrations of MDA and 4-HNE (lipid peroxidation biomarkers) being higher than normal in the brain tissues and cerebrospinal fluid samples of AD patients [84, 89]. Activities of antioxidant enzymes, superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), and peroxiredoxin (Prdx) were altered in the brain affected areas although 4-HNE levels remained unaffected [88].

Male AD patients display elevated plasma concentrations of protein carbonyls and advanced glycation end products (carboxymethyllysine and carboxyethyllysine) [90]. Furthermore, 3-nitrotyrosine (3-NT), a protein nitration product, tend to be increased in CD3C (+) T-cells from AD patients [91]. Plasma antioxidants (uric and bilirubin) are significantly decreased concurrently with reduced activities of antioxidant enzymes in AD patients [92].

Oxidative stress contributes to mitochondrial dysfunction and cellular atrophy [93] while pathological aggregations of proteins such as Aβ and tau have been reported to target mitochondria and augment ROS production [94]. OS also retards synaptic plasticity contributing to progressive memory impairment, a

distinguishing clinical symptom of AD [95]. The connection between OS and AD strongly may suggest that approaches linked to antioxidant or antioxidant defense system such phytotherapeutics use could play imperative roles in the future management of AD.
