**6. Lipid peroxidation-induced inflammation and oxidation-mediated degenerative diseases**

Degenerative disease is positioned as one of the most fatal group of diseases contributing to the mortality, poor quality of life, increasing economic problems of the sufferers with OS and inflammation being leading drivers of lipid peroxidation related pathology [135]. The most common degenerative diseases include rheumatoid arthritis (RA) [136], diabetes mellitus (DM) [137], and cardiovascular disease (CVD) [138]. Although a number of synthetic medications are used to treat these diseases, none of the current regimens are completely safe. Phytochemicals: polyphenols, carotenoids, anthocyanins, alkaloids, glycosides, saponins, and terpenes are potential sources of alternative medications to attenuate the oxidative stress and inflammation associated with degenerative diseases. Some of these active compounds have shown good promise for development into novel mediators for treating RA, DM, and CVD by targeting OS and inflammation.

#### **6.1 Phytotherapeutics and degenerative diseases**

Several synthetic regimens are used to attenuate oxidative stress and inflammation-mediated degenerative diseases, with most of them exerting considerable side effects when utilized in the treatment of CVDs [139], DM [140] and RA [141].

#### *6.1.1 Cardiovascular diseases, oxidative stress and lipid peroxidation*

CVDs are a group of diseases associated with complications of the heart and blood vessels invariably leads to coronary heart disease a major component of CVDs [135]. Lipid peroxidation associated major risk factors of CVDs include hypertension (HTN), hypercholesterolemia, diabetes, obesity, inflammation, smoking, consumption of alcohol, lack of exercise, and a familial history of heart diseases [142].

#### *6.1.2 Pathogenesis of CVDs*

Atherosclerosis occurs due to the accumulation of atherosclerotic plaques within the walls of the arteries is the major precursor of CVDs. Plaque formation originates from endothelial damage, followed by adherence of circulating monocytes and subsequent exposure to homocysteine, inflammation, increased platelet aggregation, and higher levels of oxidized low-density lipoprotein (LDL-ox) and ROS [143]. Moreover, increased serum triacylglycerols.

(TAG), cholesterol (C), increased plasma fibrinogen and coagulation factors, hyperglycemia, HTN and lipid peroxidation are crucial in the pathogenesis of CVDs [144].

#### *6.1.3 Phytochemicals and CVDs*

Polyphenols and other antioxidants from fruits, vegetables, and spices has the potential to lower CVD risks by attenuating oxidative stress and inflammatory mediators [135]. Fruit consumption in Japan protected against the risk of CVDs [145], a higher consumption of fruits and vegetables correlated with a lower risk of all-cause mortality, predominantly cardiovascular mortality [146] while high-frequency consumption of fruits and vegetables lowered plasma C-reactive protein (CRP) and homocysteine concentrations, accordingly reducing inflammation a considered high risk factor of CVDs [147]. High fruit consumption level decreased HTN and blood glucose concentration which significantly decrease the risks of CVDs [148].

**Polyphenolic extract** from the apple has a significant effect on decreasing the serum total-C and LDL-C levels in healthy individuals with relatively high body mass index (BMI), which consequently limits CVD risk [149]. Consumption of banana decreases the oxidative modification of LDL, plasma lipids, and lipoproteins and thus ultimately aids in protection from atherogenesis due to its antioxidant properties [150]. Furthermore, blueberries, strawberries, and cranberries reduce cardiovascular risk factors of lipid peroxidation, inflammation, and regulate HTN due to the presence of high concentrations of anthocyanins and ellagitannins in their skin and flesh [151, 152]. Moreover, being good sources of polyphenols, berries have a high content of micronutrients such as folate, -carotene, -carotene, potassium, vitamin C, and vitamin E, which exhibit noteworthy antioxidant activities [153].

**Citrus fruits** such as mandarins, lemons, oranges, and grapefruits contain high quantities of flavanones (naringin and hesperidin stimulate nitric oxide in endothelium) that improve significant vascular functions and the lipid profile in coronary artery diseases patients [154, 155]. Pomegranate fruit juice and peel extracts have antihypertensive, anti-atherosclerotic, antioxidant, and anti-inflammatory effects because of polyphenolic compounds including anthocyanins, catechins, and tannins, contributing to the attenuation of CVD risk factors [156].

Polyphenol-rich peach and plum juice prevent against risk factors effects for cardiometabolic disorders by decreasing the expression of plasma proatherogenic and proinflammatory molecules, intercellular cell adhesion molecule-1 (ICAM-1), monocyte chemotactic protein-1, and nuclear factor kappa B (NF-B) and by decreasing foam cell adherence to aortic arches. Furthermore, peach and plum juice reduce plasma angiotensin II activity and the expression of its receptor Agtr1 in cardiac tissues. Peach and plum polyphenols act as peroxisome proliferator activated receptor- (PPAR) agonists [157]. An *in vivo* and *ex vivo* experiment watermelon improves lipid profiles and antioxidant capacity and decreases inflammation and alters gene expression for lipid metabolism and consequently reduce CVDs risk factors [158].

**Sulfur-containing organic compounds** (organosulphur) from garlic (*Allium sativum*), onion (*Allium cepa*), and cruciferous vegetables such as broccoli, cauliflower, cabbage, and Brussels sprouts exhibited cardioprotective effects facilitated by their antioxidant and anti-inflammatory properties [159]. Garlic's sodium 2-propenyl thiosulfate is suggested to block platelet aggregation through inhibition of ADP and platelet-activating factor (PAF) [160]. The onion key flavonoid, quercetin (3,3′,4′,5,7-pentahydroxyflavone), has anti-atherosclerotic properties and accumulate in the aorta tissue where its metabolites exert antioxidant and antiinflammatory activities [161]. The bright red carotene and carotenoid pigment in tomato, lycopene, significantly reduces myocardial infarction (MI) in isoproterenol injected rats [162]. Supplementation of tomato and corn oil improves diastolic function, changes cardiac miRNA expression, and attenuates lipid hydroxy peroxidation and oxidative stress [163].

**Ginger** *(Zingiber officinale)* benefits in the treatment of CVDs exhibiting antiinflammatory as well as antithrombotic properties by inhibiting the production of NO, inflammatory cytokines, cyclooxygenase (COX), and lipoxygenase (LOX) with *Phytotherapeutics Attenuation of Oxidative Stress, Inflammation and Lipid Peroxidation… DOI: http://dx.doi.org/10.5772/intechopen.99832*

no or very few side effects as compared to nonsteroidal anti-inflammatory drugs (NSAIDs) [164, 165]. Ginger is known for its being an antioxidant, antiplatelet aggregation, positive inotropic, hypotensive, hypoglycemic and hypolipidemic in *in vitro, in vivo* studies and in human clinical trials [166].

Black pepper, and its active ingredient (piperine) influences significant decrease in the concentrations of free fatty acids, phospholipids, and triacylglycerols and an increase in the concentration of high density lipoprotein cholesterol (HDLC), thus reducing the risk of atherosclerosis [167, 168].

#### **7. Diabetes mellitus and lipid peroxidation**

#### **7.1 Pathogenesis from inflammation and lipid peroxidation**

The pathogenesis of DM is closed associated with involvement of low-grade chronic inflammation and the activation of the innate immune system [169]. Excessive concentrations of glucose and free fatty acids initiate cellular OS in the pancreatic islets and insulin-sensitive tissues including adipose tissue, leading to the activation of c-Jun N-terminal kinase (JNK) and NF-B [170]. Increases in the adipocyte proinflammatory cytokines production including tumor necrosis factor alpha (TNF-), interleukin (IL) 6, IL-1, leptin, resistin, and chemokines such as MCP-1, CC-chemokine ligand 2 (CCL2), CCL3, and CXC-chemokine ligand 8 occurs when inflammatory signaling pathways start regulating protein phosphorylation and cellular transcriptional events. Accordingly, recruitment to immune cells such as monocytes to the adipose tissues contributes to tissue inflammation. Differentiation of monocytes into macrophages creates several inflammatory cytokines, further encouraging local inflammation. Moreover, the release of cytokines and chemokines from the adipose tissues into the circulation promotes inflammation in other tissues including the pancreatic β-islets [170] worsening diabetes mellitus status.

Inflammation-induced insulin resistance build up is further escalated by JNK and IKK/NF-B which play important roles in inflammation. The stress kinase, JNK, normally phosphorylates the c-Jun component of the AP-1 transcription factor promoting insulin resistance. Phosphorylation of the serine residues in the insulin receptor substrate 1 (IRS-1) is involved [171]. Subsequently, counter-regulatory serine/threonine phosphorylation [172] inhibits insulin receptor signaling that normally occurs through a tyrosine kinase cascade [173]. The IB protein inhibitors of NF-B are the highly selected physiological substrates for IKK. The NF-B is inhibited by IB which when phosphorylated by IKK undergoes proteasomal degradation releasing the former for translocation into the nucleus, where it promotes the expression of numerous target genes whose products induce insulin resistance. IKK causes insulin resistance through the transcriptional activation of NF-B. Therefore, decreasing gene expression and improving insulin resistance may be achieved by administration of anti-inflammatory phytochemicals. Increasing adiposity is reported to upsurge inflammatory gene expression in the liver [174], which further increases the production of cytokines and chemokines aspects ameliorated by triterpenes phytotherapeutics [34]. Immune cells including monocytes and macrophages are recruited and/or activated, which leads to local insulin resistance processes that may be averted by anti-inflammatory triterpenes like Asiatic acid, maslinic acid or oleanolic acid.

Oxidative stress modifies the enzyme systems, impairs glutathione metabolism, causing lipid peroxidation and reducing vitamin C concentration and thus contributing to DM [175]. Actually, a mutual relationship exists between hyperglycemia

#### *Accenting Lipid Peroxidation*

and oxidative stress in DM with hyperglycemia fueling glucose autooxidation, NADPH oxidase activity, oxidative phosphorylation, protein glycation, and the polyol pathway, which leads to ROS generation and OS [176]. Healthy cells are damaged functionally and structurally by ROS, losing cellular integrity leading to many pathophysiological conditions.

#### **7.2 Phytochemical intervention in DM**

Was it not for their side effects, numerous synthetic drugs groups and insulin groups possess antioxidative and anti-inflammatory potential that can be used in the treatment of DM. Resultantly, the pursuit for alternative and safer treatment regimens for DM management remains open for investigation.

#### *7.2.1 Phytochemicals interventions in DM*

In streptozotocin- (STZ) induced diabetic Sprague Dawley rats, the oral administration of **naringin** (4′,5,7-trihydroxyflavonone-7-rhamnoglucoside) at 50 mg/kg/day reduces OS and increases fasting plasma insulin activity. Naringin, the foremost flavonoid in grapefruit juice, ameliorates OS and improves ATP synthesis in pancreatic -cell mitochondria and upgrades the subsequent insulin secretion by -cells [177]. Significant amelioration of -cell dysfunction, insulin resistance and hyperglycemia, reduction of TNF-, IL-6, CRP, increase in antioxidant enzyme activities, reduced NF-B expression, and upregulated adiponectin and PPAR expression have been observed through the application of naringin on diabetic Wistar albino male rats for 28 days. The positive alterations were obtained with naringin treatment at 25, 50, and 100 mg/kg/day. Furthermore, naringin effectively rescues kidney cells, -cells, and liver cells from continued pathological modifications and oxidative damage [178].

**Resveratrol** (**Figure 3**), a phytochemical, exerts potent antioxidative, antidiabetic, and anti-inflammatory activities. In the liver and spleen of STZ-induced male Long-Evans rats (type 1 DM), resveratrol administration (0.1 or 1.0 mg/kg/day) for 7 days, significantly decreased OS (including manganese-superoxide dismutase expression, superoxide anion content, protein carbonyl concentration). Also, reduction in hepatic inflammation factors (NF-B and IL-1) and decreasing the TNF- and IL-6 concentrations in spleen were observed [178].

Apples contain a principal phenolic compound called **Phlorizin** (PZ). Preexposure of PZ- docosahexaenoic acid ester (DHA) onto a lipopolysaccharide (LPS) stimulated macrophages inflammation model effectively reduced TNF-, IL-6, and COX-2 protein concentrations compared with DHA alone. However, both PZ-DHA ester and DHA have the potential to inhibit NF-B activation a proinflammatory marker. Therefore, PZ-DHA ester has the potential to quench T2DMassociated inflammation [179] and ameliorate the disease.

Diabetes mellitus is associated with the glutathione concentration reduction demonstrating the critical role of OS in its pathogenesis. Pretreatment of Ins-1E pancreatic -cells with the **flavonoid epicatechin** (present in green tea, grapes, and cocoa) prohibited tert-butyl hydroperoxide induced cell damage, ROS and p-JNK over expression. Over more, insulin secretion which indicates the protective potentiality of epicatechin against oxidative stress on -cells is restored [180].

**Pomegranate** (*Punica granatum*) fruit contains flavonoids such as anthocyanins, flavonols, ellagitannins, gallotannins, and proanthocyanidins providing beneficial effect in T2DM by reducing lipid peroxidation and OS. Also effected is the increasing of enzymatic antioxidant activity, decreasing ROS, and preventing activation of PPAR and NF-B by pomegranate [181].

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

**Anthocyanins,** found in tart cherry, alter tissue PPAR activity affecting metabolism and inflammation. The intake of tart cherry reduces retroperitoneal IL-6 and TNF- mRNA expression, NF-B activity, and plasma IL-6 and TNF concentrations while increasing retroperitoneal PPAR and PPAR mRNA expression in Zucker fatty rat model of obesity and metabolic syndrome. The risk of T2DM development tend to decrease when systemic and local inflammation, metabolic syndrome and lipid peroxidation are reduced [182].

Adipose tissue LPS-induced macrophages infiltration increased adiposity and lipid peroxidation may lead to T2DM. In an *in vitro* inflammation model where the pathologic relationships between adipocytes and macrophages were mimicked, anthocyanin-rich fractions from blackberry-blueberry beverages inhibited NO and TNF- the secretion and the phosphorylation of NF-B p65 [183] and lipid peroxidation tendency.

T2DM is associated with chronic, low-grade, systemic inflammation accompanied by an increased production of adipokines or cytokines by obese adipose tissue. Grape fruit (0.5 g/kg/ six weeks) treatment of diabetic db/db mice produced antihyperglycemic effects that were accompanied by reduced mRNA expression of proinflammatory genes such as COX-2, monocyte chemotactic protein-1, TNF-, NF-B and reduced lipid peroxidation in the liver and epididymal adipose tissue [184].

The immunomodulatory effects of a mycelial submerged culture and broth of *Grifola frondosa* **mushrooms** on splenocytes and peripheral blood cells. Two weeks of intragastric administration of fermented mycelia, broth, or their combination (1 g/kg/day) into DM Wistar rats significantly decreased the 2-hour postprandial blood glucose level, the production of T-leukocyte-derived interferon gamma (IFN-), monocyte-derived IL-4 and IL-6, and T-splenocyte derived IL-4 which treatment significantly enhanced macrophage-derived TNF- production [185] and possible decreased lipid peroxidation.

The administration of **fermented carrot juice** (by *Lactobacillus plantarum* NCU116) for five weeks in STZ-induced diabetic rats positively regulated the blood glucose concentration, hormone, and lipid metabolism, reestablished the antioxidant capacity, restored the morphology of pancreas and kidney, and upregulated the LDL receptor, cholesterol 7-hydroxylase (CYP7A1), GLUT4, and PPAR and PPAR mRNA expression [186].

In diabetic male C57BL/6 J mice, (0.5 mg/kg) treatment for 4 months with **Sulforaphane (SFN)**, an isothiocyanate found in broccoli, significantly inhibited cardiac lipid accumulation and enhanced cardiac inflammation, OS, and fibrosis. By downregulating diabetes induced PAI-1, TNF-, CTGF, TGF-, 3-NT, and 4-HNE expression, SFN ameliorated lipid peroxidation potential. Also, SFN, upregulated nuclear factor (erythroid-derived 2-) like factor 2 (Nrf2) and its downside genes, NQO1 and HO-1 in rescuing DM sequalae. Of note, SFN diminished 4-HNE-LKB1 adducts and reversed the diabetes-induced inhibition of LKB1/ AMPK and its downstream targets, including sirtuin 1, PGC-1, phosphorylated acetyl-CoA carboxylase, and carnitine palmitoyl transferase-1. Ultimately, SFN treatment of T2DM attenuate the cardiac OS-induced inhibition of the LKB1/AMPK signaling pathway, thereby preventing T2DM-induced lipotoxicity and cardiomyopathy [187].

**Onion-derived quercetin** derivatives are important flavonoids for improving diabetic conditions in both *in vivo* and *in vitro* models. Eight days of treatment with onion peel extract (1%) improved significantly glucose tolerance, liver and skeletal muscle glycogen content, and insulin receptor and GLUT4 expression in muscle tissues of STZ-induced DM in male Sprague Dawley (SD) rats. The OS-inducing dysregulations of SOD activity, increased free fatty acids plasma concentrations,

the formation of MDA, and IL-6 over expression in hepatic tissue, were significantly suppressed in this model of onion-derived quercetin treatment [188].

Traditional medicinal mushroom known as *Cordyceps militaris* are a source of **Cordycepin (3′-deoxyadenosine)**. Inhibition of NO, suppression of NF-B activation, and protein expression suppression of proinflammatory mediators that further inhibit the production of proinflammatory cytokines such as IL-1, IL-6, and TNF-α has been demonstrated in LPS-stimulated 263.7 cells treated with cordycepin. Over more, an elevated concentration of cordycepin reduced the T2DM-regulating genes such as 11-HSD1 and PPAR as well as the expression of costimulatory molecules such as ICAM-1 and B7–1/−2 [189].

**Curcumin** (a polyphenolic compound) in Turmeric (*Curcuma longa*) is the active ingredient possesses broad-spectrum biological activities such as antiinflammatory, antioxidant, and antitumor. Reduction of OS and inflammatory responses and inhibition of prostaglandin E2 (PGE2) and NOS have been observed in the injured lungs of DM rats after administration of curcumin. As a mode of action, curcumin inhibited the stimulation of NF-B, a key player in inflammatory responses [190]. Eight weeks treatment of db/db mice with curcumin improved AMPK and PPAR expression and reduced NF-B protein levels [191].

Hyperglycemia-mediated OS of DM may induce neuronal injury. **Curcuminoids,** polyphenols of turmeric, displayed protective effects against OS in the brain of STZ-induced diabetic rats by restoring the normal concentrations of lipid peroxidation and nitrite content and endogenous antioxidant marker enzymes [192]. *De novo* synthesis of glutathione and the suppression of insulin receptor expression were achieved with the administration of curcumin which attenuated insulin-induced OS in hepatic stellate cells by stimulating the expression of glutamate-cysteine ligase [193]. Pretreatment with a novel curcumin analogue (B06) at 5 M significantly reduced the high-glucose-induced overexpression of inflammatory cytokines in macrophages through the inhibition of c-Jun N-terminal kinase/NF-B activation [194].

Administration of **ginger powder** (0.5%, 1%, and 5%) in STZ-induced inbred male Wistar/NIN rats for one month protected against DM effects by modulating antioxidant enzymes, glutathione and downregulating lipid and protein oxidation [195]. Combined **garlic bulb**, **ginger rhizome**, **turmeric rhizome** (200 mg/kg body weight) treatment for 28 uninterrupted days significantly alleviated hyperglycemia and dyslipidemia, increased insulin production, enhanced GSH, and decreased lipid peroxidation in nicotinamide and STZ-induced diabetic rats [196].

Diabetic encephalopathy is one of the more severe complications of DM characterized by severely reduced body weight. **Saffron** at 40 and 80 mg/kg significantly increased the body weight and serum TNF- concentrations and decreased the blood glucose, glycosylated proteins, and advanced glycation end product (AGE) serum concentrations in DM encephalopathy rats. Additionally, saffron significantly increased the glutathione content, superoxide dismutase, and catalase but remarkably decreased the cognitive deficit and serum TNF-, and it induced NOS activity in hippocampus tissue [197].

Administration of **Crocin,** an active constituent of saffron, significantly decreased MDA ( < 0.01) and xanthine oxidase ( < 0.05) activities while elevating glutathione ( < 0.05) concentration, thus ameliorating renal injury in STZinduced rats [198]. **Safranal** is one of the components of the saffron plant which, in high-fat diet (HFD) and STZ-induced T2DM rats, treatment for a period of 4 weeks diminished OS caused by T2DM and reduced the inflammation by decreasing plasma and pancreas tissue the TNF- and IL-1 s concentrations [199].

The protective effect of **Onion** protected against OS *in vivo* where STZ-induced male diabetic Wistar rats administered 1 mL/day of *Allium cepa* solution (0.4 g

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

*Allium cepa*/rat) improved the fasting serum HDL concentration, alleviated hyperglycemia by diminishing SOD activities [200]. Another *in vivo* study also investigated the protective effects of onion against oxidative stress; 12 weeks of onion intake suppressed the diabetes-induced oxidative stress more effectively in STZinduced diabetic rats [140]. Onion powder (7% w/w) administration suppressed the glutathione peroxidase, glutathione reductase, and glutathione S-transferase activities [201].

**Mustard leaf (***Brassica juncea***)** strongly inhibits the AGE formation and free radical-mediated protein damage oral ingestion by STZ-induced diabetic rats an EtOAc fraction (50 and 200 mg/kg body weight/day/10 days) reduced the serum glucose and glycosylated protein, superoxide and nitrite/nitrate concentrations. This suggests that the EtOAc fraction of mustard leaf has the capacity to attenuate damage caused by the oxidative stress involved in diabetes and its complications [202]. Brown mustard is a high source of Asiatic acid, a triterpene with an excellent antioxidant capacity, potent anti-inflammatory [203], antihyperglycemic [204], antihyperlipidemic [35], reduction of OS while rescuing malarial infection in SD rats.

### **8. Rheumatoid arthritis (RA) and phytochemical interventions**

RA is an inflammatory, systemic autoimmune syndrome with primary degenerating articular structures involving, the cartilage (movable synovial joints- knees, shoulders, hands) and the bones (osteoarthritis and osteoporosis) as a result of pannus development over the joint surfaces (abnormal layer of fibrovascular or granulation tissues) [205]. great socioeconomic impact worldwide.

#### **8.1 Pathogenesis of RA Arise from autoimmune inflammation and OS**

The pathogenesis of RA involves A complex interplay between genetic and environmental factors leading to autoimmune inflammatory responses against the connective and synovial tissues of the joints [136]. Furthermore, increased ROS concentrations are actively involved in RA pathogenesis [206, 207]. Infiltration of the affected synovial tissues and promotion of the overexpression, release, and activity of proinflammatory cytokines [TNF-, TNF-induced NF-B, vascular endothelial growth factor (VEGF), IL-1 beta (IL-1), IL-6, IL-8, and IFN-] by T cells, B cells, and macrophages are particular findings in patients with RA [208, 209].

Responding to the proinflammatory cytokines, synoviocytes (FLS) fibroblasts flourish and produce huge quantities of cytokines, matrix metalloproteinases (MMPs), and COX-2, which progressively degrade cartilage and lead to joint obliteration [210, 211]. Oxidative stress is involved in the disintegration of cartilage through NrF2 or NFE2L2 dysregulation [212]. Activated Nrf2 binds to antioxidant response elements (AREs), resulting in the augmented expression of antioxidative enzyme [e.g., Heme oxygenase-1 (HO-1)] encoding genes [213, 214] which indicates both OS and inflammatory response are implicated in the RA pathogenesis. Resultantly, phytochemicals with anti-inflammatory capacities play a crucial role in the battle with RA.

#### **8.2 Phytochemicals against OS and inflammation in RA**

Side effects are common and unavoidable from synthetic regimens used for managing RA making alternative medicine and traditional medicine a viable source for treating the disease. Phytochemicals attenuate OS and inflammation and relieve and protection from RA.

The clinical phenomenon in patients with RA involves osteoclastogenesis which is a process where bone tissues is destroyed by osteoclasts. **Polyphenols** extracted from **dried plums** extracted polyphenols inhibit osteoclastogenesis through suppressing TNF- and NO synthase activity and by downregulating the transcription factor nuclear factor for activated T cells (NFATc1) [215]. **Cherry anthocyanins** reduce both OS (SOD and decrease serum MDA) and inflammatory mediators (decrease in TNF-) in an SD adjuvant-induced RA rat model [216].

**Resveratrol polyphenol** confers significant protective effect against an aggressive RA rat model [217]. Anti-inflammatory and antioxidative resveratrol activities influenced reduction of specific rheumatoid biomarkers activities [serum rheumatoid factor (RF), MMP-3 and cartilage oligomeric matrix protein (COMP)], immunological biomarkers [IgG and antinuclear antibody (ANA)], immunomodulatory cytokines (TNF-), and OS biomarkers [myeloperoxidase (MPO), CRP, and MDA] [217].

A natural polyphenol in mangoes, **mangiferin**, suppressed the expression of IL-1, IL-6, TNF-, and receptor activator of NF-B ligand (RANKL) via the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and the inhibition of NF-B [218]. Mangiferin also exerts strong proapoptotic effects on human synoviaderived synoviocytes when protecting against joint degeneration in RA [219].

**Kaempferol** from grapefruits inhibits synovial fibroblast proliferation by suppressing inflammatory cytokine IL-1, inhibiting the phosphorylation of ERK-1/2, p38, and JNK, preventing the activation of NF-B, and reducing OS by impeding the production of MMPs, COX-2, and PGE2 in RA-derived synovial fibroblasts [220].

#### **9. Conclusion**

Lipid peroxidation resulting from OS and inflammation are mixed up in the pathogeneses of degenerative brain disorders, DM, RA. Propositions targeting these provides means to develop viable strategies to treat these diseases using phytochemicals. Cells are furnished with antioxidant defense systems to combat the effects of OS with the Nrf2 being the master regulator of redox homeostasis. The regulator triggers the antioxidant enzyme systems. Consequently, targeting Nrf2 appears to offer a means of controlling OS. However, attenuating OS alone may not confer satisfactory protection against these diseases, in which case, targeting the classical cell survival pathway, that is, the TrkB/PI3K/Akt pathway would be required to restore cellular function. These signaling pathways upregulate pro-survival factors but suppress their pro-apoptotic counterparts.

Phytochemical with pharmacological modulation capacity may coactivate TrkB signaling mediated cell survival and Nrf2-ARE antioxidant systems. The combination offers promise for the treatment of diseases connected with OS-associated brain degeneration, glucose homeostasis derangements, and rheumatoid arthritis.

Contextually, several phytotherapeutics have been reported to protect against neuronal injury by activating TrkB/PI3K/Akt and Nrf2 signaling systems, which suggests they could be utilized to design novel therapeutic agents for NDD, ischemic stroke, TBI, and brain aging.

Phytochemicals (for example, resveratrol, tea polyphenols etc.) have been shown to promote the regeneration capacity of neurons along with their protection by dual targeting TrkB/PI3K and Nrf2-ARE signaling [81, 114]. These may have a better chance of succeeding with AD subjects.

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

Generally, the preventive and curative action of phytotherapeutics against pathological conditions [116, 221] emanate from their ability to behave as antioxidant and oxidants and that they are electron donors and electron receivers under varying environments in a pluripotential capacity which allows them to influence reduction and oxidation reactions [13, 32, 34, 35]. The negative values of redox potential probably enable the active principles to act as an antioxidant and in turn scavengers of free radicals as they are oxidized in the process. Crucially, it has been observed that the relative efficacy of antioxidant activity of the *Salix aegyptiaca* phytochemicals tends to be similar to their relative order of redox potential.

Acetylsalicylic acid has been shown to have lowest redox potential and antioxidant activity suggesting that the phytochemicals such as gallic acid, quercetin, rutin and vanillin, other than salicylates contribute to the medicinal properties of *S. aegyptiaca,* indicating a possible synergistic activity necessitating whole plant approaches in the use phytotherapeutics [222].

The interesting connection between OS, inflammation, lipid peroxidation are closely linked to initiation and progression of various diseases [223] necessitating interventions with phytochemicals to combat, at molecular level, different aspects of the biological homeostasis bringing about pathophysiological conditions of cardiovascular diseases, DM, RA and brain degenerative disorders of the old. The phytotherapeutics triterpenes Asiatic acid, maslinic and oleanolic have pleiotropic functions rendering them potent interventions for OS-related disease and lipid peroxidation.

## **Author details**

Alfred Mavondo-Nyajena Mukuwa Greanious <sup>1</sup> \*, Nesisa Ncube2 , Alfred Sibanda1 , Delton Dube1 , Francis Chikuse Farai3 and Paul Makoni4

1 Pathology Department, Faculty of Medicine, National University of Science and Technology, Bulawayo, Zimbabwe

2 Biochemistry Department, Faculty of Medicine and Health Sciences, University of Zimbabwe, Harare, Zimbabwe

3 Regional COVID-19 Response and Vaccine Roll-out Coordinator, Windhoek, Namibia

4 Research and Internationalization Office, National University of Science and Technology, Bulawayo, Zimbabwe

\*Address all correspondence to: greaniousa@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.
