**5.2 Role of flavonoids as neuroprotective against different neurodegeneration diseases**

There is a long history of using flavonoids in medicine. They are a notable therapeutic class because of their diversity, dispersion, and seclusion. Flavonoids are essential for the development of new drugs since they may be used as natural products and are the basis for many treatments [19]. Medicinal plants, vegetables, fruits, and wines all contain flavonoids. Flavonoids can bind to body proteins, and alter hormones, enzymes, transporters, and DNA. They can also chelate heavy metals and scavenge free radicals [134]. Numerous pharmacological studies demonstrate their efficacy in treating microbiological infections, cancer, cardiovascular diseases, neurological disorders, and diabetic Mellitus (DM) [135]. A recent study suggests that consuming foods high in flavonoids may improve cognitive abilities in humans [136].

In both normal and transgenic preclinical animal models of Alzheimer's disease (AD), certain flavonoids have been demonstrated to reduce the progression of the disease's pathology [137]. Foods high in flavonoids, such as chocolate, green tea, and blueberries, have good health effects as a result of their interactions with certain cellular and molecular targets [31]. The expression of neuromodulatory and neuroprotective proteins as well as the quantity and quality of neurons are increased by the interaction of flavonoids with ERK and PI3-kinase/Akt receptors [138]. They may improve cognitive performance by boosting blood flow to the brain and brain neurogenesis thanks to their favorable effects on the cerebrovascular system. Recently, many additional advantages of flavonoids were discovered [139]. Flavonoids lessen symptoms similar to AD and related neurodegenerative diseases [140]. Inhibiting the major enzymes involved in the development of amyloid plaques, oxidative stress, and neuronal death brought on by neuro-inflammation are a few potential treatments [141]. By preserving neuronal number and quality in key areas of the brain, flavonoids guard against diseases that impair cognitive function.

#### **5.3 Effectiveness of flavonoids as therapeutic approach in dementia and Alzheimer's**

In animal models, flavonoids reduce AD and cognitive dysfunctions, demonstrating their therapeutic utility in neurology. By focusing on important enzymes, flavonoids prevent the growth and accumulation of amyloid plaques (A). In an AD mouse model, anthocyanin-rich flavonoids in bilberry and black currant extracts lessen behavioral deficits and alter APP processing [138]. In a transgenic PSAPP animal model of cerebral amyloidosis, chronic therapy with tannic acid may enhance memory and behavior. Nobiletin improves A-mediated memory deficits and reduces A load in the hippocampi of transgenic rats. Grape polyphenols improve memory and lower soluble A oligomers in the brain tissues of Tg2576 rats. Citrus flavonoid luteolin decreases BACE1 activity and A peptide synthesis in APP transgenic neurons [139, 140]. Grape seed extracts rich in polyphenols and curcumin lessen the deposition of A in the brains of AD animals. Through the estrogen receptor, phosphoinositide 3-kinase, and Ak, Epigallocatechin gallate (EGCG) promotes nonamyloidogenic APP processing. Selective estrogen receptor modulators may be a treatment option since post-menopausal estrogen depletion is linked to an increased risk of AD. An alternative to estrogen-based therapy may be EGCG-mediated estrogen receptor modulation [141, 142]. For neuroprotective benefits, EGCG suppresses fibrillogenesis and A-rich amyloid fibrils. Unfolded polypeptides are prevented from converting directly into neurotoxic intermediates by contact with them. Big A fibrils may be split up into smaller proteins by EGCG, avoiding aggregation and negative effects. Cognitive deficits linked to neurodegeneration may benefit from myricetin's in vitro anti-amyloid activity [143–145]. These findings imply that flavonoids may inhibit the A-forming enzyme BACE1 and hence prevent the fibrillization process that leads to the generation of A. The neuro-modulating capacity and therapeutic potential of flavonoids need more investigation. With 15 carbon atoms organized into three rings, two of which are aromatic and connected by an oxygenated heterocyclic ring, flavonoids are polyphenolic chemicals that are obtained from plants. They are consumed by people in fruits, nuts, seeds, flowers, tea leaves, herbs, spices, and red wine [30, 146]. Recent research links dietary flavonoids to reduced risk of dementia, relief from neuronal degenerative conditions, and improved memory and learning. Studies reveal that these compounds' permeability across the blood-brain barrier (BBB) is

*Flavonoids Biosynthesis in Plants as a Defense Mechanism: Role and Function Concerning… DOI: http://dx.doi.org/10.5772/intechopen.108637*

**Figure 3.** *Shows the protective effect of flavonoids against neurodegenerative disorders. Created with BioRender.*

influenced by their structural configuration, which promotes the investigation of their therapeutic potential. Several flavonoids, including naringenin, quercetin, hispidulin, hesperetin, naringenin, and EGCG, may cross the blood-brain barrier due to their lipophilicity or interactions with BBB efflux transporters, including the Pglycoprotein. Plasma and blood flavonoids provide evidence that they may enter the brain. Following the consumption of meals or beverages high in flavonoids, human plasma contains flavonoids (**Figure 3**) [147–149].

#### **5.4 The protective and therapeutic role of flavonoids against diabetes**

Anti-diabetic flavonoids include quercetin, naringin, hesperidin, epigallocachetin gallate, apigenin, myricetin, and anthocyanins. They are antioxidants and antiinflammatory. Flavonoids have impacts on gene regulation. Cells treated with flavonoids reveal an obscure in vivo mechanism. By controlling the activity of the intestinal carbohydrate, flavanols improve glucose homeostasis [114, 150]. Numerous studies demonstrate that the anti-apoptotic properties of flavanols increase cellular replication, insulin secretion, and glucose synthesis. As a result, catechin-rich flavanol increased insulin release prompted by glucose. Increased flavonoid consumption has been linked in human studies to a decreased incidence of diabetes. In human clinical research, flavonoids seem to not affect diabetes Consumption of isoflavones was not linked to modifications in fasting insulin, glucose, or HbA1c. Individual isoflavones seldom ever have an impact on insulin sensitivity and glycemic control [151–153]. By influencing cell mass and function, Insulin sensitivity, and glucose absorption, anthocyanins may improve glucose homeostasis. Flavonoids and Type 2 Diabetes Flavonoids are plentiful, structurally unique chemicals. Over the last ten years, the antioxidant properties of flavonoids have aided diabetic patients in reducing oxidative stress. It has been established that diabetes is caused by oxidative stress. Supplementing with antioxidants has been utilized to lessen oxidative stress caused by diabetes. Flavonoids modulate transcription factors and proinflammatory mediators

and have strong in-vitro and in-vivo antioxidant and anti-inflammatory actions. T2DM may be treated by pancreatic islet isolation and transplantation [154–156]. Pancreatic transplantation and flavonoids may provide new therapeutic insights. A surplus of flavonoid molecules is also necessary. Since most flavonoids impact how complicated carbs are digested and how quickly glucose is absorbed, appropriate doses of pure single flavonoids may improve glycemia. Flavonoids fight against diabetes. As previously mentioned, signaling pathways are potential targets for treatment because they play significant roles in the pathophysiology of oxidative stress-induced diabetes. By limiting the release of cytochrome-c from mitochondria into the cytosol and inhibiting caspase activity, EGCG exhibits anti-inflammatory actions in pancreatic cells. A good target for diabetes treatment is AMPK [69, 157, 158]. As a result of EGCG's stimulation of the AMPK system, hepatic gluconeogenesis is decreased, fatty acid oxidation is improved, and mitochondrial biogenesis is controlled. In skeletal muscles, AMPK activation causes an increase in GLUT4, which facilitates glucose absorption. Hesperidin and naringin increase WAT GLUT4 while inhibiting liver GLUT2. The IRS-1-PI3-K-PKB/Akt insulin pathway was controlled by flavonoids from Oxytropis falcata Bunge chloroform extract, which decreased inflammatory cytokines by downregulating NF-B expression and increased GLUT4 expression. The flavonoid fisetin is found in foods including strawberries, apples, grapes, cucumbers, and others [159–162]. Feinstein treatment decreased glycemia, HbA1c, NF-B p65 unit, interleukin-1 beta (IL-1), and serum nitric oxide (NO) due to improved plasma insulin antioxidant status, according to animal studies. By modifying NF-epigenetics, fisetin reduced HG-triggered cytokine levels in monocytes. A diabetic dietary supplement is B's Fisetin. A flavonoid called morin may be found in wine, fruits, *Prunus dulcis*, and *Psidium guajava* [163–165]. Morin, which has anti-inflammatory properties and is useful in treating inflammatory illnesses, was demonstrated by Heeba et al. [166] to lower the cytokines IL-1, IL-6, and TNF in diabetic mice when administered at a dose of 30 mg/kg body weight. In rat liver and BRL3A cells, morin reduces fructoseinduced alterations in hepatic SphK1/S1P signals and hepatic NF-B activation with IL-1b, IL-6, and TNF. The root and fruit of Scutellaria baicalensis Georgi contain a flavonoid called baicalein, which has potent antioxidant properties [166, 167]. Baicalein reduced food intake, body weight, and HbA1c levels in diabetic rats. Baicalein reduced iNOS and TGF-1 expression, inhibited NF-B, and enhanced renal tissue structure. AGEs, TNF, NF-B activation, and histopathological changes are all decreased by baicalein. Adipocytes, skeletal muscle, cardiomyocytes, and other organs all have GLUT-4. It is a glucose transporter that is resistant to insulin. Hormone/ metabolic activity and tissue-specific response [168–170]. Insulin and muscle contraction cause it to move from its natural location in the cytoplasm to the plasma membrane, where it absorbs glucose. Insulin-resistant cells across the plasma membrane have changed intracellular GLUT-4. T2DM is a result of increased insulin resistance, inadequate insulin synthesis, and insulin resistance. According to a study, flavonoids and polyphenols increase GLUT-4 expression and glucose absorption. In adipocytes and skeletal muscle cells, quercetin and procyanidins enhance GLUT-4 mRNA. In mouse embryonic fibroblasts, flavonoids increase the expression of GLUT-4 mRNA. In skeletal muscle cells, epigallocatechin gallate (EGCG) elevates GLUT-4. Adipocyte and skeletal muscle cells treated with hesperidin and naringin had similar outcomes [171–173]. A flavonoid called Enicostema little increases the expression of the IRS-1, Akt-2, and GLUT-4 genes, which in turn stimulates the IRS-1/PI3K/Akt pathway. Clonal INS-1E cells and pancreatic human islets have shown protective benefits in response to kaempferol flavonoids. In human -cells and islets, 10 M

#### *Flavonoids Biosynthesis in Plants as a Defense Mechanism: Role and Function Concerning… DOI: http://dx.doi.org/10.5772/intechopen.108637*

kaempferol enhances viable cell concentration and inhibits apoptosis. By decreasing caspase-3 proteins and glucotoxicity and lipotoxic effects by reducing Akt and Bcl-2 anti-apoptotic activities, activating signaling pathways guards against apoptosis in cells. In chronic hyperglycemia or hyperlipidemia, cell survival is improved by cAMP-mediated signaling [174, 175]. As previously noted, kaempferol is a special antidiabetic chemical. Numerous studies have shown the relationship between flavonoids and glucose status. An effective treatment target for T2DM and insulin resistance is provided by flavonoids from banana flowers. Thus, IR/HepG2 cells consume more glucose when exposed to 10 mg/ml of enicostema littoral flavonoid. Hepatic insulin resistance may result from endoplasmic reticulum stress. In those with T2D, ER stress either increases insulin resistance or reduces insulin secretion [176–178]. Unfolded protein response (UPR) signaling is activated in diabetes by ER stress, which also increases inositol-requiring enzyme 1 (IRE1). Then, by converting dormant XPP-1 s into the active form, XBP1 activates IRE1. The IRE1-XBP1 pathway leads to insulin resistance by phosphorylating IRS-1. This method lowers insulin release from pancreatic islet cells. Insulin secretion is suppressed by pro-insulin mRNA degradation caused by overexpression of IRE1 [179–181]. The medicinal plant pomegranate has anti-diabetic effects. PGF has been used to treat diabetes for many years. Flavonoids, in particular, are anti-inflammatory and antioxidant polyphenols found in PGF extract. It reduces blood glucose, triglycerides, and insulin resistance, according to animal studies. By activating PPAR- 28, PGF has shown antihyperglycemic effects [182, 183].

Recently, Chinese researchers administered polyphenol extract PGF to diabetic rat models for 4 weeks at doses of 50 and 100 mg/kg. The results showed that increasing insulin-stimulated phosphorylation of IRS-1, Akt, and GSK-3 improved insulin sensitivity. The ER stress signals IRE1 and XBP-1 splicing are reduced by PGF. IRE1, XBPs, and CHOP were all decreased by PGF. PGF increases insulin resistance, which lowers glucose levels in T2DM rats, and this effect is likely mediated through Akt-GSK3 signaling and a decrease in ER stress. Unfolded protein response, mitochondrial oxidative stress, endoplasmic reticulum, and other signaling pathways all contribute to the development of T2DM. Flavonoids function as enzyme inhibitors, peroxide decomposers, hydrogen and electron donors, quenchers of singlet oxygen, radical scavengers, and metal chelators [184, 185]. These compounds regulate antioxidant enzymes, gene expressions, and protein expressions in oxidative stress-induced in vivo and in vitro models. Concentration, polarity, media, and other antioxidants all affect effectiveness. Diabetes has been associated with ER stress. Interest has grown in small molecules that inhibit ER stress and target UPR proteins [135, 186–188]. The bioavailability and bioefficacy of flavonoids may be increased by employing nanotechnologies, such as nanoparticulate systems. Flavonoids should not affect physiological processes that involve ROS. Significant antioxidant activity, ROS stability, receptor affinity, low toxicity, and free radical scavenging action are all desirable traits in flavonoids. It is important to think about the detection of ROS/RNS and the linked species and physiological levels (**Figure 4**).

#### **5.5 The antiviral role of flavonoids against various types of virus**

Viruses have envelopes made of protein, RNA, and DNA. The metabolism and environment of the host are necessary for reproduction and survival. They take advantage of host cells to spread [189]. Flavonoids are phytochemicals that inhibit viruses in a variety of ways. They could prevent DNA replication, protein translation,

#### **Figure 4.**

processing of polypeptides, and viral attachment and entrance into cells. The invasion of healthy cells by viruses may be stopped by them. Flavonoids might bind to viral surface proteins and stop the virus from entering host cells. While other flavonoids obstruct viral assembly, packaging, and release, some of them hinder viral transcription and replication. Flavonoids modify the immune system and reduce viral load [190]. The backbone of flavones is 2-phenyl-1-benzopyran-4-one. Flavones include apigenin, baicalein, chrysin, luteolin, tangeritin, wogonin, and 6-hydroxy flavone. Since the 1990s, when it was shown that apigenin and acyclovir boosted antiviral activity against HSV-1 and HSV-2 in cell culture, flavones have been known to have antiviral properties [191]. Apigenin is effective against HSV-1, poliovirus type 2, HCV adenoviruses and hepatitis [192]. African swine fever virus (ASFV) production is decreased by 3 log due to apigenin's suppression of viral protein synthesis [193, 194]. According to Shibata et al. [195], apigenin prevents HCV replication by lowering microRNA122 which is unique to the liver. The production of early and late HCMV proteins, as well as DNA, was reduced by baicalein, but not polymerase activity. Baicalein and its analogs may be utilized to treat Tamiflu-resistant viruses, according to novel baicalein analogs with bromine-substituted B-rings that have shown substantial activity against the H1N1 Tamiflu-resistant virus [196, 197]. In early-stage infected cells, baicalin decreased HIV-1 in vitro replication. The antiviral function of baicalin prevents the HIV-1 envelope protein from interacting with immune cells [192, 196, 197]. Against the dengue virus, baicalein and baicalin (DENV). By eliminating extracellular viral particles, they prevented the growth of DENV-2.Baicalein demonstrated a strong affinity for the DENV NS3/NS2B protein (7.5 kcal/mol) and the NS5 protein (8.6 kcal/mol), according to in silico studies [198–201]. Baicalin may prevent CHIKV infection because of its high binding affinity (9.8 kcal/mol) for the CHIKV nsP3 protein. Lutein prevents HIV-1 reactivation by blocking clade B- and C-Tat-driven LTR transactivation [202–205] . By reducing the binding of the transcription factor Sp1, luteolin prevented the reactivation of the Epstein-Barr virus (EBV). discovered that luteolin interfered with viral RNA replication. In addition to these antiviral characteristics, luteolin or luteolin-rich fractions showed antiviral efectiveness against rotavirus, CHIKV, JEV, SARS-CoV, and other viruses [192, 206, 207]. The foundation of flavonol is 3-hydroxy-2-phenylchromen-4-one. Kaempferol and quercetin showed potential as antiviral agents. For instance, manager
