A Comprehensive Review of the Pharmacological Importance of Dietary Flavonoids as Hepatoprotective Agents

The liver is a crucial organ that is involved in various kinds of metabolic activity and a very stable accessory gland for the digestive system. Long-term or persistent inflammation and oxidative stress due to any reasons have a substantial impact on the beginning and continuation of chronic diseases such as hepatocellular carcinoma, liver cirrhosis, liver fibrosis, and other hepatic conditions. There are many sources which can help the liver to be healthy and enhance its metabolic potential of the liver. Since the diet is rich origin of bioactive along with antioxidant chemicals including flavonoids and polyphenols, it can control different stages of inflammation and hepatic diseases. Numerous food sources, notably vegetables, nuts, fruits, cereals, beverages, and herbal medicinal plants, are rich in bioactive chemicals called flavonoids and their derivatives like Flavones, Anthocyanins, Iso-flavonoid, Flavanones, Flavanols, and Flavan-3-ols. Most recently occurred research on flavonoids has demonstrated that they can regulate hepatoprotective properties. This is because they are essential parts of pharmaceutical and nutraceutical products due to their hepatoprotective, antioxidative, and immune-modulating characteristics. However, the characteristics of their hepatoprotective impact remain unclear. The purpose of this comprehensive review is to survey the flavonoid structure and enriched sources for their hepatoprotective and antioxidant effects concerning liver toxicity or injury.


Introduction
Te liver is a crucial organ that is involved in various kinds of metabolic activity. Drug abuse, viral infection, excessive intake of alcohol, and biological and chemical agents, as well as correspondingly developed autoimmune assault of the hepatocyte, are just a few of the many reasons that can easily result in liver damage. Hepatic shape and function will be shattered and hampered if the damage cannot be reversed. Long-term hepatic damage could be a consequence of hepatic cirrhosis, fbrosis, fatty liver, and even also liver carcinoma, creating an epidemiological issue [1]. Currently, alternative treatment methods for several ailments are being embraced that use phytochemicals derived from natural resources. Te lack of suitable and efective hepatoprotective drugs has remained a persistent worry despite signifcant advances in modern medicine. Due to the reason of druginduced liver injury (DILI), many drugs have been taken of the market. Severe cases of liver failure can necessitate transplantation of the liver and result in organ death. Hepatic illnesses are primarily treated with plant-based medicines, and modern pharmaceuticals ofer little alleviation for hepatic ailments. But there are not many medications on the market right now to address liver diseases. Due to their strength, purity, and afordability, herbal medications have gained importance and acceptance in recent years [2]. Tere are a huge number of bioactive substances, also known as secondary metabolites, in diferent plants, including alkaloids, polysaccharides, phenylpropanoids, Flavonoids, resins, tannins, steroids, essential oils, organic acids, anthraquinones, polyphenols, and saponins. Tis is because coevolution has produced so many of these substances [3].
More than fve thousand polyphenolic chemicals with a ffteen-carbon core make up the vast family of favonoids. Except for chalcones, which have a cleaved C ring, they frequently contain two phenyl rings A and B, and a heterocyclic C ring with attached oxygen [4]. Te name of favonoids comes from the Latin word known as favus, whose meaning is "yellow," which protects plants against oxidative damage in a defensive manner, male fertility, and visual signals [5]. Flavonoids are additionally known for their name as vitamin P for humans, it is a disputed name as they do not match the characterization of vitamins, and their infuence on a variety of infammatory diseases attracts research interest [5,6]. Since the beginning of civilization, plants have been employed as traditional sources of therapeutic substances. Te phytoconstituents derived from plants and their synthetic and semisynthetic analogues have been a major pathway to new pharmaceutical products since the advent of modern medicine and single pure medications [7]. Terefore, to efectively combat this threat, safe and afordable treatment alternatives must be developed. Natural secondary metabolites have been already taken on purpose for many centuries to treat various illnesses or diseases. Between 1981 and 2010, the FDA authorized about 35% of the medicines and their compounds that were obtained from natural sources. Tese natural substances already possess strong medicinal and anti-infammatory properties. Numerous bioactive substances produced from plants, primarily favonoids, can decrease infammation by lowering the extent of potential mediators involving prostaglandin, Reactive oxygen species, and cyclo-oxygenase-2 as well as several cytokines like interleukin-6, interleukin-1, and TNFα. Flavonoids are favourable to utilize in many dietary approaches due to the wide range of bioactivities they have been linked to in the human body, including antimutagenic, antioxidant, antiviral, and anti-infammatory efects [8].

Chemical Structure of Flavonoids and Their Subclasses
Plants are a major origin of favonoids, which are phenolic metabolites that exist naturally. An orange extract that was assumed to be a novel class of vitamins during the 1930s was eventually identifed as a favonoid. Over 8000 distinct favonoids have been identifed so far and have been reported in the literature. Diferent plant tissues contain favonoids either internally or externally [8]. Te pharmaceutical and biological ascribe to favonoids such as antimalarial, cytotoxic, anticancer, cardioprotective, hepatoprotective, antileishmanial, antitrypanosomal, antiinfammatory, and neuroprotective antiamoebic and also efective in the therapy of age-related factors, diabetes, and Alzheimer's disease [8,9]. Tese qualities are typically attributed to their capacity for metal chelation, activity in scavenging free radicals, and degree of specifcity in protein binding ability. Te basic ingredient of favonoids, which come in a variety of shapes, is a ffteen-carbon skeleton linked to two benzene rings A and B by a C (heterocyclic pyrene) ring. Distinct types of favonoids vary according to the degree of oxidation and arrangement of C-ring substitution, although each compound within a class difers in the sequence of A and B-ring substitution [8]. Flavonoids can be subdivided into numerous subgroups based on the carbon in the C ring that the B ring is attached to, as well as the degree of oxidation and substitution of the ring C. Flavonoids classifed as isofavones have a B ring joined to the 3 rd position of the ring C. Neo-favonoids include those in which the B ring is attached in 4 th position, subgroups can be formed based on the structural characteristics of the ring C for all those in which ring B is attached at position 2 nd . Flavonoids are subcategorized into diferent classes including favanols or catechins, favanols, anthocyanins, favonols, favones, favanones, and chalcones which are given in Table 1 with their chemical structure [10]. Flavonoids naturally occur in plants in the form of glycosylated or methylated compounds because these structures have higher bioactivity, bioavailability, and stability. A biological tool called glycosyltransferase has been used to glycolyze favonoids, catalyzing the conjoined of a sugar moiety to an aglycone part to produce glycosides. Similar to how methyltransferase attaches methyl moieties to aglycone to create methoxides, the hydroxyl group in favonoids is methylated in the existence of this enzyme. Methylation can result in the formation of C-methylated or O-methylated molecules via the carbon or oxygen atom, respectively. Te pharmacological and biological characteristics of the methylated product relative to its parent compound were dramatically altered as a result of the methylation of favonoids, according to experimental data [11].

Flavonoids and Their Subclasses with Their Dietary Sources
Flavonoids, also known as dietary favonoids, are a class of organic compounds with a variety of phenolic metabolites that are primarily present in beverages and plant-derived food, such as fowers, bark, cereals, herbs, fruits, cocoa, tea, and wine. Depending on their chemical structure, favonoids are subcategorized into twelve distinct groups, and hardly six of them are relevant to the diet which is given in Table 2 [10].

Flavonols.
Te favonols are one of the subclasses of favonoids and are distinguished from favones by having an oxo group at the 4 th position and a 2,3-double bond present on ring C, which permits conjugation between rings (A and B) and signifcantly changes redox characteristics of favonols. Although, they are unlike favones in that they possess a hydroxyl group at position three, the sole nonphenolic one. Even though favonols and favones are highly alike, neither reduction nor oxidation of the former into the former appears to happen in plants. Higher plants have a consistent distribution of favonols that is widely dispersed in leaves, stems, fruits, and fowers. Some of the most extensively investigated aglycons comprise isorhamnetin, kaempferol, galangin, isorhamnetin, rhamnetin, quercetin, fsetin, and myricetin [12]. Onions, broccoli, tea, and fruit all contain favonols, which are represented by the glycoside(s) quercetin and kaempferol [13]. Flavonols such as isorhamnetin quercetin and rhamnocitrin have hepatoprotective activity. Dietary favonols are bioavailable compounds with signifcant therapeutic benefts such as free radical scavenging activity, hepatoprotective activity, cardioprotective, antiviral, antibacterial, and antineoplastic activity, and the metabolization operation also results in compounds with astonishing bioactivities as well as the equivalent precursors. Te incorporation of these compounds in the individual diet is strongly advised because of their undeniable health-promoting qualities since they make excellent nutraceuticals and functional food ingredients. According to studies conducted in-vitro and in vivo, favonols alter the enzymatic potency of several molecular targets, including kinases, phospholipases, ATPases, lipoxygenases (LOX), cyclooxygenases (COX), and phosphodiesterases, which can be found in the three primary types of colon, breast, and liver cancer. Tis has an impact on the corresponding biochemical pathways. Tere is a wide spectrum of  Evidence-Based Complementary and Alternative Medicine antineoplastic properties in favonols: they control the cell cycle and reactive oxygen species (ROS)-scavenging enzyme activities, promote apoptosis, and autophagy and reduce the multiplication and encroaching of cancer cells [12,14].

3.2.
Flavones. Flavones and favonols share a similar structural makeup, although the OH (hydroxyl) group on the pyran ring C3 of favones is less [15]. Diferent biological actions, such as cardioprotective, anti-infammatory, antitumour, antioxidant, antiallergic, and hepatoprotective activity are demonstrated by favones and their synthetic derivatives [16,17]. Lutein and apigenin are the two favones that are most prevalent in plant food. In addition, they are abundant in celery, artichokes, parsley, grains, and celery. Various mono-and di-glycosides of apigenin, as well as orientin and iso-orientin, are also found in black and green tea [18]. Te electronic and molecular structures of parent favone and polymethoxylated favones were explored in the theoretical investigation. A chosen class of favonoids comprises substances found naturally in synthetic favone derivatives and citrus trees. Tey have a diversity of bioactivities both in vivo and in vitro, and they can also shield plants from ultraviolet radiation [19].

Iso-Flavonoids.
Tis class of favonoids is regarded as a group possessing a ring B linked at position C3 rather than C2 in the fundamental structure [20]. Although they only have a modest range among plants, they are primarily found in the leguminous family. Globally, the prime dietary origin of isofavones is mung bean, common bean, and soybean [21]. Black peas and green beans both contain certain isofavones, including daidzein, genistein, and glycitein, in very small amounts. Tere have also been reports of several isofavonoid subtypes in microorganisms [22]. In addition, isofavonoids can be altered through polymerization, hydroxylation, or methylation to form diferent isofavonoids such as isofavonols and isofavones [23]. Isofavonoids also have great promise for treating many disorders. Daidzein and genistein are commonly known as phytoestrogens because of their oestrogenic activity in various models of animals. Tey have antidiabetic, antioxidant, and also effective against Leishmania infantum, cytotoxicity against Hep G2 cell lines, and Leishmania amazonensis [24,25]. Isofavonoids are essential for preventing cataract development in diabetic and hypertensive animal models [26].

Flavanones and Chalcones.
All citrus fruits, including lemons, oranges, and grapefruit, often include favanones, another signifcant class of compounds, and examples of this group of favonoids include naringenin, eriodictyol, and hesperetin. Tey are also termed dihydro favones, having a saturated C ring; the double bond between positions 2 nd and 3 rd is saturated in the two subgroups of favonoids, unlike favones, which is the primary structural diference between them. Te quantity of favanones has dramatically increased over the previous 15 years. While the biosynthesis process for favonoids synthesized the secondary metabolite chalcones and its derivatives. Its chemical name is 1,3-diaryl-2-propen-1-one and consists of 2 aromatic rings linked by 3C atoms. Majorly chalcones found in nature are polyhydroxylated aromatic by nature [27]. Te potential of favanones to neutralize free radicals has been related to numerous health advantages. Citrus fruits have a bitter favour in both their juice and peel because of these substances. As a hypo-lipidemic, antioxidant, cholesterollowering, and anti-infammatory agent, citrus favonoids have noteworthy pharmacological efects [10]. Psoriasis can be treated with favanones, and favonoids reduce skin infammation. According to the previous study, favonoids having a favanone backbone were helpful for skin penetration [28].

Flavan-3-Ols, Flavanols, or Catechins.
Te supreme intricate group of favonoids is known as favan-3-ols or favanols. Tey do not possess a double bond on the 2 nd and 3 rd carbon, unlike other favonoids. Tey consist of simple monomers, including catechin and also its isomer epicatechin, as well as oligomers (which range from dimers to decamers), polymers (more than 10 parts), and other derived compounds including thearubigins and theafavins).
Proanthocyanidins or condensed tannins are other names for the polymers and oligomers of favan-3-ols. Te monomeric favan-3-ols' two chiral centres at 2 nd and 3 rd Carbon form 4 isomers for one and all degrees of B-ring hydroxylation, two of which, (1)-epicatechin and (2)-catechin, are widely distributed in the environment. Another isomer, including (2)-epiafzelechin, has a more restricted distribution. By altering the cell's redox homeostasis and preventing NF-κB activation, favan-3-ols are efective against infammatory disorders. Typically, they are believed to be benefcial ingredients in a range of drinks, supplemental, herbal medicines, and whole or processed foods. In addition, they have an impact on the food's astringency, bitterness, sourness, sweetness, colour formation, and sweetness [8,29]. Proanthocyanidin, which are oligomers of favan-3-ols, are thought to be good sources in malt and barley and are the predominant source of free radical scavenging potential [30]. When it refers to nuts, pecans, and hazelnuts are excellent sources of proanthocyanidins, whereas almonds, cashews, roasted peanuts, and pistachios are only modestly rich in the compound. Flavan-3-ols are also present in sufcient amounts in rosemary, mint, sage, dark chocolate, and dill [31].
3.6. Anthocyanins. Anthocyanins are phenolic grouprelated coloured, water-soluble pigments. Even though the O atom in ring C of the fundamental favonoid structure of anthocyanin has a positive charge, it is still regarded as one of the favonoids. It is sometimes referred to as the favylium ion (2-phenylchromenylium). Anthocyanin exists as a glycoside, whereas anthocyanidin is an aglycone. Delphinidin, peonidin, malvidin, petunidin, pelargonidin, and cyanidin are the anthocyanidins that are most frequently found in herbs. Te anthocyanins that give fruits and vegetables their blue, purple, and red hues are abundant in them. Currants, Evidence-Based Complementary and Alternative Medicine grapes, berries, and several tropical fruits have signifcant anthocyanin content. Edible vegetables with high anthocyanin concentrations include leafy vegetables with hues ranging from red to purple blue, roots, grains, and tubers. Cyanidin-3-glucoside, one of the anthocyanin pigments, is the main anthocyanin present in the majority of plants. Te colourful anthocyanin pigments have historically been used as a natural food colouring. Temperature, pH, structure, and light all have an impact on the colour and stability of these pigments. When the pH is raised, anthocyanins turn blue instead of red. While possessing a positive charge on the O atom of the ring C of the fundamental structure of favonoid, anthocyanin is still characterized as one of the favonoids. It is also known as 2-phenylchromenylium ion. As a phytopharmaceutical, choleretic agent, appetite stimulant, and for the treatment of numerous other disorders, it has traditionally been used in numerous ways. Substantial pharmaceutical or nutraceutical compounds are these colourful pigments. Te bioavailability of anthocyanin as a nutraceutical is essential for preserving health and preventing disease [32]. Te scientifc community has been interested in anthocyanins because of their anticancer, antimetastatic, and antioxidant potential [33]. According to twelve scientifc studies, anthocyanin is capable of reducing apoptosis, cholinergic dysfunction, synaptotoxicity, cognitive defcits, tau hyperphosphorylation, neuronal extracellular calcium, oxidative stress, and dysfunction amyloidogenic pathway in various models of Alzheimer's [34].

Flavonoid as a Hepatoprotective Agent
Flavonoids act as hepatoprotective agents by targeting different mechanisms. Te liver is particularly susceptible to attacks from reactive oxygen species, and it is also recognized as a vital regulator that contributes signifcantly to the development of liver illnesses with a high prevalence. Mostly liver diseases are caused by hazardous chemical exposure such as carbon tetrachloride, D-galactosamine, peroxidized oil, chlorinated hydrocarbon, afatoxin, dimethylnitrosamine, thioacetamide, viral infections like Hepatitis AeE, autoimmune diseases, high doses of drug use (such as acetaminophen, and antibiotics), and excessive alcohol consumption are the main causes of hepatic diseases [14,36]. Te most prevalent chronic liver disease, known as nonalcoholic fatty liver disease (NAFLD), afects a signifcant section of the global population. NAFLD is characterized by the deposition of fat (more than 5%) in the hepatocytes in the absence of moderate alcohol consumption or additional factors of liver disease, such as autoimmune diseases, viral hepatitis, and drug-induced disorders. Te most frequent causes of chronic hepatic disease are alcohol-associated liver disease and nonalcoholic fatty liver diseases. Tey both seem to have steatohepatitis, cirrhosis, fatty liver/steatosis, hepatocellular carcinoma, and fbrosis, but there are some variances as well. In contrast, ALD is more likely than NAFLD to have infammatory cell infltration, venous sclerosis, and venous or intravenous fbrosis. Nonalcoholic fatty liver or NAFL (simple steatosis) and nonalcoholic steatohepatitis (NASH) are on the NAFLD spectrum. NASH can proceed to hepatocellular cancer and cirrhosis, both of which are diseases of the liver and are marked by hepatocyte enlargement, infammation, and diferent rate of fbrosis. Although the exact aetiology of NAFLD is unknown, new research has indicated that oxidative damage brought on by hepatic steatosis and insulin resistance could be substantial contributors to the condition and may be crucial in the development of NASH. A discrepancy between the frequency of triglyceride infow and the degree of clearance leads to fat build-up in the liver. Enhanced lipolysis in peripheral tissues is the primary cause of the majority of free fatty acids (FFAs) accumulated as triglycerides. Hyperinsulinemia, dietary fat, and enhanced lipogenesis all contribute to increased lipolysis as a result of these factors. Lipid peroxidation, oxidative stress, mitochondrial dysfunction, and infammation in hepatic tissues can arise from all of this. Due to metabolic abnormalities caused by fat deposition in the hepatic tissues, which also leads to increased mitochondrial reactive oxygen species generation and endoplasmic reticulum stress which cause the onset of infammatory steatohepatitis. NASH is an infammatory condition that primarily activates Kufer cells (KCs) and astrocytes, which promotes the build-up of collagen and causes liver fbrosis [36]. Te primary regulator in numerous experimental hepatic injury models, particularly CCl 4 -induced hepatitis, is iNOS, COX-2, and TNF-α are the proinfammatory genes that are induced by an early increase in TNF-α levels [37]. Te fve favonoids such as luteolin, Hesperetin, 3′,4′-dimethoxy hesperetin, chrysin, and apigenin help in improved superoxide dismutase, catalase, total antioxidant capacity, decreased nitric oxide synthase, nuclear factor erythroid-derived 2-related factor, and heme-oxygenase-1. Tey hindered the NF-κB signalling pathway's phosphorylation of IκBα, NF-κB, and IKK, along with the blood serum elevation of proinfammatory cytokines and alanine and aspartate aminotransferase (ALT and AST). In addition, fve favonoids reduced caspase family protein expression and raised the Bcl-2/Bax ratio to prevent hepatocyte apoptosis. Tese favonoids appear to protect the liver from acute hepatic injury brought on by D-GalN/ LPS [38].

Quercetin.
Tere are many red, green, and purplehued fruits and vegetables that contain quercetin, including red onion, green leafy vegetables, kidney beans, apples, red grapes, evergreen tea, and apple cider vinegar. However, quercetin is the compound that is most frequently studied [42,43]. Te biological activity of quercetin, which includes, antioxidant, antiviral, and anti-infammatory properties, has been demonstrated to have a wide range of biological applications, involving liver protection. It can link with transition metal ions and neutralize free radicals. Glutathione production within the body may be infuenced by quercetin, which is involved in the process by which SOD converts oxygen into H 2 O 2 and subsequently catalysis the breakdown of H 2 O 2 into H 2 O. GSH-Px (glutathione peroxidase) can precisely catalyze the reaction between GSH and H 2 O 2 , minimizing the production of peroxides and preserving regular physiological processes [44,45]. Quercetin can be efective in cholestatic liver injury. Platelets in cholestatic hepatic diseases are depleted, lose platelet granules and are unable to perform their function. Te pathophysiology of platelets hypofunction in the bile duct ligation model is infuenced by the expression of the ORAI-1 gene. Quercetin enhances store-operated calcium entry mediated by ORAI-1 and may be a promising therapeutic target in hemostatic diseases [46]. Quercetin can be employed as a hepatoprotective drug since it can efectively prevent t-BHP-induced hepatic injury in mice. Te preventive advantages towards acute hepatic injury could be attributed to the improved free radical neutralizing action, reduction in peroxidation of lipids, and enhanced antioxidant capacity [47]. Numerous advantages and therapeutic qualities of quercetin have been noted, including hepatoprotective efcacy against triptolide-induced hepatic injury. Before the administration of TP (Triptolide), treatment with Quercetin (20000, 50000, and 80000 μg/kg) reversed the changes caused by TP in a dosage range, demonstrating the ability of quercetin to prevent Triptolideinduced liver damage. One pathway driving this response was the balance between T17 and Treg cells shifting from T17 dominance to Treg dominance. Te retinoid-related orphan receptor-t, proinfammatory cytokines interleukin-6 and interleukin-17 as well as the T17 transcription factor, which was controlled by the Tim-3, and TLR4-MyD88-NF-κB signalling pathway, have also been substantially downregulated by quercetin [48]. Tere are various quercetin derivatives with hepatoprotective efects, for example, hyperoside. Hyperoside is a favonol glycoside with yellow solids and quercetin as its aglycon is called hyperoside and also referred to as quercetin 3-O-β-D-galactopyranoside. It has the potential to operate antioxidant activity to prevent hepatic oxidative stress in liver diseases. Te hydrogen peroxide-induced intracellular oxidative damage in HepG2 cell lines demonstrated the antioxidative efects of hyperoside [49]. Notably, in the presence of hyperoside, the modulation of hepatic mitogen-activated protein kinase, heme-oxygenase-1, nuclear factor erythroid 2-related factor 2, and may augment antiapoptosis and ultimately prevent chemically-driven hepatotoxicity in mice [50]. It was discovered that hyperoside, at a dose of 60000 μg/kg, can ameliorate the liver from oxidative damage and control metabolites and enzymes related to glutathione by blocking CYP4502E1. In overview, hyperoside inhibits the growth of hepatic tumour cells, arrests the cell cycle, and signifcantly reduces the expression of QKI (quaking), the activity of the Yin Yang 1(YY1) complex, and the proliferation and metastasis of hepatic tumour cells [51].

Hesperetin.
Te hesperidin metabolite hesperetin-7glucoside is more bioavailable than hesperidin itself. Hesperetin (HSP) is a favonoid that occurs naturally and has a variety of pharmacological properties. It is most frequently found in citrus fruits like grapefruit, lemons, tangerines, and sweet oranges. Hesperidin can be found in numerous fruits and vegetables, as well as other herbal preparations, besides lemons and sweet oranges. Citrus aurantium, Citrus sinensis, and Citrus limon are where it is most frequently found. On a wide scale, HSP has also been taken out of Citrus aurantifolia callus cultures. Mandarin and citrus fruit peels have high HSP concentrations [52][53][54]. 7-O-(2-(propylamino)-2oxoethyl)-hesperetin, a hesperetin derivative (HD-4d) demonstrated anti-infammatory and hepatoprotective effects on alcohol-induced hepatic injury in C57BL/6J mice, as well as observable anti-infammatory efects in ethanol and lipopolysaccharide-induced RAW264.7 cells. In addition, we found that HD-4d downregulates the expression of infammatory factors via increasing NLRP12 both in vivo and in vitro. Additional research revealed that HD-4d increased NLRP12, which in turn prevented the phosphorylation and activation of the p65 proteins. In conclusion, HD-4d stimulated NLRP12 through the NF-κB pathway to lessen liver damage and infammatory response [55]. In mice, acetaminophen (APAP)-induced acute liver damage was lessened by hesperetin. Hesperetin dramatically reduced the liver hepatocytes apoptosis caused by APAP, according to apoptosis analysis using terminal deoxynucleotidyl transferase dUTP Nick end labelling (TUNEL). Similarly, the activity of caspase 3 revealed that acetaminophen overdose considerably raised liver caspase 3 activity; however, dosedependent hesperetin suppressed the raised in caspase 3 in the liver of mice subjected to a toxic dose of acetaminophen [56]. A monomer molecule produced from hesperetin called hesperetin derivative (HD-16) with a dose of (25000, 50000, and 100000 μg/kg) showed hepatoprotective and antiinfammatory efects on a variety of hepatic disorders. On mouse hepatic fbrosis brought on by carbon tetrachloride as well as on LX-2 cells (human immortalized HSCs) triggered by transforming growth factor beta 1 (TGF-β1), HD-16 demonstrated an antifbrotic efect both in-vivo and in-vitro. Te AMPK/SIRT3 pathways were regulated by HD-16 to exert an antifbrotic efect. Te extent of damage and infammation in the fbrosis of mouse liver caused by CCl 4 was reduced, according to pharmacodynamic studies, using HD-16 [57].

Apigenin.
Apigenin (APG) is a favone belonging to the superfamily of favonoids engaged with a keto group at the 4 th carbon and substituted by hydroxy groups at the 4′, 5 th , and 7 th positions. It is a naturally existing polyphenol that is produced and retained in a diversity of fruits, vegetables, and sanitary plants including celery, vine spinach, Evidence-Based Complementary and Alternative Medicine chamomile, artichokes, propolis, oregano, and parsley, and it is found in the dried form of plants. Te highest concentration of apigenin, 45.035 µg/g, has been found in dried parsley. Additional sources of apigenin include celery seeds, which have 786.5 µg/g, dried chamomile fowers, which have 300-5000 µg/g, vine spinach, which has 622 µg/g, and Chinese celery, which has 240.2 µg/g [58,59]. In recent hepatoprotective activity, apigenin was given at a dosage of 0.1-0.2 g/kg P.O for 1 week, which lessened the concentration of the enzyme ALT and AST and decreased the seriousness of hepatic failure. It is signifcant to mention that pretreatment of apigenin increased the liver's manifestation of the proteins PPARc, and Nrf-2 as well as the activities of catalase, glutathione reductase, superoxide dismutase, and glutathione S-transferase while decreasing the levels of hepatic NF-κB. Apigenin was demonstrated to have a variety of biological efects, notably anti-infammatory and antioxidant characteristics as well as a protective impact counter to D-galactosamine/lipopolysaccharide-induced hepatic lesion in mice. Its mode of action may be based on rises in Nrf-2mediated antioxidant enzymes and modulation of NF-κB/ PPARc-mediated infammation [40]. In addition, apigenin also ameliorates edifenphos (EDF)-induced liver toxicity by protecting hepatic cells and has a mitigating efect on mitochondrial deterioration. When EDF was taken orally, the intracellular antioxidant system had been disrupted, which led to the generation of intracellular reactive oxygen species. EDF, on the other hand, encourages harmful consequences such as DNA damage, oxidative stress, decreased potential of mitochondrial membrane, generation of reactive oxygen species, stimulation of caspase 3/9 action, and the development of histo-renal histopathological abnormalities. By directly scavenging free radicals or exerting antioxidant activity, APG reduced the apoptosis and oxidative damage caused by EDF. Apigenin is an efcient dietary antioxidant that ameliorates EDF-induced oxidative stress [60].

Epicatechin.
A monomeric favanol termed epicatechin (EC) has fve hydroxyl groups substituted at positions 3, 3′, 4′, 5, and 7. It is a polyphenol and catechin by nature. It is a secondary metabolite ubiquitously present in plants and fruits such as cocoa powder, chocolate, teas, and grapes in notable concentrations. Epicatechin is an antioxidant with hepatoprotective, anti-infammatory, antiobesity, and anticancer efects. Trough the suppression of apoptosis and infammation, epicatechin seems to have a protective efect on the liver of mice with acute hepatic lesions brought on by APAP. By blocking TNF-α, interleukin-1b, interleukin-6, and additionally infammatory reaction, EC reduced immunological response and pathological damage. EC also inhibited Bax and caspase 3, subsidence of the pathway of mitochondrial apoptosis, raised in Bcl-2 to improve its antiapoptotic activity and reduced hepatic damage [41]. A dosage of 0.02-0.04 g/kg of epicatechin also reduced the severity of the hepatic sinusoidal obstruction syndrome brought on by monocrotaline by declining liver infammation and oxidative stress. Rats treated with EC had improved nuclear translocation of Nrf-2 and raised the output of its downstream antioxidant genes [61]. In hamsters, an amoebic liver abscess was successfully treated with epicatechin. 1.106 Entamoeba histolytica trophozoites were administered intraperitoneally to the Syrian golden hamster. Te EC dose (10 mg/100 g, I.P.) reduced the advancement of the liver abscess by modifying the infuence of the infammatory cytokines including interleukin-10, interleukin-1, TNF-α and aids in the removal of trophozoites to repair the liver [62].

Malvidin.
A naturally occurring favonoid substance included in plant foods is malvidin, one of the anthocyanins. An O-methylated anthocyanin derivative is a malvidin. It is a fundamental plant pigment, and its glycoside is very prevalent. Previous research showed that malvidin had a diversity of pharmacological properties, involving antioxidant, anticarcinogenic, and anti-infammatory properties. Previous literature revealed that malvidin can be efective against LPS-induced acute hepatic damage in mice. Malvidin may be able to inhibit NLRP3 infammasome activation, block proinfammatory cytokines, and mediators and reduce oxidative stress by up-regulation of the Nrf2 signalling cascade. It may also be able to attenuate autophagy and hepatic apoptosis. Tese are the main mechanisms by which malvidin may be able to reduce acute liver injury caused by LPS [39]. Malvidin-3-galactoside, often known as MV-3-gal, is the main anthocyanin monomer present in blueberries. Tis substance has a strong antioncogenesis efect on various organs, such as the liver. MV-3-gal was given to Huh-7 hepatocellular carcinoma (HCC) cell lines, which decreased cell division, stop cell cycle, and colony formation depending on the dose via inhibiting the MAPK, MMP, and PTEN/Akt pathways [63].
Many exogenous and endogenous factors induce oxidative stress and cause hepatic diseases by various means from which oxidative stress and infammation are highly concerned as they are the main targets of most favonoids. For better understanding, an illustration of the induction of liver diseases by various factors via oxidative stress and infammation along with the mechanism of action favonoids as hepatoprotective agents, by inhibiting oxidative stress and infammation is shown in Figure 1.
Tere are diferent mechanism of action of various favonoids as a result of in vivo and in vitro research studies have shown in Table 3.

Genistein.
Genistein is an isofavone that is primarily found in legumes such as fava beans, soybeans, kudzu, lupine, and Psoralea. Te chemical name for genistein is 5,7dihydroxy-3-(4-hydroxyphenyl) chromen-4-one [67]. A total of 15 carbons make up genistein, which is divided into two aromatic rings A and B, as well as one other carbon pyran ring (C), which contains the nucleus 3-phenylchromen-4-one. Positions two and three of the genistein basic carbon skeleton have a double bond. In addition, it has 3 more hydroxyl groups at positions 5 th , and 7 th of ring A and the 4 th position of ring B and also has an oxo group at position 4 of ring C [68]. It was demonstrated to have displayed a broad range of pharmacological activities, such as anti-infammatory, anticancer, antiproliferative, antioxidant, and protection against osteoporosis, and a reduction in cardiovascular-related diseases. It is an organic substance that resembles mammalian estrogens in terms of chemical structure. Numerous in-vivo and in-vitro research on the anti-infammatory potential of genistein have been conducted in the past. Te potent anti-infammatory activity of genistein is achieved by blocking several signalling pathways, including those involving prostaglandins, nuclear factor kappa-B, proinfammatory cytokines, induced nitric oxide synthase, and reactive oxygen species [69]. In a rat model of chronic liver injury, hepatic damage, and hepatic fbrosis caused by D-GalN, the hepatoprotective efect of genistein was assessed at a dose of (250 mg/kg BW) two times a week for three months. Genistein (5 mg/kg BW) was administered intragastrically as a cotreatment once a day for 12 weeks, and the functional impairment that resulted was signifcant amelioration. Tis improvement included inhibition of activation of reduced expression of SMA (alpha-smooth actin) and deposition of the collagen matrix, as well as a rise in aspartate transaminase, serum alanine transaminase and also leads to elevated expression of hepatic Smad7 [64]. Another study found that supplementing alongside 150 mg/ kg of genistein reduced the rise in ALT (alanine transaminase), AST (aspartate transaminase) activity, the decline in GSH (glutathione) level, and the amount of hepatic malondialdehyde in response to an inappropriate dose of acetaminophen [70]. Acetaminophen is a broadly used analgesic and antipyretic [71]. It is safe when taken at the appropriate dose, but an inappropriate dose of APAP (acetaminophen) can cause serious liver damage, which is one of the major factors for acute liver injury-related mortality [72]. At therapeutic concentrations, APAP is mostly metabolized by the enzymes of the UDPglucuronosyltransferase 1A subfamily and sulfotransferase into glucuronide and sulfate conjugates, respectively. NAPQI (N-acetyl-p-benzoquinone imine), a lethal and extremely toxic metabolite is generated when a tiny amount is oxidized by the CYP family, particularly CYP2E1. By covalently joining with glutathione to generate a nonreactive metabolite, small levels of the metabolite are efectively detoxifed and eliminated from the body by the liver. However, the glucuronidation and sulfation pathways saturate within 1 to 2 hours of an APAP overdose. Ten, while drug consumption is too high, CYP2E1 produces NAPQI. Large amounts of NAPQI cause the liver's GSH to be rapidly depleted and covalently bind to mitochondrial proteins to produce reactive oxygen species, which in turn leads to hepatocellular necrosis and harsh centrilobular hepatotoxicity [73]. Te sirtuins family includes SIRT1, which has been discovered as a NAD-dependent class 3 histone/protein deacetylase [74]. Widespread expression of SIRT1 and its role as a potent modulator on a variety of biochemical activities were becoming clearer, according to mounting data such as stress sensors [75], in metabolism [76], in cell survival [77], and autophagy [78].

Daidzein.
Daidzein is a compound with a low molecular weight that is synthesized from isofavone, an isomer of favone. Daidzein is a chemical compound that belongs to the class of 7-hydroxyisofavones, which are 7-hydroxyisofavones with an extended hydroxy group at position 4′. It is a dormant form of the tyrosine kinase inhibitor genistein. It is a phytoestrogen and a regulator of

Cholestatic liver injury in rats
Increase ORAI-1 gene expression Increased ORAI-1 gene-mediated SOCE leads to improved platelet function in the bile duct ligation model of cholestasis in rats [46] t-BHP induced acute liver damage in mice Scavenge free radical, increase in GSH, CAT, SOD, and decrease in serum enzyme markers i.e., ALT, AST Trough an increase in antioxidant activity, quercetin neutralizes free radicals and lowers oxidative stress [47] Hesperetin Both ethanol and lipopolysaccharide-induced RAW264.7 cells and alcohol induce mouse liver Enhance NLRP12 in two in vivo and in-vitro models which lowers infammatory factors and prevents expression and phosphorylation of P65 proteins Hesperetin stimulated NLRP12 through NF-κB to lessen infammation and liver damage [55] (HD-16) hesperetin derivative Carbon tetrachloride-induced liver fbrosis and liver infammation α-SMA, Col3α1, TIMP-1, and Col1α1 expression were inhibited in TGF-1-stimulated LX-2 cells, and activating the SIRT3/AMPK pathway also reduced carbon tetrachloride-induced liver infammation and fbrosis Hesperetin derivative-16 attenuated carbon tetrachloride-induced liver fbrosis and infammation [57] Apigenin D-galactosamine/LPS-induced liver injury Decrease in ALT, and AST, and raised the activity of superoxide dismutase, glutathione reductase, catalase, as well as Nrf-2 and PPARc protein expression, and decrease in hepatic TNF-α, and NF-κB expression Apigenin may ameliorate D-GalN/LPS-induced liver injury in mice by increased Nrf-2-mediated antioxidative enzyme and modulate the PPARc/ NF-κB mediated expression [40] Edifenphos-induced toxicity by modulating ROSmediated mitochondrial dysfunction, oxidative stress, and caspase signal pathway in rat liver and kidney Apigenin ameliorated the edifenphos-induced oxidative damage via antioxidant activity or by scavenging free radicals Apigenin reduces oxidative stress-induced damage in the liver [60] Epicatechin Acetaminophen-induced acute hepatic injury of mice Inhibit TNF-α, IL-6, and IL-1, reduce the pathway of mitochondrial apoptosis, increase Bcl-2 to amplify the antiapoptotic response, and inhibit bax caspase-3 In mice, epicatechin improves the antiapoptotic efect while decreasing the acute liver injury brought on by APAP [41] Hepatic sinusoidal obstruction syndrome by inhibiting liver infammatory and oxidative injury In rats, epicatechin increased Nrf-2 translocation and the production of its downstream antioxidant gene At a dosage of 0.02-0.04 g/kg, epicatechin reduced hepatic sinusoidal syndrome by reducing hepatic infammation and oxidative stress [61] Malvidin Lipopolysaccharide-induced acute liver injury Reduce oxidative damage by activating the Nrf2 signalling cascade, reduce infammation through blocking proinfammatory cytokines and mediators as well as NLRP3 infammasome activity resulting attenuate apoptosis, and autophagy Malvidin attenuated hepatocyte apoptosis and autophagy via an upregulating Nrf2 signalling pathway [39] 10 Evidence-Based Complementary and Alternative Medicine Evidence-Based Complementary and Alternative Medicine

Pharmacokinetics, Advantages, and Limitations of Flavonoids against Liver Diseases
In the case of liver damage, the pharmacokinetics of favonoids may be altered due to changes in liver metabolism and clearance. For example, some studies have suggested that favonoids may accumulate in the liver during liver disease, potentially leading to higher local concentrations and increased efcacy. On the other hand, other studies have reported decreased favonoid bioavailability in patients with liver disease, which may limit their therapeutic potential. Flavonoids have shown countless health benefts, their low bioavailability has been a concern. Phase 2 metabolism is known to afect the bioavailability of favonoids in humans. Usually, most favonoids undergo sulfation, methylation, and glucuronidation in the small intestine and liver, and conjugated metabolites can be found in plasma after favonoid ingestion. Despite the bioactivity expressed in diferent in vitro systems, the bioavailability of favonoids would be a determinant factor of their bioactivity in vivo studies. Terefore, enhancement of bioavailability would be of utmost importance to exert health efects in, in vivo approach. In this regard, numerous attempts have been made to increase bioavailability such as improving intestinal absorption via the use of absorption enhancers, novel delivery systems, improving metabolic stability, and changing the site of absorption from the large intestine to the small intestine [82].
Flavonoids have been reported to have an excellent safety profle (no toxicity at up to 140 g/day), with no known signifcant adverse efects. Te enthusiasm for favonoids expressed by the public has sometimes overlooked their toxicity and also consumed the favonoids exceeding the body's requirements. Te consumption of a higher dose of favonoids may lead to dysfunctioning in the multiorgan system. One of these approaches involves the use of kinetically stable nanoemulsion technology, where the lipophilic favonoids can be prepared as emulsions consisting of extremely small particle sizes (<200 nm). Te emulsifed favonoids are released slowly over time, allowing for a higher surface area for absorption, ultimately improving their absorption and bioavailability after oral administration. Te advantages of using favonoids in the treatment of liver diseases include their potential to reduce infammation, oxidative stress, and fbrosis, all of which are common features of liver damage. In addition, favonoids have been shown to have hepatoprotective efects, protecting liver cells from damage and promoting liver regeneration [83].
However, there are also limitations to the use of favonoids in liver disease treatment. As mentioned, their low bioavailability can limit their efectiveness, and their metabolism in the liver may be altered in patients with liver damage. Flavonoids may also interact with other medications or supplements, potentially leading to adverse efects. Furthermore, the optimal dosing and duration of favonoid supplementation for liver disease treatment are not well established, and more research is needed to determine their safety and efcacy in this context [84].
All the studies have revealed the favonoids as hepatoprotective but some authentic information is required for their efcacy, dose, and potential for safe use of the favonoids. For the same many clinical trials have been done and some are currently going on. Te diferent favonoids mentioned in this review were found to be efective against diferent liver-associated diseases and several studies of hepatoprotective activity of these in humans are clinically investigated an overview of important research on clinical trials of favonoids for hepatoprotection is shown in Table 4.

. Summary and Conclusion
Due to an increase in cases, liver disease or hepatotoxicity is a popular subject of growing concern. According to the above-given literature, liver conditions can be developed due to long-term infammation. Due to antioxidant, hepatoprotective, and anti-infammatory properties, dietary favonoids are important in the development and mitigation of pathological conditions. Recent clinical studies of six major hepatoprotective favonoids have confrmed benefcial efects on liver diseases by inhibiting infammation by lowering thresholds of several cytokines including interleukin-1, interleukin-6, and TNF-α, decreasing its main mediator prostaglandins, COX-2, ROS, and preventing the NF-κB/P65, IKK, and IKBα in the NF-κB signalling. According to the research, favonoids also prevent apoptosis of the liver by boosting the Bcl-2/Bax ratio and inhibiting the previously mentioned Caspase family protein. Hence favonoids in diet could be a good option for preventing hepatic conditions. However, precise, dose-dependent clinical trials are still required in the future to evaluate the hepatoprotective potential of favonoids to treat hepatic disorders with a safe approach.

Data Availability
Te supporting literature, data, and other necessary information used to support the fndings of this study are available from the corresponding author upon request.

Conflicts of Interest
Te authors declare that they have no conficts of interest.