Role of medicinal plants and their chemical constituents in ameliorating the cause for non-alcoholic fatty liver disorder—A review

Non-alcoholic fatty liver disease (NAFLD), a silent epidemic, is one of the global threats linked with various concerns that can lead to chronic liver diseases. It is the most common liver disorder in Asian and Western countries, a continuum of ailments ranging from simple steatosis to steatohepatitis, cirrhosis, and liver carcinoma. Youngsters are lured with sugary beverages and other kinds of junk foods that may affect their metabolism due to their close association with obese, type 2 diabetes mellitus. The articles were collected from various online search engines, viz., Google Scholar, PubMed, and Science Direct. Keyword combinations undertaken for the searches were NAFLD, molecular mechanism or epidemiology, dietary factors, or herbal plants. The unmet criteria of the disease should be recognized as earlier as possible to meet the required demands to maintain a healthy lifestyle. However, there are no solid evident studies for the pathogenesis and progression of NAFLD. Insulin resistance and white adipose tissue are playing a vital role in the advancement of steatosis. Herbal plants have been widely utilized to overcome the allopathic side effects and bring a permanent solution for various diseases. The primary purpose of this study is to educate about phytoconstituent’s role, such as flavonoid, saponin, polyphenol, terpenoid, and alkaloid, in ameliorating non-alcoholic steatohepatitis. Herbal plants are utilized as it is well said, “Nature is our best Physician,” it is essential to understand the presence of phytomolecule and their secondary metabolites that may be useful in treating NAFLD-associated disorders.


INTRODUCTION
Non-alcoholic fatty liver disease (NAFLD) is described as excessive fat accumulation in the liver cell without alcohol intake. It can also be caused due to viral hepatitis or druginduced autoimmune disease (Marcuccilli and Chonchol, 2016). These secondary causes include medication side effects, specific endocrine conditions, and hepatitis C virus infection. The severity of the disease ranges from mild steatosis to non-alcoholic steatohepatitis (NASH), which can further progress to cirrhosis and hepatocellular carcinoma (HCC) (Lau and Wong, 2018). NAFLD can also be called metabolic-associated fatty liver disorder due to its close association with obese, type 2 diabetes mellitus (T2DM) reported as "Metabolic Syndrome" (MetS). The absence of appropriate and sensitive non-invasive testing for NAFLD makes accurate diagnosis difficult. When the level of a liver enzyme rises in overweight or obese people with no identified cause of liver disease, or when imaging studies suggest hepatic steatosis, it is commonly diagnosed on a presumptive basis (Salt, 2004).
The prevalence of NAFLD globally is estimated to be 25% (Mundi et al., 2020). NAFLD patients mostly remain asymptomatic, and they are diagnosed at the fibrosis or cirrhosis *Corresponding Author Ilango K,Department of Pharmaceutical Chemistry,SRM College of Pharmacy,SRM Institute of Science and Technology,Chengalpattu (Dt),Tamil Nadu,ilangok67 @ gmail.com stage. People with central obesity are more likely to have NAFLD, including insulin resistance (IR) or T2DM, hypertension, excessive abdominal fat, and dyslipidemia. This group of chronic diseases is associated with an increased risk of cardiovascular disease and is referred to as the "MetS." Nearly 70% to 80% of patients have MetS or IR. Some patients experience vague right upper quadrant pain, high alanine aminotransferase (ALT), and hepatomegaly as risk factors for MetS (Hossain et al., 2016). It is also thought to be a hepatic symptom of MetS (Gottlieb and Canbay, 2019). If untreated, NAFLD progresses to hepatic inflammation and early fibrosis, indicating the onset of NASH. End-stage NAFLD symptoms include liver inflammation, fibrosis, cirrhosis, and increased risk of HCC (Eng and Estall, 2021). The present review is carried out by compiling literature from 1990 to 2021 concerning the traditional uses, phytochemistry, pharmacological activities, and toxicological aspects of various herbal plants and their role in treating NAFLD. Pieces of literature were collected from multiple online search engines, viz. Google Scholar, PubMed, Semantic Scholar, and Science Direct. Keyword combinations undertaken for the searches were NAFLD, molecular mechanism or epidemiology, dietary factors, or herbal plants.

Pathogenesis of NAFLD
In white adipose tissue (WAT), impaired insulin signaling raises lipolysis that generates fatty acid (FA). The results in substrate overload and further increased hepatic IR, with enhanced de novo lipogenesis as well as triglycerides (TG) accumulation (Buzzetti et al., 2016). Around 60% of FA for hepatic TG accumulation in NAFLD patients is derived from WAT-generated FA. 15% obtained from the diet and 25% from increased de novo lipogenesis, which is controlled through carbohydrate response element-binding protein and peroxisome proliferator-activated receptor δ (PPAR δ) (Buzzetti et al., 2014).
According to the two-hit theory, NAFLD consists of two stages of liver injury, such as intrahepatic lipid build-up and inflammatory development to NASH. During the first hepatic theory, fructose metabolism elevates intrahepatic lipid and de novo lipogenesis which inhibits mitochondrial β-oxidation of long-chain FAs. According to the second hit theory, fructose generates reactive oxygen species (ROS) that must be quenched by liver anti-oxidants and promotes protein fructosylation due to its five-membered furanose ring molecular instability. Many persons with NASH have vitamin deficiencies and a lack of antioxidant capacity to inhibit the formation of ROS, resulting in necroinflammation shown in Figure 1  .

HERBAL PLANTS IN NAFLD
Plants with active ingredients, pharmacological and toxicological effects, and their involvement in reducing the etiology of fatty liver disease are represented in Tables 1 and 3.

Phyllanthus niruri Linn.
Phyllanthus niruri is a herbal plant inhabited in Southeast Asian countries of the family Phyllanthaceae. It can treat numerous liver disorders, especially hepatitis and jaundice. Current studies show that it exhibits hepatoprotective properties on hepatitis-induced rats and is abundant in phenolic compounds and flavonoids, which is essential for a substantial anti-oxidant property. It will lower fat accumulation in the liver by lowering serum FA, decreasing IR, inhibiting α-glucosidase, cholesterol micellization, and pancreatic lipase that leads to a low amount of free fatty acid (FFA) and glucose which results in a de novo lipogenesis process with less fat accumulation in the liver. It minimizes hepatic fibrosis by reducing Malondialdehyde which is responsible for stimulating the hepatic stellate cell (Zarzour et al., 2017).
Phyllanthus niruri reveals its antiangiogenic effect against NAFLD. Additionally, it regulates adipocytokine secretion by improving insulin signaling inside the liver, which leads to lowering of fat accumulation as well as inflammation and down-regulation of [solute carrier family 10 (sodium/bile acid cotransporter) member 2] (SLC10A2), PPARγ and collagen alpha type I genes (Zarzour et al., 2018).

Phyllanthus emblica Linn.
The fruit of P. emblica, a member of the Phyllanthaceae family shows a variety of biological activities such as antiinflammatory, anti-oxidative, anti-microbial, hypolipidemic, and hepatoprotective activities. It is also observed that the fruit exhibits a hepatoprotective effect exerted by ellagic acid, flavonoids, gallic acid, vitamin C, and it could be linked to antioxidant and anti-inflammatory activities (Kirschweng et al., 2018). Some observation shows that water extract of P. emblica (WEPE) minimizes adipose tissue weights of peritoneal and epididymal fat. This helps ameliorate steatosis in the liver of highfat diet (HFD) induced rats, increase anti-oxidant enzyme activity and deplete lipid peroxidation. Thus, WEPE possibly shortens the further formation of NASH (Tung et al., 2018). WEPE helps ameliorate steatosis in the liver of HFD induced rats by increasing PPAR-α in the liver. It is also observed that in the liver tissues, the WEPE fruit decreases the messenger ribonucleic acid (mRNA) of sterol regulatory element-binding protein -1c (SREBP-1c), and in peritoneal fat pads of HFD-induced rats, it enhances the mRNA of adiponectin (Huang et al., 2017).

Phyllanthus urinaria Linn.
Phyllanthus urinaria, a member of the Phyllanthaceae family is found to have minimized necroinflammation and hepatic steatosis but has never been tested in NASH patients. In NASH patients, it is better to enhance liver histology compared with placebo. It is also found to alleviate oxidative stress and liver fat in NASH patients. It also suppresses c-Jun N-terminal kinase (JNK), cytochrome P450-2E1 (CYP2E1), interleukin-6 (IL-6), nuclear factor-kappa B (NFκB), hepatic lipid peroxides, tumor necrosis factor-α (TNF-α). It decreases the transcriptional activity of cytosine-cytosine-adenosine-adenosine-thymidine (CCAAT) and intensifies lipolytic CYP450 expression (Wong et al., 2013).

Allium sativum Linn.
Garlic is utilized as a medicinal plant in many cultures. It is a member of the Amaryllidaceae family and contains a variety of bioactive chemicals, including diallyl disulfide, S-allyl cysteine, S-methyl cysteine sulfoxide, allicin, ajoene, and SAC sulfoxide. It is also observed that regular garlic intake alleviates cancer and cardiovascular diseases. Several studies show that garlic consumption has a beneficial effect on obesity and IR, identified as a critical driver of NAFLD development. The impact of garlic on dyslipidemia (which is recognized as a significant risk factor of NAFLD) is due to increased adiponectin levels, reducing the enzyme activity involved in liver fat production, lowering intestinal absorption of TGs (Sangouni et al., 2020).

Myrica rubra (Lour.) Siebold & Zucc
Bayberry is a subtropical tree found in Southeast Asian countries that belongs to the Myricaceae family. It contains a lot of anthocyanins and phenolic acids such as sinapic, ferulic, caffeic acid, and salicylic acid. Their study suggested that specific pathological conditions such as inflammation, oxidative stress, liver steatosis has improved in experimental NASH. Bayberries are high in polyphenols, which function as an anti-inflammatory and anti-oxidant. It is having the capacity to deplete apoptosis in young individuals, lowers plasma biomarkers, and is characterized by oxidative stress and reduced inflammation. Thus, bayberry can prevent and treat the complications formed at the initial stage of NAFLD .

Curcuma longa Linn.
Curcuma longa, also known as turmeric, is a perennial herb in the family of Zingiberaceae. In Asian cuisine, turmeric is widely used as curry powder and traditionally used as a home remedy for various ailments. Curcumin exhibits a polyphenol structure and is used as renoprotective, anti-oxidant, anti-cancer, and immunomodulatory. It inhibits the synthesis of fatty liver and the development of some unsaturated fatty liver acids such as oleic acid, stearic acid, and linoleic acid; this might help ameliorate hepatic steatosis and inhabits FAs liver disease development. It also enhances oxidative stress levels and helps prevent NAFLD by reducing ROS production and preventing liver damage in steatohepatitis through decreasing cytosolic and nuclear translocation of high mobility group box 1 and NFκB as well as inducing PPAR-γ (Mansour-Ghanaei et al., 2019).
Curcumin also exhibits anti-neoplastic, antiinflammatory, and anti-bacterial properties (Ghosh, 2019). According to the findings of their study, short-term curcumin supplementation enhances hepatic transaminase levels in NAFLD patients (Panahi et al., 2017). In NASH mice, it prevents the O-GlcNAcylation pathway, which leads to anti-oxidant responses (Lee et al., 2019). Intake of this supplementation improves the glycemic and lipid index (Rahmani et al., 2016).
It is observed that curcumin can treat NAFLD mice induced with a high-fat high fructose diet by enhancing the metabolism of bile acids which is associated with nuclear erythroid 2-related factor 2 (Nrf2)/farnesoid X receptor (FXR)/Liver X receptor alpha pathway regulation and by preventing hepatic lipogenesis. It effectively restores the metabolic capability of the fatty liver by reversing the expression of CYP7A and CYP3A (Yan et al., 2018a(Yan et al., , 2018b.

Silybum marianum (Linn.) Gaertn
Silymarin is a milk thistle plant extract from the Asteraceaea family that has been used for centuries as a traditional herbal remedy for liver ailments. It contains isosilybin A and B, silydianin, silybins A and B, silychristin, and polyphenolic compounds, as well as six important flavonolignans. It also possesses anti-fibrotic, anti-inflammatory, and anti-oxidant properties (Kheong et al., 2017). It is found in Asia, Southern Europe, North and South America, North Africa, and South Australia (Camini and Costa, 2020).
The major biologically active component of S. marianum is silybin. It is not dose-dependent and can be used to treat NAFLD patients, notably NASH, compared to hepatoprotective drugs and antimetabolic disorders agents (Zhong et al., 2017). The   Curcumin Continued mechanism of action of silybin is followed by its act of interaction with various tissues. Silybin reacts through deactivating proinflammatory signals, which are acquired from activation of NFκB that is involved in the induction of the synthesis of the cytokineslike IL-1, IL-6, granulocyte-macrophage colony-stimulating factor, TNF-α (Federico et al., 2017). Silymarin inhibits free radical injury and lipid peroxidation. It is also found that silymarin can block the release of TNF-α by removing hydroxyl radicals and maintaining the average superoxide dismutase level (Navarro et al., 2019).
It is also observed that silymarin is found to shrink inflammation, and treatment can minimize IR and deplete fasting insulin levels. In NAFLD patients, silybum + phospholipids + vitamin E complex is located to enhance liver enzymes plasma level, improve echography score of liver steatosis. NASH is associated with mitochondrial dysfunction. During the process of NASH, the excess of FFA intensifies in hydrogen peroxide (H2O2) mitochondrial production, which in return oxidize mitochondrial membranes and maintain the activity of uncoupling protein-2 and carnitine palmitoyl transferase-1 (Abenavoli and Bellentani, 2013). Some studies found that milk thistle extract exhibits a reducing trend in NASH and numerical reduction in the steatosis score when differentiated with the vehicle group (Pais and Amato, 2014).

Camellia sinensis (Linn.) Kuntze
Green tea (GT), a member of the Theaceae family, is the most commonly found in East Asia. It is derived from the leaves of C. sinensis, which are high in polyphenolic components such epigallocatechin gallate, catechin, and epigallocatechin 3 gallate (EGCG). It is used as a traditional medicine in diabetes, obesity, and cardiovascular diseases. It is also observed that catechins decline lipid peroxidation levels, oxidative stress (Mansour-Ghanaei et al., 2018).
GT minimizes the cholesterol level in the liver by lowering the fat absorption from the gastrointestinal tract and elevating the reabsorption of bile acid. It also regulates liver enzymes levels and reduces lipogenesis activity by preventing the expression of adipose lipogenic genes and hepatic genes Matairesinol (Mahmoodi et al., 2020). It enhances the anti-oxidant activity and reduces the level of expression of TNF-α (Karolczak et al., 2020). GT extract (GTE) is found to improve gene expression related to lipid oxidation. It also inhibits fatty liver accumulation through activation of adenosine monophosphate kinase (AMPK) and may also increase miR-34a, which is responsible for lowering PPAR-α expression with progression of steatosis. The hepatic lipid accumulation is prevented by increasing the hepatic miR-24, which further increases the insight target-a lipogenesis inhibitor. The primary polyphenol present in GT, EGCG, attunes the many miRNAs present in hepatocytes, which involves the modulation of insulin sensitivity, lipid metabolism, apoptosis, and inflammation. Changes in the expression of miR-122, miR-107, and miR-103 and the induction of plant polyphenols can shrink hepatic steatosis. A complete mapping of the pathway is required to reveal the involvement of miR34a and miR-194 in NAFLD (Torres et al., 2019).
EGCG has been utilized to lessen fat deposition in the liver in HFD fed in mice, which acts as a murine model of NAFLD in humans via specific pathways that include signal transduction, transcriptional, autophagy, and intracellular secondary message pathway (Ushiroda et al., 2019). The risk of NAFLD is ameliorated by the presence of anti-oxidants, lipid-lowering, anti-inflammatory effects, IR, and gut dysbiosis that are present in abundance in GT (Zhou et al., 2019).

Cinnamomum verum J. Presl
Cinnamon is a spice derived from the inner bark of the tree species C. verum, which belongs to the Lauraceae family and has anti-oxidant and insulin sensitizing characteristics. Some of the in vivo and in vitro studies estimated its effect on glucose metabolism by lowering post-prandial intestinal glucose absorption by preventing α-glucosidase and pancreatic α-amylase. It also enhances glycogen synthesis, potentiates insulin receptor activity and insulin release, and inhibits gluconeogenesis. Cinnamon plays a significant role in subsequent ROS and lipid peroxidation, which is considered as a known vital process in the development of NAFLD (Askari et al., 2014).

Chlorella vulgaris Beijerink
Chlorella vulgaris is a freshwater single-celled green eukaryotic microalga in the Chlorellaceae family that can be used as a supplement to treat NAFLD. Some studies state that it is rich in essential FAs and amino acids. It also consists of a reliable amount of fiber and intracellular phytochemicals such as tocopherols, carotenoids, and ubiquinone. This medication can also be used to prevent and manage hypertension, dyslipidemia, weight loss, and hyperglycemia. The supplementation of this can ameliorate IR and fasting serum glucose. In NAFLD patients, it is found to facilitate liver function and inflammatory biomarkers (Ebrahimi-Mameghani et al., 2017).

Glycyrrhiza glabra Linn.
Glycyrrhiza glabra, popularly known as licorice, is a Fabaceae-family herbaceous perennial legume native to Western Asia, North Africa, and Southern Europe. Glycycoumarin (GCM), a compound found in licorice, has been studied for its excellent bioavailability and high efficacy against alcoholic liver disease, nonalcoholic fatty liver, and acetaminophen-induced hepatotoxicity by activating the Nrf2 anti-oxidant system, inducing autophagy, activating AMPK-mediated energy homeostasis, inhibiting oncogenic kinase T lymphokine-activated killer cell. This shows the use of GCM as a hepatoprotective agent (Zhang et al., 2020).
GCM is found to inhibit hepatocyte lipoapoptosis. It is also found to activate impaired autophagy caused by lipid metabolic disorders. GCM reduces endoplasmic reticulum stressmediated JNK and mitochondrial apoptotic pathway activation during autophagy activation (Zhang et al., 2016a(Zhang et al., , 2016b. Licorice root can also be used to treat bronchitis, stomach ulcers, viral infections, and sore throat. It is found in various countries like Italy, Russia, China, and Turkey. Glycyrrhizin exhibits antioxidant, immune-modulating activities, and anti-inflammatory properties (Hajiaghamohammadi et al., 2012).
Glycyrrhizin is considered to be a curative treatment of NASH accompanied by cholestasis. It aims for bile acid-mediated meta-inflammation and inhibits the FXR-NLRP3 inflammasome common pathway (Yan et al., 2018a(Yan et al., , 2018b.
Diammonium glycyrrhizinate obtained from licorice roots is a glycyrrhizic acid considered a vital bioactive pentacyclic triterpenoid glycoside. It consists of anti-allergic, anti-viral, antitumor, and anti-oxidant properties. Diammonium glycyrrhizinate can be used to treat NAFLD since it can enhance the damage of the liver caused by anti-inflammatory activity in the liver .

Linum usitatissimum Linn.
Flax, commonly known as common flax or linseed, is a flowering plant in the Linaceae family that is high in polyunsaturated fatty acids, especially linoleic acid, phytoestrogenic lignans, insoluble and soluble dietary fibers, anti-oxidants, and proteins. Many studies also found that flaxseeds can decrease the risk of MetS, dyslipidemia, and cardiovascular diseases. It is also found that flaxseed supplementation affects IR. A patient's flaxseed can minimize TNF-α and high sensitivity c reactive protein (Yari et al., 2016).

Flavonoids
Flavonoids are prevalent polyphenolic compounds present in nature. They are found to bind with glycosides more than aglycones regularly. Almost all flavonoids possess three rings, namely two aromatic rings and one heterocyclic ring. Based on variations in the C, ring flavonoids are divided into subclasses such as flavonols, flavanones flavones, anthocyanidins chalcones, and isoflavones. They have been proven to have beneficial effects on lipid metabolism, oxidative stress, IR, and inflammation which are considered the most critical pathophysiological pathways in NAFLD represented in Figure 2 and

Saponins
These are glycoside aglycones of three common terpenoids found in terrestrial plants. Some saponins are antipyretic, anti-cancer, and anti-bacterial. The main active ingredients in Polygala tenuifolia, Platycodon grandiflorus, Panax ginseng, and Glycyrrhiza uralensis are saponins (Liu et al., 2015a(Liu et al., , 2015bZhang et al., 2016aZhang et al., , 2016b. Saponin extract reversed the elevation in the expression levels of lipogenesis-related genes induced by fast-food diet (FFD), including MLX interacting protein-like and fatty acid synthase (FASN) in regular chow diet fed mice. The expression of FA oxidation-related genes, such as PPAR-α along with carnitine palmitoyltransferase-1, was increased in FFD mice, which improved saponin extract administration (Wang et al., 2021).
Dioscin is considered to be a natural steroidal saponin found in many herbs. It is found to show anti-fungal, anti-hyperlipidemic, and anti-tumor activity (Hsieh et al., 2013). When taken orally, it improves fat accumulation in the liver, lowers blood lipid levels, reduces TG deposition via FASN inhibition, promotes FA betaoxidation, lowers liver cholesterol, regulates the mitogen-activated protein kinase (MAPK) signaling pathway and autophagy, and decrease oxidative stress and inflammation (Liu et al., 2015a(Liu et al., , 2015b.

Alkaloids
This is a class of naturally occurring nitrogenous organic compounds. It has antifungal, antibacterial, antitumor, and analgesic properties (Kukula-Koch et al., 2016;Stegelmeier et al., 2015). It has also been shown to have a significant effect on NAFLD. Berberine an alkaloid is frequently used to treat inflammatory disorders and diarrhea in China . Berberine helps combat metabolic problems such as diabetes and obesity (Zhang et al., 2010;Zhou et al., 2011). Berberine can be used as a cholesterollowering drug due to the distinct mechanism that distinguishes it from statins (Kong et al., 2004). When rats were administered an HFD that produced hepatic steatosis, berberine restored systemic alterations in gene expression. The lncRNA MRAK052686 and its associated gene Nrf2 are implicated in the pathogenesis of NAFLD in many modules of berberine-regulated genes (Yuan et al., 2015).

Terpenoids
Terpenoids are organic compounds with several hydrocarbon isoprene units and their oxygenated derivatives in their molecular formulae. Aldehydes, alcohols, carboxylic acids, esters, and ketones are examples of oxygenated products. It can be found in abundance in nature and are the primary constituent of various plant essences and pigment resins (Arendt et al., 2016). Terpenoids have a variety of physiological functions, including

Natural Pathway Function
Flavonoid PPARα Stimulates PPARα to reduce steatosis by stimulation of β-oxidation PPAR-α inhibits NFκB to alleviate inflammation.

NFκB
It prevents NFκB translocation to the nucleus but also the transcription of genes involved in the inflammatory response by inhibiting I κB phosphorylation and the IKK complex.
Inducible NO synthase (iNOS) Flavonoids inhibit NO production and in addition, it prevents the expression of inducible NO synthase (Yamamoto and Gaynor, 2001). After 14 days clinical signs of toxidromes (raising fur, draping, tremors, excitability, miosis, mydriasis, twitching, morbidity, and so on), as well as mortality were noted. This revealed no hematological side effects at either the low or high dose. As a result, acute toxicity of P. niruri aqueous leaf extract can be ruled out, and the LD50 of the aqueous leaf extract exceeds 5,000 mg/kg b. wt (Hashem et al., 2020).
The treatment of P. niruri leaf extract to diabetic hyperlipidemic rats resulted in significant reductions in plasma glucose, total lipids, cholesterol, TGs, low density lipoprotein cholesterol, and very low-density lipoprotein (VLDL)cholesterol, as well as an increase in plasma High Density Lipoprotein (HDL)-cholesterol. Phyllanthus niruri has an effective dose of 1,000 mg/Kg (Hashem et al., 2020).
Through acute exposure in rats, the standardized WEPE fruit with an LD50 > 5,000 mg/kg is regarded as non-toxic. In mice, a dose of 10 g/kg body weight of a 50% ethanol fruit extract causes no acute toxicity .
For 20 weeks, a WEPE fruit reduced body weight and epididymal fats. It also had a more significant effect on serum AST, hepatic steatosis, and oxidative stress. The water extract also reduced SREBP-1c mRNA in the liver while increasing adiponectin mRNA in the peritoneal fat .
Both male and female patients aged 18 to 65 with positive hepatitis B surface antigen tolerate it well for 6 months. It is found that there is no difference in toxicological measures between the treatment and control groups; some participants in both of the groups suffered modest deleterious effects (Geethangili and Ding, 2018).
In the acute trial, mice were given a single dose (2 g/kg) orally. During a subchronic trial, mice were given extract at doses of 50, 100, 500, and 1,000 mg/kg for about 120 days. No significant differences were seen in blood pressure, hematological, and histology of mice. This indicated that it did not result in toxicity or mortality in mice .
In rats, glycyrrhizin has been shown to boost lipoprotein lipase expression, insulin sensitivity, and serum cholesterol levels (Eu et al., 2010;Lim et al., 2009
Garlic infusions at high doses resulted in respiratory distress, weight loss, hair loss, and epidermal loss on the ventral side. The limbs had gone numb .
In men, a higher intake of raw garlic was linked to a lower prevalence of NAFLD, but not in women. These findings imply that raw garlic consumption may protect against NAFLD .
In acute or subchronic toxicity trials in guinea pigs, rats, monkeys, and dog's turmeric/ alcoholic extract of turmeric/curcumin showed no harmful effects (even at large dosages) (Deshpande et al., 1998).
Over the course of 12 weeks, turmeric consumption reduced serum levels of glucose, leptin, insulin, and homeostatic model assessment of IR when compared to the placebo group. In comparison to the placebo group, there were no significant changes in weight, BMI, or liver enzymes (Navekar et al., 2017).

C. verum J. Presl
A 13-week repeat-dose oral toxicity research indicated that the body weights of rats were normal, kidney/liver weight and total cholesterol levels were elevated after receiving up to 2,000 mg/kg. A subsequent 8-week repeat-dose oral toxicity study disclosed that renal function increased remarkably, liver histology revealed distortions in hepatocytes, degenerative alterations in the glomerular and Bowman's capsules (Vijayakumar et al., 2021).
The acute and sub-chronic toxicities of flaxseed-derived maillard reaction product (MRP) revealed that the LD50 in rats was higher than 15.0 g/kg BW, but the ED50 of MRPs in the acute toxicology investigation was 12.3 g/kg BW. Consuming less than 0.75 g had no influence on weight, mortality, food intake, histology, gross pathology, hematology or serum biochemistry (Wei et al., 2019).
Dietary flaxseed oil reduced inflammation along with hepatic oxidative stress which helps to slow the progression of NAFLD. Flaxseed oil shows no effect on body weight change but significantly minimizes IL-6, TNF-α, and MCP-1 levels (Han et al., 2017).

Seed
C. sinensis (Linn.) Kuntze 26-week old rats were employed and administered tea flower extract (TFE). During the 14-day period, female rats' average body weight increased from 191.2 ± 5.9 g to 216.1 ± 8.3 g, whereas male rats' average body weight increased from 192.8 ± 6.1 to 289.4 ± 12.3 g. The gross pathology findings revealed no visible lesions following the sacrifice on the 14th day. As a result, no indication of acute TFE toxicity in rats was discovered .
GTE anti-inflammatory effects on gut barrier function, as well as prebiotic and antimicrobial effects on gut microbiology, help to limit the translocation of gut-derived endotoxins (e.g. LPSs) to the liver, where they would otherwise upregulate NFκB activation by Tolllike receptor-4 signaling (Hodges et al., 2020).

M. rubra (Lour.) Siebold & Zucc
There were no clinical indications or deaths in the acute oral toxicity experiment at the bayberry kernel oil feeding dose level of 9.446 g/kg body weight. Furthermore, physical examinations revealed no noticeable treatment-related health changes in the 305 mice. All groups gained weight, and no significant differences were found (Xia et al., 2013).
By increasing plasma antioxidants and inhibiting the inflammatory apoptotic response, bayberry juice can protect against NAFLD during a 4-week period . Fruit cough relief, expulsion of wind, induction of sweating, insecticide activity, and pain relief (analgesia) . Betulinic Acid (BA) is a pentacyclic lupane type triterpene (3B-hydroxy-lup-20(29) en-28-oic acid). BA can be found in various foods, medicinal herbs, and plants, mainly birch bark. It is non-toxic in mice at concentrations of up to 500 mg/ kg body weight, and the main mechanism for its hepatoprotective qualities is its anti-oxidants, which boost the body's redox system and lessen liver lipid peroxidation. By reducing hepatic steatosis via the calcium/calmodulin-dependent protein kinase-AMPK-SREBP1 signaling pathway, BA efficiently reduces intracellular lipid accumulation in liver cells, limiting fatty liver deposition. It has also altered the way MAPK pathways are controlled. BA therapy inhibits HFD-induced changes in nuclear SREBP 1c activity and hepatic TG accumulation (Quan et al., 2013).

Polyphenols
Polyphenols are considered as a diverse class of plantderived compounds that consist of various water-soluble antioxidants reported as health-promoting agents. It can be suggested in the treatment of various metabolic disorders. Their bioactive compounds are abundant in fruits, vegetables, and beverages such as coffee, tea, red wine, and dark chocolate (Abenavoli et al., 2017).
Curcumin, the yellow pigment found in the C. longa plant is derived from curry and spices. Its anti-oxidant effects have been extensively researched in the context of liver metabolism (Pan et al., 2014). Curcumin protects the liver by suppressing the expression of NFκB target genes such as monocyte chemotactic protein 1 (MCP-1), cyclooxygenase-2 (COX-2), and intercellular cell adhesion molecule-1. According to Vizzutti et al. (2010), curcumin can reduce alpha-smooth muscle actin levels in NASH mice, along with the formation of ROS and tissue inhibitors of metalloproteinases-1 secreting activated hepatic stellate cells. Curcumin alleviates NAFLD by activating Nrf2, AMPK, and nuclear receptors, altering lipid metabolism and oxidative stress, and inhibiting NLRP3 inflammasome activation and gut microbiota, reducing inflammation and steatosis (Yan et al., 2020).
Resveratrol is a phytoalexin polyphenolic molecule that has been demonstrated to assist in the pathology of NAFLD (Bujanda et al., 2008). Some of the methods used to decrease inflammation include inhibition of pro-inflammatory mediator synthesis and release, modification of eicosanoids synthesis, prevention of kupffer cell adhesion molecules, and inhibition of COX-2, nitric oxide (NO) synthase via inhibitory effects on NFκB or activator protein-1 proteins (Alarcon De La Lastra and Villegas, 2005;Jang et al., 1997).
Chloroquine inhibits autophagy in acute myeloid leukemia-12 (AML-12) cells, which suggests that resveratrol's actions are likely linked to autophagy activation (Ji et al., 2015). According to the research, resveratrol has also been shown to diminish inflammatory liver damage in methionine-choline deficient diet-induced NASH mice in addition to IL-1, IL-6, ALT, aspartate aminotransferase (AST), and TNF-α levels in the blood that have been associated with autophagy (Shen et al., 2019). Furthermore, resveratrol has been shown to heal liver injury in experimental mice by activating autophagy and reducing NFκB activation , implying that activation of autophagy could be used as an anti-inflammatory method to prevent NAFLD progression (Zhang et al., 2018)

CONCLUSION
The use of herbal medicine becomes vital for treating a variety of human ailments. The studies conducted with a deep understanding of the root cause of the disease have been applied widely to modify the ancient form of treatment to globally accepted medicines. The development of herbal medicine regarding its pathogenesis and pathway of the disease, i.e., for the NAFLD, has been widely studied and provided no prominent data with the background of the disease. There is no Food and Drug Administration approved medicines for NAFLD treatment. There is a wide rush in formulating and developing a drug either in allopathic medicine or the Indian system of medicine for the treatment of NAFLD. Herbal drugs will have a significant role in the future when the pathway of the disease is well studied with herbal plants. When compared to allopathic medicine, herbal medicine is cost-effective as it is readily available and needs only a thorough study for its scientific validation for proof of toxicity and efficacy.

AUTHOR CONTRIBUTIONS
All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. All the authors are eligible to be an author as per the international committee of medical journal editors (ICMJE) requirements/guidelines.

FUNDING
There is no funding to report.

CONFLICTS OF INTEREST
The authors report no financial or any other conflicts of interest in this work.

ETHICAL APPROVALS
This study does not involve experiments on animals or human subjects.

DATA AVAILABILITY
All data generated and analyzed are included within this research article.

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