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Nucera, S.; Bulotta, R.M.; Ruga, S.; Caminiti, R.; Serra, M.; Bava, R.; Castagna, F.; Lupia, C.; Marrelli, M.; Conforti, F.; et al. Natural Products for Non-Alcoholic Fatty Liver Disease Treatment. Encyclopedia. Available online: https://encyclopedia.pub/entry/55471 (accessed on 05 May 2024).
Nucera S, Bulotta RM, Ruga S, Caminiti R, Serra M, Bava R, et al. Natural Products for Non-Alcoholic Fatty Liver Disease Treatment. Encyclopedia. Available at: https://encyclopedia.pub/entry/55471. Accessed May 05, 2024.
Nucera, Saverio, Rosa Maria Bulotta, Stefano Ruga, Rosamaria Caminiti, Maria Serra, Roberto Bava, Fabio Castagna, Carmine Lupia, Mariangela Marrelli, Filomena Conforti, et al. "Natural Products for Non-Alcoholic Fatty Liver Disease Treatment" Encyclopedia, https://encyclopedia.pub/entry/55471 (accessed May 05, 2024).
Nucera, S., Bulotta, R.M., Ruga, S., Caminiti, R., Serra, M., Bava, R., Castagna, F., Lupia, C., Marrelli, M., Conforti, F., Statti, G., Mollace, V., & Palma, E. (2024, February 26). Natural Products for Non-Alcoholic Fatty Liver Disease Treatment. In Encyclopedia. https://encyclopedia.pub/entry/55471
Nucera, Saverio, et al. "Natural Products for Non-Alcoholic Fatty Liver Disease Treatment." Encyclopedia. Web. 26 February, 2024.
Natural Products for Non-Alcoholic Fatty Liver Disease Treatment
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This entry is adapted from the peer-reviewed paper 10.3390/scipharm91040053

Plants are an untapped natural resource; their secondary metabolites take part in a variety of pharmacological activities, making them an essential ingredient in the synthesis of novel medications and the source of reserve resources in this process. Hepatitis and liver cancer are two conditions that can result from non-alcoholic fatty liver disease (NAFLD). NAFLD is a condition that now affects a significant section of the global population. There is a need for preventative action on predisposing factors. Due to their effectiveness and few side effects, herbal medications are frequently utilized for the prevention and treatment of NAFLD.

non-alcoholic fatty liver disease (NAFLD) polyphenols plants natural products anti-steatotic compounds

1. Introduction

The liver is the most important multifunctional organ in the body. It has a particular role in the triglyceride cycle and in the synthesis of lipoproteins, which are the form of elimination of triglycerides from the liver; it also carries out biotransformation and detoxification activities and is closely involved in glucose homeostasis. Any interference with these functions can lead to the development of liver disease [1].
Among the most common liver diseases is fatty liver disease (FLD), also known as hepatic steatosis, which currently affects a large part of the world population. Its prevalence has been estimated at 20–30% in the general population (non-alcoholic fatty liver disease (NAFLD) 16–24%, nonalcoholic steatohepatitis (NASH) 2.1–6.3%), to be higher in obese people (mean prevalence 34.2%) [2].
The term steatosis generally indicates pathological processes during which there is an accumulation of lipids, generally triglycerides, in cells where it is not commonly possible to highlight them with common histochemical techniques. The primary feature of fatty liver disease is the unusual presence of TG in hepatocytes, which is produced by the esterification of free fatty acids and glycerol inside hepatocytes, which results in a variety of histological pictures: (1) simple fatty liver disease, defined by an amount of TG > 5–10% of the liver’s weight; (2) non-alcoholic fatty liver disease (NAFLD), which is triggered when fat accumulation begins to exert harmful toxic effects and the percentage of hepatocytes that contain lipid droplets is greater than 5% [3]; and (3) non-alcoholic inflammatory steatohepatitis (NASH), which can be associated with fibrosis and cirrhosis, leading to the eventual development of hepatocellular carcinoma [4].
Previous epidemiological research has shown that approximately 20% of patients with NAFLD progress to the NASH stage, which can lead to cirrhosis, portal hypertension, and hepatocellular carcinoma [5]. Once developed, 30–40% of patients with cirrhosis die from liver complications within 10 years [6].
NAFLD should be managed with a combination of exercise, calorie restriction, and progressive weight reduction through lifestyle changes [7].
To treat NAFLD, several pharmacological approaches have been tried. To reverse the comorbidities of the metabolic syndrome, existing drug therapies are mainly based on the combination of various substances. These treatments include the use of antioxidants (vitamins E and C; betaine), insulin-sensitizing drugs (thiazolidinediones and metformin), lipid-lowering drugs (statins; orlistat; probucol), cytoprotective drugs (ursodeoxycholic acid), and anti-inflammatory or antifibrotic drugs (pentoxifylline; angiotensin receptor blockers). Unfortunately, none of the suggested drugs have yet been successful [8]. Consequently, it is clear that new therapeutic options need to be investigated. Numerous natural substances have been shown to have positive effects on cellular processes involved in the onset and development of various diseases [9][10].
In recent years, research on natural products and their derivatives has had a certain ferment. The use of plants as therapeutic agents has very ancient origins and still holds considerable interest today [11].
Some valid alternatives to the treatment of NAFLD and its progression into NASH can be exemplified by using specific chemical compounds naturally produced by some plants. It is known that different plant substances can treat different conditions that coexist in this disease, including hyperglycemia, hyperlipidemia, inflammation, and oxidative stress [12][13]. There are also studies on the direct use of natural remedies for the treatment of NAFLD [14].

2. Pathophysiology of NAFLD

Fatty liver disease includes two distinct categories: alcoholic fatty liver disease (AFLD) and non-alcoholic fatty liver disease (NAFLD) [15]. The first is triggered by excessive alcohol consumption; the underlying causes of the second condition have not yet been fully clarified, but a multifactorial etiology is clearly emerging. It recognizes various elements, including obesity, associated insulin resistance (IR), type 2 diabetes mellitus, dyslipidemia, atherosclerosis, hypertension, and fatty liver disease itself [16][17].
Interestingly, these are the same risk factors associated with cardiovascular disease (CVD). In patients with NAFLD, liver enzymes have been shown to predict the incidence of CVD, independent of traditional risk factors, including C-reactive protein and metabolic syndrome (MS). Indeed, the extent of liver damage has been correlated with early carotid atherosclerosis, suggesting that both vessel and liver damage share similar inflammatory mediators [18].
For these reasons, NAFLD has recently been proposed as an early marker of atherosclerosis and endothelial dysfunction and, consequently, as a cardiovascular risk factor. Considering the wide spectrum of effects often related to NAFLD, several scientists have recently provided a more accurate terminology for this disease. The term NAFLD has been changed to “MAFLD,” meaning metabolic dysfunction associated with fatty liver disease. Therefore, NAFLD can be regarded as the hepatic manifestation of a metabolic syndrome [19][20][21].
In this MS, also the intestinal microbiota plays a key role. Recent studies have shown that, in addition to genetic predisposition and diet, the intestinal microbiota influences the hepatic metabolism of carbohydrates and lipids [22]. It also appears to affect the balance between pro-inflammatory and anti-inflammatory effectors in the liver, thereby affecting the progression of MAFLD [23]. Changes in the composition of the intestinal microbiota, in fact, increase intestinal permeability and, consequently, the translocation of bacteria and their products; this induces endotoxemia, which contributes to liver inflammation in patients with NASH [24].
Species belonging to the Gram-negative class grow during MAFLD, while those belonging to the Gram-positive class decrease [25][26]. Therefore, the gut microbiota may be a useful tool as a predictor for the progression and severity of MAFLD [27][28].
Among the first hypotheses about etiopathogenesis, we have that of Day et al., 1998 [29]. The authors proposed the so-called “two-hit” pathogenetic model to explain the appearance of NAFLD and its progression to NASH. The first “hit” is the accumulation of triglycerides in the liver (steatosis) due to several conditions. The liver may become overloaded by excessive dietary intake, increased TG synthesis, excessive influx of fatty acids into the liver as a result of lipolysis of adipose tissue, decreased export of lipids from the liver in the form of VLDL, or decreased oxidation of fatty acids. In this model, the first hit must be followed by a subsequent insult (second hit), capable of activating a consistent lipid peroxidation that generates reactive oxygen species (ROS) and cytotoxic aldehydes that trigger processes such as the transcription of NF-kB (regulator of inflammation genes), leading to necro-inflammation and fibrosis [29].
It has recently emerged that free fatty acids have a direct ability to promote liver injury and the activation of inflammation, even in the absence of a second hit [30].
The initial two-hit theory became obsolete and was reformulated in the form of a “multi-hit” hypothesis. The “hits” could be represented by several injuries, such as obesity, insulin resistance, oxidative stress, and pro-inflammatory processes [31][32].
Tilg and Moschen, 2010 [33] revised this pathogenetic reconstruction, considering NASH as distinct from simple fatty liver disease and not an evolution of the latter. The authors have proposed this new model in which multiple causal factors, acting simultaneously, are able to determine the onset of liver disease (the “parallel multiple stroke model”) [33].
According to this interpretation, steatohepatitis and steatosis represent two distinct nosological entities. Inflammation may also precede and lead to the onset of steatosis in NASH. In fact, there is evidence of patients with NASH who have almost no steatosis and of regression of steatosis in mice models with the obese phenotype ob/ob after anti-inflammatory therapy with anti-TNF-α monoclonal antibodies or metformin (also capable of reducing the expression of TNF-α).
The hypothesis of Tilg and Moshen, 2010 [33] brings to light the prominent role of factors of extrahepatic derivation in determining inflammation and secondary liver fibrosis [33].
Genetic factors, such as polymorphisms of some phospholipases, modifications of the intestinal microflora (dysbiosis)—secondary to a diet rich in fats/carbohydrates—insulin resistance, an increase in circulation of bacterial endotoxins (in relation to an altered liver sequestration function), reduced synthesis of short-chain fatty acids (capable of performing an anti-inflammatory action), and an altered expression in the intestinal epithelium of toll-like receptors (TLRs) (regulators of inflammation and involved in innate immunity), may represent “molecular mediators” of liver damage, inducing lipid accumulation in the liver, lipotoxicity, fibrosis and, finally, the onset of neoplasms.
In the next section, the causes that contribute to the onset of liver disease are analyzed.

Accumulation of Lipids and Steatosis

The control of lipid metabolism involves many critical organs, including the liver. The buildup of TG in hepatocytes is a hallmark of NAFLD. It is believed that there is an imbalance between the amount of FA input (uptake and synthesis with subsequent esterification to TGs) and outflow (oxidation and secretion), which results in hepatic steatosis. Hepatic fatty acids, used for TG synthesis, derive from diet, lipolysis of adipose tissue, or de novo lipogenesis in the presence of excess glucose [1].
According to research by Donnelly et al., 2005 [34], approximately 59% of liver-free fatty acids (FFAs) in NAFLD patients come from circulation, 26% from de novo lipogenesis, and 15% from food [34].
From the small intestine, dietary fatty acids are absorbed, organized into lipoprotein-rich particles (chylomicrons), and released into the blood and lymph. The liver receives the remaining chylomicrons, with the majority going to adipose tissue. The liver cells will not be able to get rid of the extra lipid if the fat meal is repeated often; if the exposure is just once in a while, the triglyceride elimination is accomplished quickly. Increased lipid mobilization from adipose deposits has the same result as intracellular triglyceride buildup. [35]. Typical steatosis of this kind occurs in diabetics, in which lipolysis is activated, and lipemia remains high due to insulin deficiency [36].
There are instances when lipid overflow develops inside the cell owing to increased fatty acid synthesis; this circumstance is known as de novo lipogenesis. The transcription factors SREBP-1c (sterol regulatory element binding protein-1c) and ChREBP (carbohydrate-responsive element-binding protein), which regulate the key lipogenesis genes, ensure that acetyl-CoA is converted to fatty acids in the liver. Insulin is primarily responsible for this conversion [37].
In patients with NAFLD, it is common to find an overexpression of the genes involved in the de novo synthesis of fatty acids, such as acetyl-CoA carboxylase 1 and 2 (ACC1, ACC2) and fatty acid synthase (FAS) [35].
Therefore, insulin plays a role in NAFLD appearance. Specific receptors found on the plasma membrane of the cells allow insulin to carry out its activity. When blood glucose levels rise after a meal, pancreatic beta-cells naturally generate insulin to lower them. Several target proteins are activated, and a cascade of cascading processes is set off when insulin binds to the cell receptor. Insulin is also responsible for de novo lipogenesis in the liver, as previously mentioned. Another function attributable to insulin is the inhibition of lipolysis in adipose tissue. NAFLD often develops in those who have insulin resistance. Increased consumption of free fatty acids (FFAs), hyperglycemia, which promotes the formation of free radicals (glycotoxicity), and inflammatory cytokines released by adipocytes are the key contributors to insulin resistance [38].
In the case of IR, the adipose tissue’s resistance to insulin triggers lipolysis, which increases the release of free fatty acids from the adipose tissue. These free fatty acids are then transported to the liver via the hepatic artery and portal vein, increasing the influence of hepatic fatty acids [39].
High blood glucose levels (in the context of IR) lead to hyperinsulinemia, which activates SREBP-1c and encourages de novo hepatic lipogenesis (through the malonyl- and acetyl-CoA pathways). The increased lipogenesis is also indirect due to the increased production of malonyl-CoA, which inhibits carnitine-palmitoyl transferase-1 and the entry of fatty acids into the mitochondria by reducing ꞵ-oxidation, thus increasing the accumulation of fatty acids and triglycerides [40] (Figure 1).
Figure 1. The role of insulin resistance in NAFLD. ↑: Increase of expression, concentrations, or activity.

3. Progression of Liver Damage: The Role of Oxidative Stress, Mitochondrial Dysfunction, and Endoplasmic Reticulum Stress

It has been shown that individuals with NASH have biochemical and ultrastructural lesions of the mitochondria; these lesions are not completely understood at this time, but it is thought that TNF, non-esterified fatty acids and lipoperoxidation products may be to blame individually or in combination. Non-esterified fatty acids uncouple oxidative phosphorylations in this way. This condition, which is typically accompanied by an increase in oxygen consumption, causes an increase in the production of ROS, which in turn lowers the concentration of antioxidants, causes lipoperoxidation, and mediates the release of TNF from Kupffer cells (KC), which are inflammatory cytokines that are also released by steatotic hepatocytes and increase their impact by activating Kupffer cells. ROS has a growing role in the activation of Ito cells (hepatic stellate cells (HSC)), which leads to hepatic fibrogenesis, a late effect of NASH. Liver steatosis is mostly linked to oxidative stresses, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress [41] (Figure 2).
Figure 2. Liver damage progression. Several risk factors contribute to NAFLD onset; these are highly connected and multi-compartmentalized. In addition to the involvement of the cardiovascular and lymphatic systems, cellular alterations are fundamental for the pathogenesis of this disease and concern the cellular organelles’ involvement, such as mitochondria, lysosomes, peroxisomes, and RE.

3.1. Oxidative Stress

As it was feasible to infer, a major mechanism underlying NASH is oxidative stress (OS), which is defined as an imbalance between oxidant and antioxidant chemical species. ROS are hazardous chemicals that the body’s antioxidant system must eliminate through interacting with proteins, lipids, and nucleic acids [42]. Oxidative stress is brought on by either increased ROS production in liver cells or weakened antioxidant defenses. The body’s fight against free radicals is made up of both enzymatic and nonenzymatic processes. While glutathione (GSH), ascorbic acid (vitamin C), retinol (vitamin A), and tocopherol (vitamin E) are nonenzymatic systems that can protect biomolecules and cellular structures from ROS damage by acting as electron receptors, superoxide dismutase (SOD), catalase (CAT), and GPx are examples of enzyme systems. In the context of the liver, hepatocytes counteract the harmful effects of ROS to avoid cellular damage by turning on antioxidant enzymes such as heme oxygenase 1 (HO1), NAD(P)H:Quinone Oxidoreductase 1 (NQO1), and SOD. It is significant because many of the genes responsible for encoding these antioxidant enzymes are controlled by the transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) [43]. Nrf2 protects against NAFLD in addition to activating genes that encourage the removal of ROS by negatively regulating genes that encourage lipid synthesis [44].
Damage to cell membranes and modifications to lipid, protein, carbohydrate, and DNA biomolecules are brought on by ROS [45]. OS is generated in mitochondria, peroxisomes, and ER, organelles in which oxygen consumption is high [46]. Lipid peroxidation, which causes the histological characteristics seen with NASH, is the primary modification mediated by reactive oxygen species [47]. By uncoupling the oxidative cycle, FFA promotes the expression of the microsomal monooxygenases CYP4A and CYP2E1, which are in charge of producing ROS [45]. CYP2E1 is mainly expressed in the liver, with the highest expression in hepatocytes. The ER is where CYP2E1 is mostly found, although the mitochondria also express it. A wide range of compounds, including numerous drugs, polyunsaturated fatty acids, ethanol, paracetamol, and the majority of organic solvents, are metabolized by CYP2E1. The expression of CYP2E1 mRNA and protein is regulated by a number of substances, including insulin, acetone, leptin, adiponectin, and cytokines. Because insulin inhibits the cytochrome CYP2E1, peripheral insulin resistance results in increased levels of its expression [48]. According to Chen et al., 2020, [49], OS is linked to the release of pro-inflammatory cytokines, lipid peroxidation, and disruption of phospholipid membranes, all of which cause hepatocellular damage and subsequently affect the course of NAFLD [32]. HSC, the primary cells responsible for the extracellular fibrous matrix deposition that is intimately related to liver fibrosis, are likewise activated by ROS [50].

3.2. Mitochondrial Dysfunction

Fat acid oxidation process imbalances may contribute to an excessive buildup of lipids in the liver. This process is normally proportional to the concentrations of fatty acids released by the adipose tissue following the stimulus provided by glucagon. Oxidation takes place in the three main subcellular organelles of the organism: the mitochondrion and the peroxisomes, which carry out β-oxidation, and the ER, which carries out the ω-oxidation, catalyzed by cytochrome CYP4A. Several cytochrome P450 enzymes that may hydroxylate the omega terminal carbon and, to a lesser degree, the omega 1 position of saturated and unsaturated fatty acids, as well as enzymes involved in the omega hydroxylation of different prostaglandins, are encoded by the CYP4A subfamily [51][52]. Peroxisome proliferator-activated receptor-α (PPARα), a nuclear hormone receptor that controls the oxidation and transport of fatty acids, controls the activity of some of the main enzymes in these three oxidation systems [34]. As soon as it is activated, it forms a heterodimer with the retinoid X receptor (RXR) and binds to peroxisome response elements in the genes responsible for fatty acid oxidation. According to Suhaili et al., 2017 [53], lipotoxicity and increased inward flux of FFA cause lysosomal membrane permeabilization and mitochondrial dysfunction, which in turn trigger hepatocyte apoptosis. Hepatocyte apoptosis causes an immune response that generates a release of proinflammatory cytokines; this leads to further aggravation of liver inflammation [53].
Mitochondrial β-oxidation is implicated primarily in the oxidation of short (<C8), medium (C8–C12), and long (C12–C20) chain fatty acids. As a result of this process, fatty acids gradually shorten into minor units of acetyl-CoA, which can either be condensed to create ketone bodies (oxidizable substrates that serve as an alternative source of energy for extrahepatic tissues) or enter the tricarboxylic acid cycle to further oxidize into water (H2O) and carbon dioxide (CO2). Carnitine palmitoyl-transferase 1a (CPT1a), which is in charge of moving fatty acids from the cytosol to the mitochondrion, the level of carnitine, and the substrate malonyl-CoA, which inhibits CPT1a, are the primary regulators of β-oxidation [54].
Four different dehydrogenases, each particular for the length of the fatty acid chains, catalyze the initial stage of mitochondrial β-oxidation. A single trifunctional mitochondrial protein (MTP), which catalyzes three distinct enzymatic processes (2-enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, and 3-ketoacyl-CoA thiolase), is responsible for the second, third, and fourth stages. Long-chain fatty acids (>C20) undergo a shortening process in peroxisomes before being transported to the mitochondrion, where they carry out the β-oxidation process. The long-chain dicarboxylic acids (highly toxic to the mitochondrion), generated by microsomal ω-oxidation, are metabolized by the peroxisomal β-oxidation system. Although ω-oxidation is the least important metabolization pathway, in conditions of fatty acid overload, such as obesity or diabetes, large amounts of dicarboxylic acids are formed, inducing greater activation of this metabolic pathway [55].
CPT1a expression is 50% lower in NAFLD patients, although long-chain acyl-CoA dehydrogenase (LCAD) and long-chain L-3-hydroxyacyl-CoA dehydrogenase-α (HADHα) are more expressed. Uncoupling protein 2 (UCP2), which regulates the loss of protons along the inner membrane and uncouples the oxidation energy from ATP synthesis, is a significant enzyme involved in the mitochondrial regulation of ROS. NAFLD patients have increased levels of this enzyme [55][56]. Mitochondrial damage and the increase of aberrant mitochondria in the liver generate excessive oxidative stress responsible for advancing the NAFLD course [57].

3.3. Endoplasmic Reticulum Stress

The ER is the organelle in which secretory and membrane proteins achieve correct folding, thanks to the presence of chaperones. The pathogenesis of NASH is influenced by variables including stress (short of nutrition and viral infections), increased production of misfolded proteins, and ER stress, which promotes the activation of a number of transcription factors and kinases [58]. Through the SREBP pathway, the activated transcription factors cause an increase in lipid production, as well as the transcription of proapoptotic genes. The activation of ER kinases, such as inositol-requiring enzyme 1α (IRE1α) and PKR-like ER kinase (PERK), in turn, involves the induction of stress kinases, such as c-Jun N-terminal kinase 1 (JNK1), which may contribute to the induction of apoptotic phenomena [59].

4. Natural Compounds Showing Activity towards NAFLD

Numerous studies have demonstrated the potential of antioxidants from natural sources, including foods and plant species, to prevent or treat NAFLD. Over the years, research has been able to identify alkaloids and flavonoids in addition to polyphenols. The biological effects of the flavonoid, phenolic, alkaloid, and terpene constituents are shown in Figure 3.
Figure 3. Natural compounds and targets in the progression of the NAFLD. ↑: Increase; ↓: decrease of expression, concentrations, or activity.
The following Table 1 summarizes the biological effects of the flavonoid, phenolic, alkaloid, and terpene constituents.
Table 1. Biological effects of flavonoid, phenolic, alkaloid, and terpene components.

Flavonoids Component

Effects

References

Quercetin

↓VLDL, ↓LDL, ↓TC, ↓TG,

↓FFA, ↓ALT, ↓AST,

↓PI3K/AKT pathway,

↑IRE1a/XBP1 pathway,

↓NAFLD activity score,

↓Lipid peroxidation,

↓TNFα, ↓IL-6, ↑SIRT1, ↓NF-kB, ↓iNOS, ↓TLR4

[57][58][59][60][61][62][63]

Anthocyanins

↓TC, ↓TG, ↓LDL, ↑HDL,

↓ALT, ↑PPARα, ↓TLR4,

↓MAPK pathway, ↑AMPK pathway, ↓MPO, ↓MCP,

↓Fibrosis score, ↓WAT,

↓TNFα, ↓IL-1β, ↓IL-6,

↑IL-10, ↑IL-22, ↓ROS, ↑SOD, ↓COX-2, ↓iNOS

[64][65][66][67][68][69]

Kaempferol

↓TC, ↓ALT, ↓AST, ↑GSH,

↓MDA, ↑SIRT1, ↑CPT-1a,

↓SREBP-1c, ↓FAS, ↓SCD-1,

↓PPAR, ↓C/EBP, ↑SOD,

↓NF-kB ↓PARP1, ↓FOXO-1

[70]

Hesperidin

↓TC, ↓ALT, ↓AST, ↓RBP4,

↓H-FABP, ↓ROS, ↑HO-1,

↑PI3K/AKT-Nrf2 pathway,

↑SIRT1-AMPK pathway,

↑SOD, ↑GPx, ↑GSH, ↓TNFα, ↓IL-1β, ↓IL-2, ↓IL-6, ↓NF-kB

[71][72][73][74]

Baicalein

↓TC, ↓ALT, ↓AST, ↓LDL, ↓TG, ↓FFA, ↓TNFα, ↓SREBP-1c, ↓SREBP-1c, ↓TG, ↓GLU, ↓FAS

[75][76][77]

Troxerutin

↑CYP1A1, ↑PGC-1α, ↑CPT-1 β, ↑GSH, ↑PPARα, ↓SREBP-1c, ↓ROS, ↓NF-kB, ↓FATP-1, ↓SCD1

[78][79][80]

Phenolic components

  

Resveratrol

↓TC, ↓TG, ↓ALT, ↓AST,

↑Nrf2, ↑HO-1, ↑SOD, ↑GPx, ↓ROS, ↓FAS, ↓SREBP-1c,

↓IL-1, ↓IL-6, ↓TNFα,

↑TNFβ, ↑SIRT1-AMPK pathway, ↓NF-kB

[13][44][62][81][82][83]

Curcumin

↑HDL-C, ↓ALT, ↓AST, ↓TG, ↑Leptin, ↑Nrf2/FXR/LXR pathway, ↓CYP3A, ↓CYP7A, ↓CD4+, ↓Leptin, ↓ACC, ↓FAS, ↓SREBP-1c, ↓C/EBP, ↓PPAR, ↓SCD, ↑HO-1, ↓ROS, ↑AMPK/mTOR pathway

[84][85][86][87][88]

Alkaloid components

  

Berberine

↓TC, ↓TG, ↓ALT, ↓AST, ↑FXR, ↓SREBP-1c, ↓FAS, ↑SOD, ↑GSH, ↓MDA, ↓TNFα, ↓IL-1, ↓IL-6, ↓NF-kB, ↑Nrf2/ARE, ↓TLR4, ↓MyD88, ↑MTTP, ↑CPT-1a, ↑GCK

[89][90][91][92]

Betaine

↓TC, ↓TG, ↓FFA, ↓ALT,

↓AST, ↑GSH, ↑GPx,

↓NAFLD activity score, ↑SOD, ↑CAT, ↑MDA, ↓ROS, ↓TLR4, ↓NF-kB, ↓IL-1, ↓IL-6, ↓MAPK, ↓FOXO-1

[93][94][95]

Terpenes components

  

Celastrol

↓TG, ↓FFA, ↓ALT, ↓SREBP-1c, ↑AMPKα, ↑LKB1, ↓NF-kB, ↑SIRT1, ↓TNFα, ↓IL-1β, ↓IL-6, ↓ROS, ↑Nrf2/HO-1

[96][97][98][99]

Boswellic acid

↓TC, ↓ALT, ↓AST, ↓TNFα, ↓IL-6, ↓iNOS, ↑UCP1, ↑CPT1, ↓NF-kB, ↓TGFβ, ↓COX-2

[100][101]

↑: Increase, ↓: decrease of expression, concentrations, or activity. ACC: acetyl-CoA carboxylase; AKT: serine/threonine kinase 1; ALT: alanine aminotransferase; AMPK: adenosine monophosphate-activated protein kinase; ARE: antioxidant responsive element; AST: aspartate aminotransferase; CAT: catalase; C/EBP: CCAAT/enhancer binding protein; CPT-1a: carnitine palmitoyl transferase-1; FAS: fatty acid synthase; SCD-1: stearoyl-CoA desaturase 1; FFA: free fatty acids; FOXO-1: forkhead box protein O1; GCK: germinal center kinase; GPx: glutathione peroxidase; GSH: glutathione; HO-1: heme oxygenase-1; iNOS: inducible nitric oxide synthase; IL: interleukin; IRE1a: inositol-requiring enzyme 1a; LDL: low-density lipoprotein; LKB1: liver kinase B1 (STK11); MAPK: mitogen-activated protein kinase; MDA: malondialdehyde; MPO: myeloperoxidase; MTTP: microsomal triglyceride transfer protein; MyD88: myeloid differentiation primary response gene 88; Nrf2: Nuclear factor erythroid 2-related factor 2; PI3K: phosphoinositide-3-kinase; PPARα: peroxisome proliferator-activated receptor α; RBP4: retinol-binding protein-4; ROS: reactive oxygen species; SIRT1: silent mating type information regulation 2 homolog 1; SOD: superoxide dismutase; SREBP-1c: sterol regulatory element binding protein-1c; TC: total cholesterol; TLR4: Toll-like receptor 4; TG: triglycerides; TNF: tumor necrosis factor; UCP1: uncoupling protein-1; VLDL: very low density lipoprotein; WAT: white adipose tissue; and XBP1: X-box-binding protein 1.

The following Table 2 summarizes the biological effects of the natural products.
Table 2. Biological effects of natural products in NAFLD treatment.

Plants

Effects

References

Tea (Camellia sinensis)

↓ALT, ↓AST, ↓NADPH,

↓MPO, ↓RO, ↓Lipid peroxidation

[102][103][104][105]

Curcuma (Curcuma longa)

↓TC, ↓TG, ↓LDL, ↑HDL, ↓ALT, ↓AST, ↓ROS,

↓Lipid peroxidation, ↓Cyt-c, ↓CASP 3, ↓CASP 8,

↓NF-kB, ↑AMPK,

↓SREBP-1c, ↓FAS,

[87][93][106][107]

Loquat (Eriobotrya japonica)

↓ALT, ↓AST, ↓ROS, ↓TGF,

↓Collagen

[93][94][96]

Ginkgo (Ginkgo biloba)

↓TC, ↓LDL, ↓TG, ↑HDL,

↓ALT, ↓AST, ↑CPT-1a,

↓TNFα

[98][99]

Olive tree (Olea europaea)

↓TRX-1, ↓4-HNE, ↓ROS,

↑Nrf2, ↓SOD, ↓CAT, ↓GPx,

↓IL-6, ↓IL-8, ↓TNFα

[86][100][108][109][110]

Pomegranate (Punica granatum)

↓TC, ↓TG, ↓LDL,

↑PPAR, ↑CPT-1a, ↑ACO,

↓SCD-1, ↓ALT, ↓AST

[111][112][113][114]

Milk thistle (Silybum marianum)

↑AMPK activity, ↓PPAR-γ, ↓ACC, ↓ROS, ↓FAS, ↓SIRT1, ↑CAT, ↑NAD+ homeostasis, ↑IRS-1/PI3K/Akt pathway,

↓FXR, ↓NF-kB, ↓4-HNE,

↓glutathione depletion, ↓mitochondrial hydrogen peroxide formation

[115][116][117][118][119][120]

Coffea spp.

↑SIRT3, ↑AMPK,

↓PPAR-α, ↓SREBP-1c,

↓ROS, ↑Bcl-2, ↓Bax,

↑STAT-3, ↓TLR4

[121][122][123][124][125][126][127]

Red rice (Oryza sativa)

↓TC, ↓TG, ↓HMG-CoA reductase, ↓ROS,

[128][129][130][131][132][133][134][135]

Artichoke (Cynara scolymus)

↓ALT, ↓AST, ↓ROS, ↓MDA, ↓8-deoxyguanosine, ↓CoQ9, ↓GSH

[136][137][138][139][140][141]

Soy (Glycine max)

↓TG, ↓ALT, ↓AST, ↓ROS,

↑SOD, ↑CAT, ↓FFA, ↑UCP2

[142][143][144][145]

Alfalfa (Medicago sativa)

↓LDL, ↑2-deoxy-glucose, ↑glycogen, ↓HMG-CoA reductase, ↓ACAT2

[146][147][148]

Bergamot (Citrus bergamia)

↓TC, ↓TG, ↓LDL,

↓ROS, ↑HDL,

↓Cardiomyocyte death,

↑autophagy, ↑SOD,

↑GPx, ↓MDA, ↓TNF

[149][150][151][152][153][154][155][156][157][158][159][160][161][162][163]

Rosemary (Rosmarinus officinalis)

↓ALT, ↓AST, ↓TAG, ↓FFA

↑AMPK, ↑PPAR, ↓SIRT1/p66shc pathway

[164][165][166][167][168][169][170][171][172]

Peppermint (Mentha piperita)

↓TC, ↓LDL, ↓TAG ↓CYP2B9, ↓Leptin, ↓ROS,

↓lipogenesis, ↑PPAR,

↓SREBP1

[173][174][175]

Sage (Salvia officinalis)

↓TC, ↓LDL, ↑HDL, ↓ALT, ↓AST, ↑PPAR, ↓Lipase

[176][177][178][179]

Hot pepper (Capsicum annuum)

↑TRPV1, ↑PPAR ↓IL-6, ↓TNF-α, ↓MCP-1, ↓COX-2

[180][181][182][183][184][185][186][187]

↑: Increase, ↓: decrease of expression, concentrations, or activity. 4-HNE: 4-hydroxynonenal; ACAT2: acetyl-CoA acetyltransferase 2; ACC: acetyl-CoA carboxylase; ACO: acyl-CoA oxidase; AKT: serine/threonine kinase 1; ALT: alanine aminotransferase; AMPK: adenosine monophosphate-activated protein kinase; ARE: antioxidant responsive element; AST: aspartate aminotransferase; CAT: catalase; CASP: caspase; CoQ9: coenzyme Q9; CPT-1a: carnitine palmitoyl transferase-1; CYT: cytochrome; FAS: fatty acid synthase; SCD-1: stearoyl-CoA desaturase 1; FFA: free fatty acids; FOXO-1: forkhead box protein O1; GCK: germinal center kinase; GPx: glutathione peroxidase; GSH: glutathione; HO-1: heme oxygenase-1; IL: interleukin; IRE1a: inositol-requiring enzyme 1a; LDL: low-density lipoprotein; MDA: malondialdehyde; MPO: myeloperoxidase; MTTP: microsomal triglyceride transfer protein; Nrf2: Nuclear factor erythroid 2-related factor 2; PI3K: phosphoinositide-3-kinase; PPARα: peroxisome proliferator-activated receptor α; ROS: reactive oxygen species; SIRT1: silent mating type information regulation 2 homolog 1; SOD: superoxide dismutase; SREBP-1c: sterol regulatory element binding protein-1c; TC: total cholesterol; STAT3: Signal transducer and activator of transcription 3; TAG: tryacylglicerol; TLR4: toll-like receptor 4; TG: triglycerides; TGF: transforming growth factor; TNF: tumor necrosis factor; TRPV1: Transient receptor potential vanilloid 1; TRX-1: thioredoxin-1; UCP1: uncoupling protein-1; VLDL: very low density lipoprotein; WAT: white adipose tissue; and XBP1: X-box-binding protein 1.

References

  1. Hassan, K.; Bhalla, V.; El Regal, M.E.; A-Kader, H.H. Nonalcoholic fatty liver disease: A comprehensive review of a growing epidemic. World J. Gastroenterol. 2014, 20, 12082.
  2. Younossi, Z.M.; Koenig, A.B.; Abdelatif, D.; Fazel, Y.; Henry, L.; Wymer, M. Global epidemiology of nonalcoholic fatty liver disease—Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016, 64, 73–84.
  3. Scorletti, E.; Carr, R.M. A new perspective on NAFLD: Focusing on lipid droplets. J. Hepatol. 2022, 76, 934–945.
  4. Wree, A.; Broderick, L.; Canbay, A.; Hoffman, H.M.; Feldstein, A.E. From NAFLD to NASH to cirrhosis—New insights into disease mechanisms. Nat. Rev. Gastroenterol. Hepatol. 2013, 10, 627–636.
  5. Henao-Mejia, J.; Elinav, E.; Jin, C.; Hao, L.; Mehal, W.Z.; Strowig, T.; Thaiss, C.A.; Kau, A.L.; Eisenbarth, S.C.; Jurczak, M.J. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 2012, 482, 179–185.
  6. Propst, A. Prognosis in nonalcoholic steatohepatitis. Gastroenterology 1995, 108, 1607.
  7. Nseir, W.; Hellou, E.; Assy, N. Role of diet and lifestyle changes in nonalcoholic fatty liver disease. World J. Gastroenterol. 2014, 20, 9338.
  8. Mantovani, A.; Dalbeni, A. Treatments for NAFLD: State of art. Int. J. Mol. Sci. 2021, 22, 2350.
  9. Talebi, S.; Bagherniya, M.; Atkin, S.L.; Askari, G.; Orafai, H.M.; Sahebkar, A. The beneficial effects of nutraceuticals and natural products on small dense LDL levels, LDL particle number and LDL particle size: A clinical review. Lipids Health Dis. 2020, 19, 1–21.
  10. Noce, A.; Di Lauro, M.; Di Daniele, F.; Pietroboni Zaitseva, A.; Marrone, G.; Borboni, P.; Di Daniele, N. Natural bioactive compounds useful in clinical management of metabolic syndrome. Nutrients 2021, 13, 630.
  11. Bora, K.S.; Sharma, A. The genus Artemisia: A comprehensive review. Pharm. Biol. 2011, 49, 101–109.
  12. Jo, H.K.; Kim, G.W.; Jeong, K.J.; Do, Y.K.; Chung, S.H. Eugenol ameliorates hepatic steatosis and fibrosis by down-regulating SREBP1 gene expression via AMPK-mTOR-p70S6K signaling pathway. Biol. Pharm. Bull. 2014, 37, 1341–1351.
  13. Andrade, J.M.O.; Paraíso, A.F.; de Oliveira, M.V.M.; Martins, A.M.E.; Neto, J.F.; Guimarães, A.L.S.; de Paula, A.M.; Qureshi, M.; Santos, S.H.S. Resveratrol attenuates hepatic steatosis in high-fat fed mice by decreasing lipogenesis and inflammation. Nutrition 2014, 30, 915–919.
  14. Perdomo, C.M.; Frühbeck, G.; Escalada, J. Impact of nutritional changes on nonalcoholic fatty liver disease. Nutrients 2019, 11, 677.
  15. Mills, S.J.; Harrison, S.A. Comparison of the natural history of alcoholic and nonalcoholic fatty liver disease. Curr. Gastroenterol. Rep. 2005, 7, 32–36.
  16. Moore, J.B. Non-alcoholic fatty liver disease: The hepatic consequence of obesity and the metabolic syndrome. Proc. Nutr. Soc. 2010, 69, 211–220.
  17. Masarone, M.; Federico, A.; Abenavoli, L.; Loguercio, C.; Persico, M. Non alcoholic fatty liver: Epidemiology and natural history. Rev. Recent Clin. Trials 2014, 9, 126–133.
  18. Targher, G.; Bertolini, L.; Padovani, R.; Rodella, S.; Zoppini, G.; Zenari, L.; Cigolini, M.; Falezza, G.; Arcaro, G. Relations between carotid artery wall thickness and liver histology in subjects with nonalcoholic fatty liver disease. Diabetes Care 2006, 29, 1325–1330.
  19. Kasper, P.; Martin, A.; Lang, S.; Kuetting, F.; Goeser, T.; Demir, M.; Steffen, H.-M. NAFLD and cardiovascular diseases: A clinical review. Clin. Res. Cardiol. 2021, 110, 921–937.
  20. Eslam, M.; Sanyal, A.J.; George, J.; Sanyal, A.; Neuschwander-Tetri, B.; Tiribelli, C.; Kleiner, D.E.; Brunt, E.; Bugianesi, E.; Yki-Järvinen, H. MAFLD: A consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology 2020, 158, 1999–2014.
  21. Nucera, S.; Ruga, S.; Cardamone, A.; Coppoletta, A.R.; Guarnieri, L.; Zito, M.C.; Bosco, F.; Macrì, R.; Scarano, F.; Scicchitano, M. MAFLD progression contributes to altered thalamus metabolism and brain structure. Sci. Rep. 2022, 12, 1207.
  22. Kobyliak, N.; Abenavoli, L.; Mykhalchyshyn, G.; Kononenko, L.; Boccuto, L.; Kyriienko, D.; Dynnyk, O. A multi-strain probiotic reduces the fatty liver index, cytokines and aminotransferase levels in NAFLD patients: Evidence from a randomized clinical trial. J. Gastrointest. Liver Dis. 2018, 27, 41–49.
  23. Kolodziejczyk, A.A.; Zheng, D.; Shibolet, O.; Elinav, E. The role of the microbiome in NAFLD and NASH. EMBO Mol. Med. 2019, 11, e9302.
  24. Michail, S.; Lin, M.; Frey, M.R.; Fanter, R.; Paliy, O.; Hilbush, B.; Reo, N.V. Altered gut microbial energy and metabolism in children with non-alcoholic fatty liver disease. FEMS Microbiol. Ecol. 2015, 91, 1–9.
  25. Wang, B.; Jiang, X.; Cao, M.; Ge, J.; Bao, Q.; Tang, L.; Chen, Y.; Li, L. Altered fecal microbiota correlates with liver biochemistry in nonobese patients with non-alcoholic fatty liver disease. Sci. Rep. 2016, 6, 32002.
  26. Loomba, R.; Seguritan, V.; Li, W.; Long, T.; Klitgord, N.; Bhatt, A.; Dulai, P.S.; Caussy, C.; Bettencourt, R.; Highlander, S.K. Gut microbiome-based metagenomic signature for non-invasive detection of advanced fibrosis in human nonalcoholic fatty liver disease. Cell Metab. 2017, 25, 1054–1062.
  27. Boursier, J.; Mueller, O.; Barret, M.; Machado, M.; Fizanne, L.; Araujo-Perez, F.; Guy, C.D.; Seed, P.C.; Rawls, J.F.; David, L.A. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology 2016, 63, 764–775.
  28. Ren, Z.; Li, A.; Jiang, J.; Zhou, L.; Yu, Z.; Lu, H.; Xie, H.; Chen, X.; Shao, L.; Zhang, R. Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for early hepatocellular carcinoma. Gut 2019, 68, 1014–1023.
  29. Day, C.P.; James, O.F.W. Steatohepatitis: A tale of two “hits”? Gastroenterology 1998, 114, 842–845.
  30. Liu, Q.; Bengmark, S.; Qu, S. The role of hepatic fat accumulation in pathogenesis of non-alcoholic fatty liver disease (NAFLD). Lipids Health Dis. 2010, 9, 42.
  31. Loomba, R.; Friedman, S.L.; Shulman, G.I. Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell 2021, 184, 2537–2564.
  32. Takaki, A.; Kawai, D.; Yamamoto, K. Multiple hits, including oxidative stress, as pathogenesis and treatment target in non-alcoholic steatohepatitis (NASH). Int. J. Mol. Sci. 2013, 14, 20704–20728.
  33. Tilg, H.; Moschen, A.R. Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis. Hepatology 2010, 52, 1836–1846.
  34. Donnelly, K.L.; Smith, C.I.; Schwarzenberg, S.J.; Jessurun, J.; Boldt, M.D.; Parks, E.J. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Investig. 2005, 115, 1343–1351.
  35. Kawano, Y.; Cohen, D.E. Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease. J. Gastroenterol. 2013, 48, 434–441.
  36. Goldberg, I.J. Diabetic dyslipidemia: Causes and consequences. J. Clin. Endocrinol. Metab. 2001, 86, 965–971.
  37. Nassir, F.; Ibdah, J.A. Role of mitochondria in nonalcoholic fatty liver disease. Int. J. Mol. Sci. 2014, 15, 8713–8742.
  38. Berg, A.H.; Scherer, P.E. Adipose tissue, inflammation, and cardiovascular disease. Circ. Res. 2005, 96, 939–949.
  39. Kovacs, P.; Stumvoll, M. Fatty acids and insulin resistance in muscle and liver. Best Pract. Res. Clin. Endocrinol. Metab. 2005, 19, 625–635.
  40. Pan, M.; Lai, C.; Tsai, M.; Ho, C. Chemoprevention of nonalcoholic fatty liver disease by dietary natural compounds. Mol. Nutr. Food Res. 2014, 58, 147–171.
  41. Yuzefovych, L.V.; Musiyenko, S.I.; Wilson, G.L.; Rachek, L.I. Mitochondrial DNA damage and dysfunction, and oxidative stress are associated with endoplasmic reticulum stress, protein degradation and apoptosis in high fat diet-induced insulin resistance mice. PLoS ONE 2013, 8, e54059.
  42. Morgan, M.J.; Liu, Z. Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res. 2011, 21, 103–115.
  43. Lee, J.-M.; Calkins, M.J.; Chan, K.; Kan, Y.W.; Johnson, J.A. Identification of the NF-E2-related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis. J. Biol. Chem. 2003, 278, 12029–12038.
  44. Hosseini, H.; Teimouri, M.; Shabani, M.; Koushki, M.; Khorzoughi, R.B.; Namvarjah, F.; Izadi, P.; Meshkani, R. Resveratrol alleviates non-alcoholic fatty liver disease through epigenetic modification of the Nrf2 signaling pathway. Int. J. Biochem. Cell Biol. 2020, 119, 105667.
  45. Robertson, G.; Leclercq, I.; Farrell, G.C., II. Cytochrome P-450 enzymes and oxidative stress. Am. J. Physiol. Liver Physiol. 2001, 281, G1135–G1139.
  46. Phaniendra, A.; Jestadi, D.B.; Periyasamy, L. Free radicals: Properties, sources, targets, and their implication in various diseases. Indian J. Clin. Biochem. 2015, 30, 11–26.
  47. Mansouri, A.; Demeilliers, C.; Amsellem, S.; Pessayre, D.; Fromenty, B. Acute ethanol administration oxidatively damages and depletes mitochondrial DNA in mouse liver, brain, heart, and skeletal muscles: Protective effects of antioxidants. J. Pharmacol. Exp. Ther. 2001, 298, 737–743.
  48. Weltman, M.D.; Farrell, G.C.; Hall, P.; Ingelman-Sundberg, M.; Liddle, C. Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitis. Hepatology 1998, 27, 128–133.
  49. Chen, J.; Deng, X.; Liu, Y.; Tan, Q.; Huang, G.; Che, Q.; Guo, J.; Su, Z. Kupffer cells in non-alcoholic fatty liver disease: Friend or foe? Int. J. Biol. Sci. 2020, 16, 2367.
  50. Zisser, A.; Ipsen, D.H.; Tveden-Nyborg, P. Hepatic stellate cell activation and inactivation in NASH-fibrosis—Roles as putative treatment targets? Biomedicines 2021, 9, 365.
  51. Oktia, R.T.; Okita, J.R. Cytochrome P450 4A fatty acid omega hydroxylases. Curr. Drug Metab. 2001, 2, 265–281.
  52. Hardwick, J.P.; Osei-Hyiaman, D.; Wiland, H.; Abdelmegeed, M.A.; Song, B.-J. PPAR/RXR regulation of fatty acid metabolism and fatty acid ω-hydroxylase (CYP4) isozymes: Implications for prevention of lipotoxicity in fatty liver disease. PPAR Res. 2009, 2009, 952734.
  53. Suhaili, S.H.; Karimian, H.; Stellato, M.; Lee, T.-H.; Aguilar, M.-I. Mitochondrial outer membrane permeabilization: A focus on the role of mitochondrial membrane structural organization. Biophys. Rev. 2017, 9, 443–457.
  54. Schreurs, M.; Kuipers, F.; Van Der Leij, F.R. Regulatory enzymes of mitochondrial β-oxidation as targets for treatment of the metabolic syndrome. Obes. Rev. 2010, 11, 380–388.
  55. Reddy, J.K.; Sambasiva Rao, M. Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. Am. J. Physiol. Liver Physiol. 2006, 290, G852–G858.
  56. Kohjima, M.; Enjoji, M.; Higuchi, N.; Kato, M.; Kotoh, K.; Yoshimoto, T.; Fujino, T.; Yada, M.; Yada, R.; Harada, N. Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease. Int. J. Mol. Med. 2007, 20, 351–358.
  57. Durand, M.; Coué, M.; Croyal, M.; Moyon, T.; Tesse, A.; Atger, F.; Ouguerram, K.; Jacobi, D. Changes in key mitochondrial lipids accompany mitochondrial dysfunction and oxidative stress in NAFLD. Oxid. Med. Cell. Longev. 2021, 2021, 9986299.
  58. Ron, D. Proteotoxicity in the endoplasmic reticulum: Lessons from the Akita diabetic mouse. J. Clin. Investig. 2002, 109, 443–445.
  59. Demirtas, L.; Guclu, A.; Erdur, F.M.; Akbas, E.M.; Ozcicek, A.; Onk, D.; Turkmen, K. Apoptosis, autophagy & endoplasmic reticulum stress in diabetes mellitus. Indian J. Med. Res. 2016, 144, 515–524.
  60. Zhong, Q.; Wu, Y.; Xiong, F.; Liu, M.; Liu, Y.; Wang, C.; Chen, Y. Higher flavonoid intake is associated with a lower progression risk of non-alcoholic fatty liver disease in adults: A prospective study. Br. J. Nutr. 2021, 125, 460–470.
  61. Rodriguez-Ramiro, I.; Vauzour, D.; Minihane, A.M. Polyphenols and non-alcoholic fatty liver disease: Impact and mechanisms. Proc. Nutr. Soc. 2016, 75, 47–60.
  62. Ji, G.; Wang, Y.; Deng, Y.; Li, X.; Jiang, Z. Resveratrol ameliorates hepatic steatosis and inflammation in methionine/choline-deficient diet-induced steatohepatitis through regulating autophagy. Lipids Health Dis. 2015, 14, 134.
  63. Suenaga, F.; Hatsushika, K.; Takano, S.; Ando, T.; Ohnuma, Y.; Ogawa, H.; Nakao, A. A possible link between resveratrol and TGF-β: Resveratrol induction of TGF-β expression and signaling. FEBS Lett. 2008, 582, 586–590.
  64. Zhang, P.-W.; Chen, F.-X.; Li, D.; Ling, W.-H.; Guo, H.-H. A CONSORT-compliant, randomized, double-blind, placebo-controlled pilot trial of purified anthocyanin in patients with nonalcoholic fatty liver disease. Medicine 2015, 94, e758.
  65. Zhu, W.; Jia, Q.; Wang, Y.; Zhang, Y.; Xia, M. The anthocyanin cyanidin-3-O-β-glucoside, a flavonoid, increases hepatic glutathione synthesis and protects hepatocytes against reactive oxygen species during hyperglycemia: Involvement of a cAMP–PKA-dependent signaling pathway. Free Radic. Biol. Med. 2012, 52, 314–327.
  66. Reis, J.F.; Monteiro, V.V.S.; de Souza Gomes, R.; do Carmo, M.M.; da Costa, G.V.; Ribera, P.C.; Monteiro, M.C. Action mechanism and cardiovascular effect of anthocyanins: A systematic review of animal and human studies. J. Transl. Med. 2016, 14, 315.
  67. Roth, S.; Spalinger, M.R.; Gottier, C.; Biedermann, L.; Zeitz, J.; Lang, S.; Weber, A.; Rogler, G.; Scharl, M. Bilberry-derived anthocyanins modulate cytokine expression in the intestine of patients with ulcerative colitis. PLoS ONE 2016, 11, e0154817.
  68. Zhang, Y.; Meng, Q.; Yin, J.; Zhang, Z.; Bao, H.; Wang, X. Anthocyanins attenuate neuroinflammation through the suppression of MLK3 activation in a mouse model of perioperative neurocognitive disorders. Brain Res. 2020, 1726, 146504.
  69. Karunarathne, W.A.H.M.; Lee, K.T.; Choi, Y.H.; Jin, C.-Y.; Kim, G.-Y. Anthocyanins isolated from Hibiscus syriacus L. attenuate lipopolysaccharide-induced inflammation and endotoxic shock by inhibiting the TLR4/MD2-mediated NF-κB signaling pathway. Phytomedicine 2020, 76, 153237.
  70. Zang, Y.; Zhang, D.; Yu, C.; Jin, C.; Igarashi, K. Antioxidant and hepatoprotective activity of kaempferol 3-O-β-D-(2, 6-di-O-α-L-rhamnopyranosyl) galactopyronoside against carbon tetrachloride-induced liver injury in mice. Food Sci. Biotechnol. 2017, 26, 1071–1076.
  71. Wang, X.; Hasegawa, J.; Kitamura, Y.; Wang, Z.; Matsuda, A.; Shinoda, W.; Miura, N.; Kimura, K. Effects of hesperidin on the progression of hypercholesterolemia and fatty liver induced by high-cholesterol diet in rats. J. Pharmacol. Sci. 2011, 117, 129–138.
  72. Kumar, R.; Khan, M.I.; Ashfaq, F.; Alsayegh, A.A.; Khatoon, F.; Altamimi, T.N.; Rizvi, S.I. Hesperidin Supplementation Improves Altered PON-1, LDL Oxidation, Inflammatory Response and Hepatic Function in an Experimental Rat Model of Hyperlipidemia. Indian J. Clin. Biochem. 2023, 1–7.
  73. Parhiz, H.; Roohbakhsh, A.; Soltani, F.; Rezaee, R.; Iranshahi, M. Antioxidant and anti-inflammatory properties of the citrus flavonoids hesperidin and hesperetin: An updated review of their molecular mechanisms and experimental models. Phyther. Res. 2015, 29, 323–331.
  74. Cheraghpour, M.; Imani, H.; Ommi, S.; Alavian, S.M.; Karimi-Shahrbabak, E.; Hedayati, M.; Yari, Z.; Hekmatdoost, A. Hesperidin improves hepatic steatosis, hepatic enzymes, and metabolic and inflammatory parameters in patients with nonalcoholic fatty liver disease: A randomized, placebo-controlled, double-blind clinical trial. Phyther. Res. 2019, 33, 2118–2125.
  75. Guo, H.; Liu, D.; Ma, Y.; Liu, J.; Wang, Y.; Du, Z.; Wang, X.; Shen, J.; Peng, H. Long-term baicalin administration ameliorates metabolic disorders and hepatic steatosis in rats given a high-fat diet. Acta Pharmacol. Sin. 2009, 30, 1505–1512.
  76. Xi, Y.; Wu, M.; Li, H.; Dong, S.; Luo, E.; Gu, M.; Shen, X.; Jiang, Y.; Liu, Y.; Liu, H. Baicalin attenuates high fat diet-induced obesity and liver dysfunction: Dose-response and potential role of CaMKKβ/AMPK/ACC pathway. Cell. Physiol. Biochem. 2015, 35, 2349–2359.
  77. Chen, Q.; Liu, M.; Yu, H.; Li, J.; Wang, S.; Zhang, Y.; Qiu, F.; Wang, T. Scutellaria baicalensis regulates FFA metabolism to ameliorate NAFLD through the AMPK-mediated SREBP signaling pathway. J. Nat. Med. 2018, 72, 655–666.
  78. Malinska, H.; Hüttl, M.; Oliyarnyk, O.; Markova, I.; Poruba, M.; Racova, Z.; Kazdova, L.; Vecera, R. Beneficial effects of troxerutin on metabolic disorders in non-obese model of metabolic syndrome. PLoS ONE 2019, 14, e0220377.
  79. Geetha, R.; Yogalakshmi, B.; Sreeja, S.; Bhavani, K.; Anuradha, C.V. Troxerutin suppresses lipid abnormalities in the heart of high-fat–high-fructose diet-fed mice. Mol. Cell. Biochem. 2014, 387, 123–134.
  80. Zhang, Z.; Wang, X.; Zheng, G.; Shan, Q.; Lu, J.; Fan, S.; Sun, C.; Wu, D.; Zhang, C.; Su, W. Troxerutin attenuates enhancement of hepatic gluconeogenesis by inhibiting NOD activation-mediated inflammation in high-fat diet-treated mice. Int. J. Mol. Sci. 2016, 18, 31.
  81. Faghihzadeh, F.; Adibi, P.; Rafiei, R.; Hekmatdoost, A. Resveratrol supplementation improves inflammatory biomarkers in patients with nonalcoholic fatty liver disease. Nutr. Res. 2014, 34, 837–843.
  82. Cheng, K.; Song, Z.; Zhang, H.; Li, S.; Wang, C.; Zhang, L.; Wang, T. The therapeutic effects of resveratrol on hepatic steatosis in high-fat diet-induced obese mice by improving oxidative stress, inflammation and lipid-related gene transcriptional expression. Med. Mol. Morphol. 2019, 52, 187–197.
  83. Tian, Y.; Ma, J.; Wang, W.; Zhang, L.; Xu, J.; Wang, K.; Li, D. Resveratrol supplement inhibited the NF-κB inflammation pathway through activating AMPKα-SIRT1 pathway in mice with fatty liver. Mol. Cell. Biochem. 2016, 422, 75–84.
  84. Yan, C.; Zhang, Y.; Zhang, X.; Aa, J.; Wang, G.; Xie, Y. Curcumin regulates endogenous and exogenous metabolism via Nrf2-FXR-LXR pathway in NAFLD mice. Biomed. Pharmacother. 2018, 105, 274–281.
  85. Inzaugarat, M.E.; De Matteo, E.; Baz, P.; Lucero, D.; García, C.C.; Gonzalez Ballerga, E.; Daruich, J.; Sorda, J.A.; Wald, M.R.; Cherñavsky, A.C. New evidence for the therapeutic potential of curcumin to treat nonalcoholic fatty liver disease in humans. PLoS ONE 2017, 12, e0172900.
  86. Alappat, L.; Awad, A.B. Curcumin and obesity: Evidence and mechanisms. Nutr. Rev. 2010, 68, 729–738.
  87. Kuo, J.-J.; Chang, H.-H.; Tsai, T.-H.; Lee, T.-Y. Curcumin ameliorates mitochondrial dysfunction associated with inhibition of gluconeogenesis in free fatty acid-mediated hepatic lipoapoptosis. Int. J. Mol. Med. 2012, 30, 643–649.
  88. Jazayeri-Tehrani, S.A.; Rezayat, S.M.; Mansouri, S.; Qorbani, M.; Alavian, S.M.; Daneshi-Maskooni, M.; Hosseinzadeh-Attar, M.-J. Nano-curcumin improves glucose indices, lipids, inflammation, and Nesfatin in overweight and obese patients with non-alcoholic fatty liver disease (NAFLD): A double-blind randomized placebo-controlled clinical trial. Nutr. Metab. 2019, 16, 8.
  89. Liu, Y.N.; Zhang, Z.X. Effect of berberine on a cellular model of non-alcoholic fatty liver disease. Int J Clin Exp Med 2017, 10, 16360–16366.
  90. Deng, Y.; Tang, K.; Chen, R.; Nie, H.; Liang, S.; Zhang, J.; Zhang, Y.; Yang, Q. Berberine attenuates hepatic oxidative stress in rats with non-alcoholic fatty liver disease via the Nrf2/ARE signalling pathway. Exp. Ther. Med. 2019, 17, 2091–2098.
  91. Wang, L.; Jia, Z.; Wang, B.; Zhang, B. Berberine inhibits liver damage in rats with non-alcoholic fatty liver disease by regulating TLR4/MyD88/NF-κB pathway. Turkish J. Gastroenterol. 2020, 31, 902.
  92. Yan, H.-M.; Xia, M.-F.; Wang, Y.; Chang, X.-X.; Yao, X.-Z.; Rao, S.-X.; Zeng, M.-S.; Tu, Y.-F.; Feng, R.; Jia, W.-P. Efficacy of berberine in patients with non-alcoholic fatty liver disease. PLoS ONE 2015, 10, e0134172.
  93. Chen, W.; Zhang, X.; Xu, M.; Jiang, L.; Zhou, M.; Liu, W.; Chen, Z.; Wang, Y.; Zou, Q.; Wang, L. Betaine prevented high-fat diet-induced NAFLD by regulating the FGF10/AMPK signaling pathway in ApoE−/− mice. Eur. J. Nutr. 2021, 60, 1655–1668.
  94. Zhang, W.; Wang, L.; Wang, L.; Li, X.; Zhang, H.; Luo, L.-P.; Song, J.-C.; Gong, Z. Betaine protects against high-fat-diet-induced liver injury by inhibition of high-mobility group box 1 and Toll-like receptor 4 expression in rats. Dig. Dis. Sci. 2013, 58, 3198–3206.
  95. Chen, Y.; Liu, Y.; Zhou, R.; Chen, X.; Wang, C.; Tan, X.; Wang, L.; Zheng, R.; Zhang, H.; Ling, W. Associations of gut-flora-dependent metabolite trimethylamine-N-oxide, betaine and choline with non-alcoholic fatty liver disease in adults. Sci. Rep. 2016, 6, 19076.
  96. Zhang, Y.; Geng, C.; Liu, X.; Li, M.; Gao, M.; Liu, X.; Fang, F.; Chang, Y. Celastrol ameliorates liver metabolic damage caused by a high-fat diet through Sirt1. Mol. Metab. 2017, 6, 138–147.
  97. Sun, J.; Wang, H.; Yu, J.; Li, T.; Han, Y. Protective effect of celastrol on type 2 diabetes mellitus with nonalcoholic fatty liver disease in mice. Food Sci. Nutr. 2020, 8, 6207–6216.
  98. Bakar, M.H.A.; Tan, J.S. Improvement of mitochondrial function by celastrol in palmitate-treated C2C12 myotubes via activation of PI3K-Akt signaling pathway. Biomed. Pharmacother. 2017, 93, 903–912.
  99. Yu, X.; Meng, X.; Xu, M.; Zhang, X.; Zhang, Y.; Ding, G.; Huang, S.; Zhang, A.; Jia, Z. Celastrol ameliorates cisplatin nephrotoxicity by inhibiting NF-κB and improving mitochondrial function. EBioMedicine 2018, 36, 266–280.
  100. Zaitone, S.A.; Barakat, B.M.; Bilasy, S.E.; Fawzy, M.S.; Abdelaziz, E.Z.; Farag, N.E. Protective effect of boswellic acids versus pioglitazone in a rat model of diet-induced non-alcoholic fatty liver disease: Influence on insulin resistance and energy expenditure. Naunyn. Schmiedebergs. Arch. Pharmacol. 2015, 388, 587–600.
  101. Varma, K.; Haponiuk, J.T.; Gopi, S. Antiinflammatory Activity of Boswellia. In Inflammation and Natural Products; Elsevier: Amsterdam, The Netherlands, 2021; pp. 147–159.
  102. Bose, M.; Lambert, J.D.; Ju, J.; Reuhl, K.R.; Shapses, S.A.; Yang, C.S. The major green tea polyphenol,(-)-epigallocatechin-3-gallate, inhibits obesity, metabolic syndrome, and fatty liver disease in high-fat–fed mice. J. Nutr. 2008, 138, 1677–1683.
  103. Kuzu, N.; Bahcecioglu, I.H.; Dagli, A.F.; Ozercan, I.H.; Ustündag, B.; Sahin, K. Epigallocatechin gallate attenuates experimental non-alcoholic steatohepatitis induced by high fat diet. J. Gastroenterol. Hepatol. 2008, 23, e465–e470.
  104. Chung, M.-Y.; Park, H.J.; Manautou, J.E.; Koo, S.I.; Bruno, R.S. Green tea extract protects against nonalcoholic steatohepatitis in ob/ob mice by decreasing oxidative and nitrative stress responses induced by proinflammatory enzymes. J. Nutr. Biochem. 2012, 23, 361–367.
  105. Nakamoto, K.; Takayama, F.; Mankura, M.; Hidaka, Y.; Egashira, T.; Ogino, T.; Kawasaki, H.; Mori, A. Beneficial effects of fermented green tea extract in a rat model of non-alcoholic steatohepatitis. J. Clin. Biochem. Nutr. 2009, 44, 239–246.
  106. Elahi, R.K. Preventive effects of turmeric (Curcuma longa Linn.) powder on hepatic steatosis in the rats fed with high fat diet. Life Sci. J. 2012, 9, 5462–5468.
  107. Farzaei, M.H.; Zobeiri, M.; Parvizi, F.; El-Senduny, F.F.; Marmouzi, I.; Coy-Barrera, E.; Naseri, R.; Nabavi, S.M.; Rahimi, R.; Abdollahi, M. Curcumin in liver diseases: A systematic review of the cellular mechanisms of oxidative stress and clinical perspective. Nutrients 2018, 10, 855.
  108. Porras, D.; Nistal, E.; Martínez-Flórez, S.; Pisonero-Vaquero, S.; Olcoz, J.L.; Jover, R.; González-Gallego, J.; García-Mediavilla, M.V.; Sánchez-Campos, S. Protective effect of quercetin on high-fat diet-induced non-alcoholic fatty liver disease in mice is mediated by modulating intestinal microbiota imbalance and related gut-liver axis activation. Free Radic. Biol. Med. 2017, 102, 188–202.
  109. Hoek-van den Hil, E.F.; van Schothorst, E.M.; van der Stelt, I.; Swarts, H.J.M.; van Vliet, M.; Amolo, T.; Vervoort, J.J.M.; Venema, D.; Hollman, P.C.H.; Rietjens, I.M.C.M. Direct comparison of metabolic health effects of the flavonoids quercetin, hesperetin, epicatechin, apigenin and anthocyanins in high-fat-diet-fed mice. Genes Nutr. 2015, 10, 23.
  110. Perri, M.R.; Marrelli, M.; Statti, G.; Conforti, F. Olea europaea bud extracts: Inhibitory effects on pancreatic lipase and α-amylase activities of different cultivars from Calabria region (Italy). Plant Biosyst. 2020.
  111. Jafri, M.A.; Aslam, M.; Javed, K.; Singh, S. Effect of Punica granatum Linn.(flowers) on blood glucose level in normal and alloxan-induced diabetic rats. J. Ethnopharmacol. 2000, 70, 309–314.
  112. Bagri, P.; Ali, M.; Aeri, V.; Bhowmik, M.; Sultana, S. Antidiabetic effect of Punica granatum flowers: Effect on hyperlipidemia, pancreatic cells lipid peroxidation and antioxidant enzymes in experimental diabetes. Food Chem. Toxicol. 2009, 47, 50–54.
  113. Li, Y.; Wen, S.; Kota, B.P.; Peng, G.; Li, G.Q.; Yamahara, J.; Roufogalis, B.D. Punica granatum flower extract, a potent α-glucosidase inhibitor, improves postprandial hyperglycemia in Zucker diabetic fatty rats. J. Ethnopharmacol. 2005, 99, 239–244.
  114. Xu, K.Z.-Y.; Zhu, C.; Kim, M.S.; Yamahara, J.; Li, Y. Pomegranate flower ameliorates fatty liver in an animal model of type 2 diabetes and obesity. J. Ethnopharmacol. 2009, 123, 280–287.
  115. Hajiaghamohammadi, A.A.; Ziaee, A.; Oveisi, S.; Masroor, H. Effects of metformin, pioglitazone, and silymarin treatment on non-alcoholic fatty liver disease: A randomized controlled pilot study. Hepat. Mon. 2012, 12, e6099.
  116. Salomone, F.; Barbagallo, I.; Godos, J.; Lembo, V.; Currenti, W.; Cinà, D.; Avola, R.; D’Orazio, N.; Morisco, F.; Galvano, F. Silibinin restores NAD+ levels and induces the SIRT1/AMPK pathway in non-alcoholic fatty liver. Nutrients 2017, 9, 1086.
  117. Cui, C.-X.; Deng, J.-N.; Yan, L.; Liu, Y.-Y.; Fan, J.-Y.; Mu, H.-N.; Sun, H.-Y.; Wang, Y.-H.; Han, J.-Y. Silibinin capsules improves high fat diet-induced nonalcoholic fatty liver disease in hamsters through modifying hepatic de novo lipogenesis and fatty acid oxidation. J. Ethnopharmacol. 2017, 208, 24–35.
  118. Gu, M.; Zhao, P.; Huang, J.; Zhao, Y.; Wang, Y.; Li, Y.; Li, Y.; Fan, S.; Ma, Y.-M.; Tong, Q. Silymarin ameliorates metabolic dysfunction associated with diet-induced obesity via activation of farnesyl X receptor. Front. Pharmacol. 2016, 7, 345.
  119. Haddad, Y.; Vallerand, D.; Brault, A.; Haddad, P.S. Antioxidant and hepatoprotective effects of silibinin in a rat model of nonalcoholic steatohepatitis. Evid.-Based Complement. Altern. Med. 2011, 2011, 647903.
  120. Serviddio, G.; Bellanti, F.; Giudetti, A.M.; Gnoni, G.V.; Petrella, A.; Tamborra, R.; Romano, A.D.; Rollo, T.; Vendemiale, G.; Altomare, E. A silybin-phospholipid complex prevents mitochondrial dysfunction in a rodent model of nonalcoholic steatohepatitis. J. Pharmacol. Exp. Ther. 2010, 332, 922–932.
  121. Kim, H.M.; Kim, Y.; Lee, E.S.; Huh, J.H.; Chung, C.H. Caffeic acid ameliorates hepatic steatosis and reduces ER stress in high fat diet–induced obese mice by regulating autophagy. Nutrition 2018, 55, 63–70.
  122. Zhang, S.-J.; Li, Y.-F.; Wang, G.-E.; Tan, R.-R.; Tsoi, B.; Mao, G.-W.; Zhai, Y.-J.; Cao, L.-F.; Chen, M.; Kurihara, H. Caffeine ameliorates high energy diet-induced hepatic steatosis: Sirtuin 3 acts as a bridge in the lipid metabolism pathway. Food Funct. 2015, 6, 2578–2587.
  123. Watanabe, S.; Takahashi, T.; Ogawa, H.; Uehara, H.; Tsunematsu, T.; Baba, H.; Morimoto, Y.; Tsuneyama, K. Daily coffee intake inhibits pancreatic beta cell damage and nonalcoholic steatohepatitis in a mouse model of spontaneous metabolic syndrome, tsumura-suzuki obese diabetic mice. Metab. Syndr. Relat. Disord. 2017, 15, 170–177.
  124. Ontawong, A.; Boonphang, O.; Pasachan, T.; Duangjai, A.; Pongchaidecha, A.; Phatsara, M.; Jinakote, M.; Amornlerdpison, D.; Srimaroeng, C. Hepatoprotective effect of coffee pulp aqueous extract combined with simvastatin against hepatic steatosis in high-fat diet-induced obese rats. J. Funct. Foods 2019, 54, 568–577.
  125. Vitaglione, P.; Mazzone, G.; Lembo, V.; D’Argenio, G.; Rossi, A.; Guido, M.; Savoia, M.; Salomone, F.; Mennella, I.; De Filippis, F. Coffee prevents fatty liver disease induced by a high-fat diet by modulating pathways of the gut–liver axis. J. Nutr. Sci. 2019, 8, e15.
  126. Fang, C.; Cai, X.; Hayashi, S.; Hao, S.; Sakiyama, H.; Wang, X.; Yang, Q.; Akira, S.; Nishiguchi, S.; Fujiwara, N. Caffeine-stimulated muscle IL-6 mediates alleviation of non-alcoholic fatty liver disease. Biochim. Biophys. Acta (BBA)-Molecular Cell Biol. Lipids 2019, 1864, 271–280.
  127. Brandt, A.; Nier, A.; Jin, C.J.; Baumann, A.; Jung, F.; Ribas, V.; García-Ruiz, C.; Fernández-Checa, J.C.; Bergheim, I. Consumption of decaffeinated coffee protects against the development of early non-alcoholic steatohepatitis: Role of intestinal barrier function. Redox Biol. 2019, 21, 101092.
  128. Chung, S.I.; Kim, T.H.; Rico, C.W.; Kang, M.Y. Effect of instant cooked giant embryonic rice on body fat weight and plasma lipid profile in high fat-fed mice. Nutrients 2014, 6, 2266–2278.
  129. Wang, Y.-X.; Li, Y.; Sun, A.-M.; Wang, F.-J.; Yu, G.-P. Hypolipidemic and antioxidative effects of aqueous enzymatic extract from rice bran in rats fed a high-fat and-cholesterol diet. Nutrients 2014, 6, 3696–3710.
  130. Choi, W.H.; Um, M.Y.; Ahn, J.; Jung, C.H.; Ha, T.Y. Long-term intake of rice improves insulin sensitivity in mice fed a high-fat diet. Nutrition 2014, 30, 920–927.
  131. Senadheera, S.P.A.S.; Ekanayake, S.; Wanigatunge, C. Anti-diabetic properties of rice-based herbal porridges in diabetic Wistar rats. Phyther. Res. 2014, 28, 1567–1572.
  132. Yang, C.W.; Mousa, S.A. The effect of red yeast rice (Monascus purpureus) in dyslipidemia and other disorders. Complement. Ther. Med. 2012, 20, 466–474.
  133. Klimek, M.; Wang, S.; Ogunkanmi, A. Safety and efficacy of red yeast rice (Monascus purpureus) as an alternative therapy for hyperlipidemia. Pharm. Ther. 2009, 34, 313.
  134. Childress, L.; Gay, A.; Zargar, A.; Ito, M.K. Review of red yeast rice content and current Food and Drug Administration oversight. J. Clin. Lipidol. 2013, 7, 117–122.
  135. Gerards, M.C.; Terlou, R.J.; Yu, H.; Koks, C.H.W.; Gerdes, V.E.A. Traditional Chinese lipid-lowering agent red yeast rice results in significant LDL reduction but safety is uncertain—A systematic review and meta-analysis. Atherosclerosis 2015, 240, 415–423.
  136. D’Antuono, I.; Garbetta, A.; Linsalata, V.; Minervini, F.; Cardinali, A. Polyphenols from artichoke heads (Cynara cardunculus (L.) subsp. scolymus Hayek): In vitro bio-accessibility, intestinal uptake and bioavailability. Food Funct. 2015, 6, 1268–1277.
  137. Halliwell, B.; Zhao, K.; Whiteman, M. The gastrointestinal tract: A major site of antioxidant action? Free Radic. Res. 2000, 33, 819–830.
  138. Magielse, J.; Verlaet, A.; Breynaert, A.; Keenoy, B.M.Y.; Apers, S.; Pieters, L.; Hermans, N. Investigation of the in vivo antioxidative activity of Cynara scolymus (artichoke) leaf extract in the streptozotocin-induced diabetic rat. Mol. Nutr. Food Res. 2014, 58, 211–215.
  139. Küçükgergin, C.; Aydın, A.F.; Özdemirler-Erata, G.; Mehmetçik, G.; Koçak-Toker, N.; Uysal, M. Effect of artichoke leaf extract on hepatic and cardiac oxidative stress in rats fed on high cholesterol diet. Biol. Trace Elem. Res. 2010, 135, 264–274.
  140. Jacociunas, L.V.; de Andrade, H.H.R.; Lehmann, M.; de Abreu, B.R.R.; Ferraz, A.d.B.F.; da Silva, J.; Grivicich, I.; Dihl, R.R. Artichoke induces genetic toxicity in the cytokinesis-block micronucleus (CBMN) cytome assay. Food Chem. Toxicol. 2013, 55, 56–59.
  141. Pereira, C.; Barreira, J.C.M.; Calhelha, R.C.; Queiroz, M.J.R.P.; Barros, L.; Ferreira, I.C.F.R. New insights into the effects of formulation type and compositional mixtures on the antioxidant and cytotoxic activities of dietary supplements based-on hepatoprotective plants. Food Funct. 2014, 5, 2052–2060.
  142. Imai, S. Soybean and processed soy foods ingredients, and their role in cardiometabolic risk prevention. Recent Pat. Food. Nutr. Agric. 2015, 7, 75–82.
  143. Yoon, G.-A.; Park, S. Antioxidant action of soy isoflavones on oxidative stress and antioxidant enzyme activities in exercised rats. Nutr. Res. Pract. 2014, 8, 618–624.
  144. Oh, H.-G.; Kang, Y.-R.; Lee, H.-Y.; Kim, J.-H.; Shin, E.-H.; Lee, B.-G.; Park, S.-H.; Moon, D.-I.; Kim, O.-J.; Lee, I.-A. Ameliorative effects of Monascus pilosus-fermented black soybean (Glycine max L. Merrill) on high-fat diet-induced obesity. J. Med. Food 2014, 17, 972–978.
  145. Kim, Y.; Yoon, S.; Lee, S.B.; Han, H.W.; Oh, H.; Lee, W.J.; Lee, S.-M. Fermentation of soy milk via Lactobacillus plantarum improves dysregulated lipid metabolism in rats on a high cholesterol diet. PLoS ONE 2014, 9, e88231.
  146. Gray, A.M.; Flatt, P.R. Pancreatic and extra-pancreatic effects of the traditional anti-diabetic plant, Medicago sativa (lucerne). Br. J. Nutr. 1997, 78, 325–334.
  147. Raeeszadeh, M.; Beheshtipour, J.; Jamali, R.; Akbari, A. The antioxidant properties of Alfalfa (Medicago sativa L.) and its biochemical, antioxidant, anti-inflammatory, and pathological effects on nicotine-induced oxidative stress in the rat liver. Oxid. Med. Cell. Longev. 2022, 2022, 2691577.
  148. Shi, Y.; Guo, R.; Wang, X.; Yuan, D.; Zhang, S.; Wang, J.; Yan, X.; Wang, C. The regulation of alfalfa saponin extract on key genes involved in hepatic cholesterol metabolism in hyperlipidemic rats. PLoS ONE 2014, 9, e88282.
  149. Mollace, V.; Scicchitano, M.; Paone, S.; Casale, F.; Calandruccio, C.; Gliozzi, M.; Musolino, V.; Carresi, C.; Maiuolo, J.; Nucera, S. Hypoglycemic and hypolipemic effects of a new lecithin formulation of bergamot polyphenolic fraction: A double blind, randomized, placebo-controlled study. Endocr. Metab. Immune Disord. Targets (Former. Curr. Drug Targets-Immune Endocr. Metab. Disord.) 2019, 19, 136–143.
  150. Quirino, A.; Giorgi, V.; Palma, E.; Marascio, N.; Morelli, P.; Maletta, A.; Divenuto, F.; De Angelis, G.; Tancrè, V.; Nucera, S. Citrus bergamia: Kinetics of Antimicrobial Activity on Clinical Isolates. Antibiotics 2022, 11, 361.
  151. Maiuolo, J.; Bosco, F.; Guarnieri, L.; Nucera, S.; Ruga, S.; Oppedisano, F.; Tucci, L.; Muscoli, C.; Palma, E.; Giuffrè, A.M. Protective Role of an Extract Waste Product from Citrus bergamia in an In Vitro Model of Neurodegeneration. Plants 2023, 12, 2126.
  152. Miceli, N.; Mondello, M.R.; Monforte, M.T.; Sdrafkakis, V.; Dugo, P.; Crupi, M.L.; Taviano, M.F.; De Pasquale, R.; Trovato, A. Hypolipidemic effects of Citrus bergamia Risso et Poiteau juice in rats fed a hypercholesterolemic diet. J. Agric. Food Chem. 2007, 55, 10671–10677.
  153. Mare, R.; Mazza, E.; Ferro, Y.; Gliozzi, M.; Nucera, S.; Paone, S.; Aversa, I.; Pujia, R.; Marafioti, G.; Musolino, V. A new breakfast brioche containing bergamot fiber prevents insulin and glucose increase in healthy volunteers: A pilot study. Minerva Endocrinol. 2020, 46, 214–225.
  154. Pernice, R.; Borriello, G.; Ferracane, R.; Borrelli, R.C.; Cennamo, F.; Ritieni, A. Bergamot: A source of natural antioxidants for functionalized fruit juices. Food Chem. 2009, 112, 545–550.
  155. Carresi, C.; Musolino, V.; Gliozzi, M.; Maiuolo, J.; Mollace, R.; Nucera, S.; Maretta, A.; Sergi, D.; Muscoli, S.; Gratteri, S. Anti-oxidant effect of bergamot polyphenolic fraction counteracts doxorubicin-induced cardiomyopathy: Role of autophagy and c-kitposCD45negCD31neg cardiac stem cell activation. J. Mol. Cell. Cardiol. 2018, 119, 10–18.
  156. Maiuolo, J.; Bava, I.; Carresi, C.; Gliozzi, M.; Musolino, V.; Scarano, F.; Nucera, S.; Scicchitano, M.; Bosco, F.; Ruga, S. The Effects of Bergamot Polyphenolic Fraction, Cynara cardunculus, and Olea europea L. Extract on Doxorubicin-Induced Cardiotoxicity. Nutrients 2021, 13, 2158.
  157. Navarra, M.; Ursino, M.R.; Ferlazzo, N.; Russo, M.; Schumacher, U.; Valentiner, U. Effect of Citrus bergamia juice on human neuroblastoma cells in vitro and in metastatic xenograft models. Fitoterapia 2014, 95, 83–92.
  158. Visalli, G.; Ferlazzo, N.; Cirmi, S.; Campiglia, P.; Gangemi, S.; Di Pietro, A.; Calapai, G.; Navarra, M. Bergamot juice extract inhibits proliferation by inducing apoptosis in human colon cancer cells. Anti-Cancer Agents Med. Chem. (Former. Curr. Med. Chem. Agents) 2014, 14, 1402–1413.
  159. Delle Monache, S.; Sanità, P.; Trapasso, E.; Ursino, M.R.; Dugo, P.; Russo, M.; Ferlazzo, N.; Calapai, G.; Angelucci, A.; Navarra, M. Mechanisms underlying the anti-tumoral effects of Citrus bergamia juice. PLoS ONE 2013, 8, e61484.
  160. Mollace, V.; Sacco, I.; Janda, E.; Malara, C.; Ventrice, D.; Colica, C.; Visalli, V.; Muscoli, S.; Ragusa, S.; Muscoli, C. Hypolipemic and hypoglycaemic activity of bergamot polyphenols: From animal models to human studies. Fitoterapia 2011, 82, 309–316.
  161. Musolino, V.; Gliozzi, M.; Carresi, C.; Maiuolo, J.; Mollace, R.; Bosco, F.; Scarano, F.; Scicchitano, M.; Maretta, A.; Palma, E. Lipid-lowering effect of bergamot polyphenolic fraction: Role of pancreatic cholesterol ester hydrolase. J. Biol. Regul. Homeost. Agents 2017, 31, 1087–1093.
  162. Gliozzi, M.; Walker, R.; Muscoli, S.; Vitale, C.; Gratteri, S.; Carresi, C.; Musolino, V.; Russo, V.; Janda, E.; Ragusa, S. Bergamot polyphenolic fraction enhances rosuvastatin-induced effect on LDL-cholesterol, LOX-1 expression and protein kinase B phosphorylation in patients with hyperlipidemia. Int. J. Cardiol. 2013, 170, 140–145.
  163. Musolino, V.; Gliozzi, M.; Bombardelli, E.; Nucera, S.; Carresi, C.; Maiuolo, J.; Mollace, R.; Paone, S.; Bosco, F.; Scarano, F. The synergistic effect of Citrus bergamia and Cynara cardunculus extracts on vascular inflammation and oxidative stress in non-alcoholic fatty liver disease. J. Tradit. Complement. Med. 2020, 10, 268–274.
  164. Herrero, M.; Plaza, M.; Cifuentes, A.; Ibáñez, E. Green processes for the extraction of bioactives from Rosemary: Chemical and functional characterization via ultra-performance liquid chromatography-tandem mass spectrometry and in-vitro assays. J. Chromatogr. A 2010, 1217, 2512–2520.
  165. Afonso, M.S.; de O Silva, A.M.; Carvalho, E.B.T.; Rivelli, D.P.; Barros, S.B.M.; Rogero, M.M.; Lottenberg, A.M.; Torres, R.P.; Mancini-Filho, J. Phenolic compounds from Rosemary (Rosmarinus officinalis L.) attenuate oxidative stress and reduce blood cholesterol concentrations in diet-induced hypercholesterolemic rats. Nutr. Metab. 2013, 10, 19.
  166. Labban, L.; Mustafa, U.E.-S.; Ibrahim, Y.M. The effects of rosemary (Rosmarinus officinalis) leaves powder on glucose level, lipid profile and lipid perodoxation. Int. J. Clin. Med. 2014, 5, 297–304.
  167. Harach, T.; Aprikian, O.; Monnard, I.; Moulin, J.; Membrez, M.; Béolor, J.-C.; Raab, T.; Macé, K.; Darimont, C. Rosemary (Rosmarinus officinalis L.) leaf extract limits weight gain and liver steatosis in mice fed a high-fat diet. Planta Med. 2010, 76, 566–571.
  168. Ibarra, A.; Cases, J.; Roller, M.; Chiralt-Boix, A.; Coussaert, A.; Ripoll, C. Carnosic acid-rich rosemary (Rosmarinus officinalis L.) leaf extract limits weight gain and improves cholesterol levels and glycaemia in mice on a high-fat diet. Br. J. Nutr. 2011, 106, 1182–1189.
  169. Rau, O.; Wurglics, M.; Paulke, A.; Zitzkowski, J.; Meindl, N.; Bock, A.; Dingermann, T.; Abdel-Tawab, M.; Schubert-Zsilavecz, M. Carnosic acid and carnosol, phenolic diterpene compounds of the labiate herbs rosemary and sage, are activators of the human peroxisome proliferator-activated receptor gamma. Planta Med. 2006, 72, 881–887.
  170. Wang, T.; Takikawa, Y.; Satoh, T.; Yoshioka, Y.; Kosaka, K.; Tatemichi, Y.; Suzuki, K. Carnosic acid prevents obesity and hepatic steatosis in ob/ob mice. Hepatol. Res. 2011, 41, 87–92.
  171. Zhao, Y.; Sedighi, R.; Wang, P.; Chen, H.; Zhu, Y.; Sang, S. Carnosic acid as a major bioactive component in rosemary extract ameliorates high-fat-diet-induced obesity and metabolic syndrome in mice. J. Agric. Food Chem. 2015, 63, 4843–4852.
  172. Shan, W.; Gao, L.; Zeng, W.; Hu, Y.; Wang, G.; Li, M.; Zhou, J.; Ma, X.; Tian, X.; Yao, J. Activation of the SIRT1/p66shc antiapoptosis pathway via carnosic acid-induced inhibition of miR-34a protects rats against nonalcoholic fatty liver disease. Cell Death Dis. 2015, 6, e1833.
  173. Schuhmacher, A.; Reichling, J.; Schnitzler, P. Virucidal effect of peppermint oil on the enveloped viruses herpes simplex virus type 1 and type 2 in vitro. Phytomedicine 2003, 10, 504–510.
  174. Kwon, E.-Y.; Jung, U.J.; Park, T.; Yun, J.W.; Choi, M.-S. Luteolin attenuates hepatic steatosis and insulin resistance through the interplay between the liver and adipose tissue in mice with diet-induced obesity. Diabetes 2015, 64, 1658–1669.
  175. Mesbahzadeh, B.; Akbari, M.; Zadeh, J.B. The effects of different levels of peppermint alcoholic extract on body-weight gain and blood biochemical parameters of adult male Wistar rats. Electron. Physician 2015, 7, 1376.
  176. Lima, C.F.; Valentao, P.C.R.; Andrade, P.B.; Seabra, R.M.; Fernandes-Ferreira, M.; Pereira-Wilson, C. Water and methanolic extracts of Salvia officinalis protect HepG2 cells from t-BHP induced oxidative damage. Chem. Biol. Interact. 2007, 167, 107–115.
  177. Ninomiya, K.; Matsuda, H.; Shimoda, H.; Nishida, N.; Kasajima, N.; Yoshino, T.; Morikawa, T.; Yoshikawa, M. Carnosic acid, a new class of lipid absorption inhibitor from sage. Bioorg. Med. Chem. Lett. 2004, 14, 1943–1946.
  178. Sá, C.M.; Ramos, A.A.; Azevedo, M.F.; Lima, C.F.; Fernandes-Ferreira, M.; Pereira-Wilson, C. Sage tea drinking improves lipid profile and antioxidant defences in humans. Int. J. Mol. Sci. 2009, 10, 3937–3950.
  179. Behradmanesh, S.; Derees, F.; Rafieian-Kopaei, M. Effect of Salvia officinalis on diabetic patients. J. Ren. Inj. Prev. 2013, 2, 51.
  180. Sharma, S.K.; Vij, A.S.; Sharma, M. Mechanisms and clinical uses of capsaicin. Eur. J. Pharmacol. 2013, 720, 55–62.
  181. McCarty, M.F.; DiNicolantonio, J.J.; O’Keefe, J.H. Capsaicin may have important potential for promoting vascular and metabolic health. Open Hear. 2015, 2, e000262.
  182. Hong, Q.; Xia, C.; Xiangying, H.; Quan, Y. Capsinoids suppress fat accumulation via lipid metabolism. Mol. Med. Rep. 2015, 11, 1669–1674.
  183. Li, Q.; Li, L.; Wang, F.; Chen, J.; Zhao, Y.; Wang, P.; Nilius, B.; Liu, D.; Zhu, Z. Dietary capsaicin prevents nonalcoholic fatty liver disease through transient receptor potential vanilloid 1-mediated peroxisome proliferator-activated receptor δ activation. Pflügers Arch. J. Physiol. 2013, 465, 1303–1316.
  184. Kang, J.-H.; Kim, C.-S.; Han, I.-S.; Kawada, T.; Yu, R. Capsaicin, a spicy component of hot peppers, modulates adipokine gene expression and protein release from obese-mouse adipose tissues and isolated adipocytes, and suppresses the inflammatory responses of adipose tissue macrophages. FEBS Lett. 2007, 581, 4389–4396.
  185. Lee, G.; Shin, M.K.; Yoon, D.; Kim, A.; Yu, R.; Park, N.; Han, I. Topical application of capsaicin reduces visceral adipose fat by affecting adipokine levels in high-fat diet-induced obese mice. Obesity 2013, 21, 115–122.
  186. Kang, J.; Tsuyoshi, G.; Han, I.; Kawada, T.; Kim, Y.M.; Yu, R. Dietary capsaicin reduces obesity-induced insulin resistance and hepatic steatosis in obese mice fed a high-fat diet. Obesity 2010, 18, 780–787.
  187. McCarty, M.F. High mitochondrial redox potential may promote induction and activation of UCP2 in hepatocytes during hepatothermic therapy. Med. Hypotheses 2005, 64, 1216–1219.
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Saverio Nucera
,
Rosa Maria Bulotta
,
Stefano Ruga
,
Rosamaria Caminiti
,
Maria Serra
,
Roberto Bava
,
Fabio Castagna
,
Carmine Lupia
,
Mariangela Marrelli
,
Filomena Conforti
,
Giancarlo Statti
,
Vincenzo Mollace
,
Ernesto Palma
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Update Date: 27 Feb 2024
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