Phytochemicals to Counteract the Stages of Liver Disease: Comparison
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Please note this is a comparison between Version 2 by Jessie Wu and Version 1 by Vincenzo Vestuto.

The liver is composed of several cell types, mainly including hepatocytes, cholangiocytes, stellate cells, sinusoidal cells, and Kupffer cells. Hepatocytes are the most abundant cells in the liver volume, and they perform many biological functions attributed to this organ; cholangiocytes are polarized cells that line the bile ducts within the liver and play a crucial role in the secretion and modification of bile, which is essential for the digestion and absorption of fats in the small intestine, in addition to their immunological functions; hepatic stellate cells (HSCs) are a multifaceted cell population existing as a quiescent form that can be activated when damage is induced to promote wound healing; sinusoidal endothelial cells are a specialized endothelial population that coat the hepatic sinusoids and allow for the exchange of nutrients, hormones, and waste products between the blood and the liver cells; and finally, Kupffer cells are a type of dedicated macrophage of the liver that help to remove foreign particles such as bacteria and viruses.

  • liver disease
  • inflammation
  • steatosis
  • ALD
  • NAFLD
  • ASH
  • NASH
  • angiogenesis
  • hepatocellular carcinoma
  • natural compounds

1. Quercetin

Quercetin is a flavonoid that is found in fruits such as apples, red grapes, citrus fruits, tomatoes, onions, and other green leafy vegetables. Quercetin possesses various biological and pharmacological activities, including antioxidant, antiviral, anti-inflammatory, antiproliferative, and antifibrotic effects [88,89][1][2]. In recent studies, quercetin inhibited hepatic inflammation and fibrosis in mice by downregulating the HMGB1-TLR2/4-NF-κB signaling pathway [90][3]. Moreover, it also limited hepatic fibrosis by inhibiting HSC activation and reducing autophagy by regulating crosstalk between the TGF-β1/Smads and PI3K/Akt pathways [91][4].
Nevertheless, recent data show that macrophages play a complex role in liver fibrogenesis and are directly involved in the progression and resolution of liver fibrosis [92,93][5][6]. Indeed, inflammatory cytokines released by macrophages perpetuate inflammation and activate HSCs; quercetin showed direct effects by reducing the number of hepatic macrophages and ameliorating liver fibrosis after treatment of mice with CCl4 [94][7]. In conclusion, quercetin is a flavonoid with numerous biological benefits, and because of its anti-inflammatory and antifibrotic effects, it may hold promise as a potential therapeutic agent for liver fibrosis.

2. Silybin

Silybin is a flavonolignan that exists as a mixture of two diastereomers, silybin A and silybin B, in a roughly equimolar ratio [95][8]. It is usually extracted together with other compounds from milk thistle (Silybum marianum) in a mixture called silymarin, consisting of 50–60% silybin, with the rest consisting of silydianin, silycristin, taxifolin, and other polyphenolic components [96][9]; these are known compounds with antioxidant activity [97][10]. Several pharmacological actions of silybin were identified, including antioxidant and anti-inflammatory properties, antifibrotic effects, and the modulation of insulin resistance. Specifically, in chronic inflammation, it underlies liver fibrosis and the development of cirrhosis [98][11].
The common mechanism underlying the initiation and progression of liver inflammation is oxidative stress [99][12]. NF-κB is a crucial transcriptional regulator involved in the inflammatory response and plays an essential role in controlling the inflammatory signaling pathways within the liver [100][13]. Furthermore, NF-κB is activated in virtually all chronic liver diseases, including ALD, NAFLD, viral hepatitis, and biliary liver disease [101,102,103][14][15][16]. There is increasing evidence for a general inhibition of inflammatory mediators such as NF-κB and inflammatory metabolites (e.g., prostaglandin E2 (PGE 2) and leukotriene B4 (LTB 4)) by silymarin [104][17].
In isolated rat Kupffer cells, silymarin demonstrated a weak inhibition of PGE2 formation, but showed a strong ability to block the biosynthesis of LTB4 [105][18]. This selective inhibition of LTB 4 formation by Kupffer cells and possibly other cell types may explain silymarin’s anti-inflammatory potential.
In addition, it can reduce or normalize the liver function parameters, such as transaminase levels, and improve the ultrasound parameters of liver anatomy [106][19]. Therefore, silymarin (formulation derived from Eurosil 85®) was investigated as a therapeutic option for NAFLD and NASH.
Therefore, silybin a has antioxidant and anti-inflammatory properties and may inhibit NF-κB and inflammatory metabolites, having potential to be a therapy for NAFLD and NASH, since it improves liver function and multiple ultrasound parameters used in liver ultrasonography. Silybin holds promise as a therapeutic agent for liver inflammation and fibrosis.

3. Breviscapine

Breviscapine is a crude mixture of several flavonoids from the traditional Chinese herb Erigeron breviscapus. It consists of more than 90% scutellarin and also contains baicalein, naringenin, scopoletin, kaempferol, apigenin, scutellarin, luteolin, caffeic acid, and protocatechuic acid [107][20]. It has multiple pharmacological activities, including anti-inflammatory, antioxidant, antiapoptotic, vasorelaxant, antiplatelet, anticoagulant, and myocardial protective activities [108,109][21][22]. Recent studies show that breviscapine protects against CCl4-induced liver injury by reducing proinflammatory cytokine secretion and oxidative stress [110][23]. In addition, scutellarin, the main component of breviscapine, was shown to regulate lipid metabolism and reduce oxidative stress in NAFLD [111][24].
Further studies show that in mice that are fed a high-fat diet (HFD), high-fat/high-cholesterol diet (HFHC), or methionine- and choline-deficient diet (MCD), breviscapine attenuates hepatic lipid accumulation, inflammation, and fibrosis by mediating effects via the direct inhibition of TGF-β-activated kinase 1 (TAK1) MAPKKK (mitogen-activated protein kinase kinase kinase).
TAK1, besides being an upstream protein kinase in the MAPK signaling pathway, also plays a role in activating NF-κB during the progression of NAFLD [112][25]. Because of the pivotal role of TAK1 in many physiological processes, such as inflammation, cell differentiation, and apoptosis, the inhibition of metabolic stress-induced TAK1 activation may provide a potent hepatoprotective effect [113][26]. Indeed, recent studies highlighted the important role of TAK1 in regulating hepatocyte lipid metabolism and reducing hepatocyte inflammation in NAFLD and NASH [114,115][27][28].

4. ALS-L1023

ALS-L1023 is an extract isolated from Melissa officinalis, known in natural medicine as an anti-angiogenic agent [116,117,118,119][29][30][31][32]. ALS-L1023 modulates the mRNA expression of angiogenic factors (VEGF-A and fibroblast growth factor 2 (FGF-2)), metalloproteinases (MMPs) MMP-2 and MMP-9, and their inhibitors (TIMP-1, TIMP-2, and thrombospondin (TSP-1)) [120,121][33][34]. It also reduces visceral adipose tissue (VAT) production in mice with HFD-induced NAFLD by suppressing lipid synthesis and steatosis, inflammatory cell infiltration, and collagen accumulation in the liver, thus supporting the idea that ALS-L1023 may have a great contribution to regulate the development and progression of NAFLD and consequent NASH [117,118][30][31]. In addition, this extract reduced inflammation in female ovariectomized mice with diet-induced NAFLD and rescued them from oxidative stress through Akt activation. For these reasons, ALS-L1023 is in a Phase IIa clinical trial involving patients with NAFLD. Recent studies are also evaluating whether ALS-L1023 could alleviate liver fibrosis, as antifibrotic effects are essential properties of NASH drugs. In this regard, a biochemical analysis showed that the ALS-L1023 mouse group had significantly decreased alanine transaminase and aspartate transaminase. In addition, the area of fibrosis was significantly reduced after the administration of ALS-L1023, and its antifibrotic effect was greater than that of the reference compound OCA (obeticholic acid) [122][35]. ALS-L1023 has anti-angiogenic and anti-inflammatory properties, reduces VAT production and inflammation in NAFLD, and alleviates liver fibrosis, with a significative antifibrotic effect.

5. Curcumin

Curcumin, along with demethoxycurcumin, bisdemethoxycurcumin, and cyclocurcumin, is the major phenylpropanoid compound that is found in the roots of the perennial plant Curcuma longa. It is unclear whether all four analogs have the same activity. Although curcumin was found to be the most potent in most systems [123[36][37][38][39],124,125,126], bisdemethoxycurcumin and cyclocurcumin were found to have higher activity in some studies [127,128][40][41]. There is also evidence that the mixture of all three is more potent than just one [128][41]. Curcumin has shown anti-angiogenic and other beneficial properties in several experimental models of liver injury by inhibiting the NF-κB pathway [129][42]. It prevents aflatoxin-induced liver injury [130][43] and regresses cirrhosis [131][44].
In acute CCl4 intoxication, oxidative stress and the expression of pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, and NF-κB activation are associated with some increases in several markers of liver injury and the distortion of hepatic microscopic structure; pretreatment with curcumin prevented oxidative stress, NF-κB activation, and liver injury. Similarly, in biliary cirrhosis, curcumin showed anti-fibrogenic properties associated with the downregulation of the cytokine TGF-β [132][45].
NAFLD induced in methionine- and choline-deficient (MCD) mice significantly upregulates the hexosamine biosynthetic pathway and O-GlcNAc transferase via ER stress. This model was shown to be a useful experimental model for NASH. Curcumin treatment alleviates the severity of hepatic steatosis by blocking the NF-κB signaling pathway through the inhibition of O-GlcNAcylation and enhancing antioxidant systems, including SOD1 (superoxide dismutase 1), GPx (glutathione peroxidase), and CAT (catalase) [133][46].

6. Sulforaphane

Sulforaphane (SFN) is an organosulfur compound in the isothiocyanate group that is found in high concentrations in cruciferous vegetables such as broccoli and cauliflower [134][47]. It was reported to exert a variety of bioactive effects, including antioxidant, anti-inflammatory, cytotoxic, and cytoprotective effects [135][48]. In tumor angiogenesis, SFN inhibits NF-κB-regulated VEGF expression in human prostate cancer cells [136][49]; Peng liu et al. showed that SFN interferes with the proliferation, migration, and tube formation of endothelial cells, but it is also capable of inhibiting the pro-angiogenic effect of HepG2 cells both in vitro, ex vivo, and in vivo. SFN significantly inhibits the viability and migration of HUVECs (human umbilical vein endothelial cells), which is consistent with previous findings [137][50].
SFN was shown to inhibit STAT3 (signal transducer and activator of transcription 3), and this is consistent with the reduced expression of HIF-1α and VEGF in HepG2, suggesting that STAT3/HIF-1α/VEGF may be responsible for the anti-angiogenic effects of SFN. The latter also inhibits the TGF-β-induced epithelial–mesenchymal transition of HCC via the ROS-dependent pathway [138][51]. SFN-induced Nrf2 activation was indeed confirmed by the mRNA upregulation of redox genes such as HO-1 (heme oxygenase-1), MRP2 (multidrug resistance-associated protein 2), and NQO1 (NAD(P)H quinone dehydrogenase 1) in several cell lines [139,140][52][53]. Essentially, SFN is a bioactive compound with a range of beneficial effects, including antioxidant, anti-inflammatory, cytotoxic, and cytoprotective effects, which has been shown to inhibit angiogenesis in human prostate and liver cancer cells by inhibiting NF-κB-regulated VEGF expression, and through inhibiting the STAT3/HIF-1α/VEGF pathway. SFN also induces Nrf2 activation, which may contribute to its antitumor effects.

7. Cordycepin

Cordycepin is an adenosine derivative, antimetabolite, and antibiotic from the fungus Cordyceps militaris [141][54]. Cordycepin has a broad spectrum of biological activities, including anti-inflammatory, antioxidant, antifibrotic, antiadipogenic, and antitumor activities [142,143][55][56]. Guo Z. et al. showed that it suppresses the migration and invasion of human liver cancer cells by downregulating CXCR4 [144][57]. A hallmark of NASH pathogenesis is the inflammatory response, which initially triggers the release of numerous types of proinflammatory cytokines. Cordycepin suppresses the production of proinflammatory cytokines in LPS-stimulated macrophages and exerts anti-inflammatory effects by suppressing NLRP3 activity, which is an important regulator of the inflammatory process in macrophages [145][58]. Furthermore, NLRP3 deficiency in HCC cells enhances the activity of natural killer cells to delay tumor development in the xenograft mouse model [146][59].
Tian Lan et al. also demonstrated in their study how cordycepin attenuates metabolic stress-induced NASH by preventing steatosis, inflammation, and fibrosis. Specifically, cordycepin inhibits the activation of the NF-κB signaling pathway and attenuates the secretion of proinflammatory cytokines in hepatocytes under metabolic stress. This is due to an increase in AMPK phosphorylation through an interaction with the α-subunit of AMPK. The latter acts in mice treated with NASH-inducing diets as a central regulator of fatty acid, cholesterol, and glucose homeostasis through the phosphorylation of enzymes that regulate metabolism, including ACCα (acetyl-CoA carboxylase), glycogen synthase, glucose transporter 4, and HMG-CoA (3-hydroxy-3-methyl-glutaryl-CoA) reductase [147][60]. In conclusion, cordycepin, an adenosine derivative, was shown to exhibit various biological activities, including anti-inflammatory, antioxidant, antifibrotic, anti-adipogenic, and antitumor effects. Cordycepin also enhances natural killer cell activity to delay tumor development in xenograft mice models. These findings suggest that cordycepin may have potential therapeutic applications in the treatment of liver diseases, including NASH and liver cancer.

8. Methoxyeugenol

Methoxyeugenol is a compound found in Brazilian red propolis, which is produced by Apis mellifera bees. Propolis has a long history in folk medicine and istraditionally used to treat infections, gastric disorders, and promote wound healing [148,149][61][62]. Another source of methoxyeugenol is nutmeg (Myristica fragrans Houtt.), which is used as a spice, and its use in folk medicine is reported mainly for the treatment of gastrointestinal disorders [150][63]. However, studies support its use in the treatment of nonalcoholic hepatic steatosis [151][64], as it appears to promote lipid metabolism regulation and exert anti-inflammatory effects. Bruno de Souza Basso et al. showed that methoxyeugenol promotes HSC deactivation without evidence of cell death, suggesting a reduction in the proliferative rate [152][65]. In addition, the cytokine TGF-β, a growth factor that plays an important role in the development of liver fibrosis, particularly by activating quiescent HSCs, is reduced in the same cells treated with methoxyeugenol.
Lipid metabolism is regulated by nuclear receptors known as the PPAR family, particularly, PPARα and PPARγ. Research suggests that activating PPARγ can suppress macrophage activation and inflammatory pathways mediated by NF-κB [153,154][66][67]. In light of this, PPARγ activation may enhance the phenotypic modulation of activated HSCs by restoring lipid metabolism and inhibiting inflammatory signaling. In this regard, methoxyeugenol increases PPARɣ mRNA expression. In vivo studies on the use of methoxyeugenol, administered in the CCl4-induced liver fibrosis model, attenuate the inflammatory process and fibrosis, reducing intralobular inflammation by decreasing the gene expression of TNF-α, IL-6, and IL-8, as well as NF-κB protein expression [152][65]. Overall, methoxyeugenol shows promising potential as a natural compound for the treatment of liver diseases.

9. Naringenin

Naringenin is a flavone that is found in various plants and is particularly abundant in citrus fruits [155][68]. Several studies show that it exerts multiple biological effects, including anti-inflammatory, antioxidant, and hypolipidemic effects, which are protective factors for NAFLD [156,157][69][70].
The study by Wang et al. showed that the mRNA expression levels of NF-κB, IL-1β, IL-18, and NLRP3 were improved in mice that were fed an MCD diet. In vivo experiments showed that naringenin significantly reduced the mRNA and protein levels of these factors. In addition, the hepatic triglyceride levels were not further reduced in the NLRP3−/− mice that were fed an MCD diet treated with naringenin. For further confirmation, primary hepatocytes from wild-type and NLRP3−/− mice were isolated, and NLRP3−/− cells were stimulated via LPS and oleic acid. It was found that naringenin is highly effective in preventing lipid deposition in WT primary hepatocytes, but much less effective in NLRP3−/− primary hepatocytes, demonstrating that this flavonoid acts precisely by reducing the levels of the NLRP3 inflammasome [158][71].

10. Ferulic Acid

Ferulic acid (FA) is a phenolic acid that is widely found in grains, vegetables, and plants such as Angelica sinensis. FA exhibits several biological activities, including antioxidant, anticancer, antidiabetic, and immune function-enhancing effects [159,160][72][73].
Recent studies show that FA exhibits hepatoprotective effects [161][74]. Indeed, it improves lipid metabolism and reduces liver inflammation in apolipoprotein E-deficient mice that are fed a HFD by upregulating AMPKα and downregulating lipogenic genes [162][75]. In addition, FA shows beneficial effects against oxidative stress and liver damage by activating the Nrf2/HO-1 and PPARγ pathways [163][76].
Jianzhi Wu et al. reported FA as an agent that is capable of preventing all histological changes of CCl4-induced liver fibrosis in mice by suppressing hepatic oxidative stress, inflammatory response, macrophage activation, and HSC activation through the phosphorylation of AMPK via direct binding and the consequent inhibition of PTP1B (protein tyrosine phosphatase 1B) [164][77]. Therefore, activated AMPK in hepatocytes not only suppresses apoptosis and NOX2 (NADPH oxidase 2)-derived ROS production, but also inhibits the production of endothelial pro-inflammatory cytokines [165][78]. FA is also able to prevent the nuclear translocation of NF-κB. These benefits make FA a good player in the treatment of liver fibrosis and its advanced complications.

11. Betaine

Betaine is an essential biochemical modulator of the methionine/homocysteine cycle that is originally extracted from the juice of sugar beet (Beta vulgaris) [166][79] and is also found in various microorganisms, plants, and animals [167][80]. Aqueous extracts of betaine are used in traditional Eastern medicine to treat liver disease [168][81]. Recent studies show that betaine dampens down inflammation through the activation of NF-κB during aging [169][82]. Eui-Yeun Yi et al. found that betaine suppresses angiogenesis in the in vivo Matrigel plug assay, in addition to the in vitro inhibition in tube formation, migration, and invasion assays performed on HUVECs. Betaine also inhibits NF-κB and Akt activation [170][83].
VEGF and FGF-2 are known to be key stimuli for angiogenesis [171,172][84][85]. When investigating the involvement of betaine in the expression of key angiogenic factors, it was found that the mRNA expression of FGF-2 was significantly reduced. Betaine also shows a beneficial effect of downregulating the expression of MMP-2 and MMP-9, which are key regulators of extracellular matrix turnover, through the degradation of a variety of extracellular matrix proteins. Extracellular proteolytic activity is important in the process of endothelial cell migration and invasion, which are focal events in angiogenesis [173,174][86][87]. Therefore, betaine suppresses inflammation and angiogenesis by inhibiting NF-κB and Akt activation, reducing the expression of key angiogenic factors, and regulating the extracellular matrix turnover.

12. Catechins

Catechins are a group of flavanols that are abundant in plant fruits, vegetables, and beverages. Grapes, apples, cocoa, and green tea are considered the major sources of catechins, which represent some promising candidates in the field of biomedicine [175,176,177,178][88][89][90][91]. Green tea is a widely consumed beverage globally and has been extensively researched for its potential health benefits. Studies focused on its positive effects in various diseases, including cancer, obesity, diabetes, and cardiovascular disease [179][92]. Many of the biological effects of green tea are mediated by its polyphenolic catechins, particularly (-)-epigallocatechin-3-gallate (EGCG), which accounts for 50–85% of total catechins. Several studies show how green tea in animals restores gene and protein levels of proinflammatory cytokines in galactosamine-induced hepatitis [180][93]. Similar observations were reported in CCl4-induced liver injury in rodents [181][94], where the mRNA expression levels of TNF-α, COX-2, iNOS, smooth muscle actin, TGF-1, procollagen-I, MMP-2, MMP-9, and TIMPs increased along with an increase in NF-κB activity. Treatment with green tea extract significantly reduced liver damage, oxidative stress, inflammatory response, and expression of all the analyzed pro-fibrogenic markers except for TIMP-2 and MMP-9. Other studies show that treatment with such extract inhibits the levels of IL-1, IL-6, and TNF-α [182][95]. Furthermore, vascular endothelial (VE) cadherin and Akt, which are known downstream proteins in the VEGFR-2-mediated cascade, are other target proteins by which EGCG inhibits angiogenesis [183][96]. It was also observed that pentameric procyanidins isolated from cocoa inhibit the gene expression of the tyrosine kinase ErbB2, thereby slowing down the in vitro angiogenesis of human aortic endothelial cells [184][97].

13. Puerarin

Puerarin, a natural compound extracted from Pueraria lobata, has antioxidant and anti-inflammatory effects [185][98]. Various studies show that puerarin may regulate leptin signaling through the Janus kinase 2 (JAK2)/STAT3 pathway, thereby ameliorating hepatic steatosis [186][99]. Jingxuan Zhou et al. showed that in a rat model of HFD-induced NAFLD, puerarin administration reduced the abdominal fat coefficient [187][100]. In addition, puerarin significantly reduces inflammation caused by lipid accumulation. This induces ROS overproduction and the consequent activation of the NF-κB pathway, as well as a variety of inflammatory factors, such as interleukins (IL-1β and IL-18) and TNF-α [188][101]. In addition, puerarin decreased the thiobarbituric acid reactive substances and protein carbonyl content in the livers of CCl4-treated mice by regulating the expression of phosphorylated JNK, phosphorylated c-Jun protein, and cholesterol 7a hydroxylase (CYP7A1) in the liver [189][102].

14. Resveratrol

Resveratrol (RSV) is a stilbene that is found in grape skins, blueberries, raspberries, mulberries, and peanuts. Additionally, red wine is known for its high concentration of the RSV that partly explains the relatively low incidence of cardiovascular disease despite the prevalence of HFD in populations using it [190][103]. Resveratrol has antioxidant activity in a wide range of liver diseases [190,191][103][104]. In particular, it reduces the ROS levels, enhances the activity of antioxidant enzymes (e.g., SOD, CAT), and promotes the synthesis of antioxidant molecules. RSV also influences the expression of genes involved in mitochondrial energy production through signaling pathways such as AMPK/SIRT1/Nrf2, ERK/p38 (extracellular signal-regulated kinase), and PTEN/Akt (phosphatase and tensin homologue/protein kinase B) [192][105]. By inhibiting the ubiquitination of Nrf2, it helps to maintain its crucial role in activating the transcription of various antioxidant genes, such as SOD and CAT, thereby strengthening the overall antioxidant defense system [192][105].
In NAFLD, RSV appears to have a significant role in regulating the accumulation of fibrosis through its impact on multiple crucial pathways. Indeed, RSV administration reduces portal pressure and HSC activation, and improves hepatic endothelial function in cirrhotic rats, with an overall beneficial effect on cirrhosis and portal hypertension [193,194][106][107]. Again, it is well known that RSV administration in hepatocytes causes the inhibition of mRNA expression of inflammatory mediators, including TNF-α, IL-1β, as well as TNF-α and IL-6 in cultured hepatocyte cells, and reduces the number of Kupffer CD68(+) cells recruited to the liver [195,196][108][109].

15. Fucoidan

Fucoidan, a sulfated polysaccharide containing substantial amounts of L-fucose and sulfate ester groups, is readily present in edible brown seaweeds, which are widely consumed in Asian countries due to their extensive health benefits [197,198][110][111]. An ex vivo angiogenesis assay showed that fucoidan caused a significant reduction in microvessel outgrowth and significantly reduced the expression of the angiogenesis factor VEGF-A [199][112]. Fucoidan was also evaluated for its activity in combination with sorafenib and bevacizumab in HCC. In vitro, on Huh-7 cells, fucoidan showed a potent synergistic effect with anti-angiogenic drugs and significantly reduced the HCC cell line viability in a dose-dependent manner via the inhibition of the pro-angiogenic PI3K/AKT/mTOR and KRAS/BRAF/MAPK pathways [200][113].

16. Carnosol and Carnosic Acid

Carnosol and carnosic acid are two major components of rosemary extracts that contribute to the chemopreventive, anti-inflammatory, antitumor, and antimetastatic activities of Rosmarinus officinalis [201,202][114][115]. Lopez-Jimenez et al. demonstrated for the first time that these diterpenes modulate different relevant steps of the angiogenic process by inhibiting cytokine-induced adhesion molecule expression, monocyte adhesion to endothelial cells through a mechanism related to NF-κB, and capillary tube formation via endothelial cells, in addition to inducing apoptosis in endothelial and tumor cells in vitro. These results suggest their potential use in the treatment of angiogenesis-related malignancies [203][116].

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