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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5330_Библиотеки_им_академика_М_И_Перельмана
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a metabolic pathway that is complex and tightly regulated.
DNL metabolizes additional carbohydrates into FFAs, which
are then esteried into TGs [12]. FAS catalyses the nal step
in fatty acid production [13]. Liver- specic fatty acid synthase (FAS) inhibition increased hepatocyte malonyl-CoA
levels that block fatty acid beta-oxidation. ACC catalyses a
major rate-limiting step in fatty acid biosynthesis and controls FAO by synthesizing malonyl-CoA [14]. Two important
transcription factors for fatty acid synthesis, SREBP-1c, and
ChREBP are engaged in lipid synthesis and have been linked
to promoting DNL in NAFLD. SREBP-1c controls lipid
metabolism transcriptionally [15]. The liver X receptor alpha
(LXRα) is crucial in the upregulation of SREBP-1c and
ChREBP [16].
The activity of adipokines, which are cytokines generated
by adipocytes, such as leptin and tumour necrosis factor-α
(TNF-α), which are produced in excess, also contributes to
an increase in the oxidative stress that is placed on mitochondria [17]. It is more likely for inammatory adipokines to be
active when there is a decrease in adiponectin that regulates
other chemical mediators [18]. These chemical mediators,
produced by inammatory response and cell death, activate
the hepatic stellate cells (HSCs) and stimulate collagen levels, ultimately promoting brosis and cirrhosis [19].
3 Herbal Molecules Involved
intheManagement ofLiver Cirrhosis
3.1 Alkaloids
Alkaloids are organic compounds found in plants that are
alkaline and contain nitrogen. Almost all alkaloids have
cyclic structures and substantial impacts on lipid metabolism. Importantly, alkaloids act on AMPK, enhancing
PPAR-α and carnitine palmitoyl transferase (CPT) 1 expression while decreasing SREBP-1c and PPAR-γ. Because phytochemicals in this class promote lipid catabolic metabolism
and inhibit anabolic lipid metabolism, the availability of lipids like fatty acids may be constrained [20]. In addition,
some alkaloids with potent hepatoprotective action have
been discussed below as shown in Fig.2.
3.1.1 Berberine
Berberine (BBR) is an isoquinoline alkaloid obtained from
the stem of Berberis aristate [21]. Enhancement in insulin
secretion and reversal of IR are the main functions of
BBR.BBR has shown a decrease in liver lipid accumulation
and prevention of hepatic steatosis, which simultaneously
inhibits hepatic inammation and oxidative stress by hampering lipogenesis [22]. Lipogenesis was lowered by the activating transcription factor 6 (ATF6) and SREBP-1c pathways.
SREBP-1c is a major target protein of BBR, which may have
led to the prevention of lipid deposition and endoplasmic
reticulum (ER) stress-induced activation of SREBP-1c [23].
In another experiment, through the stimulation of the adenosine 5′-monophosphate activated protein kinase (AMPK),
SREBP-1c pathways, BBR decreased liver TG production
and mitigated hepatic steatosis. The downregulation of Sirtuin
3 (SIRT3) expression might occur in rat liver [24]. The antiinammatory effect of BBR was shown by downregulating
the expression of inammation markers, like TNF-α and
IL-6. In 3T3-L1 adipocytes, BBR lowered leptin and glycerol
secretion [25]. This alkaloid decreases liver inammation in
mice by reducing the phosphorylation state of c-Jun
N-terminal protein kinase 1 (JNK1) and mRNA expression
levels. BBR has been found to signicantly reduce inammation in hepatocytes in a time and dose- dependent manner and
diminished the expressions of FAS and ACC by BBR [26].
BBR has been shown to inhibit hypoxia-inducible factor
(HIF-2α) storage, which lowered ceramide and ameliorated
IR by HIF-2α genes. Through the PP2A-AKT-GSK3 signalling pathway, BBR improved IR by promoting glycogen production [27].
3.1.2 Caeine
Caffeine (CFN) is obtained from the roasted seeds of Coffea
arabica and Coffea canephora. In individuals with NAFLD
and hepatitis C and B virus infection, drinking coffee loosens
up the liver, which might lead to reduced brosis and inammation. Liver diseases have been found to occur less often in
those who drink coffee. CFN has been shown to prevent liver
brosis by inhibiting hepatic stellate cell activation by blocking A2A receptors. New research suggests that CFN may
also positively affect angiogenesis and hepatic hemodynamics. The expression of connective tissue growth factor produced by transforming growth factor β (TGF-β) in
hepatocytes is inhibited by CFN.CFN treatment in rats with
chemically induced liver brosis has lowered their TGF-β
levels. Hepatoprotective properties are shown by chlorogenic acid (an ester of CFN) that lowered
tetrachlorobenzoquinone- induced oxidative stress and also
decreased liver brosis and collagen I and III expressions;
therefore, it must have a hepatoprotective character [28]. The
metabolic actions of CFN that protected the liver were
unclear. In hepatitis C virus-infected individuals, a higher
CFN intake was linked to a lower level of liver brosis [29].
CFN and its metabolite paraxanthine reduced hepatic brosis by preventing the liver parenchyma from secreting connective tissue growth factor and also lowered iron buildup in
the liver and ALT levels. Additionally, CFN reduced the production of alpha smooth muscle actin (α-SMA) in LX-2 cells
and promoted stellate cell deactivation. Treatment with CFN
resulted in a rise in apoptotic cells. The increased apoptosis
rate was directly correlated to the length of exposure and the
amount of CFN present. Cell migration and adhesion are all
regulated by F-actin. In response to coffee administration,
F-actin expression was signicantly lowered. Focal adhesion
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O
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O
O
O
Berberine
O
+
N
N
ON
Caffeine
N
N
Capsaicin
H
N
O
OH
O
O
O
HO
OH
NH
O
HN
O
N
N
N
N
O
O
N
N
O
N
H
O
O
Conophylline
Evodiamine
Ligustrazine
O
O
O
N
OH
O
N
O
Fig. 2 Alkaloids in the treatment of liver cirrhosis
complex and integrins trigger focal adhesion kinase (FAK),
which is important for ECM growth factor stimulation and
cell attachment and motility. CFN downregulated the HSCs
expression of FAK.CFN modulated suppressor of mothers
against decapentaplegic (SMAD)-induced production of
ECM components to enhance intracellular cAMP concentration [30].
3.1.3 Capsaicin
The primary ingredient in Genus Capsicum is capsaicin
(CSC) [31]. In obese mice, CSC showed anti-steatotic action.
Mice on a high-fat diet (HFD) had their liver fat decreased
-
O
+
N
N
O
Oxymatrine
when CSC was applied topically. CSC decreased the expression of key enzymes involved in the synthesis of fatty acids,
such as ACC and FAS, while increasing the expression of
CPT1 and cluster of differentiation 36 (CD36), which are
linked to oxidation and the inux of FFAs into the liver. Mice
treated with CSC elevated adiponectin concentration in liver
tissue. For the transient receptor potential vanilloid 1
(TRPV1) channel, CSC is a highly selective agonist, attenuating metabolic abnormalities by activating TRPV1, which
stops the progression of fatty liver in vivo. In mice, dietary
CSC, which activated TRPV1, enhanced PPAR-dependent
autophagy and thus prevented NAFLD.Additionally, AMP-
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activated protein kinase (AMPK), PPAR, uncoupling protein
1 (UCP1), and glucagon-like peptide 1 (GLP-1) were all
altered by the liver tissue’s elevated expression of TRPV1.
CSC reduced liver tissue inammation, which may have
been brought on by AMPK signalling via the TRPV1 receptor
being phosphorylated. As one of the modes of action of CSC,
a systemic increase in adiponectin levels facilitates hepatic
AMPK activation. Through the activation of AMPK, topical
CSC treatment combined with exercise reduced the symptoms of metabolic syndrome brought on by hypoestrogenism. CSC inhibited fatty liver by inhibiting lipogenesis and
increased fatty acid oxidation by activating AMPK [32].
3.1.4 Conophylline
The vinca alkaloid conophylline (CNP) is taken from the
leaves of the tropical plant Tabernaemontana divaricate. It
improved hepatic brosis diseased mice condition and cured
NASH also in mice. Additionally, the diet decreased the
expression levels of hepatic PPAR-α mRNA.PPAR-α participates in β-oxidation. Hepatic PPAR-α and its target genes,
such as CPT1 and CPT2, were upregulated in the liver by
CNP in a dose-dependent manner. CNP elevated hepatic
β-hydroxybutyrate level in a dose-dependent manner and
decreased the expression of the p62 protein, which is reported
to be preferentially destroyed during autophagy while
enhancing the expression of the autophagosomal marker
light chain 3 II (LC3-II). CNP reduced hepatic steatosis by
elevating liver β-oxidation and autophagy [33].
3.1.5 Evodiamine
One of the main elements taken from Evodia rutaecarpa is
evodiamine (EDM). ALT and histological abnormalities in
liver tissues might all be improved by EDM.EDM decreased
IL-6, TNF-α, collagen I, and collagen III.EDM decreased
the protein expression of TGF-β1, phosphorylation of SMAD
2/3 (p-SMAD 2/3), and α-smooth muscle actin (α-SMA) in
liver tissues as well as the mRNA expression of TGF-β1 and
α-SMA.EDM dose-dependently lowered the cell proliferation, hydroxyproline formation, and protein expression of
TGF-β1, p-SMAD 2/3, and α-SMA in HSCs. EDM also
reduced collagen metabolism and HSC proliferation [34].
3.1.6 Ligustrazine
Ligustrazine (LTZ) was discovered in the Chinese plant
Ligusticum wallichii. It can block calcium channels, cause
vasodilation, decrease platelet bioactivity and aggregation,
scavenge oxygen free radicals, protect the liver, and have
antibrosis properties. While lowering the expression of proteins linked to hepatic brosis and apoptosis, LTZ has also
decreased the number of foci containing CD45-positive
cells. Hepatic steatosis and hyperlipidaemia brought on by
alcohol were also eliminated. LTZ enhanced the PPAR-α and
CPT1 expressions, which decreased the number of lipid
droplets in the liver by inhibiting the gene and protein expression of SREBP-1c and FAS.LTZ diminished the alcoholmediated upregulation of SREBP-1c and downregulated the
expression of PPAR-α, resulting in increased lipogenesis and
reduced lipolysis. Furthermore, LTZ has shown antioxidant
activity by increasing the production of glutathione, SOD,
and catalase which may have been lowered by alcohol. These
results support the potency of LTZ against liver cirrhosis
[35].
3.1.7 Neferine
Nelumbo nucifera seed embryo is the source of neferine
(NFR). It has anti-oxidative, anti-inammatory, and antipulmonary brosis properties. Collagen’s primary building
block, hydroxyproline, forms the extracellular matrix
(ECM). At the level of liver cirrhosis, ECM deposition might
permanently worsen the function of the liver. NFR promoted
apoptosis of cultured hepatic stellate cells (HSCs) by reducing their stimulation. The mediator causing chronic liver disease through inammation, and brogenesis, is TGF-β1. To
form the ECM, TGF-β1 can induce HSCs to produce and
secrete collagen and bronectin. Plasma levels of ALT and
AST were dramatically reduced by NFR.Thus, NFR exhibited an antibrosis impact on the hepatic brosis brought on
by CCl4 in vivo [36].
3.1.8 Oxymatrine
Sophora avescens contains signicant amounts of oxymatrine (OXM). OXM lessened fat accumulation by regulating
the expression of miR-182. The ratio of liver to body weight,
the amount of TG, hepatic lipid buildup, and steatosis were
all decreased by OXM.Following OXM intervention, the
levels of SREBP-1c, ACC, and fatty acid synthase (FAS)
were all dramatically reduced, while the level of CPT1A was
increased in the high-fat diet (HFD)-fed rat in the experiment. In the same experiment in miR-182 knockdown rats,
SREBP-1c, ACC, and FAS levels were all elevated, but the
CPT1A level was decreased [37]. SOD, glutathione peroxidase (GPx), and choline acetyl-transferase (CAT) activity
reduced in response to As2O3, and the decline was prevented
by treatment with OXM.OXM also enhanced the expression
of Nrf2 and heme oxygenase-1 (HO-1) while reducing the
retention of arsenic in liver tissues. Through the Nrf2/HO-1
signalling pathway, OXM has shown protection against oxidative damage carried out by As2O3 [38]. PPAR-α, CPT1A,
and microsomal TG transfer protein (MTTP) mRNA and
protein levels were all signicantly raised by OXM therapy.
The nding of a reduction in lipid buildup in the liver served
as an additional conrmation of OXM-positive effects
[39]. Apart from the above discussed herbal compounds,(Table 1) enlists several phytochemicals involved in
the treatment of various liver ailments by targeting lipid
biomarkers.
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[40]
Downregulated α-SMA, COL1A1, and TGF-β1 protein
expressions and TIMP-1, TIMP-2, and MMP-2 mRNA
expressions
[41]
[42]
Upregulated the expression of PPAR-α
Downregulated TGFβ1-induced hepatocyte EMT and HSC
[43]
[44]
Upregulated Nrf2 signalling
Decreased serum AST level and inhibitedthe release of TNF-α
Activated AMPK signalling pathway decreased glucose output,
cholesterol, and TG synthesis
[46]
the expression of α-SMA and HSCs
[49]
production of IL-6, IL-1β, IFN-γ, and TNF-α
Compound name Biological source Research model Biomarkers Refs.
Betaine Vegetables like beets, spinach, etc In vivo female Sprague-Dawley rats
Table 1 Names, biological sources, experiment research models, targeted biomarkers of alkaloids
HepG2 cells in vitro Lowered both TG and low-density lipoprotein metabolism
human LX-2 HSCs
In vitro TGF-β1/SMAD cascade
In vivo male Wistar albino rats
Nuciferine Nelumbo nucifera leaf In vivo male C57BL/6J mice
Piperine Black pepper (Piper nigrum) In vivo AML-12 hepatocytes and
Trigonelline Cantaloupe, corn, onions, peas,
rats
soybeans
Sophocarpine Foxtail-like sophora herb and seed In vivo male Sprague-Dawley (SD)
In vivo male C57BL/6 mice Reduced lipid accumulation and TG [45]
In vitro AML12 cells Activated AMPK/ACC
owers, leaves, and seeds
Liensinine Nelumbo nucifera, such as its root,
Theacrine Camellia assamica In vivo male Sprague-Dawley rats Activated SIRT3/AMPK and inhibited SCD1 signals. Reduced
In vitro HepG2 cells
Kukoamine A The root barks of Lycium chinense In vivo C57 mice Increased SREBP-1c protein, decreased FAS, and ACC [47]
Tiliamosine Tiliacora racemosa In vivo male Wistar rats Reduced TG [48]
Koumine Gelsemium elegans In vivo male Sprague-Dawley rats Lowered TG, TC, LDL, ALT, AST, and MDA reduced the
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Fig. 3 Flavonoids in the
treatment of liver cirrhosis
3.2 Flavonoids
191
both SMR and its metabolites have lowered IR and hyperlipidaemia [52].
Fruits, vegetables, cereals, bark, roots, stems, owers, tea,
and wine are all good sources of avonoids, a class of natural
compounds with varying phenolic structures (Fig.3). It is
hoped that isolating these natural compounds would yield
their health benets. Therefore, avonoids are now widely
recognized as an essential component in a wide range of
nutraceutical, pharmacological, medical, and cosmetic products [50].This section explores the pathological role of avonoids (Table 2) in management of cirrhosis and other liver
ailments.
3.2.1 Naringenin
Naringenin (NGN) is a avonoid with anti-inammatory,
anti-brogenic, antioxidant, and anticancer effects. NGN has
shown protective effects in liver illnesses by inhibiting oxidative stress through the TGF pathway and preventing the
transdifferentiation of HSCs, which decreases collagen formation. Non-canonical pathways for the toll-like receptor
(TLR), TGF-β, and mitogen-activated protein kinase
(MAPK), which, when inhibited, further caused a signicant
decrease in extracellular matrix (ECM) synthesis and deposition. Through regulating lipid metabolism, NGN has demonstrated a positive effect on NAFLD and inuenced the
production and oxidation of lipids and cholesterol [51].
3.2.3 Baicalin
Baicalin (BAI) is a monomeric avonoid mainly obtained
from Scutellaria baicalensis Georgi. This active phytochem-
ical is used in the composition of herbal medicine for the
treatment of liver disease. BAI had anti-oxidative, antiinammatory, and hepatoprotective activity against different
types of liver injury caused by carbon tetrachloride, iron
overload, and acetaminophen [53]. BAI protects the liver
through its antioxidant effect by suppressing the production
of reactive oxygen species, which help to protect against
liver cirrhosis in ischemia/reperfusion injury in fatty liver
disease. BAI reduced hepatic damage by suppressing the
TLR4-mediated inammatory signalling pathway, providing
protection against post-ischemic injury in the alcoholic fatty
liver [54]. BAI boosted the activity of antioxidant response
kinases like SOD and GSH-PX while decreasing the yield of
inammatory factors, including TNF-α, IL-1β, and IL-6.
BAI also lowered the regulations of the extracellular signalregulated kinase (ERK), one of the primary targets. BAI also
downregulates SOD and GSH-Px activity to reduce oxidative stress leading to a decrease in hepatic brosis. By controlling the activity of SREBP-1c, FAS, PPAR-γ, and CPT1,
BAI can partially decrease the hepato-lipids accumulation
triggered by an MCD diet [55].
3.2.2 Silymarin
Silymarin (SMR) is the name for the avonolignans identied in milk thistle (Silybum marianum). The levels of ALT
and AST were somewhat decreased by SMR.In addition,
3.2.4 Quercetin
Quercetin (QRC), a plant pigment and more precisely a avonol, is primarily present in citrus fruits, berries, and grapes.
It is an antioxidant that could prevent cellular damage caused
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Table 2 Names, biological sources, experiment research models, targeted biomarkers of avonoids
Compound name Biological source Research model Biomarkers Refs.
Nobiletin Citrus sinensis and Citrus
limon
Dihydromyricetin Ampelopsis grossedentata In vivo mice
Rutin Fruits, tea, and wine, Ruta
graveolens
Luteolin Dendranthema morifolium In vivo Wistar rats
Scutellarin Erigeron breviscapus In vivo male C57BL/6
Genistein Soybean products
(Cordyceps sinensis)
Fisetin Fruits and vegetables In vivo male albino rats
Quercetin3-O-β-Dglucuronide
Quercitrin Fruits and vegetables In vivo female
Vitexin Ficus deltoidei and
Chrysin Passiora caerulea and
Galangin Rhizome of Alpinia
Hesperetin Citrus fruits (oranges,
Hesperidin Citrus genus In vivo HFD-fed rats
Bavachinin Fructus Psoraleae In vitro HepaRG cells Inhibited FDFT1 via the AKT/mTOR/SREBP-2
Didymin Mentha spicata In vivo HFD-fed mice
Ugonin J Helminthostachys
Hyperoside Hawthorn, artemisia
Icariin Epimedium genus In vivo male C57BL/6J
Xanthohumol Humulus lupulus, beer In vivo male Wistar rats Decreased GPx and GST; increased TBARS [77]
Breviscapine Erigeron breviscapus In vivo male C57BL/6J
Myricetin Berries, vegetables, and
Polygonum perfoliatum In vivo male SD rats; in
hawthorn
Oroxylum indicum
galangal
grapefruit, and lemons)
zeylanica
capillaris, and Hypericum
perforatum
herbs
In vivo male C57BL/6J
mice
In vivo male C57BL/6
mice
mice
In vivo male Wistar rats Downregulated JAK2/STAT3/SOCS3 signalling
vitro Q3GA gene
C57BL/6 mice
In vivo male C57BL/6J
mice
In vivo Wistar rats Upregulated RAS, ACE2, Ang (1–7), and Mas [68]
In vivo male Wistar
rats; in vitro BRL cell
In vivo male Wistar
rats; in vitro HepG2
cells
In vitro THP1 and
HepG2 cells
In vivo male C57BL/6J
mice; in vitro,
PA-induced steatotic
human HuS-E/2
In vivo Wistar male rats Altered DNL, ApoE, and BSEP; increased NRs, FXR,
mice
mice
In vivo male BALB/c
mice
Lowered HDL-C/TC ratio. Downregulation of
SREBP-2 and ACAT2
Decreased CRP, IL-6, and IL-1β
Decreased ALT, AST, γ-glutamyl transpeptidase,
LDL-C, TNF-α, and broblast growth factor 21 blocked
the PI3K/Akt/NF-κB signalling pathway
Downregulated PPAR-α, CPT1, and CPT2 suppressed
SREBP-1c, DGAT-1 and 2, ACC, TNF-α, and IL-1β.
Reduced TG
Inhibited NF-κB and TLR4 signalling pathway
Suppressed IRE1α/XBP1 pathway
Downregulated SREBP-1c, FAS, and ACC
Upregulated Beclin1 and Foxo1 proteins
pathway
Downregulated genes MMP2/9 and TIMP1
Upregulated SOCS3 protein and CD163 and CD206
inhibited CD68
Upregulated HNF4α/lipin1 signalling
Inhibited ROS mediated TXNIP induction
Upregulated PPAR-α, MCAD, and CPT1
Downregulated FFA and SREBP-1c
Reduced TG, TC, LDL-C; Downregulated TNF-α, IL-6,
and IL-1β
Increased PPAR-γ protein; activated AMPK
Decreased ALT/AST; mediated caspase 3; inhibited
BRL cell apoptosis and PI3K/AKT pathway
Upregulated SOD/GPx/HO-1; triggered the PI3K/
AKT-Nrf2 pathway; reduced ROS accumulation and
TG, TC, LDL-C levels
Suppressed GRP94, ATF6, PERK, IRE1α, IL-1β, IL-6,
and TNF-α; activated IRE1α
pathway and cholesterol synthesis
Suppressed the TLR4/NF-κB and PI3K/Akt pathways;
decreased ALT, AST; reduced the expressions of ACC,
SREBP-1c, LXRα, and FAS
Upregulated pAMPK, ACC, and CPT1; downregulated
SREBP-1c
LXRα
Upregulated of the cleaved caspase 3/9, SREBP1c, and
DGAT2; enhanced CPT1, ACC, AMPKα1, PGC1α, and
GLUT4; activated AMPKα1/PGC1α/GLTU4 pathway
Inhibited TGF-β-activated kinase 1 (TAK1)
phosphorylation; inhibited NF-κB signalling pathway;
downregulated Col1a1, Col3a1, Ctgf, and Timp1 genes;
downstream JNK/p38 activation
Blocked phosphorylation of SMAD2/Akt/MAPK;
inhibited PDGF and TGF-β1; activated JNK
phosphorylation
T. Banerjee et al.
[57]
[58]
[59]
[60,
61]
[62]
[63]
[64]
[65]
[66]
[67]
[69]
[70]
[71]
[72]
[73]
[74]
[75]
[76]
[78]
[79]
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by the toxicities of different drugs. Through several pathways, including nuclear factor kappa B (NF-κB), p53, and
phosphoinositide-3-kinase-protein kinase B/Akt (PI3K/Akt)
downregulation, QRC has been demonstrated to inhibit
apoptosis in normal cells. The anti-inammatory mechanisms of QRC also demonstrate that it inhibits many proinammatory mediators and enzymes implicated in the
processes of hepatotoxicity, including TNF-α, IL-1β, IL-6,
cyclooxygenase-2 (COX-2), and nitric oxide synthase
(iNOS) [56].
3.3 Polyphenols
Polyphenols are bioactive compound that play an important
role in the survival of the plant against harmful environmental factors including UV light and infections. Dietary plant
polyphenols have gained a lot of attention in the past decade
due to the possibility that they may improve health by acting
as antioxidants. Polyphenols may be found in a wide variety
of whole foods, including vegetables, fruits, grains, and even
certain drinks. For instance, the fresh weight of 100 grams of
grapes, apples, pears, cherries, and berries might contain
anywhere from 200 to 300mg of polyphenols [80]. Bioactive
polyphenols in the management of liver cirrhosis have been
discussed, summarized (Table 3) and illustrated below in
Fig.4.
3.3.1 Catechin
Camellia sinensis is high in polyphenolic catechin (CAT),
which directly shields progression of NAFLD.Consuming
green tea is linked to decreased levels of aminotransferases,
TGs, and atherogenic lipoproteins in the bloodstream, as
well as a reduced risk of cardiovascular disease and all-cause
mortality closely related to NAFLD as determined by human
clinical studies. Green tea CATs may prevent steatosis by
inhibiting intestinal lipid and carbohydrate absorption,
reducing adipose lipolysis and both adipose and hepatic
DNL, stimulating hepatic β-oxidation and thermogenesis,
and the improvement of insulin sensitivity [81]. While raising the quantity of the antioxidant enzyme SOD, GTP lowered inammation by lowering levels of IL-6 and TNF-α, as
well as the histological signs of liver damage. The modication of AMPK activity, as GTP-enhanced AMPK phosphorylation, may be the suggested mechanism [82].
3.3.2 Resveratrol
A naturally occurring polyphenolic substance called resveratrol (RSV) may be found in jackfruit, peanuts, and grapes. In
vivo RSV-mediated changes to the gut microbiota, associated gut metabolites, and intestinal environment redox status
helped protect C57BL/6J male mice from developing metabolic syndrome when they were given an HFD.Two RSV
gut metabolites, 4-hydroxyphenyl acetic acid and
3- hydroxyphenylpropionic acid, have demonstrated
enhanced lipid metabolism in vitro [83]. This polyphenol
stopped the downregulation of SREBP-1c and FAS brought
on by steatosis and its effect on phosphorylated AMPK.After
RSV administration, plasma ALT levels were dramatically
reduced [84].
3.3.3 Curcumin
Curcumin (CUR) is primarilyderived from Curcuma longa.
CUR liposomes improved pharmacological and anticancer
effects [85]. CUR imparted signicant reduction ofhepatic
fat levels inNAFLD patientsby reducing the serum lipogenic markers. The glycemic and lipid proles, transaminase
levels, and anthropometric measurements were also examined. The effectiveness of CUR in preventing liver outcomes
like cirrhosis and hepatocellular cancer, as well as its antisteatotic activities, is dose-dependent. Following treatment
with CUR, signicant reductions in FBS and HbA1c levels
were noted [86].
3.3.4 Chlorogenic Acid
The most prevalent antioxidant in coffee (Coffea arabica) is
chlorogenic acid (CGA), though other plants also produce it.
Coffee has anti-inammatory and antioxidant properties that
help ght cancer, cirrhosis, and liver brosis. CFN treatment
decreased lipogenesis and boosted lipid beta-oxidation in
HFD rats. The PPAR-α pathway is inactivated, which has an
anti-inammatory and antioxidant impact in addition to
reduced fat storage [87]. The control of glucose and lipid
metabolism and associated diseases, including diabetes, cardiovascular disease, obesity, cancer, and hepatic steatosis, is
thought to be impacted signicantly by CGA [88].
3.3.5 Anthocyanin
In peripheral blood mononuclear cells, anthocyanin (ACY)
supplementation signicantly reduced plasma levels of IL-1β
and IL-18in NAFLD patients relative to controls and mRNA
expression of NLRP3 inammasome components (caspase 1, IL-1β, and IL-18). NAFLD pathophysiology is related to
the activation of NLRP3 inammasomes [89]. ACY reduced
hepatic lipid buildup and mitigated oxidative stress and
hepatic inammation. Reduced lipogenesis and increased
lipolysis caused by increased PPAR-𝛼 activity were proposed as the causes of the lower hepatic fat content. One
research found enhanced AMPK pathway activity, and several studies using experimental models of NAFLD found
improved hepatic antioxidant activity following exposure to
ACY [90].
3.3.6 Mangiferin
A typical aqueous stem bark extract from Mangifera indica
exhibits strong in vitro and in vivo antioxidant activity.
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of PXR and AHR, IL-1β, IL-2, CD4+ T cell expansion,
neutrophil proliferation, and cell division; suppressed
immune cells and sIgA
[94, 95]
Attenuated M1 macrophages and increased M2
macrophages after LPS stimulation; descended cytokine
[96, 97]
(TNF-α, IL-1β, IL-6, IL-10, IL-4) level; suppressed ERK
pathway in macrophages
CHOP; increased activity of enzymic and non-enzymic
antioxidants; alleviated lipogenesis via the AMPK
pathway
[98]
Reduced hepatic levels of ROS, MDA, TNF-α, and IL-6
and the nuclear activity of NF-κB, p65; increased Nrf2 and
GSH and SOD; downregulated SREBP1, SREBP2, ACC,
[99]
FAS, and HMG-CoAR stimulated PPAR-α and CPT1A,
CPT1A, and AMPK
Activated PI3K/AKT pathway; reduced NO and ROS via
Nrf2 signalling pathways; inhibited SREBP-1c and
PNPLA3, and upregulated PPAR-α
[100]
[101]
decreased P-JNK, P-ERK, and P-P38
Improved A CC and FAS genes; increased PPAR-α and
CPT1 expression; decreased FAS and HMG-CoA
[102]
reductase expression
SREBP-1c, C/EBP1α, and FAS IL-1β, TNF-α, and
[103]
COX-2a decreased; upregulated phosphorylation of
AMPK and SIRT1
Reduced ROS formation; reduced the growth of breast and
prostate cancers
[104]
Reduced ECM production, HMGB1 release, hyaluronic
acid, and collagen IV; promoted mitochondrial biogenesis;
[105]
[106, 107]
decreased α-SMA, SMAD2/3, COL1A1 and COL3A1,
TG, and NEFA
ɑ-SMA and TGF-β1
Upregulated microRNA-467b-3p, HNF4ɑ; decrease in
glycerol-3-phosphate acyl-transferase-1; Downregulated
GPAT1
[108]
Promoted PPAR-ɑ, CPT1, and ACOX1; activated AMPK
phosphorylation; dampened TNF-α, IL-6, IL-8, and IL-1β
secretion, and NF-κB expression
Compound name Biological source Research model Biomarkers Refs.
Epigallocatechin-3-gallate Green tea (Camellia sinensis) In vivo HFD-fed mice Downregulated CYP450 enzymes inhibited the expression
Table 3 Names, biological sources, experiment research models, targeted biomarkers of polyphenols
in vitro RAW 264.7 cells
Hydroxytyrosol Virgin olive oil (Olea europaea) In vivo male C57BL/6 mice;
Rosmarinic acid Rosmarinus ofcinalis In vitro HepG2 cells Reduced ROS and p-PERK, p-IRE-1, ATF-6, p-eIF-a, and
In vivo male Wistar rats
strawberries, pomegranates, guava,
etc.
Ellagic acid Various fruits, including
L02 and HepG2 cell
Dihydrocurcumin Turmeric (Curcuma longa) In vitro human liver cell line
In vivo male SWISS mice
berries, pequi (Caryocar
brasiliense), and wine; Phyllanthus
Chicoric acid Cichorium intybus In vivo male C57BL/6 mice Decreased AST and ALT; activated AMPK/Nrf2 pathway;
Gallic acid Fruits and vegetables teas, grapes,
transgenic Zebrash
emblica
Diphlorethohydroxycarmalol Ishigeo kamurae In vitro HepG2 cells; in vivo
rats
In vivo male C57BL/6 mice;
in vitro LX2 cells
pears, berries, artichokes, and
eggplant
CAT Camellia sinensis In vivo male Sprague-Dawley
CGA Coffee (Coffea arabica), apples,
Salvianolic acid A Salvia miltiorrhiza In vivo Sprague-Dawley rats Reduced TG, TC, LDL, ALT, and AST; Downregulated
C57BL/6Jmice
In vivo male C57BL/6 mice;
6-Gingerol Zingiber ofcinale In vivo HFD male
Methyl brevifolincarboxylate Phyllanthus urinaria, Canarium
in vitro human SK-HEP-1 cell
album
Herbal Medicines fortheTreatment ofLiver Cirrhosis
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Fig. 4 Polyphenols in the treatment of liver cirrhosis
Mangiferin (MFR) is the primary polyphenolic component
of Vimang. Polyphenols have a dual synergistic effect,
making them potentially effective antioxidants against
pathological iron overload diseases such as thalassemia,
Friedreich’s ataxia, and hemochromatosis. The redox
cycling of the metal and the ligand, notably MFR, the primary catecholic polyphenol in the natural extract, might be
used to explain the improved free radical scavenging
capacity of Vimang following iron coordination. The second primary polyphenol of Vimang, MFR, is a catecholcontaining molecule that likewise has signicant
antioxidant activity; it has been shown that iron increases
its superoxide scavenging capacity [91]. Furthermore,
MFR pretreatment has been demonstrated to have a strong
hepatoprotective impact by reducing blood levels of the
inammatory mediator TNF-α, AST, ALT, alkaline phosphatase, and bilirubin. In addition, MFR prevented the
reduction of glutathione reductase, glutathione-Stransferase, SOD, and total reduced glutathione activity
and increased hepatic MDA formation in the liver of CCl4injected male Swiss albino mice [92].
3.4 Glycosides
In glycosides, a sugar moiety is attached to an aglycone
structure (Fig. 5) through an O-, S-, N-, or C-glycosidic
bond, making for yet another unique family of secondary
metabolites. The glycosidic residue is crucial for bioactivity
in several compounds. Hydrolysis of the glycosides, however, produces an active aglycone or a cytotoxic defence
chemical like hydrogen cyanide [109].
195
3.4.1 Glycyrrhizin
Glycyrrhizin (GLZ) is a naturally occurring glycoside isolated from the roots of the Glycyrrhiza uralensis. GLZ frequently employs as a avouring and sweetening factor in
sweets, drinks, chewing gum, and tobacco products. It is also
recognized for its pleasant fragrant sweet taste. GLZ helps to
protect animals from multiple types of experimental liver
damage. This active phytochemical had anti-inammatory,
antioxidant, antimicrobial, and antiviral properties. GLZ
suppressed TNF-α and CD4+ T cell-mediated cytotoxicity
[110]. The deposit of bile acids caused by cholestatic hepatic
injury in the liver and bloodstream typically causes severe
hepatic inammation and helps in the progression of brosis
and cirrhosis. GLZ stimulated the activity of the pregnane X
receptor (PXR) in hepatic cells leading to downregulate the
cholesterol 7-alpha-monooxygenase (CYP7A1) enzyme, an
essential enzyme in the production of bile acids. GLZ signicantly reduced ANIT-induced acute cholangiocyte and
protected the liver against cholestasis by increased ANIT
clearance and decreased inammation [111]. As a powerful
antioxidant, GLZ signicantly reduced caspase-3 and caspase- 9 action and inhibited hepatocyte necrosis, inammation, and brosis [112]. GLZ markedly reduced the
production of both pro-inammatory mediators, such as
TNF-α, iNOS, and COX-2 [113].
3.4.2 Paeoniorin
The primary active constituent, paeoniorin (PAE), was
found in the roots of Paeonia lactiora Pall and Paeonia
veitchii Lynch. It is a monoterpenoid glycoside molecule.
Recent ethnopharmacological studies demonstrate the
196
HO
OOH
HO
Swertiamarin
OH
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HO
O
OHOOH
O
OH
O
OO
Glycyrrhizin
OH
OH
T. Banerjee et al.
O
HO
HO
HO
OH
O
Paeoniflorin
O
O
O
OH
O
O
HO
O
O
O
O
HO
HO
HO
O
OH
OH
Vicenin-2
O
OO
O
O
Geniposide
OH
OH
O
O
O
O
OO
O
OH
O
OH
OH
HO
OH
HO
Salidroside
OH
OH
OO
OH
HO
HO
Schaftoside
O
HO
HO
OH
OH
OO
O
HO
O
OH
OH
OO
OH
OH
O
OH O
O
Fig. 5 Glycosides in the treatment of liver cirrhosis
hepatoprotective activity of PAE. A mechanistic study
investigating the metabolic effects of PAE revealed that it
primarily modulated phenylalanine, tryptophan, and tyrosine biosynthesis, linoleic acid metabolism, inositol phosphate metabolism, glycosylphosphatidylinositol-anchor
biosynthesis, and primary bile acid biosynthesis, which
may be responsible for its protective action in cholestatic
liver injury [114]. PAE signicantly reduces serum biochemical markers and prevents hepatic tissue injury, indicating that it might have effectiveness against NIT-induced
cholestasis [115]. PAE reduces PPAR-γ mRNA levels. It
lowers cholesterol by downregulating PPAR-γ-LXRα-
ABCA-1 pathway. As a potential herbal medication, PAE
has anti-NAFLD activity. Its NAFLD preventive impact
was mediated by various pathways, including the de novo
pathway, the lipid oxidation metabolism pathway, and the
cholesterol synthesis and output pathway [116]. HIF-1α
might induce liver brosis partially via mTOR. PAE
administration potentially diminished the mTOR phosphorylation and HIF-1α expression, and thus it inhibits
brogenesis. PAE also downregulates the COL III and
α-SMA genes responsible for the brosis of rats [117].
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