Oxidative Medicine and Cellular Longevity

Oxidative Medicine and Cellular Longevity / 2019 / Article

Review Article | Open Access

Volume 2019 |Article ID 3831713 | 16 pages | https://doi.org/10.1155/2019/3831713

Hydrogen Sulfide as a Novel Regulatory Factor in Liver Health and Disease

Academic Editor: Claudia Penna
Received25 Jul 2018
Accepted29 Nov 2018
Published20 Jan 2019

Abstract

Hydrogen sulfide (H2S), a colorless gas smelling of rotten egg, has long been recognized as a toxic gas and environment pollutant. However, increasing evidence suggests that H2S acts as a novel gasotransmitter and plays important roles in a variety of physiological and pathological processes in mammals. H2S is involved in many hepatic functions, including the regulation of oxidative stress, glucose and lipid metabolism, vasculature, mitochondrial function, differentiation, and circadian rhythm. In addition, H2S contributes to the pathogenesis and treatment of a number of liver diseases, such as hepatic fibrosis, liver cirrhosis, liver cancer, hepatic ischemia/reperfusion injury, nonalcoholic fatty liver disease/nonalcoholic steatohepatitis, hepatotoxicity, and acute liver failure. In this review, the biosynthesis and metabolism of H2S in the liver are summarized and the role and mechanism of H2S in liver health and disease are further discussed.

1. Introduction

Hydrogen sulfide (H2S) is a colorless and water-soluble gas with the characteristic foul odor of rotten egg [13]. At physiological pH, nearly two thirds of H2S exists as H+ and hydrosulfide anion, which subsequently decomposes to H+ and sulfide ion [4]. In mammals, H2S is produced from L-cysteine and L-homocysteine mainly by cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS). Both CSE and CBS are cytosolic enzymes [5, 6]. 3-Mercaptopyruvate sulfurtransferase (3-MST) acts in combination with cysteine aminotransferase (CAT) to produce H2S from L-cysteine in the presence of α-ketoglutarate (αKG). 3-MST and CAT are located in the mitochondria and cytosol [3, 7]. Furthermore, a recent study has shown that D-amino acid oxidase could metabolize D-cysteine to an achiral α-ketoacid, 3-mercaptopyruvate (3-MP), which is further metabolized to H2S by 3-MST in both kidney and brain [8].

H2S has been considered the third gaseous signaling molecule that plays important regulatory roles in a number of physiologic conditions, such as angiogenesis [9], vasodilatation [10], and neuronal activity [11]. The liver, the largest solid organ in the body, plays a key role in glucose and lipid metabolism, antioxidant defense, and xenobiotic metabolism [1214]. The liver is an important organ for H2S production and its clearance [3, 15]. CSE, CBS, and 3-MST have been detected in the liver, and they contribute to liver production of H2S to different extents [3, 12]. The production and catabolism of H2S in the liver are shown in Figure 1. Hepatic H2S is involved in mitochondrial biogenesis and bioenergetics, insulin sensitivity, lipoprotein synthesis, and glucose metabolism [12, 16, 17]. However, H2S also contributes to the pathogenesis and treatment of many liver diseases, such as liver cirrhosis [18], liver cancer [19], hepatic fibrosis [20], hepatic ischemia/reperfusion (I/R) injury [21], and nonalcoholic steatohepatitis (NASH) [22].

In the present review, we highlight recent studies that provide new insight into the biosynthesis and metabolism of H2S in the liver and further discuss the role and mechanism of H2S in liver health and disease.

2. H2S in Hepatic Function

2.1. H2S in Hepatic Oxidative Stress

Reactive oxygen species (ROS), the by-products of normal aerobic cellular metabolism, are considered to be important signaling molecules in many cellular processes, including cell adhesion, immune response, apoptosis, and cell survival and growth [2325]. Oxidative stress means that an imbalance develops between ROS and antioxidant systems, which is implicated in liver cancer [26], fatty liver [22], liver failure [27], and hepatic ischemia/reperfusion [28]. It has been demonstrated that increased carbonyl formation is an indicator of oxidative stress [12]. The level of carbonyl formation in the liver of CBS-deficient mice is higher when compared to the control group [29], suggesting that CBS may play a role in reducing hepatic oxidative stress. Recent studies have shown that treatment with relatively low concentrations of H2S donor (NaHS or Na2S) could decrease ROS levels, lipid peroxidation, and cytochrome P450 2E1 (CYP2E1) activity and elevate glutathione (GSH) levels and antioxidative enzyme activities like superoxide dismutase, glutathione peroxidase, catalase, and glutathione S-transferase in hepatocytes [3032]. It should be noted that administration of 500 μM NaHS could increase ROS formation through the inhibition of cytochrome c oxidase and the depletion of GSH in rat primary hepatocytes, which could lead to hepatotoxicity [33]. These results together indicate that relatively low levels of H2S could protect against hepatic oxidative stress; however, relatively high concentrations of H2S may exert opposite effects. A proper dose of H2S should be adopted to avoid H2S-induced cytotoxicity in normal liver cells when it is used for the treatment of liver diseases.

2.2. H2S in Hepatic Glucose Metabolism

The liver is crucial for the maintenance of blood glucose homeostasis by uptake of glucose in the postprandial state and conversion to triglyceride and glycogen and by production of glucose in the postabsorptive state by gluconeogenesis and glycogenolysis [34, 35]. Defects in the mechanisms by which insulin and glucose regulate hepatic glycogen metabolism disrupt blood glucose homeostasis and lead to metabolic disorders such as diabetes [35, 36] and glycogen storage disease [37]. It has been shown that the CSE activity is lower in livers of type 1 diabetic rats and peripheral blood mononuclear cells of type 1 diabetic patients [38], indicating that H2S is involved in glucose regulation [17, 39]. A recent study demonstrates that the rate of gluconeogenesis in CSE knockout mice is reduced, which can be reversed by administration of NaHS [40]. Similarly, incubation with NaHS impairs glucose uptake and glycogen storage via decreasing glucokinase activity and increasing gluconeogenesis through S-sulfhydration of pyruvate carboxylase in hepatocytes [16, 41]. These findings suggest that H2S may be a potential target in the treatment of diabetes.

2.3. H2S in Hepatic Lipid Metabolism

The liver is the main metabolic organ and plays an important role in fatty acid and cholesterol metabolism [42]. Hepatic lipid metabolism is orchestrated by a delicate interplay of hormones, transcription factors, nuclear receptors, and intracellular signaling pathways [43]. Excessive accumulation of fat in the liver disturbs its function and leads to the development of many liver diseases, such as NASH, liver cirrhosis, and liver cancer [44]. CBS deficiency in mice liver increases expression of genes induced by endoplasmic reticulum stress and genes that regulate the expression of enzymes required for cholesterol and fatty acid biosynthesis and uptake [45]. Another study indicates that the levels of triglyceride and nonesterified fatty acid are elevated and the activity of thiolase, a key enzyme in beta-oxidation of fatty acids, is decreased in the liver of CBS-deficiency mice [46]. It has been shown that the expression levels of CBS and CSE and the lipid peroxidation were increased in the liver of high-fat diet- (HFD-) fed mice [47]. In addition, tyrosol supplementation increases hepatic CSE and CBS expression and H2S synthesis in HFD-fed mice, which is associated with the attenuation of HFD-induced hepatic lipid peroxidation [48]. A recent study has revealed that administration of NaHS decreases the accumulation of lipids such as total cholesterol and triglyceride through downregulation of fatty acid synthase and upregulation of carnitine palmitoyltransferase-1 in the liver of HFD-induced obese mice [49]. S-Propargyl-cysteine (SPRC), a substrate for endogenous H2S, could reduce the lipid content both in human hepatocellular carcinoma HepG2 cells and in the liver of mice with nonalcoholic fatty liver disease (NAFLD) [50]. These findings indicate that H2S is involved in hepatic lipid metabolism and the underlying mechanisms are needed to be further investigated.

2.4. H2S in Hepatic Vasculature

The liver has a complex system of vascular supply, including the inflow of oxygenated blood through the hepatic artery and deoxygenated blood through the portal vein, as well as the outflow of deoxygenated blood through the hepatic veins to the inferior vena cava [51]. Anatomical variations in hepatic artery are of importance to surgeons in planning effective therapeutic strategies for abdominal surgical procedures [52]. The hepatic artery is involved in the pathogenesis of several diseases, such as stenosis, thrombosis, aneurysm, and pseudoaneurysm [51]. H2S plays a key role in vascular homeostasis during physiological and pathological conditions. H2S-based therapy in vascular disease is a novel area of research [53]. H2S acts as an autocrine mediator in regulation of the contraction of hepatic stellate cells (HSCs) and that a decreased expression of CSE in HSCs may lead to the increased intrahepatic resistance in rodent models of liver cirrhosis [18]. A recent study has shown that H2S differentially contributes to the microcirculatory dysfunction in both systemic and hepatic microcirculations, which can be attributed to H2S-induced differential vasoactive function on sinusoidal and presinusoidal sites within the liver [54]. Another study demonstrates that H2S increases the hepatic arterial buffer capacity and mediates vasorelaxation of the hepatic artery through activation of KATP channels [55]. However, a vasoconstrictor action of H2S on the hepatic sinusoid has been observed, which is different from the dilatory effect of H2S in presinusoidal resistance vessels [56]. More efforts should be paid to validate the different effects of H2S on hepatic vasculature.

2.5. H2S in Hepatic Mitochondrial Function

Mitochondria are double-membrane organelles whose shape is instrumental to their function in many cellular processes [57]. The major role of mitochondria is to regulate the production of energy-rich molecules such as adenosine triphosphate [58]. Mitochondria play important roles in the metabolism of glucose, lipids, and protein in the liver [59]. Under normoxic conditions, the protein expression of CBS in liver mitochondria is at a low level. Hepatic ischemia/hypoxia results in the accumulation of CBS in mitochondria and increased H2S production, which prevents hypoxia-induced mitochondrial ROS production and Ca2+-mediated cytochrome C release from mitochondria [60]. CSE-generated H2S induces liver mitochondrial biogenesis, which can be attributed to the peroxisome proliferator-activated receptor-γ coactivator-1α and peroxisome proliferator-activated receptor-γ coactivator-related protein signaling in primary hepatocytes [61]. 3-MP, the substrate of the enzyme 3-MST, stimulates mitochondrial H2S production and enhances hepatic mitochondrial electron transport and cellular bioenergetics at low concentration, while it inhibits cellular bioenergetics at a higher concentration. In addition, low concentration of H2S induces a significant increase in hepatic mitochondrial function, while a higher concentration of H2S is inhibitory [62]. These results indicate that endogenous H2S plays a physiological role in the maintenance of mitochondrial electron transport and cellular bioenergetics. Considering that different concentrations of exogenous H2S exert diverse effects on hepatic mitochondrial function, the proper dose range of exogenous H2S should be confirmed to achieve optimal hepatic mitochondrial function.

2.6. H2S in Hepatic Differentiation

A number of etiologies such as viral infections, toxic injury, and genetic or autoimmune disorders may cause severe liver dysfunction resulting in acute liver failure or chronic liver disease [63]. Liver transplantation is the primary method to treat acute liver failure and end-stage liver diseases. However, it is limited by numerous problems, including shortage of donor organs, high cost, and immune rejection [64]. To solve these problems, stem-cell-based therapeutic strategies have emerged as alternative options [63, 65]. A recent study indicates that physiological concentrations of H2S could increase the ability of human tooth-pulp stem cells (HTPC) to undergo hepatogenic differentiation [66]. Another study has revealed that H2S increases hepatic differentiation of both HTPC and human bone marrow stem cells [67]. These cells may be suitable for generation of functionally useful hepatocytes and transplantation into model animals with liver diseases. Whether H2S can play a role in hepatic differentiation of other types of cells needs to be further investigated.

2.7. H2S in Hepatic Circadian Rhythm

The circadian clock system comprises peripheral clocks in peripheral tissues and a central clock located in the suprachiasmatic nucleus of the hypothalamus [68]. Peripheral clocks in the liver contribute to maintaining liver homeostasis, including the regulation of energy metabolism and the expression of enzymes controlling the absorption and metabolism of xenobiotics [69]. Clock dysfunction leads to the development of liver diseases such as fatty liver diseases, hepatitis, cirrhosis, and liver cancer, and these disorders also disrupt clock function [68, 70]. A recent study has shown that treatment with NaHS could maintain the circadian rhythm of clock gene in isolated liver cells. It is speculated that H2S increases the activity of sirtuin 1 protein and changes the nicotinamide adenine dinucleotide+/reduced form of nicotinamide adenine dinucleotide ratio in hepatocytes to maintain the rhythm of expression of circadian clock genes, which can prevent and treat lipid metabolism-related diseases caused by the biological clock disorders [71]. In light of the key role of H2S in regulating hepatic circadian rhythm, further studies are needed to elucidate whether H2S could relieve liver diseases through hepatic circadian rhythm.

2.8. Natural Sulfur-Containing Agents in Hepatic Function

Garlic (Allium sativum), a member of the lily family, has been widely used both as a foodstuff and a traditional medicine worldwide for many centuries [7274]. Garlic oil, one of the garlic products, is usually prepared by steam distillation and has been shown to contain a number of organosulfur compounds, such as diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS), which have been considered to be the major biological agents [75, 76]. It has been reported that DAS activates nuclear receptor CAR to induce the Sult1e1 gene in the mouse liver. Whether DAS can play a role in estradiol synthesis pathways, estradiol turnover, or expression/activity of SULT1E1 in other tissues/organs needs to be clarified [74]. Another study indicates that administration of DADS or DATS increases the activities of the phase II enzymes, quinone reductase and glutathione S-transferase, and antioxidative enzyme glutathione peroxidase in rat liver cytosol, suggesting that DADS/DATS could increase the detoxification and antioxidant effects of the liver [77]. Similarly, DADS and DATS have been shown to increase the activities of both GSH reductase and GSH S-transferase in rat livers [78]. Furthermore, a recent study has shown that aldehyde dehydrogenase activity can be inhibited in vivo in the rat liver after treatment with DATS [79]. These results together indicate that natural sulfur-containing agents may play important roles in the regulation of hepatic function. Recent studies have demonstrated that DATS, DADS, and DAS can act as H2S donors [80, 81]. Whether the regulatory effects of DATS, DADS, and DAS are mediated by H2S need to be further investigated.

3. H2S in Hepatic Injury

3.1. H2S in Hepatic Fibrosis

Hepatic fibrosis results from chronic damage to the liver in conjunction with the excessive accumulation of the extracellular matrix (ECM) of predominantly type I collagen [82]. A variety of factors such as viral infections, alcohol abuse, genetic abnormalities, overload of metal ions, and autoimmunity contribute to hepatic fibrosis [82, 83]. Hepatic fibrosis is the inevitable pathological process of many chronic liver diseases, including NASH, NAFLD, and viral hepatitis [84]. Once these chronic diseases aggravate further, hepatic fibrosis may progress to liver cirrhosis or hepatocellular carcinoma (HCC) [85]. There is increasing evidence that activated hepatic stellate cells (HSCs) are the central effector cells, which play key roles in the excessive synthesis and deposition of ECM in hepatic interstitium, leading to hepatic fibrosis [82]. Despite the development made in this field, there are limited available treatments for this disease [86, 87]. It is urgent to develop novel therapeutic drugs aimed at attenuating or preventing hepatic fibrosis. It has been reported that CBS deficiency promotes fibrosis, oxidative stress, and steatosis in mice liver, suggesting that H2S is involved in hepatic fibrosis [29]. Furthermore, recent studies have shown that H2S could attenuate hepatic fibrosis both in vivo and in vitro (Table 1). Therefore, H2S may be a promising therapeutic target for the treatment of a variety of fibrotic diseases. The expression levels and roles of H2S-generating enzymes in fibrotic diseases need to be further determined. Furthermore, proper H2S-releasing agents can be designed and developed to treat fibrotic diseases in a controlled way.


Experimental modelsEffectsProposed mechanismsRefs.

Hepatic fibrosis in vivo (rat)NaHS (56 μmol/kg/day) attenuates CCl4-induced hepatic fibrosisReduction of liver expression levels of AGTR1[20]
Hepatic fibrosis in vivo (rat)NaHS solution (10 mmol/kg body weight) shows protective effects on CCl4-induced hepatic fibrosisDecreased expression of p38 and increased expression of phospho-Akt[88]
Hepatic fibrosis in vivo (rat)NaHS solution (10 mmol/kg body weight) attenuates CCl4-induced hepatic fibrosis and ECM expressionInduction of cell cycle arrest and apoptosis in activated hepatic stellate cells[89]
Hepatic fibrosis in vivo (rat)NaHS (56 μmol/kg/day) attenuates CCl4-induced hepatic fibrosisReduction of the expression of TGF-β1 and sediment of ECM in the liver tissues[90]
Hepatic fibrosis in vitro (rat)DATS (an H2S donor, 10 μM) reduces H2O2-induced upexpression of fibrotic protein in HSCsUnknown[91]

CCl4: carbon tetrachloride; AGTR1: angiotensin II type 1 receptor; TGF-β1: transforming growth factor-β1; H2O2: hydrogen peroxide.
3.2. H2S in Liver Cirrhosis

Liver cirrhosis is an increasing cause of morbidity and mortality, particularly in developed countries [92]. Liver cirrhosis is a serious condition in which scar tissue replaces the healthy tissue of the liver and regenerative nodules surrounded by fibrous bands in response to the injury [93]. Cirrhosis is the common end of progressive liver disease of various causes, leading to several chronic liver failure entailing complications including peritonitis, hepatic encephalopathy, spontaneous bacterial ascites, and esophageal varices [94]. The major clinical consequences of cirrhosis are impaired liver function, an increased intrahepatic resistance, and the development of HCC [93, 95]. In spite of current advancements in the treatment, orthotopic liver transplantation remains the only definite solution to end-stage cirrhosis [92, 94, 96]. Several studies have demonstrated that the mRNA and protein levels of hepatic CSE and the serum levels of H2S in rats are decreased in the cirrhosis group compared with those in the control group [18, 97, 98]. A hypothesis suggests that H2S may contribute to the pathogenesis of vascular dysfunction in cirrhosis [99]. In addition, treatment with NaHS could attenuate CCl4-induced liver cirrhosis, hepatotoxicity, and portal hypertension through anti-inflammation, antifibrosis, and antioxidation effects in rats, suggesting that targeting H2S may present a promising approach in alleviating liver cirrhosis and portal hypertension [31]. However, more studies are urgently needed to clarify the role and mechanism of H2S in different animal models of liver hepatitis.

3.3. H2S in Liver Cancer

Malignant liver tumors can be classified as primary or secondary (metastatic) [100]. Primary malignancies of the liver are HCC, which is the sixth most common cancer and the third leading cause of cancer-related death worldwide [101, 102]. The main etiologic factors for HCC are chronic hepatitis B virus and hepatitis C virus infection, NAFLD, and alcoholic cirrhosis [103]. Most patients with HCC are diagnosed at a late stage when curative treatments are not applicable, and the majority of death is due to tumor recurrence [104]. Thus, it is urgent to uncover novel etiological mechanisms and develop more effective approaches for the prevention and treatment of HCC [105]. In the liver, biosynthesis and clearance of H2S mainly occur in hepatic stellate cells, the major cell source of the extracellular matrix in liver fibrosis and HCC [106]. It has been shown that CSE is overexpressed in human hepatocellular carcinoma HepG2 and PLC/PRF/5 cells and contributes to the proliferation of human HCC cells [107]. Similarly, another study indicates that CSE/H2S promotes human HCC cell proliferation via cell cycle progression regulation [19]. Furthermore, CBS is overexpressed in human hepatocellular carcinoma HepG2 and SMMC-7721 cells and inhibition of endogenous CBS/H2S could reduce the viability and proliferation of SMMC-7721 cells [108]. Moreover, administration of 500 μmol/L NaHS could induce cell proliferation, migration, and angiogenesis and exhibit antiapoptotic effects in PLC/PRF/5 hepatoma cells via activation of the nuclear factor-κB (NF-κB) pathway [109]. However, treatment with 10−3 M NaHS inhibits HCC cell migration, proliferation, and division through induction of cell apoptosis [106]. P-(4-methoxyphenyl)-p-4-morpholinylphosphinodithioic acid morpholine salt (GYY4137)-mediated suppression of cell proliferation in human HCC cells may be due to direct targeting of the signal transducer and activator of the transcription 3 pathway [110]. A recent study has demonstrated that the growth and migration of human HCC cells are enhanced by 10-100 μM NaHS and dose-dependently inhibited by 600-1000 μM NaHS through epidermal growth factor receptor/extracellular signal-regulated protein kinase/matrix metalloproteinase 2 and phosphatase and tensin homolog deleted on chromosome ten/protein kinase B (PKB/AKT) signaling pathways [111]. Taken together, these results indicate that endogenous H2S or relatively low levels of exogenous H2S may promote the growth of HCC cells, while treatment with higher concentrations of exogenous H2S may exhibit anticancer effects. Therefore, knockdown/knockout of H2S-generating enzymes in cancer cells and development of H2S-releasing donors/drugs may be promising strategies for anticancer therapy.

3.4. H2S in Hepatic I/R Injury

Hepatic I/R injury is a major complication in many clinical scenarios, such as liver transplantation, trauma, hemorrhagic shock and resuscitation, liver resection, and aortic injury during abdominal surgery [112114]. Hepatic I/R injury leads to acute or chronic liver failure and increases the rate of morbidity and mortality [115]. Under different pathological conditions, hepatic I/R injury can be classified into warm and cold I/R injury according to the environmental temperature [115]. It is well known that hepatic I/R injury involves several mechanisms, including pH imbalance, calcium overload, mitochondrial dysfunction, ROS overproduction, anaerobic metabolism, activation of Kupffer cells and neutrophils, and the production of cytokines and chemokines [113, 114, 116, 117]. Despite significant improvements in surgical techniques and perioperative care, therapies to suppress hepatic I/R injury at the bedside remain limited largely due to the complex mechanisms [118]. Therefore, there is a clear need for the development of novel agents to protect the liver from I/R injury. An increasing number of studies suggest that H2S could attenuate hepatic I/R injury in several ways, such as antioxidation, anti-inflammation, antiapoptosis, and AKT activation (Table 2). These results indicate that H2S plays an important role in attenuating hepatic I/R injury, and targeting H2S may present a promising approach against I/R-induced liver injury. However, it should be noted that elevated endogenous H2S could not alleviate hepatic I/R injury in insulin-resistant rats, whereas silymarin preconditioning is able to prevent oxidative, inflammatory, nitrosative, and apoptotic injuries associated with hepatic I/R, which can be attributed to the suppression of endogenous H2S production [129]. Furthermore, a recent study suggests that brief and repeated ischemic postconditioning (IPoC) could increase the expression of CSE after I/R in diabetes mellitus, and the modulation of CSE may contribute to the renoprotective effect of IPoC [130]. Whether the expression levels of H2S-generating enzymes in hepatic I/R injury are increased need to be further investigated.


Experimental modelsEffectsProposed mechanismsRefs.

Hepatic I/R in vivo (rat)NaHS (14 μM/kg, 30 min prior to I) attenuates the severity of liver injury and inhibits the production of lipid peroxidation, serum inflammatory factors, and apoptosis-related proteinsAntioxidant and antiapoptotic activities[21]
Hepatic I/R in vivo (mouse)H2S (100 ppm, 5 min prior to R) protects the liver against I/R injuryReduction of apoptosis, necrosis, and inflammation[119]
Hepatic I/R in vivo (rat)GYY4137 (an H2S donor, 133 μM/kg, 1 h prior to I) attenuates the reduced cell viability and the increased apoptosis induced by hepatic I/RActivation of the Akt pathway regulated by miR-21[120]
Hepatic I/R in vivo (rat)NaHS (12.5, 25, and 50 μM/kg, 5 min prior to I) reduces liver damage after perioperative I/R injuryInhibition of MPTP opening and the activation of Akt-GSK-3β signaling[121]
Hepatic I/R in vivo (rat)NaHS (20 μM/kg, 30 min prior to I) reduces hepatic I/R injury in the young ratsActivation of the Nrf2 signaling pathway[122]
Hepatic I/R in vivo (rat)NaHS (5 mg/kg/d for 11 days) protects against cognitive impairment in rats undergoing hepatic I/RReduction of neuroinflammation in the hippocampus[123]
Hepatic I/R in vivo (mouse)NaHS (1 mg/kg prior to R) ameliorates hepatic I/R injury by direct and indirect antioxidant activities and by accelerating hepatic regenerationVia mechanisms involving Nrf2 and Akt-p70S6k[124]
Hepatic I/R in vivo (rat)NaHS (5 mg/kg/d for 11 days) exerts a protective effect on hepatic I/R-induced cognitive impairmentMay be associated with the NR2B subunit of the NMDA receptors[125]
Hepatic I/R in vivo (mouse)NaHS (1.5 mg/kg, 1 h prior to I) protects against hepatic I/R injuryPartly through AKT1 activation[126]
Hepatic I/R in vivo (mouse)NaHS (14 and 28 μM/kg, 30 min prior to I) attenuates hepatic I/R injuryPartly through regulation of apoptosis via inhibiting JNK1 signaling[127]
Hepatic I/R in vivo (rat)NaHS (28 μM/kg, prior to R) attenuates hepatic I/R-induced renal and cardiac injuryReduction of myocardial and renal inflammation and oxidative potential[128]
Hepatic I/R in vivo (mouse)Na2S (an H2S donor, 1 mg/kg, 5 min prior to R) protects the murine liver against I/R injuryUpregulation of intracellular antioxidant and antiapoptotic signaling pathways[30]

MPTP: mitochondrial permeability transition pore; GSK-3β: glycogen synthase kinase-3 beta; Nrf2: nuclear factor erythroid 2-related factor 2; NMDA: NR2B subunit of N-methyl-D-aspartate; JNK1: c-Jun N-terminal kinase 1.
3.5. H2S in NAFLD/NASH

NAFLD affects approximately 25% of the general adult population and is currently the most common cause of chronic liver disease worldwide [131, 132]. NAFLD is defined as the presence of >5% steatosis, no significant alcohol consumption, and no competing etiologies for hepatic steatosis [133]. Development of NAFLD is associated with metabolic syndrome, such as diabetes, obesity, and dyslipidemia [134]. NASH is considered the progressive form of NAFLD and is characterized by inflammation, hepatocellular injury, liver steatosis, and different degrees of fibrosis [135]. Despite intensive investigations, there are currently no approved therapies for NAFLD/NASH. Therefore, there is an unmet need for developing novel and effective treatments for NAFLD/NASH. Methionine is the most toxic amino acid in mammals. It has been reported that excessive methionine intake induces acute lethal hepatitis in mice lacking CSE [136]. Another study indicates that free fatty acids upregulate hepatic expression of 3-MST and subsequently inhibit the CSE/H2S pathway, leading to NAFLD [137]. In addition, exercise training can restore bioavailability of H2S and promote autophagy influx in livers of mice fed with HFD. Recently, a growing number of studies have shown that H2S could play important roles in NAFLD/NASH (Table 3). Novel H2S donors and H2S-releasing drugs can be designed and applied for the treatment of NAFLD/NASH.


Experimental modelsEffectsProposed mechanismsRefs.

NAFLD in vivo (mouse)NaHS (56 μmol/kg/day) attenuates HFD-induced NAFLDActivation of liver autophagy via the AMPK-mTOR pathway[138]
NAFLD in vivo (mouse)NaHS (50 μmol/kg/day) mitigates HFD-induced NAFLDImprovement of lipid metabolism and antioxidant potential[49]
NAFLD in vivo (mouse)NaHS (14 μmol/kg) attenuates concanavalin A-induced hepatitisInhibition of apoptosis and autophagy partly through activation of the PI3K-AKT1 signaling pathway[139]
NASH in vivo (rat)NaHS (28 μmol/kg/day) attenuates MCD-induced NASHPossibly through abating oxidative stress and suppressing inflammation[22]
NAFLD in vivo (mouse)SPRC (an H2S donor, 40 mg/kg/day) exerts a novel protective effect on MCD-induced NAFLDAntioxidative effect through the PI3K/Akt/Nrf2/HO-1 signaling pathway[50]

AMPK: adenosine monophosphate-activated protein kinase; mTOR: mammalian target of rapamycin; PI3K: phosphatidylinositol 3-kinase; MCD: methionine-choline-deficient; HO-1: heme oxygenase-1.
3.6. H2S in Hepatotoxicity

Hepatotoxicity refers to liver injury induced by different types of prescription or nonprescription drugs, such as biological agents, natural medicines, health products, dietary supplements, traditional Chinese medicines (TCMs), and small chemical molecules [140]. TCMs are abundant sources of biologically active substances which have been widely used in the prevention and treatment of human diseases [141143]. However, an increasing number of studies have shown that TCMs could induce severe adverse effects, such as hepatotoxicity [143145]. Hepatotoxicity is the leading cause of acute liver failure in the clinic and the main reason that drugs are taken off the market [146]. The wide range of culprit agents and lack of objective diagnostic tests lead to many challenges in the diagnosis and management of hepatotoxicity [147]. In spite of its low incidence in the general population, the possibility of hepatotoxicity in patients with unexplained acute/chronic liver injury needs to be considered [147, 148]. A recent study demonstrates that uranium (U) intoxication decreases endogenous H2S generation in the hepatic homogenates, while administration of NaHS can reduce U-induced acute hepatotoxicity through antioxidant and antiapoptotic signaling pathways in rats [32]. Acetaminophen overdose is one of the leading causes of drug-induced acute liver failure [149]. H2S treatment alleviates acetaminophen hepatotoxicity in mice partly through antioxidative and anti-inflammatory effects [150]. Another study indicates that H2S anions could protect against acetaminophen-induced hepatotoxicity by directly scavenging reactive N-acetyl-p-benzoquinone imine [151]. Thus, H2S has a potential therapeutic value for the treatment of hepatotoxicity.

3.7. H2S in Acute Liver Failure (ALF)

ALF is a rare multiorgan-failure disease that is usually caused by viral hepatitis, ingestion of drugs or toxic substances, or hepatic I/R injury [152]. ALF could lead to rapid deterioration of liver function with subsequent coagulopathy and encephalopathy [153]. ALF patients often require and undergo orthotopic liver transplantation or die due to shortage of donor livers [152]. The major problem in the treatment of ALF is the lack of suitable mechanistic biomarkers and broad-spectrum anti-ALF agents [154]. It has been reported that inhibition of CSE or administration of sodium thiosulfate protects against ALF by increasing thiosulfate levels and upregulating antioxidant and antiapoptotic defense in the liver [27]. Similarly, CSE deficiency protects against the development of multiorgan failure and attenuates the inflammatory response in a murine model of burn [155]. These results suggest that CSE may be a potential therapeutic target in ALF. Whether CBS or 3-MST deficiency can exert similar effects needs to be further investigated.

3.8. Natural Sulfur-Containing Agents in Hepatic Injury

An increasing number of studies have shown that the garlic constituents possess various biological activities, including anticarcinogenesis, antioxidative, antimicrobial, antihypertensive, antithrombotic, hypolipidemic, radioprotective, immunomodulatory, antidiabetic, and anti-inflammatory effects [75, 156158]. As can be seen in Table 4, many natural sulfur-containing agents could protect against hepatotoxicity mainly through antioxidative, anti-inflammatory, and antiapoptotic effects. Recent studies have shown that DATS possesses a hepatoprotective effect against carbon tetrachloride- (CCl4-) induced liver injury and ethanol-induced hepatic steatosis in rats [166169]. DADS can activate the HO-1/Nrf2 pathway, which may contribute to the protective effects of DADS against ethanol-induced liver injury [170]. Another study demonstrates that DADS increases the levels of phase II/antioxidant enzymes and decreases the levels of inflammatory mediators in CCl4-induced liver injury [158]. Protective effects of DAS were also observed in lipopolysaccharide/D-galactosamine/mercuric chloride-induced hepatic injury in rats [171, 172]. Furthermore, a recent study reveals that DATS can inhibit the profibrogenic properties and alleviate oxidative stress in hepatic stellate cells through the production of H2S [91]. Moreover, an increasing number of studies have indicated that DATS, DADS, and DAS could inhibit the growth of human liver cancer cells [173178]. More efforts should be made to determine the mechanisms of action of natural sulfur-containing agents on liver diseases, such as liver cirrhosis, hepatic I/R injury, and NAFLD/NASH.


Experimental modelsEffectsProposed mechanismsRefs.

Hepatotoxicity in vivo (rat)DATS (40 and 80 mg/kg, orally) protects against valproate-induced hepatotoxicityAntioxidative, anti-inflammatory, and antiapoptotic properties[159]
Hepatotoxicity in vivo (rat)DADS (10 ml/kg/day) attenuates acetaminophen-induced acute hepatotoxicityPossibly via the reduction of oxidative stress-mediated JNK activation and the suppression of inflammatory responses[160]
Hepatotoxicity in vivo (mouse)AMDS (50 mg/kg/day) protects against acetaminophen-induced hepatotoxicityThrough the strong attenuation of the CD45 expression and HNE formation[161]
Hepatotoxicity in vivo (rat)DATS (80 mg/kg/day) ameliorates arsenic-induced hepatotoxicityAbrogation of oxidative stress, inflammation, and apoptosis[162]
Hepatotoxicity in vivo (rat)DADS (2 ml/kg/day) protects against carbon tetrachloride-induced hepatotoxicityThrough activation of Nrf2[163]
Hepatotoxicity in vivo (rat)DAS (200 mg/kg/day) ameliorates ferric nitrilotriacetate-induced hepatotoxicityUnknown[164]
Hepatotoxicity in vivo (mouse)DATS (40 mg/kg) protects against isoniazid and rifampin-induced hepatotoxicityReduction of oxidative stress and activation of Kupffer cells[165]

AMDS: allyl methyl disulfide; HNE: human neutrophil elastase.

4. Conclusions

The liver plays a key role in glucose and lipid metabolism, antioxidant defense, and xenobiotic metabolism. The liver is one of the major organs for the production and metabolism of H2S. CSE, CBS, and 3-MST are three main H2S-generating enzymes, and they contribute to the production of H2S to different extents in the liver. Whether the liver could produce H2S via another enzyme/pathway needs to be further investigated and confirmed. H2S is the third gaseous signaling molecule that is involved in glucose and lipid metabolism, cell differentiation, and circadian rhythm in the liver. Further studies are needed to determine the effects of endogenous H2S on hepatic physiological processes. It is worth noting that H2S could exhibit two obviously opposite effects on hepatic vasculature, oxidative stress, and mitochondrial function, which can be attributed to the concentration, time frame, and reaction time of H2S, as well as the differences between disease stages or models. In light of the important roles of nitric oxide (NO) and carbon monoxide (CO) in mammalian biology, whether H2S exerts the regulatory effects by interacting with NO and/or CO should be clarified.

Recent studies indicate that treatment with exogenous H2S could protect against a number of liver diseases, including hepatic fibrosis, liver cirrhosis, NAFLD/NASH, and hepatotoxicity. Novel H2S releasing/stimulating reagents can be designed and applied to enhance the therapeutic effects. An increasing number of evidence suggests that endogenous H2S or relatively low levels of exogenous H2S can promote the growth of HCC cells, while treatment with higher concentrations of H2S for a relatively long period may exhibit anticancer effects. We speculate that there is a delicate balance between the pro- and anticancer effects induced by H2S (Figure 2). Therefore, inhibition of the generation of endogenous H2S or administration of relatively high level of exogenous H2S could be effective in suppressing tumor growth. In addition, H2S could attenuate hepatic I/R injury in several ways, such as antioxidation, anti-inflammation, antiapoptosis, and AKT activation. Nevertheless, another study has shown that the increases in endogenous H2S exacerbate hepatic I/R injury, suggesting that increased levels of H2S may exhibit opposite effects. Furthermore, inhibition of CSE could alleviate ALF through upregulation of antioxidant and antiapoptotic defense in the liver. Novel inhibitors that target H2S-generating enzymes could be designed and applied in the treatment of ALF.

In conclusion, with a deeper understanding of the precise mechanisms behind the roles of H2S in liver health and disease, H2S could be a promising therapeutic target for further preclinical and clinical research.

Conflicts of Interest

The authors declare that they have no conflicts of interest related to this work.

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (Nos. U1504817, 81670088), the Foundation of Science & Technology Department of Henan Province, China (Nos. 182102310335, 172102410019), the Natural Science Foundation of Education Department of Henan Province, China (No. 15A310017), the Science Foundation of Kaifeng City, China (Nos. 1608004, 1703016), and the Science Foundation of Henan University, China (No. yqpy20170044).

References

  1. T. V. Mishanina, M. Libiad, and R. Banerjee, “Biogenesis of reactive sulfur species for signaling by hydrogen sulfide oxidation pathways,” Nature Chemical Biology, vol. 11, no. 7, pp. 457–464, 2015. View at: Publisher Site | Google Scholar
  2. J. L. Wallace and R. Wang, “Hydrogen sulfide-based therapeutics: exploiting a unique but ubiquitous gasotransmitter,” Nature Reviews Drug Discovery, vol. 14, no. 5, pp. 329–345, 2015. View at: Publisher Site | Google Scholar
  3. R. Wang, “Physiological implications of hydrogen sulfide: a whiff exploration that blossomed,” Physiological Reviews, vol. 92, no. 2, pp. 791–896, 2012. View at: Publisher Site | Google Scholar
  4. C. Álvarez, I. García, I. Moreno et al., “Cysteine-generated sulfide in the cytosol negatively regulates autophagy and modulates the transcriptional profile in Arabidopsis,” The Plant Cell, vol. 24, no. 11, pp. 4621–4634, 2012. View at: Publisher Site | Google Scholar
  5. B. D. Paul and S. H. Snyder, “H2S signalling through protein sulfhydration and beyond,” Nature Reviews Molecular Cell Biology, vol. 13, no. 8, pp. 499–507, 2012. View at: Publisher Site | Google Scholar
  6. C. Szabo, C. Coletta, C. Chao et al., “Tumor-derived hydrogen sulfide, produced by cystathionine-β-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 30, pp. 12474–12479, 2013. View at: Publisher Site | Google Scholar
  7. D. Wu, H. Wang, T. Teng, S. Duan, A. Ji, and Y. Li, “Hydrogen sulfide and autophagy: a double edged sword,” Pharmacological Research, vol. 131, pp. 120–127, 2018. View at: Publisher Site | Google Scholar
  8. N. Shibuya, S. Koike, M. Tanaka et al., “A novel pathway for the production of hydrogen sulfide from D-cysteine in mammalian cells,” Nature Communications, vol. 4, no. 1, p. 1366, 2013. View at: Publisher Site | Google Scholar
  9. A. Papapetropoulos, A. Pyriochou, Z. Altaany et al., “Hydrogen sulfide is an endogenous stimulator of angiogenesis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 51, pp. 21972–21977, 2009. View at: Publisher Site | Google Scholar
  10. G. Yang, L. Wu, B. Jiang et al., “H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine γ-lyase,” Science, vol. 322, no. 5901, pp. 587–590, 2008. View at: Publisher Site | Google Scholar
  11. D. K. Ma, R. Vozdek, N. Bhatla, and H. R. Horvitz, “CYSL-1 interacts with the O2-sensing hydroxylase EGL-9 to promote H2S-modulated hypoxia-induced behavioral plasticity in C. elegans,” Neuron, vol. 73, no. 5, pp. 925–940, 2012. View at: Publisher Site | Google Scholar
  12. S. Mani, W. Cao, L. Wu, and R. Wang, “Hydrogen sulfide and the liver,” Nitric Oxide, vol. 41, pp. 62–71, 2014. View at: Publisher Site | Google Scholar
  13. B. Gao, W. I. Jeong, and Z. Tian, “Liver: an organ with predominant innate immunity,” Hepatology, vol. 47, no. 2, pp. 729–736, 2008. View at: Publisher Site | Google Scholar
  14. S. Liu, J. D. Brown, K. J. Stanya et al., “A diurnal serum lipid integrates hepatic lipogenesis and peripheral fatty acid use,” Nature, vol. 502, no. 7472, pp. 550–554, 2013. View at: Publisher Site | Google Scholar
  15. E. J. Norris, C. R. Culberson, S. Narasimhan, and M. G. Clemens, “The liver as a central regulator of hydrogen sulfide,” Shock, vol. 36, no. 3, pp. 242–250, 2011. View at: Publisher Site | Google Scholar
  16. Y. Ju, A. Untereiner, L. Wu, and G. Yang, “H2S-induced S-sulfhydration of pyruvate carboxylase contributes to gluconeogenesis in liver cells,” Biochimica et Biophysica Acta (BBA) - General Subjects, vol. 1850, no. 11, pp. 2293–2303, 2015. View at: Publisher Site | Google Scholar
  17. J. Pichette and J. Gagnon, “Implications of hydrogen sulfide in glucose regulation: how H2S can alter glucose homeostasis through metabolic hormones,” Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 3285074, 5 pages, 2016. View at: Publisher Site | Google Scholar
  18. S. Fiorucci, E. Antonelli, A. Mencarelli et al., “The third gas: H2S regulates perfusion pressure in both the isolated and perfused normal rat liver and in cirrhosis,” Hepatology, vol. 42, no. 3, pp. 539–548, 2005. View at: Publisher Site | Google Scholar
  19. P. Yin, C. Zhao, Z. Li et al., “Sp1 is involved in regulation of cystathionine γ-lyase gene expression and biological function by PI3K/Akt pathway in human hepatocellular carcinoma cell lines,” Cellular Signalling, vol. 24, no. 6, pp. 1229–1240, 2012. View at: Publisher Site | Google Scholar
  20. H.-N. Fan, N. W. Chen, W. L. Shen, X. Y. Zhao, and J. Zhang, “Endogenous hydrogen sulfide is associated with angiotensin II type 1 receptor in a rat model of carbon tetrachloride-induced hepatic fibrosis,” Molecular Medicine Reports, vol. 12, no. 3, pp. 3351–3358, 2015. View at: Publisher Site | Google Scholar
  21. K. Kang, M. Zhao, H. Jiang, G. Tan, S. Pan, and X. Sun, “Role of hydrogen sulfide in hepatic ischemia-reperfusion-induced injury in rats,” Liver Transplantation, vol. 15, no. 10, pp. 1306–1314, 2009. View at: Publisher Site | Google Scholar
  22. Z. L. Luo, L. J. Tang, T. Wang et al., “Effects of treatment with hydrogen sulfide on methionine-choline deficient diet-induced non-alcoholic steatohepatitis in rats,” Journal of Gastroenterology and Hepatology, vol. 29, no. 1, pp. 215–222, 2014. View at: Publisher Site | Google Scholar
  23. S. Di Meo, T. T. Reed, P. Venditti, and V. M. Victor, “Role of ROS and RNS sources in physiological and pathological conditions,” Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 1245049, 44 pages, 2016. View at: Publisher Site | Google Scholar
  24. S. J. Forrester, D. S. Kikuchi, M. S. Hernandes, Q. Xu, and K. K. Griendling, “Reactive oxygen species in metabolic and inflammatory signaling,” Circulation Research, vol. 122, no. 6, pp. 877–902, 2018. View at: Publisher Site | Google Scholar
  25. M. Schieber and N. S. Chandel, “ROS function in redox signaling and oxidative stress,” Current Biology, vol. 24, no. 10, pp. R453–R462, 2014. View at: Publisher Site | Google Scholar
  26. D. Bartolini, K. Dallaglio, P. Torquato, M. Piroddi, and F. Galli, “Nrf2-p62 autophagy pathway and its response to oxidative stress in hepatocellular carcinoma,” Translational Research, vol. 193, pp. 54–71, 2018. View at: Publisher Site | Google Scholar
  27. K. Shirozu, K. Tokuda, E. Marutani, D. Lefer, R. Wang, and F. Ichinose, “Cystathionine γ-lyase deficiency protects mice from galactosamine/lipopolysaccharide-induced acute liver failure,” Antioxidants & Redox Signaling, vol. 20, no. 2, pp. 204–216, 2014. View at: Publisher Site | Google Scholar
  28. Y. Guo, B. Hu, H. Huang et al., “Estrogen sulfotransferase is an oxidative stress-responsive gene that gender-specifically affects liver ischemia/reperfusion injury,” The Journal of Biological Chemistry, vol. 290, no. 23, pp. 14754–14764, 2015. View at: Publisher Site | Google Scholar
  29. K. Robert, J. Nehmé, E. Bourdon et al., “Cystathionine beta synthase deficiency promotes oxidative stress, fibrosis, and steatosis in mice liver,” Gastroenterology, vol. 128, no. 5, pp. 1405–1415, 2005. View at: Publisher Site | Google Scholar
  30. S. Jha, J. W. Calvert, M. R. Duranski, A. Ramachandran, and D. J. Lefer, “Hydrogen sulfide attenuates hepatic ischemia-reperfusion injury: role of antioxidant and antiapoptotic signaling,” American Journal of Physiology-Heart and Circulatory Physiology, vol. 295, no. 2, pp. H801–H806, 2008. View at: Publisher Site | Google Scholar
  31. G. Tan, S. Pan, J. Li et al., “Hydrogen sulfide attenuates carbon tetrachloride-induced hepatotoxicity, liver cirrhosis and portal hypertension in rats,” PLoS One, vol. 6, no. 10, article e25943, 2011. View at: Publisher Site | Google Scholar
  32. Y. Yuan, J. Zheng, T. Zhao, X. Tang, and N. Hu, “Hydrogen sulfide alleviates uranium-induced acute hepatotoxicity in rats: role of antioxidant and antiapoptotic signaling,” Environmental Toxicology, vol. 32, no. 2, pp. 581–593, 2017. View at: Publisher Site | Google Scholar
  33. D. H. Truong, M. A. Eghbal, W. Hindmarsh, S. H. Roth, and P. J. O'Brien, “Molecular mechanisms of hydrogen sulfide toxicity,” Drug Metabolism Reviews, vol. 38, no. 4, pp. 733–744, 2006. View at: Publisher Site | Google Scholar
  34. A. von Wilamowitz-Moellendorff, R. W. Hunter, M. García-Rocha et al., “Glucose-6-phosphate-mediated activation of liver glycogen synthase plays a key role in hepatic glycogen synthesis,” Diabetes, vol. 62, no. 12, pp. 4070–4082, 2013. View at: Publisher Site | Google Scholar
  35. M. C. Petersen, D. F. Vatner, and G. I. Shulman, “Regulation of hepatic glucose metabolism in health and disease,” Nature Reviews Endocrinology, vol. 13, no. 10, pp. 572–587, 2017. View at: Publisher Site | Google Scholar
  36. A. K. Rines, K. Sharabi, C. D. J. Tavares, and P. Puigserver, “Targeting hepatic glucose metabolism in the treatment of type 2 diabetes,” Nature Reviews Drug Discovery, vol. 15, no. 11, pp. 786–804, 2016. View at: Publisher Site | Google Scholar
  37. B. S. Hijmans, A. Boss, T. H. van Dijk et al., “Hepatocytes contribute to residual glucose production in a mouse model for glycogen storage disease type Ia,” Hepatology, vol. 66, no. 6, pp. 2042–2054, 2017. View at: Publisher Site | Google Scholar
  38. P. Manna, N. Gungor, R. McVie, and S. K. Jain, “Decreased cystathionine-γ-lyase (CSE) activity in livers of type 1 diabetic rats and peripheral blood mononuclear cells (PBMC) of type 1 diabetic patients,” The Journal of Biological Chemistry, vol. 289, no. 17, pp. 11767–11778, 2014. View at: Publisher Site | Google Scholar
  39. J. Bełtowski, G. Wójcicka, and A. Jamroz-Wiśniewska, “Hydrogen sulfide in the regulation of insulin secretion and insulin sensitivity: implications for the pathogenesis and treatment of diabetes mellitus,” Biochemical Pharmacology, vol. 149, pp. 60–76, 2018. View at: Publisher Site | Google Scholar
  40. A. A. Untereiner, R. Wang, Y. Ju, and L. Wu, “Decreased gluconeogenesis in the absence of cystathionine gamma-lyase and the underlying mechanisms,” Antioxidants & Redox Signaling, vol. 24, no. 3, pp. 129–140, 2016. View at: Publisher Site | Google Scholar
  41. L. Zhang, G. Yang, A. Untereiner, Y. Ju, L. Wu, and R. Wang, “Hydrogen sulfide impairs glucose utilization and increases gluconeogenesis in hepatocytes,” Endocrinology, vol. 154, no. 1, pp. 114–126, 2013. View at: Publisher Site | Google Scholar
  42. H. Zhou and R. Liu, “ER stress and hepatic lipid metabolism,” Frontiers in Genetics, vol. 5, p. 112, 2014. View at: Publisher Site | Google Scholar
  43. L. P. Bechmann, R. A. Hannivoort, G. Gerken, G. S. Hotamisligil, M. Trauner, and A. Canbay, “The interaction of hepatic lipid and glucose metabolism in liver diseases,” Journal of Hepatology, vol. 56, no. 4, pp. 952–964, 2012. View at: Publisher Site | Google Scholar
  44. D. B. Jump, “Fatty acid regulation of hepatic lipid metabolism,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 14, no. 2, pp. 115–120, 2011. View at: Publisher Site | Google Scholar
  45. J. Hamelet, K. Demuth, J. L. Paul, J. M. Delabar, and N. Janel, “Hyperhomocysteinemia due to cystathionine beta synthase deficiency induces dysregulation of genes involved in hepatic lipid homeostasis in mice,” Journal of Hepatology, vol. 46, no. 1, pp. 151–159, 2007. View at: Publisher Site | Google Scholar
  46. K. Namekata, Y. Enokido, I. Ishii, Y. Nagai, T. Harada, and H. Kimura, “Abnormal lipid metabolism in cystathionine beta-synthase-deficient mice, an animal model for hyperhomocysteinemia,” The Journal of Biological Chemistry, vol. 279, no. 51, pp. 52961–52969, 2004. View at: Publisher Site | Google Scholar
  47. S. Y. Hwang, L. K. Sarna, Y. L. Siow, and K. O, “High-fat diet stimulates hepatic cystathionine β-synthase and cystathionine γ-lyase expression,” Canadian Journal of Physiology and Pharmacology, vol. 91, no. 11, pp. 913–919, 2013. View at: Publisher Site | Google Scholar
  48. L. K. Sarna, V. Sid, P. Wang, Y. L. Siow, J. D. House, and K. O, “Tyrosol attenuates high fat diet-induced hepatic oxidative stress: potential involvement of cystathionine β-synthase and cystathionine γ-lyase,” Lipids, vol. 51, no. 5, pp. 583–590, 2016. View at: Publisher Site | Google Scholar
  49. D. Wu, N. Zheng, K. Qi et al., “Exogenous hydrogen sulfide mitigates the fatty liver in obese mice through improving lipid metabolism and antioxidant potential,” Medical Gas Research, vol. 5, no. 1, p. 1, 2015. View at: Publisher Site | Google Scholar
  50. W. Li, F. Ma, L. Zhang et al., “S-Propargyl-cysteine exerts a novel protective effect on methionine and choline deficient diet-induced fatty liver via Akt/Nrf2/HO-1 pathway,” Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 4690857, 17 pages, 2016. View at: Publisher Site | Google Scholar
  51. K. M. Elsayes, A. M. Shaaban, S. M. Rothan et al., “A comprehensive approach to hepatic vascular disease,” Radiographics, vol. 37, no. 3, pp. 813–836, 2017. View at: Publisher Site | Google Scholar
  52. G. Noussios, I. Dimitriou, I. Chatzis, and A. Katsourakis, “The main anatomic variations of the hepatic artery and their importance in surgical practice: review of the literature,” Journal of Clinical Medical Research, vol. 9, no. 4, pp. 248–252, 2017. View at: Publisher Site | Google Scholar
  53. K. M. Holwerda, S. A. Karumanchi, and A. T. Lely, “Hydrogen sulfide: role in vascular physiology and pathology,” Current Opinion in Nephrology and Hypertension, vol. 24, no. 2, pp. 170–176, 2015. View at: Publisher Site | Google Scholar
  54. E. J. Norris, S. Larion, C. R. Culberson, and M. G. Clemens, “Hydrogen sulfide differentially affects the hepatic vasculature in response to phenylephrine and endothelin 1 during endotoxemia,” Shock, vol. 39, no. 2, pp. 168–175, 2013. View at: Publisher Site | Google Scholar
  55. N. Siebert, D. Cantré, C. Eipel, and B. Vollmar, “H2S contributes to the hepatic arterial buffer response and mediates vasorelaxation of the hepatic artery via activation of K (ATP) channels,” American Journal of Physiology-Gastrointestinal and Liver Physiology, vol. 295, no. 6, pp. G1266–G1273, 2008. View at: Publisher Site | Google Scholar
  56. E. J. Norris, N. Feilen, N. H. Nguyen et al., “Hydrogen sulfide modulates sinusoidal constriction and contributes to hepatic microcirculatory dysfunction during endotoxemia,” American Journal of Physiology-Gastrointestinal and Liver Physiology, vol. 304, no. 12, pp. G1070–G1078, 2013. View at: Publisher Site | Google Scholar
  57. J. R. Friedman, A. Mourier, J. Yamada, J. M. McCaffery, and J. Nunnari, “MICOS coordinates with respiratory complexes and lipids to establish mitochondrial inner membrane architecture,” eLife, vol. 4, article e07739, 2015. View at: Publisher Site | Google Scholar
  58. M. M. Mehta, S. E. Weinberg, and N. S. Chandel, “Mitochondrial control of immunity: beyond ATP,” Nature Reviews Immunology, vol. 17, no. 10, pp. 608–620, 2017. View at: Publisher Site | Google Scholar
  59. F. Nassir and J. A. Ibdah, “Role of mitochondria in alcoholic liver disease,” World Journal of Gastroenterology, vol. 20, no. 9, pp. 2136–2142, 2014. View at: Publisher Site | Google Scholar
  60. H. Teng, B. Wu, K. Zhao, G. Yang, L. Wu, and R. Wang, “Oxygen-sensitive mitochondrial accumulation of cystathionine β-synthase mediated by Lon protease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 31, pp. 12679–12684, 2013. View at: Publisher Site | Google Scholar
  61. A. A. Untereiner, M. Fu, K. Módis, R. Wang, Y. J. Ju, and L. Wu, “Stimulatory effect of CSE-generated H2S on hepatic mitochondrial biogenesis and the underlying mechanisms,” Nitric Oxide, vol. 58, pp. 67–76, 2016. View at: Publisher Site | Google Scholar
  62. K. Módis, C. Coletta, K. Erdélyi, A. Papapetropoulos, and C. Szabo, “Intramitochondrial hydrogen sulfide production by 3-mercaptopyruvate sulfurtransferase maintains mitochondrial electron flow and supports cellular bioenergetics,” The FASEB Journal, vol. 27, no. 2, pp. 601–611, 2013. View at: Publisher Site | Google Scholar
  63. C. Hu and L. Li, “In vitro and in vivo hepatic differentiation of adult somatic stem cells and extraembryonic stem cells for treating end stage liver diseases,” Stem Cells International, vol. 2015, Article ID 871972, 11 pages, 2015. View at: Publisher Site | Google Scholar
  64. W. H. Liu, F. Q. Song, L. N. Ren et al., “The multiple functional roles of mesenchymal stem cells in participating in treating liver diseases,” Journal of Cellular and Molecular Medicine, vol. 19, no. 3, pp. 511–520, 2015. View at: Publisher Site | Google Scholar
  65. R. Vasconcellos, É. C. Alvarenga, R. C. Parreira, S. S. Lima, and R. R. Resende, “Exploring the cell signalling in hepatocyte differentiation,” Cellular Signalling, vol. 28, no. 11, pp. 1773–1788, 2016. View at: Publisher Site | Google Scholar
  66. N. Ishkitiev, B. Calenic, I. Aoyama, H. Ii, K. Yaegaki, and T. Imai, “Hydrogen sulfide increases hepatic differentiation in tooth-pulp stem cells,” Journal of Breath Research, vol. 6, no. 1, article 017103, 2012. View at: Publisher Site | Google Scholar
  67. M. Okada, N. Ishkitiev, K. Yaegaki et al., “Hydrogen sulphide increases hepatic differentiation of human tooth pulp stem cells compared with human bone marrow stem cells,” International Endodontic Journal, vol. 47, no. 12, pp. 1142–1150, 2014. View at: Publisher Site | Google Scholar
  68. A. L. C. Figueroa, H. Figueiredo, S. A. Rebuffat, E. Vieira, and R. Gomis, “Taurine treatment modulates circadian rhythms in mice fed a high fat diet,” Scientific Reports, vol. 6, no. 1, article 36801, 2016. View at: Publisher Site | Google Scholar
  69. Y. Tahara and S. Shibata, “Circadian rhythms of liver physiology and disease: experimental and clinical evidence,” Nature Reviews Gastroenterology & Hepatology, vol. 13, no. 4, pp. 217–226, 2016. View at: Publisher Site | Google Scholar
  70. X. Tong and L. Yin, “Circadian rhythms in liver physiology and liver diseases,” Comprehensive Physiology, vol. 3, no. 2, pp. 917–940, 2013. View at: Publisher Site | Google Scholar
  71. Z. Shang, C. Lu, S. Chen, L. Hua, and R. Qian, “Effect of H2S on the circadian rhythm of mouse hepatocytes,” Lipids in Health and Disease, vol. 11, no. 1, p. 23, 2012. View at: Publisher Site | Google Scholar
  72. J. H. Jeong, H. R. Jeong, Y. N. Jo, H. J. Kim, J. H. Shin, and H. J. Heo, “Ameliorating effects of aged garlic extracts against Aβ-induced neurotoxicity and cognitive impairment,” BMC Complementary and Alternative Medicine, vol. 13, no. 1, p. 268, 2013. View at: Publisher Site | Google Scholar
  73. S. Annamalai, L. Mohanam, V. Raja, A. Dev, and V. Prabhu, “Antiobesity, antioxidant and hepatoprotective effects of diallyl trisulphide (DATS) alone or in combination with orlistat on HFD induced obese rats,” Biomedicine & Pharmacotherapy, vol. 93, pp. 81–87, 2017. View at: Publisher Site | Google Scholar
  74. T. Sueyoshi, W. D. Green, K. Vinal, T. S. Woodrum, R. Moore, and M. Negishi, “Garlic extract diallyl sulfide (DAS) activates nuclear receptor CAR to induce the Sult1e1 gene in mouse liver,” PLoS One, vol. 6, no. 6, article e21229, 2011. View at: Publisher Site | Google Scholar
  75. C. Yang, L. Li, L. Yang, H. Lǚ, S. Wang, and G. Sun, “Anti-obesity and Hypolipidemic effects of garlic oil and onion oil in rats fed a high-fat diet,” Nutrition and Metabolism, vol. 15, no. 1, p. 43, 2018. View at: Publisher Site | Google Scholar
  76. H. L. Nicastro, S. A. Ross, and J. A. Milner, “Garlic and onions: their cancer prevention properties,” Cancer Prevention Research, vol. 8, no. 3, pp. 181–189, 2015. View at: Publisher Site | Google Scholar
  77. T. Fukao, T. Hosono, S. Misawa, T. Seki, and T. Ariga, “The effects of allyl sulfides on the induction of phase II detoxification enzymes and liver injury by carbon tetrachloride,” Food and Chemical Toxicology, vol. 42, no. 5, pp. 743–749, 2004. View at: Publisher Site | Google Scholar
  78. C. C. Wu, L. Y. Sheen, H. W. Chen, S. J. Tsai, and C. K. Lii, “Effects of organosulfur compounds from garlic oil on the antioxidation system in rat liver and red blood cells,” Food and Chemical Toxicology, vol. 39, no. 6, pp. 563–569, 2001. View at: Publisher Site | Google Scholar
  79. M. Iciek, M. Górny, A. Bilska-Wilkosz, and D. Kowalczyk-Pachel, “Is aldehyde dehydrogenase inhibited by sulfur compounds? In vitro and in vivo studies,” Acta Biochimica Polonica, vol. 65, no. 1, pp. 125–132, 2018. View at: Publisher Site | Google Scholar
  80. D. Wu, Q. Hu, and Y. Zhu, “Therapeutic application of hydrogen sulfide donors: the potential and challenges,” Frontiers in Medicine, vol. 10, no. 1, pp. 18–27, 2016. View at: Publisher Site | Google Scholar
  81. D. Liang, H. Wu, M. W. Wong, and D. Huang, “Diallyl trisulfide is a fast H2S donor, but diallyl disulfide is a slow one: the reaction pathways and intermediates of glutathione with polysulfides,” Organic Letters, vol. 17, no. 17, pp. 4196–4199, 2015. View at: Publisher Site | Google Scholar
  82. M. M. Ni, Y. R. Wang, W. W. Wu et al., “Novel insights on notch signaling pathways in liver fibrosis,” European Journal of Pharmacology, vol. 826, pp. 66–74, 2018. View at: Publisher Site | Google Scholar
  83. S. Poilil Surendran, R. George Thomas, M. J. Moon, and Y. Y. Jeong, “Nanoparticles for the treatment of liver fibrosis,” International Journal of Nanomedicine, vol. 12, pp. 6997–7006, 2017. View at: Publisher Site | Google Scholar
  84. J. Lambrecht, I. Mannaerts, and L. A. van Grunsven, “The role of miRNAs in stress-responsive hepatic stellate cells during liver fibrosis,” Frontiers in Physiology, vol. 6, p. 209, 2015. View at: Publisher Site | Google Scholar
  85. X. P. Jiang, W. B. Ai, L. Y. Wan, Y. Q. Zhang, and J. F. Wu, “The roles of microRNA families in hepatic fibrosis,” Cell & Bioscience, vol. 7, no. 1, p. 34, 2017. View at: Publisher Site | Google Scholar
  86. B. González-Fernández, D. I. Sánchez, J. González-Gallego, and M. J. Tuñón, “Sphingosine 1-phosphate signaling as a target in hepatic fibrosis therapy,” Frontiers in Pharmacology, vol. 8, p. 579, 2017. View at: Publisher Site | Google Scholar
  87. C. Y. Zhang, W. G. Yuan, P. He, J. H. Lei, and C. X. Wang, “Liver fibrosis and hepatic stellate cells: etiology, pathological hallmarks and therapeutic targets,” World Journal of Gastroenterology, vol. 22, no. 48, pp. 10512–10522, 2016. View at: Publisher Site | Google Scholar
  88. H. N. Fan, H. J. Wang, L. Ren et al., “Decreased expression of p38 MAPK mediates protective effects of hydrogen sulfide on hepatic fibrosis,” European Review for Medical and Pharmacological Sciences, vol. 17, no. 5, pp. 644–652, 2013. View at: Google Scholar
  89. H.-N. Fan, H.-J. Wang, C.-R. Yang-Dan et al., “Protective effects of hydrogen sulfide on oxidative stress and fibrosis in hepatic stellate cells,” Molecular Medicine Reports, vol. 7, no. 1, pp. 247–253, 2013. View at: Publisher Site | Google Scholar
  90. Q. Shen, Z. Qin, and A. Lu, “Preventive effect of exogenous hydrogen sulfide on hepatic fibrosis in rats,” Zhong Nan Da Xue Xue Bao Yi Xue Ban, vol. 37, no. 9, pp. 911–915, 2012. View at: Publisher Site | Google Scholar
  91. F. Zhang, H. Jin, L. Wu et al., “Diallyl trisulfide suppresses oxidative stress-induced activation of hepatic stellate cells through production of hydrogen sulfide,” Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 1406726, 13 pages, 2017. View at: Publisher Site | Google Scholar
  92. E. A. Tsochatzis, J. Bosch, and A. K. Burroughs, “Liver cirrhosis,” The Lancet, vol. 383, no. 9930, pp. 1749–1761, 2014. View at: Publisher Site | Google Scholar
  93. D. Schuppan and N. H. Afdhal, “Liver cirrhosis,” The Lancet, vol. 371, no. 9615, pp. 838–851, 2008. View at: Publisher Site | Google Scholar
  94. K. A. Kwak, H. J. Cho, J. Y. Yang, and Y. S. Park, “Current perspectives regarding stem cell-based therapy for liver cirrhosis,” Canadian Journal of Gastroenterology and Hepatology, vol. 2018, Article ID 4197857, 19 pages, 2018. View at: Publisher Site | Google Scholar
  95. A. Forner, M. Reig, and J. Bruix, “Hepatocellular carcinoma,” The Lancet, vol. 391, no. 10127, pp. 1301–1314, 2018. View at: Publisher Site | Google Scholar
  96. R. Lozano, M. Naghavi, K. Foreman et al., “Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010,” The Lancet, vol. 380, no. 9859, pp. 2095–2128, 2012. View at: Publisher Site | Google Scholar
  97. S.-B. Guo, Z.-J. Duan, Q.-M. Wang, Q. Zhou, Q. Li, and X.-Y. Sun, “Endogenous carbon monoxide downregulates hepatic cystathionine-γ-lyase in rats with liver cirrhosis,” Experimental and Therapeutic Medicine, vol. 10, no. 6, pp. 2039–2046, 2015. View at: Publisher Site | Google Scholar
  98. W. Wei, C. Wang, and D. Li, “The content of hydrogen sulfide in plasma of cirrhosis rats combined with portal hypertension and the correlation with indexes of liver function and liver fibrosis,” Experimental and Therapeutic Medicine, vol. 14, no. 5, pp. 5022–5026, 2017. View at: Publisher Site | Google Scholar
  99. M. R. Ebrahimkhani, A. R. Mani, and K. Moore, “Hydrogen sulphide and the hyperdynamic circulation in cirrhosis: a hypothesis,” Gut, vol. 54, no. 12, pp. 1668–1671, 2005. View at: Publisher Site | Google Scholar
  100. G. Khemlina, S. Ikeda, and R. Kurzrock, “The biology of hepatocellular carcinoma: implications for genomic and immune therapies,” Molecular Cancer, vol. 16, no. 1, p. 149, 2017. View at: Publisher Site | Google Scholar
  101. A. X. Zhu, D. G. Duda, D. V. Sahani, and R. K. Jain, “HCC and angiogenesis: possible targets and future directions,” Nature Reviews Clinical Oncology, vol. 8, no. 5, pp. 292–301, 2011. View at: Publisher Site | Google Scholar
  102. X. Shi, H. R. Zhu, T. T. Liu, X. Z. Shen, and J. M. Zhu, “The hippo pathway in hepatocellular carcinoma: non-coding RNAs in action,” Cancer Letters, vol. 400, pp. 175–182, 2017. View at: Publisher Site | Google Scholar
  103. S. Singh, P. P. Singh, L. R. Roberts, and W. Sanchez, “Chemopreventive strategies in hepatocellular carcinoma,” Nature Reviews Gastroenterology & Hepatology, vol. 11, no. 1, pp. 45–54, 2014. View at: Publisher Site | Google Scholar
  104. J. H. Shi and P. D. Line, “Effect of liver regeneration on malignant hepatic tumors,” World Journal of Gastroenterology, vol. 20, no. 43, pp. 16167–16177, 2014. View at: Publisher Site | Google Scholar
  105. G. Xu, J. Wang, F. Wu et al., “YAP and 14-3-3γ are involved in HS-OA-induced growth inhibition of hepatocellular carcinoma cells: a novel mechanism for hydrogen sulfide releasing oleanolic acid,” Oncotarget, vol. 7, no. 32, pp. 52150–52165, 2016. View at: Publisher Site | Google Scholar
  106. S. S. Wang, Y. H. Chen, N. Chen et al., “Hydrogen sulfide promotes autophagy of hepatocellular carcinoma cells through the PI3K/Akt/mTOR signaling pathway,” Cell Death & Disease, vol. 8, no. 3, article e2688, 2017. View at: Publisher Site | Google Scholar
  107. Y. Pan, S. Ye, D. Yuan, J. Zhang, Y. Bai, and C. Shao, “Hydrogen sulfide (H2S)/cystathionine γ-lyase (CSE) pathway contributes to the proliferation of hepatoma cells,” Mutation Research, vol. 763-764, pp. 10–18, 2014. View at: Publisher Site | Google Scholar
  108. H. Jia, J. Ye, J. You, X. Shi, W. Kang, and T. Wang, “Role of the cystathionine β-synthase/H2S system in liver cancer cells and the inhibitory effect of quinolone-indolone conjugate QIC2 on the system,” Oncology Reports, vol. 37, no. 5, pp. 3001–3009, 2017. View at: Publisher Site | Google Scholar
  109. Y. Zhen, W. Pan, F. Hu et al., “Exogenous hydrogen sulfide exerts proliferation/anti-apoptosis/angiogenesis/migration effects via amplifying the activation of NF-κB pathway in PLC/PRF/5 hepatoma cells,” International Journal of Oncology, vol. 46, no. 5, pp. 2194–2204, 2015. View at: Publisher Site | Google Scholar
  110. S. Lu, Y. Gao, X. Huang, and X. Wang, “GYY 4137, a hydrogen sulfide (H2S) donor, shows potent anti-hepatocellular carcinoma activity through blocking the STAT3 pathway,” International Journal of Oncology, vol. 44, no. 4, pp. 1259–1267, 2014. View at: Publisher Site | Google Scholar
  111. D. Wu, M. Li, W. Tian et al., “Hydrogen sulfide acts as a double-edged sword in human hepatocellular carcinoma cells through EGFR/ERK/MMP-2 and PTEN/AKT signaling pathways,” Scientific Reports, vol. 7, no. 1, article 5134, 2017. View at: Publisher Site | Google Scholar
  112. C. Nastos, K. Kalimeris, N. Papoutsidakis et al., “Global consequences of liver ischemia/reperfusion injury,” Oxidative Medicine and Cellular Longevity, vol. 2014, Article ID 906965, 13 pages, 2014. View at: Publisher Site | Google Scholar
  113. Y. Zhai, H. Petrowsky, J. C. Hong, R. W. Busuttil, and J. W. Kupiec-Weglinski, “Ischaemia-reperfusion injury in liver transplantation--from bench to bedside,” Nature Reviews Gastroenterology & Hepatology, vol. 10, no. 2, pp. 79–89, 2013. View at: Publisher Site | Google Scholar
  114. D. Wu, J. Wang, H. Li, M. Xue, A. Ji, and Y. Li, “Role of hydrogen sulfide in ischemia-reperfusion injury,” Oxidative Medicine and Cellular Longevity, vol. 2015, Article ID 186908, 16 pages, 2015. View at: Publisher Site | Google Scholar
  115. C. Hu and L. Li, “Pre-conditions for eliminating mitochondrial dysfunction and maintaining liver function after hepatic ischaemia reperfusion,” Journal of Cellular and Molecular Medicine, vol. 21, no. 9, pp. 1719–1731, 2017. View at: Publisher Site | Google Scholar
  116. Z. Ma, Z. Xin, W. Di et al., “Melatonin and mitochondrial function during ischemia/reperfusion injury,” Cellular and Molecular Life Sciences, vol. 74, no. 21, pp. 3989–3998, 2017. View at: Publisher Site | Google Scholar
  117. Y. Q. Zhang, N. Ding, Y. F. Zeng et al., “New progress in roles of nitric oxide during hepatic ischemia reperfusion injury,” World Journal of Gastroenterology, vol. 23, no. 14, pp. 2505–2510, 2017. View at: Publisher Site | Google Scholar
  118. K. L. Go, S. Lee, I. Zendejas, K. E. Behrns, and J. S. Kim, “Mitochondrial dysfunction and autophagy in hepatic ischemia/reperfusion injury,” BioMed Research International, vol. 2015, Article ID 183469, 14 pages, 2015. View at: Publisher Site | Google Scholar
  119. E. M. Bos, P. M. Snijder, H. Jekel et al., “Beneficial effects of gaseous hydrogen sulfide in hepatic ischemia/reperfusion injury,” Transplant International, vol. 25, no. 8, pp. 897–908, 2012. View at: Publisher Site | Google Scholar
  120. M. Lu, X. Jiang, L. Tong et al., “MicroRNA-21-regulated activation of the Akt pathway participates in the protective effects of H2S against liver ischemia-reperfusion injury,” Biological & Pharmaceutical Bulletin, vol. 41, no. 2, pp. 229–238, 2018. View at: Publisher Site | Google Scholar
  121. Q. Zhang, H. Fu, H. Zhang et al., “Hydrogen sulfide preconditioning protects rat liver against ischemia/reperfusion injury by activating Akt-GSK-3β signaling and inhibiting mitochondrial permeability transition,” PLoS One, vol. 8, no. 9, article e74422, 2013. View at: Publisher Site | Google Scholar
  122. X. Huang, Y. Gao, J. Qin, and S. Lu, “The role of miR-34a in the hepatoprotective effect of hydrogen sulfide on ischemia/reperfusion injury in young and old rats,” PLoS One, vol. 9, no. 11, article e113305, 2014. View at: Publisher Site | Google Scholar
  123. F. Tu, J. Li, J. Wang, Q. Li, and W. Chu, “Hydrogen sulfide protects against cognitive impairment induced by hepatic ischemia and reperfusion via attenuating neuroinflammation,” Experimental Biology and Medicine, vol. 241, no. 6, pp. 636–643, 2016. View at: Publisher Site | Google Scholar
  124. S. Shimada, M. Fukai, K. Wakayama et al., “Hydrogen sulfide augments survival signals in warm ischemia and reperfusion of the mouse liver,” Surgery Today, vol. 45, no. 7, pp. 892–903, 2015. View at: Publisher Site | Google Scholar
  125. F. P. Tu, J. X. Li, Q. Li, and J. Wang, “Effects of hydrogen sulfide on cognitive dysfunction and NR2B in rats,” The Journal of Surgical Research, vol. 205, no. 2, pp. 426–431, 2016. View at: Publisher Site | Google Scholar
  126. D. Wang, Y. Ma, Z. Li et al., “The role of AKT1 and autophagy in the protective effect of hydrogen sulphide against hepatic ischemia/reperfusion injury in mice,” Autophagy, vol. 8, no. 6, pp. 954–962, 2012. View at: Publisher Site | Google Scholar
  127. P. Cheng, F. Wang, K. Chen et al., “Hydrogen sulfide ameliorates ischemia/reperfusion-induced hepatitis by inhibiting apoptosis and autophagy pathways,” Mediators of Inflammation, vol. 2014, Article ID 935251, 16 pages, 2014. View at: Publisher Site | Google Scholar
  128. Y. Chen, Z. Liu, and X. Xie, “Hydrogen sulphide attenuates renal and cardiac injury after total hepatic ischemia and reperfusion,” The Journal of Surgical Research, vol. 164, no. 2, pp. e305–e313, 2010. View at: Publisher Site | Google Scholar
  129. N. N. Younis, M. A. Shaheen, and M. F. Mahmoud, “Silymarin preconditioning protected insulin resistant rats from liver ischemia-reperfusion injury: role of endogenous H2S,” The Journal of Surgical Research, vol. 204, no. 2, pp. 398–409, 2016. View at: Publisher Site | Google Scholar
  130. Y. Chen, L. Zhao, S. Jiang et al., “Cystathionine γ-Lyase is involved in the renoprotective effect of brief and repeated ischemic postconditioning after renal ischemia/reperfusion injury in diabetes mellitus,” Transplantation Proceedings, vol. 50, no. 5, pp. 1549–1557, 2018. View at: Publisher Site | Google Scholar
  131. Z. M. Younossi, A. B. Koenig, D. Abdelatif, Y. Fazel, L. Henry, and M. Wymer, “Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes,” Hepatology, vol. 64, no. 1, pp. 73–84, 2016. View at: Publisher Site | Google Scholar
  132. M. A. Konerman, J. C. Jones, and S. A. Harrison, “Pharmacotherapy for NASH: current and emerging,” Journal of Hepatology, vol. 68, no. 2, pp. 362–375, 2018. View at: Publisher Site | Google Scholar
  133. N. Chalasani, Z. Younossi, J. E. Lavine et al., “The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association,” The American Journal of Gastroenterology, vol. 107, no. 6, pp. 811–826, 2012. View at: Publisher Site | Google Scholar
  134. H. Yki-Järvinen, “Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome,” The Lancet Diabetes and Endocrinology, vol. 2, no. 11, pp. 901–910, 2014. View at: Publisher Site | Google Scholar
  135. S. Schuster, D. Cabrera, M. Arrese, and A. E. Feldstein, “Triggering and resolution of inflammation in NASH,” Nature Reviews. Gastroenterology & Hepatology, vol. 15, no. 6, pp. 349–364, 2018. View at: Publisher Site | Google Scholar
  136. H. Yamada, N. Akahoshi, S. Kamata et al., “Methionine excess in diet induces acute lethal hepatitis in mice lacking cystathionine γ-lyase, an animal model of cystathioninuria,” Free Radical Biology & Medicine, vol. 52, no. 9, pp. 1716–1726, 2012. View at: Publisher Site | Google Scholar
  137. M. Li, C. Xu, J. Shi et al., “Fatty acids promote fatty liver disease via the dysregulation of 3-mercaptopyruvate sulfurtransferase/hydrogen sulfide pathway,” Gut, vol. 67, no. 12, pp. 2169–2180, 2018. View at: Publisher Site | Google Scholar
  138. L. Sun, S. Zhang, C. Yu et al., “Hydrogen sulfide reduces serum triglyceride by activating liver autophagy via the AMPK-mTOR pathway,” American Journal of Physiology-Endocrinology and Metabolism, vol. 309, no. 11, pp. E925–E935, 2015. View at: Publisher Site | Google Scholar
  139. P. Cheng, K. Chen, Y. Xia et al., “Hydrogen sulfide, a potential novel drug, attenuates concanavalin A-induced hepatitis,” Drug Design, Development and Therapy, vol. 8, pp. 1277–1286, 2014. View at: Publisher Site | Google Scholar
  140. Y.-c. Yu, Y.-m. Mao, C.-w. Chen et al., “CSH guidelines for the diagnosis and treatment of drug-induced liver injury,” Hepatology International, vol. 11, no. 3, pp. 221–241, 2017. View at: Publisher Site | Google Scholar
  141. Y. Gao, S. Chu, Q. Shao et al., “Antioxidant activities of ginsenoside Rg1 against cisplatin-induced hepatic injury through Nrf2 signaling pathway in mice,” Free Radical Research, vol. 51, no. 1, pp. 1–13, 2017. View at: Publisher Site | Google Scholar
  142. P. Zhao, B. Liu, C. Wang, and Acute Liver Failure Study Team (ALFST), “Hepatotoxicity evaluation of traditional Chinese medicines using a computational molecular model,” Clinical Toxicology, vol. 55, no. 9, pp. 996–1000, 2017. View at: Publisher Site | Google Scholar
  143. S. H. Huang, C. W. Tung, F. Fülöp, and J. H. Li, “Developing a QSAR model for hepatotoxicity screening of the active compounds in traditional Chinese medicines,” Food and Chemical Toxicology, vol. 78, pp. 71–77, 2015. View at: Publisher Site | Google Scholar
  144. R. Teschke, A. Wolff, C. Frenzel, and J. Schulze, “Review article: herbal hepatotoxicity–an update on traditional Chinese medicine preparations,” Alimentary Pharmacology & Therapeutics, vol. 40, no. 1, pp. 32–50, 2014. View at: Publisher Site | Google Scholar
  145. J. Jing and R. Teschke, “Traditional Chinese medicine and herb-induced liver injury: comparison with drug-induced liver injury,” Journal of Clinical and Translational Hepatology, vol. 6, no. 1, pp. 57–68, 2018. View at: Publisher Site | Google Scholar
  146. T. J. Davern and N. Chalasani, “Drug-induced liver injury in clinical trials: as rare as hens’ teeth,” The American Journal of Gastroenterology, vol. 104, no. 5, pp. 1159–1161, 2009. View at: Publisher Site | Google Scholar
  147. N. P. Chalasani, P. H. Hayashi, H. L. Bonkovsky, V. J. Navarro, W. M. Lee, and FACG & Robert J Fontana MD on behalf of the Practice Parameters Committee of the American College of Gastroenterology, “ACG clinical guideline: the diagnosis and management of idiosyncratic drug-induced liver injury,” The American Journal of Gastroenterology, vol. 109, no. 7, pp. 950–966, 2014. View at: Publisher Site | Google Scholar
  148. E. S. Björnsson, O. M. Bergmann, H. K. Björnsson, R. B. Kvaran, and S. Olafsson, “Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland,” Gastroenterology, vol. 144, no. 7, pp. 1419–1425.e3, 2013. View at: Publisher Site | Google Scholar
  149. K. Furuta, Y. Yoshida, S. Ogura et al., “Gab1 adaptor protein acts as a gatekeeper to balance hepatocyte death and proliferation during acetaminophen-induced liver injury in mice,” Hepatology, vol. 63, no. 4, pp. 1340–1355, 2016. View at: Publisher Site | Google Scholar
  150. M. A. Morsy, S. A. Ibrahim, S. A. Abdelwahab, M. Z. Zedan, and H. I. Elbitar, “Curative effects of hydrogen sulfide against acetaminophen-induced hepatotoxicity in mice,” Life Sciences, vol. 87, no. 23-26, pp. 692–698, 2010. View at: Publisher Site | Google Scholar
  151. I. Ishii, S. Kamata, Y. Hagiya, Y. Abiko, T. Kasahara, and Y. Kumagai, “Protective effects of hydrogen sulfide anions against acetaminophen-induced hepatotoxicity in mice,” The Journal of Toxicological Sciences, vol. 40, no. 6, pp. 837–841, 2015. View at: Publisher Site | Google Scholar
  152. D. Yang, Q. Yuan, A. Balakrishnan et al., “MicroRNA-125b-5p mimic inhibits acute liver failure,” Nature Communications, vol. 7, no. 1, article 11916, 2016. View at: Publisher Site | Google Scholar
  153. J. Karkhanis, E. C. Verna, M. S. Chang et al., “Steroid use in acute liver failure,” Hepatology, vol. 59, no. 2, pp. 612–621, 2014. View at: Publisher Site | Google Scholar
  154. M. R. McGill and H. Jaeschke, “Mechanistic biomarkers in acetaminophen-induced hepatotoxicity and acute liver failure: from preclinical models to patients,” Expert Opinion on Drug Metabolism & Toxicology, vol. 10, no. 7, pp. 1005–1017, 2014. View at: Publisher Site | Google Scholar
  155. A. Ahmad, N. Druzhyna, and C. Szabo, “Cystathionine-gamma-lyase deficient mice are protected against the development of multiorgan failure and exhibit reduced inflammatory response during burn,” Burns, vol. 43, no. 5, pp. 1021–1033, 2017. View at: Publisher Site | Google Scholar
  156. K. C. Lai, C. L. Kuo, H. C. Ho et al., “Diallyl sulfide, diallyl disulfide and diallyl trisulfide affect drug resistant gene expression in Colo 205 human colon cancer cells in vitro and in vivo,” Phytomedicine, vol. 19, no. 7, pp. 625–630, 2012. View at: Publisher Site | Google Scholar
  157. T. Zeng, F. F. Guo, C. L. Zhang et al., “The anti-fatty liver effects of garlic oil on acute ethanol-exposed mice,” Chemico-Biological Interactions, vol. 176, no. 2-3, pp. 234–242, 2008. View at: Publisher Site | Google Scholar
  158. I. C. Lee, S. H. Kim, H. S. Baek et al., “The involvement of Nrf2 in the protective effects of diallyl disulfide on carbon tetrachloride-induced hepatic oxidative damage and inflammatory response in rats,” Food and Chemical Toxicology, vol. 63, pp. 174–185, 2014. View at: Publisher Site | Google Scholar
  159. A. A. Shaaban and D. S. El-Agamy, “Cytoprotective effects of diallyl trisulfide against valproate-induced hepatotoxicity: new anticonvulsant strategy,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 390, no. 9, pp. 919–928, 2017. View at: Publisher Site | Google Scholar
  160. J. W. Ko, S. H. Park, N. R. Shin et al., “Protective effect and mechanism of action of diallyl disulfide against acetaminophen-induced acute hepatotoxicity,” Food and Chemical Toxicology, vol. 109, Part 1, pp. 28–37, 2017. View at: Publisher Site | Google Scholar
  161. Y. Zhang, F. Zhang, K. Wang et al., “Protective effect of allyl methyl disulfide on acetaminophen-induced hepatotoxicity in mice,” Chemico-Biological Interactions, vol. 249, pp. 71–77, 2016. View at: Publisher Site | Google Scholar
  162. N. C. Sumedha and S. Miltonprabu, “Diallyl trisulfide ameliorates arsenic-induced hepatotoxicity by abrogation of oxidative stress, inflammation, and apoptosis in rats,” Human & Experimental Toxicology, vol. 34, no. 5, pp. 506–525, 2015. View at: Publisher Site | Google Scholar
  163. I. C. Lee, S. H. Kim, H. S. Baek et al., “Protective effects of diallyl disulfide on carbon tetrachloride-induced hepatotoxicity through activation of Nrf2,” Environmental Toxicology, vol. 30, no. 5, pp. 538–548, 2015. View at: Publisher Site | Google Scholar
  164. S. Ansar and M. Iqbal, “Amelioration of ferric nitrilotriacetate-induced hepatotoxicity in Wistar rats by diallylsulfide,” Human & Experimental Toxicology, vol. 35, no. 3, pp. 259–266, 2016. View at: Publisher Site | Google Scholar
  165. Y. Yang, L. Jiang, S. Wang, T. Zeng, and K. Xie, “Diallyl trisulfide protects the liver against hepatotoxicity induced by isoniazid and rifampin in mice by reducing oxidative stress and activating Kupffer cells,” Toxicology Research, vol. 5, no. 3, pp. 954–962, 2016. View at: Publisher Site | Google Scholar
  166. T. Fukao, T. Hosono, S. Misawa, T. Seki, and T. Ariga, “Chemoprotective effect of diallyl trisulfide from garlic against carbon tetrachloride-induced acute liver injury of rats,” BioFactors, vol. 21, no. 1-4, pp. 171–174, 2004. View at: Publisher Site | Google Scholar
  167. T. Hosono-Fukao, T. Hosono, T. Seki, and T. Ariga, “Diallyl trisulfide protects rats from carbon tetrachloride-induced liver injury,” The Journal of Nutrition, vol. 139, no. 12, pp. 2252–2256, 2009. View at: Publisher Site | Google Scholar
  168. X. Zhu, F. Zhang, L. Zhou et al., “Diallyl trisulfide attenuates carbon tetrachloride-caused liver injury and fibrogenesis and reduces hepatic oxidative stress in rats,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 387, no. 5, pp. 445–455, 2014. View at: Publisher Site | Google Scholar
  169. L. Y. Chen, Q. Chen, Y. F. Cheng et al., “Diallyl trisulfide attenuates ethanol-induced hepatic steatosis by inhibiting oxidative stress and apoptosis,” Biomedicine & Pharmacotherapy, vol. 79, pp. 35–43, 2016. View at: Publisher Site | Google Scholar
  170. T. Zeng, C. L. Zhang, F. Y. Song et al., “The activation of HO-1/Nrf-2 contributes to the protective effects of diallyl disulfide (DADS) against ethanol-induced oxidative stress,” Biochimica et Biophysica Acta (BBA) - General Subjects, vol. 1830, no. 10, pp. 4848–4859, 2013. View at: Publisher Site | Google Scholar
  171. M. Li, S. Wang, X. Li et al., “Diallyl sulfide protects against lipopolysaccharide/d-galactosamine-induced acute liver injury by inhibiting oxidative stress, inflammation and apoptosis in mice,” Food and Chemical Toxicology, vol. 120, pp. 500–509, 2018. View at: Publisher Site | Google Scholar
  172. S. Ansar and M. Iqbal, “Protective effect of diallylsulphide against mercuric chloride-induced hepatic injury in rats,” Human & Experimental Toxicology, vol. 35, no. 12, pp. 1305–1311, 2016. View at: Publisher Site | Google Scholar
  173. C. C. Wu, J. G. Chung, S. J. Tsai, J. H. Yang, and L. Y. Sheen, “Differential effects of allyl sulfides from garlic essential oil on cell cycle regulation in human liver tumor cells,” Food and Chemical Toxicology, vol. 42, no. 12, pp. 1937–1947, 2004. View at: Publisher Site | Google Scholar
  174. S. S. Ibrahim and N. N. Nassar, “Diallyl sulfide protects against N-nitrosodiethylamine-induced liver tumorigenesis: role of aldose reductase,” World Journal of Gastroenterology, vol. 14, no. 40, pp. 6145–6153, 2008. View at: Publisher Site | Google Scholar
  175. J. Wen, Y. Zhang, X. Chen, L. Shen, G. C. Li, and M. Xu, “Enhancement of diallyl disulfide-induced apoptosis by inhibitors of MAPKs in human HepG2 hepatoma cells,” Biochemical Pharmacology, vol. 68, no. 2, pp. 323–331, 2004. View at: Publisher Site | Google Scholar
  176. M. Iciek, I. Kwiecień, G. Chwatko, M. Sokołowska-Jeżewicz, D. Kowalczyk-Pachel, and H. Rokita, “The effects of garlic-derived sulfur compounds on cell proliferation, caspase 3 activity, thiol levels and anaerobic sulfur metabolism in human hepatoblastoma HepG2 cells,” Cell Biochemistry and Function, vol. 30, no. 3, pp. 198–204, 2012. View at: Publisher Site | Google Scholar
  177. D. Guyonnet, R. Bergès, M. H. Siess et al., “Post-initiation modulating effects of allyl sulfides in rat hepatocarcinogenesis,” Food and Chemical Toxicology, vol. 42, no. 9, pp. 1479–1485, 2004. View at: Publisher Site | Google Scholar
  178. L. Yi and Q. Su, “Molecular mechanisms for the anti-cancer effects of diallyl disulfide,” Food and Chemical Toxicology, vol. 57, pp. 362–370, 2013. View at: Publisher Site | Google Scholar

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