31 Our goal was to extend these observations using multiplex quantum dot labeling to search for an association between ERα expression and IL-6 expression and evidence of gp130 downstream signaling in a clinically relevant situation in human BECs in vivo. Results showed nuclear ERα expression was associated with cytoplasmic IL-6 protein expression and evidence of downstream gp130 signaling, manifest as nuclear pSTAT3 (Fig. 6A). Cystic BEC pSTAT3 expression was entirely blocked with recombinant pSTAT3 peptide (Fig. 6B). BEC from the normal liver (Fig. 6A), in contrast, were negative for IL-6 expression and showed only rare pSTAT3-positive

BECs; occasional portal-based periductal Selleck AZD6738 inflammatory cells expressed cytoplasmic IL-6 protein and pSTAT3 (Fig. 6). To determine the significance of estrogen signaling in PCL, we compared cyst BECs from three males and six premenopausal (<45 years)

and six postmenopausal (>55 years) women for immunohistochemical expression of ERα, IL-6, pSTAT3, and a variety of other growth factor and receptor proteins (vascular endothelial growth factor [VEGF], Flk-1, insulin-like growth factor 1 [IGF-1], phosphorylated IGF-1 receptor [pIGF-1R], epidermal growth factor receptor [EGFR], erythroblastic leukemia viral oncogene homolog 2 [Her2/ErbB-2]) which are known to be expressed on PCL BECs or in the cyst fluid. ERα and pSTAT3 showed a significant correlation to menopausal state. Male pSTAT3 was comparable to that of premenopausal women and likely influenced by other environmental factors Selumetinib datasheet (androgens and testosterone) or IGF-1/pIGF-1R, whose expression was slightly higher in male PCL (data not shown) (Fig. 6C). Although it is not surprising that ERα was higher in the premenopausal group, the correlation between pSTAT3 and menopausal status implicates ERα signaling in disease progression. Because many of the factors tested might influence IL-6 or manifest downstream signaling as pSTAT3, we analyzed PCL on the basis of pSTAT3 high and low expression. MCE公司 The only significant

relationship with pSTAT3 expression was IL-6 (Fig. 6D). Our results on differential regulation of BEC IL-6 mRNA and protein expression by ERα according to sex are consistent with previous studies showing that: (1) ERα expression is complex and regulated at the level of transcription, translation, and protein degradation by the ubiquitin-proteasome pathway32; (2) ERβ generally blocks or significantly reduces gene activation mediated by ERα16, 26; and (3) ERα is most closely correlated with a positive modulatory effect on BEC physiology.17 The following observations support these conclusions. Non-neoplastic female BECs and the male BEC cell line SG231 express significantly more ERα than non-neoplastic male BECs and the HuCCT-1 cell line.

10, 20, 45, 46 These findings together this website suggest that Pparγ might be antifibrogenic in HSCs. This suggestion raises the intriguing question of whether the increased expression of Pparγ following Ad-L-Fabp transduction of passaged HSCs plays a role in attenuating the activation state observed in vivo. A key question, unanswered by the current findings,

is whether the loss of LDs is a cause or consequence of HSC activation in vivo. It was recently reported that the absence of retinoid-containing LDs in HSCs in lecithin-retinol acyltransferase knockout (Lrat−/− mice) mice did not enhance HSC activation induced by bile duct ligation or by carbon tetrachloride administration.47 In this scenario, the loss of retinoid signaling was invoked as a consequence, but not a prerequisite, for HSC activation. The current findings place in context the importance of cell-specific events in lipid signaling as mediators of liver injury. It will be important, for example, to reconcile the role of these signaling events as implied from in vitro studies in isolated cell culture with their physiological functions in vivo. The current findings in germline L-Fabp−/− mice imply that there are distinctive roles for LD biology in hepatocytes and HSCs and it will be important to examine these implications using targeted cell-specific selleck deletion strategies. These

approaches will form the foundation of ongoing studies to explore some underlying mechanisms of liver injury and may allow us to place the current observations into proper perspective. Additional Supporting Information may be found in the online version of this article. “
“Advanced stages of non-alcoholic fatty liver disease (NAFLD) are highly prevalent in type 2 diabetes (T2DM), however, no diabetes-related or biochemical variable seems to be predictive of severity of NAFLD. The aim of this study was to investigate the association of several serum biomarkers with the more severe histopathological stages of NAFLD in T2DM. In a cross-sectional design, 84 T2DM patients with biopsy-proven NAFLD had adiponectin,

tumor necrosis factor-α, transforming growth factor (TGF)-β1, interleukin (IL)-6, -8 and -10, and C-reactive protein measured. NAFLD severity was evaluated by two hepatopathologists medchemexpress according to the non-alcoholic steatohepatitis (NASH) Clinical Research Network scoring system. Independent associations of cytokines with NASH and advanced fibrosis were evaluated by multivariate logistic regressions. Sixty-six patients (78.6%) had NASH, and 52 patients (61.9%) had advanced fibrosis considering the highest score between the two pathologists. Patients with NASH or with advanced fibrosis had equal cytokine levels to those without NASH or with absent/light fibrosis, except for a lower serum adiponectin (8.59 vs 12.77 μg/mL; P = 0.

10, 20, 45, 46 These findings together check details suggest that Pparγ might be antifibrogenic in HSCs. This suggestion raises the intriguing question of whether the increased expression of Pparγ following Ad-L-Fabp transduction of passaged HSCs plays a role in attenuating the activation state observed in vivo. A key question, unanswered by the current findings,

is whether the loss of LDs is a cause or consequence of HSC activation in vivo. It was recently reported that the absence of retinoid-containing LDs in HSCs in lecithin-retinol acyltransferase knockout (Lrat−/− mice) mice did not enhance HSC activation induced by bile duct ligation or by carbon tetrachloride administration.47 In this scenario, the loss of retinoid signaling was invoked as a consequence, but not a prerequisite, for HSC activation. The current findings place in context the importance of cell-specific events in lipid signaling as mediators of liver injury. It will be important, for example, to reconcile the role of these signaling events as implied from in vitro studies in isolated cell culture with their physiological functions in vivo. The current findings in germline L-Fabp−/− mice imply that there are distinctive roles for LD biology in hepatocytes and HSCs and it will be important to examine these implications using targeted cell-specific JNK inhibitor deletion strategies. These

approaches will form the foundation of ongoing studies to explore some underlying mechanisms of liver injury and may allow us to place the current observations into proper perspective. Additional Supporting Information may be found in the online version of this article. “
“Advanced stages of non-alcoholic fatty liver disease (NAFLD) are highly prevalent in type 2 diabetes (T2DM), however, no diabetes-related or biochemical variable seems to be predictive of severity of NAFLD. The aim of this study was to investigate the association of several serum biomarkers with the more severe histopathological stages of NAFLD in T2DM. In a cross-sectional design, 84 T2DM patients with biopsy-proven NAFLD had adiponectin,

tumor necrosis factor-α, transforming growth factor (TGF)-β1, interleukin (IL)-6, -8 and -10, and C-reactive protein measured. NAFLD severity was evaluated by two hepatopathologists MCE公司 according to the non-alcoholic steatohepatitis (NASH) Clinical Research Network scoring system. Independent associations of cytokines with NASH and advanced fibrosis were evaluated by multivariate logistic regressions. Sixty-six patients (78.6%) had NASH, and 52 patients (61.9%) had advanced fibrosis considering the highest score between the two pathologists. Patients with NASH or with advanced fibrosis had equal cytokine levels to those without NASH or with absent/light fibrosis, except for a lower serum adiponectin (8.59 vs 12.77 μg/mL; P = 0.

Therefore, we decided to use PBDL for this study. In BDL lobes, F4/80-positive cells were increased. The Ale-lip treatment succeeded in deleting F4/80-positive cells (Fig. 1A). Thus, Ale-lip injection can be utilized as a new tool for Kupffer cell depletion. Inflammatory cytokines mainly produced from Kupffer cells were up-regulated in BDL lobes, whereas the Ale-lip treatment markedly inhibited the production of TNF-α

and IL-1β (Fig. 1B). Kupffer cell-depleted mice showed an increase of Nutlin-3a solubility dmso injured lesion in BDL lobes and serum ALT level after the surgery (Fig. 1C). Interestingly, 24 hours after common BDL (Supporting Fig. 2) as well as PBDL (Fig. 1C), there were no significant differences in histological liver injury and elevated ALT activities between control and Kupffer cell-depleted mice. These findings indicate that Kupffer cells were not involved in the early stage of liver damage that occurs by BDL, but in the late JNK pathway inhibitors stage. As previously reported,20 treatment with TNF-α plus GalN strongly induced hepatocyte destruction and massive hemorrhage with apoptotic cells in nonligated lobes of PBDL animals, whereas hemorrhagic damage and hepatocyte apoptosis were blunted in BDL lobes (Supporting Fig. 3A-C). Kupffer cell depletion itself did not induce hepatocyte apoptosis (Supporting Fig. 3D). In Kupffer cell-depleted livers, GalN plus TNF-α treatment induced hemorrhagic liver damage and hepatocyte apoptosis

with the cleavage of poly (ADP-ribose) polymerase (PARP), which is the downstream target of caspase-3, both in nonligated and BDL lobes (Fig. 2A-C). In the BDL lobes, proliferation cell nuclear antigen (PCNA) or Ki67-positive hepatocytes were increased with up-regulation of cyclin E expression (Fig. 2D-F), indicating that BDL induces hepatocyte regeneration. In Kupffer cell-depleted livers the expressions of PCNA, Ki67, and

cyclin E were decreased (Fig. 2D-F). Thus, Kupffer cells are important for survival and regeneration of hepatocytes after BDL. Fibrosis was induced in BDL lobes as demonstrated by Sirius red staining, hydroxyproline content, expression of α-smooth muscle actin (α-SMA) and desmin, MCE and messenger RNA (mRNA) expression of collagen-α1(I) and transforming growth factor (TGF)-β1 (Fig. 3). Kupffer cell-depleted mice showed reduced fibrosis in BDL lobes (Fig. 3). The number and the activation of HSCs were decreased by Kupffer cell depletion as assessed by desmin and α-SMA expression, respectively. These results suggest that the decrease in the fibrogenic response by Kupffer cell depletion is due to a lack of signal from Kupffer cells to activate and proliferate HSCs. To further elucidate the mechanisms by which Kupffer cells contribute to BDL-mediated functional changes in liver injury, survival of hepatocyte, regeneration, and fibrosis, we focused on ASMase. The protein level of ASMase (Supporting Fig.

Our data demonstrate that miR-200a is frequently down-regulated in HCC tissues in comparison with the adjacent noncancerous hepatic tissues, a finding that is consistent with other reports.35, 36 Reduced levels of the histone H3 acetylation at the mir-200a promoter and increased levels of HDAC4 mRNA were also observed in HCCs. Because HDAC4 alone is enzymatically inactive, CCI-779 in vitro it may suppress the transcription of miR-200a and induce the histone H3 deacetylation at the mir-200a promoter by recruiting catalytically active HDACs into transcriptional

corepressor complexes.37 Therefore, further investigations are required to fully elucidate the nature of HDAC4-containing repressor complexes at the mir-200a promoter. In addition to miR-200a, the miR-200 family also includes miR-200b, miR-200c, miR-141, and miR-429, with miR-200b, miR-200a, and miR-429 being located on chromosome 1 and miR-200c and miR-141 being located on chromosome 12. Both clusters are encoded

as polycistronic transcripts. Our results show that HDAC4 regulates the expression of the miR-200b, miR-200a, miR-429 cluster, but does not regulate the other cluster. Other reports have demonstrated that HDAC inhibitors induce up-regulation of miR-200c,15, 17 and therefore we speculated that other HDACs may participate in the regulation of the miR-200c and miR-141 cluster. Interestingly, we observed that miR-200a, in turn, negatively regulated HDAC4 expression by directly targeting the complementary sites in the 3′-UTR selleck products of HDAC4 mRNA, generating a double negative feedback loop. Feedback loops are common in many genetic pathways involving miRNAs, and they seem to enhance the robustness of gene networks.38 A significant inverse correlation was also observed between HDAC4 and miR-200a in human HCC tissues. Copy number alterations of

miR-200a and HDAC4 were not found in HCC tissues compared with matched controls. Other proteins such as ZEB1,24 SIRT1,22 p53,39 and gata-binding factors23 can also regulate the expression of miR-200a. Therefore, there is an intricate mechanism regulating the expression of miR-200a and HDAC4 in HCCs. Further investigations are required to elucidate whether the up-regulation of HDAC4 or the down-regulation of miR-200a is the initial 上海皓元 factor of this loop in HCC. Recently, many studies have demonstrated that miRNAs may affect the epigenetic mechanism. For instance, miR-152 induced aberrant DNA methylation in HCC by targeting the DNA methyltransferase 1, as demonstrated in our previous study.40 Other miRNAs, such as miR-148a/b,41 miR-1,20 and miR-449a19, have also been reported to target epigenetic modifying enzymes and modulate the epigenetic transcriptional-regulatory process. However, whether miRNAs can affect the histone acetylation level in HCC remains largely unknown.

The assumption of a gradual increase learn more in antiviral effectiveness that explains

the initially slow decrease in viral load still needs to be validated, even though it is supported by the observation that the active forms of mericitabine in vitro take ∼48 hours to accumulate to steady-state triphosphate levels.13 It is noteworthy that RBV, which needs to be phosphorylated to its monophosphate, diphosphate, and triphosphate analogues, when given as monotherapy also induces a monophasic viral decline consistent with the variable effectivenss assumption.29 Second, our model does not distinguish between the cytidine and the uridine triphosphates, which could have slightly different potencies selleck products and are expected to accumulate at different rates. Third, it is hard to precisely estimate ε1, ε2, and δ, because they have overlapping effects on the viral load decline. At least one additional sampling measurement between days 1 and 4 would be necessary to estimate more precisely the initial antiviral effectiveness, ε1. However, the fact that the CE and the VE models provided very similar estimates of ε and δ (Tables 1 and 2) is an indication that these parameters were precisely estimated, and consequently that infected cell loss/death

may be playing a minor role in the overall viral load decline. Lastly, for the sake of parameter identifiability, the target cell level was assumed constant throughout the study period. The kinetics of HCV MCE RNA rebound after the end of treatment may be affected by the increased availability of target cells,30 and hence our estimates of the rate at which antiviral effectiveness decays after the end of treatment may not be as reliable

as we would wish. Recent developments in viral dynamic modeling have emphasized the interplay between the kinetics of intracellular viral RNA and the extracellular viral kinetics measured by serum levels of HCV RNA.31 Within the context of such models it has been shown that the initial rate of decline of serum HCV RNA is proportional to the ability of drug to block the late stages of virion production (i.e., assembly/secretion).32 If a drug does not block virion assembly/secretion, there may be release of preformed virions during the first phase of viral decline that masks the intrinsic plasma HCV clearance rate.32 Thus the slow initial viral decline observed with mericitabine may reflect the fact that blocking NS5B has only a minimal effect on blocking virus assembly/secretion into the circulation. However, even if a minimal effect in blocking virus assembly/secretion is taken into account using a model that incorporates intracellular events,32 a gradual decrease in the virus production rate, as in the VE model, is still required to fit the data (not shown).

The assumption of a gradual increase SCH 900776 order in antiviral effectiveness that explains

the initially slow decrease in viral load still needs to be validated, even though it is supported by the observation that the active forms of mericitabine in vitro take ∼48 hours to accumulate to steady-state triphosphate levels.13 It is noteworthy that RBV, which needs to be phosphorylated to its monophosphate, diphosphate, and triphosphate analogues, when given as monotherapy also induces a monophasic viral decline consistent with the variable effectivenss assumption.29 Second, our model does not distinguish between the cytidine and the uridine triphosphates, which could have slightly different potencies this website and are expected to accumulate at different rates. Third, it is hard to precisely estimate ε1, ε2, and δ, because they have overlapping effects on the viral load decline. At least one additional sampling measurement between days 1 and 4 would be necessary to estimate more precisely the initial antiviral effectiveness, ε1. However, the fact that the CE and the VE models provided very similar estimates of ε and δ (Tables 1 and 2) is an indication that these parameters were precisely estimated, and consequently that infected cell loss/death

may be playing a minor role in the overall viral load decline. Lastly, for the sake of parameter identifiability, the target cell level was assumed constant throughout the study period. The kinetics of HCV 上海皓元 RNA rebound after the end of treatment may be affected by the increased availability of target cells,30 and hence our estimates of the rate at which antiviral effectiveness decays after the end of treatment may not be as reliable

as we would wish. Recent developments in viral dynamic modeling have emphasized the interplay between the kinetics of intracellular viral RNA and the extracellular viral kinetics measured by serum levels of HCV RNA.31 Within the context of such models it has been shown that the initial rate of decline of serum HCV RNA is proportional to the ability of drug to block the late stages of virion production (i.e., assembly/secretion).32 If a drug does not block virion assembly/secretion, there may be release of preformed virions during the first phase of viral decline that masks the intrinsic plasma HCV clearance rate.32 Thus the slow initial viral decline observed with mericitabine may reflect the fact that blocking NS5B has only a minimal effect on blocking virus assembly/secretion into the circulation. However, even if a minimal effect in blocking virus assembly/secretion is taken into account using a model that incorporates intracellular events,32 a gradual decrease in the virus production rate, as in the VE model, is still required to fit the data (not shown).

HSCs are liver pericytes that reside in the space between parenchymal cells and sinusoidal endothelial cells of the liver.[2] HSCs are rich in vitamin A and store nearly 80% of retinoids of the whole body in its lipid droplets in the cytoplasm.[3, 4] Interestingly, recent studies[5-15] suggest that HSCs participate in the liver immunity. In this paper, we review the recent development in HSC-mediated

immunity and the significance of these new observations. HCV represents one of the major causes of liver fibrosis. The rate of progression of liver fibrosis varies widely in the chronic HCV infection, and progresses to cirrhosis within 20 years in an estimated 20–30% of individuals with chronic HCV infection.[16] The role of HSCs in FK506 in vivo HCV-mediated liver fibrosis has been well documented. HCV-infected hepatocytes release transforming growth factor-β1 (TGF-β1) and other profibrogenic factors that differentially modulate HSC expression of ABC294640 several key genes involved in liver fibrosis.[17] HCV infection-induced hepatocyte

apoptosis is a common feature in chronic HCV infection.[18, 19] Apoptosis results in the generation of apoptotic bodies (ABs), which are subsequently cleared by phagocytosis. Several studies showed that HSCs have the ability to engulf ABs through phagocytosis, which can trigger a profibrogenic response.[20, 21] It was reported that ABs derived from HCV-infected Huh7 cells exhibited a more pronounced effect on profibrotic genes expression in HSCs than HCV-negative ABs.[22] Besides the indirect effects of HCV on HSCs function through infected

hepatocytes, several studies[23-26] 上海皓元 indicated that there is also a direct contact between HCV and HSCs. The potential interaction between HSCs and HCV is suggested by the observation that HSCs express high levels of CD81 protein,[23] a key entry coreceptor for HCV.[24] It has been demonstrated that the HCV E2 protein can directly bind to CD81 on HSC surface, inducing fibrogenic effects on HSCs.[25] In addition to HCV envelope protein, HCV core and nonstructural proteins have also been shown to affect HSC functions.[26] Recombinant HCV core and NS3 proteins could increase intracellular calcium concentration and reactive oxygen species production in activated HSCs.[26] HCV core protein could increase HSC proliferation, and NS3-NS5 protein preferentially induced pro-inflammatory cytokines in HSCs. The roles of HSCs in HCV infection-mediated liver fibrosis are summarized in Table 1. HSCs have recently been implicated to play a novel role in the liver immunity. It was reported that HSCs could induce vigorous natural killer T (NKT) cell responses in vitro and in vivo, and promote homeostatic proliferation of NKT cells.[13] In addition, HSCs could elicit antigen-specific T cells and inhibit bacterial infection in a Listeria monocytogenes infection model.

In addition, TLC failed to further decrease PM-MRP2 in cells transfected with PD-MARCKS. These results suggest that phosphorylation of MARCKS is necessary for the TLC-induced retrieval of MRP2. see more The aim of the present study was to further define the mechanism by which TLC induces the retrieval of MRP2. The present study showed that TLC increased PM localization of PKCϵ, and a kinase-dead DN-PKCϵ

inhibited TLC-induced MRP2 retrieval. In addition, DN-PKCϵ inhibited TLC-induced increases in the phosphorylation of MARCKS, and PD-MARCKS inhibited TLC-induced MRP2 retrieval. These results suggest that TLC-induced MRP2 retrieval involves the activation of PKCϵ followed by the phosphorylation of MARCKS, as discussed later. PKCϵ has been suggested to be involved in TLC-induced cholestasis.9 However, this conclusion is based on indirect evidence. The strongest evidence in favor of this hypothesis is the reversal of TLC-induced membrane translocation of PKCϵ and cholestasis by tauroursodeoxycholate.9 In

the present study, we tested this hypothesis more directly by using DN-PKCϵ. As previously reported in rat hepatocytes,5, 10 TLC induced the translocation of PKCϵ to the PM and the retrieval of MRP2 from the PM in HuH-NTCP cells selleck compound as well as rat hepatocytes. TLC failed to induce MRP2 retrieval when cells were transfected with kinase-dead DN-PKCϵ, and this indicates that the PKCϵ kinase activity is needed for TLC-induced MRP2 retrieval. This is the first direct demonstration of a role for PKCϵ in MRP2 retrieval by TLC. Our MCE studies also provide evidence for PKCϵ-mediated phosphorylation of MARCKS by TLC. MARCKS is a PKC substrate and binds noncovalently to PM.12 MARCKS phosphorylation leads to its translocation to the cytosol in chromaffin cells.18 A previous study35 reported that PMA translocated MARCKS from the PM to the cytosol in HepG2 cells, and this effect, based on inhibition by chemical inhibitors of

PKCs, appeared to be mediated via Ca2+-dependent and Ca2+-independent PKCs. However, whether PMA phosphorylated MARCKS was not determined. In the present study, we observed that TLC induced phosphorylation of MARCKS, increased the cytosolic levels of pMARCKS, and decreased PM-MARCKS. Thus, TLC-mediated phosphorylation of MARCKS results in the dissociation of MARCKS from the membrane. In addition, TLC-induced MARCKS phosphorylation was inhibited in cells transfected with DN-PKCϵ. These results suggest that TLC, acting via PKCϵ, phosphorylates MARCKS and results in the dissociation of MARCKS from the PM. The present study suggests that MARCKS phosphorylation by PKCϵ is involved in MRP2 retrieval by TLC. This is supported by the fact that TLC failed to induce MRP2 retrieval in cells transfected with PD-MARCKS (Fig. 7).

In addition, 60.7% of the patients enrolled received rituximab-based chemotherapy, which has been demonstrated as able to increase the HCV replication in anti-HCV–positive patients.7 In conclusion, neither occult HCV infection nor its reactivation under strong immunosuppressive chemotherapy were found in the present study in oncohematological patients who were anti-HCV- and HCV RNA–negative. Our data and those of others6, 8 suggest the nonexistence of occult HCV infection. Nicola Coppola M.D., Ph.D.*, Mariantonietta Pisaturo M.D.*, Salvatore Guastafierro M.D.†, Gilda Tonziello M.D.*, Antonello Sica M.D., Ph.D.†, Caterina

Sagnelli Ph.D.*, Maria Giovanna Ferrara M.D.†, Evangelista Sagnelli M.D.* ‡, * Department of Public Medicine, Section Dabrafenib of Infectious Diseases, Naples, Italy, † Haematology Unit, Second University of Naples, Naples, Italy, ‡ Division of Infectious Diseases, Azienda Ospedaliera Sant’Anna e San Sebastiano di Caserta, Caserta, Italy. “
“Platelets contain not only hemostatic factors but also many growth factors that play important roles in wound healing and tissue repair. Platelets have already been used

for the promotion of tissue regeneration in the clinical setting, such as dental implantation and plastic surgery. Thrombocytopenia, which is frequently found in patients with chronic liver disease and cirrhosis, is due to various causes such as decreased thrombopoietin production and accelerated platelet destruction caused by hypersplenism. However, the relationship between thrombocytopenia and hepatic pathogenesis GSK1120212 molecular weight and the role of platelets in chronic liver disease are poorly understood. In acute liver injury, it is reported that platelets are recruited to the liver and contribute medchemexpress to liver damage by promoting the induction of chemotactic factors and the accumulation

of leukocytes in the liver, whereas platelets or mediators released by platelets can have a protective effect against liver injury. In this review, we highlight the recent accumulated knowledge concerning the role of platelets in chronic liver disease and acute liver injury. Chronic liver disease (CLD), which results in liver cirrhosis and an increased risk of carcinogenesis, is a major cause of mortality and morbidity in many countries.[1, 2] Liver fibrosis represents the consequences of a sustained wound healing response to chronic liver injury induced by a variety of causes including viral infection, alcohol abuse, autoimmune disorders, drug use, cholestasis, and metabolic diseases.[3, 4] Currently, liver transplantation is the only curative approach for end-stage liver cirrhosis, but this process is associated with serious problems, such as graft shortage in living-donor liver transplantation, surgical complications, organ rejection, and high cost.