Search

Background: The adenosine-adenosine receptor pathway plays important roles in the immune system and inflammation. Four adenosine receptors (i.e., A1R, A2AR, A2BR, and A3R) have been identified. However, the roles of these receptors were different in the disease progress and even play opposite roles in the same disease. This study aims to investigate the roles of A1R/A2AR/A2BR/A3R activation in liver fibrosis. Methods: Intraperitoneal injection of CCl4 into C57BL/6 mice was used to induce liver fibrosis in the models. Adenosine receptor agonists CCPA, CGS21680, BAY 60-6583, and namodenoson were used for A1R/A2AR/A2BR/A3R activation, respectively. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were used to evaluate the liver function. Hematoxylin and eosin (H&E) staining was used to investigate the pathological damage. Masson staining and Sirius Red staining were performed to evaluate the degree of collagen deposition. CCK8 and scratch assays were used to investigate the proliferation and migration ability of hepatic stellate cells (HSCs). Results: By using liver fibrosis mouse models, we observed that the A1R and A2AR agonists aggravated liver fibrosis, characterized by increasing ALT and AST levels, more serious liver pathological damage, and collagen deposition. However, the A2BR and A3R agonists alleviated liver fibrosis. Moreover, the A1R and A2AR agonist treatment promotes the proliferation and migration of HSC line LX2, while A2BR and A3R agonist treatment inhibited LX2 proliferation and migration. Consistently, A1R and A2AR agonist treatment elevated the expression of a-SMA and Col1a1 in LX2, whereas A2BR and A3R agonist treatment inhibited the expression of a-SMA and Col1a1 in LX2 cells. Additionally, 5'-N-ethylcarboxamidoadenosine (NECA), a metabolically stable adenosine analog, alleviated liver fibrosis and inhibited LX2 cell activity, proliferation, and migration. Conclusion: This study demonstrated the different roles of A1R/A2AR/A2BR/A3R during liver fibrosis development via regulating the HSC activity and proliferation. [ABSTRACT FROM AUTHOR]

This article explores the potential of melatonin to mitigate circadian clock disturbances in mice with fibrosis and human hepatic stellate cells. The study found that treatment with carbon tetrachloride (CCl4) resulted in fibrosis and dysregulation of circadian clock genes in mice, but melatonin administration prevented these changes. Additionally, melatonin exposure upregulated clock gene expression in human hepatic stellate cells. These findings provide new insights into the molecular pathways involved in the protective effects of melatonin in liver fibrosis. [Extracted from the article]

The liver is a major metabolic organ and an immunologically complex organ. It produces and uses many substances such as acute phase proteins, cytokines, chemokines, and complementary components to maintain the balance between immunity and tolerance. Interleukins are important immune control cytokines, that are produced by many body cells. In liver injury, interleukins are produced in large amount by various cell types, and act as pro-inflammatory (e.g. interleukin (IL)-6, IL-13, IL-17, and IL-33) as well as anti-inflammatory (e.g. IL-10) functions in hepatic cells. Recently, interleukins are regarded as interesting therapeutic targets for the treatment of liver fibrosis patients. Hepatic cells such as hepatocytes, hepatic stellate cells, and hepatic macrophages are involved to the initiation, perpetuation, and resolution of fibrosis. The understanding of the role of interleukins in such cells provides opportunity for the development of therapeutic target drugs. This paper aims to understand the functional roles of interleukins in hepatic and immune cells when the liver is damaged, and suggests the possibility of interleukins as a new treatment target in liver fibrosis. [ABSTRACT FROM AUTHOR]

Background: Hepatic fibrosis (HF) is characterized by activation of hepatic stellate cells (HSCs) and extensive deposition of extracellular matrix components, especially collagens. However, effective antifibrotic therapies are still lacking. Recently, circular RNAs (circRNAs) have been identified as novel regulators of HF. Methods: circRNAs profile was screened by RNA sequencing and the location of circ_0008494 was confirmed by fluorescence in situ hybridization assay in human HF tissues. Bioinformatics analysis was used for result prediction and dual-luciferase reporter, together with AGO-RIP and biotin-coupled miRNA capture assays, were used to determine miR-185-3p/collagen type I alpha 1 chain (Col1a1) as the target of circ_0008494. A stable circ_0008494-interfering human HSCs cell line was constructed and used to determine the regulatory mechanism of circ_0008494/miR-185-3p/Col1a1 axis. Results: circ_0008494 was abundantly and significantly over-expressed in human HF tissues and located at the cytoplasm of HSCs. Together, dualluciferase reporter, AGO-RIP and biotin-coupled miRNA capture assays confirmed that circ_0008494 acted as a sponge of miR-185-3p. Cell functional experiments and rescue assays demonstrated suppressing circ_0008494 could inhibit activation, proliferation, migration of HSCs and promote their apoptosis through miR-185-3p. In particular, the HF indicator, Col1a1, was validated as the direct target of miR-185-3p and the suppression of circ_0008494 inhibited the expression of Col1a1 by releasing miR-185-3p. Conclusion: Knocking down circ_0008494 inhibited HSCs activation through the miR-185-3p/Col1a1 axis. circ_0008494 could be a promising treatment target for HF. [ABSTRACT FROM AUTHOR]

Non alcoholic steatohepatitis (NASH) is the inflammatory reaction of the liver to excessive accumulation of lipids in the hepatocytes. NASH can progress to cirrhosis and hepatocellular carcinoma (HCC). Fatty liver is the hepatic manifestation of metabolic syndrome. A subclinical inflammatory state is present in patients with metabolic alterations like insulin resistance, type-2 diabetes, obesity, hyperlipidemia, and hypertension. Platelets participate in immune cells recruitment and cytokines-induced liver damage. It is hypothesized that lipid toxicity cause accumulation of platelets in the liver, platelet adhesion and activation, which primes the immunoinflammatory reaction and activation of stellate cells. Recent data suggest that antiplatelet drugs may interrupt this cascade and prevent/improve NASH. They may also improve some metabolic alterations. The pathophysiology of inflammatory liver disease and the implication of platelets are discussed in details. [ABSTRACT FROM AUTHOR]

Tissue fibrosis causes debilitating human diseases such as liver cirrhosis, heart failure, chronic kidney disease and pulmonary insufficiency. It is a dynamic process orchestrated by specific subsets of monocyte-macrophages, fibroblasts, pericytes and hepatic stellate cells. Fibrosis is linked to tissue inflammation. Pro-inflammatory macrophages promote fibrosis by driving myofibroblast differentiation and macrophage myofibroblast transition. Myofibroblasts express α-smooth muscle cell actin (α-SMA) and secrete extracellular matrix (ECM) proteins notably collagen I and III. Deposition of ECM proteins at injury sites and interstitial tissues distorts normal structure and impairs vital functions. Despite advances in the mechanisms of fibrosis at cellular, molecular and genetic levels, prevention and treatment of fibrotic diseases remain poorly developed. Recent reports suggest that 5-methoxytryptophan (5-MTP) is effective in attenuating injury-induced liver, kidney, cardiac and pulmonary fibrosis. It inhibits macrophage activation and blocks fibroblast differentiation to myofibroblasts. Furthermore, it inhibits hepatic stellate cell differentiation into myofibroblasts. As 5-MTP is an endogenous molecule derived from tryptophan catabolism via tryptophan hydroxylase pathway, it is well-suited as a lead compound for developing new anti-fibrotic drugs. This article provides an overview of 5-MTP synthesis, and a critical review of its anti-fibrotic activities. Its mechanisms of actions and potential therapeutic value will be discussed. [ABSTRACT FROM AUTHOR]

The liver is a major metabolic organ and an immunologically complex organ. It produces and uses many substances such as acute phase proteins, cytokines, chemokines, and complementary components to maintain the balance between immunity and tolerance. Interleukins are important immune control cytokines, that are produced by many body cells. In liver injury, interleukins are produced in large amount by various cell types, and act as pro-inflammatory (e.g. interleukin (IL)-6, IL-13, IL-17, and IL-33) as well as anti-inflammatory (e.g. IL-10) functions in hepatic cells. Recently, interleukins are regarded as interesting therapeutic targets for the treatment of liver fibrosis patients. Hepatic cells such as hepatocytes, hepatic stellate cells, and hepatic macrophages are involved to the initiation, perpetuation, and resolution of fibrosis. The understanding of the role of interleukins in such cells provides opportunity for the development of therapeutic target drugs. This paper aims to understand the functional roles of interleukins in hepatic and immune cells when the liver is damaged, and suggests the possibility of interleukins as a new treatment target in liver fibrosis.

Primary sclerosing cholangitis is a complex pathological condition, characterized by chronic inflammation and fibrosis of the biliary epithelium. Without proper clinical management, progressive bile ducts and liver damage lead to cirrhosis and, ultimately, to liver failure. The known limited role of current drugs for treating this cholangiopathy has driven researchers to assess alternative therapeutic options. Some herbal remedies and their phytochemicals have shown anti-fibrotic properties in different experimental models of hepatic diseases and, occasionally, in clinical trials in primary sclerosing cholangitis patients; however their mechanism of action is not completely understood. This review briefly examines relevant studies focusing on the potential anti-fibrotic properties of Silybum marianum , Curcuma longa , Salvia miltiorrhiza , and quercetin. Each natural product is individually reviewed and the possible mechanisms of action discussed. [ABSTRACT FROM AUTHOR]

Dysregulation of the circadian clock machinery is a critical mechanism in the pathogenesis of fibrosis. This study aimed to investigate whether the antifibrotic effect of melatonin is associated with attenuation of circadian clock pathway disturbances in mice treated with carbon tetrachloride (CCl4) and in human hepatic stellate cells line LX2. Mice received CCl4 5 mL/g body weight i.p. twice a week for 4 or 6 weeks. Melatonin was given at 5 or 10 μg/kg/day i.p., beginning 2 weeks after the start of CCl4 administration. Treatment with CCl4 resulted in fibrosis evidenced by the staining of α-smooth muscle actin (α-SMA) positive cells and a significant decrease of peroxisome proliferator-activated receptor (PPARa) expression. CCl4 led to a lower expression of brain and muscle Arnt-like protein 1 (BMAL1), circadian locomotor output cycles kaput (CLOCK), period 1-3 (PER1, 2, and 3), cryptochrome 1 and 2 (CRY1 and 2) and the retinoic acid receptor-related orphan receptor (RORa). The expression of the nuclear receptor REV-ERBa showed a significant increase. Melatonin significantly prevented all these changes. We also found that melatonin (100 or 500 mM) potentiated the inhibitory effect of REV-ERB ligand SR9009 on α-SMA and collagen1 expression and increased the expression of PPARa in LX2 cells. Analysis of circadian clock machinery revealed that melatonin or SR9009 exposure upregulated BMAL1, CLOCK, PER2, CRY1, and RORa expression, with a higher effect of combined treatment. Findings from this study give new insight into molecular pathways accounting for the protective effect of melatonin in liver fibrosis. [ABSTRACT FROM AUTHOR]

The activation of hepatic stellate cells (HSCs) is a central event in the progression of liver fibrosis. Multiple studies proved that DNA methylation might accelerate HSCs activation. However, the specific pathogenesis of liver fibrosis remains not fully addressed. Our laboratory performed Genome methylation screening to find out the methylated gene in mice with liver fibrosis. The pilot experiments showed that the promoter of prostacyclin synthase (PTGIS) gene was hypermethylated in CCl4-induced liver fibrosis mouse model. Moreover, the down-regulated PTGIS expression can be restored by DNMTs-RNAi and 5-aza-2-deoxycytidine (5-azadC), an inhibitor of DNA methyltransferase (DNMTs). Methylation-specific PCR (MSP) showed that the methylation status of PTGIS in HSC-T6 cells cultures with TGF-β1 (10 ng/mL) was elevated compared with control group. Chromatin immunoprecipitation (ChIP) assay indicated that PTGIS methylation was mainly induced by DNMT1 and DNMT3b. We further investigated the function of PTGIS in liver fibrosis by Recombinant Hepatic-adeno-associated virus (rAAV8)- PTGIS overexpression. The data indicated that overexpression of PTGIS in mouse liver accompanied by elevated apoptosis-related proteins expression in primary HSCs. Conversely, PTGIS silencing mediated by RNAi enhanced the expression of α-SMA and COL1a1 in vitro. Those results illustrated that adding PTGIS expression inhibits the activation of HSCs and alleviates liver fibrosis. Therefore, our study unveils the role of PTGIS in HSCs activation, which may provide a possible explanation for CCl4-mediated liver fibrosis. [ABSTRACT FROM AUTHOR]

Hepatic stellate cells (HSCs) migration, an important bioprocess, contributes to the development of liver fibrosis. Our previous studies have found the potent activity of dioscin against liver fibrosis by inhibiting HSCs proliferation, triggering the senescence and inducing apoptosis of activated HSCs, but the molecular mechanisms associated with cell migration were not clarified. In this work, iTRAQ (isobaric tags for relative and absolution quantitation)-based quantitative proteomics study was carried out, and a total of 1566 differentially expressed proteins with fold change ⩾2.0 and p < 0.05 were identified in HSC-T6 cells treated by dioscin (5.0 μg/mL). Based on Gene Ontology classification, String and KEGG pathway assays, the effects of dioscin to inhibit cell migration via regulating SDC-4 were carried out. The results of wound-healing, cell migration and western blotting assays indicated that dioscin significantly inhibit HSCT6 cell migration through SDC-4-dependent signal pathway by affecting the expression levels of Fn, PKCα, Src, FAK, and ERK1/2. Specific SDC-4 knockdown by shRNA also blocked HSC-T6 cell migration, and dioscin slightly enhanced the inhibiting effect. Taken together, the present work showed that SDC-4 played a crucial role on HSC-T6 cell adhesion and migration of dioscin against liver fibrosis, which may be one potent therapeutic target for fibrotic diseases. [ABSTRACT FROM AUTHOR]