Search

The essence of hepatic fibrosis is the imbalance of the formation and degradation of extracellular matrix in the liver tissue. Hepatic fibrosis is a necessary stage for the progression of various chronic liver diseases to cirrhosis. Early inhibition of the occurrence and development of hepatic fibrosis is very important in the treatment of liver diseases. Platelets release a variety of cytokines, which promote hepatocyte proliferation and liver parenchyma regeneration while activating endothelial cells, inducing leukocyte recruitment, aggravating microvascular dysfunction, and participating in the process of liver fibrosis. In this paper, the research progress of antiplatelet drugs in hepatic fibrosis is reviewed, in order to provide new diagnosis and treatment ideas for hepatic fibrosis. [ABSTRACT FROM AUTHOR]

The core of hepatic fibrosis is the activation of hepatic stellate cells. Through the lipopolysaccharide/TLR4/MyD88/NF-KB signal transduction pathway, the inflammatory response in the liver is directly enhanced, and then returns to promote the activation of hepatic stellate cells. And TLR4/MyD88/NF-κB signaling pathway can directly regulate the activation of NLRP3 inflammasome and is an important pathway for activating hepatic stellate cells. TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway is regulated by upstream microRNAs. These miR-NAs can significantly regulate the inflammatory response of the liver and the activation behavior of hepatic stellate cells, affecting the formation of liver fibrosis. Previous studies have found that the active ingredient of Guangxi specialty ethnic medicine, plumbagin, has a definite anti liver fibrosis effect, but its mechanism of action is not clear. This paper provides a review of the research progress on the above issues, and further research ideas have been derived from this, stating that" the anti liver fibrosis effect of plumbagin is achieved by regulating miRNA/TLR4/MyD88/NF-κB inflammatory pathway and activating downstream NLRP3 inflammasome". [ABSTRACT FROM AUTHOR]

Simple Summary: The incidence of hepatocellular carcinoma (HCC) in patients with non-alcoholic fatty liver disease (NAFLD) has increased in recent years. Compared to HCC caused by other chronic liver diseases, NAFLD-related HCC is often detected later, because it more commonly arises before cirrhosis has occurred. Because of this late diagnosis, NAFLD-related HCC is often more advanced at time of diagnosis, resulting in fewer curative treatment options. Most research in the pathogenesis of HCC has focused on the disease processes in hepatocytes, the most abundant type of liver cells. However, other cell types, such as cells of the immune system and cells that regulate connective tissue formation, also play an important role in the development of NAFLD-related HCC, both by contributing to the development of HCC itself and by interfering with the immune system's ability to attack cancer cells. In this paper, we review the role of different cell types in the development of NAFLD-related HCC. Hepatocellular carcinoma (HCC) in the setting of non-alcoholic fatty liver disease (NAFLD)-related cirrhosis and even in the pre-cirrhotic state is increasing in incidence. NAFLD-related HCC has a poor clinical outcome as it is often advanced at diagnosis due to late diagnosis and systemic treatment response is poor due to reduced immune surveillance. Much of the focus of molecular research has been on the pathological changes in hepatocytes; however, immune cells, hepatic stellate cells, liver sinusoidal endothelial cells and the extracellular matrix may play important roles in the pathogenesis of NAFLD-related HCC as well. Here, we review the role of non-parenchymal cells in the liver in the pathogenesis of HCC in the context of NAFLD-NASH, with a particular focus on the innate and the adaptive immune system, fibrogenesis and angiogenesis. We review the key roles of macrophages, hepatic stellate cells (HSCs), T cells, natural killer (NK) cells, NKT cells and liver sinusoidal endothelial cells (LSECs) and the role of the extracellular matrix in hepatocarcinogenesis within the steatotic milieu. [ABSTRACT FROM AUTHOR]

Hepatic sinusoidal endothelial cell is a highly differentiated cell in hepatic sinusoid, and plays an important role in the occurrence and development of hepatic fibrosis. The dysfunction of hepatic sinusoidal endothelial cells is considered to be the key cause of a variety of liver diseases. At present, the researches on hepatic fibrosis at home and abroad are mainly focused on inhibiting the activation of hepatic stellate cells and accelerating the hydrolysis of extracellular matrix. However, there are few studies on the important role of the structure and function of hepatic sinusoidal endothelial cells in hepatic fibrosis. This paper reviews the research progress on the effect of hepatic sinusoidal endothelial cells on hepatic fibrosis and its regulatory mechanism in recent years. This paper summarizes the results of the research on the structural characteristics of hepatic sinusoidal endothelial cells, secretion of fibrosis-related cytokines and regulation of hepatic stellate cells activation in the development of hepatic fibrosis. [ABSTRACT FROM AUTHOR]

Nanomaterials are widely used in biomedical applications such as drug delivery, bioimaging, and photothermal therapy. For example, graphene oxide (GO) nanomaterials are among the most popular drug delivery vehicles in treating liver diseases due to their tunable chemical/physical properties, and biocompatibility. However, it has been reported that nanomaterials tend to accumulate in livers. The biophysical impact of the accumulation in liver cells remains unclear, and it may cause the liver fibrosis in the long run. The activation of hepatic stellate cells (HSCs) is one of the key initial steps of liver fibrosis. In this paper, we explored the geometric effect (nanosheets vs. quantum dots) of GO nanomaterials on human HSCs, in terms of cell viability, fibrotic degree, mobility and regulation pathways. Our study showed that GO nanosheets could significantly reduce HSCs cell viability and mobility. The protein expression levels of TGFβRⅡ/Smad2/Smad3 decreased, corresponding to a trend of attenuating fibrotic degree. However, the expression level of α-SMA, a maker protein of fibrosis, increased and contradicted with the projection. Further investigation on mitochondria showed that GO nanosheets disrupted mitochondria membrane and membrane potentials. We found that while modulating fibrotic effect through the TGF-β pathway, GO nanosheets induced oxidative stress and activated HSCs through reactive oxygen species(ROS)pathway. This was confirmed by the decreased expression level of α-SMA after co-incubation of GO nanosheets and n-acetyl cysteine (NAC) with HSCs. GO quantum dots decreased α-SMA expression level at 100 mg/l, along with decrease in GAPDH expression level and constant expression level of β-actin. The correlation between GAPDH and α-SMA remains to be explored. Our study suggested that the biophysical impacts of GO nanomaterials on HSCs are geometry-dependent. Both GO nanosheets and quantum dots can be adapted for attenuating liver fibrosis with further investigation on mechanisms. • The effect of graphene oxide nanomaterials on hepatic stellate cells is geometry-dependent. • Graphene oxide nanosheets triggered TGF-β pathway with disruption of cytoskeleton. • Graphene oxide nanosheets increased oxidative stress by physical interaction with mitochondria. • Graphene oxide nanosheets triggered two counteracting regulation pathways that offset anti-fibrotic effect. • Graphene oxide quantum dots demonstrated anti-fibrotic effect and distinctly decreased GAPDH expression level. [ABSTRACT FROM AUTHOR]

Leptin is a hormone produced mainly by white adipose tissue, and is closely associated with hepatic stellate cell activation. After binding with its functional receptor, leptin can affect the activation of hepatic stellate cells through JAK2/STAT3, PI3K/Akt, MAPK and other signaling pathways and related molecules. The activation of hepatic stellate cells is a key link in the occurrence and development of hepatic fibrosis. In this paper, the relationship between leptin and the signaling pathways and molecules related to hepatic stellate cell activation in the occurrence and development of liver fibrosis is reviewed, in order to provide evidence for the treatment of hepatic fibrosis. [ABSTRACT FROM AUTHOR]

Hepatic fibrosis is considered as a kind of repair response of liver to various chronic injury factors. Progressive liver fibrosis can lead to the development of cirrhosis and even hepatocellular carcinoma. Current researches have indicated that liver fibrosis is reversible. Several signaling pathways are involved in the occurrence and development of liver fibrosis, among which Notch signaling pathway plays a critical role in liver fibrogenesis. In this paper, the research progress of Notch signaling pathway in liver fibrogenesis is reviewed. [ABSTRACT FROM AUTHOR]

[Objective] The paper was to observe the effects of Guangxi Hepu pearl hydrolysate on proliferation and apoptosis of human hepatic stellate cells. [Method] The inhibition rate against the proliferation of human hepatic stellate cells was determined by MTT colorimetry after co-in-cubation with pearl hydrolysate for 48 h. The percentage of early and late apoptotic cells was determined by flow cytometry (Annexin V-FITC/PI staining). [Result] Low, medium and high concentrations of pearl hydrolysate could inhibit the proliferation of human hepatic stellate cells, and the inhibition rates at 48 h were 12.4%, 27.4% and 37.8%, respectively. The low, medium and high concentrations of pearl hydrolysate could induce the apoptosis of cells. The percentages of total apoptotic cells (early apoptotic + late apoptotic) at 48 h were 8.97%, 16.09% and 26.98%, respectively. [Conclusion] Pearl hydrolysate can inhibit the proliferation of human hepatic stellate cells and induce the apoptosis of these cells, which may be the mechanism of anti-hepatic fibrosis effect of pearl hydrolysate. These effects are dose-dependent. It is also found that the above cellular effects of high dose pearl hydrolysate are stronger than those of colchicine and compound Biejiaruangan tablets. [ABSTRACT FROM AUTHOR]

Background Numerous documents have indicated a critical role of autophagy in alcoholic liver fibrosis (ALF), but few papers have reported its function in hepatic stellate cells (HSCs) activation. The current study aimed to investigate the regulation effect of autophagy in HSCs activation, in further to explore the underlying mechanism involved. Methods HSC-T6 cells were treated with ethanol, 3-MA (autophagy inhibitor) or rapamycin (autophagy inducer), and cells were also transfected with si-Nrf2 or si-Keap1. Moreover, ALF animal model was established and Nrf-2 (−/−) , Keap1 (−/−) mice were purchased. The level of autophagy, the expression of α-SMA and CoL1A1, and Nrf2 antioxidant response were evaluated in stellate cells and livers. Results Ethanol treatment in cultured cells increased autophagy, oxidative stress level and promoted HSCs activation. Inhibition of autophagy reversed alcohol-induced HSCs activation and suppressed HSCs oxidative stress. Nrf2-Keap1-ARE pathway was involved in HSCs activation and oxidative stress regulated by autophagy. In addition, through in vivo study, we found that inhibition of autophagy could alleviate alcoholic fatty liver injury in ALF model mice and Nrf2 signaling was involved in autophagy regulated HSCs activation. Conclusion These data implicated mechanisms underlying autophagy in regulating the fibrogenic response in HSCs activation. [ABSTRACT FROM AUTHOR]

Unfolded protein response (UPR) triggered as a consequence of ER stress has been shown to be involved in the development of different pathologies, including fibrotic disorders. In the present paper we explore the role played by UPR on a key fibrogenic parameter in the liver: collagen type I levels in activated hepatic stellate cells (HSC). Using Brefeldin A (BFA) as an ER stress inducer we found that UPR correlated with enhanced mRNA and protein levels of collagen type I in a cell line of immortalized non-tumoral rat HSC. Analysis of the three branches of UPR revealed the activation of IRE1α, PERK and ATF6 in response to BFA, although PERK activation was shown not to be involved in the fibrogenic action of BFA. BFA also activated p38 MAPK in an IRE1α-dependent way and the p38 MAPK inhibitor SB203580 prevented the increase in collagen type I mRNA and protein levels caused by BFA, suggesting the involvement of this kinase on this effect. Analysis of Smad activation showed that phosphorylated nuclear levels of Smad2 and 3 were increased in response to BFA treatment. Inhibition of Smad3 phosphorylation by SIS3 prevented the enhancement of collagen type I levels caused by BFA. Pretreatment with IRE1α and p38 MAPK inhibitors also prevented the increased p-Smad3 accumulation in the nucleus, suggesting an IRE1α-p38 MAPK-Smad pathway to be responsible for the fibrogenic action of BFA on HSC. [ABSTRACT FROM AUTHOR]

There is long-standing evidence that male and female rat livers differ in enzyme activity. More recently, differences in gene expression profiling have also been found to exist; however, it is still unclear whether there is morphological expression of male/female differences in the normal liver. Such differences could help to explain features seen at the pathological level, such as the greater regenerative potential generally attributed to the female liver. In this paper, hepatocytes ( HEP), Kupffer cells ( KC) and hepatic stellate cells ( HSC) of male and female rats were examined to investigate hypothesised differences in number, volume and spatial co-localisation of these cell types. Immunohistochemistry and design-based stereology were used to estimate total numbers, numbers per gram and mean cell volumes. The position of HSC within lobules (periportal vs. centrilobular) and their spatial proximity to KC was also assessed. In addition, flow cytometry was used to investigate the liver ploidy. In the case of HEP and KC, differences in the measured cell parameters were observed between male and female specimens; however, no such differences were detected for HSC. Female samples contained a higher number of HEP per gram, with more binucleate cells. The HEP nuclei were smaller in females, which was coincident with more abundant diploid particles in these animals. The female liver also had a greater number of KC per gram, with a lower percentage of KC in the vicinity of HSC compared with males. In this study, we document hitherto unknown morphological sexual dimorphism in the rat liver, namely in HEP and KC. These differences may account for the higher regenerative potential of the female liver and lend weight to the argument for considering the rat liver as a sexually dimorphic organ. [ABSTRACT FROM AUTHOR]

Hepatic fibrosis is a wound healing response to insults and as such affects the entire world population. In industrialized countries, the main causes of liver fibrosis include alcohol abuse, chronic hepatitis virus infection and non-alcoholic steatohepatitis. A central event in liver fibrosis is the activation of hepatic stellate cells, which is triggered by a plethora of signaling pathways. Liver fibrosis can progress into more severe stages, known as cirrhosis, when liver acini are substituted by nodules, and further to hepatocellular carcinoma. Considerable efforts are currently devoted to liver fibrosis research, not only with the goal of further elucidating the molecular mechanisms that drive this disease, but equally in view of establishing effective diagnostic and therapeutic strategies. The present paper provides a state-of-the-art overview of in vivo and in vitro models used in the field of experimental liver fibrosis research. [ABSTRACT FROM AUTHOR]

Hepatic stellate cells (HSCs) are the source of fibre in the liver which can produce a large number of extracellular matrix via proliferation and activation, and this is the central link of hepatic fibrosis. Following further research on hepatic fibrosis, signal transduction involved in the activation of HSCs have been researched as a pepular topic. This paper generalizes the main signaling transduction pathways involved in activation of HSCs and Hedgehog/Gli pathway, and introduces recent advances in related research. It is promising to make new breakthroughs in the prevention and treatment of hepatic fibrosis through in-depth study of these signaling pathways. [ABSTRACT FROM AUTHOR]

Simple Summary: Liver cancer and tumours spreading from other organs to the liver are associated with high death rates. Current treatments include surgical removal of the tumour and chemotherapy. Unfortunately, patients are often re-diagnosed with liver nodules in the years after cessation of the treatment. Therefore, scientists are looking for alternative treatment strategies, and these include targeting the tumour environment. The tumour environment includes the cancer-associated fibroblasts, which could be an interesting target for therapy in combination with current strategies. In this review paper we summarize the current models to investigate the effect of the tumour on the cancer-associated fibroblasts. Not many studies focus on the cancer-associated fibroblasts in non-animal models and this should improve in order to better understand the role of the cancer-associated fibroblasts and to evaluate the potential of cancer-associated fibroblast-directed therapies. Primary and secondary liver cancer are the third cause of death in the world, and as the incidence is increasing, liver cancer represents a global health burden. Current treatment strategies are insufficient to permanently cure patients from this devastating disease, and therefore other approaches are under investigation. The importance of cancer-associated fibroblasts (CAFs) in the tumour microenvironment is evident, and many pre-clinical studies have shown increased tumour aggressiveness in the presence of CAFs. However, it remains unclear how hepatic stellate cells are triggered by the tumour to become CAFs and how the recently described CAF subtypes originate and orchestrate pro-tumoural effects. Specialized in vitro systems will be needed to address these questions. In this review, we present the currently used in vitro models to study CAFs in primary and secondary liver cancer and highlight the trend from using oversimplified 2D culture systems to more complex 3D models. Relatively few studies report on the impact of cancer (sub)types on CAFs and the tumour microenvironment, and most studies investigated the impact of secreted factors due to the nature of the models. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) incidence is rising. This paper summarises the current state of knowledge and recent discoveries in the cellular and physiological mechanisms leading to the development of liver cancer, especially HCC, and liver metastases. After reviewing normal hepatic cytoarchitecture and immunological characteristics, the paper addresses the pathophysiological factors that cause liver damage and predispose to neoplasia. Particular attention is given to chronic liver diseases, metabolic syndrome and the impact of altered gut microbiota, disrupted circadian rhythm and psychological stress. Improved knowledge of the multifactorial aetiology of HCC has important implications for the prevention and treatment of this cancer and of liver metastases in general. [ABSTRACT FROM AUTHOR]

A wide variety of beneficial effects have been attributed to curcumin, a major polyphenol from the golden spice Curcuma longa known as turmeric, including amelioration of severe complications of type 2 diabetes such as hepatic fibrosis, retinopathy, neuropathy and nephropathy. In the present issue of BJP, Lin and colleagues reveal new mechanisms by which curcumin inhibits the activation of hepatic stellate cells in vitro, a hallmark of non-alcoholic steatohepatitis and hepatic fibrogenesis associated with type 2 diabetes mellitus. They demonstrated that curcumin suppresses the advanced glycation end-products (AGEs)-mediated induction of the receptor for AGEs ( RAGE) gene expression by increasing PPARγ activity and stimulating de novo synthesis of glutathione. As a result, downstream elements of RAGE-activated pathways are inhibited, which prevents oxidative stress, inflammation and hepatic stellate cell activation. This report suggests that curcumin may have potential as an anti-fibrotic agent in type 2 diabetes and opens the door to the evaluation of curcumin therapeutic effects in liver conditions of different aetiology and in other disorders linked to the impairment of PPARγ activity, such as obesity and atherosclerosis. LINKED ARTICLE This article is a commentary on Lin et al., pp. 2212-2227 of this issue. To view this paper visit [ABSTRACT FROM AUTHOR]