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ObjectiveNon-alcoholic fatty liver disease (NAFLD) is a common prelude to cirrhosis and hepatocellular carcinoma. The genetic rs641738 C>T variant in the lysophosphatidylinositol acyltransferase 1 (LPIAT1)/membrane bound O-acyltransferase domain-containing 7, which incorporates arachidonic acid into phosphatidylinositol (PI), is associated with the entire spectrum of NAFLD. In this study, we investigated the mechanism underlying this association in mice and cultured human hepatocytes.DesignWe generated the hepatocyte-specific Lpiat1 knockout mice to investigate the function of Lpiat1 in vivo. We also depleted LPIAT1 in cultured human hepatic cells using CRISPR-Cas9 systems or siRNA. The effect of LPIAT1-depletion on liver fibrosis was examined in mice fed high fat diet and in liver spheroids. Lipid species were measured using liquid chromatography-electrospray ionisation mass spectrometry. Lipid metabolism was analysed using radiolabeled glycerol or fatty acids.ResultsThe hepatocyte-specific Lpiat1 knockout mice developed hepatic steatosis spontaneously, and hepatic fibrosis on high fat diet feeding. Depletion of LPIAT1 in cultured hepatic cells and in spheroids caused triglyceride accumulation and collagen deposition. The increase in hepatocyte fat content was due to a higher triglyceride synthesis fueled by a non-canonical pathway. Indeed, reduction in the PI acyl chain remodelling caused a high PI turnover, by stimulating at the same time PI synthesis and breakdown. The degradation of PI was mediated by a phospholipase C, which produces diacylglycerol, a precursor of triglyceride.ConclusionWe found a novel pathway fueling triglyceride synthesis in hepatocytes, by a direct metabolic flow of PI into triglycerides. Our findings provide an insight into the pathogenesis and therapeutics of NAFLD.

The morbidity and mortality of hepatic fibrosis caused by various etiologies are high worldwide, and the trend is increasing annually. At present, there is no effective method to cure hepatic fibrosis except liver transplantation, and its serious complications threaten the health of patients and cause serious medical burdens. Additionally, there is no specific drug for the treatment of hepatic fibrosis, and many drugs with anti-hepatic fibrosis effects are in the research and development stage. Recently, remarkable progress has been made in the research and development of anti-hepatic fibrosis drugs targeting different targets. We searched websites such as PubMed, ScienceDirect, and Home-ClinicalTrials.gov and found approximately 120 drugs with anti-fibrosis properties, some of which are in phase Ⅱ or Ⅲ clinical trials. Additionally, although these drugs are effective against hepatic fibrosis in animal models, most clinical trials have shown poor results, mainly because animal models do not capture the complexity of human hepatic fibrosis. Besides, the effect of natural products on hepatic fibrosis has not been widely recognized at home and abroad. Furthermore, drugs targeting a single anti-hepatic fibrosis target are prone to adverse reactions. Therefore, currently, the treatment of hepatic fibrosis requires a combination of drugs that target multiple targets. Ten new drugs with potential for development against hepatic fibrosis were selected and highlighted in this mini-review, which provides a reference for clinical drug use.

Fibrosis is an inherent response to chronic damage upon immense apoptosis or necrosis. Transforming growth factor-beta1 (TGF-β1) signaling plays a key role in the fibrotic response to chronic liver injury. To develop anti-fibrotic therapeutics, we synthesized a novel small-molecule inhibitor of the TGF-β type I receptor kinase (ALK5), EW-7197, and evaluated its therapeutic potential in carbon tetrachloride (CCl₄) mouse, bile duct ligation (BDL) rat, bleomycin (BLM) mouse, and unilateral ureteral obstruction (UUO) mouse models. Western blot, immunofluorescence, siRNA, and ChIP analysis were carried out to characterize EW-7197 as a TGF-β/Smad signaling inhibitor in LX-2, Hepa1c1c7, NRK52E, and MRC5 cells. In vivo anti-fibrotic activities of EW-7197 were examined by microarray, immunohistochemistry, western blotting, and a survival study in the animal models. EW-7197 decreased the expression of collagen, α-smooth muscle actin (α-SMA), fibronectin, 4-hydroxy-2, 3-nonenal, and integrins in the livers of CCl₄mice and BDL rats, in the lungs of BLM mice, and in the kidneys of UUO mice. Furthermore, EW-7197 extended the lifespan of CCl₄mice, BDL rats, and BLM mice. EW-7197 blocked the TGF-β1-stimulated production of reactive oxygen species (ROS), collagen, and α-SMA in LX-2 cells and hepatic stellate cells (HSCs) isolated from mice. Moreover, EW-7197 attenuated TGF-β- and ROS-induced HSCs activation to myofibroblasts as well as extracellular matrix accumulation. The mechanism of EW-7197 appeared to be blockade of both TGF-β1/Smad2/3 and ROS signaling to exert an anti-fibrotic activity. This study shows that EW-7197 has a strong potential as an anti-fibrosis therapeutic agent via inhibition of TGF-β-/Smad2/3 and ROS signaling.

To dynamically analyze the differential m6A methylation during the progression and reversal of hepatic fibrosis. We induced hepatic fibrosis in C57/BL6 mice by intraperitoneal injection of CCl4. The reversal model of hepatic fibrosis was established by stopping drug after continuous injection of CCl4. Dynamic m6A methylation was evaluated using MeRIP-Seq in the progression and reversal of hepatic fibrosis at different stages. During the hepatic fibrosis, differential m6A methylation was mainly enriched in processes associated with oxidative stress and cytochrome metabolism, while differential m6A methylation was mainly enriched in processes associated with immune response and apoptosis in the hepatic fibrosis reversal. m6A methylation plays an important role in the progression and reversal of hepatic fibrosis.

Chronic liver injury may result in hepatic fibrosis, which can progress to cirrhosis and eventually liver failure. There are no drugs that are specifically approved for treating hepatic fibrosis. The natural product honokiol (HNK), a bioactive compound extracted from Magnolia grandiflora, represents a potential tool in the management of hepatic fibrosis. Though HNK has been reported to exhibit suppressive effects in a rat fibrosis model, the mechanisms accounting for this suppression remain unclear. In the present study, the anti-fibrotic effects of HNK on the liver were evaluated in vivo and in vitro. In vivo studies utilized a murine liver fibrosis model, in which fibrosis is induced by treatment with carbon tetrachloride (CCl4). For in vitro studies, LX-2 human hepatic stellate cells (HSCs) were treated with HNK, and expression of markers of fibrosis, cell viability, the transforming growth factor-β (TGF-β1)/SMAD signaling pathway, and autophagy were analyzed. HNK was well tolerated and significantly attenuated CCl4-induced liver fibrosis in vivo. Moreover, HNK decreased HSC activation and collagen expression by downregulating the TGF-β1/SMAD signaling pathway and autophagy. These results suggest that HNK is a new potential candidate for the treatment of hepatic fibrosis through suppressing both TGF-β1/SMAD signaling and autophagy in HSCs.

The occurrence and progression of hepatic fibrosis (HF) is accompanied by inflammatory damage. Immune genes play a pivotal role in fibrogenesis and inflammatory damage in HF by regulating immune cell infiltration. However, the immune mechanisms of HF are inadequately studied. Therefore, this research aims to identify the immune genes and biological pathway which involved in fibrosis formation and inflammatory damage in HF and explore immune target-based therapeutics for HF. The expression dataset GSE84044 of HF was downloaded from the GEO database. The crucial module genes for HF were screened according to weighted gene co-expression network analysis (WGCNA). The crucial module genes were mapped to immune-related genes obtained from the ImmPort database to obtain the hepatic fibrosis immune genes (HFIGs). In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses were performed on HFIGs. Then, the protein-protein interaction (PPI) network was conducted on HFIGs and hub genes were identified from the PPI network. Moreover, immune infiltration analysis was performed to identified correlation between hub gene and immune cell infiltration. To verify the reliability of the GSE84044 expression profile data analysis, a rat model of CCl4-induced HF was established, followed by transcriptome sequencing and immunofluorescence analysis and quantitative reverse transcription (q-PCR) experiments were performed in HF rats and normal rat liver tissues. Finally, CMAP platform was used to explore immune target-based therapeutics for HF. In the bioinformatics analysis of GSE84044 data, 98 HFIGs were screened. These genes were mainly involved in inflammation-related biological pathways such as NOD-like receptor signaling pathway, NF-kappa B signaling pathway, Toll-like receptor signaling pathway and PI3K-Akt signaling pathway. From the PPI network, 10 hub genes were identified, including CXCL8, IL18, CXCL10, CD8A, IL7, PTPRC, CCL5, IL7R, CXCL9 and CCL2. Immune infiltration analysis showed that immune cells like neutrophils, natural killer (NK) cells, macrophages M1 and macrophages M2 were significantly correlated with the hepatic fibrosis process and hub gene expression was significantly correlated with these immune cells. Notably, most of the biological pathways HFIGs riched and all the hub gene expression except CXCL8 were validated in subsequent transcriptome and qRCR experiments. Finally, 15 small molecule compounds with the potential to reverse the high expression of hub genes were screen out as potential therapeutic agents for HF. The immune genes CXCL8, IL18, CXCL10, CD8A, IL7, PTPRC, CCL5, IL7R, CXCL9 and CCL2 may play an essential role in the fibrosis formation and inflammatory damage in HF. The outcomes of this research provide a basis for the study of the immune mechanisms of HF and contribute to the diagnosis and prevention and treatment of HF in clinical practice.

This meta-analysis aimed to determine the efficacy of curcumin in preventing liver fibrosis in animal models. A systematic search was conducted on studies published from establishment to November 2023 in PubMed, Web of Science, Embase, Cochrane Library, and other databases. The methodological quality was assessed using Sycle's RoB tool. An analysis of sensitivity and subgroups were performed when high heterogeneity was observed. A funnel plot was used to assess publication bias. This meta-analysis included 24 studies involving 440 animals with methodological quality scores ranging from 4 to 6. The results demonstrated that curcumin treatment significantly improved Aspartate aminotransferase (AST) [standard mean difference (SMD) = -3.90, 95% confidence interval (CI) (-4.96, -2.83), < 0.01, I = 85.9%], Alanine aminotransferase (ALT)[SMD = - 4.40, 95% CI (-5.40, -3.40), < 0.01, I = 81.2%]. Sensitivity analysis of AST and ALT confirmed the stability and reliability of the results obtained. However, the funnel plot exhibited asymmetry. Subgroup analysis based on species and animal models revealed statistically significant differences among subgroups. Furthermore, curcumin therapy improved fibrosis degree, oxidative stress level, inflammation level, and liver synthesis function in animal models of liver fibrosis. Curcumin intervention not only mitigates liver fibrosis but also enhances liver function, while concurrently modulating inflammatory responses and antioxidant capacity in animal models. This result provided a strong basis for further large-scale animal studies as well as clinical trials in humans in the future. https://www.crd.york.ac.uk/prospero/, identifier CRD42024502671.

The aim of this research was to investigate the effect of amygdalin on hepatic fibrosis in rats. Amygdalin was purified and identified from the seeds of . Sprague Dawley rats in the control and model groups were administered water. Sprague Dawley rats were divided into the low-, middle-, and high-dose amygdalin groups that received 20, 40, and 80 mg kg amygdalin, respectively. whereas the silymarin group was treated with 50 mg kg silymarin. The control and model groups were administered water. Liver tissue analysis revealed significantly lower activities of ALT, AST, ALP, SOD, and MDA in the drug-treated groups compared to the model group. Serum analysis revealed significantly lower HYC and C-IV in the middle-dose amygdalin-treated group compared to the model group. The histopathological changes were less severe in the drug-treated groups as observed by the formation of pseudolobuli and decreased collagen fiber deposition. Hepatic fibrosis-related genes were expressed at significantly lower levels in the amygdalin-treated groups than in the model group. Amygdalin from represents a therapeutic candidate for hepatic fibrosis prevention and treatment.

Coronavirus disease 19 (COVID-19) has affected over 112 million people and killed more than 2.5 million worldwide. When the pandemic was declared, Spain and Italy accounted for 29% of the total COVID-19 related deaths in Europe, while most infected patients did not present severe illness. We hypothesised that shared genomic characteristics, distinct from the rest of Europe, could be a contributor factor to a poor prognosis in these two populations. To identify pathways related to COVID-19 severity, we shortlisted 437 candidate genes associated with host viral intake and immune evasion from SARS-like viruses. From these, 21 were associated specifically with clinically aggressive COVID-19. To determine the potential mechanism of viral infections, we performed signalling pathway analysis with either the full list (n = 437) or the subset group (n = 21) of genes. Four pathways were significantly associated with the full gene list (Caveolar-mediated Endocytosis and the MSP-RON Signalling) or with the aggressive gene list (Hepatic Fibrosis/Hepatic Stellate Cell (HSC) Activation and the Communication between Innate and Adaptive Immune Cells). Single nucleotide polymorphisms (SNPs) from the ±1 Mb window of all genes related to these four pathways were retrieved from the dbSNP database. We then performed Principal Component analysis for these SNPs in individuals from the 1000 Genomes of European ancestry. Only the Hepatic Fibrosis/HSC Activation pathway showed population-specific segregation. The Spanish and Italian populations clustered together and away from the rest of the European ancestries, with the first segregating further from the rest. Additional in silico analysis identified potential genetic markers and clinically actionable therapeutic targets in this pathway, that may explain the severe disease.

The liver and pancreas are closely associated organs that share a common embryological origin. They display amphicrine properties and have similar exocrine organization with parenchymal cells, namely, hepatocytes and acinar cells, secreting bile and pancreatic juice into the duodenum via a converging network of bile ducts and pancreatic ducts. Here we compare and highlight the similarities of molecular mechanisms leading to liver and pancreatic cancer development. We suggest that unraveling tumor development in an organ may provide insight into our understanding of carcinogenesis in the other organ.