Panaxydol extracted from Panax ginseng inhibits NLRP3 inflammasome activation to ameliorate NASH-induced liver injury.

Activation of NOD-like receptor protein 3 (NLRP3) inflammasome exacerbates liver inflammation and fibrosis in nonalcoholic steatohepatitis (NASH), suggesting that development of inflammasome inhibitor can become leading candidate to ameliorate NASH. Panax ginseng (P. ginseng) contains numerous bioactive natural components to reduce inflammation.

Extracellular vesicles in fatty liver promote a metastatic tumor microenvironment.

Liver metastasis is a major cause of death in patients with colorectal cancer (CRC). Fatty liver promotes liver metastasis, but the underlying mechanism remains unclear. We demonstrated that hepatocyte-derived extracellular vesicles (EVs) in fatty liver enhanced the progression of CRC liver metastasis by promoting oncogenic Yes-associated protein (YAP) signaling and an immunosuppressive microenvironment.

ERdj5 protects goblet cells from endoplasmic reticulum stress-mediated apoptosis under inflammatory conditions.

Endoplasmic reticulum stress is closely associated with the onset and progression of inflammatory bowel disease. ERdj5 is an endoplasmic reticulum-resident protein disulfide reductase that mediates the cleavage and degradation of misfolded proteins. Although ERdj5 expression is significantly higher in the colonic tissues of patients with inflammatory bowel disease than in healthy controls, its role in inflammatory bowel disease has not yet been reported.

Hepatic TREM2 macrophages express matrix metalloproteinases to control fibrotic scar formation.

Liver cirrhosis is characterized by the extensive deposition of extracellular matrix such as fibril collagen, causing dysfunction and failure of the liver. Hepatic macrophages play pivotal roles in the transition from inflammatory to restorative properties upon hepatic injury. In particular, scar-associated macrophages (SAMacs) control liver fibrosis with the representative expression of matrix metalloproteinase (MMP).

Hyaluronan synthase 2, a target of miR-200c, promotes carbon tetrachloride-induced acute and chronic liver inflammation via regulation of CCL3 and CCL4.

Liver fibrosis occurs during wound healing after repeated liver injury and is characterized by extensive extracellular matrix deposition. We previously identified hyaluronan synthase 2 (HAS2) as a driver of liver fibrosis and hepatic stellate cell (HSC) activation. Developing strategies to suppress HSC activation is key to alleviating liver fibrosis, and HAS2 is an attractive candidate for intervention.

Crosstalk between Oxidative Stress and Inflammatory Liver Injury in the Pathogenesis of Alcoholic Liver Disease.

Alcoholic liver disease (ALD) is characterized by the injury, inflammation, and scarring in the liver owing to excessive alcohol consumption. Currently, ALD is a leading cause for liver transplantation. Therefore, extensive studies (in vitro, in experimental ALD models and in humans) are needed to elucidate pathological features and pathogenic mechanisms underlying ALD.

Hepatokines and Non-Alcoholic Fatty Liver Disease: Linking Liver Pathophysiology to Metabolism.

The liver plays a key role in maintaining energy homeostasis by sensing and responding to changes in nutrient status under various metabolic conditions. Recently highlighted as a major endocrine organ, the contribution of the liver to systemic glucose and lipid metabolism is primarily attributed to signaling crosstalk between multiple organs via hepatic hormones, cytokines, and hepatokines. Hepatokines are hormone-like proteins secreted by hepatocytes, and a number of these have been associated with extra-hepatic metabolic regulation.

Exosomal microRNAs as diagnostic and therapeutic biomarkers in non-malignant liver diseases.

The liver is a vital organ responsible for various physiological functions, such as metabolism, immune response, digestion, and detoxification. Crosstalk between hepatocytes, hepatic macrophages, and hepatic stellate cells is critical for liver pathology. Exosomes are small extracellular vesicles (50-150 nm) that play an important role in cell-cell or organ-organ communication as they transfer their cargo, such as protein, DNA, and RNA to recipient cells or distant organs.

Global Spread of a Local Fire: Transmission of Endoplasmic Reticulum Stress via Connexin 43.

Endoplasmic reticulum (ER) stress is essential in the development of obesity, insulin resistance, and hepatosteatosis. In the latest issue of Cell Metabolism, Tirosh et al. (2020) demonstrate that intracellular ER stress can be transmitted to neighboring hepatocytes via connexin 43, thus propagating ER stress and promoting hepatosteatosis and insulin resistance.

Inhibition of hyaluronan synthesis by 4-methylumbelliferone ameliorates non-alcoholic steatohepatitis in choline-deficient L-amino acid-defined diet-induced murine model.

Hyaluronan (HA) as a glycosaminoglycan can bind to cell-surface receptors, such as TLR4, to regulate inflammation, tissue injury, repair, and fibrosis. 4-methylumbelliferone (4-MU), an inhibitor of HA synthesis, is a drug used for the treatment of biliary spasms. Currently, therapeutic interventions are not available for non-alcoholic steatohepatitis (NASH).

Gα signaling in metabolic diseases.

As the key governors of diverse physiological processes, G protein-coupled receptors (GPCRs) have drawn attention as primary targets for several diseases, including diabetes and cardiovascular disease. Heterotrimeric G proteins converge signals from ~800 members of the GPCR family. Among the members of the G protein α family, the Gα family members comprising Gα and Gα have been referred to as gep oncogenes.

Hyaluronan synthase 2-mediated hyaluronan production mediates Notch1 activation and liver fibrosis.

Hyaluronan (HA), a major extracellular matrix glycosaminoglycan, is a biomarker for cirrhosis. However, little is known about the regulatory and downstream mechanisms of HA overproduction in liver fibrosis. Hepatic HA and HA synthase 2 (HAS2) expression was elevated in both human and murine liver fibrosis.

NOD-like receptor C4 Inflammasome Regulates the Growth of Colon Cancer Liver Metastasis in NAFLD.

Nonalcoholic fatty liver disease (NAFLD) enhances the growth and recurrence of colorectal cancer (CRC) liver metastasis. With the rising prevalence of NAFLD, a better understanding of the molecular mechanism underlying NAFLD-associated liver metastasis is crucial. Tumor-associated macrophages (TAMs) constitute a large portion of the tumor microenvironment that promotes tumor growth.

Inflammation and Liver Cancer: Molecular Mechanisms and Therapeutic Targets.

Hepatocellular carcinoma (HCC) is associated with chronic inflammation and fibrosis arising from different etiologies, including hepatitis B and C and alcoholic and nonalcoholic fatty liver diseases. The inflammatory cytokines tumor necrosis factor-α and interleukin-6 and their downstream targets nuclear factor kappa B (NF-κB), c-Jun N-terminal kinase (JNK), and signal transducer and activator of transcription 3 drive inflammation-associated HCC. Further, while adaptive immunity promotes immune surveillance to eradicate early HCC, adaptive immune cells, such as CD8 T cells, Th17 cells, and B cells, can also stimulate HCC development.

MEK inhibition suppresses K-Ras wild-type cholangiocarcinoma in vitro and in vivo via inhibiting cell proliferation and modulating tumor microenvironment.

PD901, a MEK inhibitor, has been demonstrated of therapeutic efficacy against cholangiocarcinoma (CCA) harboring K-Ras oncogenic mutations. However, most CCA exhibit no K-Ras mutations. In the current study, we investigated the therapeutic potential of PD901, either alone or in combination with the pan-mTOR inhibitor MLN0128, for the treatment of K-Ras wild-type CCA in vitro using human CCA cell lines, and in vivo using AKT/YapS127A CCA mouse model.

Gα12 ablation exacerbates liver steatosis and obesity by suppressing USP22/SIRT1-regulated mitochondrial respiration.

Nonalcoholic fatty liver disease (NAFLD) arises from mitochondrial dysfunction under sustained imbalance between energy intake and expenditure, but the underlying mechanisms controlling mitochondrial respiration have not been entirely understood. Heterotrimeric G proteins converge with activated GPCRs to modulate cell-signaling pathways to maintain metabolic homeostasis. Here, we investigated the regulatory role of G protein α12 (Gα12) on hepatic lipid metabolism and whole-body energy expenditure in mice.

Interventional Potential of Recombinant Feline Hepatocyte Growth Factor in a Mouse Model of Non-alcoholic Steatohepatitis.

Hepatocyte growth factor (HGF) is a multifunctional pleiotropic protein involved in tissue regeneration, protection, angiogenesis, anti-inflammatory and anti-fibrotic responses, and tumorigenesis, through binding to its receptor MET. Recombinant HGF protein has been shown to mitigate various liver disease models, such as alcohol-induced liver injury, hepatic ischemia-reperfusion injury, and fibrosis. This study aimed to investigate the anti-inflammatory, anti-fibrotic, and anti-lipogenic effects of exogenous administration of feline HGF on a non-alcoholic steatohepatitis (NASH) mouse model.

The contribution of toll-like receptor signaling to the development of liver fibrosis and cancer in hepatocyte-specific TAK1-deleted mice.

Hepatocyte death is associated with liver inflammation, fibrosis and hepatocellular carcinoma (HCC). Damaged cells trigger inflammation through activation of Toll-like receptors (TLRs). Although the role of TLR4 in HCC development has been reported, the role of TLR9 in the development of HCC remains elusive.

TRIF Differentially Regulates Hepatic Steatosis and Inflammation/Fibrosis in Mice.

Background & Aims: Toll-like receptor 4 (TLR4) signaling is activated through 2 adaptor proteins: MyD88 and TIR-domain containing adaptor-inducing interferon-β (TRIF). TLR4 and MyD88 are crucial in nonalcoholic steatohepatitis (NASH) and fibrosis. However, the role of TRIF in TLR4-mediated NASH and fibrosis has been elusive.

TNFα in liver fibrosis.

Hepatocyte death, inflammation, and liver fibrosis are the hallmarks of chronic liver disease. Tumor necrosis factor-α (TNFα) is an inflammatory cytokine involved in liver inflammation and sustained liver inflammation leads to liver fibrosis. TNFα exerts inflammation, proliferation, and apoptosis.