SIRT6 Is a Key Regulator of Pancreatic β-Cell Survival and Function During Aging.

Pancreatic β-cell function declines with age, but the underlying mechanism is poorly understood. In this study, we attempted to address how to reverse β-cell aging. Our data showed that sirtuin 6 (SIRT6) overexpression can reduce age-associated DNA damage, cell death, and functional decline in β-cells.

Erratum: Author correction to "Up-regulation of glyclipid transfer protein by bicyclol causes spontaneous restriction of hepatitis C virus replication" [Acta Pharm Sin B 9 (2019) 769-781].

[This corrects the article DOI: 10.1016/j.apsb.

The Patatin-Like Phospholipase Domain-Containing 3 148M Variant Exacerbates Alcohol-Induced Liver Injury and Tumorigenesis in Mice.

Patatin-like phospholipase domain-containing 3 (PNPLA3) protein 148M variant is strongly associated with cirrhosis and hepatocellular carcinoma (HCC); however, the underlying mechanisms remain elusive. This study aimed to elucidate the role of the PNPLA3 variant in alcohol-related HCC development. Control and humanized PNPLA3 transgenic mice were fed with an ethanol-containing diet for 12 weeks.

Targeting the ER stress sensor IRE1 protects the liver from fibrosis through the downregulation of the proteostasis factor P4HB/PDIA1.

Background Aims: Collagen is the main cargo of the secretory pathway, contributing to hepatic fibrogenesis due to extensive accumulation of extracellular matrix. An excess of collagen deposition is a characteristic feature of several chronic liver diseases. Collagen overproduction imposes pressure on the secretory pathway, altering endoplasmic reticulum (ER) proteostasis.

Advancing the Metabolic Dysfunction-Associated Steatotic Liver Disease Proteome: A Post-Translational Outlook.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver disorder with limited treatment options. This review explores the role of post-translational modifications (PTMs) in MASLD pathogenesis, highlighting their potential as therapeutic targets. We discuss the impact of PTMs, including their phosphorylation, ubiquitylation, acetylation, and glycosylation, on key proteins involved in MASLD, drawing on studies that use both human subjects and animal models.

Impact of Total Ionizing Dose on Radio Frequency Performance of 22 nm Fully Depleted Silicon-On-Insulator nMOSFETs.

In this paper, the degradation mechanism of the RF performance of 22 nm fully depleted (FD) silicon-on-insulator nMOSFETs at different total ionizing dose levels has been investigated. The RF figures of merit (the cut-off frequency , maximum oscillation frequency ) show significant degradation of approximately 14.1% and 6.

ATG14 plays a critical role in hepatic lipid droplet homeostasis.

Background & Aims: Autophagy-related 14 (ATG14) is a key regulator of autophagy. ATG14 is also localized to lipid droplet; however, the function of ATG14 on lipid droplet remains unclear. In this study, we aimed to elucidate the role of ATG14 in lipid droplet homeostasis.

The endoplasmic reticulum stress sensor IRE1 regulates collagen secretion through the enforcement of the proteostasis factor P4HB/PDIA1 contributing to liver damage and fibrosis.

Collagen is one the most abundant proteins and the main cargo of the secretory pathway, contributing to hepatic fibrosis and cirrhosis due to excessive deposition of extracellular matrix. Here we investigated the possible contribution of the unfolded protein response, the main adaptive pathway that monitors and adjusts the protein production capacity at the endoplasmic reticulum, to collagen biogenesis and liver disease. Genetic ablation of the ER stress sensor IRE1 reduced liver damage and diminished collagen deposition in models of liver fibrosis triggered by carbon tetrachloride (CCl ) administration or by high fat diet.

Sirtuin 6 protects against hepatic fibrogenesis by suppressing the YAP and TAZ function.

Hepatic fibrosis occurs in response to prolonged tissue injury in the liver, which results in abnormal accumulation of extracellular matrix. Hepatic stellate cells (HSCs) have been suggested to play a major role in liver fibrosis. However, the molecular mechanisms remain incompletely understood.

A high-fat diet catalyzes progression to hyperglycemia in mice with selective impairment of insulin action in Glut4-expressing tissues.

Insulin resistance impairs postprandial glucose uptake through glucose transporter type 4 (GLUT4) and is the primary defect preceding type 2 diabetes. We previously generated an insulin-resistant mouse model with human GLUT4 promoter-driven insulin receptor knockout (GIRKO) in the muscle, adipose, and neuronal subpopulations. However, the rate of diabetes in GIRKO mice remained low prior to 6 months of age on normal chow diet (NCD), suggesting that additional factors/mechanisms are responsible for adverse metabolic effects driving the ultimate progression of overt diabetes.

SIRT6 controls hepatic lipogenesis by suppressing LXR, ChREBP, and SREBP1.

Fatty liver disease is the most prevalent chronic liver disorder, which is manifested by hepatic triglyceride elevation, inflammation, and fibrosis. Sirtuin 6 (Sirt6), an NAD-dependent deacetylase, has been implicated in hepatic glucose and lipid metabolism; however, the underlying mechanisms are incompletely understood. The aim of this study was to identify and characterize novel players and mechanisms that are responsible for the Sirt6-mediated metabolic regulation in the liver.

Sestrin Proteins Protect Against Lipotoxicity-Induced Oxidative Stress in the Liver via Suppression of C-Jun N-Terminal Kinases.

Background & Aims: Sestrin 1/2/3 (Sesn1/2/3) belong to a small family of proteins that have been implicated in the regulation of metabolic homeostasis and oxidative stress. However, the underlying mechanisms remain incompletely understood. The aim of this work was to illustrate the collective function of Sesn1/2/3 in the protection against hepatic lipotoxicity.

Signal Transduction and Molecular Regulation in Fatty Liver Disease.

Fatty liver disease is a major liver disorder in the modern societies. Comprehensive understanding of the pathophysiology and molecular mechanisms is essential for the prevention and treatment of the disease. Remarkable progress has been made in the recent years in basic and translational research in the field of fatty liver disease.

SIRT6 Protects Against Liver Fibrosis by Deacetylation and Suppression of SMAD3 in Hepatic Stellate Cells.

Background & Aims: Nonalcoholic steatohepatitis (NASH) is a chronic liver disease that is manifested clinically by an increase in hepatic triglycerides, inflammation, and fibrosis. The pathogenesis of NASH remains incompletely understood. Sirtuin 6 (Sirt6), a nicotinamide adenine dinucleotide-dependent deacetylase, has been implicated in fatty liver disease; however, the underlying molecular mechanisms in the NASH pathogenesis are elusive.

Identification of benzothiazones containing a hexahydropyrrolo[3,4-]pyrrol moiety as antitubercular agents against MDR-MTB.

IMB1603, a spiro-benzothiazone compound discovered by our lab, displayed potent anti-MTB activity and . In this study, we reported a series of new BTZs containing the hexahydropyrrolo[3,4-]pyrrol moiety based on the structure of IMB1603. Among them, BTZs 11 and 24 displayed potent anti-MTB (MIC < 0.

Amino acid prodrugs of NVR3-778: Design, synthesis and anti-HBV activity.

A series of amino acid prodrugs of NVR3-778, a potent anti-HBV candidate currently under phase II clinical trial, were designed and synthesized as new anti-HBV agents. Except for 1e, all of them displayed roughly comparable anti-HBV activity (IC, 0.28-0.

Causal relationships between NAFLD, T2D and obesity have implications for disease subphenotyping.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D) and obesity are epidemiologically correlated with each other but the causal inter-relationships between them remain incompletely understood. We aimed to explore the causal relationships between the 3 diseases.

Methods: Using both UK Biobank and publicly available genome-wide association study data, we performed a 2-sample bidirectional Mendelian randomization analysis to test the causal inter-relationships between NAFLD, T2D, and obesity.

Erratum: Author correction to 'Up-regulation of glycolipid transfer protein by bicyclol causes spontaneous restriction of hepatitis C virus replication' [Acta Pharmaceutica Sinica B 9 (2019) 769-781].

[This corrects the article DOI: 10.1016/j.apsb.

Up-regulation of glycolipid transfer protein by bicyclol causes spontaneous restriction of hepatitis C virus replication.

Bicyclol is a synthetic drug for hepatoprotection in clinic since 2004. Preliminary clinical observations suggest that bicyclol might be active against hepatitis C virus (HCV) with unknown mechanism. Here, we showed that bicyclol significantly inhibited HCV replication and in hepatitis C patients.

Sesn3 deficiency promotes carcinogen-induced hepatocellular carcinoma via regulation of the hedgehog pathway.

Sestrin 3 (Sesn3) belongs to a small protein family that has been implicated in multiple biological processes including anti-oxidative stress, anti-aging, cell signaling, and metabolic homeostasis. However, the role of Sesn3 in hepatocellular carcinoma (HCC) remains unclear. Here we generated a Sesn3 knockout mouse model and induced HCC development by a combination of a single dose of diethylnitrosamine and chronic feeding of a choline deficient-high fat diet.

The epigenetic regulator SIRT6 protects the liver from alcohol-induced tissue injury by reducing oxidative stress in mice.

Background & Aims: As a nicotinamide adenine dinucleotide-dependent deacetylase and a key epigenetic regulator, sirtuin 6 (SIRT6) has been implicated in the regulation of metabolism, DNA repair, and inflammation. However, the role of SIRT6 in alcohol-related liver disease (ALD) remains unclear. The aim of this study was to investigate the function and mechanism of SIRT6 in ALD pathogenesis.

Sestrin 3 Protects Against Diet-Induced Nonalcoholic Steatohepatitis in Mice Through Suppression of Transforming Growth Factor β Signal Transduction.

Sestrin 3 (Sesn3) belongs to the three-member sestrin protein family. Sestrins have been implicated in antioxidative stress, adenosine monophosphate-activated protein kinase and mammalian target of rapamycin signal transduction, and metabolic homeostasis. However, the role of Sesn3 in the development of nonalcoholic steatohepatitis (NASH) has not been previously studied.

Bicyclol Attenuates Liver Inflammation Induced by Infection of Hepatitis C Virus Repressing ROS-Mediated Activation of MAPK/NF-κB Signaling Pathway.

Treatment with direct-acting antivirals (DAAs) cures most patients infected with hepatitis C virus (HCV) in the real world. However, some patients, especially those with the underlying advanced liver disease, have a limited reduction of liver injury after achieving a sustained viral response (SVR). Bicyclol was widely used in clinics for the treatment of a variety of liver injuries but with an unknown mechanism for the treatment of hepatitis C.

Hepatitis C: From inflammatory pathogenesis to anti-inflammatory/hepatoprotective therapy.

Hepatitis C virus (HCV) infection commonly causes progressive liver diseases that deteriorate from chronic inflammation to fibrosis, cirrhosis and even to hepatocellular carcinoma. A long-term, persistent and uncontrolled inflammatory response is a hallmark of these diseases and further leads to hepatic injury and more severe disease progression. The levels of inflammatory cytokines and chemokines change with the states of infection and treatment, and therefore, they may serve as candidate biomarkers for disease progression and therapeutic effects.