A community-led initiative to de-risk and advance Parkinson's disease therapeutic targets.

Identifying effective therapeutic targets for Parkinson's disease (PD) is challenging, with no current disease-modifying therapies available. To address this, The Michael J. Fox Foundation for Parkinson's Research launched the Targets to Therapies (T2T) initiative, uniting experts to prioritize and validate promising targets.

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.

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.

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.

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.