siRNA nanoparticle targeting Usp20 lowers lipid levels and ameliorates metabolic syndrome in mice.

Atherosclerotic cardiovascular disease (ASCVD) is closely correlated with elevated low-density lipoprotein cholesterol (LDL-C). In feeding state, glucose and insulin activate mTORC1 that phosphorylates the deubiquitylase USP20. USP20 then stabilizes HMG-CoA reductase (HMGCR), thereby increasing lipid biosynthesis. In this study, we applied clinically approved lipid nanoparticles (LNPs) to encapsulate the siRNA targeting Usp20. We demonstrated that silencing of hepatic Usp20 by siRNA decreased body weight, improved insulin sensitivity and increased energy expenditure through elevating UCP1. In Ldlr-/- mice, silencing Usp20 by siRNA decreased lipid levels and prevented atherosclerosis. This study suggests that the RNAi-based therapy targeting hepatic Usp20 has a translational potential to treat metabolic disease.

Hyperactivation of SREBP induces pannexin-1-dependent lytic cell death.

Sterol-regulatory element binding proteins (SREBPs) are a conserved transcription factor family governing lipid metabolism. When cellular cholesterol level is low, SREBP2 is transported from the endoplasmic reticulum to the Golgi apparatus where it undergoes proteolytic activation to generate a soluble N-terminal fragment, which drives the expression of lipid biosynthetic genes. Malfunctional SREBP activation is associated with various metabolic abnormalities. In this study, we find that overexpression of the active nuclear form SREBP2 (nSREBP2) causes caspase-dependent lytic cell death in various types of cells. These cells display typical pyroptotic and necrotic signatures, including plasma membrane ballooning and release of cellular contents. However, this phenotype is independent of the gasdermin family proteins or mixed lineage kinase domain-like (MLKL). Transcriptomic analysis identifies that nSREBP2 induces expression of p73, which further activates caspases. Through whole-genome CRISPR-Cas9 screening, we find that Pannexin-1 (PANX1) acts downstream of caspases to promote membrane rupture. Caspase-3 or 7 cleaves PANX1 at the C-terminal tail and increases permeability. Inhibition of the pore-forming activity of PANX1 alleviates lytic cell death. PANX1 can mediate gasdermins and MLKL-independent cell lysis during TNF-induced or chemotherapeutic reagents (doxorubicin or cisplatin)-induced cell death. Together, this study uncovers a noncanonical function of SREBPs as a potentiator of programmed cell death and suggests that PANX1 can directly promote lytic cell death independent of gasdermins and MLKL.

Similar neurotoxin expression profiles of traditional Chinese scorpion medicine material between juvenile and adult Mesobuthus martensii scorpions revealed by multiple strategic proteomics.

ETHNOPHARMACOLOGICAL RELEVANCE: The Mesobuthus martensii scorpions, called as "Quanxie", are known Chinese medicinal material base on the "Combat poison with poison" strategy for more than one thousand years, and still widely used to treat various diseases according to the Pharmacopoeia of the People's Republic of China nowadays. AIM OF STUDY: The study aims to investigate the similarity of scorpion neurotoxins at the protein level between the juvenile and adult Mesobuthus martensii scorpions as Chinese medicine materials. MATERIALS AND METHODS: The second-, third- and fourth-instar, and adult Mesobuthus martensii scorpions were collected for the characterization of neurotoxin expression through multiple strategic proteomics, including undigested scorpion venom, endopeptidase-digested, and undigested scorpion telson extract for the sample analysis. RESULTS: Based on the known 107 scorpion neurotoxins from the genomic and transcriptomic analysis of adult Mesobuthus martensii scorpions, the multiple strategic proteomics first revealed that neurotoxins exhibited more stability in telson extract than secreted venom. In the reported transcripts of scorpion neurotoxins, approximately 53%, 56%, 66% and 78% of neurotoxins were detected through undigested scorpion venom, the endopeptidase Arg-C-, Lys-C-digested telson extract, and undigested telson extract strategies, respectively. Nearly 79% of scorpion neurotoxins detected in third-instar Mesobuthus martensii scorpions represent the largest number of scorpion neurotoxins from proteomic analysis to date. Moreover, a total of 84% of scorpion neurotoxins were successfully identified at the protein level, and similar neurotoxin expression profiles in second-, third- and fourth-instar, and adult Mesobuthus martensii scorpions were first revealed by the multiple strategic proteomics. CONCLUSION: These findings for the first time demonstrate the similar neurotoxin expression profiles between the juvenile and adult Mesobuthus martensii scorpions as Chinese medicinal material, which would serve as a paradigm for further toxin analysis from different venomous animals.

Scutellarin ameliorates diabetic nephropathy via TGF-ß1 signaling pathway.

Breviscapine, a natural flavonoid mixture derived from the traditional Chinese herb Erigeron breviscapus (Vant.) Hand-Mazz, has demonstrated a promising potential in improving diabetic nephropathy (DN). However, the specific active constituent(s) responsible for its therapeutic effects and the underlying pharmacological mechanisms remain unclear. In this study, we aimed to investigate the impact of scutellarin, a constituent of breviscapine, on streptozotocin-induced diabetic nephropathy and elucidate its pharmacological mechanism(s). Our findings demonstrate that scutellarin effectively ameliorates various features of DN in vivo, including proteinuria, glomerular expansion, mesangial matrix accumulation, renal fibrosis, and podocyte injury. Mechanistically, scutellarin appears to exert its beneficial effects through modulation of the transforming growth factor-ß1 (TGF-ß1) signaling pathway, as well as its interaction with the extracellular signal-regulated kinase (Erk) and Wnt/ß-catenin pathways.