Pyroptosis, a type of Gasdermin-mediated cell death, contributes to an exacerbation of inflammation. To test the hypothesis that GSDME-mediated pyroptosis aggravates the progression of atherosclerosis, we generate ApoE and GSDME dual deficiency mice. As compared with the control mice, GSDME−/−/ApoE−/− mice show a reduction of atherosclerotic lesion area and inflammatory response when induced with a high-fat diet. Human atherosclerosis single-cell transcriptome analysis demonstrates that GSDME is mainly expressed in macrophages. In vitro, oxidized low-density lipoprotein (ox-LDL) induces GSDME expression and pyroptosis in macrophages. Mechanistically, ablation of GSDME in macrophages represses ox-LDL-induced inflammation and macrophage pyroptosis. Moreover, the signal transducer and activator of transcription 3 (STAT3) directly correlates with and positively regulates GSDME expression. This study explores the transcriptional mechanisms of GSDME during atherosclerosis development and indicates that GSDME-mediated pyroptosis in the progression of atherosclerosis could be a potential therapeutic approach for atherosclerosis.

ObjectiveThis study aimed to investigate the inhibition of human important phase II metabolic enzyme sulfotransferases (SULTs) by phthalate monoesters, which are important metabolites of phthalate esters (PAEs).MethodRecombinant SULT-catalyzed metabolism of p-nitrophenol (PNP) was employed as the probe reactions of SULTs to investigate the inhibition of 8 kinds of phthalate monoesters towards SULT isoforms. An in vitro incubation system was utilized for preliminary screening, and 100 μM of phthalate monoesters was used. Inhibition kinetics were carried out to determine the inhibition of SULTs by phthalate monoesters.ResultMultiple phthalate monoesters have been demonstrated to exert strong inhibition potential towards SULT1A1, SULT1B1, and SULT1E1, and no significant inhibition of phthalate monoesters towards SULT1A3 was found. The activity of SULT1A1 was strongly inhibited by mono-hexyl phthalate (MHP), mono-octyl phthalate (MOP), mono-benzyl phthalate (MBZP), and mono-ethylhexyl phthalate (MEHP). Monobutyl phthalate (MBP), MHP, MOP, mono-cyclohexyl phthalate (MCHP), and MEHP significantly inhibited the activity of SULT1B1. MHP, MOP, and MEHP significantly inhibited the activity of SULT1E1. MOP was chosen as the representative phthalate monoester to determine the inhibition kinetic parameters (Ki) towards SULT1B1 and SULT1E1. The inhibition kinetic parameters (Ki) were calculated to be 2.23 μM for MOP-SULT1B1 and 5.54 μM for MOP-SULT1E1. In silico docking method was utilized to understand the inhibition mechanism of SULT1B1 by phthalate monoesters.ConclusionsAll these information will be beneficial for understanding the risk of phthalate monoester exposure from a new perspective.

Pyroptosis is a proinflammatory form of programmed cell death in response to inflammation. It involves in the pathogenesis and outcomes of atherosclerosis characterized by NLRP3 inflammasome assembly, membrane pore formation, cell swelling, pro-inflammatory mediator and cytokine release. There are known pyroptosis molecular pathways including the caspase-1 depended canonical signaling pathway and the caspase-4/5/11 determined non-canonical signaling pathway. It is essential to explore the connection among NLRP3 inflammasome, pyroptosis and atherosclerosis, which may shed light on the potential therapeutic strategies that target pyroptosis in atherosclerotic treatment.

IntroductionPatients with stroke usually suffer from varying degrees of movement dysfunction, which seriously affects their quality of life, especially for the upper limb dysfunction. Therefore, this study aims to compare the effects of different repetitive transcranial magnetic stimulation (rTMS) modalities on upper limb motor function and daily activities in patients with stroke.Methods and analysisRelevant research will be collected systematically from PubMed, Web of Science, Embase, Cochrane Library, ProQuest, Wanfang Database, China National Knowledge Infrastructure and Chinese Scientific and Journal Database (VIP) about randomised controlled trials of rTMS in the stroke treatment range from the establishment to November 2020. Primary outcomes will be obtained from scales measuring the upper limb motor function like Upper Extremity Fugl-Meyer Assessment Scale, Wolf Motor Function Test, Jebsen-Taylor Hand Function Test, Action Research Arm Test and Box and Block Test. The secondary outcomes include modified Barthel Index and adverse events (such as vertigo, headache and epilepsy), with the goal of assessing patients’ activities of daily living and the safety of treatment. In order to avoid personal bias in the included studies, two reviewers will conduct the data extraction and quality evaluation independently, and all data analyses will be performed by Generate Mixed Treatment comparison software V.0.14.3 and Stata V.16.0.Ethics and disseminationThe network meta-analysis (NMA) in this study does not require ethical approval because the data analysis will be used only to evaluate the rTMS treatment efficacy without patients’ private information. In addition, the results will be disseminated in international conference reports and peer-reviewed manuscripts.PROSPERO registration numberCRD42020212253.