Gut microbial co-metabolite 2-methylbutyrylcarnitine exacerbates thrombosis via binding to and activating integrin α2ß1.

Thrombosis represents the leading cause of death and disability upon major adverse cardiovascular events (MACEs). Numerous pathological conditions such as COVID-19 and metabolic disorders can lead to a heightened thrombotic risk; however, the underlying mechanisms remain poorly understood. Our study illustrates that 2-methylbutyrylcarnitine (2MBC), a branched-chain acylcarnitine, is accumulated in patients with COVID-19 and in patients with MACEs. 2MBC enhances platelet hyperreactivity and thrombus formation in mice. Mechanistically, 2MBC binds to integrin α2ß1 in platelets, potentiating cytosolic phospholipase A2 (cPLA2) activation and platelet hyperresponsiveness. Genetic depletion or pharmacological inhibition of integrin α2ß1 largely reverses the pro-thrombotic effects of 2MBC. Notably, 2MBC can be generated in a gut-microbiota-dependent manner, whereas the accumulation of plasma 2MBC and its thrombosis-aggravating effect are largely ameliorated following antibiotic-induced microbial depletion. Our study implicates 2MBC as a metabolite that links gut microbiota dysbiosis to elevated thrombotic risk, providing mechanistic insight and a potential therapeutic strategy for thrombosis.

Clinical characteristics and therapeutic strategy for patients with spontaneous isolated abdominal aortic dissection.

Objective: Spontaneous isolated abdominal aortic dissection (SIAAD) is a rare aortic emergency and not yet fully understood. This study aims to report the characteristics and treatments of 31 patients with SIAAD in the past 12 years. Methods: A total of 31 consecutive patients with SIAAD between 2010 and 2022 were included. The clinical manifestations, treatment strategies, and outcomes were reviewed. Following the SVS/STS reporting standard, we compared the clinical characteristics with different locations of primary entry, or different numbers of dissected zones. Furthermore, we compared the effects of surgical and conservative therapies on the outcome during the follow-up. Results: Among the 31 patients with SIAAD, 16 (51.6%) were in the acute phase on admission. The primary entry of SIAAD was mainly located in Zone 9 (67.7%). Most patient presented with dissection involving 1 or 2 aortic zones (61.3%). In addition, 35.5% and 64.5% of SIAADs involved the visceral and iliac arteries, respectively. Compared with asymptomatic SIAADs, the symptomatic ones had longer dissection lengths (P = 0.008) and tended to involve iliac artery more frequently (P = 0.098). There were differences in the number of dissected aortic zones (P = 0.005) among patients with primary entry located in Zone 5 (Supraceliac aorta), Zone 6-8 (Paravisceral aorta) and Zone 9 (Infrarenal aorta). The involvement of visceral artery (P = 0.039) and iliac artery (P = 0.006) was significantly different between the subgroups of SIAAD involving one, two, and three or more aortic zones. The cumulative incidence of adverse false lumen progression events was significantly lower (P = 0.000) and the rate of false lumen thrombogenesis or disappearance was higher in patients receiving surgery (P = 0.001). The cumulative all-cause mortality was 9.7% at 1-year, and 19.7% at 5-year, with no significant difference between surgical and conservative therapies. Conclusions: Clinical features of SIAAD vary depending on the location of the primary entry and the number of dissected aortic zones. Although surgery was not associated with a lower all-cause mortality compared with conservative therapy, it was associated with a lower incidence of adverse false lumen progression and a higher rate of aortic remodeling.

Celastrol directly binds with VAMP7 and RAB7 to inhibit autophagy and induce apoptosis in preadipocytes.

Obesity is one of the most prevalent chronic metabolic diseases, and induction of apoptosis in preadipocytes and adipocytes is a potential strategy to treat obesity. Celastrol represents one of the most robust anti-obesity phytochemicals so far, yet its direct binding target remains elusive. Here, we determined that celastrol could induce apoptosis in preadipocytes via mitochondrial mediated pathway. Further study clarified that celastrol inhibited the fusion of autophagosome and lysosome to prohibit autophagy, leading to cell apoptosis. By conducting virtual screening and genetic manipulation, we verified that overexpression of VAMP7 and RAB7 could block the effects of celastrol on inhibiting autophagy and inducing apoptosis. The Surface Plasmon Resonance study confirmed the direct binding of celastrol with VAMP7 and RAB7. The functional study illustrated the inhibition of RAB7 GTPase activity after celastrol treatment. Moreover, celastrol induced comparable apoptosis in murine epididymal adipose tissue, human preadipocytes and adipocytes, but not in human hepatocytes. An inhibitory effect on differentiation of human primary visceral preadipocytes was also observed. In conclusion, celastrol exhibited inhibitory effect of autophagy via direct binding with VAMP7 and RAB7, leading to an increase in preadipocytes apoptosis. These results advance our understanding in the potential application of celastrol in treating obesity.

Screening plasma metabolites as potential biomarkers for type B aortic dissection.

Background: Aortic dissection (AD) is a serious aortic disease. Although current imaging methods can provide accurate diagnosis for AD, they do not include essential biological information. The aim of this study is to identify plasma metabolites for the risk and severity of type B AD (TBAD). Methods: In this cross-sectional study, we enrolled 16 hypertensive patients with TBAD and 7 hypertensive patients without TBAD in Jieyang People's Hospital between December 2021 and April 2022. After plasma metabolomics analysis, a metabolites risk score (MRS) model was conducted through logistic regression and least absolute shrinkage and selection operator (LASSO) regression to predict the risk of TBAD. Subsequently, TBAD group was divided into uncomplicated and complicated TBAD subgroups for further screening for metabolites related to the severity of TBAD. Results: Three metabolites, including 1,5-anhydro-D-glucitol, D-(+)-sucrose and PC(O-16:0/0:0) were related to the risk of TBAD. Compared to hypertensive patients without TBAD, the abundance of 1,5-anhydro-D-glucitol and D-(+)-sucrose were significantly increased while PC(O-16:0/0:0) was significantly reduced in hypertensive patients with TBAD (P<0.001). We subsequently built an MRS model based on these three metabolites. Furthermore, we found that hydrocinnamic acid (r=0.741, P<0.001) was independently correlated with the TBAD severity, while glycine deoxycholic acid (r=-0.538, P=0.008) and glycochenodeoxycholic acid (r=-0.538, P=0.008) were inversely correlated with the TBAD severity independently. Conclusions: The present study screened out three plasma metabolites associated with the risk of TBAD, constructed an MRS model, and identified three metabolites that were independently associated with the severity of TBAD. These findings may serve to identify more TBAD-related biomarkers and shed light on exploring potential mechanisms of TBAD.

Comparison of Management for Central Venous Stenosis With or Without Previous Catheter Placement.

Objective: To compare central venous stenosis/occlusion with or without previous jugular catheter placement history. Methods: Data of patients with central vein stenosis/occlusion receiving endovascular intervention in our hospital from January 2015 to December 2018 were collected and analyzed. Results: Twenty-nine patients with previous jugular catheter placement history (CVC group) and 33 patients (excluded two with technical failure) without such history (non-CVC group) are included in this study. Previous jugular catheter placement history raised the risk of postintervention recurrence 1.02 times (CVC group vs. non-CVC group, HR = 2.02 95%CI: 0.91-4.48). The primary patency rate at 6, 12, 18, and 24 months was 76.9, 54.2, 45.5, and 25.0% separately in the CVC group and 80.6, 70.0, 67.9, and 44.4% separately in the non-CVC group. The assisted primary patency rate at 6, 12, 18, and 24 months was 92.3, 91.7, 86.4, and 68.8% separately in the CVC group and 93.5, 90.0, 82.1, and 61.1% separately in the non-CVC group. Patients in the CVC group received a higher frequency of reintervention (0.7 times/year/patient vs. 0.3 times/year/patient). There was no significant difference in the assisted primary patency rate between the two groups. Different primary interventions (angioplasty alone, bare metal stent, stent graft) did not affect primary patency and assisted primary patency, but percutaneous transluminal stenting (PTS) with a bare metal stent had a significant lower primary patency rate between 3 and 24 months compared with PTS with a stent graft (p = 0.011). Conclusion: Central venous stenosis/occlusion with a previous jugular catheter placement history develops symptoms earlier and had a worse prognosis after endovascular intervention. More efforts are needed to carry out end-stage kidney disease life plan to reduce the harm of evitable catheter placement.

Identification of the Crucial Gene in Overflow Arteriovenous Fistula by Bioinformatics Analysis.

Objective: The aim was to study the preliminary screening of the crucial genes in intimal hyperplasia in the venous segment of arteriovenous (AV) fistula and the underlying potential molecular mechanisms of intimal hyperplasia with bioinformatics analysis. Methods: The gene expression profile data (GSE39488) was analyzed to identify differentially expressed genes (DEGs). We performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of DEGs. Gene set enrichment analysis (GSEA) was used to understand the potential activated signaling pathway. The protein-protein interaction (PPI) network was constructed with the STRING database and Cytoscape software. The Venn diagram between 10 hub genes and gene sets of 4 crucial signaling pathways was used to obtain core genes and relevant potential pathways. Furthermore, GSEAs were performed to understand their biological functions. Results: A total of 185 DEGs were screened in this study. The main biological function of the 111 upregulated genes in AV fistula primarily concentrated on cell proliferation and vascular remodeling, and the 74 downregulated genes in AV fistula were enriched in the biological function mainly relevant to inflammation. GSEA found four signaling pathways crucial for intimal hyperplasia, namely, MAPK, NOD-like, Cell Cycle, and TGF-beta signaling pathway. A total of 10 hub genes were identified, namely, EGR1, EGR2, EGR3, NR4A1, NR4A2, DUSP1, CXCR4, ATF3, CCL4, and CYR61. Particularly, DUSP1 and NR4A1 were identified as core genes that potentially participate in the MAPK signaling pathway. In AV fistula, the biological processes and pathways were primarily involved with MAPK signaling pathway and MAPK-mediated pathway with the high expression of DUSP1 and were highly relevant to cell proliferation and inflammation with the low expression of DUSP1. Besides, the biological processes and pathways in AV fistula with the high expression of NR4A1 similarly included the MAPK signaling pathway and the pathway mediated by MAPK signaling, and it was mainly involved with inflammation in AV fistula with the low expression of NR4A1. Conclusion: We screened four potential signaling pathways relevant to intimal hyperplasia and identified 10 hub genes, including two core genes (i.e., DUSP1 and NR4A1). Two core genes potentially participate in the MAPK signaling pathway and might serve as the therapeutic targets of intimal hyperplasia to prevent stenosis after AV fistula creation.