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.

Mesenchymal Stem/Stromal Cells Therapy for Metabolic Syndrome: Potential Clinical Application?

Mesenchymal stem/stromal cells (MSCs), a class of cells with proliferative, immunomodulatory, and reparative functions, have shown therapeutic potential in a variety of systemic diseases, including metabolic syndrome (MetS). The cluster of morbidities that constitute MetS might be particularly amenable for the application of MSCs, which employ an arsenal of reparative actions to target multiple pathogenic pathways simultaneously. Preclinical studies have shown that MSCs can reverse pathological changes in MetS mainly by inhibiting inflammation, improving insulin resistance, regulating glycolipid metabolism, and protecting organ function. However, several challenges remain to overcome before MSCs can be applied for treating MetS. For example, the merits of autologous versus allogeneic MSCs sources remain unclear, particularly with autologous MSCs obtained from the noxious MetS milieu. The distinct characteristics and relative efficacy of MSCs harvested from different tissue sources also require clarification. Moreover, to improve the therapeutic efficacy of MSCs, investigators have explored several approaches that improved therapeutic efficacy but may involve potential safety concerns. This review summarized the potentially useful MSCs strategy for treating MetS, as well as some hurdles that remain to be overcome. In particular, larger-scale studies are needed to determine the therapeutic efficacy and safety of MSCs for clinical application.

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 Four Lymph Node Stage Methods for Predicting the Prognosis of Distal Cholangiocarcinoma Patients After Surgery.

BACKGROUND: The metastatic status of regional lymph nodes is an effective risk factor for the prognosis of distal cholangiocarcinoma (dCCA). But existing lymph node staging is not accurate enough and is susceptible to interference. This study aims to explore the predictive ability of the log odds of positive lymph nodes (LODDS) staging system of dCCA compared with existing lymph node staging systems. METHODS: A total of 928 dCCA patients were selected from the Surveillance, Epidemiology, and End Results (SEER) database as the training cohort, and 207 dCCA patients from West China Hospital who underwent surgery were reviewed as the validation cohort. The least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression were conducted to identify the most meaningful factors relevant to prognosis. The performance of four lymph node stage systems was compared by a model-based approach. RESULT: Age at diagnosis, pathological grade, American Joint Committee on Cancer (AJCC) tumor 7th T stage, tumor size, radiotherapy, chemotherapy, and lymph node stage system were independent prognostic factors. The model with the LODDS system had a better model fit with the highest C-index (0.679) and 1-/3-/5- area under the receiver operating characteristic curve (AUC) (0.739/0.671/0.658) as well as the lowest Akaike information criterion (AIC) (5,020.52). External validation results from 207 dCCA patients showed a C-index of 0.647 and 1-/3-/5-AUC of 0.740/0.683/0.589. Compared with the lymph node ratio (LNR), AJCC 8th N system, and 7th N system, the 5-year net reclassification improvement (NRI) of the LODDS system was 0.030 (95% CI: -0.079 to 0.147), 0.042 (95% CI: -0.062 to 0.139), and 0.040 (95% CI: -0.057 to 0.146), respectively. The integrated discrimination improvement (IDI) of LODDS improved compared with the LNR model (0.016; 95% CI: -0.001 to 0.036), AJCC 8th N system (0.020; 95% CI: 0.003-0.037), and AJCC 7th N system (0.019; 95% CI: 0.002-0.036). Decision curve analysis (DCA) also shows a greater net benefit of LODDS. In lymph node-negative patients, LODDS reveals a positive linear relationship with the hazard ratio (HR). The stage capacity of LODDS in a subgroup analysis stratified by examined lymph node number (ELNN) was consistent. CONCLUSIONS: The LODDS lymph node stage system has superior predictive performance as compared with the LNR, AJCC 7th, and 8th lymph node stage systems. Meanwhile, LODDS has a more detailed staging ability and good stability.

The Profile of Secondary Glaucoma in China: A Study of Over 10,000 Patients.

BACKGROUND: Few studies have investigated the epidemiology of secondary glaucoma (SG) in China. This study analyzed the current profile of admitted patients with SG at the largest ophthalmic center in China. METHODS: SG cases were retrieved retrospectively by International Classification of Disease-10 clinical coding data from January 2010 to December 2019. Demographic data, etiologies, and the management of SG were analyzed. The ratios of the etiologies were compared with previously reported data from other regions. The etiologies and management between the 2010 to 2014 group and the 2015 to 2019 group were compared. RESULTS: A total of 11,730 cases were enrolled. The mean age of the patients with SG was 44.45±19.45 years old. Men (66.94%) were more vulnerable than women (33.06%). The etiologies of SG in 2010 to 2019 were trauma (28%), vascular disease (18%), lens-induced (9%), inflammation (11%), drug-induced (2%), anterior segment surgery (7%), posterior segment surgery (11%), syndrome-associated (4%), and tumors (1%). Compared with other regions, our data have a higher proportion of trauma and vascular disease-associated SG. Compared with 2010 to 2014, trauma-induced SG declined, and drug-induced SG, anterior segment surgery, and syndrome-associated SG increased in 2015 to 2019 (P<0.001). Vascular disease-associated SG cases were older than trauma-induced SCs and had a higher percentage in retired patients (P<0.001), whereas trauma-induced SGs were more prevalent in pediatric patients than vascular disease-related SGs (P<0.001). In addition, the application of drainage device implantation, cataract surgery, and cyclophotocoagulation increased, whereas trabeculectomy and anterior chamber paracentesis and cyclocryotherapy decreased in 2015 to 2019 (P<0.005). CONCLUSION: Although the etiology spectrum has changed during the last 10 years, trauma and vascular disease are still common causes of SG in southern China. Traditional antiglaucoma surgery decreased gradually, and more advanced treatments emerged for its treatment. Up-to-date knowledge of SGs reflects the impact of economic development and ophthalmic service improvement on SGs and is of great value for ophthalmologists to detect SGs early and manage them in a timely manner.

Tumor-Targeting Multifunctional Nanoprobe for Enhanced Photothermal/Photodynamic Therapy of Liver Cancer.

Numerous researchers have committed to the development of combined therapy strategies for tumors, since their use in the treatment of tumors has more ideal therapeutic outcomes. In the study, we designed and prepared gold nanostars with CD147 modified on the surface and then efficiently loaded a photosensitive drug IR820 to construct a multifunctional nanoprobe. Due to the protection effect of gold, the nanoprobe has oxygen/heat energy generation capability and can also efficiently deliver the loaded drugs inside the tumor cells. Moreover, the nanoprobe has excellent photothermal/photodynamic therapeutic outcomes. The observation by photoacoustic real-time imaging validated the outstanding tumor-targeting characteristics of our nanoprobe. Finally, in the in vivo treatment experiment, the nanoprobe achieved ideal tumor-suppressive effects after the photothermal/photodynamic therapy. In summary, the findings of this experiment are useful in the development of new combined tumor therapy strategies based on nanomaterials.

[A three dimensional fractal simulation of the lung bronchial tree].

The lungs are naturally irregular and asymmetrical organ in anatomy. The conducting bronchial trees in the lungs display complex self-similar structure. We have established the host mesh coordinates of the right lung on the basis of the anatomical data from the literature. A three-dimensional fractal model of the conducting airways was set up by calculating the coordinates of the mass centers of the divided blocks, searching the branch direction and determining branch lengths with the use of the drawing tool OpenGL. Specific data of the lengths at various grades, branching angles, and capillary diameters were obtained. As a result, the computed data were identical with those of the existing statistical data. The fractal covering dimensionality obtained in the computation of this model was 2.19, which is very close to the ideal dimensionality, 2.17, from the literature. The present model has laid the foundation for further research of the gas diffusion and transfer performance in the lungs using the fractal concept, and furthermore, it helps to save the computer memories and fastening the graphic transfer.