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Background It has been reported that the triglyceride-glucose (TyG) index may serve as a simple and credible surrogate marker of insulin resistance (IR). However, its association with macrovascular and microvascular damage is unclear. Accordingly, the objective of the present study is to investigate the association of macrovascular and microvascular damage with the TyG index. Methods A total of 2830 elderly participants from the Northern Shanghai Study (NSS) were enrolled. The TyG index was calculated as ln[fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. Parameters of vascular damage, including carotid-femoral pulse wave velocity (cf-PWV), brachial-ankle pulse wave velocity (ba-PWV), ankle–brachial index (ABI), carotid intima–media thickness (CMT), carotid plaque, estimated glomerular filtration rate (eGFR) and the urine albumin-to-creatinine ratio (UACR), were measured and calculated. Results In univariate logistic regression, an increased TyG index was associated with a higher risk of cf-PWV > 10 m/s, ba-PWV > 1800 cm/s, ABI < 0.9, microalbuminuria (MAU) and chronic kidney disease (CKD). In multivariable logistic regression, there was a significant increase in the risk of cf-PWV > 10 m/s (OR = 1.86, 95% confidence interval [95% CI] 1.37–2.53, P for trend  < 0.001), ba-PWV > 1800 cm/s (OR = 1.39, [95% CI] 1.05–1.84, P for trend = 0.02), MAU (OR = 1.61, [95% CI] 1.22–2.13, P for trend  < 0.001) and CKD (OR = 1.67, [95% CI] 1.10–1.50, P for trend = 0.02) after adjustment for age, sex, BMI, waist circumference, smoking habit, hypertension, family history of premature CVD, diabetes, HDL-C, LDL-C, insulin therapy and statin therapy. However, no significant relationship was observed between the TyG index and lower extremity atherosclerosis, carotid hypertrophy or carotid plaque. Conclusion An elevated TyG index was significantly associated with a higher risk of arterial stiffness and nephric microvascular damage. This conclusion lends support to the clinical significance of the TyG index for the assessment of vascular damage.

Background The application of multiparametric magnetic resonance imaging (mpMRI) for diagnosis of prostate cancer has been recommended by the European Association of Urology (EAU), National Comprehensive Cancer Network (NCCN), and European Society of Urogenital Radiology (ESUR) guidelines. The purpose of this study is to systematically review the literature on assessing the accuracy of mpMRI in patients with suspicion of prostate cancer. Method We searched Embase, Pubmed and Cochrane online databases from January 12,000 to October 272,018 to extract articles exploring the possibilities that the pre-biopsy mpMRI can enhance the diagnosis accuracy of prostate cancer. The numbers of true- and false-negative results and true- and false-positive ones were extracted to calculate the corresponding sensitivity and specificity of mpMRI. Study quality was assessed using QUADAS-2 tool. Random effects meta-analysis and a hierarchical summary receiver operating characteristic (HSROC) plot were performed for further study. Results After searching, we acquired 3741 articles for reference, of which 29 studies with 8503 participants were eligible for inclusion. MpMRI maintained impressive diagnostic value, the area under the HSROC curve was 0.87 (95%CI,0.84–0.90). The sensitivity and specificity for mpMRI were 0.87 [95%CI, 0.81–0.91] and 0.68 [95%CI,0.56–0.79] respectively. The positive likelihood ratio was 2.73 [95%CI 1.90–3.90]; negative likelihood ratio was 0.19 [95% CI 0.14,-0.27]. The risk of publication bias was negligible with P  = 0.96. Conclusion Results of the meta-analysis suggest that mpMRI is a sensitive tool to diagnose prostate cancer. However, because of the high heterogeneity existing among the included studies, further studies are needed to apply the results of this meta-analysis in clinic.

Several studies have assessed the effect of angiotensin II receptor blockers (ARBs) on peripheral endothelial dysfunction as measured by flow-mediated vasodilatation (FMD), a widely-used indicator for endothelial function. We conducted a meta-analysis to investigate the effect in comparison to placebo or no treatment and other antihypertensives. MEDLINE, Cochrane library and EMBASE were searched to September 2013 for randomized controlled trials (RCTs) that assessed the effect of ARBs versus placebo or no treatment and other antihypertensives (angiotensin-converting enzyme inhibitors (ACEIs), calcium channel blockers (CCBs), β-blockers, diuretics) by forearm FMD. Furthermore, we also use meta-regression to analyze the relationship between the endothelial function and the duration of ARBs treatments. In 11 trials including 590 patients, ARBs (n = 315) significantly improved FMD (1.36%, 95% confidence internal [CI]:1.28 to 1.44) versus placebo or no treatment (n = 275). In 16 trials that included 1028 patients, ARBs (n = 486) had a significant effect (0.59%, 95% CI: 0.25 to 0.94) on FMD when compared with other antihypertensives (n = 542). In 8 trials, ARBs (n = 174) had no significant effect (-0.14%, 95% CI: -0.32 to 0.03) compared with ACEI (n = 173). Compared with others, the benefits of ARBs, respectively, were 1.67% (95% CI: 0.65 to 0.93) in 7 trials with CCBs, 0.79% (95% CI: 0.42 to 1.01) with β-blockers in 3 trials and 0.9% (95% CI: 0.77 to 1.03) with diuretics in 3 trials. Importantly, we found ARBs were less effective in a long time span (95% CI: -1.990 to -0.622) than the first 6 months (95% CI: -0.484 to 0.360). This study shows that ARBs improve peripheral endothelial function and are superior to CCBs, β-blockers and diuretics. However, the effect couldn't be maintained for a long time. In addition, there was no significant difference between ARBs and ACEI.

Background The management of advanced clear cell renal cell carcinoma (ccRCC) remains a major challenge in clinical practice, and the construction of more reliable prognostic prediction models and the further elucidation of key molecular mechanisms of tumor progression are topics in urgent need of in-depth investigation. Methods We used CIBERSORT to estimate the proportion of 22 tumor-infiltrating immune cell types in the TCGA-KIRC cohort. Weighted gene co-expression network analysis, least absolute shrinkage and selection operator regression analysis were used to build risk prediction models. Expression patterns and clinical significance of TRAF2 were determined through bioinformatics analysis, real-time qPCR, Western Blot, immunohistochemistry. GSEA analysis, transmission electron microscopy, 2D/3D colony formation assay, cell migration and invasion assay, and tube-formation assay were used to investigate the underlying function and mechanism of the TRAF2/M2 macrophage/autophagy axis. Results We constructed a novel prognostic prediction model based on M2 macrophage-related genes, which was identified as an accurate, independent and specific prognostic risk model for ccRCC patients. A reliable nomogram was constructed to predict 1-, 3-, and 5-year overall survival for patients with ccRCC. As one of the constituent genes of the risk model, TRAF2 was determined to be upregulated in ccRCC and associated with poor clinical prognosis. We found that TRAF2 promotes malignant progression of ccRCC by regulating macrophage polarization, migration and angiogenesis. Mechanistically, we found that TRAF2 promotes the polarization of M2 macrophages, and this chemotaxis is achieved in an autophagy-dependent pathway. Orthotopic tumor growth assay results revealed that TRAF2 plays a key role as a promotor of ccRCC growth and metastasis. Conclusions In conclusion, this risk model is highly predictive of prognostic in ccRCC patients, which is expected to promote improved treatment evaluation and comprehensive management of ccRCC. Moreover, our findings reveal that the TRAF2/M2 macrophage/autophagy axis plays a key regulatory role in the malignant progression of ccRCC, and suggest that TRAF2 is a potential novel therapeutic target for advanced ccRCC.

Cardiac aging, particularly cardiac cell senescence, is a natural process that occurs as we age. Heart function gradually declines in old age, leading to continuous heart failure, even in people without a prior history of heart disease. To address this issue and improve cardiac cell function, it is crucial to investigate the molecular mechanisms underlying cardiac senescence. This review summarizes the main mechanisms and key proteins involved in cardiac cell senescence. This review further discusses the molecular modulators of cellular senescence in aging hearts. Furthermore, the discussion will encompass comprehensive descriptions of the key drugs, modes of action and potential targets for intervention in cardiac senescence. By offering a fresh perspective and comprehensive insights into the molecular mechanisms of cardiac senescence, this review seeks to provide a fresh perspective and important theoretical foundations for the development of drugs targeting this condition.

Necroptosis, a type of programmed cell death, has been increasingly linked to cardiovascular disease development, yet its role in dilated cardiomyopathy (DCM) remains unclear. In this study, we analyzed the GSE5406 dataset from the GEO database to explore necroptosis-related prognostic signatures in DCM using LASSO regression. We identified five necroptosis-related genes (BID, CAMK2B, GLUL, HSP90AB1, CHMP5) that define a necroptosis-related signature with strong predictive value, evidenced by ROC curve areas of 0.852 and 0.957 in training and test sets, respectively. Our analyses, including GO and GSEA enrichment, focused on pathways associated with high necroptosis-related scores (NRS) and revealed significant immune cell infiltration. Notably, nTreg and iTreg cells were enriched in the high NRS group, while CD8 naive T cells and CD8 T cells positively correlated with NRS. Small molecule drugs fenofibrate, procyclidine, and tienilic acid emerged as potential therapeutic agents for high-risk patients, with fenofibrate showing efficacy in inhibiting DCM progression in an inflammatory animal model. These findings underscore the clinical relevance of necroptosis-related genes in assessing DCM progression and prognosis and highlight their potential for targeted therapeutic development.

Background Idiopathic pulmonary fibrosis (IPF) is the most common type of interstitial pneumonia. Lung cancer, mainly non-small cell lung cancer (NSCLC), is a complication of idiopathic pulmonary fibrosis. IPF is also an independent risk factor of lung cancer. Some studies have shown that the complement system can promote the progression of interstitial pulmonary fibrosis. In addition, C1q has also demonstrated to exert a tumor-promoting effect in many tumors. However, the role of C1q in idiopathic pulmonary fibrosis and lung cancer still remain unclear. Methods We selected common differentially expressed genes in IPF and non-small cell lung cancer using datasets from GEO, and investigated common hub gene. The hub genes were validated in IPF by establishing mouse model of IPF and using another four datasets from the GEO. Multiple databases were analyzed including those of Kaplan–Meier Plotter, Tumor Immune Estimation Resource (TIMER2.0) and the Human Protein Atlas (HPA) for NSCLC. Results In this study, 37 common DEGs were identified in IPF and NSCLC including 32 up-regulated genes and 5 down-regulated genes, and C1q was identified as common hub gene. The methylation status of C1q decreased and the expression levels of C1q increased in both lung cancer and idiopathic pulmonary fibrosis. The prognosis of non-small cell lung cancer and IPF patients with high levels of C1q is poor. Conclusions These results show that C1q participates in pulmonary fibrosis and non-small cell lung cancer, and may be a potential diagnostic / prognostic biomarker or a therapeutic target.

NLR Family CARD Domain Containing 5 (NLRC5), an important immune regulator in innate immunity, is involved in regulating inflammation and antigen presentation. However, the role of NLRC5 in vascular remodeling remains unknown. Here we report the role of NLRC5 on vascular remodeling and provide a better understanding of its underlying mechanism. Nlrc5 knockout ( Nlrc5 −/− ) mice exhibit more severe intimal hyperplasia compared with wild-type mice after carotid ligation. Ex vivo data shows that NLRC5 deficiency leads to increased proliferation and migration of human aortic smooth muscle cells (HASMCs). NLRC5 binds to PPARγ and inhibits HASMC dedifferentiation. NACHT domain of NLRC5 is essential for the interaction with PPARγ and stimulation of PPARγ activity. Pioglitazone significantly rescues excessive intimal hyperplasia in Nlrc5 −/− mice and attenuates the increased proliferation and dedifferentiation in NLRC5-deficient HASMCs. Our study demonstrates that NLRC5 regulates vascular remodeling by directly inhibiting SMC dysfunction via its interaction with PPARγ. NLRC5 is known for its role in inflammation and antigen presentation. Here Luan et al. find that NLRC5 protects mice from intimal hyperplasia following vascular injury, and regulates the response of vascular smooth muscle cells to injury through direct interaction with PPARγ.

The inflammatory response of lung tissue and abnormal proliferation of pulmonary artery smooth muscle cells are involved in the pathogenesis of high-altitude pulmonary hypertension (HAPH). Halofuginone (HF), an active ingredient derivative of Chang Shan ( Dichroa febrifuga Lour. [Hydrangeaceae]), has antiproliferative, antihypertrophic, antifibrotic, and other effects, but its protective effects on HAPH remains unclear. In the present study, we evaluated the efficacy of HF on HAPH by establishing a 6000 m HAPH rat model. Male Sprague–Dawley rats were divided into normoxia, normoxia + halofuginone (1 mg/kg), hypoxia, and hypoxia + halofuginone (1 mg/kg) groups. The results showed that HF (1 mg/kg) could prevent hypoxia-induced hemodynamic abnormalities, right ventricular hypertrophy, and pulmonary vascular remodeling in rats. We further detected the expression levels of inflammatory factors interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α) and proliferative/antiproliferative indicators proliferating cell nuclear antigen (PCNA), cyclin-dependent kinase 6 (CDK6), Cyclin D1, p21 in lung tissue, and found that HF could attenuate the lung tissue inflammatory response and proliferative response in HAPH rats. In addition, we also examined the expression levels of transforming growth factor-β1 (TGF-β1), Smad2/3 and p-Smad2/3 in lung tissue, and found that HF exerted therapeutic effects by inhibiting the TGF-β1/Smad signaling pathway.

Background The research of the sensitivity and specificity point-of-care testing (POCT) of D-dimer as a diagnostic protocol for differential diagnosis of Stanford Type A aortic syndrome (hereafter as TAAS) mimicking ST-elevated myocardial infarction (STEMI) with regular STEMI in the emergency department is limited. Methods Full medical information of 32 patients confirmed TAAS and 527 patients confirmed STEMI from January 1st, 2016 to October 1st, 2021 were retrospectively analyzed in Shanghai Tenth People’s Hospital of Tongji University. Results The baseline characteristics of two groups of patients were well-balanced post propensity score matching (PSM) analysis, and each group had 32 patients enrolled. Patients in the STEMI group had higher positive cardiac troponin I (cTNI) (0.174 ng/ml vs. 0.055 ng/ml, P  = 0.008) results but lower D-dimer (0.365μg/ml vs. 31.50μg/ml, P  < 0.001) results than the TAAS group. The D-dimer cutoff value of 2.155μg/ml had the best sensitivity of 100% and specificity of 96.9%, and the positive predictive value (PPV) as well as the negative predictive value (NPV) of the cutoff value were 96.9 and 100%, respectively, in total 64 patients, the area under the curve (AUC) values were 0.998 (95% CI:0.992-1.000, P  < 0.001) for the D-dimer. No significant correlation between the D-dimer concentration and the time from symptoms onset to first medical contact in both groups (TAAS group: r = − 0.248, P  = 0.170; STEMI group: r  = − 0.159, P  = 0.383) or significant correlation between D-dimer and creatine clearance (TAAS group: r  = − 0.065, P  = 0.765; STEMI group: r  = 0.222, P  = 0.221). The total in-hospital mortality for the patients with TAAS presenting as STEMI was 62.5% (20/32). The mortality rate for TAAS patients confirmed by computed tomography angiography (CTA) was significantly lower (40% vs. 82.4%, P  = 0.014) than the mortality rate for TAAS patients confirmed by coronary angiography (CAG) and had a longer average survival time (log-rank = 0.015), less peri-surgical complications especially gastrointestinal hemorrhage (0.00% vs. 55.6%, P  < 0.001). CTA diagnosis can reduce the mortality rate by 67.5% (95%CI:0.124-0.850, P  = 0.16). Conclusions The POCT D-dimer with cut-off 2.155μg/ml would be useful to rule-out TAAS mimicking STEMI from regular STEMI prior to reperfusion therapy. CTA diagnosis is effective in reducing the probability of perioperative complications and lowering perioperative mortality than CAG diagnosis in TAAS patients.