Lei Feng

Background: Thoracic aortic dissection (TAD) is a life‐threatening vascular disease that lacks effective pharmacological treatment. Canonical transient receptor potential (TRPC) channels are involved in regulating various cardiovascular functions, yet their roles in TAD have not been elucidated. Methods: Three‐week‐old male mice were administered β‐aminopropionitrile dissolved in drinking water for 28 days to induce TAD formation. The effects of TRPCs on TAD were explored in vitro and in vivo. RNA sequencing of thoracic aortas was performed to investigate the mechanism by which TRPCs regulate TAD progression. Results: Among the TRPC family members, TRPC1 expression was markedly increased in aortas from β‐aminopropionitrile–induced TAD mice along with the downregulation of the vascular smooth muscle cell (SMC) contractile markers smooth muscle α‐actin and smooth muscle 22. Compared with control littermates, SMC‐specific TRPC1 deficiency in mice alleviated β‐aminopropionitrile–induced TAD formation characterized by decreased aortic rupture, reduced maximal thoracic aortic diameters, and less elastin degradation. Conversely, SMC‐specific knock‐in of TRPC1 exacerbated TAD development in mice. Unbiased RNA sequencing showed that TRPC1 knockout in vascular SMCs inhibited the expression of inflammatory factors and chemokines in thoracic aortas during the early stage of β‐aminopropionitrile administration. Mechanistically, TRPC1 induced the proinflammatory phenotypic transition of vascular SMCs by activating the calcineurin/nuclear factor‐κB pathway, thereby contributing to vascular inflammation and TAD development. Conclusions: Our study identified TRPC1 as a novel endogenous pathogenic factor for vascular SMC inflammatory phenotypic transition and TAD formation and provided new insights for a comprehensive understanding of the mechanisms during TAD. Blocking the TRPC1/calcineurin/nuclear factor‐κB signaling suppressed TAD progression, which may be a promising strategy to address TAD.

Diabetic retinopathy (DR) is a leading cause of vision loss, yet its systemic proteomic mediators remain largely elusive. This study aimed to identify causal plasma proteins, map their cell-type-specific localization in the retina, and experimentally validate their expression under disease-relevant stress. We conducted a proteome-wide association study (PWAS) integrating UK Biobank plasma pQTL data (N = 53,022) with DR GWAS summary statistics. Causal relationships were inferred utilizing summary-data-based Mendelian randomization (SMR) and Bayesian colocalization. Prioritized candidates were mapped to the Human and Mouse Retina Cell Atlases via single-nucleus RNA sequencing (snRNA-seq). Finally, to substantiate the computational findings, in vitro validation of COL4A1 was performed in ARPE-19 cells cultured under hyperglycemic conditions utilizing quantitative real-time PCR (qPCR) and transcriptomic dataset re-analysis. The PWAS identified 26 proteins significantly associated with DR. Subsequent causal inference prioritized 12 high-confidence candidates, including GSTT2B, COL4A1, PAM, and GALNT3. Notably, GSTT2B emerged as a Tier-1 protective causal protein (Z = −3.609; P_SMR = 1.22 × 10⁻⁴). snRNA-seq mapping revealed that GSTT2B is robustly expressed in Müller glia and the retinal pigment epithelium (RPE), whereas COL4A1 is prominently enriched in vascular compartments. These specific expression signatures exhibited partial conservation across species with notable cell-type specific variations. Crucially, in vitro validation confirmed that COL4A1 mRNA expression is significantly upregulated under high-glucose stress. Furthermore, druggability analysis highlighted actionable targets, identifying GSTT2B as a highly probable causal mediator and COL4A1 as a prioritized candidate for structural intervention. This study provides robust genetic, single-cell, and experimental evidence implicating specific plasma proteins in DR pathogenesis. The identification of GSTT2B-mediated protective pathways and the hyperglycemia-induced upregulation of COL4A1 offer a high-resolution molecular atlas to guide drug repositioning and precision therapeutic strategies.

BACKGROUND: Dysfunction of endothelial cells manifests early in pulmonary arterial hypertension and represents a critical therapeutic target. Nevertheless, the limited efficacy of single-target interventions underscores the need for innovative strategies that enable precise therapeutic modulation. METHODS: The TRPV4 (transient receptor potential vanilloid 4)-KCa2.3 (small-conductance calcium-activated potassium channel 3) interaction was validated in experimental pulmonary hypertension mice using co-immunoprecipitation and fluorescence (Förster) resonance energy transfer. Based on structure-guided molecular docking, a small-molecule candidate, JNc-455, was rationally designed. RESULTS: Dissociation of the TRPV4-KCa2.3 complex was confirmed by both co-immunoprecipitation and fluorescence (Förster) resonance energy transfer analyses in lung tissues from patients with pulmonary arterial hypertension and experimental pulmonary hypertension mice. Endothelial cell-specific recombinant adeno-associated virus-mediated disruption of the complex promoted both the initiation and progression of pulmonary hypertension in vivo. Guided by these findings, we developed a series of compounds aimed at restoring TRPV4-KCa2.3 coupling. Among them, JNc-455 demonstrated significant therapeutic efficacy without overt toxicity. However, this effect was absent in endothelial TRPV4-deficient mice (TRPV4 _EC ^−/− ), indicating that the action of JNc-455 critically depends on the structural integrity of the complex. CONCLUSIONS: This study investigates the critical role of the TRPV4-KCa2.3 complex in pulmonary arterial hypertension and, based on these findings, facilitates drug development and screening, thereby identifying JNc-455 as a promising novel therapeutic candidate for pulmonary arterial hypertension.

Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness driven by elevated intraocular pressure from compromised aqueous outflow. While genome-wide association studies have identified numerous risk loci, specific candidate proteins and their cellular mechanisms remain elusive. We employed a multi-omics framework integrating UK Biobank plasma proteomics (N = 53,022) and large-scale POAG GWAS summary statistics. We performed a Proteome-Wide Association Study, Mendelian Randomization, and Bayesian colocalization to infer causality. Identified candidates were mapped to human and mouse ocular scRNA-seq atlases to characterize cell-type specificity, followed by druggability assessments. We prioritized five putative causal proteins, with SEL1L and TFPI demonstrating the strongest evidence. Cross-species scRNA-seq revealed that SEL1L and SERPINF1 are robustly expressed in the trabecular meshwork (TM), particularly the juxtacanalicular tissue, implicating them in outflow resistance. Conversely, TFPI and SLC9A3R2 localize to Schlemm’s canal endothelium, suggesting a role in modulating barrier function. Pathway analyses highlighted endoplasmic reticulum protein processing and coagulation cascades. This study maps putative causal POAG proteins to conventional outflow pathway cells, highlighting SEL1L as a novel target for TM homeostasis and TFPI for drug repurposing, thereby providing data-driven hypotheses to facilitate precision glaucoma therapeutics.

Obesity is associated with the gut microbiome. Here, we report that gut commensal Clostridia bacteria regulate host energy balance through the tryptophan‐derived metabolite indole‐3‐propionic acid (IPA). IPA acts as an endogenous leptin sensitiser to counteract obesity. Mechanistically, IPA is secreted from the gut into the circulation, and then targets to the STAT3 in the hypothalamic appetite regulation centre, promoting its phosphorylation and nuclear translocation, which enhances the body's response to leptin, and regulates the balance between appetite and energy metabolism. The in vitro pull‐down assays involving site‐directed mutagenesis demonstrate that Trp623 in the SH2 domain is the key binding site for STAT3‐IPA interaction. High‐fat diet (HFD), rather than genetic factors, induces excessive secretion of antimicrobial peptides by Paneth cells, inhibiting the growth of Clostridia in the gut and resulting in decreased production of the beneficial metabolite IPA. IPA or Clostridium sporogenes supplement effectively controls weight gain, improves glucose metabolism, and reduces inflammation in DIO mice. IPA fails to achieve such effects in ob/ob mice, while exogenous leptin administration restores the therapeutic effect of IPA. Our study suggests that the IPA‐based gut‐brain axis regulates host metabolism, and supplementation with microbiome‐derived IPA could be a promising intervention strategy for treating obesity.

Cardiac remodeling serves as the underlying pathological basis for numerous cardiovascular diseases and represents a pivotal stage for intervention. The excessive activation of β-adrenergic receptors (β-ARs) assumes a crucial role in cardiac remodeling. Nonetheless, the underlying molecular mechanisms governing β-AR-induced cardiac remodeling remain largely unresolved. In the present study, we identified Src tyrosine kinase as a key player in the cardiac remodeling triggered by excessive β-AR activation. Our findings demonstrated that Src mediates isoproterenol (ISO)-induced cardiac hypertrophy, fibrosis, and inflammation in vivo. Furthermore, Src facilitates β-AR-mediated proliferation and transdifferentiation of cardiac fibroblasts, and hypertrophy and cardiomyocytes in vitro. Subsequent investigations have substantiated that Src mediates β-AR induced the extracellular signal-regulated protein kinase (ERK1/2) signaling pathway activated by β-AR. Our research presents compelling evidence that Src promotes β-AR-induced cardiac remodeling in both in vivo and in vitro settings. It establishes the promoting effect of the β-AR/Src/ERK signaling pathway on overall cardiac remodeling in cardiac fibroblasts and underscores the potential of Src as a therapeutic target for cardiac remodeling.

Silybin is a flavonolignan extracted from the seeds of Silybum marianum that has been used as a dietary supplement for treating hepatic diseases and components of metabolic syndrome such as diabetes, obesity and hypertension. Transient receptor potential vanilloid 4 (TRPV4) channels are Ca²⁺-permeable, nonselective cation channels that regulate vascular endothelial function and blood flow. However, the relationship between silybin and TRPV4 channels in small mesenteric arteries remains unknown. In our study, we carried out a molecular docking experiment by using Discovery Studio v3.5 to predict the binding of silybin to TRPV4. Activation of TRPV4 with silybin was detected via intracellular Ca²⁺ concentration ([Ca²⁺]_i) measurement and patch clamp experiments. The molecular docking results showed that silybin was likely to bind to the ankyrin repeat domain of TPRV4. [Ca²⁺]_i measurements in mesenteric arterial endothelial cells (MAECs) and TRPV4-overexpressing HEK293 (TRPV4–HEK293) cells demonstrated that silybin induced Ca²⁺ influx by activating TRPV4 channels. The patch clamp experiments indicated that in TRPV4–HEK293 cells, silybin induced TRPV4-mediated cation currents. In addition, in high-salt-induced hypertensive mice, oral administration of silybin decreased systolic blood pressure (SBP) and significantly improved the arterial dilatory response to acetylcholine. Our findings provide the first evidence that silybin could induce mesenteric endothelium-dependent vasodilation and reduce blood pressure in high-salt-induced hypertensive mice via TRPV4 channels, thereby revealing the potential effect of silybin on preventing endothelial dysfunction-related cardiovascular diseases.

Background The best type of resuscitation fluids for severe sepsis and septic shock patients remains unclear. The aim of this study was to evalute the effacy of different concentrations of albumin on reducing the mortality rate of theses patients by meta-analysis. Methods PubMed, EMBASE and Web of Science databases were used for screening the relevant studies. Ramdonized controlled trials (RCTs) were eligible if they compared the effects of albumin with crystalloid on mortality in severe sepsis and septic shock patients. Data were examined and extracted by two reviewers independently. Any disagreements were resolved by consensus with or without the help from a third reviewer. Data including mortality, sample size of the patients and resuscitation endpoints were extracted. Meta-analysis was carried out using STATA version 16.0, based on the corresponding odds ratios with 95% confidence intervals. Results Eight studies with a total of 5124 severe sepsis patients and 3482 septic shock patients were included in this study. Compared with crystalloid, the use of albumin slightly reduced the 90-day mortality of severe sepsis patients [OR 0.91 (0.80, 1.02); P = 0.11] and significantly improved the outcome of septic shock patients [OR 0.85 (0.74, 0.99); P = 0.04]. Further analysis showed a potentially benenifical role of both 4–5% and 20% albumin on reducing the mortality of severe sepsis patients. The use of 20% albumin significantly decreased the 90-day mortality of septic shock patients [OR 0.81 (0.67, 0.98); P = 0.03], which was better than 4–5% albumin and crystalloid. Conclusions Albumin treatment, particularly 20% albumin, significantly reduced the 90-day mortality in septic shock patients. Either 4–5% or 20% of albumin may work better than crystalloid in improving the survival rate of patients with severe sepsis, but more relative RCTs are required for validation.