Objective: The best type of resuscitation fluids for sepsis and septic shock patients remains unclear. The aim of this study was to evaluate the efficacy of different concentrations of albumin on reducing the mortality rate of theses patients by meta-analysis. Materials and Methods: PubMed, EMBASE, and Web of Science databases were used for screening the relevant studies. Randomized controlled trials (RCTs) were eligible if they compared the effects of albumin with crystalloid on mortality in patients with sepsis and septic shock. 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 based on the corresponding odds ratios with 95% confidence intervals. Results: Eight studies with a total of 5124 septic patients and 3482 septic shock patients were included in this study. Compared with crystalloid, the use of albumin may represent a trend toward reduced the 90-day mortality of septic patients (OR 0.91 [0.80, 1.02]; P = .11) and significantly improved the outcome of septic shock patients (OR 0.85 [0.74, 0.99]; P = .04). Further analysis showed a potentially beneficial role of both 4% to 5% and 20% albumin on reducing the mortality of septic patients. The use of 20% albumin significantly decreased the 90-day mortality of septic shock patients (OR 0.81 [0.67, 0.98]; P = .03), which was better than 4% to 5% albumin and crystalloid. Conclusions: Albumin treatment, particularly 20% albumin, significantly reduced the 90-day mortality in septic shock patients. Both 4% to 5% and 20% of albumin may work better than crystalloid in improving the survival rate of patients with sepsis, but more relative RCTs are required for validation.

The p47^phox is a key regulatory subunit of Nox2-containing NADPH oxidase (Nox2) that by generating reactive oxygen species (ROS) plays an important role in Angiotensin II (AngII)-induced cardiac hypertrophy and heart failure. However, the signalling pathways of p47^phox in the heart remains unclear. In this study, we used wild-type (WT) and p47^phox knockout (KO) mice (C57BL/6, male, 7-month-old, n = 9) to investigate p47^phox-dependent oxidant-signalling in AngII infusion (0.8 mg/kg/day, 14 days)-induced cardiac hypertrophy and cardiomyocyte apoptosis. AngII infusion resulted in remarkable high blood pressure and cardiac hypertrophy in WT mice. However, these AngII-induced pathological changes were significantly reduced in p47^phox KO mice. In WT hearts, AngII infusion increased significantly the levels of superoxide production, the expressions of Nox subunits, the expression of PKCα and C-Src and the activation of ASK1 (apoptosis signal-regulating kinase 1), MKK3/6, ERK1/2, p38 MAPK and JNK signalling pathways together with an elevated expression of apoptotic markers, i.e., γH2AX and p53 in the cardiomyocytes. However, in the absence of p47^phox, although PKCα expression was increased in the hearts after AngII infusion, there was no significant activation of ASK1, MKK3/6 and MAPKs signalling pathways and no increase in apoptosis biomarker expression in cardiomyocytes. In conclusion, p47^phox-dependent redox-signalling through ASK1, MKK3/6 and MAPKs plays a crucial role in AngII-induced cardiac hypertrophy and cardiomyocyte apoptosis.

Background: The proteome is a key source of therapeutic targets. We conducted a comprehensive Mendelian randomization analysis across the proteome to identify potential protein markers and therapeutic targets for abdominal aortic aneurysm (AAA). Methods and Results: Our study used plasma proteomics data from the UK Biobank, comprising 2923 proteins from 54 219 individuals, and from deCODE Genetics, which measured 4907 proteins across 35 559 individuals. Significant proteomic quantitative trait loci were used as instruments for Mendelian randomization. Genetic associations with AAA were sourced from the AAAgen consortium, a large‐scale genome‐wide association study meta‐analysis involving 37 214 cases and 1 086 107 controls, and the FinnGen study, which included 3869 cases and 381 977 controls. Sequential analyses of colocalization and summary‐data‐based Mendelian randomization were performed to verify the causal roles of candidate proteins. Additionally, single‐cell expression analysis, protein–protein interaction network analysis, pathway enrichment analysis, and druggability assessments were conducted to identify cell types with enriched expression and prioritize potential therapeutic targets. The proteome‐wide Mendelian randomization analysis identified 34 proteins associated with AAA risk. Among them, 2 proteins, COL6A3 and PRKD2, were highlighted by colocalization analysis, summary‐data‐based Mendelian randomization, and the heterogeneity in an independent instrument test, providing the most convincing evidence. These protein‐coding genes are primarily expressed in macrophages, smooth muscle cells, and mast cells within abdominal aortic aneurysm tissue. Several causal proteins are involved in pathways regulating lipid metabolism, immune responses, and extracellular matrix organization. Nine proteins have already been targeted for drug development in diabetes and other cardiovascular diseases, presenting opportunities for repurposing as AAA therapeutic targets. Conclusions: This study identifies causal proteins for AAA, enhancing our understanding of its molecular cause and advancing the development of therapeutics.

Endothelial dysfunction, characterized by a decline in endothelial physiological functions, is a significant aspect of cardiovascular aging, contributing notably to arterial stiffness, atherosclerosis, and hypertension. Transient receptor potential channel V4 (TRPV4), a key member of Ca²⁺‐permeable channels, plays a crucial role in maintaining vascular functions. However, the role and mechanisms of TRPV4 in aging‐related endothelial dysfunction remain incompletely understood. Here, we demonstrated a marked reduction in endothelial TRPV4 function without alterations in its expression, leading to abnormal endothelial Ca²⁺ signaling and impaired vasodilation in aging mesenteric arteries. Employing transcriptome sequencing, co‐IP, and PLA assays, we characterized G protein‐coupled receptor 35 (GPR35) interacting with TRPV4, and abnormally enhanced interactions were found in aging endothelial cells. Subsequently, we revealed that intensive GPR35‐TRPV4 interaction significantly contributes to endothelial dysfunction during aging, utilizing TRPV4 endothelial‐specific knockout (TRPV4_EC^−/−), AAV‐FLT1‐shRNA (GPR35) mice, and GPR35 overexpressed/knocked‐down HUVECs. Furthermore, molecular docking analysis and subsequent co‐IP and pressure myograph experiments indicated that both Thonningianin A and Carfilzomib efficiently restored the GPR35‐TRPV4 interaction, preventing endothelial dysfunction and vasodilation impairment. Our study identifies the crucial role of GPR35‐TRPV4 interaction in aging‐associated abnormal endothelial function and vascular tone modulation. Restoring GPR35‐TRPV4 interaction via Thonningianin A or Carfilzomib represents a promising precision approach for aging‐related endothelial dysfunction.

Background: Myeloproliferative neoplasms (MPN), a group of chronic hematologic neoplasms, are driven by inflammatory mechanisms that influence disease initiation and progression. Emerging evidence highlights the gut microbiome and plasma metabolome as pivotal immunomodulators, yet their causal roles in MPN pathogenesis remain uncharacterized. Methods: We conducted a two-sample Mendelian randomization (MR) analysis to systematically evaluate causal relationships between 196 gut microbial taxa, 526 plasma metabolites, and MPN risk. Instrumental variables were derived from genome-wide association studies (GWASs) of microbial/metabolite traits. Validation utilized 16S rRNA sequencing data from NCBI Bioproject PRJNA376506. Mediation and multivariable MR analyses elucidated metabolite-mediated pathways linking microbial taxa to MPN. Results: Our MR analysis revealed that 7 intestinal taxa and 17 plasma metabolites are causally linked to MPN. External validation confirmed the three taxa’s differential abundance in MPN cohorts. Mediation analysis revealed two mediated relationships, of which succinylcarnitine mediated 14.5% of the effect, and lysine 27.9%, linking the Eubacterium xylanophilum group to MPN. Multivariate MR analysis showed that both succinylcarnitine (p = 0.004) and lysine (p = 0.040) had a significant causal effect on MPN. Conclusions: This study identifies novel gut microbiota–metabolite axes driving MPN pathogenesis through immunometabolic mechanisms. The validated biomarkers provide potential therapeutic targets for modulating inflammation in myeloproliferative disorders.

Background: Vascular inflammation triggers endothelial dysfunction, a pivotal factor in the pathogenesis of diabetic vascular complications. Complement component 1q (C1q), a crucial component of the immune system, is implicated in inflammation and immune responses. However, its role in modulating endothelial function in diabetes remains poorly understood. In this study, we aimed to investigate how C1q influences endothelial inflammation in diabetes and the underlying signaling mechanisms involved. Methods: Gene expression in the aortas of streptozotocin‐induced mice or primary endothelial cells was detected using real‐time quantitative polymerase chain reaction, western blot, and immunofluorescence staining. Molecular docking identified dl ‐citrulline as a target for C1qa. Dihydroethidium staining was used to assess vascular reactive oxygen species generation, while Evans blue staining was used to evaluate vascular permeability. Results: Here, we demonstrated that the upregulation of C1q in the aortic endothelial cells significantly reduces the expression of Nr4a1 (orphan nuclear receptor 4a1) and activates the nuclear factor κB signaling pathway, leading to vascular damage. Increasing Nr4a1 expression can mitigate C1q‐induced vascular injury. Additionally, the small molecule dl ‐citrulline downregulates C1q expression and alleviates endothelial inflammation in diabetes. Overexpression of Hoxa3 (homeobox a3), an upstream negative regulator of C1q transcription, protects against diabetic vascular injury. Conclusions: Together, these findings highlight that C1q downregulation ameliorates endothelial inflammation in diabetes, providing mechanistic insights for developing therapeutic strategies against diabetic vascular complications.