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关键词： Subarachnoid hemorrhage   G -protein-coupled receptor 40   NLRP3 inflammasome   Neuroinflammation   IL-1 beta   Exosome  

摘要： Subarachnoid hemorrhage is one type of strokes with high mortality and disability and there exists several mechanisms in SAH pathology. G-protein-coupled receptor 40 (GPR40) is proven to exert anti-inflammatory effects in several central nervous system (CNS) diseases. However, the precise role of GPR40 in SAH pathogenesis remains largely unknown. In this study, both in vivo and in vitro SAH models were used to investigate the mechanism of GPR40 attenuating neuroinflammation after SAH onset. We found that GPR40 expression in microglia decreased, which promoted IL-1 beta secretion and aggravated neuronal death after SAH onset. The GPR40 agonist GW9508 attenuated neuronal damage and ameliorated neurological deficits in SAH-model mice. Mechanistically, GPR40 in microglia inhibited pyroptosis, and cytokine production via inhibiting NLRP3/caspase-1/IL-1 beta pathway. Then the level of IL-1 beta secreted by microglia and transported to neurons via exosome were decreased, which down-regulated glutaminase, counteracted glutamate accumulation, and facilitated neuronal survival. These results revealed that GPR40 is a novel regulator that inhibits microglia-mediated neuroinflammation and is a potential therapeutic target in SAH therapy.

关键词： colony stimulating factor‐1   colony stimulating factor‐1 receptor   interleukin‐34   microglia   oligodendrocyte progenitor cells   white matter  

摘要： Colony stimulating factor-1 receptor (CSF-1R) signaling is necessary for microglia development and maintenance throughout life. The CSF-1R ligands, CSF-1 and interleukin-34 (IL-34), are indispensable for microglia survival in white matter and gray matter, respectively. While CSF-1 has been studied to a greater extent, the role of IL-34 in microglia function and in the brain overall is much less understood. Here, we examined the region-specific effects of intracerebroventricular (i.c.v.) CSF-1 and IL-34 administration on microglia and oligodendrocyte lineage cells in mice at two timepoints. At 3 days post-intervention, IL-34 increased microglial CD68 levels and the microglia population in the hippocampal CA1 region, whereas CSF-1 increased the microglia population in the corpus callosum. Furthermore, CSF-1, but not IL-34, reduced the oligodendrocyte progenitor cell population in the corpus callosum. These effects were no longer observed at 7 days, revealing the transient nature of the microglial response. Together, these findings demonstrate that in addition to relying on specific signals for survival, microglia respond differently to CSF-1R ligands in a brain microenvironment-dependent manner. These findings highlight the need to better understand microglia in the context of their location, which could provide key insights into the pathogenesis of neuroimmune disorders that predominantly affect gray matter or white matter areas.

关键词： systemic sclerosis   microvasculopathy   fibrosis   immune dysregulation   avenciguat   inflammation   interferon  

摘要： Objectives The soluble guanylate cyclase (sGC) stimulator riociguat is approved for the treatment of pulmonary arterial hypertension and may have antifibrotic effects. However, in fibrotic tissues, oxidative stress and hypoxia can render sGC insensitive to sGC stimulators. sGC activators overcome this limitation. Here, we characterize the novel sGC activator, avenciguat, in preclinical models of *** Human microvascular endothelial cells-dermal (HMVEC-d) cultured in hypoxic conditions and activated human platelet-rich plasma were incubated with varying doses of avenciguat, and the levels of TGF-beta 2 and human CXC chemokine family ligand 4 (CXCL4) were measured, respectively. Treatment with avenciguat was analysed in mice with bleomycin-induced dermal and pulmonary *** Avenciguat reduced hypoxia-induced synthesis of TGF-beta 2 by HMVEC-d and inhibited CXCL4 release by platelets. Moreover, avenciguat demonstrated antifibrotic effects on bleomycin-induced dermal and pulmonary fibrosis. RNA sequencing of affected skin uncovered a unique profile distinguishing avenciguat from riociguat. Avenciguat treatment resulted in deeper regulation of IFN-1 signalling and genes associated with immune response vs riociguat *** In preclinical studies, avenciguat shows the potential to influence vascular, fibrotic and immune-related processes in murine models of SSc. These studies suggest that it may offer therapeutic benefit across multiple aspects of SSc pathophysiology and support the rationale for further investigation in a Phase II clinical trial (VITALISScE (TM);NCT05559580) of avenciguat in SSc.

关键词： Agmatine   Sepsis   Intestinal injury   AhR   Anti-inflammation  

摘要： Background: Sepsis-related intestinal injury is essential in multi-organ dysfunction induced by the systemic inflammatory response. Agmatine (AGM) has anti-inflammatory, antioxidative, and immunomodulatory properties. However, no reports of AGM alleviating sepsis-related intestinal injury have been found. Therefore, this study intends to investigate the protective effects of AGM on sepsis-related intestinal injury and its potential mechanism. Methods: We first established a sepsis model by lipopolysaccharide (LPS) or cecum ligation perforation (CLP), and then used H&E staining, transmission electron microscopy (TEM), and TUNEL to examine the pathological changes in rat intestines after AGM treatment. ELISA was used to detect expression levels of inflammatory factors in ileal tissues and biochemical indexes of infectionin in serum. TNF-alpha induced Caco-2 cell inflammation model was established in vitro, and cell activity and proliferative capacity were detected by CCK8 and EdU after AGM treatment. The Caco-2 cell inflammation model with high or low expression of Aryl hydrocarbon receptor (AhR) was established, and whether AGM exerts anti-inflammatory effects via AhR/STAT3/IL-10 pathway was investigated using molecular docking, Co-IP, and Western Blot. Results: The histopathological staining demonstrated that AGM significantly reduced intestinal injury and the content of inflammatory factors IL-1(3, IL-6, and TNF-alpha, improved systemic infection and the survival rate of septic mice, and restored intestinal barrier function in CLP rats. In vitro, AGM improved cell viability and proliferative capacity of the Caco-2 cell inflammation model. AGM inhibits inflammatory factor expression by activating AhR, decreasing HIF-1 protein expression, and activating the STAT3/IL-10 signaling pathway. Discussion and conclusion: AGM has the potential to ameliorate sepsis-related intestinal injury via the AhR-STAT3IL-10 pathway, thereby offering theoretical basis for clinical treatm

关键词： Pelteobagrus fulvidraco   Interleukin 21   Interleukin 21 receptor   Molecular cloning   Gene expression   Intestinal immunity  

摘要： Interleukin 21 (IL-21) is a member of the IL-2 family and a pleiotropic cytokine that exerts its effects by binding to its receptor complex (IL-21R alpha and gamma chain). Due to the critical role and multifunctionality of IL-21, its functions have been extensively studied in mammals;however, there has been limited research on IL-21 in teleosts. In this study, the cDNA sequences of Pf_IL-21, Pf_IL-21R alpha.1, Pf_IL-21R alpha.2, Pf_gamma c1 and Pf_gamma c2 genes were cloned from yellow catfish (Pelteobagrus fulvidraco). Four alpha-helices and two q-helices were found in Pf_IL-21, one alpha-helices and three q-helices were found in Pf_IL-21R alpha.1/2, and four alpha-helices and three q-helices were found in Pf_gamma c1/2. Quantitative real-time PCR analysis revealed high levels of mRNA expressions of Pf_IL-21 and its four receptors in mucosal and immune-related tissues of healthy yellow catfish. The mRNA expressions of these five genes in peripheral blood leukocytes (PBLs) were found to be regulated after stimulation with lipopolysaccharides (LPS), phytohaemagglutinin (PHA) and polyinosinic-polycytidylic acid (Poly I:C). Following Edwardsiella ictaluri infection, the mRNA expressions of these genes were significantly up-regulated in peripheral blood, hindgut, swim bladder, and other mucosal or immune-related tissues. In addition, the impact of recombinant (r) Pf_IL-21 protein on the intestinal microbiota and histological structure following E. ictaluri infection was examined. The results showed that E. ictaluri infection resulted in a decline in intestinal microbiota richness and diversity, while Fusobacteriota and Cetobacterium abnormally increased, and hindgut exhibited significant pathological alterations. However, the injection of rPf_IL-21 led to a restoration of intestinal microbiota richness and diversity, accompanied by an increase in certain beneficial bacteria and a better recovery of the hindgut structure. These findings suggest that Pf_IL-21 and its four

关键词： Acute kidney injury   Multi-omics integration   Therapeutic target discovery   Drug repurposing  

摘要： Acute kidney injury (AKI) remains a critical condition with limited pharmacological options. Bioactive molecules, including cytokines, receptors, and enzymes, play central roles in AKI pathogenesis, but systematic efforts to identify translational targets remain limited. In this study, we implemented a multi-omics integrative framework to nominate and validate candidate targets for AKI. Using genetically informed screens anchored on a curated set of potentially actionable genes, we identified five prioritized candidates, CD46, IL6R, KLRC1, LEAP2, and SMOX, with strong biological plausibility and therapeutic potential. Bulk and single-cell RNA sequencing data revealed cell-type-specific enrichment, particularly in proximal tubules, immune subsets, and endothelium under AKI conditions. Pathway enrichment highlighted shared involvement in cytokine signaling, antigen presentation, and metabolic stress responses. In silico drug repurposing revealed several clinically approved compounds (e.g., tacrine, raloxifene hydrochloride, tretinoin) with strong predicted binding to CD46, IL6R, and SMOX. In vivo experiments demonstrated that pharmacological inhibition of SMOX significantly alleviated tubular injury, preserved renal function, and reduced oxidative stress. In vitro studies further confirmed the protective effects of SMOX inhibition by maintaining epithelial cell integrity and viability in renal tubular cells, while suppressing oxidative damage.

关键词： Assymptomatics   ELISA   IFN‐γ   IL‐12   feline   leishmaniasis   parasite load  

摘要： Visceral leishmaniasis is a potentially fatal zoonosis with an increasing incidence. Most infected felines present the disease in its subclinical form and demonstrate greater resistance to parasitemia than dogs. However, the role of cellular immunity in felines is still poorly understood. This study measured serum levels of interleukin (IL)-12 and interferon-gamma (IFN-γ) in asymptomatic cats naturally infected with antibodies against Leishmania spp. and in uninfected cats. IL-12 and IFN-γ were measured in serum samples by ELISA. Parasite load quantification was performed on DNA from bone marrow samples using qPCR. Cats naturally infected by Leishmania spp. showed significantly higher serum levels of IL-12 and IFN-γ compared to control animals. IL-12 showed a positive correlation with IFN-γ suggesting a regulatory role of IL-12 in activating the Th1 immune response, which enhances macrophage function and promotes intracellular parasite elimination. Additionally, IL-12 showed a moderate negative correlation with parasite load, indicating a protective effect of IL-12 in feline leishmaniasis. These findings suggest that IL-12 and IFN-γ play critical roles in modulating the feline immune response against parasitic infection, possibly contributing to the control of parasite replication and in the prevention of clinical signs. The immune response observed in felines could be explored for future immunotherapeutic approaches, helping to mitigate the progression of leishmaniasis in cats and reducing the risk of transmission in endemic regions.

关键词： Pulmonary arterial hypertension   Broiler   Transcriptomics   Network pharmacology   Piperine  

摘要： Pulmonary arterial hypertension (PAH) is a chronic, progressive vasculopathy characterized by a sustained elevation in pulmonary vascular resistance and remodeling of pre-capillary pulmonary arterioles, leading to right ventricular failure and often death. This study explores the potential of piperine, a bioactive dietary alkaloid, in mitigating PAH pathogenesis using a broiler chicken model. Network pharmacology analysis identified the IL-6/ STAT3 signaling pathway as key anti-PAH targets of piperine. In vivo experiments demonstrated that piperine treatment significantly reduced PAH-associated mortality, suppressed inflammatory cytokine production, and attenuated pulmonary vascular remodeling in the chicken model. Mechanistically, the observed protective effects were linked to the downregulation of IL-6 expression and STAT3 phosphorylation, along with the suppression of NF-kappa B p65 activation. Furthermore, piperine inhibited hypoxia-induced proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) in vitro, reinforcing its role in preventing vascular remodeling. Collectively, these findings underscore the potential of piperine as a functional food component with cardiopulmonary protective properties, proposing its utility as a potential dietary intervention for the management of PAH.

关键词： HLA‐B   NGS   novel allele   null allele  

摘要： Three novel HLA-B alleles, HLA-B*08:336 N, HLA-B*18:258 N and HLA-B*51:425 N were identified in bone marrow donors.