Search Results (35,643)

Snakebite envenoming remains a major global health challenge. Naja atra (N. atra) envenomation induces severe acute kidney injury (AKI), largely driven by snake venom phospholipase A₂ (SVPLA₂). Increasing evidence suggests that immune dysregulation, in addition to direct cytotoxicity, contributes to delayed renal injury. Here, we investigated whether N. atra SVPLA₂ exposure is associated with macrophage immunometabolic remodeling and functional changes relevant to AKI progression. In vivo, AKI was induced in C57BL/6J mice by intraperitoneal administration of N. atra venom, followed by treatment with the SVPLA₂ inhibitor varespladib. In vitro, bone marrow–derived macrophages were exposed to venom with or without varespladib. N. atra venom exposure was associated with extensive tubular apoptosis, increased renal macrophage abundance, and elevated kidney injury biomarkers. Macrophages exhibited a shift toward a pro-inflammatory polarization signature accompanied by reduced efferocytic capacity. Targeted metabolomics revealed coordinated increases in glycolytic intermediates together with upregulation of key glycolytic enzymes. Pharmacological inhibition of SVPLA₂ partially restored macrophage metabolic features and efferocytic capacity and was accompanied by attenuation of renal injury. Together, these findings support a model in which SVPLA₂ exposure is associated with macrophage immunometabolic remodeling and impaired apoptotic cell clearance during venom-induced AKI. Full article

Background: Metabolic disorder-associated fatty liver disease (MASLD) is closely related to obesity and type 2 diabetes. Its pathogenesis involves many factors, including mitochondrial dysfunction, endoplasmic reticulum stress and intestinal flora disorders. Notoginsenoside R1 (NGR1) is a key bioactive component of Panax notoginseng. The purpose of this study was to investigate the therapeutic effect of notoginsenoside R1 (NGR1) on metabolic disorder-associated steatohepatitis (MASH) and its potential mechanism. Methods: Mice were fed a choline-deficient, L-amino acid-defined high-fat diet (CDAHFD) for 6 weeks and received NGR1 (50/100 mg/kg/day) in the last 3 weeks. The role of NGR1 was evaluated by developing metabolomics, proteomics and functional analysis. In addition, the effects of NGR1 on lipid droplet content, mitochondrial function and fatty acid oxidation in hepatocytes were also verified. Results: NGR1 improved MASH progression in CDAHFD-fed mice, significantly reduced liver triglyceride content from 31.2 ± 5.1 mmol/g to 20.5 ± 4.8 mg/g (p < 0.001), free fatty acid from 0.12 ± 0.03 mmol/g prot to 0.06 ± 0.028 mg/g (p < 0.001), TNF-α (p < 0.01), IL-1β (p < 0.001), α-SMA (p < 0.05) and Collagen1A1 levels (p < 0.01), as well as serum ALT and AST concentrations (p < 0.001), and alleviated hepatomegaly and lipid droplet accumulation. Metabolomics and proteomics analysis showed that NGR1 normalized liver metabolism in MASH mice and upregulated mitochondrial OXPHOS components, including NADH: ubiquinone oxidoreductase core subunit S2 (NDUFS2), and effectively reversed CDAHFD-induced mitochondrial dysfunction. Mitochondrial membrane potential and ATP production were restored. Conclusions: This study confirmed that NGR1 has significant therapeutic potential for MASH and improves mitochondrial function by upregulating NDUFS2. This study provides new insights for the future clinical treatment of MASH. Full article

Background: Coxsackievirus B2 (CVB2) causes a range of diseases, including hand, foot, and mouth disease; myocarditis; acute flaccid paralysis; meningitis; and encephalitis. However, no specific antiviral drugs or vaccines are currently available for CVB2. Methods: We used plaque purification, virus titre determination, and serial passaging to screen and identify an inactivated CVB2 vaccine candidate strain, KM31-C05, which exhibited high viral titres and good genetic stability. Comprehensive biological characterization of this candidate strain was performed, including phylogenetic analysis, virulence assessment in BALB/c mice, one-step growth curve analysis, optimization of the multiplicity of infection, as well as determination of viral load, pathological evaluation, and immunohistochemical analysis in tissues of BALB/c suckling mice post-challenge. An experimental inactivated vaccine was prepared using KM31-C05 to evaluate its immunogenicity and protective efficacy. Results: The viral titres of KM31-C05 reached 10⁸ CCID50/mL. After 20 serial passages, only three amino acid mutations were identified (VP3-G165V, VP1-N84K, and VP1-D129N). Although the two VP1 mutations were located in surface-exposed loops, the strain maintained high neutralizing titres across passages, indicating good genetic stability. However, whether these sites affect virulence and replication requires further investigation. Phylogenetic analysis revealed that this strain belonged to genotype C, which is consistent with the strains circulating in mainland China in recent years. The experimental inactivated vaccine prepared from KM31-C05 induced effective neutralizing antibodies (1:128–1:256) in BALB/c mice and provided complete protection to suckling mice against lethal challenge with this CVB2 strain in maternal antibody protection experiments. Conclusions: KM31-C05 demonstrates potential as a CVB2 vaccine candidate in China and provides a theoretical basis for the development of a CVB2 vaccine. Full article

The cuticular plate, a dense F-actin meshwork anchoring stereocilia in auditory hair cells (HCs), undergoes dynamic remodeling during development, but its structural transitions remain poorly understood. Here, we identified two distinct structural domains associated with this maturation. First, a transient F-actin-free area emerges within the lateral periphery of the developing cuticular plate, presenting as a crescent-shaped region that disappears upon HC maturation. Second, the lateral margin of the mature cuticular plate itself remodels into a persistent step-like structure, exhibiting cell-type-specific geometries in inner versus outer HCs. The consistent coincidence between Gαi-GPSM2 complex disruption and aberrant development of both structures in mutant mice implies a role for this complex in their formation. Additionally, microtubules spatially complemented F-actin distribution, suggesting coordinated cytoskeletal regulation. These findings revealed a sophisticated developmental program for cuticular plate maturation. Full article

Objective: Based on previous findings on the Lingguizhugan (LGZG)-mediated gut–liver axis, this study clarifies the therapeutic mechanisms of LGZG in metabolic dysfunction-associated steatotic liver disease (MASLD), with a focus on the gut microbiota–bile acid–TGR5 (GPBAR1) axis. Methods: C57BL/6J mice were fed a high-fat diet (HFD) for 8 weeks to induce MASLD, followed by 4-week LGZG intervention (21.57 g/kg/day, oral gavage). Metabolic phenotypes, gut microbiota (16S rRNA sequencing), serum/hepatic bile acids (targeted metabolomics), and molecular targets (qPCR/Western blot) were analyzed. Results: LGZG significantly alleviated HFD-induced obesity, insulin resistance, and hepatic steatosis, while enhancing whole-body energy expenditure (increased oxygen consumption (VO₂), and heat production (p < 0.05). It also reduced serum ALT (p < 0.001) and AST levels (p < 0.01). Mechanistically, LGZG remodeled the gut microbiota, specifically increasing Akkermansia, Bifidobacterium and Lachnospiraceae_NK4A236_group while decreasing Lactobacillus. This shift inhibited the intestinal FXR-Fgf15 axis, concurrently activating the hepatic alternative bile acid synthesis pathway (upregulating CYP27A1 and CYP7B1 protein expression; p < 0.001 and p < 0.01, respectively). Consequently, systemic accumulation of non-12α-hydroxylated bile acids (non-12-OH BAs) such as hyocholic acid (HCA) and 7-ketolithocholic acid (7-ketoLCA) occurred—known TGR5 agonists and intestinal FXR antagonists. These changes elevated serum GLP-1 levels (p < 0.05) and activated adipose TGR5-cAMP/PKA/CREB signaling. The metabolic benefits primarily originated from non-12-OH BAs enrichment and TGR5-mediated adipose browning, not hepatic FXR activation. Conclusions: Our findings show that LGZG ameliorates MASLD by remodeling bile acid profiles via intestinal FXR-Fgf15 axis inhibition and hepatic alternative synthesis pathway activation. This study highlights the TGR5-targeting properties of LGZG, providing a mechanistic basis for its therapeutic use in metabolic disorders. Full article

Mycobacterium tuberculosis (Mtb) remains a significant public health threat, responsible for 1.6 million deaths in 2021. The development of new treatments is particularly urgent for immunocompromised individuals, including those with Mtb/HIV coinfection, who experience severe disease outcomes. Previous studies demonstrated that blockade of VEGFR1, a receptor expressed on monocytes that mediates their recruitment to infection sites, limits Mtb-induced pathology in immunocompetent mice of both Mtb-resistant (C57BL/6J) and Mtb-susceptible (B6.C3H-sst1) strains. The present study extends these findings by evaluating the VEGFR1/2 blockade strategy in immunocompromised hosts. Treatment with the VEGFR1/2 blocker SU5416 (semaxanib) reduced monocyte infiltration into the lungs of Mtb-infected immunocompromised RAG1KO mice without affecting bacterial protection. Reduced monocyte recruitment improved lung pathology. VEGFR1/2 blockade also decreased the number of NK cells in the lungs of RAG1KO mice. Notably, an elevated ratio and increased absolute number of neutrophil granulocytes were observed in the Mtb-infected lungs of both immunocompetent and immunocompromised mice following SU5416 administration. However, this increase in neutrophils did not exacerbate lung pathology, as most recruited granulocytes remained within the lung vasculature. The beneficial effect of VEGFR1/2 blockade in RAG1KO animals suggests that further investigation of VEGFR blockers, such as SU5416, as adjunctive therapy to anti-tuberculosis drug regimens for immunocompromised populations with tuberculosis is warranted. Full article

Objectives: Interstitial lung disease (ILD) is a major cause of morbidity and mortality in patients with systemic sclerosis (SSc). This study aimed to evaluate interobserver variability and the relationship between lung ultrasonography (LUS) findings and histological fibrosis severity in a bleomycin (BLM)-induced mouse model of SSc. Materials and Methods: Twenty female BALB/c mice were randomly assigned to a control group (n = 10) or a BLM-treated group (n = 10). Pulmonary fibrosis was induced by daily subcutaneous administration of BLM for three weeks. Two blinded observers (a radiologist and a rheumatologist) performed LUS using a high-frequency linear probe and calculated scores based on B-line distribution. Lung fibrosis was evaluated by Masson’s trichrome staining and quantified using the Ashcroft scoring system. Interobserver agreement was assessed with Cohen’s kappa, and correlations were analyzed using Spearman’s rank test. Results: Control mice exhibited normal lung architecture, whereas all BLM-treated mice developed moderate to severe fibrosis, with significantly higher Ashcroft scores. LUS revealed multiple B-lines, pleural irregularities, and loss of A-lines in BLM-treated mice. LUS scores were considerably higher in the BLM group (p < 0.001). Radiologist-assessed scores showed a strong correlation with Ashcroft scores (ρ = 0.78), while rheumatologist-assessed scores demonstrated a moderate correlation (ρ ≈ 0.62). Interobserver agreement was moderate, with discrepancies mainly in intermediate fibrosis stages. Conclusions: LUS is a useful non-invasive method for semiquantitative assessment of pulmonary fibrosis in this SSc model. Its correlation with histological severity supports clinical relevance, while moderate interobserver variability highlights the need for standardized protocols and training. Full article

Background/Objectives: Coronaviruses are a family of positive-sense RNA viruses that cause respiratory and gastrointestinal disease in mammals and birds. Their zoonotic nature and high mutability make them a pandemic threat. UNICOR-v is a pre-pandemic, pan-coronavirus vaccine composed of an adjuvanted mix of twelve synthetic peptides originating from conserved regions within Nsp12 and M coronavirus proteins containing clusters of predicted T-cell epitopes. Here, we evaluate the immunogenicity of UNICOR-v and its efficacy against Middle East Respiratory Syndrome-related coronavirus (MERS). Methods: Animals were vaccinated with an adjuvanted equimolar mix of UNICOR-v. Humoral and cellular immunogenicity were assessed 28 days later through ELISA and FLUOROSpot. Vaccine efficacy was assessed in a DPP4 knock-in (HDPP4-KI) mouse model where mice were challenged post-vaccination with a lethal or non-lethal dose of MERS-CoV-MA. Results: Vaccination with UNICOR-v induced high IgG titers in both mice and rabbits and cellular secretion of pro-inflammatory cytokines. Vaccination with UNICOR-v, or passive serum transfer, significantly reduced viral lung titers 4 days post-infection compared to placebo. Vaccination induced lower immune cell infiltration in the alveolar space and increased repair of the cells lining the major airways in vaccinated mice, translating to increased survival rate compared to placebo. Conclusions: These data demonstrate the ability of conserved T-cell epitopes to protect against MERS-CoV infection, supporting further characterization of the breadth of protection of UNICOR-v against other coronaviruses that affect humans and livestock, following a One Health approach to control this highly zoonotic family of viruses. Full article

Pharmacological antidepressant treatments alter the molecular and functional reactivity of stress-sensitive neural networks. However, how classical versus rapid-acting antidepressants differentially modulate acute stress-induced transcriptional responses across brain regions remains unclear. Here, we compared imipramine and ketamine in mice exposed to acute swim stress, assessing transcriptional adaptations across the frontal cortex, hippocampus, and striatum. Swim stress induced significant widespread activation of cFOS, which led to drug-specific modulations: imipramine primarily significantly dampened cortical and striatal cFOS expression, whereas ketamine preserved stress-evoked neuronal activation. In contrast, hippocampal activation was significantly robust but largely unaffected, indicating that acute antidepressant drug effects during stress coping preferentially target cortical and striatal plasticity mechanisms. In contrast, BDNF expression was altered only within the striatal region, where imipramine attenuated the stress-related increase in BDNF expression. Statistical analysis of behavioral outcomes during the swim stress confirmed a shared facilitation of active coping, yet these similar outcomes emerged from distinct molecular programs. Together, the data demonstrate that the treatment effects of the two substances diverge mechanistically, revealing cortical and striatal transcriptional signatures of classical versus rapid-acting antidepressant action. While these findings suggest potential translational relevance for understanding distinct mechanisms, further studies in humans are required to validate these signatures and their clinical implications. Full article

In this study, the active components in the seed of Mangifera indica L. were isolated, the main chemical components were identified, and then their antioxidant activities and their effects on liver injury and intestinal microbiota were evaluated. The results showed that all the components of mango column chromatography exhibited antioxidant activity. F2 had the lowest IC₅₀ value of 93.61 μg/mL and exhibited the strongest DPPH radical scavenging activity. Given its superior overall antioxidant activity, F2 was selected for further compositional analysis and activity evaluation. UPLC-MS/MS analysis showed that the isolated components of mango F2 contained 11 active ingredients, including mangiferin, gallic acid and quercetin. The results showed that specific mango fractions significantly reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and showed a protective effect on liver injury induced by alcohol. rRNA sequencing analysis showed that high alcohol intake could reduce the species diversity of intestinal microbiota in mice, and mango fractions could effectively alleviate this phenomenon. High alcohol intake decreases the relative abundance of Bacteroidota and increases the abundance of Bacillota and Thermodesulfobacteriota phyla. The high-dose mango group alleviated the above changes, which was manifested by an increase in the relative abundance of Bacteroidota and Thermodesulfobacteriota bacteria. The relative abundance of families such as Muribaculaceae in the high-dose mango group decreased compared to the model group. This study provides a scientific basis for the analysis and high-value utilization of mango components, and provides a new alternative for protecting against alcoholic liver injury and regulating intestinal microbiota. Full article

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) pose a significant burden on the healthcare system. The mechanisms underlying the pathophysiology of ALI/ARDS are widely studied. However, currently, there are no clinically approved drugs that can effectively reduce the high mortality of patients. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are an increasingly popular class of medications. Their FDA approval was driven by the beneficial effects in patients with type 2 diabetes mellitus. Notably, recent studies are beginning to recognize the role of GLP-1 RAs in immunomodulation and anti-inflammatory responses across various organs, including the lungs. Animal models of ALI demonstrate the potential of these medications for treatment and prophylaxis. Observational studies suggest that patients taking GLP-1 RAs experienced fewer pulmonary complications. Here, we reviewed reports on their impact on the respiratory system in animal models of ALI and in clinical trials. Their effects in the intensive care unit setting and conditions predisposing to ALI/ARDS were also summarized. The mechanisms of action of GLP-1 RAs were reviewed based on in vitro studies using various lung cell types, and experimental approaches. Moreover, the roles of the pharmaceutical industry and patent law in extending the scope of GLP-1 RAs beyond obesity and diabetes were also described. Full article

Neonicotinoids are widely used pesticides that have caused a catastrophic decrease in bee and bumblebee populations worldwide. In addition to insects, neonicotinoids induce toxic effects in other species, including lizards, birds, and mammals. Previous studies have shown that gestational exposure to thiacloprid promotes transgenerational effects in the testes and thyroid. In this project, we described the epigenetic effects of thiacloprid on prostate tissue in directly exposed F1 and non-directly exposed F3 outbred Swiss male mice. We used paraffin sections for morphological analysis and frozen tissue for immunofluorescence analysis, RT–qPCR, and protein analysis. We purified histones and analyzed them through Western blot. We used ChIP–qPCR for histone H3K4me3 occupancy analysis. A tendency to increase in epithelial hyperplasia in F1 but not in F3 prostate was detected. Elevated levels of phosphorylated histone H3 at serine 10, a marker of mitosis, in both the F1 and F3 prostates were noted. A significant increase in the level of the Ki-67 marker of proliferation was detected in the F1 but not in the F3 anterior prostate. Hox gene expression was upregulated in the F1 and downregulated in the F3 prostate. The changes in gene expression were positively associated with histone H3K4me3 alterations at the promoters of the Hoxa and Hoxb13 genes. We determined that regions of Hox genes that play important roles in prostate development had altered DNA methylation in the sperm of F1 and F3. These alterations in DNA methylation were negatively related to gene expression. This is an observational study, as it was part of our previous research on the effects of thiacloprid on the testis and thyroid. Our analysis revealed that gestational exposure to thiacloprid induced an increase in cell proliferation in the prostates of directly exposed F1. Some persistent epigenetic alterations in the prostate of F3 males were not associated with phenotypic changes. Full article

Transdifferentiation of one cell type into another occurs under normal physiological conditions. Adipose tissue is an important metabolic and endocrine organ involved in the onset and progression of various diseases. Previous studies have shown that fibroblasts can transdifferentiate into adipocytes. Here, we demonstrate that CX3CR1-derived cells can also transdifferentiate into adipocytes. Additionally, RFP⁺ SVF cells and mature adipocytes were identified in different adipose tissues of Cx3cr1^cre: Rosa26^Td mice. Cold exposure enhances the adipogenic transdifferentiation of RFP⁺ cells, whereas a high-fat diet (HFD) inhibits this process. Mechanistically, we found that PPARγ regulates transdifferentiation, suggesting its role in the differentiation of CX3CR1-derived cells into adipocytes, thus offering new insights into the origin of adipocytes in the body. Full article

Background/Objectives: Primary dysmenorrhea is a common gynecological disorder characterized by painful uterine contractions. Danggui Buxue Decoction (DBD) is used to treat menstrual irregularities, but its mechanism in primary dysmenorrhea remains unclear. This study investigated the efficacy of DBD against dysmenorrhea and its calcium signaling-related mechanism. Methods: DBD components were analyzed by UPLC–Orbitrap MS. Isolated uterine muscle strips precontracted with oxytocin (OT, 50 ng/mL) or KCl (60 mM) were used to assess the effects of DBD and its active compounds (Quercetin, Formononetin, Ononin, Ferulic acid, Senkyunolide I, Calycosin, Ligustilide, Calycosin-7-O-β-D-glucoside). Ca²⁺-dependent experiments, intracellular calcium release assays, and inhibitor treatments (Nifedipine, 2-APB) were performed to evaluate the involvement of L-type calcium channels and the IP₃R pathway. A primary dysmenorrhea model induced by estradiol benzoate and oxytocin was used to assess the analgesic effects, histopathology, inflammatory factors, and IP₃/Ca²⁺-related proteins and genes following DBD and Quercetin treatment. Results: A total of 161 compounds were identified in DBD. DBD and its eight active constituents relaxed OT (50 ng/mL) or KCl (60 mM)-induced uterine contractions, with Quercetin, Calycosin, and Ligustilide showing particularly prominent relaxant activity. These three compounds suppressed extracellular calcium influx and intracellular calcium release through the blockade of L-type calcium channels and IP₃R. In vivo, DBD and Quercetin alleviated pain, reduced inflammation, and decreased uterine Ca²⁺ and IP₃ levels in dysmenorrhea mice. Conclusions: DBD and its active component Quercetin promote uterine relaxation by lowering Ca²⁺ levels, which is achieved through suppression of L-type calcium channels and the IP₃/Ca²⁺ pathway. This contributes to their therapeutic action against primary dysmenorrhea. Full article

Studies have shown that IL-10 has therapeutic potential for inflammatory diseases. However, it is challenging to use IL-10 as a therapeutic drug because it also possesses pro-inflammatory functions. To reduce these pro-inflammatory effects of IL-10, we have designed three IL-10 mutants using structure-based computational design technology. We demonstrated that these mutants exhibited significantly lower activity in IL-10-responsive cell lines than wild-type IL-10. Using recombinant adeno-associated virus (rAAV8) vectors expressing wild-type or mutant IL-10 molecules, we performed gene therapy experiments in IL-10 KO mice. The results showed that our vectors mediated high levels of transgene expression. Importantly, IL-10 gene therapy increased body weight gain, reduced colon injury, and prevented the development of inflammatory bowel disease (IBD). Moreover, IL-10 mutant gene therapy elicited significantly lower stimulation of CD8 T and NK cells compared with the wild-type IL-10 group. In summary, our IL-10 mutants provide a protective effect comparable to wild-type IL-10 in the IL-10 KO mouse model, suggesting that they may potentially have reduced pro-inflammatory function. While rigorous investigations of safety and efficacy in different disease models will be required, these results indicate the therapeutic potential of IL-10 mutant gene therapy for inflammatory diseases such as IBD. Full article