Search Results (4,014)

It is unknown whether the glucagon-like peptide-1 (GLP-1) receptor agonists have a significant protective effect against acute islet injury. High mobility group box 1 (HMGB1) is a damage-associated molecular pattern (DAMP) molecule released from stressed or injured pancreatic β-cells, which triggers inflammatory responses through toll-like receptor 4 (TLR4) signaling. This study investigated the protective effect and mechanism of liraglutide on acute islet injury induced by low doses of streptozotocin (STZ). The results showed that liraglutide pretreatment preserved the structural integrity of pancreatic islets, improved insulin levels and glucose tolerance, and significantly reduced the incidence of diabetes in STZ-treated mice. Liraglutide was also found to inhibit STZ-induced release of HMGB1 and reduce the expression of TLR4 and inflammatory factors IFN-γ, IL-1β, and CXCL10. Moreover, administration of exogenous HMGB1 or antagonism of the GLP-1 receptor diminished liraglutide’s protective effects. These findings suggest that liraglutide has a strong protective effect on STZ-induced acute islet injury, most likely through the inhibition of HMGB1 release, which provides an experimental basis for the application of liraglutide as a protective agent for acute islet injury. Full article

Background/Objectives: Drug-coated balloons (DCBs) deliver paclitaxel to the vessel wall and leave nothing behind, which makes them mechanistically appealing here, yet head-to-head data confined to the isolated popliteal/SFA segment are still scarce. We directly compared 12-month hemodynamic, symptomatic, and patency loss outcomes between DCB and plain old balloon angioplasty (POBA) in this anatomical setting. Methods: We retrospectively reviewed 401 consecutive endovascular procedures performed at a single center between January 2021 and December 2024 for isolated popliteal and/or SFA disease, comprising 179 DCB and 222 POBA cases. 12-month endpoints of composite clinical success, asymptomatic recovery, and composite patency loss were analyzed. The composite patency loss endpoint was further fitted to a multivariable logistic regression with baseline ABI, baseline Rutherford category, lesion length, and total occlusion as covariates. The composite patency loss endpoint was further fitted to a multivariable logistic regression with baseline ABI, baseline Rutherford category, lesion length, and total occlusion as covariates, designated as the principal effect estimate. Kaplan–Meier cumulative incidence plots are presented descriptively only. Results: The study population comprised 401 patients (mean age 68.4 ± 10.6 years; 316 male [78.8%]), with 179 in the DCB arm (mean age 65.3 ± 10.5 years; 80.4% male) and 222 in the POBA arm (mean age 71.0 ± 9.8 years; 77.4% male). DCB-treated lesions started out more advanced: longer (94.5 ± 48.2 vs. 82.7 ± 43.3 mm; p = 0.010), more often totally occluded (39.7% vs. 19.4%; p < 0.001), and weighted toward TASC II C/D (p < 0.001). Mean ABI improved by +0.27 in both arms, with no detectable between-arm difference (p = 0.860; within-arm p < 0.001 in each). Asymptomatic recovery at 12 months was more common after DCB (62.0% vs. 51.4%; p = 0.033; OR 1.55, 95% CI 1.04–2.31), and composite patency loss was roughly halved (6.7% vs. 12.6%; p = 0.050; OR 0.50, 95% CI 0.25–1.01). Documented TLR (4.5% vs. 7.2%; p = 0.251) and composite clinical success (86.6% vs. 82.4%; p = 0.255) did not reach significance. Conclusions: Across 401 real-world procedures in isolated popliteal and/or SFA disease, mean ABI gain was identical between arms, yet DCB delivered measurably more complete symptomatic recovery and a near-significant halving of composite patency loss at 12 months, with both signals robust to multivariable adjustment. In this real-world setting, DCB was associated with more complete symptomatic recovery and a numerically lower composite patency loss rate; these findings are hypothesis-generating and require confirmation in adequately powered randomized trials. Full article

Background: Cisplatin-induced cardiotoxicity is associated with oxidative stress, inflammation, and apoptosis; however, the role of CD38-Sirt3 signaling remains unclear. This study investigated whether apigenin protects against cisplatin-induced cardiac injury via modulation of CD38-Sirt3 signaling. Methods: Male Sprague Dawley rats were assigned to three groups, (1) Control, (2) Cisplatin (5 mg/kg), and (3) Pretreatment with apigenin (50 mg/kg/day) plus cisplatin groups. Then, left ventricular (LV) function, cardiac injury, oxidative stress, inflammation, apoptosis, and CD38-Sirt3 signaling-related proteins were assessed. Results: Cisplatin impaired LV function and induced cardiac injury, oxidative stress, inflammation, and apoptosis in rats. These changes were accompanied by increased cardiac CD38 and decreased cardiac Sirt3 and SOD2 expression. Apigenin significantly improved LV function (%LVEF and %LVFS), reduced cardiac injury (LDH, CK-MB), attenuated oxidative stress, suppressed inflammatory responses (TNF-α, IL-1β, p-NF-κB, TLR-4), and inhibited apoptosis (Bax/Bcl-2, cleaved caspase-3). Notably, apigenin improved cardiac SOD2 expression and reversed the alteration of CD38-Sirt3 signaling in cisplatin-treated rats. Conclusions: This study provides evidence that cisplatin-induced cardiotoxicity is associated with alterations in CD38-Sirt3 signaling. Apigenin attenuated LV dysfunction and cardiac injury, reduced oxidative stress, inflammation, and apoptosis, potentially through CD38-Sirt3 signaling. These findings highlight the cardioprotective potential of apigenin against cisplatin-induced cardiotoxicity. Full article

Sepsis is a life-threatening syndrome characterized by a dysregulated host response to infection and progressive organ dysfunction. Although early antimicrobial therapy, source control, hemodynamic resuscitation, and organ support remain the foundations of care, these approaches do not directly reverse the cellular mechanisms that connect systemic inflammation to multi-organ failure. Mitochondrial dysfunction has emerged as a central mechanism linking impaired oxygen utilization, oxidative and nitrosative stress, immune-cell metabolic reprogramming, inflammatory amplification, and organ injury. During sepsis, inflammatory mediators, nitric oxide, microcirculatory abnormalities, calcium dysregulation, and metabolic stress converge on mitochondria, impairing oxidative phosphorylation and promoting mitochondrial reactive oxygen species/reactive nitrogen species (ROS/RNS) generation. When mitochondrial quality-control programs, including fission, fusion, mitophagy, and mitochondrial biogenesis, fail to restore network integrity, damaged mitochondria accumulate and become persistent sources of oxidative stress and danger signals. Mitochondrial damage-associated molecular patterns, particularly mitochondrial DNA, oxidized mitochondrial DNA, cardiolipin, ATP, and N-formyl peptides, activate innate immune pathways such as TLR9-MyD88-NF-kappaB, the NLRP3 inflammasome, and cGAS-STING signaling. In parallel, mitochondrial metabolism shapes macrophage activation, neutrophil function, T-cell competence, pyruvate-lactate handling through the pyruvate dehydrogenase complex, and the transition between hyperinflammation and immunosuppression. Clinical translation remains challenging because sepsis is biologically heterogeneous and mitochondrial dysfunction is dynamic, tissue-specific, and influenced by disease stage. This review synthesizes current knowledge on mitochondrial dysfunction in sepsis, emphasizing oxidative and nitrosative stress, mitochondrial quality control, mitochondrial damage-associated molecular pattern (DAMP) signaling, immunometabolism, organ-specific injury, candidate biomarkers, clinical translational strategies for mitochondria-targeted therapy, and future approaches based on multi-omics and artificial intelligence-assisted patient stratification. We argue that future therapeutic development should move beyond nonspecific antioxidant supplementation toward time-sensitive, phenotype-informed, and biomarker-guided mitochondrial medicine. Full article

Endometritis—inflammation of the endometrial lining—imposes a substantial reproductive and economic burden in both human gynecology and livestock production, where it is a leading cause of recurrent implantation failure in humans and the costliest reproductive disorder in cattle. Conventional management is overwhelmingly antibiotic-based, yet escalating antimicrobial resistance, tissue and milk residues, microbiota disruption and high relapse rates have eroded its efficacy and acceptability, creating an urgent need for mechanism-based, host-directed alternatives. Here we synthesize the expanding evidence positioning dietary flavonoids and traditional Chinese medicine (TCM) formulations as such interventions. Across diverse compounds and preparations, anti-endometriotic activity converges on a tractable set of molecular nodes: TLR4/NF-κB signaling, the NLRP3 inflammasome–pyroptosis axis, the Keap1/Nrf2/HO-1 antioxidant program, PI3K/AKT and PPAR-γ signaling, ferroptosis, and the gut–uterus microbial–metabolite axis. Veterinary field studies report cure rates and fertility outcomes rivaling first-line antibiotics, while integrative case reports show benefit in antibiotic-refractory human chronic endometritis. Translation remains constrained by poor bioavailability, formulation heterogeneity, over-reliance on lipopolysaccharide-only models and a scarcity of randomized trials—barriers now addressable through nanocarrier delivery, network-pharmacology-guided standardization and biomarker-stratified designs. Flavonoids and TCM are best viewed not as substitutes for antibiotics but as a mechanistically rational, multi-target strategy aligned with One Health antimicrobial stewardship. Full article

The present study aimed to evaluate the role of ascorbic acid in alleviating ammonia-induced muscle quality deterioration and to clarify its regulatory effects on apoptosis, texture, and flavor-related metabolites in rainbow trout (Oncorhynchus mykiss). The results demonstrated that ascorbic acid alleviated ammonia stress-induced inflammatory and apoptotic damage by regulating toll like receptor 5 (TLR5), myeloid differentiation primary response 88 (MyD88), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression, thereby contributing to the restoration of myofibrillar integrity, reduced extracellular gaps, and increased shear force from 14.18 N to 18.26 N (p < 0.05). Ascorbic acid modulated ammonia handling and ion-exchange responses by upregulating glutamine synthetase (GS) expression from approximately 2.3-fold to 6.7-fold and increasing ornithine and citrulline accumulation. Alterations in tricarboxylic acid cycle-related metabolites further suggested that energy metabolism may be involved in the physiological adaptation to ammonia stress. Meanwhile, the ascorbic acid reduced the accumulation of key off-flavor compounds (1-octene-3-alcohol and (E)-2-nonenal), attenuating the earthy–moldy and fishy flavor. This research proposes a potential strategy to improve muscle quality in live transportation. Full article

Epilepsy is a chronic neurological disorder prevalent worldwide, characterized by recurrent episodes of epileptic seizures. The primary current treatment approach is pharmacological, aimed at reducing the intensity and frequency of seizures, though it does not provide a cure. Neuroinflammation plays a central role in epilepsy by activating glial cells and stimulating the release of inflammatory mediators, further disrupting the balance between excitation and inhibition, thereby promoting the onset and recurrence of seizures. Furthermore, persistent inflammatory processes induce synaptic remodeling and the formation of dysfunctional neural circuits, establishing a pathological cycle in which inflammation and epileptic activity feed into each other. In this regard, natural products represent an important avenue for the discovery of new treatments. Thus, this review aimed to relate the role of the main inflammatory targets (Inflammasome/NLRP3, NF-κB, MAPK, mTOR, COX-2/PGE2, and TLR4/HMGB1) to epilepsy and to investigate in the literature natural products acting through these pathways in the treatment of epileptic seizures. Consequently, inflammatory pathways have emerged as critical targets in epilepsy, highlighting the importance of strategies capable of modulating neuroinflammatory processes. In this context, natural products stand out as promising therapeutic alternatives, given their multitarget mechanisms of action, potential to attenuate neuroinflammation and neuronal hyperexcitability. Full article

Irritable bowel syndrome (IBS) and metabolic dysfunction-associated steatotic liver disease (MASLD) are two of the most common gastroenterological conditions worldwide. Traditionally viewed as unrelated, with one serving a canonical functional role and the other a purely metabolic function, these two processes have recently been linked by compelling evidence, challenging their traditional segregation and pointing to a significant, biologically relevant association. This review aims to evaluate the current evidence for a potential causal contribution of IBS to hepatic steatosis, critically examining the proposed pathophysiological mechanisms via the gut–liver axis while acknowledging that the available data are primarily observational. Notably, epidemiological studies demonstrate a 1.4–2.0-fold increased association between IBS and MASLD, independent of obesity and metabolic syndrome, though causality remains to be established. The primary mechanism is increased intestinal permeability (“leaky gut”) leading to endotoxemia, activation of hepatic toll-like receptor 4 (TLR4) receptors, and subsequent de novo lipogenesis. The relationship is bidirectional, with steatosis also worsening gut barrier function. Therefore, we highlight emerging evidence suggesting that irritable bowel syndrome, particularly the diarrhea-predominant subtype (IBS-D), may contribute to hepatic steatosis through plausible biological mechanisms, though direct causal evidence in humans remains limited. Accordingly, routine screening for metabolic dysfunction-associated steatotic liver disease (MASLD) may be warranted in patients with long-standing IBS-D. Full article

Sepsis is a life-threatening condition characterized by a dysregulated host response to infection, leading to multi-organ dysfunction. Toll-like receptor signaling via MYD88- and TRIF-dependent pathways plays a central role in this process; however, its temporal and tissue-specific dynamics remain incompletely understood. The aim of this study was to investigate time-dependent transcriptional changes in MYD88- and TRIF-dependent signaling pathways across multiple organs in a murine model of sepsis. mRNA expression of MYD88, IRAK1, IRAK4, NF-kB, CCL4, CCL20, CCR2, IFN-β, IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-8, IL-10, IL-18, Klotho, KLF4, HOXA5, NANOG and HIF1α was quantified using qRT-PCR in intestinal, kidney, liver and lung tissues at 24, 48, and 72 h following cecal ligation and puncture-induced sepsis in male C57BL/6J mice. Significant upregulation of innate immune signaling molecules, cytokines, chemokines, and interferon-related genes was observed in all tissues compared with controls. Genes associated with hypoxia and cellular regulation were also increased. These responses were tissue-specific and progressively intensified over time. Sepsis represents a dynamic, time-dependent, and tissue-specific process characterized by sustained activation of immune and hypoxic pathways, providing potential targets for time-stratified therapeutic strategies. Full article

The continuous evolution of the SARS-CoV-2 virus, marked by the emergence of new variants, poses a significant threat to the efficacy of existing vaccines. However, a promising approach to addressing vaccine failure caused by viral mutations (particularly in the spike protein) is the development of a variant-proof (conserved), non-spike, multiepitope universal nanostructure vaccine with multifunctionality, biocompatibility, self-adjuvanticity, and structural similarity to pathogens in terms of size and shape. This study aimed to design a self-assembled nanostructure vaccine (SANV) featuring pentameric and trimeric coiled-coil peptide motifs, as well as other functional motifs, including epitopes, TAT, PADRE, and adjuvant. The cytotoxic T lymphocyte (CTL), helper T lymphocyte (HTL), and B lymphocyte (BL) epitopes of SANV were screened from the IEDB with more than 50% individual predicted population coverage (PPC) and fused using linkers to enable self-assembly. The multimerization of the 24 SANV monomers was modeled using the GalaxyHomomer and AlphaFold web servers. Subsequently, the leading SANV constructs with (SANVa9) and without (SANVb6) adjuvant were analyzed for their physicochemical profiles and assessed for antigenicity, allergenicity, solubility, and antioxidant potential. Furthermore, the molecular interactions, specificity, and stability of SANVa9 and SANVb6 with the broadly neutralizing sarbecovirus antibody 5817 and toll-like receptors (TLR2, TLR3, and TLR7) were analyzed using molecular docking and simulation over a 100-nanosecond time scale. Finally, the comparative immune simulation profiles of SANVa9 and SANVb6 with controls indicated stronger, broad-spectrum immune responses that could be translated into in vitro and in vivo studies and warrant further evaluation before clinical use. Full article

Background: Lipopolysaccharide (LPS) functions as a Toll-like receptor 4 (TLR4) agonist that triggers innate immunity; however, structural variations between pathogenic and commensal bacteria distinctly influence its immunostimulatory profile. This study evaluated the immunostimulatory activity of LPS derived from the commensal bacterium Hafnia alvei and explored its potential as an exploratory vaccine adjuvant. Methods: Cytokine induction was evaluated in immune cells across diverse host species, and receptor activation was assessed via reporter assays. To investigate in vivo immunogenicity and preliminary tolerability, H. alvei LPS was formulated into a prototype oil-in-water (O/W) emulsion utilizing ovalbumin (OVA) as a model antigen. Results: LPS from H. alvei strain BA2000346 exhibited immunostimulatory activity comparable to that of Escherichia coli, while inducing greater TNF-α expression than pathogenic Salmonella and Pseudomonas strains. Distinct from E. coli LPS, it demonstrated the capacity to activate both TLR4 and the mannose-recognizing Dectin-2 receptor in reporter systems. This cytokine induction was consistent across various strains and host species. Furthermore, the prototype O/W emulsion formulation enhanced antigen-specific humoral and cellular immune responses while demonstrating preliminary tolerability based on body-weight monitoring and visual clinical observation. Conclusions: H. alvei-derived LPS exhibits TLR4 and Dectin-2 agonist activity in vitro. When synergized with an O/W emulsion delivery system, it provides a preliminary indication of cross-species stimulatory potential and supports further investigation as a hypothesis-generating platform for future vaccine adjuvant development. Full article

Acute liver failure (ALF) is characterized by a rapid decline in liver function, leading to metabolic and organ failure. This study employed liver metabolomics, Nuclear Factor kappa-B (NF-κB) signaling pathway analysis, and inflammatory factor profiling to investigate the therapeutic mechanisms of xanthoxylin in ALF. Xanthoxylin administration led to increased antioxidant levels and reduced markers of inflammation and tissue damage. Xanthoxylin downregulated the messenger RNA (mRNA) expression of Nitric Oxide Synthase (NOS), Interleukin-1β (IL-1β), Interleukin-6 (IL-6), Tumor Necrosis Factor-α (TNF-α), NF-κB, Inhibitor of NF-κB α (IκBα), and Toll-like receptor 4 (TLR4), and inhibited the protein expression of p-p38 and p-p65 while upregulating B-cell CLL/Lymphoma 2 (Bcl-2) and B-cell Lymphoma-x (Bcl-xl). Metabolomic analysis identified 41 differentially expressed metabolites, 20 of which showed strong correlations with pharmacodynamic parameters. These 20 candidate metabolite signatures are involved in amino acid and carboxylic acid metabolic pathways, with potential links to glycolysis and the tricarboxylic acid (TCA) cycle. Together, these findings suggest that xanthoxylin exerts therapeutic effects against ALF by modulating the IκBα/NF-κB signaling pathway and related metabolic pathways, providing a scientific basis for understanding its multi-target mechanism. Full article

Objectives: Neuroinflammation is recognized as a significant characteristic of Alzheimer’s disease (AD). Currently, there is a notable absence of effective pharmacological agents to prevent or treat neuroinflammatory processes associated with AD. Heat shock protein 70 (HSP70) is pivotal in the progression of neuroinflammation. In this study, we explored the potential of maltol, a Maillard reaction product derived from red ginseng, as a therapeutic agent for neuroinflammation. Methods: In vitro, HMC3 microglial cell models were developed to examine the regulatory effects of gradient concentrations of maltol (12.5, 25, 50 μM) on the TLR4/MyD88/NF-κB p65 signaling pathway, neuroinflammation, and pyroptosis. Analyses of the GEO database and Gene Set Enrichment Analysis (GSEA) were performed to identify the core targets of maltol, followed by HSP70 gene silencing experiments to validate the targeted regulatory mechanism. Results: Maltol significantly mitigated LPS-induced neuronal damage and cognitive deficits in mice. It effectively suppressed microglia-mediated neuroinflammation and pyroptosis, reversed oxidative stress-induced neuronal ferroptosis, and inhibited neuronal apoptosis. In vitro experiments demonstrated that maltol obstructed TLR4/MyD88 binding, thereby inhibiting NF-κB p65-mediated neuroinflammation and pyroptosis, while also alleviating excessive ROS accumulation to enhance oxidative stress and ferroptosis. Bioinformatics analysis identified HSP70 as a crucial target for the anti-inflammatory and antioxidant effects of maltol. Subsequent gene silencing experiments confirmed that maltol exerted its inhibitory effects on LPS-induced neuroinflammation and pyroptosis in an HSP70-dependent manner. Conclusions: Maltol exhibits significant protective effects against Alzheimer’s disease-related neuroinflammation, oxidative stress, pyroptosis, and ferroptosis through the targeting of HSP70. This study elucidates the molecular mechanisms by which maltol improves neuroinflammatory injury and provides a novel theoretical foundation and therapeutic strategy for the intervention of Alzheimer’s disease neuroinflammation using traditional Chinese medicine. Full article

This study focuses on the synthesis of glucovanillin mediated by UGT109A1 and its mechanism against Type 2 Diabetes Mellitus (T2DM). Recombinant UGT109A1 successfully synthesized glucovanillin from vanillin using UDP-Glc as the sugar donor. Through network pharmacology, 140 potential targets were identified. Seven key targets were further screened using LASSO and SVM-RFE algorithms. Among these, SLC5A1 and ADK showed strong diagnostic potential, with AUC values ranging from 0.85 to 0.89. Immune infiltration analysis linked these core targets to M2 macrophages. Single-cell transcriptomics revealed that ADK is widely expressed but enriched in B cells, while TLR9 is confined to plasmacytoid dendritic cells (pDCs). Cell-to-cell communication analysis identified a pDC-to-B cell signaling axis. In vitro assays demonstrated that glucovanillin exhibits concentration-dependent inhibitory activity against α-glucosidase with moderate potency, with an IC₅₀ of 413.84 ± 12.80 μM. Molecular docking, 200 ns molecular dynamics simulations (MD), and MM/PBSA calculations showed that glucovanillin binds more strongly to α-glucosidase (−7.4 kcal/mol) than vanillin (−5.4 kcal/mol). Therefore, the glycosylation mediated by UGT109A1 enhanced the bioactivity and targeting specificity of vanillin. In summary, glucovanillin exerts anti-T2DM effects through a dual mechanism involving α-glucosidase inhibition and regulation of key targets, making it a promising lead compound for T2DM treatment. Full article

Background/Objectives: Acute lung injury (ALI) currently lacks safe and effective therapeutic strategies with low toxicity. Lonicerae japonicae flos, a traditional herb and functional food, contains polyphenols as its principal active components. This study investigated whether Lonicerae japonicae flos polyphenols (LJP) could exert protective effects against lipopolysaccharide (LPS)-induced ALI in mice. Methods: Eighty-four male C57BL/6J mice were randomly divided into seven groups and treated daily for 7 days with LJP (200, 100, or 50 mg/kg), liproxstatin-1 (10 mg/kg), dexamethasone (5 mg/kg), or saline (control and model groups). Subsequently, another thirty-six mice were used for the fecal microbiota transplantation (FMT) experiment. All groups except the control group received intratracheal instillation of LPS (5 mg/kg) to induce ALI. Results: LJP treatment significantly ameliorated lung histopathological damage and gut microbiota dysbiosis. Lung proteomics analysis revealed the enrichment of the NF-κB and ferroptosis pathways. Mechanistically, LJP downregulated pro-inflammatory factors (IL-6, TNF-α, and IL-1β) by suppressing activation of the TLR4/MyD88/NF-κB pathway. Meanwhile, LJP upregulated SOD and GSH levels, thereby suppressing the accumulation of ROS, GSSG, Fe²⁺, and MDA, which were closely related to the activation of the Nrf2/HO-1 and Sirt3/Nrf2/GPX4 pathways. Furthermore, LJP modulated the gut microbiota and promoted short-chain fatty acid (SCFA) production by elevating the relative abundance of Akkermansia muciniphila and Faecalibaculum. Intriguingly, FMT results confirmed that the LJP-derived gut microbiota markedly alleviated lung tissue injury and intestinal barrier damage in ALI mice. Conclusions: This study demonstrated that LJP could reshape the gut microbiota to enhance the production of SCFAs and inhibit inflammation-related ferroptosis in ALI mice. Full article