Search Results (4,020)

Heat stress (HS) is a major issue affecting productivity and physiological responses in dairy cattle. Advances in gene function research have made it possible to identify favorable genotypes for HS tolerance. This study evaluates the combined effects of temperature–humidity index (THI) and genomic load of favorable SNPs in the genes GRM8, SMAD3, and TLR4 on daily milk yield (DMY), rectal temperature (RT), and gene expression in Holstein cows (n = 160). Environmental conditions ranged from thermoneutral to severe HS, allowing the assessment of genotype by environment interactions. A subset of cows (n = 40) was selected based on genomic load to evaluate gene expression under opposite thermal conditions. Results showed that increasing THI was associated with reduced DMY and increased RT, with more pronounced effects in cows carrying fewer favorable genotypes. Slope analyses revealed that cows with higher genomic load exhibited a moderate decline in DMY and lower increase in RT, indicating enhanced resilience to HS. Significant THI × genomic load interactions were detected above a threshold of 79 units (p < 0.05). Gene expression analyses supported these findings, showing differential expressions of GRM8, SMAD3, and TLR4 under HS conditions. The functional and predictive value of these genes as markers of thermotolerance could help producers by supporting their application in genetic selection programs, thus providing another tool to combat HS and improve resilience and productivity in dairy systems. Full article

Metabolic dysfunction-associated steatohepatitis (MASH; formerly non-alcoholic steatohepatitis, NASH) is characterized by oxidative stress, inflammatory activation, hepatocellular injury, and progressive liver dysfunction. However, the global transcriptomic landscape underlying stress-induced hepatic injury remains incompletely understood. In this study, we employed a methionine–choline-deficient (MCD) diet-induced murine model to characterize the phenotypic and transcriptomic alterations associated with liver injury. Male C57BL/6J mice were fed either a control or MCD diet, and hepatotoxicity was assessed by survival analysis, body and liver weight measurements, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, histopathological examination, RNA sequencing, quantitative real-time PCR (qRT-PCR), and tumor necrosis factor-alpha (TNF-α) enzyme-linked immunosorbent assay (ELISA). MCD feeding markedly reduced survival and body weight while inducing hepatomegaly and significant elevations in serum ALT and AST, indicating severe hepatocellular injury. Histopathological analysis demonstrated hepatic steatosis, hepatocellular ballooning, and lobular inflammation without histological evidence of fibrosis. Transcriptomic profiling revealed extensive gene expression remodeling, characterized by activation of inflammatory pathways, enrichment of MAPK-related signaling, dysregulation of lipid metabolism, suppression of antioxidant defense systems, impairment of cytochrome P450-mediated detoxification, and upregulation of apoptosis-associated genes. qRT-PCR further validated the differential expression of representative genes involved in inflammatory signaling (Tlr4, Nfkb1, Nlrp3, and Casp1), MAPK signaling (Fos), xenobiotic metabolism (Cyp4f18), lipid metabolism (Apoa4 and Lpl), extracellular matrix remodeling (Mmp12), and oxidative stress responses (Sod1 and Gstp1). In addition, elevated serum TNF-α levels provided protein-level evidence supporting activation of the TLR4/NF-κB/TNF-α/NLRP3 inflammatory axis. Although fibrosis-associated transcriptional responses were detected, the absence of histological fibrosis suggests transcriptional priming of fibrogenic pathways rather than established fibrogenesis. Collectively, these findings provide a transcriptomic framework linking oxidative stress, impaired detoxification, inflammatory activation, and stress-responsive signaling to MCD-induced hepatic injury. The MCD model provides a valuable experimental platform for characterizing hepatic stress-response transcriptomes and for generating hypotheses that can subsequently be evaluated in environmentally relevant toxicological models. Nevertheless, caution should be exercised when extrapolating these findings to obesity-associated human MASLD, as the MCD model lacks key metabolic features of the human disease, including obesity and insulin resistance. Therefore, the present findings should be interpreted primarily as transcriptomic signatures of stress-induced hepatic injury rather than as a direct representation of the pathophysiological processes underlying human obesity-associated MASLD. Full article

Ulomoides dermestoides (Yangchong) is a tenebrionid beetle used in traditional medicine across Asia and Latin America. While crude extracts show effects on inflammation, oxidative stress, and other conditions, systematic integration of its bioactive substances, mechanisms, and translational potential is lacking. This review consolidates its chemical basis, comprising volatile benzoquinones, terpenes, and alkenes, alongside non-volatile fatty acids, proteins (antioxidant enzymes, glycoproteins), and phenolics. Pharmacological evidence indicates multi-target modulation of reactive oxygen species (ROS), cytokines, leukocyte recruitment, endothelial activation, and thromboinflammation. Recent advances include proteomic identification of antioxidant protein complexes, neuroprotection in a Parkinson’s disease model, chromosome-level genome assembly, and isolation of the UDP-glucose pyrophosphorylase 2a (UGP2A) glycoprotein, which alleviates thrombosis partly via toll-like receptor 4/myeloid differentiation primary response 88 (TLR4/MyD88)-mediated endothelial anti-inflammatory effects. However, most evidence remains preclinical, relying on non-standardized crude extracts, and benzoquinone-containing fractions display potential cytotoxicity and genotoxicity. Future research should integrate bioassay-guided isolation, structural characterization, multi-omics, pharmacokinetic/pharmacodynamic (PK/PD) analysis, standardized quality markers, and rigorous safety evaluation to transform U. dermestoides from an empirical insect-derived medicinal resource into a scientifically validated source of preclinical antioxidant and anti-inflammatory candidate substances. Full article

The concurrent circulation of influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has unveiled complex host–pathogen interactions governed by temporal dynamics of innate immune activation. This narrative review synthesizes evidence from human air–liquid interface (ALI) epithelial models, animal studies (hamster, ferret), clinical cohorts, and randomized controlled trials (2015–2026) to delineate the molecular mechanisms underlying viral interference between these two major respiratory pathogens. Prior IAV infection induces a robust type I/III interferon (IFN) response and broad interferon-stimulated gene (ISG) upregulation that restricts subsequent SARS-CoV-2 replication within a critical 24–72 h temporal window. Conversely, SARS-CoV-2 employs a multi-layered immune evasion strategy that blunts IFN induction, providing minimal heterologous protection. Simultaneous co-infection tends to exacerbate disease severity. Host genetic determinants, including OAS1 and TLR7 variants, modulate interference capacity. Therapeutically, early pegylated IFN-λ shows clinical benefit, while experimental evidence from in vitro and animal models suggests oseltamivir may paradoxically reduce IAV-induced interference. These findings underscore the need for multi-pathogen diagnostics, temporally informed clinical decision-making, and IFN-based therapeutic strategies during co-circulation periods. Full article

Background/Objective: An obesogenic diet triggers intestinal inflammation and oxidative stress, leading to epithelial barrier dysfunction and increased risk of metabolic disorders. This study investigated the mechanisms by which quercetin protects intestinal integrity in high-fat diet (HFD)–fed mice. Methods: Mice were fed an HFD or a low-fat diet (LFD) with or without 1% quercetin, intestinal gene and protein expression, microRNA levels, permeability, and circulating intestinal biomarkers were assessed. Results: Mice fed an HFD with quercetin (HFDQ) showed a 17% improvement in intestinal barrier integrity with increased expression of tight junction and mucin genes and proteins. The nuclear translocation of the nuclear factor-κB (NF-κB) p65 subunit in the ileum decreased by 34%, whereas its acetylation was reduced by 50–57% throughout the intestine, with downregulation of NF-κB-regulated pro-inflammatory genes and proteins. Quercetin increased the nuclear factor erythroid 2-related factor 2 (NRF2) by ~ 25% across intestinal segments and upregulated antioxidant enzyme genes. It suppressed toll-like receptor 4 (TLR4) by 50% and restored AMP-activated protein kinase (AMPK) and sirtuin 1 to levels comparable to those in LFD mice. Altered microRNAs (miRNA-16, 200b, 122, 34a, and 21) supported these molecular changes. Quercetin also restored short-chain fatty acid receptors and serotonin transporters that were affected by HFD. Plasma lipopolysaccharide (LPS), cluster of differentiation 14, LPS-binding protein, and myeloperoxidase activity decreased by 36, 31, 42, and 37%, while glucagon-like peptide-1 increased by 23%. Conclusions: Quercetin protects epithelial barrier integrity against HFD-induced intestinal inflammation and oxidative stress via the AMPK-mediated NF-κB and NRF2 signaling pathways. Full article

The bacterial and toxin methods of cancer treatment date back 130 years. This paradigm rests on nonspecific bacterial-toxin-generated immunotherapy. This high-risk oncology research is experiencing a renaissance of methods that are among the most effective yet. Glioblastomas and other resistant cancers are the modern touchpoint, because of remission history following sepsis. Spurred by recent research deaths, we discuss protocols IRBs should consider in live bacterial or synthetic immuno-stimulatory trials. Human systemic inflammatory response syndrome immunology is unique due to non-functioning SIGLEC-13 and 17, which control excessive Toll-like receptor 4 (TLR-4) signaling. This is not a technicality like human CD8+/CD4+ T cells. SIGLEC-13&17 consequences are profound; humans are ≈330–200,000 times more sensitive to LPS/endotoxin than mice and rats. This human TLR-4 difference also applies to gene therapy and should inform the results from any animal model, including non-human primates. Clinical TLR-4 stimulation takes two forms: bacterial infection and sterile TLR-4 stimulators, and treatments differ. The stereotactic injection of calculated amounts of adjuvants like endotoxin, venoms/components, or synthetic alternatives may be safer than live bacteria. Inadequate planning for risk elements, basic predictive models, and treatments will likely cause death. Full article

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