Search Results (2,459)

Background/Objective: Sepsis-associated acute kidney injury (SA-AKI) is a substantial contributor to mortality in critically ill patients. This study aimed to investigate the impact of gum acacia (GA) and dexamethasone (DEX) combination on lipopolysaccharide (LPS)-induced SA-AKI in rats. Methods: Thirty-six male Sprague Dawley rats were separated into six groups, including the control, GA group, LPS-induced AKI group, DEX + LPS group, GA + LPS group, and GA + DEX + LPS group. AKI was induced in rats using LPS (10 mg/kg, i.p.). GA was administered orally (7.5 g/kg) for 14 days before LPS injection, and DEX was injected (1 mg/kg, i.p.) 2 h after LPS injection. Results: LPS injection significantly (p < 0.05, vs. control group) impaired renal function, as evidenced through increased levels of kidney function biomarkers, decreased creatinine clearance, and histopathological alterations in the kidneys. LPS also significantly (p < 0.05, vs. control group) elevated levels of oxidative stress markers, while it reduced levels of antioxidant enzymes. Furthermore, LPS triggered an inflammatory response, manifested by significant (p < 0.05, vs. control group) upregulation of Toll-like receptor 4, myeloid differentiation primary response 88, interleukin-1β, tumor necrosis factor-α, and nuclear factor-κB, along with increased expression of high-mobility group box 1. Administration of GA significantly ameliorated LPS-induced renal impairment by enhancing antioxidant defenses and suppressing inflammatory pathways (p < 0.05, vs. LPS group). Furthermore, GA-DEX-treated rats showed improved kidney function, reduced oxidative stress, and attenuated inflammatory markers (p < 0.05, vs. LPS group). Conclusions: The GA-DEX combination exhibited potent renoprotective effects against LPS-induced SA-AKI, possibly due to their antioxidant and anti-inflammatory properties. These results suggest that the GA-DEX combination could be a promising and effective therapeutic agent for managing SA-AKI. Full article

Background: Obese women have a significantly higher risk of bearing breast tumors that are resistant to therapies and are associated with poorer prognoses/treatment outcomes. Breast cancer-promoting action of obesity is often attributed to elevated levels of insulin, glucose, inflammatory mediators, and misbalanced estrogen production in adipose tissue under obese conditions. Metabolic endotoxemia, characterized by chronic presence of extremely low levels of bacterial endotoxin (lipopolysaccharide [LPS]) in the circulation, is a less explored obesity-associated factor. Results: Here, utilizing in vitro and in vivo models of breast carcinoma (BC), we report that subclinical levels of LPS typical for metabolic endotoxemia enhance the malignant phenotype of breast cancer cells and accelerate breast tumor progression. Conclusions: Our study, while focusing primarily on the direct effects of metabolic endotoxemia on breast tumor progression, also suggests that metabolic endotoxemia can contribute to obesity–breast cancer link. Thus, our findings add novel mechanistic insights into how obesity-associated metabolic changes, particularly metabolic endotoxemia, modulate the biological and clinical behavior of breast carcinoma. In turn, understanding of the mechanistic aspects underlying the association between obesity and breast cancer could help inform better strategies to reduce BC risk in an increasingly obese population and to suppress the breast cancer-promoting consequences of excess adiposity. Full article

Reactive oxygen species (ROS) play a dual role as both essential signaling molecules and harmful mediators of damage. Imbalances in the redox state of the liver can overwhelm antioxidant defenses and promote mitochondrial dysfunction, oxidative damage, and inflammation. Complex feedback loops between ROS and immune signaling pathways are a hallmark of pathological liver conditions, such as hepatic ischemia–reperfusion injury (IRI). This is a major cause of liver transplant failure and is of increasing significance due to the increased use of marginally discarded livers for transplantation. This review outlines the major enzymatic and metabolic sources of ROS in hepatic IRI, including mitochondrial reverse electron transport, NADPH oxidases, cytochrome P450 enzymes, and endoplasmic reticulum stress. Hepatocyte injury activates redox feedback loops that initiate immune cascades through DAMP release, toll-like receptor signaling, and cytokine production. Emerging regulatory mechanisms, such as succinate accumulation and cytosolic calcium–CAMKII signaling, further shape oxidative dynamics. Pharmacological therapies and the use of antioxidant and immunomodulatory approaches, including nanoparticles and redox-sensitive therapeutics, are discussed as protective strategies. A deeper understanding of how redox and immune feedback loops interact is an exciting and active area of research that warrants further clinical investigation. Full article

Lipopolysaccharide (LPS), the defining outer membrane component of Gram-negative bacteria, is a potent immunostimulant recognized by Toll-like receptor 4 (TLR4). While extensively studied for its roles in immune activation and barrier disruption, the potential function of LPS as a developmental cue remains largely unexplored. By leveraging Caenorhabditis elegans and its genetic and gnotobiotic advantages, we screened a panel of Escherichia coli LPS biosynthesis mutants. This screen revealed that the loss of outer core glycosylation in the ∆rfaG mutant causes significant developmental delay independent of bacterial metabolism. Animals exhibited developmental delay that was rescued by exogenous LPS or amino acid supplementation, implicating that LPS triggers nutrient-sensing signaling. Mechanistically, this developmental arrest was mediated by the host FOXO transcription factor DAF-16, which is the key effector of insulin/IGF-1 signaling (IIS). Our findings uncover an unprecedented role for microbial LPS as a critical regulator of host development, mediated through conserved host IIS pathways, fundamentally expanding our understanding of host–microbe crosstalk. Full article

Acute hepatopancreatic necrosis disease (AHPND), caused by the bacterium Vibrio parahaemolyticus, is a major threat to global shrimp aquaculture. In this study, we evaluated the therapeutic effects of phage therapy in Litopenaeus vannamei challenged with AHPND-causing Vibrio parahaemolyticus. Phage application at various concentrations significantly improved shrimp survival, with the 1 ppm group demonstrating the highest survival rate. Enzymatic assays revealed that phage-treated shrimp exhibited enhanced immune enzyme activities, including acid phosphatase (ACP), alkaline phosphatase (AKP), and lysozyme (LZM). In addition, antioxidant defenses such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-PX), and total antioxidant capacity (T-AOC) significantly improved, accompanied by reduced malondialdehyde (MDA) levels. Serum biochemical analyses demonstrated marked improvements in lipid metabolism, particularly reductions in triglyceride (TG), total cholesterol (TC), and low-density lipoprotein (LDL), alongside higher levels of beneficial high-density lipoprotein (HDL). Transcriptomic analysis identified 2274 differentially expressed genes (DEGs), notably enriched in pathways involving fatty acid metabolism, peroxisome functions, lysosomes, and Toll-like receptor (TLR) signaling. Specifically, phage treatment upregulated immune and metabolic regulatory genes, including Toll-like receptor 4 (TLR4), myeloid differentiation primary response protein 88 (MYD88), interleukin-1β (IL-1β), nuclear factor erythroid 2-related factor 2 (Nrf2), and peroxisome proliferator-activated receptor (PPAR), indicating activation of innate immunity and antioxidant defense pathways. These findings suggest that phage therapy induces protective immunometabolic adaptations beyond its direct antibacterial effects, thereby providing an ecologically sustainable alternative to antibiotics for managing bacterial diseases in shrimp aquaculture. Full article

Background/Objectives: The incidence and prevalence of ischemic stroke, a leading cause of death and disability worldwide, are significantly higher in older adults than in younger individuals. Senescence induces a variety of biological changes that influence the pathogenesis of diseases such as ischemic stroke, thereby necessitating age-specific medical treatments. However, the molecular mechanisms underlying age-related differences in ischemic stroke progression remain poorly understood. Methods: We compared the histological and molecular features of ischemic stroke in a photothrombotic mouse model, focusing on 9-week-old (young) and 90-week-old (old) mice. Results: We found that microglial accumulation at the infarct region of the cerebral cortex was significantly lower in old mice than in young ones. This reduction in the microglial response was accompanied by a decrease in the morphological robustness of the astrocytes forming the glial scar. Furthermore, the mRNA expression of proinflammatory cytokines CXCL10, CCL2, and TNF-α, which were upregulated in the infarct region, was considerably higher in the old mice than in the young ones. Cytokine expression was well correlated with the mRNA levels of Toll-like receptor 4 (TLR4), a key regulator of neuroinflammation in old mice, but less correlated with them in young mice. Interestingly, Tlr4 mRNA expression in young mice was negatively correlated with the mRNA expression of the epigenetic regulator HDAC7, whereas this correlation was positive in old mice. Conclusions: These findings suggest that age-dependent changes in epigenetic regulation, such as the interaction between HDAC7 and TLR4, may contribute to the distinct pathological progression of ischemic stroke in older individuals. Full article

Background/Objective: Early-onset neonatal sepsis (EOS), defined as infection occurring within the first 72 h after birth, remains a major contributor to neonatal morbidity and mortality worldwide. Although advances in perinatal care have improved overall outcomes, the diagnosis of EOS continues to be challenging. Clinical presentations are often nonspecific, laboratory confirmation is often delayed, and immune responses vary considerably among neonates. Expanding our understanding of the molecular mechanisms underlying EOS is essential in enhancing early detection, refining risk stratification, and guiding therapeutic strategies. This systematic review aims to synthesize the available information on the molecular pathways involved in EOS, focusing on pathogen-induced inflammation, systemic immune responses, sterile inflammatory processes, interactions between infectious and non-infectious pathways, as well as emerging molecular diagnostic approaches. Methods: A comprehensive review of original research articles and reviews published between January 2015 and January 2025 was conducted; studies were included based on their focus on human neonates and their analysis of molecular or immunological mechanisms relevant to EOS pathogenesis, immune dysregulation, or novel diagnostic strategies. Results: Pathogen-driven inflammation typically involves the activation of Toll-like receptors (TLRs), the recruitment of neutrophils, and the release of pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α, particularly in response to vertical transmission of organisms like Escherichia coli and Streptococcus agalactiae. Systemic inflammatory responses are marked by cytokine dysregulation, contributing to multi-organ dysfunction. Sterile inflammation, often initiated by hypoxia–reperfusion injury or intrauterine stress, amplifies susceptibility to sepsis. Interactions between immune, metabolic, and endothelial pathways further exacerbate tissue injury. Recent advances, including transcriptomic profiling, microRNA-based biomarkers, and immune checkpoint studies, offer promising strategies for earlier diagnosis and individualized therapeutic options. Conclusions: EOS arises from a complex interplay of infectious and sterile inflammatory mechanisms. A deeper molecular understanding holds promise for advancing correct diagnostics and targeted therapies, aiming to improve neonatal outcomes. Full article

Systemic lupus erythematosus (SLE) is characterized by autoimmune dysregulation, elevated autoantibody production, and persistent inflammation, predisposing patients to atherosclerosis (AS). Atherogenesis is dependent on lipid homeostasis and inflammatory processes, with the formation of lipid-laden, macrophage-derived foam cells (MDFC) essential for atherosclerotic lesion progression. Elevated cholesterol levels within lipid rafts trigger heightened pro-inflammatory responses in macrophages via Toll-like receptor 9 (TLR9). Artesunate (ART), an artemisinin derivative sourced from Artemisia annua, exhibits therapeutic potential in modulating inflammation and autoimmune conditions. Nonetheless, its impact and mechanisms in SLE-associated AS (SLE-AS) remain largely unexplored. Our investigation demonstrated that ART could effectively ameliorate lupus-like symptoms and atherosclerotic plaque development in SLE-AS mice. Moreover, ART enhanced cholesterol efflux from MDFC by upregulating ABCA1, ABCG1, and SR-B1 both in vivo and in vitro. Moreover, ART reduced cholesterol accumulation in bone marrow-derived macrophages (BMDMs), thereby diminishing TLR9 recruitment to lipid rafts. ART also suppressed TLR9 expression and its downstream effectors in the kidney and aorta of SLE-AS mice, attenuating the TLR9-mediated inflammatory cascade in CPG2395 (ODN2395)-stimulated macrophages. Through bioinformatics analysis and experimental validation, PPARγ was identified as a pivotal downstream mediator of ART in macrophages. Depleting PPARγ levels reduced the expression of ABCA1, ABCG1, and SR-B1 in macrophages, consequently impeding cholesterol efflux. In conclusion, these findings suggest that ART ameliorates SLE-AS by restoring cholesterol homeostasis through the PPARγ-ABCA1/ABCG1/SR-B1 pathway and suppressing lipid raft-driven TLR9/MyD88 inflammation. Full article

Povidone-iodine (PVP-I), a widely used aquaculture disinfectant, remains poorly understood in terms of sublethal toxicity and damage reversibility. This study employed Macrobrachium rosenbergii as the model organism to evaluate the acute toxicity and sublethal effects of PVP-I through a 4-day exposure experiment followed by a 7-day depuration period. Acute toxicity tests enabled the determination of 24–96 h median lethal concentrations (LC₅₀), with the 96 h LC₅₀ being 5.67 mg/L and the safe concentration (SC) being 1.37 mg/L. Based on this, three sublethal concentrations (1.14, 1.89, and 2.84 mg/L) were tested over a 4-day exposure followed by a 7-day depuration period. Investigated endpoints included gill ultrastructure, apoptosis, and antioxidant and immune-related gene expression. Subacute exposure at 1.89 and 2.84 mg/L induced mitochondrial vacuolization, upregulated apoptosis-related genes (Cyt-c, Caspase-3, Bok), and downregulated antioxidant gene expression (SOD, CAT, GSH-Px). The high-concentration group also showed sustained Toll-like receptor (Toll) gene overexpression and acid phosphatase (ACP) gene suppression. After depuration, antioxidant gene expression normalized; however, apoptotic markers in gill tissue remained impaired. Overall, high PVP-I concentrations cause irreversible gill damage via mitochondrial-mediated apoptosis, whereas lower concentrations (≤1.14 mg/L) allow for greater recovery. These results offer crucial toxicodynamic insights for safer PVP-I use and risk assessment in M. rosenbergii aquaculture. Full article

Background/Objectives: Sepsis-induced cardiomyopathy (SIC) is a serious clinical disorder with a high death rate. Qifu decoction (QFD) is a renowned traditional Chinese medicine with documented pharmacological actions, such as anti-inflammatory, anti-oxidant and anti-apoptosis activities, and it has good therapeutic effects on cardiovascular diseases. This study aimed to reveal the cardioprotective effects and underlying mechanisms of QFD against SIC. Methods: Electrocardiography, histopathological examination, and biochemical indicator determination were carried out to investigate the cardioprotective effects of QFD in the treatment of LPS-induced SIC mice. Metabolomics and network pharmacology strategies were employed to preliminarily analyze and predict the mechanisms of QFD against SIC. Molecular docking and Western blot were further applied to validate the core targets and potential pathways for the treatment of SIC in in vitro and in vivo models. Results: It was found that QFD considerably enhanced cardiac function; attenuated myocardial injury; and reduced the serum levels of LDH, CK-MB, IL-1β, and TNF-α by 28.7%, 32.3%, 38.6%, and 36.7%, respectively. Metabolomic analysis showed that QFD could regulate seven metabolic pathways, namely, glutathione metabolism; alanine, aspartate, and glutamate metabolism; arachidonic acid metabolism; glycerophospholipid metabolism; purine metabolism; sphingolipid metabolism; and fatty acid metabolism. Network pharmacology suggested that the anti-SIC effect of QFD may be mediated through the TNF, toll-like receptor, NOD-like receptor, NF-κB, and PPAR signaling pathways. Additionally, 26 core targets were obtained. Molecular docking revealed that active ingredients such as formononetin, kaempferol, quercetin, and (R)-norcoclaurine in QFD had a high affinity for binding to PPARα and TLR4. Further Western blot validation indicated that QFD could regulate the protein levels of NLRP3, TLR4, NF-κB, IL-6, TNF-α, COX2, sPLA2, PPARα, CPT1B, and CPT2. Conclusions: This study demonstrates that QFD can alleviate SIC by suppressing the TLR4/NF-κB/NLRP3 inflammatory pathway and modulating impaired FAO through the activation of the PPARα/CPT pathway, highlighting QFD as a promising candidate drug for SIC treatment. Full article

Background/Objectives: Atractylodes lancea (Thunb.) DC. [Asteraceae] (ALR)-derived exosome-like nanoparticles (ALR-ELNs) exhibit anti-neuroinflammatory effects in microglial cells. However, the associated mechanisms and pathways are unknown. We aimed to characterize the effects of ALR-ELNs on inflammatory responses of BV-2 microglial cells to lipopolysaccharide (LPS) using RNA sequencing. Methods: ALR-ELNs were fractionated from ALR. BV-2 microglial murine cells were stimulated with LPS after treatment with ALR-ELNs. RNA sequencing was performed to analyze variations in mRNA levels. Ingenuity pathway analysis (IPA) was performed to investigate the mechanism of action of ALR-ELNs. mRNA expression was assessed using real-time quantitative polymerase chain reaction (qPCR). Results: The expression of 651 genes was downregulated, whereas that of 1204 genes was upregulated in LPS-stimulated BV2 cells pretreated with ALR-ELNs. The IPA showed that the effects of ALR-ELNs on inflammation took place through pathogen-influenced signaling. Network analysis via IPA showed that the Toll-like receptor (TLR) is involved in the suppression of inflammation by ALR-ELNs. The qPCR analysis showed that pretreatment with ALR-ELNs significantly reduced TLR4 mRNA expression. Conclusions: ALR-ELNs suppress the release of inflammatory mediators by downregulating TLR4 expression, which is a novel mechanism by which ALR-ELNs act on microglia. Identifying active ingredients in ALR-ELNs that downregulate TLR4 expression can advance the development of therapeutic drugs for neuroinflammatory diseases. Full article

The developmental processes of microglia follow a general pattern, from immature amoeboid (activated) cells to fully ramified (inactivated) surveilling microglia. However, little is known about the mechanisms controlling the transition of microglia from an activated to an inactivated state during brain development. Due to the complexity of microenvironmentally dynamic changes during neuronal differentiation, interactions between developing nerve cells and microglia might be involved in this process. Extracellular vesicles (EVs) are cell-released particles that serve as mediators of cellular crosstalk and regulation. Using neural progenitor cells (NPCs) and a long-term neuron culture system, we found that EVs derived from NPCs or developing neurons possessed differential capacity on the induction of microglial activation. The exposure of microglia to NPC- or immature neuron (DIV7)-derived EVs resulted in the higher expression of protein and mRNA of multiple inflammatory cytokines (e.g., TNF-α, IL-1β, and IL-6), when compared with mature neuron-derived EVs. Exploration of the intracellular signaling pathways revealed that MAPK signaling, IκBα phosphorylation/degradation, and NF-κB p65 nuclear translocation were strongly induced in microglia treated with NPC- or immature neuron-derived EVs. Using a pharmacological approach, we further demonstrate that Toll-like receptor (TLR) 7-mediated activation of NF-κB and MAPK signaling cascades contribute to EV-elicited microglial activation. Additionally, the application of conditioned media derived from microglia treated with NPC- or immature neuron-derived EVs is found to promote the survival of late-developing dopaminergic neurons. Thus, our results highlight a novel mechanism used by NPCs and developing neurons to modulate the developmental phases and functions of microglia through EV secretion. Full article

The B-cell adapter for PI3K (BCAP) is a protein that connects membrane receptor signaling to the PI3K pathway. In fibroblasts or dendritic cells, priming the cGAS nucleic-acid-sensing pathway increases BCAP expression and enhances type I interferon (IFN-I) production upon lipopolysaccharide (LPS) stimulation. These findings corroborate the idea that BCAP may bias cytokine production toward IFN during inflammation, indicating its potential involvement in IFN-driven diseases like systemic lupus erythematosus (SLE). We investigate the role of BCAP in regulating the inflammatory response in SLE and its relationship with IFN-mediated inflammation. BCAP gene expression and IFN signature were analyzed in 36 subjects with SLE and 20 healthy controls. Two cellular models were used to assess BCAP’s role in LPS response and IFN signaling after cGAS stimulation. We found a correlation between BCAP and interferon-stimulated gene (ISG) expression in SLE. In a cellular model, tofacitinib and anifrolumab, acting as IFN signaling “inhibitors”, blocked BCAP overexpression triggered by cGAS, confirming BCAP as an ISG. Additional studies in BCAP^−/− cells revealed that, in the absence of BCAP, these cells exhibited diminished IFN production upon LPS stimulation following prior exposure to cGAMP. Overall, BCAP is an ISG that acts as a positive regulator of Toll-like receptor 4-mediated IFN production. We speculate that its increased expression in SLE may contribute to a positive feedback loop, enhancing IFN production during bacterial infections. Full article

Fasciola gigantica (F. gigantica) is a vital parasite that causes fasciolosis. Liver fluke infections affect livestock animals, and the Fasciola species (Fasciola spp.) vaccine has been tested for many types of these diseases. Currently, computer-based vaccine design represents an attractive alternative for constructing vaccines. Thus, this study aimed to design the epitopes of linear B-cells (BCL) and helper T lymphocytes (HTL) using an immunoinformatic approach and to investigate in silico and the mice’s immune response. A non-conserved host region, overlapping F. gigantica cathepsin B proteins (FgCatB), and the highest conserved residue percentages were the criteria used to construct epitopes. The GPGPG linker was used to link epitopes in the multi-epitope Fasciola gigantica cathepsin B (MeFgCatB) peptide. The MeFgCatB peptide has high antigenicity, non-allergenicity, non-toxicity, good solubility, and a high-quality structure. The molecular docking between the MeFgCatB peptide and Toll-like receptor 2 (TLR-2) was evaluated. The IgM, IgG1, and IgG2 levels were elevated in silico. In mice, the MeFgCatB peptide was synthesized and administered as an injection. The MeFgCatB-specific IgG1 and IgG2a levels were elevated after week 2, showing a predominance of IgG1. The rFgCatB1, rFgCatB2, and rFgCatB3 were detected using the MeFgCatB peptide-immunized sera. The MeFgCatB peptide-immunized sera were detected at approximately 28–34 kDa in the whole body. In addition, the MeFgCatB immunized sera can positively signal at the caecal epithelium in the NEJ, 4WKJ, and adult stages. In summary, the MeFgCatB peptide is able to induce mixed Th1/Th2 immune responses with Th2 dominating and to detect the native protein of F. gigantica. The MeFgCatB peptide should help against F. gigantica in future experiments. Full article

There is a present need to develop alternative biotherapeutic drugs to mitigate the exacerbated inflammatory immune responses characteristic of sepsis. The potent endotoxin lipopolysaccharide (LPS), a major component of Gram-negative bacterial outer membrane, activates the immune system via Toll-like receptor 4 (TLR4), triggering macrophages and a persistent cascade of inflammatory mediators. Our previous studies have demonstrated that Fh15, a recombinant member of the Fasciola hepatica fatty acid binding protein family, can significantly increase the survival rate by suppressing many inflammatory mediators induced by LPS in a septic shock mouse model. Although Fh15 has been proposed as a TLR4 antagonist, the specific mechanisms underlying its immunomodulatory effect remained unclear. In the present study, we employed a quantitative proteomics approach using tandem mass tag (TMT) followed by LC-MS/MS analysis to identify and quantify differentially expressed proteins that participate in signaling pathways downstream TLR4 of macrophages, which can be dysregulated by Fh15. Data are available via ProteomeXchange with identifier PXD065520. Based on significant fold change (FC) cut-off of 1.5 and p-value ≤ 0.05 criteria, we focused our attention to 114 proteins that were upregulated by LPS and downregulated by Fh15. From these proteins, TNFα, IL-1α, Lck, NOS2, SOD2 and CD36 were selected for validation by Western blot on murine bone marrow-derived macrophages due to their relevant roles in the NF-κB, iNOS, oxidative stress, and phagosome signaling pathways, which are closely associated with sepsis pathogenesis. These results suggest that Fh15 exerts a broad spectrum of action by simultaneously targeting multiple downstream pathways activated by TLR4, thereby modulating various aspects of the inflammatory responses during sepsis. Full article