Search Results (11,969)

Fermentation is widely used to enhance the bioactivity of herbal phytochemicals through microbial bioconversion. Rehmannia glutinosa contains catalpol, an iridoid glycoside with metabolic and immunomodulatory potential; however, its efficacy in the unfermented form is limited. This study investigated whether fermentation enhances catalpol production and improves metabolic and immune-regulating functions via glucagon-like peptide-1 receptor (GLP-1R) signaling. Rehmannia glutinosa extract was fermented under optimized conditions, and catalpol and iridoid precursor levels were quantified to assess bioconversion efficiency. Biological effects were evaluated in intestinal epithelial cells, macrophages, and an Artemia model, focusing on glucose transport, GLP-1 secretion, dipeptidyl peptidase-4 (DPP-4) expression, mucosal defense, and GLP-1R/protein kinase A/cAMP response element-binding protein (PKA/CREB) signaling. Fermentation significantly increased catalpol content while reducing iridoid precursors. The fermented extract suppressed intestinal glucose absorption by downregulating sodium–glucose cotransporter 1 (SGLT1) and glucose transporter 2 (GLUT2). It also enhanced GLP-1 secretion and reduced DPP-4 expression, leading to activation of GLP-1R/PKA/CREB signaling. This activation increased mucin 2 (MUC2) expression and promoted anti-inflammatory. Full article

Diabetic peripheral neuropathy (DPN) remains a leading cause of disability in diabetes, yet current care is largely symptomatic and does not directly address early neurovascular-immune pathology. This narrative review synthesizes clinical, redox, vascular, and immunological evidence into a peripheral nerve neurovascular unit (PNVU)/blood–nerve barrier (BNB)-centered framework for DPN. First, the review outlines the diagnostic and translational endpoint landscape of DPN, emphasizing that commonly used clinical, neurophysiological, small-fiber, and imaging-based tools capture important disease domains but do not directly assess early BNB dysfunction. It then reviews the anatomical and functional basis of the PNVU and BNB, including endoneurial microvascular endothelial cells, pericytes, basement membrane components, immune cells, and tight-junction proteins. Next, it discusses how chronic hyperglycemia and dyslipidemia drive metabolic-to-vascular coupling, redox imbalance, antioxidant defense failure, advanced glycation end products (AGEs), receptor for AGEs (RAGE), and nuclear factor-κB (NF-κB) signaling, endothelial activation, leukocyte recruitment, macrophage polarization, and junctional disassembly, culminating in increased BNB permeability and exposure of peripheral nerves to pro-inflammatory and neurotoxic mediators. Finally, it evaluates incretin-based therapies—including glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors, DPP-4is), and emerging multi-agonists—as potential modulators of oxidative and inflammatory stress within this framework. Although semaglutide and related agents show mechanistic plausibility and preclinical promise, direct evidence for incretin-mediated BNB stabilization in human DPN remains limited. By reframing DPN as a redox-driven neurovascular-immune disorder, this review highlights barrier-focused biomarkers, translational endpoints, and hypothesis-generating therapeutic opportunities that require clinical validation. Full article

Leukemia inhibitory factor (LIF), a member of the interleukin-6 (IL-6) cytokine family, is a well-characterized myokine with pleiotropic regulatory effects on skeletal muscle. LIF modulates several fundamental cellular processes, including myoblast proliferation, apoptosis, angiogenesis, and energy metabolism. Exercise upregulates LIF expression in skeletal muscle, thereby promoting satellite cell activation, proliferation, myoblast differentiation, and angiogenesis, facilitating physiological muscle hypertrophy, and suppressing myocyte apoptosis and muscle atrophy. In addition, LIF plays a critical role in modulating the inflammatory and extracellular matrix remodeling following exercise-induced muscle damage, thereby supporting efficient muscle repair and regeneration. This review elaborates on the biological mechanisms by which LIF regulates skeletal muscle atrophy and contributes to the enhancement of skeletal muscle function. It also highlights the biological characteristics of myogenic LIF and discusses future directions for basic and applied research on exercise interventions targeting LIF signaling pathways. Full article

Neuroinflammation is increasingly implicated in depression pathogenesis, yet the underlying mechanisms are still unclear. This study explores whether PSMB4/MHC-I signaling in the cerebrospinal fluid (CSF)-contacting nucleus mediates neuroinflammatory depression. A persistent neuroinflammation-associated depression model was established in mice by repeated intracerebroventricular lipopolysaccharide (LPS) administration. Depressive-like behaviors were evaluated using established assays. Neuroinflammatory responses and target protein expression were assessed by immunofluorescence, Western blotting, RT-qPCR, and laser capture microdissection. Neuronal activity was mapped by c-Fos staining and manipulated using chemogenetics, alongside pharmacological and genetic interventions. Repeated LPS administration induced significant depressive-like behaviors and obvious neuroinflammation in the CSF-contacting nucleus. Under these conditions, neuronal activity in this nucleus was selectively enhanced. Crucially, chemogenetic activation of these neurons alleviated depressive phenotypes, whereas their inhibition induced depression. Molecularly, LPS significantly upregulated PSMB4 and MHC-I expression. Pharmacological suppression of upstream neuroinflammation reversed this PSMB4 upregulation, and targeted PSMB4 knockdown reduced MHC-I expression, ultimately ameliorating depressive-like behaviors. These findings identify the CSF-contacting nucleus as a critical node in neuroinflammation-induced depression and reveal a novel PSMB4/MHC-I signaling axis linking central inflammatory responses to behavioral deficits. Full article

Background/Objectives: Post-traumatic joint contracture (PTJC) is a common complication in orthopedic surgery characterized by fibrosis and restricted joint mobility. Previous work by our multi-arm study demonstrated that nintedanib monotherapy could effectively mitigate PTJC by targeting fibroblast activation pathways. Since PTJC involves multiple simultaneously activated signaling pathways, we hypothesized that combination therapy targeting both inflammation and fibrosis might be advantageous for improving outcomes. As a candidate for combination treatment with nintedanib, bosentan, an endothelin receptor antagonist that modulates inflammatory responses, was chosen to assess whether this approach could improve the prevention of PTJC. Methods: Thirty-nine Sprague Dawley rats were randomized evenly into three groups after undergoing a standardized hyperextension trauma of the knee and K-wire arthrodesis over a period of two weeks. The experimental groups (n = 13 each) received a combination (COMB) of nintedanib (5 mg/kg/d, twice daily) and bosentan (50 mg/kg/d, twice daily), or nintedanib (5 mg/kg/d, twice daily) alone throughout the immobilization period. The control group (n = 13), meanwhile, was given a placebo. Joint mobility was evaluated quantitatively by measuring the contracture angle (CA) and resistance to extension. Additionally, tissue from the posterior joint capsule was collected for histological analysis. Quantitative PCR was used to analyze tissue and assess the expression levels of genes involved in the pro-fibrotic process, including, Il-6, Tgf-β, Nf-κb, Ctgf, and α-Sma. Statistical analysis involved Kruskal–Wallis and ANOVA tests with post hoc methods, with significance defined at p < 0.05. Results: Both combination therapy and nintedanib monotherapy significantly reduced the contracture angle compared to placebo (p ≤ 0.05 and p ≤ 0.01, respectively), with no significant difference between treatments. Histological analysis showed significantly fewer myofibroblasts in the COMB and nintedanib groups versus placebo (p < 0.05). α-SMA expression was significantly decreased by 8-fold (COMB) and 11-fold (nintedanib) compared to placebo (p < 0.05), with no differences between treatments. No significant differences were detected in upstream pro-fibrotic gene expression among groups. Conclusions: Based on results comparable to those achieved with nintedanib monotherapy, the additional administration of bosentan does not appear to offer any further benefit at the given experimental setup. Full article

Autoimmune diseases are characterized by chronic inflammation, immune dysregulation, and excessive oxidative stress, which collectively contribute to a progressive tissue damage and organ dysfunction. Although conventional immunosuppressive and anti-inflammatory therapies remain the main therapeutic approach, their clinical efficacy is often limited by poor pharmacokinetic properties, low tissue selectivity, systemic toxicity, and adverse effects following long-term administration. In this context, antioxidant-based nanoformulations have emerged as promising multi-target therapeutic strategies for the modulation of oxidative and inflammatory pathways involved in autoimmune disorders. This review focuses on polymeric and non-polymeric nanoformulations designed to improve the solubility, stability, bioavailability, controlled release, and targeted delivery of antioxidant and anti-inflammatory agents for autoimmune disease treatment. Recent advances in nanocarrier systems applications, including nanogels, poly(lactic-co-glycolic acid) (PLGA), polyethylene glycol (PEG), polymethacrylate, chitosan, hyaluronic acid, hydroxyapatite (HAP), lipid-based and ROS-responsive nanosystems, are discussed. The therapeutic potential of nanoencapsulated steroidal and non-steroidal anti-inflammatory drugs, antioxidant compounds, enzymes, inorganic elements, and nucleic acid-binding systems is evaluated through preclinical and limited clinical evidence. Many of these reported nanoformulations exhibit enhanced therapeutic efficacy, improved tissue targeting, reduced systemic toxicity, and the ability to simultaneously modulate oxidative stress and inflammatory signaling pathways. Despite the encouraging findings, important challenges remain regarding clinical translation, long-term safety, reproducibility, and large-scale production. In overall, antioxidant nanoformulations represent a promising and evolving platform for the development of more effective and targeted therapies against autoimmune diseases. Full article

High-phenolic extra-virgin olive oil (EVOO) is a chemically dynamic bioactive matrix in which cultivar, ripening stage, processing, storage, and digestion shape the final profile of phenolic alcohols and secoiridoids. In inflammatory bowel disease (IBD), chronic intestinal inflammation is associated with barrier dysfunction, dysbiosis, systemic immune activation, endothelial injury, platelet hyperreactivity, and increased cardiovascular risk. This narrative review evaluates whether EVOO phenolics may intersect the gut–endothelium–platelet axis linking IBD to vascular and thromboinflammatory complications. The review focuses on hydroxytyrosol, tyrosol, oleuropein- and ligstroside-derived secoiridoids, oleocanthal, and oleacein, with emphasis on their biosynthetic origin, processing-driven transformations, bioavailability, metabolism, and biological targets. Current evidence supports plausible effects on epithelial barrier integrity, TLR4/NF-κB signalling, Nrf2-mediated antioxidant defence, oxidised LDL formation, endothelial activation, and platelet-related pathways. Nevertheless, direct clinical evidence in IBD patients remains limited, and most cardiovascular-relevant findings are extrapolated from non-IBD human trials, animal studies, or in vitro models. Chemically characterised, biomarker-anchored intervention trials are needed before high-phenolic EVOO can be considered a validated strategy for modifying cardiovascular risk in IBD. Full article

NDRG1 protein engages with the orphan nuclear receptor NR4A1, effectively suppressing the transcriptional activity of NF-κB and influencing the inflammatory response. However, the specific roles of the NDRG family and NR4A transcription factors in inflammatory bowel disease (IBD) remain poorly defined, particularly regarding potential differential mechanisms between ulcerative colitis (UC) and Crohn’s disease (CD). We hypothesize that NDRG–NR4A interactions are differentially regulated in UC versus CD, contributing to disease-specific modulation of NF-κB signaling and inflammatory responses. Therefore, the aim was to analyze gene and protein expression of both protein families (NDRGs: NDRG1, NDRG2, NDRG3, and NDRG4; and NR4A: NR4A1, NR4A2, and NR4A3), their contributions to UC and CD, and their association with disease severity. In this cross-sectional and comparative study, we assess gene and protein expression of NR4A and NDRG1-4 in 38 UC patients, 10 CD patients, and 18 controls. Gene and protein expression levels were measured by RT-PCR (mucosa) and immunohistochemistry (colonic tissue), respectively. The colonic mucosa from remission UC patients showed upregulation of NDRG2 and the nuclear receptor genes NR4A1-3 compared with controls. NDRG4 was upregulated in active UC patients compared with controls. NDRG1 was downmodulated in active and remission UC patients compared with controls. All differences were statistically significant (p < 0.05). Decreased NR4A2 gene expression was associated with high-sensitivity C-reactive protein (p = 0.030) and erythrocyte sedimentation rate levels (p = 0.001). Our results provide the first evidence of differential alterations in the NDRG–NR4A axis in UC and CD, which could modulate NF κB signaling and the inflammatory profile differently in each disease, opening the possibility of new therapeutic options. Full article

In this Reply, we address the criticisms raised by Franzini, Valdenassi, and Chirumbolo concerning our study on the effects of ozonized saline solution (O3SS) on microglial polarization and endothelial responses in vitro. We clarify that the primary aim of the original work was mechanistic, relying on rigorously controlled cellular models that are universally recognized as essential preclinical tools in translational medicine. We reaffirm the validity of our experimental approach, including the preparation and characterization of O3SS based on empirically validated methodologies, direct ozone quantification, and standardized protocols consistent with the existing literature and clinical practice. Concerns regarding ozone chemistry, dose relevance, and hypochlorite formation are addressed through analytical validation, biological threshold considerations, and the use of certified assays. We further justify the choice of BV2 microglia and HUVEC cells as established and widely used models for investigating inflammatory and vascular pathways under reproducible conditions. Statistical analyses, gene expression interpretation, and the absence of comparative pharmacological agents are discussed in the context of the study’s focused objectives. Finally, we place our findings within the established framework of ozone as an indirect pro-oxidant that elicits adaptive redox signaling (“oxidative eustress”), emphasizing the translational relevance of in vitro systems for elucidating early mechanistic events. Overall, we maintain that our study provides a robust, balanced, and evidence-based contribution to the understanding of ozone-derived redox biology. Full article

Gestational diabetes mellitus (GDM) is increasingly recognized as a complex pathology rooted in systemic and organelle-level dysfunction, specifically involving chronic low-grade inflammation (CLGI), mitochondrial impairment, and endoplasmic reticulum (ER) stress. Central to this pathophysiology is mitochondrial dysfunction, characterized by reduced respiration, impaired metabolic flexibility, and dysregulated fission/fusion machinery, which fuels a self-perpetuating cycle of reactive oxygen species (ROS) production. Concurrently, chronic ER stress triggered by hyperglycemia and lipotoxicity activates the unfolded protein response (UPR), further amplifying redox imbalance through the Endoplasmic Reticulum Oxidoreductin 1/Protein Disulfide Isomerase (ERO1/PDI) axis and bridging metabolic toxicity to inflammation via c-Jun N-terminal kinase (JNK) and nuclear factor kappa-light-chain–enhancer of activated B cells (NF-κB) signaling. The Advanced Glycation Endproducts (AGEs) and the Receptor for Advanced Glycation Endproducts (RAGE) axis act as a molecular catalyst that sequester antioxidants and drive pro-inflammatory feedback loops. These converging mechanisms culminate in profound placental maladaptation, including structural abnormalities like chorangiosis and functional defects in nutrient transport mediated by hyperactive mechanistic target of rapamycin complex 1 (mTORC1) signaling. This review article provides insight into recent evidence to elucidate the meta-inflammatory environment of GDM, where modest but sustained elevations in biomarkers like Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) disrupt redox homeostasis and impair insulin signaling pathways through the activation of stress-sensitive kinases. By integrating these molecular perspectives, the article underscores the necessity of targeting the systemic inflammatory and oxidative continuum spanning pre-conception to the antenatal period through lifestyle interventions and emerging therapeutic strategies to mitigate GDM risk and improve maternal–fetal outcomes. Full article

Background/Objectives: Rotenone (RT)-induced neurotoxicity is widely used to model Parkinsonism-like nigrostriatal injury and recapitulates several PD-relevant pathological features, including oxidative stress, mitochondrial dysfunction, neuroinflammation, and dopaminergic neurochemical disturbance. Loganin (LG), an iridoid glycoside isolated from Cornus officinalis, has been reported to possess antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective properties. However, its protective effects in a unilateral stereotaxic RT lesion model have not been fully elucidated. This study aimed to investigate the neuroprotective potential of LG against RT-induced Parkinsonism-like pathology in rats and to explore the possible involvement of antioxidant-related signaling mechanisms. Methods: Adult male Wistar rats were randomly assigned to twelve experimental groups (n = 8/group), including control, sham, RT, sham + LG, RT + LG, RT + trigonelline (TG) + LG, and RT + selegiline (SL). RT was stereotaxically injected once into the right substantia nigra pars compacta (SNpc) on Day 0 to induce unilateral nigrostriatal injury. LG was administered orally once daily from Day 1 to Day 21 at doses of 3, 10, and 30 mg/kg. TG was given intraperitoneally 30 min before LG treatment, while SL served as a reference antiparkinsonian drug. Behavioral assessments and biochemical analyses were conducted to evaluate motor dysfunction, oxidative and nitrosative stress, endogenous antioxidant status, mitochondrial dysfunction, inflammatory and apoptotic responses in the SNpc, and striatal catecholamine disturbances. Results: RT lesioning produced significant motor deficits, oxidative and nitrosative stress, depletion of endogenous antioxidant defenses, mitochondrial dysfunction, inflammatory and apoptotic activation in the SNpc, and abnormalities in striatal catecholamine levels. LG treatment significantly attenuated these pathological changes, with more pronounced protective effects observed at 10 and 30 mg/kg. Co-administration of TG partially weakened the beneficial effects of LG, suggesting the possible involvement of antioxidant defense-related signaling while not providing direct proof of a single pathway. SL also ameliorated RT-induced behavioral and biochemical abnormalities. Conclusions: These findings suggest that LG confers multi-target neuroprotective effects against RT-induced Parkinsonism-like features in rats. The protective actions of LG were associated with attenuation of oxidative stress, mitochondrial dysfunction, neuroinflammation, apoptosis, and catecholaminergic disturbances. Because the pathway analysis remains pharmacological and indirect, additional studies using direct molecular validation are warranted before LG can be considered a disease-modifying candidate for PD-related neurodegeneration. Full article

Background/Objectives: This study aimed to develop a novel tumor-associated macrophage (TAM)-targeting nanoplatform to improve the solubility and bioavailability of camptothecin (CPT) and achieve active targeted drug delivery for enhanced anti-tumor immunotherapy. Methods: We constructed a sialic acid-disulfide bond-camptothecin (SA-SS-CPT) nanowire system. Sialic acid was used as a targeting ligand to specifically recognize the overexpressed Siglec-E receptor on TAMs. Upon cellular internalization, the disulfide bond was designed to respond to intracellular glutathione (GSH), enabling controlled drug release. Results: The SA-SS-CPT nanowires significantly improved CPT solubility and enabled targeted delivery to TAMs. Following GSH-responsive cleavage and CPT release, the nanowires induced DNA damage in TAMs, activating the cGAS-STING signaling pathway. This promoted TAM polarization toward the M1 phenotype, enhanced pro-inflammatory and anti-tumor immune responses, and inhibited tumor immune escape. Furthermore, SA-SS-CPT synergistically improved the efficacy of PD-L1 blockade immunotherapy, remodeling the tumor immune microenvironment. Conclusions: The SA-SS-CPT nanoplatform effectively targets TAMs, repolarizes them to an anti-tumor M1 phenotype, and activates the cGAS-STING pathway. It shows strong potential for overcoming tumor immune escape and synergizing with PD-L1 checkpoint blockade to achieve significant tumor clearance. Full article

Mastitis limits yak dairy production and is associated with lipopolysaccharide (LPS)-mediated inflammation in yak mammary epithelial cells (YMECs). This study aimed to investigate the protective effect of caffeic acid (CA) against LPS-induced cellular injury and to elucidate the underlying mechanisms, with a particular focus on autophagy regulation via the NF-κB signaling pathway. LPS exposure strikingly reduced cellular viability and increased intracellular reactive oxygen species (ROS) levels, accompanied by activation of the NF-κB pathway. Furthermore, it increased the expression of pro-inflammatory cytokines (TNF-α, IL-8, and IL-1β). In addition, LPS enhanced endoplasmic reticulum (ER) stress and Ca²⁺ dysregulation, increased LC3-II/LC3-I ratio, and reduced synthesis of α-casein and β-casein. Pretreatment with CA resulted in the effective alleviation of these alterations by restoring cellular viability, suppressing inflammatory responses, and normalizing autophagy-related markers. Additionally, inhibition of Nrf2 reversed the partial reversal of the protective effects of CA, resulting in increased ROS accumulation and autophagy activation, but did not impact NF-κB suppression. These findings indicate that CA attenuates LPS-induced inflammatory injury in YMECs involved in both Nrf2-dependent and independent pathways. These findings provide a mechanistic analysis of yak mastitis pathogenesis and CA potential as a natural therapeutic for improving mammary health and milk quality in yak dairy systems. Full article

Regulatory T cells (Tregs, CD4⁺ CD25⁺ Foxp3⁺) play a crucial role as a core cell subset in maintaining immune homeostasis in the ocular immune-privileged microenvironment. This review systematically summarizes the stage-specific regulatory mechanisms of Treg cells in common inflammatory diseases such as keratitis, uveitis, and dry eye syndrome, including intercellular interactions, signal pathway mediation, and cytokine network regulation, as well as key experimental evidence (animal/cell models and clinical sample data) and research progress in targeted therapy. Studies have shown that Treg cells maintain ocular immune balance by secreting anti-inflammatory cytokines (such as IL-10 and TGF-β), regulating signaling pathways (STAT, PI3K/AKT, SIRT1, etc.), and interacting with immune cells (macrophages, dendritic cells). Their functions are regulated by multiple factors such as cytokine networks, epigenetic modifications, and delivery vectors. Targeted interventions based on Treg cells (cell therapy, drug intervention, and signaling pathway regulation) and combined treatment strategies have shown good anti-inflammatory potential. This article, in light of current research limitations (such as insufficient analysis of cell heterogeneity and the disconnect between basic and clinical research), proposes future research directions, providing a theoretical basis for the understanding of the pathogenesis of inflammatory eye diseases and the development of new immunomodulatory therapies, and establishing a complete research framework of “mechanism–evidence–treatment”. Full article

Butyrophilin-like 2 (BTNL2) is an immunomodulatory molecule critically involved in regulating the host immune response to infection with the avirulent Mycobacterium tuberculosis strain H37Ra. However, its functional role in modulating pyroptosis and associated inflammatory responses remains incompletely characterized. Here, we demonstrate that BTNL2 deficiency exacerbates pyroptosis and the inflammatory response in H37Ra-infected murine peritoneal macrophages via two distinct pathways. First, the loss of BTNL2 induces excessive mitochondrial damage, which leads to aberrant release of mitochondrial DNA (mtDNA) and accumulation of mitochondrial reactive oxygen species (mtROS), thereby triggering NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasome activation and gasdermin D (GSDMD)-mediated pyroptosis. Second, cytosolic mtDNA accumulation hyperactivates the cGAS–STING signaling axis, resulting in transcriptional upregulation of NLRP3 and consequent amplification of pro-inflammatory cytokine production. Collectively, these findings demonstrate that BTNL2 acts as a regulator of mitochondrial homeostasis and innate immune balance during H37Ra infection in primary peritoneal macrophages. The results provide mechanistic insights into BTNL2 function in the context of H37Ra-induced pyroptosis. Full article