Search Results (10,587)

Toll-like receptor 3 (TLR3) initiates antiviral and inflammatory responses exclusively through the adaptor protein TRIF (TIR-domain-containing adapter-inducing interferon-β). In contrast, MyD88 (myeloid differentiation primary response 88), a central adaptor for most other TLRs, is traditionally considered dispensable for TLR3 signaling. Here, we demonstrate that MyD88 directly contributes to TLR3-mediated NF-κB activation and cytokine production in macrophages. Bone marrow-derived macrophages (BMDMs) from MyD88 deficient mice exhibited significantly attenuated NF-κB activation in response to the TLR3 agonist polyinosinic–polycytidylic acid (poly(I:C)) compared to wild-type cells, as evidenced by the reduced phosphorylation of NF-κB p65 and IκBα, as well as IκBα degradation. Consistently, pro-inflammatory cytokine production, including IL-6, TNF-α, and IFN-β, was attenuated in MyD88-deficient BMDMs in vitro following stimulation by poly(I:C) or poly(A:U), another TLR3 agonist. Blood concentrations of IL-6, TNF-α, and IFN-β were significantly reduced in both TRIF-deficient mice and MyD88-deficient mice challenged by the i.p. injection of poly(I:C). Mechanistic analyses revealed that MyD88 physically associates with activated TLR3 upon poly(I:C) stimulation, and that TLR3 engagement triggered MyD88 oligomerization, which was absent in TLR3 or TRIF deficient macrophages. Our findings highlight a previously unrecognized dual-adaptor mechanism for TLR3, wherein MyD88 recruitment amplifies NF-κB signaling dynamics by bridging TLR3 to the canonical NF-κB activation cascade and robust cytokine induction. This study expands the paradigm of TLR3 signaling by establishing MyD88 as a direct contributor to TLR3-driven innate immune responses, offering new insight into cross-talk between MyD88-dependent and -independent pathways. Full article

Age-related macular degeneration (AMD) progresses to vision-threatening dry and wet forms, with no effective dry AMD treatments available. The sulfated polysaccharide (GNP, 25.8 kDa) derived from Gelidium crinale exhibits diverse biological activities and represents a potential source of novel therapeutic agents. This study employed a hydrogen peroxide (H₂O₂)-induced oxidative stress and epithelial–mesenchymal transition (EMT) model in retinal pigment epithelial (RPE) cells to investigate GNP’s protective mechanisms against both oxidative damage and EMT. The results demonstrated that GNP effectively suppressed oxidative stress, with the 600 μg/mL dose significantly inhibiting excessive reactive oxygen species (ROS) generation to levels comparable to untreated controls. Concurrently, at concentrations of 200–600 μg/mL, GNP inhibited NF-κB signaling and increased the Bax/Bcl-2 ratio, effectively counteracting H₂O₂-induced oxidative damage and cell apoptosis. Furthermore, in H₂O₂-treated ARPE-19 cells, 600 μg/mL GNP significantly reduced the secretion of N-cadherin (N-cad), Vimentin (Vim), and α-smooth muscle actin (α-SMA), while increasing E-cadherin (E-cad) expression, consequently inhibiting cell migration. Mechanistically, GNP activated the Nrf2/HO-1 pathway, thereby mitigating oxidative stress. These findings suggest that GNP may serve as a potential therapeutic agent for dry AMD. Full article

Discrimination between normal (fresh/non-frozen) and frozen-thawed beef is crucial for ensuring food safety. This paper proposed a novel, non-destructive and real-time you only look once for normal and frozen-thawed beef discrimination (YOLO-NF) model using deep learning techniques. The simple, parameter-free attention module (SimAM) and the squeeze and excitation (SE) attention mechanism were introduced to enhance the model’s performance. A total of 1200 beef samples were used, with their images captured by a charge-coupled device (CCD) camera. In the model development, specifically, the training set comprised 3888 images after data augmentation, while the validation set and test set each included 216 original images. Experimental results on the test set showed that the YOLO-NF model achieved precision, recall, F1-Score and mean average precision (mAP) of 95.5%, 95.2%, 95.3% and 98.6%, respectively, significantly outperforming YOLOv7, YOLOv5 and YOLOv8 models. Additionally, gradient-weighted class activation mapping (Grad-CAM) was adopted to interpret the model’s decision basis. Moreover, the model was deployed on the web interface for user convenience, and the discrimination time on the local server was 0.94 s per image, satisfying the requirements for real-time processing. This study provides a promising technique for high-performance and rapid meat quality assessment in food safety monitoring systems. Full article

Background/Objectives: Streptococcus pyogenes (Group A Streptococcus, GAS) is a major human pathogen that causes a wide spectrum of diseases. While mild infections like pharyngitis and impetigo are common, severe and invasive infections, though less frequent, pose significant health risks, particularly in children. In recent years, the re-emergence of hypervirulent GAS strains has heightened global concern. Nowadays, the absence of universally accepted guidelines compels clinicians to rely on a combination of clinical judgment, microbiological data and available evidence to manage these infections effectively. Our aim was to assess the current management of invasive GAS (iGAS) infections in Italy and the variability in therapeutic and preventive approaches. Methods: A web-based current clinical practice survey about invasive and severe GAS infections was designed according to the Checklist for Reporting of Survey Studies (CROSS) methodology and circulated among the members of the Italian Society of Pediatric Infectious Diseases (SITIP). Results: The survey reveals that while many practices are commonly shared among clinicians, particularly regarding first-line therapies (penicillin or ceftriaxone depending on the infection site), significant uncertainties remain, particularly about the use of combined antibiotic regimens and supportive treatments. The use of combined antibiotic regimens was considered appropriate as first-line therapy for STSS, NF and brain abscesses. Clindamycin was the preferred agent for combination with beta-lactam for most infections, except for brain abscesses, where linezolid was favored. However, there was disagreement regarding the optimal timing for de-escalation to beta-lactam monotherapy. Responses varied widely concerning the indications and dosages for IVIG, as well as the use of corticosteroids. Conclusions: Addressing the burden of invasive GAS (iGAS) infections in children requires enhanced surveillance, early recognition, prompt treatment and preventive strategies. Further work to increase surveillance, e.g., developing national registries, and to standardize the management of the disease, e.g., developing country-specific guidelines, is essential to build solid evidence on the most effective approaches. Full article

Six dietary groups were supplemented with graded vitamin C (VC) levels: VC1 (control, 0.39 g/kg), VC2 (0.51 g/kg), VC3 (0.66 g/kg), VC4 (0.81 g/kg), VC5 (0.97 g/kg), and VC6 (1.11 g/kg). Largemouth bass (Micropterus salmoides) with an initial weight of 2.21 ± 0.00 g were fed these diets for 8 weeks to evaluate the effects of different VC levels on growth performance, immune response, and heat stress resistance. Heat stress was induced at a constant temperature of 33.00 ± 0.16 °C for one week. The VC3 and VC4 groups showed significantly improved growth performance (FBW, WGR, SGR) compared to VC1 (p < 0.05). VC4 exhibited lower ALT and AST levels before and after heat stress. Antioxidant capacity (T-AOC, GSH-Px, CAT) was significantly enhanced in VC3–VC5, with VC5 showing the highest after stress activity (except CAT). Expression of pro-inflammatory genes (nf-κb, il-8) was downregulated in VC4 and VC5, while anti-inflammatory il-10 was upregulated in VC4 after stress. Apoptosis-related genes (bcl-2, caspase, bax) and TUNEL assays indicated the strongest anti-apoptotic effects in VC3 and VC4 under heat stress (p < 0.05). These findings suggest that VC supplementation in low-fishmeal diets enhances growth, immune response, apoptosis resistance, and acute heat stress tolerance in fish. Full article

Inflammatory muscle loss results from excessive inflammatory responses, causing muscle damage and weakness. In the current investigation, we evaluated the protective effects of diphlorethohydroxycarmalol (DPHC) against tumor necrosis factor-alpha (TNF-α)-induced skeletal muscle inflammation and muscle loss and elucidated the underlying mechanisms. Furthermore, the effect of DPHC on swimming performance was confirmed under TNF-α-induced inflammatory muscle loss-conditioned zebrafish by assessing the swimming number, distance moved, time spent swimming, frequency of swimming zebrafishes in an upstream swim track (Zone A). In vivo behavioral endurance test results indicated that TNF-α treatment significantly decreased the number of swimming zebrafish and swimming distance in Zone A compared with the Control. Meanwhile, the DPHC treatment significantly increased the number of swimming zebrafish and swimming distance in Zone A compared to TNF-α-induced zebrafish. These findings indicate that DPHC treatment effectively improved the swimming performance of TNF-α-induced zebrafish. In an additional study, TNF-α significantly induced inflammatory muscle loss by upregulating nuclear factor kappa light chain enhancer of activated B cells (NF-κB) mitogen activated protein kinase (MAPK) associated proteins and MuRF-1 in the skeletal muscle tissues of TNF-α-induced zebrafish. However, DPHC administration significantly counteracted TNF-α-induced inflammation and muscle loss by downregulating NF-Κb and MAPK-associated proteins, as well as the muscle degradation-related proteins MuRF-1 and MAFbx, in the skeletal muscle tissues of TNF-α-induced zebrafish. In summary, our research findings demonstrated that DPHC from Ishige okamurae could be used for the development of nutraceuticals or functional foods targeting inflammatory muscle loss. Full article

Ulcerative colitis (UC) is a chronic inflammatory bowel disease marked by disruption of the intestinal barrier and gut microbiota imbalance, leading to significant impairment in patient quality of life. This study investigated the therapeutic efficacy of a synbiotic formulation composed of purified fucoidan from bloom-forming Sargassum horneri and the probiotic Lactobacillus plantarum in a dextran sulfate sodium (DSS)-induced zebrafish model of UC. Polysaccharides from S. horneri were extracted using Celluclast-assisted extraction and fractionated via DEAE anion-exchange chromatography, resulting in six fucoidan fractions. The sixth fraction (SH-F), with a molecular weight of 254 kDa, showed the highest fucose, sulfate contents, and demonstrated the highest effect on promoting L. plantarum growth. Structural analysis revealed that SH-F contained α-L-Fucp-(1→3), α-L-Fucp-(1→4), β-D-Galp-(1→2,3,4), α-L-Fucp-(1→3,4), and terminal α-L-Fucp residues where Fuc₁(SO₃)₁, Gal1Fuc₁(SO₃)₁, and Fuc₂(SO₃)₂ were the most common glycans. Synbiotic administration significantly attenuated DSS-induced colonic shrinkage, inhibited pro-inflammatory cytokines (IL-6, TNF-ɑ, and IL-1β), restored tight junction proteins (ZO-1, occludin), and downregulated the iNOS, COX2, and NF-κB signaling pathway in adult zebrafish. 16S rRNA gene sequencing revealed restoration of gut microbial diversity and increased abundance of beneficial bacterial taxa to improve DSS-induced UC. These findings highlight the potential synergistic effects of SH-F and L. plantarum as a combinatorial strategy to regulate gut inflammation and enhance epithelial barrier function, potentially offering new insights and therapeutic opportunities for UC intervention. Full article

Autism spectrum disorder (ASD) is a neurodevelopmental condition marked by social/communication deficits and behavioral abnormalities, with neuronal apoptosis and immune-inflammatory dysregulation implicated in its pathogenesis. Marine-derived polysaccharides, particularly those from Enteromorpha prolifera (PEPs), exhibit neuroprotective and anti-inflammatory properties—yet their therapeutic potential for ASD remains unexplored. Major monosaccharide components of PEPs were identified as rhamnose, xylose, glucose, glucuronic acid, galactose, and ribose through ion chromatography analysis. Infrared spectroscopy confirmed PEPs as pyranose-type polysaccharides with α-glycosidic bonds and uronic acids, while gel permeation chromatography showed a predominant molecular weight of 3.813 kDa (83.919%). To explore the therapeutic potential of PEPs in ASD, a comprehensive method combining network pharmacology, molecular docking, and in vitro validation was conducted. A total of 235 ASD-related target proteins were predicted, with enrichment analyses indicating significant involvement in pathways such as neuroactive ligand–receptor interaction and the MAPK signaling pathway. In vitro assays using valproic acid (VPA)-induced HT22 neuronal cells showed that PEPs significantly attenuated apoptosis. Western blot analysis further confirmed the downregulation of HSP90AA1, cleaved CASP3/pro-CASP3, p-NF-κB1/NF-κB1, p-AKT1/AKT, and p-mTOR/mTOR, as well as the upregulation of IκBα after PEPs treatment. These findings suggest that PEPs exert neuroprotective effects through the modulation of apoptosis and inflammation-related signaling pathways, supporting their potential as a promising candidate for further study in ASD. Full article

Neuropathic pain is a chronic condition driven by intertwined mechanisms of oxidative stress, inflammation, and cellular senescence. Nerve injury and metabolic stress elevate reactive oxygen and nitrogen species, disrupt mitochondrial function, and activate the DNA-damage response, which stabilizes p53 and induces p16/p21-mediated cell-cycle arrest. These events promote a senescence-associated secretory phenotype (SASP) rich in cytokines, chemokines, and prostanoids that amplify neuroimmune signaling. In the spinal dorsal horn and dorsal root ganglia, microglia and astroglia respond to redox imbalance and danger cues by engaging NF-κB and MAPK pathways, increasing COX-2–dependent prostaglandin synthesis, and releasing mediators such as IL-1β and BDNF that enhance synaptic transmission and reduce inhibitory tone through KCC2 dysfunction. At the periphery, persistent immune-glial cross-talk lowers activation thresholds of nociceptors and sustains ectopic firing, while impaired autophagy and mitophagy further exacerbate mitochondrial dysfunction and ROS production. Collectively, these processes establish a feed-forward loop in which redox imbalance triggers senescence programs and SASP, SASP perpetuates neuroinflammation, and neuroinflammation maintains central sensitization—thereby consolidating a self-sustaining redox–senescence–inflammatory circuit underlying neuropathic pain chronicity. Full article

N6-methyladenosine (m6A) is a dynamic RNA modification that critically modulates gene expression in immune responses. While m6A regulators such as WTAP are implicated in inflammatory and autoimmune diseases, the mechanisms governing their expression during innate immune activation remain unclear. Here, we demonstrate that WTAP expression in human CD14⁺ monocytes is upregulated upon lipopolysaccharide (LPS) stimulation and is associated with alternative promoter usage leading to distinct mRNA isoforms. Bioinformatic analysis and pharmacological inhibition reveal that the transcription factor RELA (NF-κB pathway) directly contributes to this promoter-specific induction. Functional analyses show that both WTAP isoforms encode identical proteins, indicating transcriptional, rather than post-transcriptional, regulation. These findings uncover a novel NF-κB-dependent mechanism regulating WTAP isoform expression in activated monocytes, providing insight into the epitranscriptomic modulation of inflammation and potential dysregulation in autoimmune disease. Full article

This review explores the pharmacological potential of chondroitin sulfate and fucoidan as immunomodulatory agents targeting N-acetylgalactosaminidase (nagalase) to normalize immune responses. Nagalase, an enzyme produced by tumor and virus-infected cells, contributes to immune suppression by deactivating macrophage-activating factor. Both chondroitin sulfate and fucoidan, as representatives of glycosaminoglycans and heteropolysaccharides, exhibit significant potential in inhibiting nagalase activity, thereby restoring immune functionality. Chondroitin sulfate, a key component of the extracellular matrix, demonstrates anti-inflammatory and tissue-regenerative properties by modulating nuclear factor (NF)-κB pathways and cytokine expression. Fucoidan, a sulfated polysaccharide derived from brown seaweed, enhances immune responses through macrophage and natural killer cell activation, while also exhibiting antiviral and anticancer activities. This dual action positions these compounds as promising agents for therapeutic interventions in chronic inflammatory conditions, cancer, and infectious diseases. The synergistic effects of chondroitin sulfate and fucoidan highlight their potential to address the root causes of immune dysregulation. This review aims to elucidate the underlying mechanisms of action and explore the clinical applications of these compounds within the framework of innovative immunotherapeutic strategies. However, current evidence is limited by the predominance of preclinical studies and variability in experimental models. Well-designed clinical trials are needed to validate their efficacy for therapeutic use. Full article

This study aimed to evaluate the regenerative effects of various microcurrent waveforms in cast-induced gastrocnemius muscle atrophy in rabbits, integrating both in vitro and in vivo analyses. After two weeks of enforced hindlimb immobilization via casting, twenty-four rabbits were divided into four groups and treated for two weeks: Group-1 (control) received sham microcurrent, Group-2 was treated with a square waveform microcurrent, Group-3 with a sine waveform, and Group-4 with a triangular waveform. Treatments were administered daily for one hour. Calf circumference, muscle thickness (via ultrasound), tibial nerve CMAP, muscle fiber CSA, and protein expression (via Western blot analysis) were assessed. Among the groups, the sine waveform microcurrent resulted in significantly enhanced recovery across all measured parameters (p < 0.05), showing superior improvements in muscle thickness, CMAP amplitude, and fiber CSA. Immunohistochemical analysis revealed increased expression of proliferation and angiogenesis markers, including BrdU, PCNA, VEGF, and PECAM-1, while Western blotting demonstrated robust upregulation of myogenic regulatory factors such as MyoD and myogenin. Furthermore, levels of inflammatory and apoptotic markers, including TNF-α, NF-κB, and cleaved caspase-3, and stress response proteins, including p-CHK1 and p-CHK2, were markedly reduced. Collectively, these findings indicate that sine waveform microcurrent stimulation most effectively promotes muscle regeneration in both dexamethasone-induced C2C12 myoblasts and cast-induced muscle atrophy, underscoring its therapeutic potential and warranting further studies to optimize clinical application parameters. Full article

Zanthoxyli Pericarpium (ZP), the dried pericarp of mature fruits of Zanthoxylum schinifolium Siebold and Zucc., has traditionally been used in East Asian medicine for its medicinal properties, but its therapeutic potential in periodontitis has not been elucidated. In the present study, we investigated the effects of ZP on ligature-induced experimental periodontitis (EPD) in male Sprague Dawley rats. Animals were assigned to vehicle control, ligature control, ZP-treated (25, 50, and 100 mg/kg), or indomethacin-treated (5 mg/kg) groups (n = 10 per group) and orally administered the respective treatments daily for 10 days after ligature placement. ZP significantly reduced anaerobic bacterial proliferation and inflammatory cell infiltration in gingival tissue. ZP suppressed the production of inflammatory mediators, such as tumor necrosis factor-α and interleukin-1β, in both gingival tissues and lipopolysaccharide-stimulated RAW 264.7 macrophages, through inhibition of the mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways. In addition, ZP decreased myeloperoxidase activity and reduced matrix metalloproteinase-8 expression, thereby preserving collagen areas. ZP also restored the receptor activator of NF-κB ligand/osteoprotegerin (RANKL/OPG) balance, leading to a reduction in osteoclast numbers and their occupancy on the alveolar surface, and it effectively ameliorated horizontal alveolar bone loss. Furthermore, ZP exhibited antioxidant effects by lowering malondialdehyde levels and inducible nitric oxide synthase activity in gingival tissues. Statistical analysis was performed using ANOVA followed by a post hoc test, with significance set at p < 0.05. These findings indicate that ZP mitigates periodontitis through combined antimicrobial, anti-inflammatory, antioxidant, and anti-resorptive actions, supporting its potential as a therapeutic candidate for periodontitis. Full article

Brazilian red propolis (BRP) has emerged as a promising source of multifunctional phytochemicals with potent anti-inflammatory activity. This review provides a comprehensive analysis of the anti-inflammatory effects of BRP’s bioactive compounds, their molecular targets, and their mechanisms of action. Isolated compounds from BRP (such as formononetin, biochanin A, daidzein, calycosin, medicarpin, vestitol, and neovestitol) have demonstrated the ability to modulate critical pro-inflammatory signaling pathways, including NF-κB, TLR4, JAK/STAT, and PI3K/AKT, while concurrently activating antioxidant and cytoprotective responses via the Nrf2/HO-1 axis. These effects are further supported by the suppression of pro-inflammatory cytokines, regulation of immune cell infiltration and activation, inhibition of inflammasome components such as NLRP3, induction of autophagy, and polarization of macrophages and microglia from a pro-inflammatory (M1) to an anti-inflammatory (M2) phenotype. Collectively, these findings reinforce the potential of BRP as a rich source of multifunctional phytochemicals with broad therapeutic relevance for chronic inflammation and related pathologies. Future research should address the identified knowledge gaps by employing rigorous in vitro and in vivo toxicity assessments, exploring structure–activity relationships, and leveraging advanced delivery systems to optimize bioavailability. Such methodological approaches will be essential for translating the promising biological activities of BRP compounds into clinically viable therapeutic agents. Full article