Search Results (25,578)

Ultraviolet (UV) irradiation stimulates melanogenesis in melanocytes and melanin transfer to keratinocytes, where the former is mediated by pleiotropic factors such as SCF, α-MSH, and endothelin-1 (ET-1) secreted by keratinocytes. Therefore, the interaction between melanocytes and keratinocytes after UVB exposure appears to be critical to stimulating melanogenesis. The factors that are responsible for inflammation, one of the key biological processes, are crucial to forming the chronic inflammatory microenvironment in solar lentigines (hereafter called age spots). While chronic inflammation is thought to be involved in hyperpigmentation, the molecular mechanisms through which microinflammation affects melanocyte activation in age spots have not been elucidated. In our study, immunohistochemical analysis showed that the expression of the inflammatory factor IL-6R is enhanced in age spots. Specifically, in cultured keratinocytes irradiated with 10 mJ/cm² UVB, the expression of IL-6R was upregulated in UVB exposure- and age-dependent manners, and the co-culture of melanocytes with UVB-irradiated keratinocytes further demonstrated that melanocyte dendrites increased in length and number in a keratinocyte-age-dependent manner. Moreover, the suppression of IL-6R function in keratinocytes by an IL-6R-specific neutralizing antibody, Tocilizumab, inhibited melanocyte dendricity. These results indicate that the age- and UVB-dependent upregulation of IL-6R in keratinocytes stimulates melanocyte dendricity, which may also contribute to excessive melanin deposition in age spots. Full article

This study investigated the pro-inflammatory and pro-oxidative effects of popular electronic cigarette aerosols (ECAs) compared with conventional cigarette smoke (CS) in the cultured human alveolar epithelial cell line (A549). Using cytotoxicity assays and four ECAs, substantial differences in biological impact were observed. CS exposure led to significant declines in cell viability and pronounced morphological changes, consistent with the presence of toxic combustion byproducts. Most ECAs caused negligible cytotoxicity except for the tobacco-flavoured variant, which demonstrated marked toxicity. DNA damage and altered cell cycle profiles were minor. Oxidative stress analysis revealed stable superoxide dismutase activity but notable glutathione depletion, especially with watermelon- and strawberry-flavoured ECAs, and unaltered mitochondrial transmembrane potential, indicating the importance of individual flavour additives in cellular antioxidant defence. Inflammatory markers, such as TNF-α, NF-κB, and IL-6, were differentially elevated across the CS and ECA groups, with IL-6 consistently increased, underscoring its role in regulating epithelial cells. Advanced double fluorescence analysis revealed increased cellular heterogeneity and inflammation, which was distinct for all ECA flavours. Overall, the findings demonstrate considerable heterogeneity in biological effects among ECA flavourings and propose a simple ECA biomonitoring model. The results emphasise the necessity for individualised toxicity assessments, especially regarding subclinical inflammation and potential long-term health outcomes. Full article

Activation of cGAS, a receptor recognizing cytosolic DNA, in macrophages might be associated with rabies (an RNA virus) through mitochondrial damage. A similar mortality rate was observed between cGAS-deficient (cGAS-/-) and wild-type (WT) mice post-CVS-11 strain injection. However, 2 out of 12 cGAS-/- mice (but not WT) survived for 15 days post-injection. At 7 days post-infection, less severe brain inflammation in cGAS-/- mice was demonstrated by the viral abundance in the hippocampus, the expression of proinflammatory genes (TNF-α and IL-1β), and the Evans blue dye assay (blood–brain barrier defect) with the presence of higher anti-inflammatory genes (TGF-β and arginase-1). Fecal Proteobacteria was more prominent in the infected WT mice, while serum cytokines (TNF-α and IL-1β) were similar in both mouse strains. There were less prominent responses against the rabies virus in cGAS-/- macrophages than in WT cells, as indicated by supernatant IL-6 and the gene expression of TLR-3, RIG-1, MDA-5, and iNOS. On the other hand, mitochondrial injury and cGAS activation were more prominent in WT macrophages over cGAS-/- cells, as indicated by cGAS expression, supernatant cGAMP (a secondary messenger of cGAS), and mitochondrial oxidative stress (MitoSox) together with a decrease in mitochondrial DNA and maximal respiration (extracellular flux analysis). In conclusion, (i) rabies-damaged mitochondria led to cGAS activation that was less severe in cGAS-/- than in WT, (ii) rabies-induced dysbiosis was demonstrated, and (iii) cGAS manipulation and gut–brain axis-associated inflammation warrants further investigation. Full article

Background: Neurological disorders are the leading cause of disability, affecting over three billion people worldwide. Amyotrophic lateral sclerosis (ALS) is among the most feared and uniformly fatal neurodegenerative diseases, with no therapy capable of restoring lost function. Methods: We report the first application of therapeutic fever to ALS using Computerized Brain-Guided Intelligent Thermofebrile Therapy (CBIT²). This fully noninvasive treatment, delivered through an FDA-approved computerized platform, digitally reengineers the 1927 Nobel Prize-recognized malarial fever therapy into a modern treatment guided by the Brain–Eyelid Thermoregulatory Tunnel. CBIT² induces therapeutic fever through synchronized hypothalamic feedback, activating heat shock proteins, which are known to restore proteostasis and neuronal function. Case presentation: A 56-year-old woman was diagnosed with progressive ALS at the Mayo Clinic, with electromyography (EMG) demonstrating fibrillation and fasciculation indicative of denervation corroborated by neurological and MRI findings; the patient was informed that she had an expected survival of three to five years. A neurologist from Northwestern University confirmed the diagnosis and thus maintained the patient on FDA-approved ALS drugs (riluzole and edaravone). Her condition rapidly worsened despite pharmacological treatment, and she underwent CBIT², resulting in (i) electrophysiological reversal with complete disappearance of denervation; (ii) biomarker correction, including reductions in neurofilament and homocysteine, IL-10 normalization (previously linked to mortality), and robust HSP70 induction; (iii) restoration of gait, swallowing, respiration, speech, and cognition; (iv) reconstitution of tongue structure; and (v) return to complex motor tasks, including golf, pickleball, and swimming. Discussion: This case provides the first documented evidence that ALS can be reversed through digitally reengineered fever therapy aligned with thermoregulation, which induces heat shock response and upregulates heat shock proteins, resulting in the patient no longer meeting diagnostic criteria for ALS and discontinuation of ALS-specific medications. Beyond ALS, shared protein-misfolding pathology suggests that CBIT² may extend to Alzheimer’s, Parkinson’s, and related disorders. By modernizing this Nobel Prize-recognized therapeutic principle with computerized precision, CBIT² establishes a framework for large-scale clinical trials. A century after fever therapy restored lost brain function and so decisively reversed dementia paralytica such that it earned the 1927 Nobel Prize in Medicine, CBIT² now safely harnesses the therapeutic power of fever through noninvasive, intelligent, brain-guided thermal modulation. Amid a global brain health crisis, fever-based therapies may offer a path to preserve thought, memory, movement, and independence for the more than one-third of humanity currently affected by neurological disorders. Full article

Foxp3+ regulatory T (Treg) cells play a pivotal role in inducing immune tolerance. The expression of Foxp3 in Treg cells depends on the stability of transcription factors that are directly linked to the molecular interplay between Stat5a and cyclin-dependent kinase CDK8/19. In this study, dendritic cells obtained from C57BL/6 male mice were co-cultured with CD4⁺ splenocytes obtained from Balb/c male mice to obtain alloantigen-specific CD4⁺ T cells. Next, these alloantigen-specific CD4⁺ T cells were cultured with the addition of the CDK8/19 inhibitor AS2863619 compound, TGF-β1, and IL-2 to induce their transdifferentiation into alloantigen-specific CD4⁺ Foxp3+ Treg cells. The efficacy of this cocktail in promoting the transdifferentiation of activated CD4⁺ lymphocytes into alloantigen-specific Treg cells (ag-Tregs) was further evaluated using Nanostring gene expression profiling, flow cytometry, ELISA, and in vivo migration assays. The results showed that the addition of the AS2863619 compound along with IL-2 generated effector memory ag-Tregs exhibiting tolerogenic activity, migration properties, and mechanisms for regulating immune homeostasis in the spleen. In conclusion, these findings suggest that the AS2863619-derived effector memory Tregs possess functional properties that support immune tolerance and regulate homeostasis in the spleen, thereby regulating the affinity of naïve T cells to alloantigens, highlighting their potential relevance in transplantology. Full article

Neurological damage, a debilitating condition closely associated with chronic neuroinflammation, currently lacks disease-modifying treatments, with management limited to symptomatic relief. Vitamins B6 (VB6), B12 (VB12), and proteolipid protein 1 (PLP-1) exhibit multimodal neuroprotective and anti-inflammatory effects; however, their therapeutic potential is limited by low bioavailability and inadequate ability to cross the blood–brain barrier (BBB). To address these limitations, we developed an ursolic acid-based nanoparticle system for the intranasal co-delivery of VB6, VB12, and recombinant PLP-1. The PLP-1 model predicted by AlphaFold3 was used for molecular docking. The docking results confirmed high-affinity binding interactions with VB6 and VB12, elucidating the mechanistic basis of their synergy. In vitro studies using a glucose-deprived PC12 cell injury model identified an optimal synergistic molar ratio of 10:1:2 (VB6: VB12: PLP-1). This combination significantly upregulated neuroprotective markers (PLP-1 and PGC-1α) and downregulated the pro-inflammatory cytokine TNF-α. In a mouse model of neural damage, the nano-encapsulated combination therapy demonstrated improved pharmacokinetics and significantly attenuated neuroinflammation and oxidative stress in brain tissue. This was evidenced by lower TNF-α and IL-1β levels and elevated GSH and SOD concentrations compared to free drug controls. The treatment regimen showed no detectable hepatorenal toxicity. Our findings demonstrate that this nanoformulation represents a safe, effective, and promising disease-modifying strategy to treat vestibular dysfunction by synergistically targeting its underlying neuroimmunological mechanisms. Full article

Endometriosis involves oestrogen-dependent chronic inflammation and the abnormal proliferation of ectopic endometrial tissue. Conventional hormonal therapies suppress systemic oestrogen, but do not fully address local oxidative and inflammatory signalling. This review provides a mechanistic synthesis of recent molecular evidence. This evidence is on four FDA-recognized (Food and Drug Administration) medicinal plants. These are Curcuma longa, Zingiber officinale, Glycyrrhiza glabra, and Silybum marianum. The review highlights their capacity to modulate key intracellular pathways. These pathways are implicated in endometriosis. The review covers the integration of phytochemical-specific actions within NF-κB- (nuclear factor kappa-light-chain-enhancer of activated B cells), COX-2-(Cyclooxygenase-2), PI3K/Akt-(PI3K/Akt signaling pathway), Nrf2/ARE-(Nuclear factor erythroid 2–related factor 2) and ERβ-(Estrogen receptor beta) mediated networks, which jointly regulate cytokine secretion, apoptosis, angiogenesis and redox balance in endometrial lesions. Curcumin downregulates COX-2 and aromatase while activating Nrf2 signalling, shogaol from ginger suppresses prostaglandin synthesis and induces caspase-dependent apoptosis, isoliquiritigenin from liquorice inhibits HMGB1-TLR4–NF-κB (High Mobility Group Box 1, Toll-like receptor 4) activation, and silymarin from milk thistle reduces IL-6 (Interleukin-6) and miR-155 (microRNA-155) expression while enhancing antioxidant capacity. Together, these phytochemicals demonstrate pharmacodynamic complementarity with hormonal agents by targeting local inflammatory and oxidative circuits rather than systemic endocrine axes. This mechanistic framework supports the rational integration of phytotherapy into endometriosis management and identifies redox-inflammatory signalling nodes as future translational targets. Full article

Osteoarthritis (OA), the most prevalent form of arthropathy, is characterized by progressive degradation of cartilage, synovial inflammation, and other pathological changes that gradually affect the entire joint. Once regarded as a purely degenerative disease with minimal immune involvement, recent evidence reveals that chronic low-grade inflammation, insidiously fueled by the destructive crosstalk between cartilage and synovium, plays a key role in OA pathophysiology. Among the immune cells involved, eosinophils have emerged as unexpected yet significant contributors, exhibiting both pro-inflammatory and immunoregulatory properties. Traditionally associated with allergic responses and antiparasitic defense, eosinophils can also secrete anti-inflammatory cytokines along with specialized pro-resolving lipid mediators (SPMs) that promote macrophage polarization toward reparative M2 phenotypes. Eosinophils may sustain inflammation or, conversely, act as “silent modulators” that subtly shape the immune microenvironment and support tissue homeostasis. This immunological plasticity positions them at the intersection of joint damage and repair. This article explores emerging evidence on eosinophil activity in OA, emphasizing their dual nature and potential as therapeutic targets to shift the joint milieu from a pro-inflammatory state toward resolution. Understanding eosinophil-mediated pathways may pave the way for novel strategies to reduce synovial inflammation, preserve cartilage integrity, and improve clinical outcomes. Full article

The H6N6 avian influenza virus has expanded its host range from birds to mammals. Some strains can now bind to human-like receptors, raising concerns about human infection. Although H6N6 is a low-pathogenic avian influenza virus (LPAIV), it is unclear whether it triggers pyroptosis in human lungs, a process linked to cytokine storms in infections like H7N9. Here, we found that the chicken-origin H6N6 LPAIV can effectively replicate in and infect human alveolar macrophages and their M1 macrophages. Viral infection of M1 macrophages upregulated the mRNA levels of NLRP3, caspase-1, and Gasdermin D (GSDMD). Subsequently, caspase-1 was activated and cleaved GSDMD protein into its N-terminal fragment (GSDMD-N), which formed pores in the cell membrane and triggered the release of IL-1β and IL-18. Further analysis demonstrated that inhibition of the NLRP3/Caspase-1/GSDMD pathway by specific inhibitors attenuated pyroptosis in infected M1 macrophages. In summary, our study revealed that H6N6 virus infection induces M1 macrophage pyroptosis via the NLRP3/caspase-1/GSDMD pathway. Notably, M1 macrophages inherently produce pro-inflammatory cytokines; their pyroptosis, accompanied by the release of IL-1β and IL-18, can amplify inflammation and potentially trigger a cytokine storm in the lungs. These findings reveal novel pathogenic mechanisms and potential therapeutic targets for avian influenza viruses. Full article

Lycium barbarum L. (abbreviated to L. barbarum), a traditional dual-use plant as food and medicine, contains polysaccharides from Lycium barbarum L. (LBPs) as its key bioactive component. This study aimed to examine the phenotypic characteristics, polysaccharide content, and their correlation with activity across various commercial grades of L. barbarum. Five commercial grades of L. barbarum were selected for analysis to determine their phenotypic characteristics and polysaccharide content. High-performance liquid chromatogram-diode array detection (HPLC-DAD) and ¹H NMR were employed to analyze the monosaccharide composition of LBPs, of which their hypoglycemic activity was further valuated. Results revealed significant differences in fruit weight and diameter among different grades (p < 0.05), while floating rate and bulk density remained unaffected by grades. Variations were observed in the chromaticity coordinates, with the c values showing notable differences (p < 0.01). Polysaccharide content tended to increase with higher grades and smaller fruit sizes, ranging from 1.94% to 5.69%. The polysaccharides in different contained monosaccharides of Man, Rha, Ara, Gal, Glc, GalA, GlcA and Xyl, with Ara and Gal being predominant. Identified through ¹H NMR spectra, the peak intensity of Ara increased from lower to higher grades, and the arrangement of the chemical shifts reflected distinct commercial grade characteristics. The inhibitory concentration (IC₅₀) against α-amylase and α-glucosidase ranged from 0.418 to 1.345 mg/mL, and 0.474 to 1.052 mg/mL, respectively, indicating good hypoglycemic activity within this range. The main monosaccharide groups Ara, Gal, and GalA were identified as key contributors to enzyme inhibition. Collectively interpreting the phenotypic features, polysaccharide content, monosaccharide composition, NMR data and activity profiles, Ara, Gal and GalA emerge as signature monosaccharide components of LBPs. These results provide novel theoretical insights for L. barbarum quality assessment. Full article

Objectives: Bovine coronaviruses (BCoV) are endemic worldwide, causing diarrhea, winter dysentery, and bovine respiratory disease in newborn calves. These lead to higher calf mortality, reduced growth of fattening cows, and lower milk production in adult cows, resulting in significant losses to the cattle industry. Since commercial preventive drugs are not available in China, and existing treatments can only reduce the mortality of sick calves without fundamental control, the development of safe and effective vaccines is crucial. Methods: Two mRNA vaccines targeting the BCoV spiny receptor-binding domain (S-RBD) were prepared: XBS01 and XBS02. These two mRNAs, optimized for coding by AI and encapsulated in lipid nanoparticles (LNPs), were injected intramuscularly into mice (10 μg per mouse, twice, 2 weeks apart); a blank control group was not immunized. Serum antibodies, memory B/T cell activation and cytokine secretion were assessed by ELISA, flow cytometry and ELISpot. Results: Both vaccines induced humoral and cellular immunity:anti-S-RBD IgG titers were higher than those of the control group, and there was memory B-cell production and T-cell activation. XBS02 was superior to XBS01 in terms of peak antibody, memory B-cell frequency, T-cell activation rate, and IFN-γ/IL-2 secretion, and showed a stronger Th 1 response. Conclusions: Both BCoV S-RBD mRNA vaccines had good immunogenicity, with XBS02 providing better protection. This study supports the optimization and application of BCoV mRNA vaccines and accumulates data for mRNA technology in veterinary practice. Full article

Osteoarthritis (OA) involves cartilage breakdown and inflammation. This study compares juvenile and OA chondrocytes in gene expression, metabolism, and kinase activity, and tests mechanical stimulation to better understand cartilage health and degeneration. Juvenile (jCH) and OA (pCH-OA) primary chondrocytes were mechanically stimulated using the Flexcell™ FX5K system. Gene expression, protein phosphorylation, and metabolism were analyzed pre- and post-stimulation. Principal component analysis and effect size analyses identified molecular and signaling differences. Gene expression revealed significant differences between jCH and pCH-OA, with COL1 and RUNX2 upregulated in jCH, and MMP3 and ACAN downregulated. PCA revealed distinct expression patterns and marker correlations. Cyclic tensile strain affected biomarkers such as RUNX2, IL8, TLR4, BMP2, and MMP1 in a cell type-specific manner. Metabolic profiling indicated lower ROS and NAD⁺/NADH, and higher glutamate, lactate, and formate, with changes primarily driven by mechanical stimulation rather than cell type. Protein analysis showed altered AKT, STAT3, and MAPK phosphorylation, reflecting different mechanotransduction in healthy versus OA chondrocytes. Juvenile and OA chondrocytes show distinct molecular, metabolic, and signaling profiles, with mechanical stimulation driving key biomarker and metabolic changes. These differences highlight altered mechanotransduction in OA, providing insights into cartilage degeneration and potential therapeutic targets. Full article

Background: Chitosan and Lavandula angustifolia (lavender) exhibit antibacterial, antioxidant, and anti-inflammatory effects, making them potential candidates for managing infected wounds. This study investigated the therapeutic efficacy of a chitosan nanoparticle-loaded hydrogel, lavender extract, and their combination in treating Staphylococcus aureus-infected wounds in rats. Methods: Forty-eight male Sprague-Dawley rats (250–350 g, 8–10 weeks) were divided into six groups: healthy control, infected untreated, Fucidin, lavender extract, chitosan hydrogel, and chitosan–lavender combination. Wound healing was evaluated on days 3, 7, and 14 using clinical assessment, histopathology, and biochemical markers. Non-parametric statistical tests were applied, with significance set at p < 0.05. Results: The chitosan–lavender group showed the most pronounced healing response, with significantly reduced WBC counts, lower levels of TNF-α, IL-6, and MDA, and enhanced SOD activity (p < 0.05). Histological analysis confirmed superior re-epithelialization, granulation tissue development, collagen deposition, and wound contraction in chitosan-based treatments, particularly their combination, compared to lavender or Fucidin alone (p < 0.001). Inflammatory infiltrates, angiogenesis, necrosis, and hemorrhage were also notably reduced across treated groups. Conclusion: Combining chitosan hydrogel with lavender extract exerts synergistic antibacterial and wound healing effects, offering a promising alternative therapy for infected wounds. Full article

Long-duration space missions expose astronauts to galactic cosmic radiation (GCR), a complex spectrum of high-charge, high-energy (HZE) ions that pose significant risks of chronic tissue injury. To model these effects, we examined intestinal outcomes in wild-type mice 5 months after low-dose (50 cGy) 33-ion mixed-field GCR simulation (GCRsim). GCRsim induced sustained DNA double-strand breaks (DSBs) and oxidative stress, as shown by elevated γH2AX foci and 4-HNE staining. Intestinal epithelial cells (IECs) exhibited pronounced senescence, marked by increased SA-β-gal activity, p16 upregulation, LaminB1 loss, and induction of senescence-associated secretory phenotype (SASP) cytokines (Cxcl10, IL-6, IL-1β, Icam1). GCRsim also elevated circulating LINE-1 DNA and reduced expression of DNA-degrading nucleases (DNase2, TREX1), indicating impaired extracellular DNA clearance. Targeted molecular study revealed persistent activation of the cGAS–STING pathway, with elevated cGAS, STING, pTBK1, pIKKα/β, and nuclear pIRF3, pIRF7, and p65, consistent with chronic innate immune signaling. Functionally, GCRsim altered nutrient absorption gene expression—upregulating glucose transporters (Slc2a2, Slc2a5, Slc5a1) and gut hormones (Cck, Gip), while downregulating cholesterol/fat transporters (Npc1, Npc1l1). Biochemical markers supported intestinal injury, with decreased serum citrulline and increased intestinal fatty acid-binding protein (I-FABP), indicating barrier compromise. Collectively, these findings demonstrate that GCRsim drives sustained intestinal dysfunction, highlighting the need for countermeasures to protect GI health during deep-space missions. Full article

Artistic gymnastics is one of the most physically demanding sports, characterized by a high incidence of both acute and chronic injuries. Although previous research has primarily focused on biomechanical and training-related factors, the multifactorial etiology of injuries—including molecular and genetic aspects—remains insufficiently explored. This systematic review aimed to synthesize current evidence on the causes, mechanisms, and prevention of injuries in artistic gymnastics, with particular emphasis on biomechanical, molecular, and genetic determinants of injury risk and athletic performance. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines and was registered in the PROSPERO database (Registration No: CRD420251167521). Electronic databases (PubMed, KoBSON, and Google Scholar) were searched for studies published between 2015 and 2025 using the keywords “gymnastics injuries,” “overuse injuries,” “injury prevention,” “biomechanics,” “IL-6,” “TNF-α,” and “miRNA biomarkers.” Nineteen studies met the inclusion criteria and were analyzed based on injury incidence, localization, mechanisms, and molecular and genetic associations. The majority of injuries were localized in the joints of both upper and lower extremities, particularly during puberty and at higher competitive levels. Repetitive loading, improper technique, and insufficient recovery were identified as the main etiological factors. Molecular biomarkers such as IL-6, TNF-α, and miRNAs (miR-155, miR-146a) were found to play key roles in inflammatory responses, while genetic polymorphisms including ACTN3 R577X, ESR1 rs2234693, and CYP19A1 rs936306 were associated with flexibility, explosive strength, and susceptibility to injury. Injury prevention in artistic gymnastics requires a personalized and multidisciplinary approach that integrates biomechanical, clinical, molecular, and genetic data. Incorporating molecular and genetic profiling into training and rehabilitation programs may enhance early detection of overuse conditions and optimize both health and performance outcomes in gymnasts. Full article