Background Immunotherapy targets for oral squamous cell carcinoma (OSCC) are scarce. Immunogenic cell death (ICD) mediated anti-tumor immunity provides a new direction for prognosis evaluation and treatment of OSCC, but the related core markers and targeting strategies are not clear. Objectives This study aims to systematically identify ICD-related core prognostic markers for OSCC, construct an effective prognostic risk model, and explore potential targeted immunotherapy strategies against these core markers. Methods In this study, the OSCC transcriptome and single-cell sequencing data of TCGA and GEO databases were integrated. ssGSEA and WGCNA were used to screen the differentially expressed genes related to ICD, and Cox regression was used to construct a prognostic model. The expression characteristics of core genes were verified by single-cell analysis and immunohistochemistry. Drug candidates were screened by DGIdb drug prediction and molecular docking. In vitro cell experiments were performed to verify its regulatory effect on CD8+ T cell-mediated anti-tumor immunity. Results CTLA4, TNFRSF4, and CD5 were selected as core prognostic genes according to the hazard ratio (HR) < 0.7 and the genes with excessive confidence intervals were removed. The risk model constructed in this study could stratify OSCC patients into distinct prognostic groups, with area under the curve (AUC) values for 1-, 2-, and 3-year overall survival reaching 0.625, 0.600, and 0.604 in the training set, and 0.673, 0.667, and 0.661 in the validation set. The TNFRSF4 expression signal was concentrated in T cell clusters. The small molecule Compound 1 was predicted as a potential drug to target TNFRSF4, and the binding energy of TNFRSF4 was -9.6 kcal/mol. TNFRSF4 protein expression was upregulated in CD8+ T cells co-cultured with OSCC cells after C1 treatment (P < 0.05). Compound 1 could activate CD8+ T cells, enhancing tumor-killing activity and inducing apoptosis of OSCC cells (P < 0.05). Conclusion CTLA4, TNFRSF4, and CD5 can be used as prognostic markers of OSCC, and TNFRSF4 is a potential immunotherapy target. Compound 1 may activate CD8+ T cell-mediated anti-tumor immunity by targeting TNFRSF4, which provides a new strategy for the immunosensitization therapy of OSCC.
Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss. This review summarizes recent advances in therapeutic strategies, with particular emphasis on gene therapy, stem cell approaches, and modulation of autophagy. Methods Recent literature on established and emerging therapeutic approaches for ALS was reviewed, focusing on disease-modifying therapies, gene-based interventions, stem cell therapies, autophagy modulation, and related translational developments. Results Recent literature highlights both established disease-modifying treatments, such as riluzole, edaravone, and tofersen, and emerging approaches, including antisense oligonucleotides, RNA interference, genome editing, stem cell transplantation, and autophagy-enhancing compounds. These strategies target key pathogenic mechanisms, including genetic mutations, neuroinflammation, and protein aggregation. While conventional pharmacological therapies offer limited benefit, novel molecular and cellular interventions demonstrate potential to modify disease progression. Gene therapies target mutation-specific pathways, stem cell-based therapies promote neuroprotection and immune modulation, and autophagy inducers aim to clear misfolded proteins. Despite encouraging preclinical and early clinical outcomes, challenges remain in delivery efficiency, disease heterogeneity, and biomarker development. Conclusion Therapeutic development in ALS is shifting toward precision medicine. Integration of personalized interventions and validated biomarkers is essential to improve treatment efficacy and patient outcomes.
Background Cytotoxic CD8+ T lymphocytes kill cancer cells and thus contribute to anti-tumor immunity during immunotherapy. Sushi repeat containing protein X-linked (SRPX) is dysregulated in glioblastoma (GBM), but its functional roles remain incompletely understood. Objectives This study aimed to elucidate the functional role of SRPX in mediating malignant phenotypes of GBM cells and promoting CD8⁺ T lymphocyte apoptosis in GBM in vitro. Methods SRPX and cAMP response element binding protein 1 (CREB1) expression were analyzed in human GBM specimens and cell lines. Functional consequences of SRPX manipulation were assessed by cell proliferation, colony formation, migration, and invasion. CD8+ T cells were co-cultured with GBM cells and checked for apoptosis with TUNEL staining. The transcriptional regulation of SRPX by CREB1 was validated through chromatin immunoprecipitation (ChIP) and dual-luciferase assays. Results SRPX mRNA and protein levels were significantly elevated in GBM tumors compared with peritumoral tissues (p < 0.001). High SRPX expression predicted poor prognosis of GBM patients. SRPX knockdown reduced EdU-positive cells by 36–40%, colony formation by 60–70%, wound closure by 25–30%, and invasive cells by 45–62% across two GBM cell lines (all p < 0.01). SRPX overexpression increased CD8⁺ T cell apoptosis by ∼1.5–2-fold, whereas SRPX silencing decreased it by ∼50% (p < 0.001). Mechanistically, CREB1 bound to the SRPX promoter (p < 0.001) and activated its transcription, as confirmed by luciferase assays (∼70% reduction in activity upon CREB1 knockdown, p < 0.01). CREB1 silencing reduced GBM cell proliferation, migration, and invasion, and decreased CD8⁺ T cell apoptosis (all p < 0.001); all these effects were partially reversed upon SRPX re-expression (all p < 0.01). Conclusions Within the limitations of in vitro models, the CREB1/SRPX axis promotes CD8⁺ T cell apoptosis and is associated with enhanced proliferation, migration, and invasion in GBM cell lines. These in vitro findings suggest a candidate immunomodulatory mechanism that warrants further investigation in physiologically relevant models. Importantly, all conclusions are strictly confined to in vitro experimental systems; animal data were withdrawn due to irreproducible quality and are not included, and no in vivo or clinical implications can be drawn from the present study.
Background Osteoarthritis (OA) is a degenerative joint disease characterized mainly by cartilage degeneration, with a global incidence of approximately 3.6%. Homeobox D11 (HOXD11) is downregulated in OA cartilage and is associated with OA progression. Objectives The aim of this study was to explore the impact of HOXD11 on IL-1β-induced chondrocyte injury. Methods The cell counting kit-8 assay was employed to detect cell viability. The western blot assay was used to evaluate the levels of target proteins and transfection efficiency in cells. Lactate dehydrogenase release was detected using a lactate dehydrogenase detection kit. The apoptosis rate of cells was detected by flow cytometry. The secretion of inflammatory factors in the cell culture supernatant and cells was detected by enzyme-linked immunosorbent assay, qRT-PCR and western blot. Co-immunoprecipitation was used to detect ubiquitination modification. Results HOXD11 was lowly expressed and tripartite motif containing 15 (TRIM15) was highly expressed in interleukin-1β (IL-1β)-induced ATDC5 cells. Overexpression of HOXD11 could inhibit IL-1β-induced apoptosis and release of inflammatory factors in ATDC5 cells. Mechanistically, TRIM15 could mediate the ubiquitination modification and degradation of HOXD11, thereby accelerating IL-1β-induced ATDC5 cell injury. Conclusions TRIM15 promotes IL-1β-induced chondrocyte damage by mediating the ubiquitination modification and degradation of HOXD11, which might provide a potential strategy for the treatment of OA.
Background Diabetic nephropathy (DN) is characterized by mesangial cell (MC) injury, extracellular matrix (ECM) deposition, and inflammatory imbalance, yet the upstream transcriptional mechanisms remain poorly understood. Objectives This study aimed to dissect transcriptomic features of DN MCs and elucidate key regulatory axes through integrative transcriptomics and functional validation. Methods GSE96804 and GSE209781 datasets were integrated to identify differentially expressed genes (DEGs) common to DN glomeruli and MCs. Intersecting DEGs were subjected to GO and KEGG enrichment analyses. Core transcription factors and downstream effectors were identified using transcription factor (TF) enrichment analysis and random forest machine learning. In high glucose (HG)-induced MCs, overexpression, ChIP-qPCR, dual-luciferase reporter, and functional rescue experiments were performed to validate regulatory mechanisms and effects on cell injury. Results Integrative transcriptomics identified 63 genes commonly dysregulated in DN glomeruli and MCs. Transcription factor enrichment revealed nuclear factor I/C (NFIC) as a key upstream regulator, significantly downregulated in DN. Dual-specificity phosphatase 1 (DUSP1) was identified as the core downstream effector, showing strong positive correlation with NFIC (r = 0.746, P < 0.001). Mechanistically, NFIC directly bound to the DUSP1 promoter to initiate its transcription, and HG-induced DUSP1 downregulation was reversed by NFIC overexpression. Functionally, NFIC overexpression attenuated HG-induced ECM deposition, oxidative stress, and inflammatory responses. DUSP1 silencing reversed these protective effects, confirming DUSP1 as a key downstream mediator. Conclusion NFIC inhibits HG-induced MC injury by directly activating DUSP1 transcription, thereby suppressing ECM deposition, oxidative stress, and inflammation.
Background Osteoporosis is a bone disease characterized by reduced bone mass and microstructural deterioration, leading to increased fragility and fracture risk, which significantly impairs patient health and quality of life. Although SMAD family member 5 (SMAD5) has been reported to be downregulated in osteoporosis and to facilitate osteogenic differentiation, its underlying mechanisms remain poorly defined. Methods Human bone marrow mesenchymal stem cells (hBMSCs) were characterized using flow cytometry. Protein expression was examined by Western blot, and proliferation was measured via EdU assay. Osteogenic differentiation was induced using dexamethasone, β-glycerophosphate, and ascorbic acid, and assessed through alkaline phosphatase and alizarin red staining. SMAD5-interacting molecules were identified using UbiBrowser, STRING, BioGRID, and DeeP-PLA databases. Interactions between NEDD4 and SMAD5, and between SMAD5 and HDAC1, were confirmed by co-immunoprecipitation (Co-IP). Results SMAD5 knockdown inhibited hBMSC proliferation, early osteogenic differentiation, and late mineralization. NEDD4 promoted SMAD5 ubiquitination and degradation, while SMAD5 overexpression reversed the inhibitory effect of NEDD4 on osteogenesis. HDAC1 deacetylated SMAD5, and SMAD5 upregulation alleviated the suppression of osteogenic differentiation caused by HDAC1 overexpression. Conclusion NEDD4 and HDAC1 independently reduce SMAD5 protein levels and inhibit osteogenic differentiation in hBMSCs, via mediating ubiquitin-dependent degradation and deacetylation of SMAD5 respectively.
Background Ion channels are crucial regulators of cellular signaling and homeostasis, and their failure is associated with various clinical illnesses, including neurological disorders, cardiovascular diseases, and cancer. This review seeks to analyze the changing dynamics of ion channel pharmacology, emphasizing both conventional and innovative therapeutic approaches, new molecular targets, and translational obstacles. Methods A thorough examination of recent developments in ion channel research was performed, emphasizing traditional and novel pharmacological strategies, such as small-molecule modulators, allosteric regulators, biologics, and nucleic acid-based therapeutics. Special emphasis was placed on recently validated targets, including Transient Receptor Potential (TRP) channels, Acid-Sensing Ion Channels (ASICs), Piezo mechanosensitive channels, and other potassium channel subtypes. The therapeutic potential of microbial ion channels as specific antibacterial targets was also investigated. Technological breakthroughs such as cryo-electron microscopy (cryo-EM), artificial intelligence (AI)-assisted drug development, CRISPR-based gene editing, and sophisticated drug delivery systems were assessed on their potential to address existing pharmacological difficulties. Results Recent advancements have broadened the range of therapeutically significant ion channel targets and facilitated the creation of more selective and effective modulators. Structural insights derived from cryo-EM and AI-assisted modeling have enabled rational medication design and enhanced subtype selectivity. Innovative methodologies like pharmacogenomics and precision medicine are improving the optimization of therapies tailored to individual patients. Microbial ion channels are a promising but underutilized category of antibacterial targets owing to their structural differences from human orthologs. Notwithstanding these advancements, difficulties persist, including off-target toxicity, subtype selectivity, and blood-brain barrier permeability. Conclusions Ion channels constitute a dynamic and promising arena for next-generation precision therapies. The ongoing combination of structural biology, artificial intelligence, gene-editing technologies, and targeted delivery methods is anticipated to expedite the advancement of safer and more effective ion channel–based medicines customized for specific patient profiles.
Background Pathological changes in Alzheimer's disease (AD) begin decades before clinical symptoms appear, highlighting the urgent need for non-invasive, reliable, and cost-effective blood-based biomarkers for early detection and staging. Objectives To identify plasma proteomic biomarkers for early diagnosis and staging of AD. Methods DIA-based high-resolution mass spectrometry was applied to plasma samples from 53 AD patients and 36 controls. A total of 2943 proteins with ≥70% valid values were quantified. Bioinformatics analyses identified dysregulated proteins and pathways, and machine learning models were trained and validated using cross-validation methods to construct diagnostic biomarker panels. Results AD patients showed downregulation of mitochondrial, nuclear, and plasma membrane proteins. Enrichment analysis highlighted alterations in cellular respiration and oxidative phosphorylation. Machine learning identified two biomarker panels: MBP (Myelin Basic Protein) /SOD2 (manganese superoxide dismutase) distinguished AD from controls (AUC=0.795; 70% accuracy, 58% specificity, 89% sensitivity), while MBP/PSMD10 (26S proteasome non-ATPase regulatory subunit 10) yielded an AUC of 0.996 for distinguishing mild-to-moderate AD within this strictly controlled pilot cohort (AUC=0.996; 94% accuracy, 100% specificity, 87% sensitivity). Conclusion The MBP/PSMD10 panel represents an exploratory, stage-specific candidate signature requiring rigorous cross-validation in heterogeneous, real-world prospective cohorts.
Background PD-1/PD-L1 immunotherapy has transformed lung cancer treatment, but resistance and variable responses persist due to tumor immune microenvironment (TIME) heterogeneity. Methods We review advances using single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and AI-assisted immunoprofiling that dissect TIME heterogeneity at unprecedented resolution. Key findings on tumor heterogeneity, T cell exhaustion, myeloid polarization, and stromal reprogramming are synthesized. Results Multi-omics integration has uncovered resistance mechanisms and identified predictive biomarkers (e.g., T cell inflamed signature, myeloid score, CAF activation status). Translational applications include TIME-based patient stratification, combination strategies, and neoadjuvant immunotherapy. Limitations include high cost, lack of standardization, and batch effects. Conclusion Overcoming future translational bottlenecks—cost reduction, workflow standardization, and functional validation—requires spatiotemporal multi-omics and AI-driven trials. This review provides a concise roadmap for precision immuno-oncology in lung cancer. (Figure 1)
Background The pathological healing process of keloids is characterized by the persistent proliferation of fibroblasts and an imbalance between extracellular matrix (ECM) synthesis and degradation. Objective This study aims to elucidate the key molecular regulators and signaling pathways involved in collagen deposition and ECM remodeling, and to identify novel therapeutic targets for keloid management. Methods An integrated analysis was performed combining transcriptomic data from the Gene Expression Omnibus (GSE218007) and proteomic profiling of keloid and normal skin tissues. Key targets were selected by intersecting differentially expressed genes (DEGs) and proteins (DEPs) with fibrosis-related gene sets from the GeneCards database and further refined using a random forest (RF) machine learning algorithm. Additionally, weighted gene co-expression network analysis was constructed to identify clinically significant modules. Functional validation was conducted using quantitative real-time polymerase chain reaction analysis, Western blotting, Transwell migration assay, and wound-healing assay in keloid fibroblasts (HKF-SV40). Mechanistic studies involved chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays to investigate transcriptional regulation. Results Asporin (ASPN) was identified as a hub gene exhibiting the most pronounced upregulation in keloid fibroblasts. ASPN was associated with the transforming growth factor-beta (TGF-β) signaling pathway. ASPN knockdown significantly inhibited collagen deposition by downregulating collagen type I Alpha 1 chain (COL1A1) and collagen type III Alpha 1 chain (COL3A1), facilitated ECM remodeling by upregulating matrix metalloproteinase 1 (MMP1) and matrix metalloproteinase 3 (MMP3), and suppressed cell migration. Furthermore, ASPN silencing reduced the expression of alpha-smooth muscle actin (α-SMA) and inactivated the TGF-β/SMAD signaling pathway. Mechanistically, the transcription factor activating transcription factor 3 (ATF3) transcriptionally activated ASPN expression. Further, ATF3 knockdown inhibited collagen deposition, cell migration and the TGF-β/SMAD pathway activation, while promoting ECM remodeling; however, these effects were reversed by ASPN overexpression. Conclusion The ATF3/ASPN axis might promote collagen deposition and fibrotic progression by activating the TGF-β/SMAD signaling pathway. These findings suggest that targeting the ATF3/ASPN axis may offer a promising therapeutic strategy for keloids.
Background Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide. Dysregulation of circadian clock genes (CCGs) plays a vital role in the progression of various cancers, including HCC. However, comprehensive bioinformatic analyses evaluating the prognostic significance of CCGs in HCC remain limited. Objective This study aimed to develop a CCG-based prognostic signature and evaluate its predictive value relative to conventional TNM staging. Methods Differential expression analysis of CCGs between HCC and normal tissues was performed using The Cancer Genome Atlas (TCGA) and GSE76427 datasets. A protein-protein interaction network was constructed, and pathway enrichment analysis was conducted. A prognostic signature was developed using LASSO‑Cox regression, and its predictive performance was evaluated through survival analysis, time‑dependent ROC curves, and independent validation. Results Differential expression analysis identified 232 CCGs dysregulated in HCC. This study constructed a four-gene prognostic signature (DUSP13, HAAO, FLT3, IL1RN) to stratify patients into high- and low-risk groups. The high‑risk group exhibited significantly shorter overall survival (P < 0.0001). Notably, multivariate Cox regression validated the risk score as an independent prognostic factor (HR = 12.86, P < 0.05), with predictive performance (1-, 3-, and 5-year AUCs: 0.700, 0.669, and 0.638) that complements conventional staging. A nomogram integrating the risk score with clinical variables showed improved calibration over TNM stage alone, although the improvement was only moderate. Conclusion The four-CCG signature provides independent prognostic information beyond TNM staging in HCC. However, these findings are derived entirely from in silico analysis and require experimental validation before clinical translation.
Background Chronic kidney disease (CKD) is a major global public health problem with a standardized global prevalence of 15–20%, and renal fibrosis serves as a common irreversible pathological feature of all progressive CKDs, ultimately leading to end-stage renal disease (ESRD). While metabolic reprogramming and epigenetic dysregulation have been identified as core interrelated mechanisms, current clinical interventions remain limited to symptomatic care due to the incomplete elucidation of the complex regulatory network involved. Role of lactylation Lactylation, a novel histone post-translational modification that uses lactate—a core glycolytic metabolite—as the substrate, establishes a direct molecular bridge between glycolytic metabolism and epigenetic regulation. This modification has emerged as a research hotspot in renal fibrosis, influencing metabolic states, inflammatory responses, and fibrogenesis by modulating protein function and key gene transcription. Research progress This review systematically elaborates on the theoretical basis of lactylation (discovery, molecular mechanism, and biological functions) and the core pathophysiological characteristics and regulatory mechanisms of renal fibrosis from the perspective of metabolic-epigenetic crosstalk. It systematically reviews the theoretical basis of lactylation and the research progress in regulating key pathological processes of renal fibrosis, including epithelial-mesenchymal transition (EMT), fibroblast activation, and inflammatory microenvironment regulation. Challenges and controversies The review summarizes the unresolved scientific controversies, methodological limitations, and technical challenges in this field, such as the lack of specific lactylases and the poor specificity of detection antibodies. Furthermore, the review discusses field-specific ethical frameworks and clinical translation barriers unique to metabolic-epigenetic research in nephrology. Future directions Potential therapeutic targets and key translational research directions are proposed. The review specifically highlights the influence of sex and age on lactylation dynamics and advocates for the development of selective modulators, non-invasive detection methods, and large-scale clinical cohort studies. Conclusion By integrating theoretical foundations, mechanistic insights, and ethical considerations, this review provides a comprehensive academic perspective for studying the metabolic-epigenetic regulatory network of renal fibrosis, laying a theoretical foundation for developing novel targeted therapeutic strategies.
Background Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common functional gastrointestinal disease. Buzhong Yiqi Decoction combined with Fuzi Lizhong Decoction (BZFZ) has been clinically prescribed for IBS-D treatment. However, the precise mode of action and active components have not yet been elucidated. Objectives This study aims to assess the ability of BZFZ to treat IBS-D and to elucidate the underlying mechanism. Methods First, the identification of the active components and targets among BZFZ, IBS-D, and neuroprotection was performed through network pharmacology, network construction, Venn analysis, bioinformatics, machine learning, and molecular docking. Next, an IBS-D rat model was constructed to investigated the role of BZFZ in vivo. Moreover, the effects of BZFZ were assessed based on the fecal output, fecal water content (FWC), abdominal withdrawal reflex (AWR), and sucrose preference test. The factors that regulated the BZFZ effects on IBS-D were estimated using ELISA, western blot, and immunohistochemistry. Results Four targets (MET, RAP1A, IRAK1, and AGTR1) related to the neuroprotection effect of BZFZ in IBS-D patients were identified. BZFZ treatment significantly improved diarrhea, visceral sensitivity, depressive behavior, and intestinal permeability induced by IBS-D by increasing the abundance of intestinal tight junctions, decreasing the levels of pro-inflammatory cytokines (all P < 0.05). The expression of IRAK1 was upregulated in IBS-D rats, accompanied by elevated P-JNK, P-ERK, and P-P38 within the MAPK signaling pathway (all P < 0.05). BZFZ treatment decreased IRAK1 levels and inhibited the MAPK signaling pathway (all P < 0.05). Conclusions These results demonstrated that BZFZ alleviated depression and intestinal symptoms and restored the intestinal barrier function of IBS-D, accompanied with inhibition of the IRAK1/MAPK signaling pathway, offering significant insights into the potential molecular mechanisms of BZFZ.
In species distribution modeling (SDM), the environmental representativeness effect hinders the comparison and generalization of discrimination statistics, as their values are context-dependent and may vary without reflecting actual differences in model accuracy. To address this issue, a harmonization approach based on the uniform distribution of suitability values has been proposed, demonstrating effectiveness when true absence data are available. However, in most cases, models solely rely on presence records and use background points instead of true absences, posing additional validation challenges. This study simulates habitat suitability and presence-absence data, and evaluates the robustness of several validation indices: background-based AUC (AUCb), its harmonized version (uAUCb), and two variations of the Boyce index. The results show that the Boyce index remains unaffected by the representativeness effect, whereas AUCb varies across scenarios, confirming the influence of the representativeness effect on SDM results with background data. Harmonization through uAUCb successfully makes values comparable, but its reliability depends on sample size, requiring at least 100 presences and 10000 background points.
The rising challenge of antimicrobial resistance creates an urgent need for new antimicrobial agents. In this study, a series of polynuclear pyrene-based pyrazole derivatives was designed and synthesized using an efficient synthetic method. The structures of the synthesized compounds were confirmed by standard spectroscopic techniques, including NMR and mass spectrometry. The antimicrobial activity of these compounds was evaluated in vitro against selected Gram-positive and Gram-negative bacterial strains, and their potency was determined using minimum inhibitory concentration (MIC) values. Pyrazole 4g displayed promising antibacterial and antifungal activity against S. aureus, producing an inhibition zone of about 35mm and against A. flavus, with an inhibition zone of 41mm respectively. Among the tested compounds, pyrazole 4g showed the most promising antibacterial and antifungal activity, with low MIC values of 8.0 mu g/mL against Staphylococcus aureus and 14.0 mu g/mL against Aspergillus flavus, comparable to standard drugs. Molecular docking studies supported the experimental results (Delta G = -9.2 kcal/mol) by revealing stable binding modes and key hydrogen-bond and hydrophobic interactions within bacterialtar-get enzymes. Structure-activity relationship analysis highlighted the importance of the pyrazole core and suitable heterocyclic substitution for enhanced antimicrobial activity. Overall, these findings suggest that heterocyclic biphenyl-based pyrazoles are promising lead compounds for further antimicrobial development.
Background: Lactobacillus species are widely used as probiotics and may influence host immunity, but their effects on tumor progression are context-dependent. Objective: To evaluate whether oral exposure to a tumor-derived Lactobacillus rhamnosus isolate is associated with pancreatic tumor growth, gut microbiota alterations, and immune changes in a mouse model. Methods: A human pancreatic tumor-derived L. rhamnosus isolate was studied in vitro and in vivo. Pancreatic cancer cell lines were treated with bacterial culture supernatant to assess proliferation and migration. C57BL/6J mice bearing subcutaneous KPC tumors received oral gavage or intratumoral injection of L. rhamnosus. Cecal microbiota was analyzed by 16S rRNA sequencing. Tumor immune infiltration was evaluated by immunohistochemistry and flow cytometry. Results: L. rhamnosus supernatant showed no significant effects on pancreatic cancer cell proliferation or migration in vitro (all p > 0.05). Oral exposure to L. rhamnosus was associated with accelerated tumor growth (1402 +/- 421 vs. 1018 +/- 348 mm & sup3;; p = 0.0239), whereas intratumoral injection showed no effect (p > 0.05). Oral exposure was also associated with reduced intratumoral CD8(+) T-cell infiltration (0.29% +/- 0.26% vs. 0.69% +/- 0.23%; p = 0.0097) and lower T helper 1 (Th1) cell proportion (1.1% +/- 0.5% vs. 3.9% +/- 2.2%; p = 0.0068). No significant differences were observed in tumor-associated macrophages, regulatory T cells, or myeloid-derived suppressor cells (all p > 0.05). Conclusion: In this mouse model, oral exposure to this L. rhamnosus isolate was associated with accelerated tumor growth, altered gut microbiota, and reduced intratumoral T-cell infiltration. Causality was not established; these findings are observational and hypothesis-generating.
Background: Acute myocardial infarction (AMI) is one of the leading causes of death worldwide. Objectives: This study aims to identify key genes associated with AMI using bioinformatics and explore their functions. Methods: In this study, weighted gene coexpression network analysis (WGCNA) and machine learning were used to filter out ORM1 in AMI from the proteomic dataset (PXD028664). The protein expression of ORM1, ACSL4, GPX4, and FIH1 was detected using western blot. An in vitro model of hypoxia/reperfusion (H/R) injury was established with AC16 cells. Cell viability was measured with the cell counting kit-8 (CCK-8) method. The levels of lactate dehydrogenase (LDH), malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), and Fe2+ were analyzed with commercial kits. The pro-inflammatory factors, including tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and IL-6, were determined via ELISA. Flow cytometry was used to measure reactive oxygen species (ROS) and cell apoptosis. Results: Increased ORM1 protein expression in AMI patients from the dataset and the hospital was observed. ORM1 exhibited significant diagnostic value for AMI. Knocking down of ORM1 alleviated cell apoptosis, inflammatory response, oxidative stress, and ferroptosis in H/R-induced AC16 cells. Furthermore, ORM1 downregulation reduced the activation of TLR4 and p-p65. Conclusions: The ORM1 regulated cell apoptosis, inflammatory response, oxidative stress, and ferroptosis in H/R-induced AC16 cells via the TLR4/NF-kappa B pathway, providing novel insights for understanding the regulatory mechanism and therapeutic strategy of AMI.
Objective: Tenascin-C (TNC) has emerged as an endogenous damage-associated molecular pattern (DAMP) molecule that sustains the inflammatory milieu in RA joints, because it acts not merely as a structural matrix component but as an active mediator of inflammation, tissue remodeling and joint destruction. This review summarizes the multifaceted role of TNC in the pathogenesis and progression of RA. Methods: A literature search was performed using the PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar and the publications from January 2000 to March 2026, including foundational studies, recent advances and clinical investigations of TNC as a biomarker were considered. Studies focusing exclusively on TNC in non-arthritic conditions were excluded. Results: The search yielded over 100 published articles. Important reports and studies were reviewed, and pursued for further relevant publications. Only the most relevant publications are discussed with relation to TNC role in RA. Conclusion: Tenascin-C (TNC) functions as a persistent DAMP in rheumatoid arthritis, linking innate and adaptive immunity through TLR4-mediated inflammatory signaling, which sustains pro-inflammatory cytokine production. It enhances T-cell activation, autoantibody generation, and promotes synovial fibroblast hyperplasia via alpha 9 beta 1 integrin and EGFR crosstalk, driving chronic synovitis. Citrullinated TNC acts as an autoantigen, stimulating ACPA production and worsening disease severity. Elevated TNC levels in serum and synovial tissue highlight its potential as a biomarker. Targeting pathological TNC isoforms or domains such as FBG offers a promising precision therapeutic strategy to inhibit RA progression while preserving normal tissue repair mechanisms.
