This study explored how oxidative stress induced by hydrogen peroxide alters metabolite levels in submandibular and parotid salivary gland acinar cells. We investigated the impact of oxidative stress on the metabolite profiles of two salivary gland cell lines and examined differences in response. Rat-derived immortalized acinar epithelial cell lines from the parotid and submandibular salivary glands were exposed to 50 μM and 150 μM hydrogen peroxide for 24 h. Metabolite levels were then analyzed using liquid chromatography mass spectrometry, and succinate levels were independently assessed using a succinic acid quantification kit. We observed a metabolic divergence between the two cell types. Succinate, fumarate, malate, and aspartate levels were increased in parotid gland cells but decreased in submandibular gland cells. Conversely, NADPH levels increased in submandibular gland cells but remained below the limit of detection in parotid gland cells. Both cell types exhibited glutathione depletion and oxidized glutathione accumulation. Notably, submandibular gland cells exhibited a distinct metabolic shift in response to 150 μM hydrogen peroxide exposure. Submandibular gland cells demonstrated superior redox adaptability compared to the metabolic vulnerability observed in parotid gland cells. These findings provide a metabolic basis for the differential radiosensitivity of salivary glands and may inform biomarker discovery for monitoring and preserving gland function in oxidative stress-related diseases.
To investigate the effects of exercise on bone marrow stem cells (BMSCs) and determine underlying molecular network mechanisms through bioinformatics analysis combined experimental validation. Target genes related to exercise and BMSCs were retrieved from the Gene Cards database and deduplicated, then performed bioinformatics analysis including Venny analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein-protein interaction (PPI) and cystoscope to find hub genes. In animal experiment, 9-month-old male C57BL/6J mice were subjected to 4 months of treadmill exercise training (12 m/min, 1 h/day, 5 days/week) and the BMSCs from femur were cultured in vitro, and cell viability, the expression of cell senescence-related factors (P16, P21) and inflammatory factors (IL-6, IL-1β) were detected, and the vital role of IL-6, IL-1β was determined in vitro study. 131 common targets were found via Venn diagram analysis. The STRING database and Cytoscape software identified several core molecules such as IL-1β, IL6, TNF, and stat3, etc. GO enrichment analysis revealed that these common targets were primarily involved in biological processes such as negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway, leukocyte chemotaxis, and positive regulation of protein phosphorylation; cellular components such as extracellular space and lysosome; and molecular functions such as receptor ligand activity and chemokine activity. KEGG pathway analysis showed that the related genes were enriched in pathways including diabetic cardiomyopathy, IL-17 signaling pathway, and HIF-1 signaling pathway. Moreover, treadmill exercise results in a significant cell viability increase, which is related to the inhibition of IL-1β, IL-6 and P16, P21. Whereas the knockdown of IL-1β, IL-6 confirmed their vital role in the status of BMSC's rejuvenation. The present data concluded that running exercise increase effectively the physical viability to rejuvenate BMSCs, and underlying mechanism is associated with the inhibition of inflammatory factors and senescence-related factors.
Bisphenol A (BPA), an industrial compound widely used in plastics and food packaging, has been implicated in the development of various diseases. This study aims to elucidate the molecular toxicity mechanisms of BPA in hepatocellular carcinoma (HCC), providing a theoretical foundation for the prevention and treatment of HCC. By retrieving BPA and HCC-associated genes from multiple databases and identifying their intersections, we performed protein-protein interaction (PPI) analysis and visualization of the intersecting genes. Potential mechanisms were explored through Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis. Core genes were identified using the Degree algorithm. Their expression levels in HCC were validated using the TCGA database, and Kaplan-Meier survival curves were constructed to demonstrate the impact of high versus low expression of these core genes on HCC patient prognosis. ROC curves were employed to assess the diagnostic performance of these core genes for HCC. The relationship between key prognostic genes and HCC immune cell infiltration was analyzed. Finally, molecular docking was utilized to further investigate the interactions between key prognostic genes and BPA. A total of 101 intersecting genes were identified in BPA and HCC by multi-database analysis.GO and KEGG functional enrichment analysis showed that these intersected genes could affect HCC progression through multiple pathways.Five prognostic core genes, SRC, PPARG, HSP90AA1, MAPK3 and ESR1, were differentially expressed in HCC and were associated with poor prognosis of HCC patients. The ROC curves showed that the five prognostic core genes had good diagnostic and predictive properties. Meanwhile, an immune infiltration analysis suggested that the five prognostic genes had an important regulatory role in the immune microenvironment of HCC. In addition, molecular docking analysis further confirmed the potential interaction between BPA and the five prognostic core genes. The results suggest that SRC, PPARG, HSP90AA1, MAPK3 and ESR1 play crucial roles in the development of HCC promoted by BPA. This provides new theoretical insights into the molecular mechanisms by which BPA promotes disease progression in HCC and offers potential therapeutic targets for early diagnosis, prognostic assessment, and targeted therapy for HCC.
Accurate animal models are essential for elucidating the pathogenesis of ulcerative colitis (UC). The widely used dextran sodium sulfate-induced UC (DSS-UC) model inadequately reflects the refractory nature of human UC. This study compared the traditional Chinese medicine (TCM)-based SKYD-UC model with the DSS-UC model to identify a more representative model. Network pharmacology was used to analyze the fundamental TCM syndrome of UC and to identify differential targets and pathways between DSS-UC and SKYD-UC. Both UC animal models were subsequently established, and body weight, organ indices, disease activity index (DAI) scores, colon length, mucosal damage, and serum biomarkers (IL-6, TNF-α, MPO, GSH-Px, GAS, and MTL) were evaluated. Among the seven TCM syndromes, SKYD-UC presented the greatest number of targets and pathways, highlighting its fundamental importance. Specifically, 464 and 703 unique targets were identified for DSS-UC and SKYD-UC, respectively. DSS-UC unique targets were predominantly associated with inflammation, immune regulation, and cellular signaling. In contrast, SKYD-UC targets encompass a broader range of biological processes, including mitochondrial dysfunction, extracellular matrix remodeling, and pathways related to systemic UC complications. These findings were validated in animal experiments. Compared with the DSS-UC model, the SKYD-UC model demonstrated more severe damage, including pronounced spleen and thymus atrophy (p < 0.01), higher DAI scores (p < 0.01), shorter colons (p < 0.05), worse inflammation (elevated IL-6 and MPO) and gastrointestinal dysfunction (reduced GAS and elevated MTL) (p < 0.01), and unique kidney yang deficiency damage (elevated kidney index, p < 0.01), along with sustained weight loss. While both models reflect inflammation and immune dysregulation, the SKYD-UC model better simulates the refractory nature of UC, offering an effective animal model for UC research.
The rhizosphere is a critical hotspot of plant-microbe interactions, where Plant Growth-Promoting Rhizobacteria (PGPR) play key roles in nutrient mobilization, growth promotion and stress tolerance. This study aimed to isolate and characterize PGPR from the rhizosphere of chilli (Capsicum annuum L.). Twenty-three morphologically distinct isolates were obtained and evaluated through morphological, biochemical, enzymatic and molecular approaches. Most isolates exhibited catalase and nitrate reduction activities, while carbohydrate utilization profiles revealed broader metabolic versatility in Lysinibacillus macroides compared to Lysinibacillus fusiformis. Enzymatic screening uncovered a high prevalence of protease, urease, amylase, cellulase and lipase production, key traits linked to nutrient cycling and rhizosphere colonization. Quantitative assessment of protease and lipase activities revealed significant inter-isolate variation, with isolates 4.1 and 2.B exhibiting comparatively higher enzyme indices. Pot tray validation showed that rhizobacterial inoculation enhanced seed germination and early seedling growth, with isolates 4.1 and 2.B performing best. Molecular identification confirmed isolates 4.1 and 2.B as L. fusiformis and L. macroides, respectively, supported by phylogenetic analysis. The dominance of diverse rhizobacterial strains and their hydrolytic enzyme activities reflects their ecological adaptability in semi-arid soils. These findings highlight L. fusiformis and L. macroides as promising biofertilizer candidates for chilli cultivation, offering eco-friendly alternatives to chemical fertilizers and contributing to sustainable, climate-resilient agriculture.
Current evidence show that exercise has beneficial effects on skeletal muscle function in individuals with chronic kidney disease (CKD). The STAT3 signaling pathway and the apelin axis (apelin receptor, APLNR- and ligands, -apelin and/or -elabela), participate in the processes of kidney inflammation and fibrosis and both may be involved in muscle wasting during CKD. Herein we report that STAT3 pathway and APLNR are in fact involved in the muscle impairment concomitant to CKD in experimental model and in adult individuals with CKD. Male BALB/c mice were first submitted to an 8-week ladder climbing resistance training (RT) protocol and further were submitted to doxorubicin-induced experimental CKD with or without use of the STAT3 inhibitor (Stattic). The GSE157712 dataset was used to assess the muscle transcriptome profile of CKD patients. Bioinformatics' analysis of gene set enrichment analysis (GSEA) and gene ontology (GO) were performed and the APLNR was found to be a central component of muscle response over kidney stress. Mice from the RT protocol showed a protective effect of blocking STAT3 against kidney and muscle injury markers, while both CKD individuals and CKD mice reported alterations in the APLNR muscle expression. In conclusion, the muscle tissue function is affected during CKD, which can be attenuated by a protective and synergistic effect of exercise and STAT3 inhibition. Thus, APLNR appears as a key gene associated with muscle dysfunction in CKD patients and its muscle expression can be regulated by resistance exercise.
Intervertebral disc degeneration (IVDD) is a prominent etiology of lower back pain. Type 2 diabetes (T2D), the most prevalent metabolic disorder, may expedite IVDD progression through mechanisms involving hyperglycemia, advanced glycation end products, and microvascular complications. We aim to identify the biomarkers for T2D and IVDD. We retrieved two datasets pertaining to IVDD and T2D respectively from the Gene Expression Omnibus (GEO) database. Initially, differential expression analysis was conducted to identify differentially expressed genes (DEGs) in each group. Subsequently, machine learning algorithms including Boruta algorithm, Random Forest (RF), Support Vector Machine (SVM), and Extreme Gradient Boosting (XGBoost) were utilized to explore co-biomarkers for IVDD and T2D by analyzing the intersection of DEGs sets between the two groups. The clinical diagnostic value of these biomarkers was evaluated using ROC curve. Additionally, we employed the CYBERSORT and Single-cell sequencing to investigate the infiltration of immune cells in two diseases. Finally, the expression of biomarkers and the correlation between BCAA and IVDD was experimentally validated. AMBP, a shared biomarker of IVDD and T2D, were identified using differential analysis and machine learning algorithms. In addition, CYBERSORT analysis and single-cell sequencing results revealed significant correlations between AMBP and cellular immunity. Finally, experimental validation on clinical samples and HNPC cells confirmed upregulation of AMBP, and the correlation between BCAA metabolism and AMBP. AMBP, as the shared biomarker between IVDD and T2D, has great clinical diagnostic value, which therefore may be a potential regulatory factor for two diseases.
Breeding male birds face high energetic demands due to simultaneous investment in reproduction and feather moult, yet the metabolic consequences of parasitic infection during this period are poorly understood. To address this gap, we focused on non-moulting and actively moulting breeding adult male village weavers (Ploceus cucullatus) to investigate how microfilariae infection affects host biochemical energy status and overall condition. Using plasma glucose, triglycerides, β-hydroxybutyrate, and body mass adjusted for structural size as integrative markers, we examined how infection influences energy allocation and imposes physiological costs during this critical life-history stage. Specifically, we aimed to: (i) determine whether microfilariae infection and active moult influence short-term energy availability by examining plasma glucose concentrations, and whether absolute body mass modulates the effect of infection; and (ii) evaluate the combined and independent effects of infection and moult on lipid and ketone metabolism, while incorporating absolute body mass and size-corrected body condition index (BCI) to assess overall energetic reserves and physiological trade-offs. A total of 128 breeding males were trapped and screened for microfilariae and moult status. Our results indicate infected birds that are actively moulting experienced higher β-hydroxybutyrate, lower glucose and reduced BCI, when compared with the non-infected birds that were non-moulting. On the other hand, non-infected male birds that were also non-moulting maintained higher triglyceride levels. Our regression analyses indicate both infection and moult independently increased ketone concentrations and decreased triglycerides (P < 0.05), with no significant interaction for most markers. However, for β-hydroxybutyrate, the interaction may approach significance (P = 0.08), which suggest a marginal tendency toward non-additive effects. These results highlight a 'double burden,' where concurrent parasitism and moult constrain energy allocation, shifting metabolism from carbohydrates toward lipid catabolism. This study may provide mechanistic insight into how microfilariae infection amplifies energetic costs during high-demand life-history stages in breeding male village weavers.
To investigate the mutational characteristics of cervical cancer in Xinjiang and their relationships with tumor driver genes and affected signaling pathways. Twenty-nine pairs of cervical cancer tissues and matched peripheral blood samples were subjected to Whole Exome Sequencing. Somatic mutation sites and tumor mutational burden were identified, and core mutational signatures using non-negative matrix factorization (NMF). Driver genes were screened, and pathway enrichment analysis was performed to clarify the associations between core oncogenic pathways and driver genes. A total of 10,076 nonsynonymous mutations in the coding region were identified. High-frequency mutated genes included members of the MUC family, HRNR, and NBPF1. Single-base substitutions were dominated by C > T (38.63%). Three core mutational signatures were identified: Signature A (undefined), Signature B (APOBEC-mediated deamination), and Signature C (endogenous damage/mismatch repair deficiency). Samples were divided into two groups based on these signatures: Group 1 (high C > G/C > T mutations) and Group 2 (high C > T mutations). Eleven driver genes were identified; among SLC24A1 was a driver gene in both the overall samples and subgroups, suggesting it is a key driver gene in cervical cancer. Gene mutations were mainly enriched in five pathways: NOTCH, RTK-RAS, WNT, Hippo and PI3K. Subgroup pathway signatures consistent with the overall cohort, differing only in mutation frequencies. This study clarified cervical cancer genomic heterogeneity, revealed core mechanisms (APOBEC activation and endogenous DNA damage), and confirmed SLC24A1 as key driver gene. It provides important genomic evidence for elucidating the pathogenesis of cervical cancer and exploring potential therapeutic targets.
Cadmium is a toxic heavy metal found in the atmosphere. Its frequent exposure can lead to neurodegeneration. Medicinal plants are scavengers of free radicals that could result from exposure to heavy metals. In this study, the neuroprotective effect of the aqueous extract of Mondia whitei fruit (AEMW) against cadmium chloride (CdCl2)-induced neurotoxicity was investigated using an in silico and in vivo approach. The biological constituents in the AEMW were identified using high-performance liquid chromatography, and the compounds were docked against a target protein related to neurodegeneration. Rats were exposed to CdCl2 at 5 mg/kg for 5 days and co-treated with AEMW (250 or 500 mg/kg) for 7 days via oral administration. The levels of biogenic amines and activities of cholinergic and oxidative stress biomarkers were also evaluated. The molecular docking and ligand interactions of this study identified rutin, quercetin and kaempferol as the hit compounds with binding affinities of -15.197, -12.181 and -11.327 kcal/mol for acetylcholinesterase (AChE), and 10.325, -7.168 and -6.558 kcal/mol for human serotonin transporter (SERT), respectively. Cadmium chloride caused a significant (p < 0.05) elevation in the activities of AChE and BChE, and the levels of dopamine, serotonin and malondialdehyde with a significant (p < 0.05) decrease in the antioxidant activities. Co-administration of CdCl2 with AEMW, especially at the dose of 500 mg/kg, attenuated the effect of CdCl2 in the rats. Similar effect was also observed in the rat's brain histology. Therefore, AEMW could be a potential cholinesterase inhibitor to manage neuronal damage caused by heavy metal.
Hepatocyte growth factor activator inhibitor type-1 (HAI-1) plays pivotal roles in epithelial integrity and tumour biology. Although implicated in various malignancies, its expression profile and prognostic value in bladder cancer (BC) remain incompletely defined. High levels of HAI-1 ectodomain in urine have previously been reported to be associated with poor prognosis in BC patients. This study aimed to determine the relationships between tissue and urine levels of HAI-1 and clinical outcomes in BC. This study used immunohistochemistry to measure HAI-1 expression across 770 BCs of all stages and grades. HAI-1 expression was scored on the basis of the percentage of positive cancer cells, subcellular localisation, and staining intensity. Additionally, HAI-1 (SPINT1) mRNA expression was compared with protein levels in tissue and urine. HAI-1 was highly expressed in low-grade, early-stage disease with strong membranous staining. Reduced overall HAI-1 expression, loss of membranous staining and increased cytoplasmic staining correlated with higher stage and grade and shorter survival. SPINT1 mRNA levels were positively correlated with membranous HAI-1 staining intensity (p = 0.005). Urinary levels of HAI-1 were negatively associated with the fraction of HAI-1 positive cancer cells and membranous staining intensity (p < 0.05). A positive correlation was observed between SPINT1 expression and urinary HAI-1 levels (p < 0.05). The Urobasal A subtype had lower urinary HAI-1 ectodomain levels than other subtypes. HAI-1 expression may serve as a biomarker of tumour differentiation and prognosis in BC. Increased ectodomain shedding into the urine, rather than increased expression, likely explains the higher urine HAI-1 levels seen in more aggressive tumours.
The Breast Cancer gene 1 (BRCA1) and Breast Cancer gene 2 (BRCA2) genes are pivotal human tumor suppressor genes that are essential for preserving genomic stability. Mutations in BRCA1 and BRCA2 prevent homologous recombination, which is regulated by cell cycle checkpoints, thereby hindering the repair of double-stranded DNA. The ultimate result of genomic instability is characterized by altered transcriptional control and abnormal expression of essential cell-cycle proteins. As significant genetic factors, any mutations in the BRCA1 and BRCA2 genes substantially elevated a woman's risk of getting ovarian and breast cancer, often resulting in the development of these cancers earlier in life. Treatment of breast and ovarian cancer brought on by BRCA gene mutations focuses heavily on germline BRCA-mutated (gBRCAm) testing, targeted therapies such as Poly (ADP-ribose) polymerase inhibitors (PARP inhibitors), in addition to other options such as traditional chemotherapy and immunotherapy. This systematic review examines the crucial role of BRCA1 and BRCA2 in DNA repair, as well as how their mutations contribute to the development of inherited gynecological malignancies, and potential treatments targeting BRCA-deficient tumors. Also discusses resistance mechanisms to PARP inhibitors, the potential for combination therapies (PARP inhibitors + immune checkpoint inhibitors), and Advances in nanotechnology-based drug delivery, dynamic biomarker development, and CRISPR-based gene repair for BRCA mutations as future challenges and direction for curable patient.
Antibody-drug conjugates (ADCs), bispecific T-cell engagers (TCEs), and chimeric antigen receptor (CAR)-T cells require truly tumor-restricted surface antigens to minimize on-target/off-tumor toxicity. To identify such antigens, we interrogated two complementary RNA-seq resources: (i) the Genotype-Tissue Expression (GTEx) atlas spanning diverse normal tissues and (ii) the Cancer Genome Atlas colon adenocarcinoma cohort (TCGA-COAD). Candidate membrane-protein transcripts were defined by low median GTEx expression (<1 RPKM across all normal tissues) and marked upregulation (≥10-fold) in TCGA colon tumors. Only two genes met these stringent criteria, with the little-studied nucleotide-sugar transporter SLC35D3 emerging as the leading candidate. Pan-cancer analysis of the TCGA datasets confirmed its selective enrichment in colorectal carcinoma and in pheochromocytoma/paraganglioma, while GTEx data showed near-background expression in essential organs including brain, heart, liver, lung, and kidney. Protein-level validation with immunohistochemistry on > 250 tissue-microarray cores revealed SLC35D3 positivity in 53% of colorectal cancers, 40% of small-cell lung cancers, and 24% of pancreatic neuroendocrine tumors, whereas vital normal organs were uniformly negative. Although SLC35D3 has been annotated as mainly localized to the endoplasmic reticulum and early endosomes, our analyses revealed its presence on the plasma membrane, which was corroborated by flow cytometry in SLC35D3 mRNA-positive cancer cell lines but not in negative control. Taken together, these transcriptomic and proteomic findings establish SLC35D3 as a tumor-selective surface antigen broadly represented in aggressive malignancies yet virtually absent from critical normal tissues, highlighting it as a promising new candidate for next-generation ADCs, TCEs, and CAR-T therapies in colorectal and neuroendocrine carcinomas.
This study investigated the ameliorative potential of a saponin derived from Dioscorea bulbifera bulbils in mitigating experimentally induced cardiotoxicity in adult male Wistar rats. Forty-eight rats were divided into eight groups (n = 6). Group A received distilled water, and Group B received doxorubicin (10 mg/kg). Groups C and D received SRF (50 or 100 mg/kg) for 14 days. Groups E and F received doxorubicin with SRF, while Groups G and H were pretreated with SRF before doxorubicin on day 15. Blood and heart tissues were collected for analysis after euthanasia. Rats in the doxorubicin-only group (Group B) exhibited significant elevations in serum cardiac injury markers, including lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB), along with increased systolic and diastolic blood pressures and elevated malondialdehyde (MDA) levels. Conversely, activities of key antioxidant enzymes-superoxide dismutase (SOD) and catalase (CAT)-were markedly reduced. Enhanced glycogen accumulation, Caspase-3 activation, and CD4 expression further indicated heightened oxidative stress and apoptosis. Treatment with SRF, particularly in the pre- and co-administration protocols, significantly attenuated these alterations. The saponin-rich fraction of Dioscorea bulbifera bulbils demonstrated substantial cardioprotective potential against doxorubicin-induced cardiac injury, likely through its antioxidant and anti-apoptotic mechanisms.
Subclinical hypothyroidism (SCH), defined by elevated thyroid-stimulating hormone (TSH) with normal circulating thyroid hormones, is a common endocrine disorder that frequently remains clinically silent. Emerging evidence suggests that even mild thyroid dysfunction may influence lipid metabolism and contribute to early cardiovascular risk. However, the extent to which TSH levels reflect lipid abnormalities in SCH remains controversial. This study aimed to evaluate the influence of SCH on lipid metabolism and to determine whether TSH levels are associated with alterations in lipid profile parameters and atherogenic cardiovascular risk markers. A cross-sectional comparative study was conducted including 40 participants: 20 patients diagnosed with SCH and 20 euthyroid controls matched for demographic characteristics. Serum concentrations of TSH, free triiodothyronine (FT3), and free thyroxine (FT4) were measured alongside lipid profile parameters, including total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). The LDL/HDL ratio was calculated as an indicator of atherogenic cardiovascular risk. Independent sample t-tests were applied to compare study groups, and linear regression analysis was performed to evaluate associations between TSH levels and lipid parameters. Individuals with SCH demonstrated significant lipid alterations compared with euthyroid controls. Triglyceride levels were significantly higher (165.7 ± 60.8 vs. 92.9 ± 39.8 mg/dL; p = 0.0136), while HDL-C levels were significantly lower (50.8 ± 12.4 vs. 58.6 ± 11.3 mg/dL; p = 0.0136). The LDL/HDL ratio was also significantly elevated in the SCH group (2.25 ± 1.05 vs. 1.57 ± 0.56; p = 0.0027), indicating a more atherogenic lipid profile. In contrast, total cholesterol and LDL-C showed modest but statistically non-significant increases. Regression analysis revealed weak and non-significant correlations between TSH levels and lipid parameters. SCH is associated with unfavorable lipid alterations characterized by elevated triglycerides, reduced HDL-C, and an increased LDL/HDL ratio, suggesting early atherogenic risk despite normal thyroid hormone levels. These findings highlight the importance of comprehensive lipid assessment in SCH and suggest that the LDL/HDL ratio may serve as a more sensitive indicator of cardiovascular risk than TSH alone.
Although studies have shown that the androgen receptor (AR) is associated with tumor progression and malignant regulation, its role in the tumor immune microenvironment and predictive value for prognosis and immunotherapy response in various cancer types have not been systematically analyzed. In this paper, multi-omics techniques was used to analyze AR comprehensively. A comprehensive pan-cancer analysis revealed that the AR was expressed in a variety of tumors, especially as a risk factor for poor prognosis in gastric cancer. In addition, gene set enrichment analysis showed that the AR promotes cell proliferation and tumor cell invasion and regulates anti-tumor response. Immune score, immune cell infiltration, and anticancer immune cycle analysis showed that high AR levels were correlated with low infiltration of CD4+ T cells and NKT cells, high infiltration of Th2 cells and MDSCs, negatively correlated with antigen-presenting molecules, and positively correlated with various immune-negative regulatory molecules. Single-cell sequencing highlighted the heterogeneous expression of ARs in different cell types, particularly in epithelial cells, where high AR levels were associated with the enhanced activity of tumor-promoting pathways. In conclusion, this study highlights the potential of the AR as a novel biomarker for gastric cancer prognosis and immunotherapy efficacy, expanding its applicability in the development of new antitumor drugs.
Strategies that specifically target the integrated stress response (ISR) as a therapeutic approach in sepsis remain largely unexplored. This study aimed to identify and validate ISR-related biomarkers in sepsis. This study used 529 ISR-related genes (ISRRGs) alongside sepsis datasets. First, differentially expressed gene between sepsis and normal samples, key module genes associated with sepsis, and ISRRGs were intersected to identify candidate genes. Next, biomarkers were selected through three machine learning methods. Subsequently, enrichment analysis, immune infiltration analysis, regulatory network analysis, and drug prediction were conducted. Finally, the biomarkers were experimentally validated using RT-qPCR. Four biomarkers of sepsis (DYRK2, BCL2, NUP93, and NFATC2) were identified; collectively, these biomarkers are associated with the enrichment of translation initiation in sepsis. A total of 783 significantly upregulated pathways and 1203 significantly downregulated pathways were identified. These biomarkers were co-regulated by multiple microRNAs and transcription factors. Importantly, 726 drugs were predicted to interact with these biomarkers. Additionally, RT-qPCR results demonstrated that the expression levels of DYRK2, BCL2, NUP93, and NFATC2 differed significantly between sepsis and normal samples. DYRK2, BCL2, NUP93, and NFATC2 were identified as biomarkers of sepsis, offering new diagnostic and therapeutic targets for its treatment.
Extracellular signal-regulated kinase 5 (ERK5), a unique member of the mitogen-activated protein kinase (MAPK) family, plays a critical role in cell fate determination due to its distinct structure. This review aims to systematically summarize the central role of the ERK5 signaling pathway in cell specification and differentiation. Substantial evidence indicates that, by integrating diverse extracellular signals and regulating key transcription factors, ERK5 precisely controls the fate specification and differentiation of various cell types, including stem cells, neural cells, immune cells, endothelial cells, and osteoblasts. Furthermore, aberrant MEK5/ERK5 signaling is closely linked to the pathogenesis and progression of various diseases, particularly cancer, and is associated with drug resistance. By delineating the signaling mechanisms and functions of ERK5 across different cellular contexts, this review seeks to deepen the understanding of its physiological and pathological activities and to provide new potential targets and insights for regenerative medicine and cancer therapy.
Interleukin-11 (IL-11) is a cytokine involved in inflammatory processes and a previous study showed that blocking or knocking down IL11 in mice prolongs a healthy lifespan. This study investigates DNA methylation (DNAm) changes in the IL11 and IL-11 receptor subunit alpha (IL-11RA) gene across ages to explore age-related epigenetic patterns that may influence IL-11 production and pathway sensitivity. A genome-wide DNAm database focusing on Cytosine-phosphate-Guanine (CpG) sites within the IL11 and IL11RA was analyzed. Hierarchical regression analyses examined the relationship between DNAm, age, and the squared age term for quadratic associations. The database comprised 10,297 samples (5156 males and 5141 females) with a mean age of 53.9 years (SD = 14.1 years). The majority of IL11 and IL11RA CpG sites in the TSS1500 and 3'UTR regions exhibited significant inverse U-shaped associations with age. DNAm levels were low during youth, increased in middle age (40s-50s), and decreased again in older age. The observed inverse U-shaped DNAm patterns in the IL11 and IL11RA suggest non-linear age-related regulation that may influence IL-11 expression and sensitivity. These findings indicate that IL-11 may have different roles across life stages and suggest that therapeutic interventions targeting IL-11 should consider age-specific effects.
In the present investigation, the development and comparative assessment of sacchachitosan-based transdermal films loaded with biosynthesized silver nanoparticles (AgNPs) for wound-healing applications were reported. Sacchachitosan, a fungal chitosan obtained from Ganoderma lucidum, was mixed with gelatin and glycerol to improve film flexibility, bio-adhesiveness, and moisture retention. Silver nanoparticles were added to the transdermal film as an antimicrobial agent and a cross-linking agent. Transdermal films were prepared by solvent casting with different concentrations of AgNPs, and characterised by field-emission scanning electron microscopy (FE-SEM), High-Resolution Transmission electron microscopy (HR-TEM), Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and inductively coupled plasma atomic emission spectroscopy (ICP-OES). The optimized formulation showed tensile load values of 0.94 N (maximum), length up to 83.4 mm, with significantly increased mechanical flexibility. Controlled drug release was maintained for 24 h (R2 = 0.9471) and provided effective skin permeation kinetics (R2 = 0.9852). Antimicrobial studies showed inhibition zones of up to 22 mm for E. coli and Proteus, and about ≈20 mm for A. niger and C. albicans respectively, while degradation ranged from 52.3% to 81.9% under physiological conditions. Bioadhesive strength reached 79 g in higher concentration of SNPs formulations. The results of cytocompatibility demonstrated that >70% cell viability in optimal films (SF1-SF4), while excessive AgNPs concentration (SF5-SF7) decreased viability to below 30%, suggesting dose-dependent cytotoxicity. Hemolysis remained within acceptable limits in lower-concentration formulations. Mushroom produced sacchachitosan was found to exhibit better hydrophilicity (contact angle 40°) than traditional chitosan, higher antimicrobial activity and superior film stability. These findings highlight sacchachitosan-based nanocomposite films as promising sustainable biomaterials for advanced wound management, while emphasizing the need for nanoparticle optimization to balance antimicrobial efficacy and biocompatibility.