Search Results (1,710)

Oxidative stress is a key contributor to the pathogenesis of immune-mediated diseases through its effects on cellular metabolism, mitochondrial function, immune signaling pathways, and inflammatory tissue injury. Disruption of redox homeostasis promotes metabolic reprogramming and persistent activation of innate and adaptive immune responses, contributing to disease progression across multiple inflammatory and autoimmune disorders. Recent advances in high throughput molecular technologies have generated large scale multi-omics datasets that enable comprehensive investigation of redox-associated mechanisms at a systems level. Integration of these datasets with computational analytical approaches has facilitated the identification of multidimensional molecular signatures associated with disease development and progression. This systematic review evaluates studies applying computational frameworks to analyze redox-related molecular data in immune-mediated diseases including multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, Sjögren’s syndrome, and inflammatory bowel disease. Across the reviewed studies, oxidative stress associated with molecular signatures were consistently linked to immune activation, mitochondrial metabolism, and inflammatory signaling pathways. Computational analyses also identified regulatory genes involved in antioxidant defense and metabolic regulation, as well as pathways associated with regulated cell death. These findings highlight the translational potential of computational redox analysis for biomarker discovery, disease stratification, and development of targeted therapeutic strategies aimed at restoring redox balance and improving clinical management of immune-mediated diseases. Full article

Delayed cerebral ischemia (DCI) is a major complication of aneurysmal subarachnoid hemorrhage (aSAH), strongly associated with neurological deterioration and poor outcomes. Its pathophysiology remains incompletely understood and involves multiple interacting processes. Increasing evidence highlights the role of redox imbalance triggered by hemoglobin breakdown and the subsequent generation of reactive species, leading to vascular dysfunction, impaired nitric oxide signaling, and inflammatory activation This review aims to summarize current knowledge on redox-related mechanisms involved in DCI and to explore the potential role of the peroxiredoxin (PRDX) family in this setting. A narrative review of experimental and preclinical studies was performed, focusing on molecular pathways associated with vascular regulation, cellular injury, and antioxidant defense. Particular attention was given to the distribution and biological functions of PRDX isoforms within the central nervous system. This work addresses a topic not previously systematically discussed, the potential involvement of PRDX proteins in aSAH-related complications. By integrating available data, it provides a conceptual framework linking PRDX to mechanisms relevant for DCI. The manuscript serves as a starting point for future research, particularly translational and clinical studies in humans, which are necessary to verify the relevance of these findings and to better understand their potential clinical implications. Full article

Background/Objectives: Clear cell renal cell carcinoma is the most common subtype of kidney cancer and exhibits marked biological heterogeneity, even among tumors of the same histological grade. Although tumor grade remains a key prognostic parameter, the molecular alterations associated with tumor differentiation are not fully understood. This study aimed to evaluate grade-dependent tissue-level expression patterns of proteins involved in cellular stress response, growth regulation, stemness, and apoptosis in clear cell renal cell carcinoma. Methods: Protein expression of heat shock protein 70, insulin-like growth factor 1, octamer-binding transcription factor 4, and apoptosis-inducing factor were analyzed in human clear cell renal cell carcinoma samples and normal renal cortex. Low-grade and high-grade tumors were compared using immunofluorescence staining combined with semi-quantitative and quantitative image analysis. The proportion of positive signals and the number of positive cells were assessed across tissue compartments. In addition, publicly available transcriptomic data from The Cancer Genome Atlas kidney renal clear cell carcinoma cohort were analyzed to explore associations between gene expression levels and overall survival. Results: Distinct grade-dependent expression patterns were observed for all investigated proteins. Heat shock protein 70, insulin-like growth factor 1, and octamer-binding transcription factor 4 showed a higher expression in normal renal tissue with a progressive reduction across tumor grades. In contrast, apoptosis-inducing factor exhibited increased expression in tumor tissue, particularly in low-grade tumors, with a relative decrease in high-grade carcinomas. Stromal compartments of tumor tissue showed minimal or no expression for most markers. Transcriptomic survival analysis did not reveal significant differences in overall survival between high- and low-expression groups for any of the investigated genes. Grade-stratified transcriptomic analysis of the TCGA KIRC cohort revealed consistent patterns for HSP70 family members and OCT4, with progressive grade-dependent mRNA reduction toward higher grades, while IGF1 showed an inverse mRNA trend and AIFM1 showed a uniform reduction across all tumor grades without a clear inter-grade pattern. Conclusions: The findings demonstrate that stress response, growth-related, stemness-associated, and apoptotic proteins display distinct grade-dependent tissue-level expression patterns in clear cell renal cell carcinoma, with the expression profiles of high-grade tumors being of particular translational interest given the aggressive clinical behavior and therapeutic resistance characteristic of this disease stage. These alterations appear to reflect tumor differentiation and biological behavior rather than independent prognostic value, highlighting the complexity of molecular regulation in renal tumorigenesis. Full article

Trastuzumab is the first humanised monoclonal antibody (Mab) developed for breast cancer (BC) therapy. The high affinity of Trastuzumab Fab-domain binding to the human epidermal growth factor receptor 2 (HER2) receptor, with a K_d value of <1 nM, is also accompanied by Fc domain interaction with Fc-receptors in natural killer cells and leukocytes, enabling the killing of tumour cells through antibody-directed cellular cytotoxicity (ADCC). Trastuzumab blocks the over-expressed HER2 receptor-mediated dimerization and consequent intracellular signalling, leading to cancerous growth. However, the trastuzumab resistance (TR) became the major problem within 1 year of treatment. The mutation in phosphatidylinositol 3′-kinase (PI3K) pathway, cross-talk with estrogen receptors, over-expression of Mucin 1 (MUC1) protein, insulin-like growth factor I receptor, etc., are key pathways involved in TR. In this review, we have provided a molecular view of TR and the possible remedies for overcoming TR using BC stem cell (BCSC)-based therapy, PI3K pathway inhibitors, MUC1-based treatment, etc. We have also analysed the patents and clinical trials from the pre-TR and post-TR era to rationalise the possible steps to overcome TR. Our analysis implies that Trastuzumab monotherapy no longer applies to HER2+ BC treatment. Further, combination therapy using other antibodies like pertuzumab and protein kinase inhibitors and targeting pathways like the ubiquitin proteasome pathway will be the future option for BC Treatment. Overall, this review provides a detailed summary of the molecular mechanisms involving TR and its potential ways of evasion, based on updated information from published research articles, clinical trial outcomes, and patent data. Full article

Background: The dorsal raphe nucleus (DRN) produces and distributes serotonin, while the hypothalamus (HYP) uses serotonergic signals to regulate physiological processes in chickens. Coconut oil (COCO), rich in medium-chain fatty acids, is rapidly absorbed without re-esterification. Methods: Day-old broilers (Ross 708 male, n = 160) were distributed into two dietary treatments with five replicates of 16 birds each. The birds were fed a corn–soybean meal (SBM) basal diet supplemented with 3% of poultry fat (CON) or coconut oil (COCO). The body-weight gain (BWG), feed intake (FI), and feed conversion ratio (FCR) were recorded over a 3-week period, and the data were subjected to a t-test. Untargeted metabolomic analysis by high-performance liquid chromatography (HPLC-MS) was used to evaluate the influence of the type of dietary fat on metabolite profiles in the DRN, HYP, and plasma of broiler chickens. Principal component analysis (PCA) was used to identify unique metabolites, and ANOVA was used to identify the metabolites that were significantly abundant (p < 0.05). The metabolites were then annotated using the KEGG and HMDB databases. Results: Birds in the COCO treatment gained more weight on average (0.8446 kg/bird) than birds in the CON group (0.8132 kg/bird; p = 0.0496). Five metabolites associated with multiple significant cellular processes, such as brain function, energy metabolism, and neurotransmission, showed similar differential expression patterns, while two metabolic pathways (butanoate metabolism and alanine, aspartate and glutamate metabolism) were identified. Conclusions: The dietary inclusion of COCO improves BWG in poultry and enhances their overall well-being by modulating metabolite profiles, supporting neurotransmission, and enriching the metabolic pathways essential for growth and brain function. Full article

Cytometry-based single-cell proteomics (CySCP) has emerged as a powerful tool for analyzing cellular heterogeneity at the protein level because of its ability to reveal dynamic cell states and response patterns through high-dimensional protein expression profiling in thousands of individual cells. However, detailed summaries of quantification, processing and analysis of CySCP data remain limited. This review provides comprehensive perspectives on CySCP, including quantification technologies, analysis pipelines, annotation strategies, and resource platforms. Specifically, first, the strengths and limitations of the detection platforms are discussed. Second, comprehensive data processing steps, including compensation, transformation, normalization, batch effect correction, signal cleaning, and doublets, debris or dead cells removal, are described in detail. Third, various strategies for cell type annotation, including manual gating, unsupervised clustering, supervised/semi-supervised classification, and fully automated approaches, are illustrated. Fourth, emerging CySCP databases, as critical resources for facilitating antibody validation, panel optimization, and open-access data sharing, are summarized. In summary, this review provides a comprehensive guide for the use of CySCP to obtain novel biological insights at the single-cell protein level. Full article

Due to its high efficiency and safety, oocyte vitrification finds broad application in many fields of life sciences, such as clinical assisted reproduction and conservation of animal genetic resources. However, vitrification may cause cellular damage and reduce the quality of oocytes and their cumulus cells (CCs), which could be closely related to disorders in lipid metabolism. At present, the impact of vitrification upon the lipid profile of oocytes and CCs has not been systematically elucidated. In this study, we used porcine germinal vesicle cumulus–oocyte complexes (COCs) as a model to analyze their lipid characteristics after vitrification and in vitro maturation (IVM), utilizing untargeted lipid metabolomics. Our results showed that an overall count of 37 down-regulated and 8 up-regulated differential lipids was identified in the vitrified oocytes. Pathway analysis confirmed the enrichment in glycerophospholipid metabolism and fat digestion and absorption, etc. Combined with transcriptomic analysis, three enriched pathways were revealed, including the AMPK signaling pathway, metabolic pathways, and fatty acid elongation. On the other hand, a total of four down-regulated and eight up-regulated differential lipids were detected in the vitrified CCs. Pathway enrichment implicated autophagy, glycerophospholipid metabolism, etc. A joint analysis of metabolomic and transcriptomic data revealed four enrichment pathways, including cholesterol metabolism, fat digestion and absorption, regulation of lipolysis in adipocytes, and metabolic pathways. Notably, the supplementation of lysophosphatidylcholine during IVM attenuated oxidative stress, enhanced mitochondrial activity, and enhanced the viability and embryonic development of cryopreserved porcine oocytes. The results indicate that vitrification alters lipids in oocytes and CCs, and the supplementation of lipids plays a role in improving the quality of vitrified oocytes. Full article

Background/Objectives: Viral respiratory tract infections (VRTIs) in patients with diabetes mellitus (DM) are characterized by a severity gap rather than an infection gap. This review synthesizes evidence from the 2023–2026 respiratory seasons to provide a post-pandemic framework for managing the synergistic metabolic and viral threats in this population. Materials and Methods: A scoping review of literature from PubMed, Scopus, and Embase (2023–2026) was conducted, focusing on clinical outcomes and mechanistic interactions between DM and emerging respiratory pathogens. Results: Recent data identify human Metapneumovirus (hMPV) and adenovirus as significant threats to diabetic hosts, with mortality risks equivalent to seasonal influenza (HR 1.00 for hMPV vs. influenza). The two-hit model combines a baseline of innate immune paralysis, characterized by impaired neutrophil chemo-taxis and mechanical SP-D dysfunction, with a cellular signaling environment primed for cytokine overreaction by epigenetic metabolic memory. The stress hyperglycemia ratio (SHR) has emerged as a promising predictor of mortality compared to absolute glucose or HbA1c, with a proposed threshold of ≥1.14 identifying patients at 3.5-fold increased risk for mechanical ventilation. Precision management should consider the prudent suspension of SGLT2 inhibitors to mitigate euglycemic DKA risks and considering the early use of GLP-1 receptor agonists for their hypothesized pulmonary anti-inflammatory properties. Conclusions: Closing the mortality gap may require a shift from generic viral care to a precision model that treats metabolic susceptibility with high clinical priority alongside the treatment of the viral pathogen. Full article

Carcinoma showing thymus-like differentiation (CASTLE) is a rare malignancy arising in the thyroid or neck, with an uncertain cellular origin that complicates both diagnosis and treatment. To better understand its molecular underpinnings and identify potential therapeutic avenues, we conducted integrated whole-exome and transcriptome sequencing on six CASTLE and six thymic carcinoma samples. Whole-exome sequencing (WES) was performed on all 12 samples, while RNA sequencing was successful for 1 CASTLE and 6 thymic carcinoma samples. Our analysis included somatic mutation profiling, mutational signature deconvolution, differential gene expression, and characterization of tumor microenvironment for the cases with available data, with comparisons to genomic data from other thyroid cancers. CASTLE tumors demonstrated a higher median tumor mutational burden than thymic carcinoma and lacked the common BRAF and RAS mutations typically found in thyroid cancers. They harbored alterations in genes such as TRHDE, cilia-associated genes (ANKS6, CFAP46, DNAH6), and Wnt signaling components (TRRAP, BCL9L), as well as mutational signatures suggestive of mismatch repair deficiency and oxidative damage. MSIsensor-pro analysis of the WES data provided support for the potential for mismatch repair deficiency in a subset of CASTLE samples. Exploratory transcriptomic analysis from a single CASTLE case showed downregulation of thyroid follicular markers and an “immune-hot”, lymphocyte-rich microenvironment, closely resembling that of thymic carcinoma. While these findings require validation in larger cohorts, they support a thymic origin for CASTLE and establish its molecular distinction from follicular-derived thyroid cancers. The immunogenic tumor landscape suggests that immune checkpoint inhibitors, particularly those targeting PD-1/PD-L1, may be a promising therapeutic strategy, alongside emerging targets for precision oncology. Full article

Background: Pancreatic adenocarcinoma (PAAD) is a highly malignant cancer posing severe clinical challenges. Although the dual role of pyroptosis in tumor progression is increasingly recognized, the prognostic value of its molecular heterogeneity in PAAD remains underexplored. Methods: We integrated multi-omics data and applied interpretable machine learning to construct a predictive framework centered on pyroptosis heterogeneity. Using non-negative matrix factorization (NMF) on pyroptosis-related genes (PRGs), patients were classified into distinct molecular subtypes. Evaluating 117 machine learning combinations, we employed random survival forest (RSF) to build the final model, followed by comprehensive internal and external validation. SHapley Additive exPlanations (SHAP) analysis provided global and local interpretability. Clinical potential was assessed via nomogram, drug sensitivity prediction, single-cell analysis, and immunohistochemical validation. Results: We identified two biologically distinct pyroptosis subtypes and developed a ten-gene pyroptosis subtype-associated gene signature (PSAGS). PSAGS demonstrated robust performance across training, test, and multiple external validation cohorts, outperforming most published models. Multivariate analysis confirmed its independent prognostic value, and a PSAGS-based nomogram exhibited clinical utility. PSAGS-stratified subgroups showed differential responses to immunotherapy, chemotherapy, and targeted agents. Single-cell analysis revealed cell type-specific links between PSAGS scores and pyroptosis activity, indicating that high-PSAGS malignant cells foster an immunosuppressive microenvironment through extracellular matrix (ECM)-mediated signaling. Protein-level validation confirmed upregulation of signature genes in PAAD tissues. Conclusions: This work presents a biologically reliable prognostic model for personalized PAAD management and elucidates how pyroptosis heterogeneity drives tumor progression through cellular interactions. Full article

Chronic kidney disease (CKD), especially diabetic kidney disease (DKD), is characterized not only by progressive loss of renal function but also by profound metabolic disturbances, including insulin resistance (IR). Emerging evidence implicates gut-derived uremic toxins as mediators linking intestinal dysbiosis to metabolic and renal injury. Several microbial metabolites, for example, indoxyl sulfate, p-cresyl sulfate, and trimethylamine-N-oxide, are known to accumulate in CKD due to decreased renal excretion and altered tubular secretion. In vitro and in vivo experiments indicate that these gut-derived nephrotoxins impair insulin signaling pathways in cells. This results in increased production of reactive oxygen species, activation of stress kinases, higher levels of inflammatory cytokines, and inhibitory serine phosphorylation of insulin receptor substrates. Consequently, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling is impaired, reducing cellular glucose uptake. At the same time, these toxins induce endothelial dysfunction and mitochondrial damage, not only causing systemic IR but also contributing to the progression of kidney disease. Observational data link higher plasma toxin levels with components of IR, rapid loss of renal function as measured by estimated glomerular filtration rate, and a high risk of cardiovascular events in CKD patients. Although causality in humans remains unproven, interventions targeting the microbiota, toxin binding, and oxidative stress pathways show promise. We propose an integrated gut–kidney–metabolic framework in which dysbiosis-driven toxin production may amplify IR and DKD progression. Full article

Myocardial fibrosis is a key pathological process driving the progression of cardiovascular diseases toward heart failure, closely linked to persistent inflammation and immune dysregulation. Among CC chemokines, CCL17 has emerged as an important mediator connecting immune cell dynamics with fibrotic remodeling. This review outlines current understanding of the cellular sources, regulatory mechanisms, and functional roles of CCL17, with particular attention to its impact on regulatory T cell (Treg) recruitment through ligand-biased signaling. Beyond this mechanism, CCL17 likely operates within a broader inflammatory network, with potential interactions involving CCR2⁺ macrophages and IL-17-related pathways. Experimental studies show that disruption of CCL17 signaling attenuates fibrosis and improves cardiac function, while clinical data link elevated circulating CCL17 to cardiac dysfunction and adverse outcomes. However, the absence of clinical trials and the redundancy of chemokine networks remain key challenges for translation. Overall, CCL17 may serve as a biomarker and therapeutic target, although its clinical application will require a more integrated, network-based understanding. Full article

Chronic low-grade inflammation, altered microvascular support, and progressive stress-related cellular dysfunction are major contributors to tissue aging and impaired repair. Dermal fibroblasts are central regulators of these processes because they integrate cytokine-related signaling, redox balance, and extracellular matrix homeostasis. Increasing evidence indicates that endogenous bioelectrical activity may influence these cellular functions by shaping upstream regulatory conditions linked to downstream molecular responses. In the present study, we investigated the molecular effects of the Radio Electric Asymmetric Conveyer Anti-Inflammatory Cellular Treatment delivered under Inside Blue Zone conditions (REAC ACT-IBZ) in human dermal fibroblasts (HFF1). Cells were exposed to nine standardized treatment sessions, and molecular changes were assessed by RT-qPCR, ELISA, and immunofluorescence analysis complemented by supportive semi-quantitative fluorescence intensity assessment. REAC ACT-IBZ exposure was associated with increased SIRT1 and VEGF expression and with transcriptional modulation of selected cytokine-related genes, including IL-1α, IL-1β, IL-2, and IL-8. Immunofluorescence analysis, complemented by supportive semi-quantitative fluorescence intensity assessment, showed a pattern consistent with increased FOXO1 and SIRT1 staining and reduced mTOR staining in treated cells. Overall, these findings identify a molecular profile associated with REAC ACT-IBZ exposure in human dermal fibroblasts, involving stress-response regulators, angiogenesis-related signaling, and selective cytokine-related transcriptional changes. Within the limits of the present in vitro model, the data support the view that endogenous bioelectrical modulation may interact with molecular networks relevant to tissue homeostasis and inflammaging. Full article

Restless legs syndrome (RLS) is one of the most prevalent sleep disorders, yet its diagnosis continues to rely almost entirely on subjective symptom descriptions. This persistent dependence on phenomenology reflects the absence of reliable biological markers to aid in the process of diagnosis or monitoring. However, there is accumulating molecular evidence that suggests that RLS is associated with systemic biological alterations. These extend beyond the traditional paradigm of iron deficiency. The present scoping review synthesizes the current research on circulating serum biomarkers investigated in RLS outside classical iron indices. A comprehensive search of PubMed, Scopus, and Web of Science databases identified 1050 records, of which 50 studies met eligibility criteria and were included. In the processing of data, clusters emerged into several recurring biological domains, including dysregulated iron regulatory signaling (hepcidin), low-grade immune activation, oxidative stress, and neuroaxonal injury markers. High-throughput omics studies reveal molecular network perturbations involving inflammatory pathways, complement activation, metabolic signaling, and cellular stress responses. Biomarker associations appear stronger when linked to objective motor burden. These findings suggest that RLS may involve multifarious molecular changes detectable in the serum. Consequently, this can support the transition from symptom-based diagnosis toward biomarker-informed stratification, which may enable more precise disease characterization and improved diagnostic accuracy. Full article

The effective treatment of neurodegenerative diseases (NDDs), such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, remains a critical challenge in modern medicine. Given the limitations of current therapies, alternative strategies to slow neurodegeneration are urgently needed. This study presents a critical review of the current evidence regarding low-dose ionizing radiation (IR) as a promising modality for modulating neurodegenerative processes. This study examines current experimental data on the effects of low-dose IR (LDIR) on cellular protective and compensatory mechanisms, including evidence from in vivo models of NDDs. Our analysis demonstrates that LDIR enhances antioxidant activity and DNA repair, stimulates autophagy and neuroplasticity, and modulates neuroinflammatory signaling. Collectively, these findings support the hypothesis of the neuroprotective potential of LDIR, underscoring its translational viability provided that strict dosimetric guidelines are followed and individual biological responses are rigorously monitored. Full article