Search Results (10,237)

Bisphenol A (BPA) is a common industrial chemical primarily used in the manufacture of plastics, and it has been found in more than 90% of people worldwide. As an endocrine disruptor, BPA can impair reproduction, development, immunity, metabolism, and cognition; it also disturbs immune balance and thus fosters chronic inflammation. A number of population-based studies have indicated a link between environmental BPA exposure and atopic dermatitis (AD). Nevertheless, the detailed molecular pathways connecting BPA to AD remain poorly understood. AD is the leading chronic recurrent inflammatory skin disorder, characterized by severe itching and repeated eczema-like lesions. Its prevalence is roughly 13% among children and 5% among adults, and its global incidence continues to rise, imposing heavy health and economic burdens on societies. To clarify whether and how BPA may promote or worsen AD, we carried out a comprehensive computational study that integrated network toxicology, transcriptomic data, machine learning, molecular docking, and molecular dynamics simulations. From the CTD, ChEMBL, and SwissTargetPrediction databases, we collected 5701 potential BPA targets; from GeneCards and OMIM, we obtained 3270 genes linked to AD. The overlap between these two gene sets gave a group of common candidate genes. Enrichment analyses using GO and KEGG showed that these common genes were significantly overrepresented in the PI3K-Akt signaling pathway, Th17 cell differentiation, and the JAK-STAT signaling pathway—all central to immune and inflammatory regulation. We then built a protein–protein interaction (PPI) network by submitting the common genes to the STRING database and employed Cytoscape to extract hub genes from that network. By integrating human AD transcriptomic profiles with the hub genes and applying two machine learning techniques (LASSO and SVM), we identified six core toxic targets of BPA in AD: TIGIT, JAK3, IL22, S100A8, CCL2, and FCER1G. These six targets fall into two main functional categories: immune dysregulation and inflammatory cell infiltration. Subsequent molecular docking and molecular dynamics simulation experiments confirmed that BPA binds well to all six targets and can form stable complexes with them. Collectively, our findings offer a preliminary experimental foundation for future investigations into the pathogenesis of BPA-induced AD and provide important molecular evidence for understanding how environment–gene interactions contribute to complex inflammatory skin diseases such as AD. Full article

Background: Oculopharyngodistal myopathy (OPDM) is a rare disorder with progressive ptosis, ophthalmoplegia, and oral incompetence, which pose challenges to management. While surgical interventions for blepharoptosis have been reported, addressing concurrent facial muscle weakness remains a significant challenge in comprehensive disease management. Case: A 59-year-old woman with OPDM exhibited severe ptosis and oral incompetence. Despite undergoing prior cosmetic interventions, these symptoms had progressively worsened over 10 years. Preoperative evaluation revealed complete ptosis with a margin reflex distance 1 (MRD-1) of 0 mm and preserved Bell’s phenomenon. A two-stage reconstruction using fascia lata grafting corrected ptosis with a frontalis sling and restored oral competence with U-shaped grafts anchored to the zygomatic arches. Results: At 3 years and 6 months postoperatively, eyelid elevation had improved without corneal exposure, and oral competence was restored, resolving drooling. Conclusions: Semi-dynamic reconstruction using fascia lata grafting effectively addresses ptosis and oral incompetence in OPDM, improving visual and swallowing functions and enhancing quality of life. Full article

Background/Objectives: Managing bone diseases demands novel, natural compounds to bypass the heavy side effects of current therapies. Honey is well-known for its therapeutic traits, yet we know very little about how specific floral varieties impact bone tissue. This study confronts this gap by comparing how acacia, chestnut, and coriander honeys drive human osteoblast behavior in vitro. Methods: After mapping the phenolic/flavonoid profiles and antioxidant capacities of these honeys, we tested them on hFOB 1.19 human osteoblasts. We tracked cell migration via scratch assays and validated osteogenic maturation through Alkaline Phosphatase (ALP) activity and Alizarin Red (AR) mineralization over 7 days. Confocal time-lapse imaging with pharmacological inhibitors monitored intracellular calcium dynamics, while gene shifts were analyzed via qRT-PCR. Results: Coriander honey (CH) packed the highest polyphenol levels and antioxidant power. Biologically, while all honeys accelerated scratch closure, CH drove cell motility most potently. Remarkably, a 7-day treatment with these honeys sparked a significant and robust increase in ALP activity and mineralization, surpassing the osteogenic induction observed with standard osteoinductive media. Mechanistically, CH triggered a sharp [Ca²⁺] spike, relying on external calcium entry and IP3-dependent internal release via PLC activation. qRT-PCR confirmed this anabolic shift via OPG and OPN upregulation. Conclusions: Honey exerts pronounced multi-level osteopromotive effects at both the functional and transcriptional levels, tightly linked to its botanical source. Among the variants, coriander honey stands out for its exceptional ability to fast-track osteoblast migration, differentiation, and early mineral deposition. Therefore coriander honey represents a promising in vitro candidate that warrants further preclinical evaluation for bone repair applications. Full article

Single-cell RNA sequencing (scRNA-seq) has emerged as a transformative technology for resolving cellular heterogeneity and deciphering gene regulatory networks in complex tissues. Despite challenges such as incomplete genome annotation, technical variability across platforms, and limitations in robust cell-type annotation, scRNA-seq has substantially advanced our understanding of the developmental processes, physiological regulation, and disease responses in pigs, an economically and biomedically important species, thereby providing insights into traits of agricultural and translational relevance. By profiling transcriptomes at the single-cell resolution, scRNA-seq enables the identification of rare cell populations, dynamic cellular states, and lineage trajectories that are critical for reproduction, growth, immunity, and metabolic homeostasis. Recent porcine scRNA-seq studies have generated high-resolution cellular atlases spanning embryos, reproductive organs, immune tissues, skeletal muscle, and the gastrointestinal tract, revealing cell-type-specific regulatory mechanisms associated with reproductive performance, muscle accretion, adipogenesis, immune competence, and intestinal functionality. This review summarizes the fundamental principles and analytical strategies of scRNA-seq, highlights its major applications in porcine biology and production, and discusses current challenges as well as future perspectives for integrating single-cell technologies into livestock science. Full article

Background/Objectives: Immune surveillance is increasingly recognized as a modifier of myeloproliferative neoplasm (MPN) initiation and evolution, yet the contribution of the NKG2D receptor and its ligands MICA/MICB to CALR-mutated disease remains unclear. Methods: We performed high-resolution next-generation sequencing genotyping of MICA and MICB in 43 patients with CALR-mutated MPN (WHO 2022 criteria) and compared the allele and haplotype distributions with those of 156 healthy Bulgarian controls and 85 patients with JAK2 V617F-positive MPN. Associations were tested using age- and sex-adjusted additive generalized linear models; bi-locus haplotypes were evaluated using haplotype score methods. In a genotyped subgroup (35 CALR-mutated MPN patients and 105 controls), functional KLRK1 (NKG2D) polymorphisms were analyzed for haplotype-level associations. We also performed 700 ns molecular dynamics simulations of selected MICA variants in complex with NKG2D and reanalyzed publicly available single-cell RNA-sequencing data (GSE117826) and RNA-sequencing data from CRISPR/Cas9-edited CALR-mutant iPSC-derived megakaryocytes to evaluate MICA/MICB expression. Results: MICA*004:001 was significantly associated with CALR-mutated MPN versus controls (p = 0.004; Bonferroni-adjusted p = 0.047), while MICB*008:001 showed only nominal association. Exploratory haplotype analyses identified a MICA*009:01-MICB*004:001 haplotype associated with CALR-mutated status (p = 0.008) and a KLRK1 G-A-G-T haplotype (rs1049174-rs2617160-rs2246809-rs2617170) associated with increased CALR-mutated MPN risk (OR = 3.61; p = 0.029). Transcriptomic reanalysis indicated a higher fraction of CALR-mutant stem and progenitor cells expressing detectable MICA/MICB transcripts, and heterozygous CALR-mutant megakaryocytes exhibited higher MICA expression than the wild type. Conclusions: Together, these data support an exploratory immunogenetic and transcriptomic link between the NKG2D-MICA/MICB axis and CALR-mutated MPN, but direct protein-level and functional studies are required before mechanistic or therapeutic conclusions can be drawn. Full article

Multidrug resistance (MDR) remains a major obstacle in cancer therapy, driving treatment failure and disease progression across diverse malignancies. A key determinant of MDR is the overexpression of ATP-binding cassette (ABC) transporters, particularly P-glycoprotein (P-gp/ABCB1), which actively effluxes structurally diverse chemotherapeutic agents and reduces their intracellular accumulation. Despite extensive investigation, clinically effective strategies to overcome P-gp-mediated resistance remain limited. This review provides a comprehensive analysis of the molecular mechanisms underlying P-gp function, including its structural organization, regulation of expression, and role in cellular drug disposition. We highlight the interplay between P-gp activity, oxidative stress, metabolic reprogramming and the tumor microenvironment, emphasizing the complexity of MDR as a dynamic and adaptive process. Emerging therapeutic approaches targeting P-gp-mediated resistance are also discussed, including natural bioactive compounds, nanotechnology-based drug delivery systems, polymeric carriers and novel anticancer agents designed to evade efflux mechanisms. Integrating mechanistic insights with advanced pharmacological strategies may improve intracellular drug retention and therapeutic efficacy. A deeper understanding of P-gp-driven MDR is essential for the development of effective interventions aimed at overcoming drug resistance and improving clinical outcomes in cancer patients. Full article

Background/Objectives: Obesity-associated non-alcoholic fatty liver disease (NAFLD) drives systemic metabolic stress and accelerates chronic kidney disease, yet the mechanistic links remain unclear. Mitochondrial dysfunction has emerged as a central mediator of obesity-induced organ injury. Here, we investigated renal mitochondrial remodeling in a rat model of obesity-associated NAFLD (Ob-NAFLD) and examined the effects of metformin. Methods: Female Zucker rats (obese fa/fa and lean Fa/Fa) were fed an AIN-93G diet for eight weeks, followed by 10 weeks of metformin treatment in designated groups. Kidney tissues were analyzed using biochemical assays, immunoblotting, blue native PAGE, in-gel activity assays, and histological evaluation. Results: In Ob-NAFLD rats, renal ATP levels were elevated despite reduced electron transport chain (ETC) Complex III and increased Complex V expression, reflecting compensatory ATP synthase hyperactivity uncoupled from efficient oxidative phosphorylation. Mitochondrial dynamics were disrupted such that inhibitory phosphorylation of DRP1 was reduced, promoting fission, and total OPA1 expression was decreased with a shift in short-to-long isoform balance, indicating impaired fusion and cristae remodeling. Notably, ATPase inhibitory factor 1 (IF1), a checkpoint that limits ATP synthase overdrive, remained stably expressed, suggesting an adaptive ceiling or failed protective control under chronic metabolic stress. Metformin partially alleviated bioenergetic stress by lowering ATP and modestly restoring Complex III, yet ETC imbalance and structural remodeling persisted, revealing the limitations of metabolic modulation alone. Conclusions: These findings position entrenched mitochondrial dysregulation as a mechanistic bridge linking obesity-driven liver disease to kidney injury. Therapeutic strategies combining metabolic interventions with targeted restoration of ETC coordination, mitochondrial dynamics, and regulatory checkpoints such as IF1 may be required to fully restore renal mitochondrial health and prevent the progression of metabolic kidney disease. Full article

Medical image analysis is a cornerstone of modern healthcare, yet conventional single-modal deep learning often struggles with the unique physical constraints and structural variability inherent in data acquired from diverse medical sensors. Recently, Vision-Language Models (VLMs) have sparked a paradigm shift by bridging the semantic gap between visual sensor signals and clinical narratives. Following the PRISMA guidelines, 167 representative studies are systematically synthesized in this review to provide a comprehensive roadmap of VLM technological evolution and clinical utility. First, rather than treating VLMs as generic feature extractors, their underlying mechanisms are uniquely distilled into seven core operational principles, which are then explicitly mapped to downstream applications such as few-shot diagnosis, prompt-driven segmentation, and multi-task foundation models. To facilitate intuitive evaluation, a rigorous quantitative cross-comparison of current benchmark architectures is presented. Crucially, this review goes beyond highlighting successes by critically assessing prevalent clinical bottlenecks, including zero-shot segmentation failures, multi-modal hallucinations in diagnosing rare diseases, and the prohibitive computational complexity associated with 3D volumes and gigapixel whole slide images. Finally, a novel, forward-looking framework is proposed: the transition from static “image-text alignment” to dynamic “multi-source sensor-driven intelligence”. By addressing both physical sensor constraints and algorithmic limitations, this survey offers actionable insights for developing trustworthy, sensor-aware clinical diagnostic agents. Full article

Hepatic ischemia–reperfusion injury (HIRI) is a major cause of postoperative liver dysfunction and adverse outcomes in hepatectomy, liver transplantation, and hemorrhagic shock. Among the multiple mechanisms implicated in HIRI, mitochondria are recognized as central organelles that integrate metabolic failure, oxidative stress, inflammation, and cell death. During ischemia, interruption of oxygen and nutrient supply impairs oxidative phosphorylation, depletes ATP, disrupts ionic homeostasis, and renders mitochondria highly vulnerable to subsequent injury. Upon reperfusion, reoxygenation triggers excessive reactive oxygen species production, calcium overload, mitochondrial permeability transition pore opening, and release of damage-associated molecular patterns, thereby amplifying hepatocellular injury and sterile inflammatory responses. As a key component of mitochondrial quality control, mitophagy plays a context-dependent role in HIRI. Appropriate activation of mitophagy facilitates the clearance of damaged mitochondria, limits oxidative stress, restrains inflammasome activation, and preserves hepatocellular homeostasis, whereas insufficient or dysregulated mitophagy contributes to mitochondrial accumulation and aggravates liver injury. This review summarizes mitochondrial alterations during the ischemic and reperfusion phases, outlines the major mitophagy pathways involved in HIRI and discusses recent advances in upstream regulation, disease-specific dysregulation, and mitophagy-targeted interventions. A better understanding of the dynamic and biphasic nature of mitophagy in HIRI may provide a stronger theoretical basis for precision liver-protective strategies and future translational therapies. Full article

As healthcare data grows in volume and complexity, the use of association rule mining (ARM) and frequent itemset mining (FISM) in disease analysis holds great potential for data-driven decision-making, personalized treatment strategies, and disease prevention. This study introduces an extensible, interactive, self-developed visualization tool designed specifically for ARM and FISM, enabling the intuitive exploration of medical datasets. The tool incorporates an innovative preprocessing method that binarizes datasets from various scaling systems using a systematic multi-threshold evaluation, ensuring standardized analysis across diverse data sources. Its interactive design empowers users to dynamically explore relevant patterns individually, enhancing both the interpretability and usability of customized results. In addition, the tool integrates exploratory statistical assessments to support the interpretation and comparison of resulting association rules (ARs) and frequent itemsets (FISs). In this paper, we evaluate the tool using two pilot datasets: one on symptoms for long COVID and one on incorporating rare diseases (RDs) while also providing sample datasets for user testing. Full article

Type 2 diabetes mellitus (T2DM) is a highly prevalent and devastating chronic metabolic disease worldwide, with pathogenesis centrally characterized by insulin resistance and pancreatic β-cell dysfunction. Accumulating evidence has demonstrated that glucose metabolic reprogramming represents an adaptive metabolic shift from oxidative phosphorylation to aerobic glycolysis in cells in response to a hyperglycemic microenvironment. This shift acts as an upstream important event driving the initiation and progression of T2DM. This review summarizes the characteristics of glucose metabolic reprogramming in insulin-sensitive target organs under T2DM conditions, including the liver, skeletal muscle, adipose tissue and pancreatic β-cells. It also discusses four major downstream effector mechanisms: mitochondrial energy metabolism disturbance, augmented oxidative stress, disruption of mitochondria-associated endoplasmic reticulum membranes (MAMs) coupled with calcium homeostasis imbalance, and systemic inflammatory response. On this basis, we summarize the intervention strategies targeting the above signaling pathways, including antioxidant therapy, restoration of MAMs integrity and calcium homeostasis, systemic anti-inflammatory intervention, and multi-target regulatory effects of traditional Chinese medicine. Current studies indicate that early intervention in downstream stress events is induced by glucose metabolic reprogramming. This is particularly true for the preservation of MAMs’ integrity; restoration of calcium homeostasis; and inhibition of NLRP3 inflammasome activation, the latter of which is expected to block or delay the progression from prediabetes to clinical T2DM. Nevertheless, substantial gaps still remain in the understanding of the dynamic regulatory mechanisms of MAMs, tissue-specific therapeutic targets, and relevant clinical translational research. Future integration of multi-omics technologies will provide novel therapeutic strategies and theoretical foundations for the early prevention and treatment of T2DM. Full article

Background/Objectives: Tumor-infiltrating lymphocyte (TIL) therapy is an important option for patients with metastatic melanoma progressing after standard systemic therapy, but real-world data on treatment delivery, toxicity monitoring, and immune recovery remain limited. We evaluated clinical outcomes, treatment tolerance, immune reconstitution, and cardiac biomarker dynamics across three Mayo Clinic sites. Methods: We retrospectively analyzed adults with metastatic melanoma who received lymphodepleting chemotherapy followed by TIL infusion and high-dose interleukin-2 (IL-2) between April 2024 and December 2025. Clinical outcomes, treatment delivery, and adverse events were assessed. Longitudinal immune monitoring included CD4 and CD8 T-cell counts, CD4:CD8 ratio, and immunoglobulin G (IgG) at baseline and follow-up. In a prespecified cardiac sub-cohort, high-sensitivity troponin (hs-Tn) was measured during IL-2 administration to evaluate associations with cardiac events and IL-2 interruption. Results: Thirty-six patients underwent TIL infusion. The objective response rate was 50.0%, including complete responses in 13.9%, and the disease control rate was 72.2%. Median progression-free survival was 3.61 months, and median overall survival was 12.94 months. M1d disease was associated with inferior overall survival on univariable analysis (HR 6.55, 95% CI 2.03–21.17; p = 0.002), with attenuation after multivariable adjustment. Receipt of ≥3 IL-2 doses was associated with longer overall survival on univariable analysis (HR 0.20, 95% CI 0.06–0.64; p = 0.007), but this association also attenuated after adjustment. Longitudinal immune monitoring demonstrated persistent CD4 lymphopenia through 6 months, sustained inversion of the CD4:CD8 ratio, and declining IgG at months 3 and 6. In the cardiac sub-cohort (24 patients; 87 IL-2 doses), post-dose hs-Tn ≥15 ng/L was associated with clinically significant cardiac events (OR 9.6, 95% CI 1.5–60.6; p = 0.016) and IL-2 interruption (OR 3.4, 95% CI 1.1–10.7; p = 0.036). For cardiac events, hs-Tn ≥15 ng/L had 100% sensitivity and 100% negative predictive value. Conclusions: In routine practice, TIL therapy was feasible and active in metastatic melanoma. M1d disease identified a subgroup with poor survival, peri-dose hs-Tn showed promise as a tool to support safer IL-2 delivery, and prolonged CD4 suppression with IgG decline suggests that recovery after TIL therapy extends beyond initial hematologic reconstitution. These findings support prospective validation of biomarker-guided IL-2 monitoring and extended post-treatment immune surveillance. Full article

Circadian rhythms impose temporal organization on immune function, shaping host responses to infection, injury, and chronic disease. While transcriptional control by core clock components such as CLOCK and BMAL1 has been extensively characterized, this paradigm alone cannot explain the rapid and dynamic nature of immune signaling. Emerging evidence identifies post-translational modifications (PTMs)—including phosphorylation, ubiquitination, and acetylation—as critical regulators that confer speed, reversibility, and specificity to inflammatory pathways. Here, we propose the concept of a “Chrono-PTM axis,” in which circadian timing and PTM-dependent signaling are functionally integrated to govern immune activation thresholds. We discuss how PTMs not only regulate core clock machinery but also temporally gate key innate immune pathways, including NF-κB signaling and inflammasome activation, thereby controlling cytokine production at multiple levels. Furthermore, we highlight the role of immunometabolism in supplying essential cofactors that couple cellular energetic states to PTM dynamics, linking metabolic oscillations to inflammatory outputs. Disruption of this axis contributes to the pathogenesis of autoimmune diseases, cancer, and tissue-specific inflammatory disorders. Finally, we outline emerging therapeutic opportunities targeting the Chrono-PTM axis, including chronotherapy and PTM-directed interventions, and identify critical gaps in temporal proteomics and translational studies. Elucidating the integration of circadian and post-translational regulation will provide a unifying framework for understanding immune homeostasis and may enable time-informed precision immunotherapy. Full article

Introduction: Hematologic malignancies account for a significant proportion of the global cancer burden. Immunotherapy is currently one of the key treatment modalities used in the management of these diseases. Objective: This study aimed to assess the physical fitness of patients with chronic lymphoid malignancies receiving monoclonal antibody-based therapy compared with healthy individuals. Materials and Methods: The study included 99 ambulatory patients being treated for hematologic malignancies—33 with chronic lymphocytic leukemia, 32 with multiple myeloma, and 34 with follicular lymphoma—as well as 43 healthy individuals. All participants underwent the Two-Minute Step Test, the 30-Second Sit-to-Stand Test, and the Timed Up and Go Test. Results: Patients with hematologic malignancies, regardless of diagnosis, were characterized by significantly lower lower-limb strength (H(3, N = 142) = 24.779, p < 0.0001), as well as poorer agility and dynamic balance (H(3, N = 142) = 24.993, p < 0.0001). Patients diagnosed with multiple myeloma and follicular lymphoma also exhibited lower cardiorespiratory endurance (H(3, N = 142) = 13.223, p = 0.0042). Age was a significant predictor of physical fitness. However, in an analysis treating diagnosis as a categorical variable with the control group as the reference category, patients with hematologic malignancies also had significantly lower physical fitness scores than controls. Conclusions: Patients with chronic lymphoid malignancies receiving monoclonal antibody-based therapy exhibit reduced physical fitness regardless of hematologic diagnosis. Patient age is an additional factor associated with physical fitness. Full article

Circulating tumor DNA (ctDNA) has emerged as a transformative tool in cancer diagnostics, enabling the non-invasive detection of tumor-derived DNA fragments released into the bloodstream through cellular lysis or active secretion. ctDNA measurement has demonstrated its clinical usefulness, including early cancer detection, identification of resistance mechanisms, and screening of asymptomatic individuals. In addition to prognosis, ctDNA analysis is increasingly used to guide adaptive treatment strategies by detecting minimal residual disease and tracking tumor evolution in real time. Recent advances in artificial intelligence are poised to further enhance the clinical impact of ctDNA, transforming it from a passive monitoring biomarker into a dynamic molecular sensor integrated into predictive clinical decision models. However, broad implementation of ctDNA-based assays in routine practice requires rigorous prospective validation, cross-platform standardization, and regulatory approval to unlock its full potential in precision oncology. Full article