Search Results (15,235)

Alpha-1 antitrypsin deficiency (AATD) represents a paradigmatic genetic disorder with well-characterized hepatic manifestations but relatively underexplored pulmonary implications. While liver involvement has been extensively reviewed, the underlying mechanisms of lung disease progression remain poorly understood, particularly regarding immunological pathways and inflammatory processes. The pathophysiology involves defective alpha-1 antitrypsin (AAT) production, including AAT variants that induce neutrophil elastase activity, causing progressive alveolar destruction and sustained inflammation, leading to emphysema, as one of the main components of chronic obstructive pulmonary disease (COPD). AATD and smoking represent major risk factors for COPD, the third leading cause of death worldwide at present. In AATD patients, neutrophils, which constitute the majority of circulating leukocytes, become dysregulated. Under normal conditions, cells perform essential functions, including phagocytosis and neutrophil extracellular trap formation (NETosis); in AATD, however, they accumulate excessively in alveolar spaces due to impaired elastase control. The accumulation of Z-AAT polymers within epithelial cells creates a pathological cycle, acting as chemoattractants that sustain pro-inflammatory responses and contribute to chronic obstructive pulmonary disease development. In addition, monocytes, representing a smaller fraction of leukocytes, migrate to inflammatory sites and differentiate into macrophages while secreting AAT with anti-inflammatory properties. However, in PiZZ patients, this protective mechanism fails, as polymer accumulation within cells reduces both AAT secretion and the number of protective human leukocyte antigen(HLA)-DR-monocyte subsets. In particular, macrophages demonstrate remarkable plasticity, switching between pro-inflammatory M1 (classically activated macrophages) and tissue-repairing M2 (alternatively activated macrophages) phenotypes based on environmental cues. In AATD, this adaptive capability becomes compromised due to intracellular polymer accumulation, leading to impaired phagocytic function and dysregulated cytokine production and ultimately perpetuating chronic inflammation and progressive tissue damage. Recent advances in induced pluripotent stem cell (iPSC) technology have facilitated alveolar epithelial cell (AEC) generation, in addition to the correction of AATD mutations through gene editing systems. Despite the limitations of AAT correction, iPSC-derived organoid models harboring AATD mutations can deliver important insights into disease pathophysiology, while gene editing approaches help demonstrate causality between specific mutations and observed phenotypes. Therefore, in this review, we investigated recent studies that can serve as tools for gene editing and drug development based on recently developed iPSC-related technologies to understand the pathogenesis of AATD. Full article

Proteasome subunit beta type-9 (PSMB9), a member of the proteasome beta subunit family, encodes the pivotal β1i component of the immunoproteasome. PSMB9 plays a crucial role in antigen processing and presentation; however, its comprehensive role in orchestrating a tumor-immune landscape and regulating the anti-tumor immune responses remains unexplored. Here we investigated the context-dependent functions of PSMB9 by integrating multi-omics data from The Cancer Genome Atlas, Genotype-Tissue Expression database, Human Protein Atlas, Tumor Immunotherapy Gene Expression Resource, and multiple other databases. Moreover, we explored the predictive value of PSMB9 in multiple immunotherapy cohorts and investigated its functional relevance in CAR-T therapy using genome-scale CRISPR/Cas9 screening, gene knockout cell line in vitro, and clinical cohort validation. We found widespread dysregulation in PSMB9 across cancers, predominantly upregulated in most malignancies and associated with advanced pathological stages in specific contexts. PSMB9 was also broadly and negatively correlated with tumor stemness indices. Crucially, PSMB9 expression was robustly linked to anti-tumor immunity by being significantly correlated with immune-pathway activation (e.g., IFN response, cytokine signaling), immune regulatory and immune checkpoint gene expression, and enhanced infiltration of T cells across nearly all tumor types. Consequently, elevated PSMB9 predicted superior response to immune checkpoint inhibitors in multiple cohorts, showing comparable predictive power to established predictive signatures. Furthermore, CRISPR/Cas9 screening identified PSMB9 loss as a novel mechanism of resistance to CD19 CAR T cell therapy, with PSMB9-deficient tumor cells exhibiting a survival advantage under CAR-T pressure, supported by trends in clinical CAR-T outcomes. Our study uncovers PSMB9 as a previously unrecognized critical regulator of the tumor immune landscape in a pan-cancer scope, whose expression orchestrates key immune processes within the tumor microenvironment and serves as a potent biomarker for patient prognosis. Critically, we first established PSMB9 as a novel prognostic indicator for both checkpoint blockade and CAR-T cell therapies, highlighting its dual role as a crucial immune modulator and a promising biomarker for guiding T cell-based immunotherapy strategies across diverse human cancers. Full article

Peripartum depression (PPD) represents a significant public health concern, affecting 10–17% of women globally. Traditional monoaminergic treatments demonstrate limited efficacy and delayed onset of action. The glutamate–GABA imbalance hypothesis provides a novel theoretical framework for understanding depression pathophysiology and developing targeted therapeutic interventions. This review examines emerging pharmacotherapeutic approaches targeting glutamatergic and GABAergic neurotransmitter systems for PPD treatment. Search criteria targeted randomized clinical trials investigating GABA-A-positive allosteric modulators (brexanolone, zuranolone, and ganaxolone) and NMDA receptor antagonists (ketamine and esketamine) in PPD patients. Brexanolone was the first neurosteroid to receive FDA approval for PPD, while zuranolone also shows promise. Ketamine and esketamine are also associated with reduced PPD risk, particularly with perioperative administration during cesarean delivery, though benefits are predominantly short-term. These glutamate–GABA pathway modulators represent novel therapeutic alternatives with rapid onset profiles. Further investigation and research are needed to optimize dosing protocols and patient selection criteria and to establish long-term efficacy before PPD treatment guidelines can be drafted. Full article

Cancer cachexia is a multifactorial syndrome characterized by metabolic dysregulation, inflammation, and progressive loss of skeletal muscle mass. Frequently observed in colorectal cancer patients, it is associated with poor clinical outcomes and reduced treatment tolerance. Current therapies provide limited benefit, underscoring the need for integrative approaches. Grape seed polyphenols, particularly oligomeric proanthocyanidins, have demonstrated potential to modulate catabolic signaling, mitochondrial dysfunction, and inflammatory responses involved in cachexia pathophysiology. This review integrates preclinical and clinical evidence on the use of grape seed-derived products, highlighting their effects on NF-κB and AMPK pathways, redox homeostasis, and gut–muscle axis. Furthermore, the nutritional composition and bioactive properties of grape seed flour—rich in fiber and phenolic compounds—are discussed in the context of nutraceutical applications. A clinical trial currently underway in Brazil aims to evaluate the effects of grape seed flour supplementation in colorectal cancer patients with cachexia. Altogether, grape-derived compounds offer a safe, low-cost, and mechanistically grounded strategy for improving nutritional status and resilience in oncological care. Full article

Background: Periodontal disease is a common chronic inflammatory disease affecting the oral cavity involving the tissues supporting teeth. It is a significant oral health concern worldwide, particularly amongst individuals living with human immunodeficiency virus (HIV). Biological aging is associated with a natural decline in the immune system, which can also affect the severity of periodontitis and other potential risk factors. In people living with HIV (PLWH), the contribution of both the HIV infection and the aging process can lead to increased susceptibility to periodontal disease. Objectives: This paper aims to review the recent literature about the relationships between HIV infection and early aging and their impact on periodontitis, and to inform interested clinicians about the current literature on the intersection between and within these topics. Methods: This review explores the recent literature on the complex relationship between HIV, aging, and periodontitis. The PubMed, ScienceDirect, and Medline databases were used to find clinical research studies within the last 10 years to identify significant correlations between HIV, aging, and periodontitis. Results: These studies identify key pathogens, molecules, or cellular pathways that contribute to a more comprehensive understanding of the pathophysiologic processes that link HIV, aging, and periodontitis. This complex relationship is multifactorial, involving immune dysfunction, microbial dysbiosis, and inflammatory pathways that still need further research. Conclusions: Overall, this exploration through molecular and cellular mechanisms underlying the relationships between aging, HIV, and periodontitis can provide therapeutic implications for dental clinicians to prevent and treat their affected patients. Full article

Virtual reality (VR) has emerged as a transformative tool in the treatment of phobias and the cultivation of emotional resilience. This study aims to explore the potential of VR to create controlled, immersive environments that facilitate exposure therapy, enabling individuals to confront and desensitize themselves to their fears in a safe and personalized manner. The flexibility of VR systems allows therapists to tailor scenarios to the unique needs of patients, addressing specific phobias such as acrophobia, arachnophobia, and social anxiety disorders. Beyond phobia treatment, VR’s capacity to simulate challenging or stress-inducing scenarios presents opportunities for fostering emotional resilience by building adaptive coping mechanisms and reducing stress responses over time. The integration of biofeedback and machine learning further enhances VR applications, enabling real-time adjustments based on physiological and psychological responses. In this article, the current advancements, underlying mechanisms, and challenges in leveraging VR technology for therapeutic purposes are discussed with a focus on its implications for mental health care. By combining immersive technology with evidence-based practices, VR offers a promising pathway for improving mental health outcomes and expanding the accessibility of therapeutic interventions. Full article

WWOX and HIF1α proteins are involved in cancer progression; their functions are closely related. WWOX binds HIF1α through its WW domains, sequestering it in the cytoplasm and inhibiting its transcriptional activity. This study evaluates the prognostic significance of the WWOX/HIF1A interaction across cancers, breast cancer subtypes, glioblastoma (GBM), low-grade glioma (LGG), and hepatocellular carcinoma (HCC) through gene expression and pathway analysis focused on metabolism, ECM, and epithelial–mesenchymal transition. In breast cancer, metabolic pathways correlated with good prognosis in basal subtypes. HER2 subtypes showed enrichment in DNA replication pathways. Luminal A subtypes showed favourable prognosis via TNF and PI3K/AKT signalling, while luminal B subtypes had poor prognosis tied to metabolic activity; genes associated with good prognosis mirrored those tied to poor prognosis in luminal A. In HCC, enhanced metabolic activity was associated with good prognosis. In contrast, poor prognosis involved TNF signalling and cytoskeleton-related pathways, indicating more aggressive tumour behaviour. In LGG, good prognosis was linked to metabolic and cAMP pathways, while poor outcomes involved TNF, cell cycle, apoptosis, and focal adhesion pathways. GBM showed similar patterns: metabolic and cAMP pathways indicated better outcomes, while NFKB, TNF, JAK-STAT, and PI3K/AKT pathways marked poor prognosis. These findings suggest the WWOX/HIF1A ratio is a robust prognostic marker and a possible guide for developing targeted treatments. Full article

Background and Clinical Significance: Acquired angioedema (AAE) is a rare and potentially life-threatening condition characterized by acquired deficiency of C1-inhibitor (C1-INH) resulting in hyperactivation of the classical complement pathway. AAE occurs in association with malignancies or autoimmune diseases. Infectious triggers are rarely encountered, and the underlying mechanisms have yet to be completely clarified. Case Presentation: This case involves a previously healthy 19-year-old male who was admitted with Mycoplasma pneumonia and oral ulcers, subsequently developing unilateral facial angioedema. Laboratory studies demonstrated reduced C4, decreased levels and activity of C1-INH, and reduced C1q, all consistent with acquired C1-INH deficiency. These findings were attributed to the presence of cold agglutinins, which are frequently observed in Mycoplasma pneumoniae infections. Following treatment with icatibant, a bradykinin B2 receptor antagonist, the patient’s angioedema resolved rapidly. An exhaustive workup found no evidence of underlying systemic disorders, and the patient did not experience any angioedema attacks following resolution of the infection. Conclusions: The presence of cold agglutinins, commonly associated with Mycoplasma infections, can precipitate a decline in C1-INH levels, resulting in complement pathway dysregulation. This disruption leads to an excess of bradykinin, followed by increased vascular permeability and localized edema. Full article

Introduction: Neuroinflammation is a common pathological hallmark of Coronavirus Disease 2019 (COVID-19) and epilepsy; however, their shared immunogenomic mechanisms remain poorly defined. This study explores shared immune-inflammatory transcriptomic signatures and identifies potential repositioning therapeutics. Methods: We integrated single-cell RNA-seq data from peripheral blood mononuclear cells (PBMCs) of COVID-19 patients and healthy donors (GSE149689), and bulk RNA-seq data from hippocampal tissue of patients with Temporal Lobe Epilepsy with Hippocampal Sclerosis (TLE-HS) and healthy controls (GSE256068). Common Differentially Expressed Genes (DEGs) were identified and subjected to GO/KEGG enrichment, a PPI network, hub gene detection (cytoHubba), and transcriptional regulation analysis (ENCODE-based TF/miRNA networks). Drug repositioning was performed using the LINCS L1000 database. Results: We identified 25 DEGs shared across datasets, including 22 upregulated genes enriched in cytokine–cytokine receptor interaction, NF-κB, and Toll-like receptor pathways. PPI analysis revealed a CX3CR1–TLR4-centered immune module. Gabapentin emerged as a promising repositioning candidate with potential to downregulate CX3CR1, TLR4, and selectin P ligand (SELPLG). Receiver Operating Characteristic (ROC) analysis confirmed the diagnostic value of these targets (AUC > 0.90 in epilepsy). A mechanistic model was proposed to illustrate Gabapentin’s dual action on microglial polarization and cytokine suppression. Conclusions: Our results reveal a shared CX3CR1–TLR4–NF-κB inflammatory axis in COVID-19 and epilepsy, supporting Gabapentin as a potential dual-action immunomodulator. These findings reveal a previously underappreciated immunomodulatory role for Gabapentin, providing mechanistic rationale for its repositioning in neuroinflammatory conditions beyond seizure control. Full article

Background and Objectives: Metformin, a staple in diabetes care, has recently emerged as a candidate chemotherapeutic agent. In vitro studies suggest that metformin inhibits cancer growth by altering cellular metabolism and enhancing immune responses. Clinical observations further indicate that it suppresses key tumor-promoting pathways such as mTOR and STAT3. This review critically evaluates the therapeutic potential of metformin in oncology through the lens of precision medicine. This review integrates evidence from molecular mechanisms, clinical studies, biomarker-driven trial designs, and the regulatory challenges that continue to delay its approval for oncologic use. Methods: A structured literature search (2015–2025) identified 63 relevant studies, including preclinical, clinical, and translational research. Conclusions: Although metformin shows consistent anticancer effects in laboratory and animal models, its clinical benefits in patients are variable. This inconsistency is likely due to tumor heterogeneity and a lack of biomarker-based patient selection in trials. Targeting these shortcomings through biomarker-enriched, tumor-specific clinical trials is essential to define metformin’s role as a repurposed agent in precision oncology. Full article

Objectives: Patients with rare diseases in China face extremely high medical expenses. The current coverage framework remains inadequate in terms of coverage depth and proactive risk control, underscoring an urgent need for institutional reform. Methods: This study employs a policy content analysis approach to review the current landscape of rare disease protection in China. Drawing on risk management theory and the health capital model, it constructs an analytical framework to examine potential institutional reforms through the lens of risk response pathways and the efficiency of health investment. Results: The findings reveal that basic medical insurance (BMI) provides limited financial protection for patients with rare diseases. Among China’s 31 provincial-level administrative centers, 24 have set general outpatient reimbursement ceilings under the urban and rural resident basic medical insurance (URRBMI) at 1000 RMB or less. In comparison, 24 cities have set outpatient reimbursement limits under the urban employee basic medical insurance (UEBMI) at 6000 RMB or less. The security system relies predominantly on the BMI, while supplementary mechanisms have failed to provide effective support or continuity in coverage. Current policies are generally reactive, with coverage typically triggered only after a confirmed diagnosis and often lacking early intervention or preventive strategies. Conclusions: China’s rare disease security system urgently requires structural improvements in coverage depth and proactive risk management. The proposed Dedicated Insurance Scheme for Rare Diseases (DISRD) presents a feasible and sustainable model for China’s multi-tiered system of securing rare diseases. It provides valuable institutional insights for other countries and regions seeking to build public health systems with proactive risk control capabilities. Full article

Background/Objectives: Systemic toxicities to key organs like the heart, liver, and kidneys impair the efficacy of chemotherapy in cancer treatment. These toxicities are caused by oxidative stress, inflammation, mitochondrial malfunction and ferroptosis, causing clinical morbidity and possibly impaired adherence to treatment. This review, also, examines how magnesium, selenium, zinc and vitamin D protect against chemotherapy-induced cardiotoxicity, hepatotoxicity and nephrotoxicity. Methodology: A complete literature search of PubMed (MEDLINE), Scopus, Cochrane Library and Embase was used to synthesize data till 29 June 2025. Studies included randomized and non-randomized trials, cohort studies, case series (≥3 patients), and relevant systematic reviews. To contextualize pathways, preclinical in vivo and in vitro studies were studied independently. Patients undergoing systemic chemotherapy and magnesium, selenium, zinc or vitamin D therapies were eligible. Supplementation’s safety and organ-specific toxicity were investigated. Results: Magnesium protected against cisplatin-induced nephrotoxicity via modulating renal transporters and oxidative defenses across chemotherapy regimens. Selenium supplementation has strong antioxidant and anti-inflammatory characteristics, especially in avoiding cardiac and hepatic injury, although its nephroprotective potential was formulation-dependent. Zinc’s activity was connected to metallothionein-mediated redox stabilization, inflammatory regulation, and cardiac and hepatic resilience. Vitamin D and its analogs reduced cardiotoxicity and nephrotoxicity through mitochondrial preservation and immunomodulatory signaling. Conclusions: To date, magnesium, selenium, zinc, and vitamin D have been shown to reduce chemotherapy-related organ toxicities. Preclinical studies are promising, but randomized clinical trials are needed to prove therapeutic effectiveness and oncologic safety. Full article

Background: LUAD, the most common subtype of lung cancer, particularly in non-smokers, is significantly influenced by air pollution from fine particulate matter (PM). One suspected method by which PM contributes to cancer progression is through angiogenesis, which promotes tumor growth and metastasis. This study was conducted to explore the impact of long-term PM exposure on the progression of LUAD, focusing on angiogenesis promotion. Methods: We conducted an integrative bioinformatics analysis incorporating epidemiological and transcriptomic datasets from public repositories (TCGA and GEO) to evaluate differential VEGFA expression in LUAD tissues and its relationship to regional PM exposure. In vitro and in vivo assays using PM-adapted NSCLC cell lines and murine xenograft models served as secondary confirmatory experiments supporting the computational results. Results: Epidemiological analysis revealed a strong positive correlation between long-term PM exposure and lung adenocarcinoma mortality across U.S. states (r = 0.7638, p < 0.0001), underscoring a population-level impact. Bioinformatics analysis identified a significant upregulation of VEGFA in NSCLC tumors from regions with high PM levels, with VEGFA overexpression also associated with poorer patient survival. Gene ontology and pathway enrichment analyses implicated angiogenesis-related processes. These findings were supported by experimental models, in which long-term PM exposure on human and murine LUAD cell lines (A549, H1299, and LLC) induced VEGFA and p-ERK overexpression. Furthermore, PM-exposed cells enhanced angiogenesis processes, as evidenced by increased endothelial cell tube formation and migration in vitro, and promoted tumor vascularization in a xenograft model. These pro-angiogenesis effects were abrogated following inhibition of the MAPK signaling pathway or blockade of VEGFA. Conclusions: Our findings reveal a compelling molecular link between PM exposure and NSCLC progression, centered on VEGFA-driven angiogenesis and urging the need to reduce ambient PM exposure to mitigate its oncogenic impact. Full article

Arteriovenous (AV) access complications remain a major cause of morbidity in hemodialysis patients, influenced by multiple factors, including endothelial inflammation induced by uremia. In this study, we investigated the mechanisms underlying the upregulation of endothelial chemokines interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) by indolic uremic toxins, as well as their association with AV access complications in hemodialysis patients. In cultured human endothelial cells, IL-8 and MCP-1 were upregulated by indolic uremic toxins through activation of their receptor, the aryl hydrocarbon receptor (AHR), and non-canonical TGF-β pathway involving TAK1/p38 MAPK/AP-1 signaling. In a retrospective observational study of 204 hemodialysis patients, baseline serum IL-8 or MCP-1 were positively correlated with indolic uremic toxins and TGFβ1. Additionally, serum IL-8 ≥ 40.26 pg/mL and serum MCP-1 were independently associated with an increased risk of AV access complications over a 2-year period. In conclusion, we demonstrated that indolic uremic toxins promote endothelial inflammation by inducing IL-8 and MCP-1 expression via AHR activation and non-canonical TGF-β signaling. Clinically, elevated serum IL-8 and MCP-1 were independently associated with an increased risk of AV access complications in hemodialysis patients. Full article

Digital twin is a mathematical model that virtually represents a physical object or process and predicts its behavior at future time points. These simulation models enable a deeper understanding of tumorigenic processes and improve biomarker discovery in cancer research. Tumor microenvironment is marked by dysregulated signaling pathways, where kinases and phosphatases serve as critical regulators and promising sources for biomarker discovery. These enzymes operate within multiscale and context-dependent processes where spatial and temporal coordination determine cellular outcomes. Digital Twin technology provides a platform for multimodal and multiscale modeling of kinase and phosphatase processes at the patient-specific level. These models have the potential to transform biomarker validation processes, enhance the prediction of therapeutic responses, and support precision decision-making. In this review, we present the major alterations affecting kinases and phosphatase functions within the tumor microenvironment and their clinical relevance as biomarkers, and we address how digital twins in oncology can augment and refine each stage of the biomarker discovery pipeline. Introducing this emerging technology for cancer biomarker discovery will assist in accelerating its adoption and translation into precision diagnostics and targeted therapies. Full article