Search Results (1,376)

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is closely associated with dysfunction of the gut–brain axis. Exercise and diet exert neuroprotective effects on PD by regulating the gut–brain axis, yet the overall mechanisms underlying this regulation remain to be systematically elucidated. This article reviews the characteristic changes in gut microbiota during the progression of PD and the pathological mechanisms involving gut–brain axis dysfunction. It systematically outlines the intrinsic mechanisms by which gut microbiota modulate the onset and development of PD from the perspectives of metabolism, immunity and inflammation, neuroendocrinology, and the temporal and causal relationships between gut microbiota and PD. On this basis, the discussion focuses on the regulation of the gut–brain axis through exercise to improve PD, with emphasis on remodelling the composition and diversity of gut microbiota, enhancing gut barrier and blood–brain barrier (BBB) functions, regulating immune and inflammatory homeostasis, upregulating the expression of neurotrophic factors and promoting neuroplasticity, as well as the synergistic effects of exercise and diet. In parallel, the independent and synergistic effects of dietary interventions (e.g., high-fibre and Mediterranean diets) are discussed. In addition, the effects of different types of exercise on alleviating PD by regulating gut–brain axis are analysed. This review aims to provide new insights and a scientific basis for the prevention and intervention of PD. Full article

Aspergillosis encompasses a heterogeneous spectrum of diseases caused by filamentous fungi of the genus Aspergillus, ranging from allergic airway disorders and chronic pulmonary infection to rapidly progressive invasive disease. Aspergillus fumigatus is the predominant pathogen worldwide, although other species, including Aspergillus flavus, Aspergillus terreus and cryptic species, contribute to morbidity and may exhibit intrinsic or acquired antifungal resistance. Early and accurate laboratory diagnosis is essential for timely treatment, appropriate antifungal selection, and stewardship. Traditional culture remains foundational, enabling confirmation of viable organisms, species-level identification, and antifungal susceptibility testing, but sensitivity is limited and turnaround times are prolonged. Non-culture approaches—including galactomannan, β-D-glucan, lateral flow assays, PCR, and next-generation sequencing—enhance diagnostic sensitivity, facilitate early detection, and allow identification of resistance-associated mutations. Optimal diagnostic performance is achieved through integrated, multimodal strategies combining laboratory tests with clinical and radiological findings. In invasive disease, concurrent use of biomarkers and molecular assays improves specificity and positive predictive value, while in allergic bronchopulmonary aspergillosis, immunological markers remain central. Future directions include standardised molecular protocols, novel antigenic and host-based biomarkers, and cost-effective, risk-adapted diagnostic algorithms to refine detection, guide therapy, and improve patient outcomes. Full article

Daylight Saving Time (DST) creates abrupt, externally imposed circadian disruptions that can impair sleep regulation, hormonal balance, cognitive performance, and emotional stability. Although these effects are known in the general population, individuals with chronic mental illness, whose circadian systems are often intrinsically dysregulated, may face increased neuropsychological consequences. This comprehensive review synthesizes evidence from chronobiology, psychiatry, neuroscience, and population health to examine how DST-related circadian misalignment impacts cognitive functioning, mood regulation, suicidality risk, and symptom exacerbation across psychological disorders such as depression, anxiety disorders, bipolar disorder, post-traumatic stress disorder, attention-deficit/hyperactivity disorder, and psychotic disorders. Following the Scale for the Assessment of Narrative Review Articles (SANRA) guidelines, a search of PubMed, PsycINFO, Scopus, and Google Scholar was conducted to identify studies published from 2000–2026 examining DST, circadian rhythm disruption, neuropsychological outcomes, and chronic mental illness. Empirical, theoretical, and mechanistic studies were included to ensure comprehensive synthesis. Across conditions, DST, particularly spring forward transitions, is associated with increased sleep disturbance, impaired executive functioning, reduced attention and working memory, heightened emotional reactivity, increased depressive symptoms, elevated risk of manic episodes, and short-term increases in suicidality. Neurobiological mechanisms include altered melatonin secretion, cortisol dysregulation, Hypothalamus Pituitary Axis (HPA-axis) activation, and clock-gene desynchrony. DST may function as a modifiable negative environmental influence capable of affecting neuropsychological functioning in vulnerable populations. These findings underscore the need for clinical awareness, preventive strategies, and policy reconsiderations, including calls to eliminate seasonal time changes. Standardizing DST-related research outcomes and expanding longitudinal, multi-site studies will be essential for advancing this emerging field. Full article

Background: Nitrous oxide (N₂O) is increasingly used as a recreational drug, leading to neurological and systemic toxicities. However, due to the rapid elimination and minimal alteration of nitrogen oxides, the short direct detection window complicates the assessment of N₂O exposure. Method: In this study, we investigated the effects of chronic N₂O exposure on plasma metabolites using an untargeted metabolomics approach in a mouse model. C57BL/6 mice were exposed to 90,000 ppm N₂O (1 h, twice daily for 28 days) or room air. Plasma samples were analyzed via UHPLC -Triple TOF -MS. Orthogonal partial least squares discriminant analysis (OPLS-DA) and receiver operating characteristic (ROC) curves were used to identify differential metabolites. Result: A total of 35 differential metabolites were identified. Eight metabolites with an area under the curve (AUC) > 0.90 were selected as candidate biomarkers, including up-regulated SOPC and PC(16:0/16:0) (suggesting disrupted phospholipid remodeling and membrane integrity), and down-regulated DL-tryptophan, creatine, ectoine, indole, His-Ser, and Ile-Pro. Pathway enrichment analysis revealed significant alterations in glycine, serine and threonine metabolism; phenylalanine, tyrosine and tryptophan biosynthesis; protein digestion and absorption; and tryptophan metabolism. Conclusions: Our data indicate that chronic N₂O exposure disrupts multiple amino acid-related metabolic pathways (e.g., tryptophan-kynurenine pathway) and phospholipid homeostasis. The identified metabolite changes, along with vitamin B₁₂, homocysteine, and methylmalonic acid, may constitute a specific metabolic fingerprint for N₂O exposure. These findings help reveal the intrinsic mechanistic links underlying metabolic disorders induced by N₂O exposure. Full article

Arrhythmogenic cardiomyopathy (ACM) is a genetic myocardial disorder marked by progressive cardiomyocyte loss, fibro-fatty replacement, ventricular arrhythmias, and risk of sudden cardiac death. Traditionally considered a structural and electrical disease driven by desmosomal dysfunction, emerging evidence redefines ACM as an inflammatory cardiomyopathy in which immune activation plays a central role. This review integrates genetic, molecular, experimental, and clinical data to highlight inflammation as a unifying feature of ACM. Desmosomal gene variants impair cell adhesion and also activate cardiomyocyte-intrinsic inflammatory pathways, including nuclear factor of kappa B (NFκB) and glycogen synthase kinase 3β (GSK3β) signaling, promoting cytokine release, immune cell recruitment, and fibrotic remodeling. Preclinical studies suggest inflammation precedes structural changes, indicating it may be an initiating event rather than a secondary response. Clinical and pathological findings support this model, with inflammatory infiltrates, circulating cytokines, and autoantibodies observed across disease stages. These processes often present as episodic “hot phases” resembling myocarditis, thus complicating diagnosis. The inflammatory landscape involves both innate and adaptive immunity, along with stromal and neuronal remodeling, contributing to arrhythmogenesis through gap junction disruption, calcium-handling abnormalities, and fibrosis. Environmental factors such as exercise, stress, and metabolic disturbances further modulate inflammatory pathways and disease expression. Therapeutically, this evolving perspective supports immunomodulatory approaches, including inhibition of NFκB, GSK3β, and cytokine signaling. Early clinical data on immunosuppressive and cytokine-directed therapies are promising, especially during active inflammatory phases, while gene-based strategies specifically address the underlying genetic defects. In conclusion, ACM should be recognized as an inflammatory cardiomyopathy shaped by interactions between genetic susceptibility and immune dysregulation. Integrating genetic and immunologic profiling may improve diagnosis, risk stratification, and treatment, ultimately leading to refined personalized therapeutic strategies. Full article

Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is a chronic inflammatory disorder of the gastrointestinal tract that imposes an increasing global health burden. Conventional pharmacological treatments are often limited by systemic side effects and insufficient drug accumulation at inflamed intestinal sites. Enzyme-responsive polymeric drug delivery systems have emerged as a promising strategy to overcome these limitations by enabling site-specific and controlled drug release within the pathological microenvironment of the colon. This review summarizes recent advances in enzyme-responsive polymeric platforms designed for IBD therapy. We first discuss the altered enzymatic landscape in the intestinal microenvironment of IBD, including host-derived inflammatory enzymes such as esterases, matrix metalloproteinases, and hyaluronidase, as well as microbiota-derived enzymes such as azoreductase, cellulase, and amylase. These enzymes provide intrinsic biological triggers for selective polymer degradation and drug release. We then categorize enzyme-responsive polymeric delivery systems according to the enzymes involved and highlight representative material design strategies, including polymer prodrugs, core–shell nanocarriers, enzyme-degradable hydrogels, and polysaccharide-based carriers. Particular emphasis is placed on the multifunctional roles of polymers that enable targeted delivery, mucosal adhesion, and therapeutic synergy through bioactive degradation products. Finally, current challenges and future directions toward multi-stimuli-responsive systems and clinically translatable polymeric nanomedicine for precision IBD therapy are discussed. Full article

Melanin is a biological pigment known for its broadband UV-Vis absorption and structural disorder, which collectively determine its chromatic response. In this study, melanin–silica hybrid materials were synthesized via sol–gel processing under different catalytic conditions (acid, base, sequential acid–base) and using distinct silica precursors (TEOS and sodium metasilicate) to investigate how the inorganic matrix modulates the optical properties of the synthetic melanin. Colorimetric analysis revealed significant variations in lightness among the hybrids, while the chromatic coordinates remained characteristic of eumelanin. The material obtained via the sequential acid–base route exhibited the lowest lightness and highest absorption, indicating more efficient pigment dispersion, whereas the system derived from silicate precursors showed the highest lightness and lowest absorption, suggesting increased light scattering and/or pigment aggregation. Materials prepared under purely acidic and basic conditions displayed intermediate optical behavior. Electron Microscopy revealed distinct morphologies associated with each synthesis pathway, ranging from dense lamellar structures to compact aggregates and hierarchical assemblies, directly influencing light scattering mechanisms. Thermal analysis confirmed effective stabilization of melanin within the silica networks, with significantly reduced mass loss compared to the pure pigment. Confocal microscopy revealed detectable fluorescence only in selected systems, indicating variations in pigment dispersion and aggregation state. Overall, the results demonstrate that the chromatic response of melanin–silica hybrids is governed not only by the intrinsic properties of the pigment, but also by the structural organization of the inorganic matrix. Sol–gel processing thus provides a versatile strategy for tuning the optical behavior of melanin-based materials through controlled interfacial interactions. Full article

Ubiquitin-specific protease 7 (USP7/HAUSP) is one of the most studied deubiquitinating enzymes and plays a crucial role in regulating numerous cellular processes, making it a promising therapeutic target. In the nucleus, USP7 partially colocalizes with PML nuclear bodies (PML-NB)—multifunctional membraneless organelles involved in post-translational modifications and protein complexes assembly. The molecular basis and functional significance of this association remain uncharacterized. In this study, comparison of USP7 and PML interactomes revealed a significant overlap of 166 shared proteins. Functional enrichment analysis showed that USP7 and PML may operate within a common molecular context related to transcriptional regulation, chromatin remodeling, and DNA damage responses. Furthermore, these processes are also linked to cellular senescence and human aging (CellAge and GenAge databases). Focused analysis of overlaps between the USP7 interactome and core PML-NB proteins identified 61 proteins forming a dense “small-world” network. Most are prone to liquid–liquid phase separation, are intrinsically disordered, and serve as substrates for SUMOylation or ubiquitination. These findings not only expand our understanding of the molecular functions of USP7 but also highlight PML-NB as an important cellular context for investigating mechanisms associated with USP7 activity. Full article

Background/Objectives: SHP2 (PTPN11) is a key regulator of RAS/MAPK signaling and a well-validated target in cancer and developmental disorders. Designing ligands for its catalytic site is challenging due to the pocket’s intrinsic flexibility and the presence of conserved structural water molecules critical for ligand recognition, which limits traditional discovery approaches. This study aimed to systematically identify and prioritize novel SHP2-binding candidates using a computational strategy that accounts for these challenges. Methods: An integrative computational workflow was applied, combining water-aware docking, large-scale virtual screening of 714,409 compounds, MM/GBSA binding free-energy analysis, AI-driven chemical space modeling using ChemBERTa, and microsecond-scale molecular dynamics (MD) simulations. The high-resolution catalytic PTP domain of SHP2 structure was analyzed to identify conserved water molecules (W711, W716, W726, W776) essential for reproducing the crystallographic binding mode of the reference ligand 3LU. Candidates were prioritized based on docking scores, physicochemical criteria, structural inspection, MM/GBSA energetic profiles, and occupancy of distinct chemical space regions. Results: Seven compounds were selected. SwissADME analysis confirmed favorable drug-likeness and GI absorption, with no BBB permeation. ChemBERTa embeddings revealed substantial structural novelty relative to known SHP2 inhibitors. 1 μs molecular dynamics simulations suggested stable binding of compound 4 (2-(3-methyl-2,6-dioxopurin-7-yl)acetate) and persistent interactions with the conserved water network. MM/GBSA evaluation subsequently highlighted its energetically coherent profile. Conclusions: The workflow prioritizes compound 4 as a promising and structurally innovative SHP2-binding candidate. This integrative strategy provides a generalizable approach for targeting proteins with flexible pockets, critical water networks, and limited scaffold diversity, offering a roadmap for challenging computational ligand-prioritization projects. Full article

Mitral valve prolapse represents the most common cause of primary mitral regurgitation in Western countries and has traditionally been viewed as a disorder driven by valvular incompetence and chronic volume overload. Within this paradigm, left ventricular enlargement was expected to correlate with regurgitant severity. However, patients with myxomatous bileaflet prolapse often exhibit left ventricular dilatation disproportionate to the degree of regurgitation, leading to the hypothesis of an intrinsic myocardial disease process. Cardiovascular magnetic resonance imaging has challenged this concept through the identification of doming volume, a previously unrecognized systolic blood compartment located between the mitral annular plane and the ventricular surface of prolapsing leaflets. This volume is mechanically coupled to ventricular contraction and contributes to total ventricular volume load independently of transvalvular regurgitation. Recognition of doming volume provides a physiological explanation for excessive ventricular remodeling observed in bileaflet prolapse and Barlow disease. Doming volume has important implications for imaging assessment. Its common exclusion from echocardiographic volumetric measurements may result in underestimation of left ventricular end-systolic volume, overestimation of ejection fraction, and underestimation of regurgitant burden, contributing to discordance between echocardiographic and cardiovascular magnetic resonance-derived measurements. Cardiovascular magnetic resonance enables comprehensive assessment, allowing accurate quantification of ventricular volumes, mitral regurgitation severity, doming volume, and myocardial tissue characteristics. Integration of doming volume into the evaluation of mitral valve prolapse improves physiological consistency between imaging findings and ventricular remodeling. However, further evidence is required before doming volume assessment can be incorporated into operative clinical indications or decision-making thresholds. Full article

Glucose-6-phosphate dehydrogenase (G6PD) deficiency impairs NADPH generation through the pentose phosphate pathway, resulting in reduced glutathione regeneration and increased vulnerability to oxidative stress. While its clinical significance is well described in hemolytic disorders, its impact on tumor biology and chemosensitivity remains poorly characterized. Cisplatin, a backbone agent in the management of nasopharyngeal carcinoma (NPC), exerts its cytotoxicity through the formation of DNA adducts and the robust induction of reactive oxygen species (ROS) activity. We report a patient with non-keratinizing NPC and a G6PD variant, a (class III) deficiency, who demonstrated a rapid and pronounced objective response to cisplatin-based induction and concurrent chemoradiotherapy. Unfortunately, the patient also exhibited signs of rapid and persistent hematologic (platelets and white cells) toxicity. Notably, no hemolytic events occurred. A narrative review of the available literature indicates that G6PD-deficient cells exhibit a reduced antioxidant reserve, increased cisplatin-induced DNA damage, and impaired activation of ROS-detoxifying pathways. A few clinical observations similarly report enhanced tumor responsiveness in G6PD-deficient individuals, although the evidence is sparse and heterogeneous. Preclinical data support the notion that diminished NADPH availability amplifies cisplatin-triggered oxidative injury, thereby increasing tumor susceptibility. This case adds to emerging evidence that G6PD deficiency may potentiate cisplatin efficacy in NPC by exploiting intrinsic redox vulnerabilities. While preliminary, these findings suggest the potential utility of metabolic phenotyping in treatment stratification. Prospective studies are needed to define the predictive value, safety, and therapeutic implications of G6PD status in cisplatin-based regimens. Full article

Empowered by nanotechnology, messenger RNA (mRNA) therapeutics have shown a rapid evolution post COVID-19 from a conceptual platform to a clinically validated modality, and they diversified into oncology, cardiovascular diseases, and rare disorders. As a template for in situ protein production, it offers several advantages over traditional proteins and DNA drugs. The intrinsic stability of mRNA and its sensitivity to innate immune sensing hinder its capacity for immediate cellular entry, necessitating its need for a delivery system to obtain optimal therapeutic potential. This review explores the innovations in nanocarrier engineering, design principles for lipid nanoparticles-mRNA (LNPs) platforms, and their clinical translation across the prominent indications. It also addresses their safety, immunogenicity, and scalability while addressing the key limitations and manufacturing scalability through comparative platform analysis. Although LNPs usually dominate their delivery through encapsulation and manufacturability, their limitations, like repeat dose reactogenicity and liver tropism, require next-generation designs like SORT lipids, stimuli-responsive hybrids for extrahepatic targeting. In oncology, LNP-mRNA drives the neoantigen vaccines, and rare diseases leverage the transient enzyme replacement. While the safety profiles highlight the innate immune tuning through nucleoside mods and lipid biodegradability, chronic administration risks are still persistent. While there are novel scalability options like microfluidic mixing to support the production gaps in organ selectivity and durability, their adoption is hindered. We outline the future directions to perceive mRNA’s full potential as a broader therapeutic class. Full article

Hajdu–Cheney syndrome (HCS) is a rare genetic skeletal disorder caused by truncating variants of NOTCH2, characterized by progressive bone resorption and marked phenotypic heterogeneity. Despite advances in understanding Notch signaling in skeletal biology, longitudinal clinical data tracking disease evolution from early childhood through adolescence are lacking. Here, we report a rare longitudinal intrafamilial observation of HCS in a mother and her son carrying the same NOTCH2 pathogenic variant, providing novel insights into disease evolution and therapeutic response. Over extended follow-up, the son exhibited early vertebral fragility despite preserved or supranormal bone mineral density (BMD), whereas the mother developed severe osteoporosis, progressive acro-osteolysis, and multiple vertebral fractures. Longitudinal analysis revealed a dissociation between vertebral fragility and densitometric decline, challenging the paradigm that low BMD is the primary driver of skeletal morbidity in HCS. Treatment responses differed between the two patients, with bisphosphonate therapy in the son associated with stabilized BMD without altering vertebral structural progression, and denosumab in the mother associated with increased BMD, but not preventing progression of acro-osteolysis. Additionally, the emergence of extra-skeletal features during adolescence expands the phenotypic spectrum of HCS and suggests previously unrecognized systemic involvement. These data highlight intrinsic limitations of current therapeutic strategies and emphasize the need for targeted interventions addressing sustained Notch2 activation. Our findings contribute to the understanding of the natural history and therapeutic challenges of HCS, providing the framework for future mechanistic and translational research. Full article

Milk production in dairy herds is determined by both intrinsic and extrinsic factors, with reproductive efficiency serving as a primary determinant. Infectious, nutritional, and management-related challenges can reduce this efficiency. Following parturition, cows are more susceptible to clinical disorders due to a temporary loss of integrity in the cervix, vagina, and vulva, which allows environmental bacteria to ascend and alter the vaginal microbiota. These microbial changes may disrupt endocrine responses related to conception and contribute to repeat breeder cow syndrome (RBCS), which is defined as failure to conceive after three or more inseminations. This study investigated associations among cultivable vaginal bacteria, circulating progesterone and glucose concentrations, and reproductive performance in 30 fourth-parity Holstein cows with a body condition score of 3.5. Cows were classified by reproductive history as repeat breeders (RBCS; n = 14) or controls (CTL; n = 16). Vaginal mucosal samples were collected at insemination and cultured on blood agar and MacConkey media under aerobic and microaerobic conditions. Bacterial identification was conducted using Gram staining and standard biochemical assays. Blood samples were collected at insemination, on day 5 post-insemination, and every two days thereafter to measure progesterone and glucose concentrations. Fertility outcomes were analyzed using PROC GLIMMIX, and hormonal data were analyzed using mixed models with repeated measures. The bacterial genera identified included Bacillus, Escherichia coli, Staphylococcus, Klebsiella, Proteus, Streptococcus, and Actinomyces. Progesterone and glucose concentrations did not differ significantly between groups (p > 0.05). However, the fertility rate (p < 0.05; CTL:87.50% vs. RBCS:57.14%) and number of attempts to conceive (p < 0.001; CTL:2.5 vs. RBCS:6.7) differed statistically between treatments. A higher prevalence of S. hyicus was detected in RBCS cows, and E. coli, S. hyicus, and Proteus spp. were more frequently detected in non-pregnant cows. These findings suggest that the identified cultivable vaginal bacteria are associated with reproductive status in dairy cows. Full article

Background/Objectives: Diabetes is a chronic metabolic disorder affecting global health, where early prediction can significantly reduce disease severity. Methods: This research proposes an interpretable multi-metric fuzzy distance-based ensemble (MMFDE) that integrates multi-variant gradient-boosting classifiers (GBM, LightGBM, XGBoost, and AdaBoost) through a novel fuzzy fusion mechanism designed for intrinsic interpretability. Unlike conventional ensembles relying on opaque averaging or voting, MMFDE transforms base classifier predictions into a high-dimensional fuzzy space quantified via a weighted hybrid distance incorporating Euclidean, Manhattan, Chebyshev, and cosine metrics against ideal diabetic and non-diabetic reference vectors. These distances are translated into membership degrees with the help of exponentially decaying functions, which give clinicians calibrated confidence scores for every prediction. Comprehensive SHAP analysis identifies important clinical risk factors (glucose, BMI, and diabetes pedigree function), which show concordance with the medical literature, thereby giving greater clinical trust. Results: Experimental evaluations on two publicly available datasets, Hospital Frankfurt Germany Diabetes Dataset (HFGDD) and Pima Indians Diabetes Dataset (PIDD), show that MMFDE outperforms all base models with a significant accuracy of 94.83% and Area Under the Curve (AUC) of 97.66% on HFGDD and three different levels of interpretability: geometric transparency via distance-based decisions, confidence-calibrated uncertainty estimates, and feature-level explanations via SHAP. The confidence thresholds enabled in the framework support risk stratification clinical workflows with high-confidence predictions for automated screening and cases with moderate/low confidence flagged out for review by the clinician. Conclusions: By demonstrating that high performance and interpretability need not be mutually exclusive, MMFDE advances trustworthy AI for clinical decision support, addressing the critical need for transparent and clinically actionable diabetes prediction systems. Full article