Search Results (949)

Alzheimer’s (AD) and Parkinson’s disease (PD) are prominent neurodegenerative disorders characterized by early synaptic loss, which correlates more closely with clinical symptoms than neuronal death. This synaptic impairment is primarily driven by disruptions in synaptic vesicle (SV) trafficking, a critical process for maintaining synaptic integrity through a tightly regulated cycle involving clustering, docking-priming, Ca²⁺-triggered fusion, and endocytosis. In AD, amyloid-β (Aβ) oligomers interfere with SNARE-mediated fusion and endocytosis, while hyperphosphorylated tau obstructs vesicle mobility and docking, resulting in cumulative toxicity that aggravates SV defects. Conversely, in PD, α-synuclein (α-syn) aggregation alters vesicle clustering, membrane fusion, and recycling, and these effects are further influenced by Leucine-rich repeat kinase 2 (LRRK2)-Rab-related trafficking defects and the selective vulnerability of dopaminergic terminals. Different from previous reviews that address synaptic dysfunction in a broader manner, the present review is specifically organized around the SV trafficking cycle and compares both shared presynaptic endpoints and disease-specific upstream mechanisms in AD and PD. In addition, recent mechanism-oriented therapeutic strategies are summarized. This vesicle-cycle-centered perspective may provide a clearer framework for understanding presynaptic pathology and for guiding the development of earlier and more targeted interventions. Full article

HIV-associated neurocognitive disorders (HAND) persist despite combination antiretroviral therapy (cART) and can be exacerbated by repeated cocaine (COC) exposure. Because COC, HAND, and cART independently disrupt medial prefrontal cortex (mPFC) function, their combined neurotoxic impact is a critical clinical concern. Using patch-clamp electrophysiology in HIV-1 transgenic (Tg) and non-Tg rats, we examined mPFC pyramidal neuron activity following repeated exposure to COC and/or cART. In non-Tg rats, COC and cART independently increased neuronal firing, trending toward an additive hyperactive effect when combined. Conversely, HIV-1 Tg rat neurons exhibited plateaued excitability, with no further firing elevations induced by COC or cART. Under intense depolarizing stimuli, treated neurons displayed overactivation-induced firing declines. These findings indicate that while COC and cART additively disrupt mPFC function in non-Tg rats, excitability mechanisms appear saturated in the HIV-1 Tg model. This restricted experimental context highlights the overlapping neurobiological impacts of cART and stimulant use, providing foundational insights into the comorbidity of COC use disorder and HAND. Full article

Menopause represents a key transitional phase in women’s health, characterized by declining estrogen levels and increased risk for cardiometabolic, musculoskeletal, and urogenital disorders. Beyond its endocrine roots, emerging evidence highlights the gut microbiome as a critical modulator of systemic hormonal balance. This review synthesizes current understanding of the bidirectional relationship between estrogen and the gut microbiome and its implications for women’s health during menopause. Evidence from current studies reveals distinct findings across populations, reflecting the complexity of estrogen regulation in part by the gut microbiome (i.e., estrobolome). While no ideal gut microbial composition has been identified for women across stages of perimenopause, likely due to geographically unique gut microbiome profiles among healthy women, greater microbial diversity has been positively associated with improved estrogen regulation. Conversely, reduced diversity and altered Firmicutes/Bacteroidetes ratios have been linked to biomarkers of inflammation during perimenopause, which is a key driver across many perimenopausal symptoms. Although hormone replacement therapy remains the primary clinical intervention during perimenopause, we highlight emerging evidence on the adjuvant potential of diet, synbiotics, phytoestrogens, and strain-specific probiotics in modulating the estrogen–gut microbiome axis for improved health span trajectories and better symptom management. Future longitudinal studies integrating diet, gut microbiome profiles and symptom trajectories are essential to clarify these mechanisms across ethnicity and geography. Ultimately, understanding localized diet–microbiome interactions will enable the development of accessible, personalized, and non-hormonal strategies to complement and increase agency in proactive management during the perimenopausal transition. Full article

Infertility is a prevalent clinical issue which disrupts normal human life and exerts an impact on fertility rates within the population. The increase in environmental pollutants, including acetyl tributyl citrate (ATBC), has given rise to concerns regarding their potential toxicity in infertility-related disorders. Icariin exhibits therapeutic effects on infertility, yet its mechanism of action against plasticiser-induced reproductive disorders remains unclear. This study aims to elucidate the potential toxicological targets and molecular mechanisms of ATBC-induced infertility, as well as the therapeutic targets and mechanisms of icariin in treating ATBC-induced reproductive disorders, through network toxicology, molecular-docking techniques and molecular dynamics simulation. Utilising the component-target database SwissTargetPrediction, the Similarity Ensemble Approach, PharmMapper, the ChEMBL database, and disease databases including the Therapeutic Target Database, OMIM, GeneCards, and DrugBank, 63 targets for ATBC-induced infertility and 33 targets for icariin treatment were identified. Screening via the STRING platform and Cytoscape 3.10.1 software yielded four core targets for ATBC-induced infertility—HSP90AA1, PIK3CA, CASP3, HRAS—and four core targets for icariin treatment—IL6, TNF, STAT3, and INS. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that ATBC-induced infertility correlates with pathways including pathways in cancer, prostate cancer, and PI3K-Akt signalling pathways. Conversely, the core targets of icariin therapy for related reproductive disorders are closely associated with tumour-associated signalling pathways and the AGE-RAGE signalling pathway. Molecular-docking and molecular dynamics simulation further confirmed the strong binding interactions between ATBC and infertility-related targets, as well as between icariin and core targets for treating reproductive disorders. This provides a theoretical foundation for understanding ATBC’s toxicological targets and the complex molecular mechanisms underpinning icariin’s treatment of infertility. It informs the development of strategies for icariin to prevent and treat infertility caused by exposure to ATBC-containing plastics or excessive ATBC contact. Full article

Early diagnosis of glaucoma remains challenging due to its asymptomatic onset and multifactorial pathological mechanisms. Growing evidence indicates that metabolic disorders and systemic molecular alterations play significant roles in glaucoma pathogenesis. However, reliable biomarkers and corresponding specific mechanisms remain unclear. In this study, we employed a multi-omics approach that encompassed metabolomics, transcriptomics, and Mendelian randomization to investigate the association between glaucoma and 35 types of blood and urine biomarkers. Metabolic pathway analysis was conducted using pathway enrichment analysis of differentially expressed genes based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Our study indicated that glaucoma contributed to elevated calcium concentration (OR = 1.044, 95% CI: 1.002–1.088, p = 0.039) in blood and urine, mediated by cell membrane calcium channels and calcium release from intracellular storage. Conversely, glucose was found to contribute to high glaucoma risk (OR = 1.324, 95% CI: 1.143–1.533, p = 0.0002), mediated by increased aqueous humor production, elevated intraocular pressure, endoplasmic reticulum stress, and oxidative stress. Validation experiments showed that calcium levels in blood, urine, and retina were elevated in the glaucoma group, and elevated glucose levels significantly reduced the 661W cell viability and induced apoptosis. This study offers new insights into the specific mechanisms linking blood and urine biomarkers to glaucoma, contributing to its prevention and screening. Full article

Background: The etiopathogenesis of juvenile systemic lupus erythematosus (JSLE), a complex and complicated illness, is unknown. Genetic, environmental, and dysregulated immune system responses are all thought to contribute to the disease’s etiology. Important immunological molecules that regulate different immune cells and are associated with autoimmune disorders are TNFSF4 and IKZF1. Thus, our purpose was to discover if TNFSF4 and IKZF1 mutations left the Egyptian population genetically predisposed to SLE. Methods: Using real-time polymerase chain reaction (RT-PCR), polymorphism analysis of the TNFSF4 rs1234315 C/T and IKZF1 rs11980379 C/T genes was performed on extracted DNA from JSLE patients and healthy controls. Results: TNFSF4 frequencies (rs1234315 T allele, CT, TT genotypes, dominant and recessive models) were substantially associated with a higher incidence of JSLE (p < 0.05) compared to healthy controls. Conversely, IKZF1 frequencies (rs11980379 T allele, TC, TT genotypes, and dominant model) significantly correlated with a lower incidence of JSLE. Furthermore, the TC + CC rs11980379 genotype was identified as significantly associated with lower kidney biopsy grades and a lower incidence of lupus nephritis. Conclusions: Our findings suggest that TNFSF4 and IKZF1 polymorphisms affect vulnerability to juvenile SLE. Full article

Dementia represents a major healthcare challenge, as pathological changes often occur years before overt symptoms. Early manifestations such as mild cognitive impairment (MCI) and subjective cognitive decline (SCD) represent critical transitional stages between normal aging and dementia. Thus, distinguishing these conditions (i.e., MCI and SCD) and determining their potential evolution into dementia remains crucial. However, current clinical tools, mainly neuroimaging and neuropsychological assessments, are not always clearly interpretable and are often resource-intensive. In recent years, artificial intelligence (AI), including machine learning (ML) and deep learning (DL), has demonstrated promising potential in early detection, progression prediction, and differential diagnosis of neurocognitive disorders. This systematic review aims to synthesize current evidence on the application of AI-based approaches to improve diagnostic accuracy and prognostic assessments in dementia. A comprehensive literature search of studies published between 2015 and 2025 was conducted across PubMed/MEDLINE, Scopus, and Web of Science, following PRISMA 2020 guidelines. Studies were evaluated for data modality, methodological rigor, performance metrics, and clinical applicability. Seventeen (17) studies, of which twelve (12) are primary studies and five (5) are secondary studies, examining AI applications in detecting and diagnosing neurocognitive disorders (NCDs) in adults with dementia, MCI, or SCD were included. Results indicate that AI models, particularly DL applied to neuroimaging, electrophysiological data, speech and language features, biomarkers, and digital behavioral data, achieve high diagnostic accuracy in distinguishing MCI, Alzheimer’s disease, and healthy aging. Predictive models also show potential in forecasting conversion from MCI to dementia and monitoring cognitive trajectories via wearable or smart-home technologies. Nonetheless, heterogeneity, limited external validation, and methodological inconsistencies hinder clinical translation. In conclusion, AI represents a rapidly evolving and promising tool for early detection and monitoring of neurocognitive disorders. Collectively, the reviewed studies underscore the need for standardized pipelines, larger multicenter datasets, and explainable AI frameworks to enable effective clinical implementation. Full article

The interaction between Angiostrongylus vasorum and the vascular endothelium of the host plays a key role in the pathogenesis of canine angiostrongylosis. The adult stage of A. vasorum resides in right ventricles and pulmonary arteries of dogs and foxes and maintains close contact with the endothelium, whose activation may contribute to the hemostatic and hemorrhagic disorders observed in infected animals. However, the molecular mechanisms underlying this endothelial dysfunction remain poorly understood. To investigate this interaction, an in vitro model of vascular endothelial cells was stimulated with the adult A. vasorum homogenate. Quantitative proteomic analysis, combined with bioinformatic tools, identified 691 and 6011 protein groups in the cell supernatants and the cell lysates, respectively. Of these, 213 proteins in the cell supernatants (193 up-regulated and 20 down-regulated) and 564 in the cell lysates (358 up-regulated and 206 down-regulated) showed differential expression compared to control cells. Up-regulated proteins included TFPI, CD59, VWF, ANGPT2, MMRN1, and FLT1, which are involved in endothelial activation, angio-genesis, and coagulation regulation. Conversely, C3, SERPINE1, SERPINB2, PLAU, PLAUR, and ICAM1 were down-regulated, suggesting modulation of fibrinolysis, inflammation, and cell adhesion pathways. These findings indicate that adult A. vasorum homogenate induces a multifactorial endothelial activation characterized by dysregulation of coagulation, complement, and vascular remodelling pathways. Future studies focusing on the temporal and molecular characterization of endothelial responses to excretory/secretory antigens in both definitive and accidental hosts will further clarify the mechanisms of vascular pathology and parasite tolerance. Full article

The islet amyloid polypeptide (IAPP) is a peptide hormone playing key biological roles, including glucose homeostasis and regulation of food intake, conferring high therapeutic potential to treat metabolic disorders. Nonetheless, IAPP is mainly known as the major component of the amyloid fibrils observed in the pancreatic islets of patients afflicted with type 2 diabetes, and the accumulation of these insoluble protein deposits correlates closely with the loss of pancreatic β-cells. The inherent aggregation propensity of this peptide hormone is not only associated with the pathogenesis of type 2 diabetes but also complicates the design of IAPP derivatives for the treatment of metabolic disorders. Accordingly, elucidating the molecular mechanisms by which IAPP self-assembles into amyloid fibrils is critical to identify chemical strategies to arrest aggregation, as well as to design safe and stable IAPP-derived therapeutics. This review aims at presenting the different mechanistic models of IAPP aggregation and how to exploit this information to identify inhibitors of amyloid formation and non-aggregating peptide agonists. After discussing the conformational conversions allowing IAPP to undergo a mainly disordered monomeric conformation into ordered cross-β-sheet quaternary supramolecular structures, we present chemical strategies to prevent amyloid deposition and to develop non-aggregating peptide-based therapeutics. Full article

Introduction: Immune checkpoint inhibitors (ICIs) have transformed the treatment of metastatic melanoma; however, predictive markers of therapeutic response remain poorly defined. This study systematically assesses clinical, histological, and molecular predictors associated with survival outcomes in melanoma patients treated with ICIs. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines, a systematic search was conducted in MEDLINE, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) for studies published between January 2018 and October 2025. Eligible studies reported associations between predictive factors and overall survival (OS) or progression-free survival (PFS) in adult melanoma patients receiving ICIs. Pooled hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) from univariate (UVA) and multivariate analyses (MVA) were synthesized using random-effects meta-analyses. Results: Sex was not a consistent predictor (contradictory effects; PFS heterogeneity I² ≈ 90%), whereas older age predicted worse OS (MVA continuous: HR 1.05, 95% CI 1.02–1.08; UVA ≥ 65 vs. <65: HR 1.70, 95% CI 1.36–2.12). Poor performance status, assessed using the Eastern Cooperative Oncology Group (ECOG) scale, strongly predicted inferior outcomes (ECOG ≥ 1 vs. 0: MVA OS HR 2.01, 95% CI 1.61–2.51; MVA PFS HR 1.49, 95% CI 1.18–1.88; ECOG ≥ 2 vs. <2: MVA OS HR 2.24, 95% CI 1.79–2.81). Elevated lactate dehydrogenase (LDH) was consistently associated with poorer survival (MVA OS HR 1.71, 95% CI 1.53–1.91; MVA PFS HR 1.61, 95% CI 1.41–1.85), whereas body mass index (BMI) > 25 kg/m² was associated with improved OS (HR 0.82, 95% CI 0.68–0.98). Higher disease burden predicted worse prognosis (Stage IV vs. III: MVA OS HR 1.57, 95% CI 1.16–2.13; >2 metastatic sites vs. ≤2: MVA OS HR 2.38, 95% CI 1.40–4.07; brain metastases: MVA OS HR 1.69, 95% CI 1.30–2.20; MVA PFS HR 1.52, 95% CI 1.00–2.33). Histologic and molecular factors showed prognostic value: ulceration worsened OS (UVA HR 2.08, 95% CI 1.25–3.44) and PFS (UVA HR 2.97, 95% CI 1.39–6.32); acral subtype had poorer OS than cutaneous melanoma (MVA HR 2.99, 95% CI 1.63–5.48); high tumor mutational burden (TMB) improved PFS (UVA HR 0.47, 95% CI 0.33–0.70); and cutaneous immune-related adverse events (irAEs) were associated with favorable outcomes (skin disorders: UVA OS HR 0.26, 95% CI 0.14–0.47; UVA PFS HR 0.50, 95% CI 0.34–0.74). In contrast, detectable circulating tumor DNA (ctDNA) predicted markedly worse PFS (MVA HR 4.72, 95% CI 2.31–9.65) and a non-significant trend toward worse OS (MVA HR 3.34, 95% CI 0.96–11.67). Liver metastases and programmed death-ligand 1 (PD-L1) expression were not significantly associated with survival. Discussion: This meta-analysis synthesizes evidence on clinicopathologic, laboratory, and histopathologic predictors of immunotherapy outcomes in metastatic melanoma. Performance status, age, LDH, BMI, and metastatic burden consistently correlated with prognosis, while ulceration, disease stage, and TMB emerged as key histologic determinants. Conversely, PD-L1 and gender showed no consistent predictive value, whereas cutaneous immune-related adverse events and ctDNA reflected favorable and poor outcomes, respectively. These findings highlight the multifactorial nature of immunotherapy response and support the further development of integrated prognostic models to refine patient stratification and optimize treatment outcomes. Full article

Myocarditis is a complex inflammatory myocardial disease. Although traditionally regarded as exclusively immune-mediated, recent evidence highlights the significant role of underlying genetics on susceptibility, phenotypic variability, and long-term prognosis. This narrative review examines the evolving genetic architecture of myocarditis and its relationship to inherited cardiomyopathies, integrating mechanistic insights from molecular, imaging, and clinical studies. Variants in desmosomal genes such as desmoplakin (DSP) and plakophilin-2 (PKP2) are increasingly linked to recurrent myocarditis that may evolve into arrhythmogenic cardiomyopathy, supporting the concept of a genetically predisposed myocardium in which inflammatory stressors can act as triggers. Truncating variants in titin (TTN) and Filamin C (FLNC) are associated with fulminant or dilated phenotypes. Conversely, mutations in Lamin A/C (LMNA), Desmin (DES), and BCL2-Associated Athanogene 3 (BAG3) contribute to inflammatory myocardial remodeling and other forms of inherited cardiomyopathies. These findings collectively have the potential to redefine myocarditis as an inflammatory disorder influenced by genetic factors. Furthermore, advancements in genetic testing and multi-omics approaches show promise in enhancing diagnostic accuracy and informing management strategies. Full article

Inflammatory bowel diseases (IBDs) and metabolic disorders are increasingly recognized as interconnected conditions that frequently coexist and influence each other’s clinical course. Accumulating evidence indicates that patients with IBD face a substantial burden of obesity, metabolic syndrome, metabolic dysfunction-associated steatotic liver disease, osteoporosis, and type 2 diabetes. These associations appear to be driven by shared and interacting mechanisms, including intestinal barrier disruption, gut microbiota dysbiosis, chronic systemic inflammation, and adipose tissue-mediated immunometabolic pathways. Metabolic comorbidities may worsen IBD activity, reduce response to therapy, increase complications, and contribute to higher health care utilization. Conversely, intestinal inflammation and commonly used treatments, particularly corticosteroids, can adversely affect glucose metabolism, lipid metabolism, body composition and bone homeostasis. Advanced therapies have demonstrated variable metabolic effects, some of which may be beneficial through suppression of systemic inflammation. Recognition of these bidirectional interactions highlights the importance of routine metabolic screening and integrated, multidisciplinary management. Lifestyle interventions, nutritional optimization and individualized therapeutic strategies represent central parts of comprehensive management. Full article

Background: The principal glial cells of the retina, Müller glia, play a central role in retinal regeneration in teleost fish and have recently attracted attention as potential sources of neuronal regeneration in mammals. Objectives: In this study, we examined whether SV40-immortalized rat Müller glia could be directed toward neuronal differentiation using a non-genetic approach with defined culture conditions. Methods: Comprehensive transcriptomic profiling by RNA sequencing indicated that changes in culture medium alone could induce transcriptional reprogramming toward a neuronal lineage. Results: Specifically, expression of Müller glia-related genes decreased, while a subset of photoreceptor-related transcription factors and specific genes showed altered expression, suggesting early-stage induction toward a photoreceptor-like fate. This finding suggests that even immortalized cells may exhibit activation of neuronal genes through non-genetic culture interventions. Gene set enrichment analysis further revealed upregulation of pathways related to the synaptic vesicle cycle, metabolic activation, oxidative stress defense, and lysosomal function, consistent with initiation of neuronal differentiation. Conversely, pathways associated with cell cycle regulation and stemness signaling were downregulated, reflecting a transition from a proliferative to a differentiation-prone state. Collectively, these results provide preliminary molecular markers for early neuronal induction and potential targets for chemical screening. Conclusions: Importantly, this strategy enables neuronal-like differentiation of Müller glia without genetic manipulation, offering a safe and cost-effective platform. Overall, our findings may support the development of in vitro models for retinal neuroregeneration and facilitate research toward regenerative therapies for retinal disorders. Full article

Vitamin D, a fat-soluble vitamin functioning as a hormone via the vitamin D receptor (VDR), is critical for calcium homeostasis and bone health. Vitamin D deficiency is linked to nutritional rickets, osteomalacia, and increased risk of non-communicable diseases such as cancer and diabetes. While serum 25(OH)D₃ is used to assess vitamin D status, its active form, 1α,25(OH)₂D₃, exerts context-dependent effects on calcium metabolism. Nonetheless, the therapeutic utility of native vitamin D is limited in certain pathologies. In chronic kidney disease (CKD), the renal conversion of 25(OH)D₃ to active 1α,25(OH)₂D₃ is compromised, necessitating the use of active synthetic analogs to bypass this metabolic defect. Furthermore, for dermatological and oncological disorders requiring supraphysiological dosing, synthetic analogs have been designed to dissociate beneficial anti-proliferative effects from the severe hypercalcemia induced by high-dose 1α,25(OH)₂D₃. VDR mediates transcriptional responses, modulated by co-regulators and chromatin remodeling complexes. Recent discoveries include non-genomic VDR pathways and SCAP (SREBP cleavage-activating protein)-dependent signaling that modulate lipid metabolism. Despite promising preclinical results, most synthetic VDR agonists fail to show efficacy in cancer therapy due to calcemic toxicity. However, compounds like eldecalcitol are effective in osteoporosis, especially in low-calcium-intake populations. Selective VDR modulators, akin to SERMs, exhibit tissue-specific effects. Moreover, novel VDR antagonists such as ZK168281 demonstrate potential to suppress hypercalcemia and vitamin D toxicity by inhibiting transcriptional activity and altering VDR localization. These agents may enable anti-inflammatory or anti-proliferative actions without calcemic risks. Understanding the nuanced biology of vitamin D and its analogs offers new avenues for therapeutic intervention beyond bone metabolism, including managing hyperparathyroidism, granulomatous diseases, and inflammation-associated disorders. Full article

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by recurrent abdominal pain and altered bowel habits that significantly impair patients’ quality of life. Dietary triggers of IBS symptoms are common, and consequently, diet-based treatments are often prescribed. We conducted a review of current evidence on dietary interventions for IBS, focusing specifically on the evaluation of the scientific rationale and effectiveness of the most commonly adopted diets. Clinical trials and guideline recommendations were analyzed to assess each diet’s efficacy in symptom relief and patient adherence. Traditional dietary advice, although not a structured diet, but rather a set of lifestyle and dietary recommendations, is commonly recommended as first-line therapy and provides a solid base for symptom improvement in almost half of patients with IBS. Conversely, the low-FODMAP diet is a strict dietary pattern characterized first by the exclusion and then by the gradual and personalized reintroduction of several foods. Several clinical trials have demonstrated the efficacy of a low-FODMAP diet in reducing global IBS symptoms, and due to the established evidence, it is now incorporated into many clinical guidelines as a second- or even first-line approach for patients with IBS. Limited data supports the starch- and sucrose-reduced diet as an option for symptom relief, with evidence stemming from the relatively recent finding of hypomorphic variants of the sucrose-isomaltase gene in a subset of patients with IBS. Nonetheless, its application in clinical practice is still very limited. Data on gluten-free diet is more controversial as although it may benefit a subset of patients with IBS, strong evidence is still lacking for identifying the best candidates for a restrictive diet with a high burden in terms of economical, psychological and social costs. Beyond exclusion diets, a few studies on the Mediterranean diet suggest it may be a potential option with benefits that go beyond IBS symptom relief. Overall, dietary modification can significantly alleviate IBS symptoms. Tailoring recommendations to individual patient triggers may further enhance outcomes. Full article