Search Results (1,327)

Polycystic ovarian syndrome (PCOS) is a complex endocrine and metabolic disorder that affects reproductive health, metabolic function, and long-term cardiovascular health in women of reproductive age. The syndrome is characterized by hyperandrogenism, chronic anovulation, insulin resistance, oxidative stress, and ovarian microenvironment remodeling. While current treatments focus on symptom relief through hormone regulation, insulin sensitizers, or ovulation induction, there is a need to target the underlying molecular and cellular processes that drive disease progression and infertility. Breakthroughs in reproductive and metabolic medicine have led to the development of next-generation therapeutics for PCOS that aim to restore ovarian function at the molecular level. Nanoparticle- and nanofiber-based drug delivery systems offer targeted delivery to the ovaries, improved bioavailability, and controlled release of insulin sensitizers, antioxidants, and anti-androgens. Metabolic reprogramming strategies that target insulin resistance, mitochondrial dysfunction, and autophagy have emerged as potential disease-modifying interventions. In addition, AI-enabled precision medicine approaches are reshaping PCOS management through phenotype-based classification, predictive modeling, and personalized fertility optimization. In this review, we highlight recent advancements in understanding the molecular pathophysiology of PCOS and introduce novel therapeutics that harness intelligent drug delivery, ovarian microenvironment restoration, and AI-based interventions. We discuss the potential of these innovative strategies to update PCOS management options for long-term ovarian restoration and fertility. Full article

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

Diffuse midline gliomas (DMGs) are rare but highly aggressive central nervous system (CNS) tumors that can present in both pediatric and adult populations. These tumors were redefined in the 2016 WHO classification of CNS tumors based on integrated histopathological and molecular features, and were initially designated as “DMG, H3 K27M-mutant”. In the 2021 WHO update, DMGs were incorporated into the newly defined category of primarily pediatric-type diffuse high-grade gliomas, and nomenclature was changed to “DMG, H3 K27-altered” to encompass additional molecular drivers beyond the canonical H3 K27M mutation. Clinically, DMGs arise as expansile, infiltrating tumors within midline structures and may present as non-enhancing or enhancing lesions on imaging. Diagnosis is based on neuroimaging and molecular confirmation by immunohistochemistry or sequencing when tissue is available. DMGs are categorized as WHO grade 4 malignant tumors due to their aggressive biology leading to rapid and infiltrative growth. Owing to their deep and midline location, surgical resection is typically not feasible. Radiation therapy is the backbone of treatment, but there is no standard regimen of chemotherapy that has demonstrated durable efficacy. Recent progress in therapeutic approaches has led to a major breakthrough on 6 August 2025 when the U.S. Food and Drug Administration granted the accelerated approval of dordaviprone (ONC201), marking it as the first systemic therapy for progressive DMG harboring H3 K27M mutation. Other novel approaches, including chimeric antigen receptor (CAR) T-cell directed therapies and convection-enhanced delivery, are actively under investigation. We aim to comprehensively review DMGs, including the recent insights into their biology, the evolving therapeutic landscape, and the opportunities to fuel this new momentum against one of the most formidable gliomas. Full article

Inflammation, as a basic pathological process, is critically implicated in the pathogenesis and progression of numerous diseases. Picrorhizae rhizoma is a type of traditional Chinese medicine with prominent anti-inflammatory effect. And picroside II, a representative iridoid compound, is the major bioactive constituent of Picrorhizae rhizoma. Over recent decades, picroside II has garnered extensive research interest owing to its remarkable pharmacological efficacy. Accumulating evidence has validated that picroside II exerts significant anti-inflammatory effects in the prevention and treatment of various systemic diseases. This review comprehensively summarizes and updates the latest research advances of picroside II, systematically elaborating its anti-inflammatory molecular mechanisms, pharmacokinetic profiles, and safety evaluation characteristics. The integrated data and analyses in this review aim to provide solid theoretical support, reliable evidence, and novel insights for the in-depth mechanism research, rational medicinal development, and future clinical translation and application of picroside II. Full article

Silicone food contact materials (FCMs) pose potential health risks due to the migration of siloxanes. This study presents a comprehensive migration profiling of 35 siloxanes (cyclic D3–D22 and linear L2–L14) from 30 silicone FCMs, with migration tests rigorously conducted under worst-case intended-use scenarios to ensure conservative and reliable exposure estimates. Methodological innovations include an expanded analytical scope, age-stratified exposure assessment across seven age groups, and a multi-tiered risk evaluation framework. The results reveal that migration behaviors were affected by simulant polarity, siloxane solubility, and silicone thermal stability. The risk evaluation framework integrates aggregate migration limits for total cyclic (D3–D13) and total cyclic plus linear siloxanes (D3–D13, L3–L13), complemented by individual siloxane assessment via Risk Quotient (RQ) and Threshold of Toxicological Concern (TTC) approaches. While the total migration of cyclic siloxanes exceeded the proposed action limit of 12 mg/kg for adults in several samples and 2 mg/kg for children in most samples, granular assessment revealed divergent risks: Cyclic D4 and D5 showed negligible risk (RQ < 5). In contrast, D3 migration posed a potential concern (RQ > 5), especially for individuals aged >13 years. Notably, the estimated exposures to 14 siloxanes with low molecular weight (<1000 Da), including highly prevalent D6 and L12 with detection frequency >90%, exceeded the TTC threshold across all age groups, highlighting unaddressed risks that are not captured by aggregate action limits. This work underscores the need for substance-specific, age-specific risk evaluations and regulatory updates for silicone FCMs. Full article

Oral lichen planus (OLP) is a chronic, T cell-mediated inflammatory disorder classified by the World Health Organization as an oral potentially malignant disorder (OPMD). Despite decades of research, its precise etiology remains incompletely understood and involves a complex interplay between genetic predisposition, environmental triggers, and autoimmune-like responses. This review provides a comprehensive update on OLP pathogenesis, emphasizing the role of CD8 positive cytotoxic T lymphocyte-driven basal keratinocyte apoptosis and the skewing of the T-cell receptor (TCR) repertoire. We highlight the significance of the epidermal growth factor receptor (EGFR) signaling pathway as a molecular bridge between chronic inflammation and epithelial proliferation. Furthermore, we discuss a stepwise therapeutic approach that prioritizes the management of the oral microenvironment—specifically Candida colonization and periodontal health—before escalating to immunosuppressive agents. Finally, we explore emerging precision medicine frontiers, including IL-17/IL-23 inhibitors and JAK inhibitors, alongside traditional Japanese Kampo medicine (Hange-shashin-to) and systemic adjuncts like Cepharanthine, offering a contemporary perspective on modern OLP management. This integrative framework redefines OLP not merely as a chronic inflammatory disorder, but as an immunologically sustained, microenvironment-driven, potentially malignant condition. Full article

Avian orthoavulavirus 1 (AOaV-1), commonly known as Newcastle disease virus (NDV), despite widespread vaccination, remains a significant threat to domestic chickens (Gallus gallus domesticus). Currently available live-attenuated NDV vaccines are derived from genotypes I and II lentogenic strains, whereas genetically divergent velogenic strains predominantly caused recent NDV outbreaks. This study examined the extent of genotypic divergence between NDV vaccine strains and field strains using phylogenetic and multivariate analyses of two major antigenic and virulence-associated genes: fusion (F) and haemagglutinin-neuraminidase (HN). A total of 121 full-length NDV-F and 81 NDV-HN gene sequences, representing reported NDV genotypes, were downloaded from GenBank and analysed using maximum-likelihood (ML) phylogenetic trees and principal coordinates analysis (PCoA). The phylogeny revealed genotype-specific clustering for both genes, consistent with current NDV classification. NDV vaccine strains belonging to genotypes I and II formed distinct clades, segregated from the majority of NDV field strains, including velogenic or virulent NDV genotypes. The principal coordinates analysis of both genes further confirmed the phylogenetic clustering of NDV genotypes, indicating increased genomic heterogeneity. These findings suggest genetic segregation of divergent velogenic or virulent genotypes from lentogenic NDV vaccines, requiring biological experiments for determining their efficacy against field strains. This study highlights the importance of molecular surveillance of NDV to monitor its genomic diversity, which is crucial for developing strategies to combat NDV outbreaks in domestic chickens. This study provides an updated, NDV-glycoprotein-gene-based comparative analysis across reported NDV genotypes using phylogenetic and multivariate approaches. Full article

Preeclampsia (PE), pregnancy-associated high blood pressure linked to organ damage, affects 3–8% of all pregnancies and results worldwide in 70,000 maternal and 500,000 perinatal deaths each year. Untreated PE may progress to eclampsia with long-term health implications for both mother and child. Non-invasive prenatal diagnosis or screening applies cell-free DNA approaches and offers a less invasive and more economical method for early diagnosis and prediction of various pregnancy complications. Recently, cell-free assays, particularly blood-based cell-free DNA and RNA analysis, have shown great potential in early PE prediction and diagnosis. Here, we provide an updated review of the current understanding and discoveries of PE, focusing on recent publications (1 January 2019–30 December 2025) of liquid biopsy-derived circulating fetal cells (circulating trophoblasts and fetal nucleated red blood cells), cell-free DNA, cell-free RNA and small extracellular vesicles (i.e., exosomes). We aim to discuss the conceptual framework and technical evolution of liquid biopsy applications in preeclampsia pathogenesis, prediction and diagnosis. Progressing novel screening and diagnostic molecular biomarkers have high potential to facilitate early detection for patients at risk of PE. Liquid biopsy-based screening strategies may aid in providing timely intervention and treatment. Full article

Mast cells, characterized by a broad repertoire of surface receptors, are increasingly recognized for activation pathways extending beyond the classical IgE/FcεRI axis, particularly in the context of neurogenic inflammation. Substance P (SP), a neuropeptide of the tachykinin family, is a potent activator of mast cells, inducing the release of histamine, cytokines, and other inflammatory mediators. Through complex bidirectional communication, mast cells and SP play a pivotal role in neuro–immune interactions. This narrative review provides an updated overview of mast cell–SP crosstalk, with a focus on underlying molecular mechanisms, receptor-mediated signaling pathways, and their contribution to pathophysiological processes. In addition, we aim to reinterpret established clinical models within the spectrum of pseudoallergic conditions and to explore innovative, etiology-driven therapeutic strategies. Finally, we discuss future perspectives and highlight the need for robust translational models to support clinical and pharmacological research. Full article

Infectious pancreatic necrosis virus (IPNV), a member of the family Birnaviridae, is a major pathogen of farmed salmonids and an important model in fish virology. Despite its small genome, which encodes only five viral proteins, IPNV exhibits complex molecular processes that govern genome expression, replication, and particle assembly. Comprehensive descriptions of the molecular biology and replication cycle of IPNV were largely established in reviews published in the mid-1990s, whereas more recent reviews have primarily focused on virulence determinants, epidemiology, or host–virus interactions. This review provides an updated synthesis of available experimental knowledge on the molecular biology of IPNV by integrating classical and recent studies addressing virion architecture, genome organization, and the functions of viral proteins. Particular attention is given to the molecular events involved in the viral replication cycle, including virus entry, genome transcription, translation and replication in the cytoplasm, polyprotein processing by the viral protease, and the coordination between genome replication and virion assembly. When appropriate, experimental observations from the related Avibirnavirus infectious bursal disease virus are considered to provide additional context for molecular mechanisms conserved within the family Birnaviridae. Together, these studies outline the current understanding of the molecular processes governing IPNV replication and morphogenesis. Full article

Background/Objectives: Methicillin-resistant Staphylococcus aureus (MRSA) causes hospital- and community-acquired infections. MRSA is a highly diverse strain that includes several epidemic clones, including CC45. A previous study conducted among MRSA isolates in Kuwait identified CC45 in two isolates in the early 2000s. This study provides an update on the prevalence and molecular characteristics of CC45 among MRSA isolates in Kuwait hospitals, during 2016–2022. Methods: A total of 13,276 MRSA isolates were collected during 2016–2022 and typed using antibiogram, DNA microarray, Staphylococcal protein A (spa) typing, pulsed-field gel electrophoresis (PFGE), and multi-locus sequence typing (MLST). Results: CC45 was detected in 87 (0.65%) of the 13,276 MRSA isolates. The isolates were resistant to fusidic acid (n = 71), erythromycin (n = 16), and inducible clindamycin resistance (n = 15). Twenty-one isolates were resistant to multiple antibiotics. Spa typing identified 19 types, with t362 (n = 35) and t132 (n = 27) as the dominant types. DNA microarray identified seven genotypes with CC45-MRSA-[IV + fus] (n = 36) and CC45-MRSA-[VI + fus] (n = 30) as the dominant types. MLST identified six sequence types (STs): ST7119, ST508, ST45, ST46, ST9548, and ST10699. PFGE clustered the isolates into two major types, A and B, with type A being the major type (n = 83), mostly consisting of CC45-MRSA-[IV + fus] isolates. The CC45-MRSA-[IV + fus] and CC45-MRSA-[VI + fus] genotypes were detected throughout the study period (2016–2022), whereas the other genotypes were detected less frequently. Conclusions: The CC45-MRSA circulating in Kuwait hospitals comprises genetically diverse isolates that may have originated from different sources. The emergence of multidrug resistance among the isolates poses challenges for therapy and infection prevention. Full article

Cancer is an alarming health concern and economic burden in both developed and developing countries. Recently, there has been a growing demand for new alternative medications with more effectiveness and fewer harmful effects. During the past decades, a set of chemotherapeutic agents has been developed to fight against a large spectrum of cancer types. Unfortunately, their use is associated with a high level of toxicity; they are expensive, also, and their deployment is restricted by the emergence of cellular resistance. Plant-based components are garnering attention due to their low toxicity, selectivity, efficiency, and ease of accessibility. Alkaloids are one of these targeted compounds. Indeed, they are a highly diverse group with basic heterocyclic nitrogen-containing alkaloids that exhibit potent anticancer effects against a large panel of solid and liquid tumors, such as lung, breast, leukemia, liver, and colon cancer. The main molecular mechanisms involved in alkaloids’ anticancer effect are the induction of apoptosis via the extrinsic and intrinsic pathways, DNA damage, and the inhibition of cell cycle progression. Amazingly, these auspicious compounds exhibited strenuous inhibitory effects against a whole range of key enzymes involved in cancer progression and metastasis, such as Cytochrome P450 (CYP450), Cyclooxygenase-2 (Cox-2), Lysine-Specific Demethylase 1 (LSD1), Poly [ADP-ribose] polymerase (PARP), and topoisomerase, mainly through two action modes, namely irreversible and reversible inhibition. Furthermore, several conventional extraction methods have been developed to extract bioactive compounds from natural matrices, such as Soxhlet and hot water extraction. However, these techniques have many drawbacks, as they require a large amount of organic solvents, which not only affect human health but also generate severe environmental issues. To overcome these limitations, multiple eco-extraction techniques have emerged as potential alternatives to traditional extraction methods such as ultrasonic extraction, microwave-assisted extraction, and supercritical fluid extraction. In fact, they are considered eco-friendly and efficient technologies with less time and solvent consumption. Overall, this review aims to provide an updated overview of the most prominent anticancer alkaloids that have not been well reviewed already, as well as the main green extraction techniques relevant to the extraction of antineoplastic alkaloids. Full article

Canine parvovirus (CPV) is a major pathogen causing severe gastroenteritis in dogs. Since its emergence, CPV has undergone continuous evolution, leading to the predominance of variants such as CPV-2a, CPV-2b, and CPV-2c. To characterize the genetic features and evolutionary trends of CPV-2 at a regional level, 775 fecal samples were collected from domestic and stray dogs with suspected CPV-2 infection in Shanghai between 2016 and 2025. The overall positivity rate was 23.2% (180/775); incidence was substantially higher in stray dogs (30.2%) than in domestic dogs (15.9%). Thirty-one CPV-2 strains were successfully isolated. Temporal analysis revealed a pronounced genotype shift: isolates from 2016 to 2020 were predominantly New CPV-2a, whereas CPV-2c became the dominant genotype from 2021 through 2025. Sequence analysis identified the polymorphism of VP2 gene and characteristic mutations F267Y, Y324I, N426E, Q370R and A440T in CPV-2c strains. A novel I447M mutation was detected in several isolates. Phylogenetic analysis showed that Shanghai isolates formed distinct clusters; CPV-2c strains were closely related to the Asian lineage. Structural modeling indicated that mutations at residues L87M, T101I, Y267F, A297S, G300A, Y305D, I324Y, Q370R, N426E, A440T, and I447M may alter the tertiary structure of the VP2 protein, potentially affecting antigenicity and receptor recognition. Collectively, these results demonstrate the complete genotype replacement of CPV-2 in Shanghai; CPV-2c is now predominant. Identification of the novel I447M mutation and structural analysis of key amino acid substitutions provide insight into CPV molecular evolution. These findings suggest that vaccines primarily based on older CPV-2 or CPV-2b genotypes offer suboptimal protection, highlighting the need for updated vaccine strategies targeting prevalent CPV-2c variants. Full article

Human transglutaminases (hTGs) are Ca²⁺-dependent enzymes that catalyze protein crosslinking, deamidation and other post-translational modifications, thus acting as key stabilizers of tissue architecture and modulators of protein function across diverse physiological contexts. This family comprises eight catalytically active members, TG1-7, the blood coagulation factor FXIII, and the inactive structural protein Band 4.2 of the erythrocyte membrane. Recent structural and biochemical advances have refined our understanding of the molecular principles governing transglutaminase function. Thus, current evidence reveals how domain organization and catalytic architecture integrate calcium binding, nucleotide-dependent regulation in TG2 and proteolytic activation in selected isoforms to control enzymatic activity. In this review, we provide an updated and comprehensive overview of the active hTGs, combining structural, biochemical and functional data to explain how closely related enzymes achieve isoform-specific regulation and distinct biological roles. We further examine how disruption of these mechanisms contributes to human pathology, highlighting representative examples in autoimmunity, inherited disorders and complex diseases. By integrating recent biochemical and structural findings with disease-associated evidence, we aim to offer a coherent framework for understanding how TG regulation underlies their diverse biological functions and clinical relevance. Full article

Diabetes mellitus is a rapidly escalating worldwide health issue that involves intricate molecular, metabolic, and systemic dysregulation. In addition to hyperglycemia, disease pathogenesis involves β-cell dysfunction, insulin resistance, mitochondrial dysfunction, endoplasmic reticulum stress (ER stress), redox imbalance, lipotoxicity, chronic inflammation, and inappropriate epigenetic modifications. New evidence also emphasizes the participation of mechanotransduction, ion channel signaling, circadian regulation, and organ cross-talk among the pancreas, liver, adipose tissue, skeletal muscle, heart, brain, and gut in modulating disease heterogeneity and progression. This review highlights updates of molecular mechanisms in diabetes, focusing on the β-cell response to stress, the AMPK–Sirtuin 1 (or PGC-1α) signaling pathway, mitochondrial quality control, mechanosensitive ion channels, immunometabolic crosstalk, and epigenetic regulation. We consider the increasing importance of multi-omics methods for early identification of pathogenic signatures and integration of artificial intelligence to enable precision stratification and therapeutic tailoring. Finally, we highlight novel experimental and translational tools, such as iPSC-derived β-cells or organoids, CRISPR-based gene editing, sophisticated metabolic imaging, and electrophysiology. Taken together, this review shifts the paradigm of diabetes as a system-level network disease and emphasizes the importance of data-driven multi-target strategies for prevention and reduction in long-term complications. Full article