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Aortic aneurysm (AA) and aortic dissection (AD) are catastrophic aortic disorders characterized by progressive structural weakening or acute medial tearing, often resulting in rupture and high mortality. Their complex and heterogeneous pathogenesis-spanning extracellular matrix degradation, vascular smooth muscle cell dysfunction, inflammation, and dysregulated signaling-necessitates robust experimental systems. Diverse animal and engineered models have been developed to capture key features of these diseases, yet each recapitulates only specific aspects of human pathology. This review aims to: (1) systematically summarize current experimental models of AA and AD, including chemical, genetic, and combined systems; (2) provide a decision tree for selecting mouse models of AA and AD for vascular research; (3) evaluate model-specific strengths, limitations, and translational relevance, while highlighting emerging technologies such as vascular organoids and engineered 3D platforms that may bridge gaps between preclinical research and human disease. This review presents an integrated framework linking aortic pathology to model-specific mechanisms, illustrating how extracellular matrix (ECM) failure, smooth muscle cell remodeling, inflammation, and biomechanical stress drive AA and AD. We further emphasize the translational hierarchy across mouse, large-animal, and organoid models, providing guidance for rational model selection in therapeutic discovery. By systematically summarizing classical and emerging mouse models of AA and AD, this review provides a structured framework to guide model selection and future mechanistic studies in the field.
The HIPPOCRATES project is a 5-year, international research partnership dedicated to studying and treating psoriatic disease. Integrating Patient Research Partners (PRPs) into large scientific groups, particularly those heavily focused on preclinical or laboratory-based science, is challenging. This paper details a midterm evaluation of how effectively PRPs have been engaged in the HIPPOCRATES project. Our evaluation used a mixed-method approach comprising 7 dedicated reflective PRP meetings, 2 midterm surveys among PRPs and researchers, a modified World Café discussion, and 5 structured dialogue meetings. We used descriptive statistics and pragmatic constant comparative analysis. Substantial PRP input occurred early during the project's presubmission phase, which resulted in a formal strategy for patient involvement. However, 3 years after approval, significant differences emerged between researcher and PRP perspectives. Compared with researchers, PRPs reported more challenges, had differing expectations, and perceived a lower overall impact. Although PRPs were highly motivated at the start and contributed significantly to clinical components, motivation decreased for some regarding the laboratory components. This was attributed to highly technical language, long contract negotiations, and a lack of clear opportunities for input or tangible results. Consortium members collaboratively agreed upon a set of specific changes during the 5 dialogue sessions. Despite the early and substantial involvement of PRPs in the initial study design, the PRPs themselves rated their influence on HIPPOCRATES lower than the researchers did. Further evaluation over the next 2 years will show whether the jointly developed solutions successfully enhance their impact on future research outcomes.
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease in which loss of immune tolerance, chronic inflammation, and metabolic reprogramming are closely interconnected. Fatty acid amides (FAAs) are endogenous lipid mediators that include N-acylethanolamines (NAEs), such as anandamide (AEA), palmitoylethanolamide (PEA), oleoylethanolamide (OEA), palmitoleoylethanolamide, and linoleoylethanolamide, as well as primary fatty acid amides such as palmitamide, octadecanamide, and oleamide. The evidence base for FAA metabolism in SLE should be interpreted at two levels. First, direct human multi-omics evidence now supports disease-associated alteration of several FAA-class serum metabolites: a serum proteome-metabolome study identified palmitoleoylethanolamide, linoleoylethanolamide, palmitamide, and octadecanamide among candidate metabolite biomarkers for SLE classification. Second, a targeted endocannabinoid study found increased 2-arachidonoylglycerol (2-AG) and enhanced diacylglycerol lipase (DAGL) activity in peripheral blood mononuclear cells, whereas AEA, PEA, and OEA were not significantly different from healthy controls. Because 2-AG is an endocannabinoid but not an FAA, these data support broader endocannabinoidome dysregulation rather than universal NAE dysregulation. Mechanistic evidence is primarily derived from lupus mouse models: PEA is reduced in serum and spleen of MRL/lpr mice and suppresses TLR9-induced IL-6 production, dendritic-cell and B-cell activation, IgM production, and B-cell proliferation; FAAH is upregulated in B cells from a lupus-prone Sle2z model and FAAH inhibition reduces receptor revision, RAG expression, and polyreactive autoantibody production; nano-encapsulated AEA reduces inflammatory cytokines and lesion severity in a murine model of cutaneous lupus erythematosus. Collectively, these findings indicate that FAA-related pathways are relevant to SLE, although current evidence remains heterogeneous, species-specific, and insufficient to establish causality in patients. Future work should combine targeted lipidomics, cell-type-resolved enzyme profiling, immune perturbation assays, and organ-specific phenotyping to determine whether FAA metabolism contributes to disease pathogenesis, biomarker development, or adjunctive therapy in defined SLE subsets.
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Abdominal aortic aneurysm (AAA) is driven by chronic inflammation and extracellular matrix (ECM) degradation. Elastase-2 (Ela-2) is a conserved chymotrypsin-like serine protease encoded by the human gene CELA2A and its murine ortholog Cela2a, and it generates angiotensin II and contributes to cardiovascular remodeling. However, its role in AAA remains undefined. This study characterizes Ela-2 in human (AAA n = 41; controls n = 21) and experimental AAA. Ang II-infused wild-type (Wt) and Cela2a Knockout (Cela2a-/-, Cela2a KO) mice were analyzed for Ela-2 expression, cytokines, and ECM markers. Human AAA showed marked Ela-2 upregulation, elevated IL-6/IL-8/CCL5, macrophage infiltration, and increased Osteopontin N-terminal fragment (OPN-N) alongside MMP-2/9 activity. WT + Ang II mice recapitulated this phenotype with aortic dilation, inflammation, ECM disruption, and OPN-N accumulation, whereas Cela2aKO mice +Ang II were protected. Structural modeling confirmed active site conservation enabling angiotensin cleavage and ECM proteolysis. Ela-2, encoded by the human gene CELA2A, emerges as a key proteolytic driver of AAA progression and a promising therapeutic target.
The complex, interconnected nature of dental, oral, and craniofacial tissues poses significant challenges for conventional in vitro models. Oral and maxillofacial organoids have emerged as advanced three-dimensional technologies capable of reproducing selected microstructures and biological functions of native tissues. This review aimed to summarize recent advances in these technologies and evaluate their potential clinical applications in dentistry. A narrative literature review was conducted using PubMed, Web of Science, Scopus, and Google Scholar, with particular focus on studies published between 2020 and 2026. The search terms included 'organoids', 'oral and maxillofacial diseases', 'tissue engineering', 'regeneration', and 'precision medicine'. Relevant studies addressing organoid development, bioengineering strategies, and clinical applications in dentistry were analysed. Recent advances have enabled the development of various oral and maxillofacial organoids, including tooth-germ, salivary gland, taste bud, oral cancer, lingual epithelial, and maxillofacial cartilage organoids. Advances in patient-derived organoids through construction strategies, such as spontaneous self-assembly of stem cells, biomaterial-assisted fabrication, and precision engineering, enhance their physiological properties and support personalized medicine. Despite these advances, several challenges remain that restrict clinical translation, including limited vascularization, lack of immune system integration, structural variability, scalability, and standardization issues. Oral and maxillofacial organoids represent promising experimental platforms for regenerative dentistry, disease modelling, drug screening, and tissue regeneration. Combining organoids with microfluidic technologies to create organ-on-a-chip devices and linking multiple chips represents important advances towards the reliable, large-scale generation of physiologically relevant oral and maxillofacial organoids for both research and clinical applications. Oral organoid systems may provide clinical platforms for personalized therapy, regenerative applications, and translational research while reducing reliance on conventional animal models. Among current models, oral cancer and salivary gland organoids demonstrate promising translational potential, given their functional validation and scalability.
Rheumatoid arthritis (RA) is a biologically heterogeneous immune-mediated disease characterized by substantial variability in therapeutic response. Despite the availability of multiple conventional synthetic, biologic, and targeted synthetic disease-modifying antirheumatic drugs (DMARDs), many patients fail to achieve adequate disease control or experience secondary loss of efficacy, underscoring the need for predictive biomarkers that can guide treatment selection. This narrative review was based on a structured literature search of PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar, covering publications from January 2000 to June 2026, with earlier landmark studies included when relevant. Literature selection followed PRISMA-informed principles, although the review was not designed as a formal systematic review. Unlike previous reviews that mainly catalogue RA biomarkers by analytical platform, drug class, or clinical use, this review integrates conventional and emerging biomarkers within a tissue-immunophenotype-centered framework. We critically evaluate clinical, serological, pharmacological, molecular, imaging, and tissue-based biomarkers according to biological plausibility, reproducibility, level of validation, clinical actionability, and translational readiness. Established markers such as rheumatoid factor, anti-citrullinated protein antibodies, acute-phase reactants, drug concentrations, and anti-drug antibodies remain clinically useful but provide incomplete insight into mechanism-specific therapeutic response. In contrast, synovial pathotypes, fibroblast and macrophage subsets, B-cell niches, tertiary lymphoid structures, single-cell and spatial omics, and ligand-receptor interaction networks offer a mechanistically richer view of treatment response and resistance. We conclude that precision medicine in RA will require integrated biomarker panels combining clinical, pharmacological, molecular, and synovial tissue data. The key future direction is the development of scalable, externally validated, and clinically interpretable models capable of assigning synovial endotypes and supporting mechanism-based therapeutic selection.
Scientific evidence regarding AKI and acute kidney care has advanced in recent years. However, a knowledge gap remains on the implementation of these evidence-based practices (EBPs) into clinical care. Implementation science (IS) is focused on ensuring that this knowledge is translated in an effective, efficient and sustainable fashion. 1) Define the current status of IS; 2) Define a roadmap for accelerating IS with a focus on patient/care partner advocacy, digital tool application, social determinants of health, and resource-limited settings; and 3) Develop a robust and broad research agenda incorporating IS methodology into the programs. ADQI XXXV was conducted through a modified Delphi process with virtual meetings preceding an in-person meeting. Five workgroups were determined a priori to focus on 1) IS definitions and methods applicable to AKI and acute kidney care; 2) IS literature in AKI and acute kidney care; 3) Innovations in IS to accelerate the adoption, adherence to, and sustainment of EBPs in AKI and acute kidney care; 4) IS methods in resource-limited settings; and 5) Recommendations to identify and evaluate EBPs that are ready for implementation or de-implementation. Prior to the in-person meeting, each workgroup met virtually to review the literature and develop framework questions to address their objectives. During the two-day in person meeting, through iterative discussions, questions and supporting statements were finalized. These questions and statements were agreed upon through voting to achieve consensus, defined as agreement of ≥80%. We report a structured multidisciplinary consensus for defining the role of IS in AKI and acute kidney care. Future programs should address these consensus questions and apply these statements along with IS methodology in the translation of science into clinical practice and the implementation/de-implementation of EBPs in clinical care.
The microbiome is increasingly recognized as a master regulator of immune homeostasis and a key environmental factor associated with the pathogenesis of autoimmune diseases (ADs). This review comprehensively synthesizes current knowledge on how microbial communities and their metabolites may contribute to ADs' development through microbial-immune interactions, dysbiosis, and the involvement of viral and fungal components within an integrated inter-kingdom ecosystem. We propose an operational definition of microbiome biomarkers as measurable microbiome-associated features reflecting disease susceptibility, activity, prognosis, or therapeutic response and categorize them into three classes: taxonomic, functional/metabolic, and host-microbiome interaction-derived biomarkers. We critically evaluate the evidence for specific microbial signatures as biomarkers for early diagnosis, disease monitoring, and prediction of therapeutic responses, incorporating evidence grading that distinguishes validated biomarkers from those that remain exploratory and discussing shared versus disease-specific signatures across ADs. The translational potential of microbiome-targeted interventions, including probiotics, prebiotics, and fecal microbiota transplantation, is examined within a personalized medicine framework, with barriers to clinical implementation explicitly addressed. Key confounding factors such as diet, geographic origin, and medication use are highlighted as critical variables shaping microbiome signatures independently of disease. Looking forward, the convergence of multi-omics technologies and artificial intelligence for biomarker discovery, multi-omics integration, and clinical validation promises to unravel the complex microbiome-immune crosstalk, enabling more accurate diagnosis, prognostic stratification, and ultimately, individualized microbiota-informed therapy.
Understanding the sensory nervous system's precise innervation of visceral organs remains a major challenge in systems neuroscience, particularly for designing neuromodulatory therapies. Here, we introduce a digital twin of the rodent stomach that combines high-resolution structural images and nerve-specific mapping onto a common coordinate scaffold. Using a pipeline developed within the NIH SPARC (Stimulate Peripheral Activity to Relieve Conditions) framework, we used immunohistochemistry (fluorescence and chromogenic) and anterograde tracing to label Calcitonin gene-related peptide (CGRP) axons and tracer-labeled spinal afferents in the whole stomach flat-mounts, digitized the axons, and registered axon data from nerve tracing experiments. These datasets were integrated into a standard scaffold, enabling cross-specimen alignment and annotation. The scaffold promotes integration of topographically anatomical and physiological metadata into the scaffold to enable simulation of neuromodulatory input effects, advances research on targeted nerve stimulation to improve organ function, and supports iterative development of closed-loop bioelectronic devices. The scaffold is publicly available via the SPARC Portal and supports modular extension to other species and organ systems. Our methodology contributes to a better understanding of the visceral afferent nervous system and multi-organ connectome, as well as establishing a reproducible computational framework for mapping and manipulating autonomic pathways in visceral organs, with applications spanning basic neuroanatomy to translational clinical intervention.
Plastic particles have been detected in human testicular tissue, raising concerns about potential effects on male reproductive health. This systematic review synthesizes experimental evidence from mammalian in vitro and in vivo studies evaluating the effects of MNP exposure on Leydig cell structure and function. A systematic search of PubMed, Scopus, Embase, and Web of Science identified 19 eligible studies. Study selection, data extraction, and risk-of-bias assessment were performed independently by two reviewers using ToxRTool for in vitro studies and SYRCLE for in vivo studies. Certainty of evidence was evaluated using the GRADE framework. Across experimental models, MNP exposure was associated with particle internalization, oxidative stress, mitochondrial and endoplasmic reticulum dysfunction, reduced cell viability, activation of apoptotic pathways, and impaired testosterone synthesis. Together, the available experimental evidence supports the biological plausibility that MNP exposure may impair Leydig cell function and testosterone synthesis, although the overall certainty of evidence remains limited.
Neurodegenerative diseases represent a growing health concern that is projected to become more prevalent and affect more people in the upcoming decades. One of the most complicated components of recent neurodegenerative disease therapies is the penetration and delivery of therapeutics to the central nervous system (CNS), which are hindered via the blood-brain barrier (BBB). In response, innovative treatment approaches leveraging noninvasive techniques including nanosized drug delivery systems and intranasal (IN) administration with higher treatment efficacy and patient satisfaction are developing as potential options. IN administration delivers medications directly to the brain through both the olfactory and trigeminal pathways, with the olfactory pathway representing the primary route for nose-to-brain transport. Among various IN platforms, chitosan (CS)-based hydrogels have attracted considerable attention because of their excellent biocompatibility, biodegradability, mucoadhesive properties, and ability to enhance drug permeation by prolonging nasal residence time and transiently modulating epithelial tight junctions. This review critically summarizes recent advances in CS-based hydrogels for IN drug delivery for the treatment of brain diseases including Alzheimer's disease (AD), Parkinson's disease (PD), depressive manifestations, ischemia,brain tumors,epilepsy, seizures, and schizophrenia. In addition, the review discusses the relationships between hydrogel design and therapeutic performance, highlights current translational challenges, and outlines future perspectives for the clinical development of CS-based IN hydrogel systems.
The lack of robust evidence regarding long-term pulmonary outcomes after COVID-19 hampers the development of effective, evidence-based follow-up strategies for affected patients. To prospectively identify patients at risk of persistent pulmonary impairment after COVID-19 based on clinical and inflammatory profiles, aiming to support individualized follow-up strategies and precision medicine approaches. In this prospective cohort study, adults hospitalized with COVID-19 underwent inflammatory profiling within 24 hours of ICU admission using a 65-plex biomarker panel. Unsupervised k-means clustering was applied to identify distinct inflammatory phenotypes. Diffusing capacity for carbon monoxide (DLCO), total lung capacity (TLC), forced expiratory volume in one second (FEV1), maximal inspiratory pressure (MIP), and functional assessments were evaluated at 6 and 12 months. Linear mixed models were used to identify predictors of long-term pulmonary outcomes. Two inflammatory phenotypes were identified: high-inflammatory (ThHigh) and low-inflammatory (ThLow). At 12 months, patients in the ThHigh group exhibited significantly higher DLCO values compared with those in the ThLow group (β = 9.44; 95% CI, 4.36 to 14.52), independently of demographics, comorbidities, and disease severity. In contrast, FEV1 was significantly lower in the ThHigh cluster than in the ThLow cluster (β = -4.05; 95% CI, -7.91 to -0.19). No significant associations were observed between inflammatory phenotypes and TLC or MIP. Inflammatory phenotypes during acute COVID-19 are associated with distinct patterns of long-term pulmonary recovery, supporting the use of early risk stratification strategies to identify patients at risk for persistent respiratory dysfunction.
Peritoneal dialysis is a widely used treatment for kidney failure; however, peritoneal dialysis-related infections (exit-site, tunnel infection, peritonitis) occur frequently. The effect of standardised nurse and patient training on peritoneal dialysis infections is uncertain. The aim of this study was to determine whether implementing an international guideline-based standardised training curriculum for nurse trainers and new peritoneal dialysis patients reduces the risk of peritoneal dialysis-related infections compared with existing local training practices. Targeted Education ApproaCH to improve Peritoneal Dialysis (TEACH-PD) was a pragmatic, investigator-initiated, cluster-randomised controlled trial conducted in Australia and New Zealand. Adult patients 18 years of age or older with kidney failure who required training for incident peritoneal dialysis treatment and who were able to provide written informed consent were eligible. Clusters were randomised 1:1 to either the standardised training curriculum or usual care. Participant data and infection outcomes were routinely collected in national patient registries. The primary outcome was time to first peritoneal dialysis-related infection (exit site infection, tunnel infection, or peritonitis). Secondary outcomes were the first of each individual infection type in the primary composite outcome, catheter removal, haemodialysis transfer, all-cause death and quality of life. This trial was registered with ClinicalTrials.gov, number NCT03816111. Between 22 July 2019 and 29 September 2023, 42 clusters were randomised: 21 to the standardised training group and 21 to the usual care group. Overall, 1462 incident peritoneal dialysis patients were included; 667 were assigned to the standardised training group and 795 to the usual care group. A peritoneal dialysis-related infection occurred in 296 of 667 patients in the standardised training group and 297 of 795 patients in the usual care group (sub-hazard ratio 1.230, 95% confidence interval [CI] 1.004-1.507, p = 0.0457). Secondary outcomes were similar in the two groups. Among patients commencing peritoneal dialysis, the use of a standardised training curriculum for nurses and patients based on the International Society for Peritoneal Dialysis guidelines increased peritoneal dialysis-related infection. Implementation-focused research is needed to identify which elements of training require standardisation and where individualisation is most beneficial to support safe, sustainable and patient-centred peritoneal dialysis care. The TEACH-PD trial is funded by MRFF Clinical Trials Activity: Rare Cancers, Rare Diseases and Unmet Need Grant Opportunity; National Health & Medical Research Council BEAT-CKD Program Grant; Health Research Council of New Zealand grant; Metro South Health Research Support Scheme Research Fund-Health System and Health Economics Project Grant; Queensland Health; South Western Sydney Research Small Grant Scheme; International Society for Peritoneal Dialysis; Translational Research Institute Australia; Amgen and Baxter Healthcare (Vantive).
Neonatal bilirubin encephalopathy is primarily characterized by central auditory dysfunction and cognitive impairments. However, the precise molecular mechanisms underlying bilirubin-induced neurotoxicity remain poorly understood, hindering the development of effective therapeutic strategies. Using kinase activity prediction tools based on quantitative phosphoproteomics, we identified ROCK2 (Rho-associated protein kinase 2) as a critical kinase regulating the phosphorylation of proteins associated with bilirubin exposure. Molecular docking and MicroScale Thermophoresis assays revealed a strong binding affinity between bilirubin and ROCK2. Interestingly, bilirubin increased ROCK2 protein expression without affecting its mRNA levels, and cycloheximide chase assays revealed enhanced ROCK2 stability, implicating post-translational regulation. While bilirubin did not directly activate ROCK2 kinase activity in vitro, it elevated phosphorylation of its substrate LIMK1, suggesting that ROCK2 accumulation amplifies downstream signaling. In primary rat neurons, ROCK2 inhibitors (Belumosudil and Y-27632) ameliorated bilirubin-induced loss of mitochondrial membrane potential and neuronal cell death. Furthermore, using ROCK2 inhibitors and Rock2+/- mice, we demonstrated that modulation of ROCK2 significantly alleviated bilirubin-induced auditory deficits and cognitive impairments. These behavioral improvements were linked to restored excitatory synaptic transmission in the cochlear nucleus and reduced dendritic damage in hippocampal neurons. These findings position ROCK2 as a promising molecular target for therapeutic intervention in bilirubin encephalopathy.
The scale of IVF centres currently ranges from small, stand-alone units to large networked organizations operating across multiple regions or countries. This diversity in organizational models may influence clinical outcomes, patient experience, professional practice, innovation and long-term sustainability. In parallel with broader healthcare trends, the fertility sector has undergone rapid consolidation over the last decade, prompting renewed debate regarding the relationship between centre size, governance structures, quality of care and efficiency. This opinion paper critically examines the strengths and limitations of both small and large IVF centres, with particular attention to the concepts of critical mass, technology adoption, human resources, quality management and professional autonomy. Beyond size alone, the discussion also covers how evolving governance models, particularly the growing influence of managerial and financial decision making, may reshape scientific leadership and clinical practice within fertility centres. Importantly, the authors acknowledge the scarcity of high-quality comparative evidence linking organizational scale to live birth outcomes or patient-reported measures. Rather than advocating for a single optimal size, they propose the concept of a 'sustainable or balanced scale', defined as an organizational equilibrium where operational robustness, leadership, science and innovation coexist with uncompromising personalized, patient-centred care.
To investigate the anti-inflammatory mechanisms of Hudi enteric-coated capsule (HDEC) and its major bioactive constituent, polydatin, in ulcerative colitis (UC). Mouse models of colitis were established by transplantation adoptive transfer of CD45RBhighCD4+ T cells and treated with or without HDEC/polydatin. Therapeutic efficacy was evaluated by assessing disease activity, colon length, and histopathological damage. The differentiation of Th1, Th17, and Treg cells was analyzed using quantitative real-time polymerase chain reaction and flow cytometry. In vitro cultures of mouse and human CD4+ T cells were utilized to assess the immunomodulatory activity. RNA sequencing, Western blotting, and immunofluorescence were used to explore the underlying mechanism. Molecular docking, molecular dynamics, and surface plasmon resonance (SPR) assays were employed to confirm the interaction between polydatin and KEAP1. Treatment with HDEC and polydatin significantly ameliorated murine colitis and mucosal damage. Mechanistically, polydatin directly binds to KEAP1 to promote NFE2L2 nuclear translocation. This NFE2L2 activation reduces intracellular oxidative stress, thereby inhibiting pathogenic Th1/Th17 differentiation and enhancing Treg generation. Importantly, these effects were consistently validated in human CD4+ T cells and UC mucosal tissues. HDEC and polydatin alleviate UC by targeting the KEAP1-NFE2L2 axis to reduce oxidative stress, thereby restoring the Th1/Th17/Treg balance. This highlights polydatin as a promising KEAP1-targeting agent with strong translational potential.
Fragile X syndrome (FXS), the leading genetic cause of intellectual disability, arises from FMR1 gene silencing and the subsequent loss of the RNA-binding protein FMRP. N6-methyladenosine (m6A) is a prevalent mRNA modification essential for post-transcriptional regulation. FMRP binds and regulates the stability of m6A-containing transcripts. However, how FMRP deficiency impacts transcriptome-wide m6A modifications in FXS remains unknown. To address this, we generated cortical neurons from induced pluripotent stem cells (iPSCs) derived from healthy individuals and FXS patients. Electrophysiology recordings revealed synaptic and neuronal network defects in FXS iPSC-derived neurons. Transcriptome-wide analysis revealed striking m6A hypermethylation predominantly affecting synapse-associated transcripts. Mechanistically, we demonstrated that FMRP deficiency drives the aberrant translational upregulation of core m6A writers, a causal relationship definitively validated using CGG-corrected isogenic control lines. Targeted genetic knockdown of the m6A writer METTL3 successfully rescued synaptic phenotypes in FXS neurons, whereas its overexpression in control neurons phenocopied these synaptic defects, confirming the causal role of m6A dysregulation in FXS pathology. Notably, pharmacological intervention with the METTL3 inhibitor STM-2457 normalized methylation on synapse-associated transcripts and restored synaptic transmission in FXS neurons. Together, our findings uncover an FMRP-dependent epitranscriptomic mechanism contributing to FXS pathogenesis and suggest a promising avenue for m6A-targeted therapies.
Kaempferol (KAE), a natural flavonoid, has emerged as a promising multi-target antineoplastic agent characterized by high efficacy and minimal systemic toxicity. Moving beyond fragmented descriptive summaries, this comprehensive review provides a highly integrated conceptual framework of KAE's anticancer mechanisms. Specifically, KAE orchestrates tumor eradication by enforcing cell cycle arrest across multiple phases and triggering a complex, interconnected network of programmed cell death. We highlight how reactive oxygen species and endoplasmic reticulum stress serve as central upstream nodes driving the mechanistic crosstalk among apoptosis, lethal autophagy, gasdermin E-mediated pyroptosis, and ferroptosis. Furthermore, KAE actively remodels the tumor microenvironment by inhibiting angiogenesis and repolarizing tumor-associated macrophages, thereby converting immunosuppressive "cold" tumors into immune-active "hot" tumors. Notably, this review introduces the emerging prebiotic-like crosstalk between KAE and the gut microbiome, providing a strong mechanistic rationale for its synergistic application with immune checkpoint inhibitors. As a potent chemosensitizer, KAE also overcomes multidrug resistance and mitigates chemotherapy-induced toxicities. Finally, we critically evaluate current translational bottlenecks-including the disparity between supraphysiological in vitro concentrations and clinical pharmacokinetics, the lack of robust in vivo validations, and the long-term biosafety of emerging nano-delivery systems. By addressing these critical limitations, this review offers strategic perspectives to bridge the gap from preliminary bench research to future precision oncological practice.