Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to heterogeneous clinical outcomes, suggesting that dysregulated host immune responses and inflammation contribute to divergent disease trajectories. We examined early immune correlates of disease severity using 32-week-old C57BL/6J mice and evaluated whether modulation of regulatory T cells (Tregs) would alter disease outcome. Oral administration of the CDK8/19 inhibitor AS2863619 did not markedly improve early weight loss, gross lung inflammatory scores, bronchoalveolar lavage fluid (BALF) viral RNA levels, or histopathological findings. Despite this limited impact on clinical outcomes, AS2863619 increased the frequency of KLRG1+ subsets in lung Foxp3+ CD4+ Tregs at 5 days post-infection. Across infected animals, lung Foxp3+ CD4+ Treg numbers inversely correlated with early weight loss. In parallel, several BALF inflammatory cytokines and chemokines were associated with disease severity, and the frequency of KLRG1+ Tregs inversely correlated with multiple inflammatory mediators. These findings indicate that endogenous lung Treg numbers and KLRG1+ Treg frequencies were linked to a less inflammatory airway milieu during acute SARS-CoV-2 infection.
Growth hormone not only promotes growth and development via inducing insulin-like growth factor-1 produced by the liver but also regulates glucose and lipid metabolism of peripheral organs, including the liver, adipose tissue, and muscle. Particularly, the relationship between growth hormone and adipose tissue has been recognized since the 1950s. More intensive research focusing on it is emerging, fueled by the new conception that adipose tissue is not merely a passive reservoir for fat storage but a highly active organ with endocrine and metabolic capabilities. As for it, earlier findings have illuminated the effects of growth hormone on adipose tissue, including lipolysis and lipogenesis, adipocyte proliferation and differentiation, adipose cytokine secretion, white fat browning, and adipose tissue fibrosis. Subsequently, recent research has uncovered its involvement in promoting adipose tissue aging, regulating the adipose tissue immune microenvironment, and governing adipocyte subgroup composition. More importantly, decreased serum levels of growth hormone detected in patients with obesity are associated with glucose and lipid metabolism dysfunction. Therefore, this review aims to examine the impact of growth hormone on adipose tissue under the physiological context or pathological contexts based on patients and animal models characterized by either excessive or diminished growth hormone action to indicate a complex interplay of mutual regulatory mechanisms between adipose tissue and growth hormone. Subsequently, the alterations of growth hormone levels in obesity and their implications for glucose-lipid metabolism and adipose tissue have also been reviewed. Therefore, the review will offer novel perspectives on the role of growth hormone in the progression of obesity based on the new conception of adipose tissue and its potential use in therapeutic interventions for obesity.
Nitrous oxide (N2O) is a potent greenhouse gas pollutant, but the mechanisms by which different earthworm ecotypes regulate N2O emissions in latosolic red soils remain poorly understood. To address this issue, a microcosm incubation experiment was conducted using three earthworm ecological categories, epigeic Eisenia foetida, endogeic Pontoscolex corethrurus, and anecic Pheretima guillelmi, to investigate their effects on N2O emissions, soil nitrogen-cycling processes, microbial communities, and nitrogen-cycling functional genes in latosolic red soil. The results showed that the three earthworm ecological categories differentially affected N2O emissions by altering soil physicochemical properties, regulating related enzyme activities, and promoting inorganic nitrogen transformation, with endogeic and anecic earthworms exerting stronger stimulatory effects. Earthworm activity reshaped microbial community interactions and altered the relative abundances of key functional genes involved in nitrification, denitrification, assimilatory nitrate reduction, and dissimilatory nitrate reduction to ammonium (DNRA). Integrated analysis indicated that earthworms may jointly influence soil nitrogen transformation and N2O emissions by modifying the soil environment, promoting soil nitrogen transformation processes, and regulating microbial community structure and the relative abundance of nitrogen-cycling functional genes. Due to differences in activity patterns and disturbance intensity, the effects of different earthworm ecological categories varied substantially, with cumulative N2O emissions generally following the order: anecic > endogeic > epigeic.
This review synthesizes the emerging evidence positioning irisin, a myokine released during physical activity, as a critical molecular link in chronic obstructive pulmonary disease (COPD) airway remodeling. Clinically, irisin deficiency is consistently observed in COPD and correlates with key features including reduced physical activity, respiratory muscle weakness, sarcopenia, emphysema severity, and exacerbation risk, supporting a hypothesis of a "muscle-lung crosstalk" axis. At the cellular level, irisin exerts direct protective effects on airway structural cells by preserving epithelial barrier integrity via anti-apoptotic and antioxidant mechanisms, while modulating airway smooth muscle tone, proliferation, and extracellular matrix dynamics. Mechanistically, these actions converge on core signaling networks centered on AMPK activation, coordinating downstream pathways such as PGC-1α-mediated mitochondrial regulation, mTOR-dependent autophagy, and SIRT1-driven anti-inflammatory cascades. Emerging layers of complexity involve non-coding RNAs, extracellular vesicles, integrin αVβ5 receptor signaling, and intracellular interactions like Enolase 1 (ENO1) ubiquitination. Collectively, these findings form an "exercise/pharmacology-irisin-airway structural cell-signaling pathway-airway remodeling" framework. Beyond irisin, other adipomyokines (leptin, adiponectin, BDNF, and erythropoietin) exhibit distinct-often opposing-inflammatory and immune profiles in COPD, underscoring a broader multi-hormone network. Future directions should focus on validating irisin as a clinical biomarker and exploring irisin-based therapeutic interventions, which represent a promising avenue for improving COPD management.
To map and characterize device damage and malfunction associated with dual defibrillator use in defibrillation and cardioversion, which is increasingly employed in both elective and emergency settings, and to identify knowledge gaps relevant to practice and future research. We conducted a scoping review in accordance with JBI methodology and PRISMA-ScR. PubMed, Embase, CINAHL, CENTRAL, and grey literature were searched without language or date restrictions. Regulatory adverse event databases were also searched. Eligible sources reported device damage or malfunction associated with two external defibrillators delivering shocks within one second or less of each other. Twenty-nine records from 2016 to 2026 were included: five published sources and 24 regulatory adverse event reports. Published sources comprised two randomised trials, one survey study, one case report, and one ad-hoc retrospective study. Across five published sources, eight events of lasting device damage and four temporary malfunctions were identified. In published studies, all reported damage events were reported in association with double simultaneous defibrillation or dual cardioversion. Across 24 regulatory reports, 11 records described device damage and 16 described malfunctions. Reported damage was often not recognized during the index event and was instead identified on post-use testing or later routine self-checks. Device damage and malfunction during dual defibrillator use are documented in both published and regulatory sources. Damage may remain occult until later testing, creating risk beyond the index case. Standardized prospective reporting and routine post-use device testing should be considered wherever dual defibrillator use is employed.
Allantoin plays a major role in nitrogen mobilization as well as abiotic stress tolerance in plants, and uricase enzyme is the key rate-limiting enzyme for the biosynthesis of allantoin in peroxisomes. However, the molecular mechanisms underlying stress-induced allantoin accumulation as well as enhanced uricase activity, along with the evolutionary conservation, structural diversification, and regulatory characteristics of plant uricase enzymes, remain poorly understood. This study investigates evolutionary relationships, functional variations and catalytic mechanisms of the uricase enzymes among 157 plant species. Phylogenetic analysis grouped these species into three major clades, indicating a progression from microalgae to higher plants. Motif analysis revealed the presences of a conserved Pfam01014 (uricase) domain across the species. Uricase activity analysis of 22 representative species showed the highest activity in ureidic legumes, including Vigna radiata and Glycine max, and the lowest in non-leguminous species such as Cucumis sativus. Moreover, promoter analysis of the Uricase gene identified diverse cis-regulatory elements associated with stress, hormone responses and plant development. Structural modelling, docking and sequence alignments revealed conserved substrate-binding residues. Biophysical characterization of recombinantly purified uricase from Oryza coarctata using fluorescence spectroscopy demonstrated uric acid binding with a dissociation constant (KD) of 10.89 μM, positive cooperativity, and a Michaelis constant (KM) of 23.96 μM. Circular dichroism showed a conformational shift from α-helix to β-sheet upon ligand binding and molecular dynamics simulations supported stable urate interactions in O. coarctata. This work highlights the evolutionary conservation and functional divergence of uricase, featuring unique catalytic adaptations in ureidic legumes.
Enterovirus 71 (EV71) is the main causative agent of severe hand, foot, and mouth disease (HFMD) in children. Dysregulation of microRNAs (miRNAs) has been associated with HFMD progression, but the underlying regulatory mechanisms remain incompletely characterized. Rhabdomyosarcoma cells (RD) and human glioblastoma astrocytoma cells (U87-MG) were infected with EV71 at varying multiplicities of infection. In vivo, 5-day-old C57BL/6 mice, with C57 mice treated with STM2457 were intraperitoneally injected with a lethal dose of EV71. Molecular analyses included Western blotting, co-immunoprecipitation, and RNA immunoprecipitation. Clinical blood samples from HFMD patients were used for validation. In this study, we found that EV71 infection increased METTL3 expression and m6A methylation levels in the flanking regions of pri-miR-146a, promoting miR-146a maturation, which in turn suppresses TRAF6 and IRAK1 expression and inhibits IFN-I production, affecting the progression of EV71-induced HFMD. Co-immunoprecipitation and immunofluorescence assays demonstrated interaction between METTL3 and DGCR8, as well as nuclear co-localization of METTL3 with DGCR8. Furthermore, this regulatory mechanism was also confirmed through the intraperitoneal injection of STM2457 (a METTL3 inhibitor) to intervene in EV71 infection. Finally, detection conducted on clinical blood samples of HFMD demonstrated the specificity of IRAK1 in detecting severe HFMD. These findings will not only aid in understanding the mechanisms by which EV71 infection impacts the host immune system but also provide a scientific basis for identifying early diagnostic biomarkers and developing new therapeutic strategies.
Methcathinone (MCAT), a synthetic cathinone structurally analogous to amphetamine, poses substantial public health concerns due to its high addictive liability and pronounced neurotoxicity. In the present study, rat models of MCAT-induced neurotoxicity were established using low (0.5 mg/kg), medium (5 mg/kg), and high (20 mg/kg) doses. Cognitive function was assessed using the Morris water maze, while hippocampal synaptic morphology and ultrastructure were examined via Golgi staining and transmission electron microscopy. To elucidate the underlying molecular mechanisms, whole-transcriptome sequencing was performed to profile mRNAs, miRNAs, circRNAs, and lncRNAs in the hippocampus across exposure groups relative to controls. Differential expression analysis identified extensive transcriptional alterations, including 1646, 1539, and 1477 DEmRNAs; 32, 28, and 23 DEmiRNAs; 749, 728, and 753 DEcircRNAs; and 391, 369, and 371 DElncRNAs in the low-, medium-, and high-dose groups, respectively. Functional enrichment analyses consistently implicated synapse-related processes and neurodegeneration-associated pathways. Notably, activity-dependent immediate-early genes (c-Fos, Nr4a1, Arc, Egr1, Egr2, and Npas4) were uniformly downregulated across all exposure levels, indicating impaired neuronal activity-dependent transcriptional responses. Integration of multi-layered transcriptomic data enabled the construction of circRNA-miRNA-mRNA and lncRNA-miRNA-mRNA competing endogenous RNA (ceRNA) networks, revealing extensive post-transcriptional regulatory interactions. A core ceRNA network was identified, comprising 6 hub mRNAs, 9 miRNAs, 95 lncRNAs, and 146 circRNAs. Quantitative RT-PCR validation demonstrated high concordance with RNA-seq results, supporting the robustness of the dataset. These findings demonstrate that MCAT induces cognitive deficits and synaptic structural impairments by disrupting activity-dependent gene expression and neurotrophic signaling through complex ceRNA-mediated regulatory networks. This study provides novel mechanistic insights into MCAT-induced neurotoxicity and identifies potential molecular targets for therapeutic intervention in psychostimulant-related cognitive dysfunction.
KIAA0101, also known as proliferating cell nuclear antigen (PCNA) clamp-associated factor (PCLAF), is a small PCNA-interacting protein linking DNA replication, DNA damage tolerance, cell-cycle progression, and genome maintenance. Aberrant KIAA0101 expression occurs across multiple human malignancies and is frequently associated with aggressive clinicopathological features, therapy resistance, and poor survival. Beyond its canonical role as a proliferation-associated PCNA cofactor, emerging evidence obtained from bulk transcriptomics, single-cell sequencing, and spatially resolved analyses suggests that KIAA0101-high tumor states mark proliferative, stem-like, immune-excluded, and treatment-resistant ecosystems. However, research in this field remains limited by descriptive correlations, small retrospective cohorts, isoform-blind assays, and incomplete mechanistic validation. In this review, we synthesize current evidence on the structural features, regulatory networks, cellular functions, disease-specific roles, immune-microenvironmental associations, and translational relevance of KIAA0101 in cancer. We emphasize that its immune-related effects are more plausibly mediated through indirect regulatory routes, including NF-κB- and Wnt/β-catenin-associated programs, rather than through the direct transcriptional control of immune checkpoint genes. We further discuss therapeutic strategies targeting the KIAA0101-PCNA interface, KIAA0101 degradation, RNA interference/CRISPR-based suppression, and rational combinations with DNA damage response inhibitors or approved targeted agents. Future work should prioritize isoform-resolved detection, non-PCNA interactome mapping, immune-competent functional models, and biomarker-driven validation to determine whether KIAA0101 can be advanced from a cancer-associated molecule to a clinically actionable biomarker or therapeutic vulnerability.
Eukaryotic genomes are pervasively transcribed, producing a vast repertoire of RNA molecules. In plants, diverse RNA species play pivotal roles in regulating growth, development, and responses to environmental stimuli. The activities of RNAs are determined not only by their nucleotide sequences but are also shaped by multiple regulatory mechanisms, including processing, turnover, chemical modifications, and higher-order structure formation-each contributing critically to phenotypic outcomes. Over the past decade, technological advances, particularly in high-throughput sequencing and genome editing, have substantially deepened our understanding of RNA regulation; concurrently, research in this field has expanded from foundational studies in Arabidopsis to encompass a broad range of crop species. Building upon this expanded knowledge, this review provides a comprehensive overview of the regulation and functions of RNAs in plants. Specifically, we discuss the roles and molecular mechanisms of diverse RNA types, the roles of RNA structures and modifications in regulatory processes, and the translational application of RNA-based strategies for improving agronomic traits. Finally, we outline future research directions and offer perspectives on harnessing RNA regulation to advance crop improvement.
Metabolic diseases, including type 2 diabetes mellitus, obesity, and metabolic dysfunction-associated steatotic liver disease, are major global health challenges, sharing features such as disrupted glucose-lipid homeostasis, mitochondrial dysfunction, and chronic low-grade inflammation. Among mammalian sirtuins, SIRT7, though poorly characterized, is important for chromatin state, metabolic flux, mitochondrial function, and inflammatory responses in metabolically active tissues. Clinical and preclinical studies link dysregulated SIRT7 to multiple metabolic diseases, with tissue-specific effects on hepatic lipogenesis, insulin signaling, adipose function, and even metabolism-related hepatocellular carcinoma. Despite advances in the development of SIRT7-targeted inhibitors, significant challenges remain, including the absence of selective activators, limited structural characterization, incomplete understanding of tissue-specific regulatory mechanisms, and potential dose-dependent effects. This review integrates current knowledge on SIRT7-mediated regulatory networks and discusses emerging efforts to develop selective SIRT7 modulators, including structural-guided approaches based on AlphaFold models.
Microplastics (MPs) persist in environment, exerting long-term stress on aquatic ecosystems. As pivotal primary producers, microalgae are highly sensitive to environmental stress, with their growth and physiology impaired by MPs. Most existing MP toxicology studies are limited to short-term exposure (< 5 days) and macroscopic microalgal physiological indicators. Here, typical aquatic microalgae Scenedesmus obliquus (Chlorophyta) and Synechococcus sp. (Cyanophyta) were selected as test organisms to explore their response and regulatory mechanisms under acute and prolonged polyvinyl chloride (PVC) MP exposure by monitoring dynamic intracellular dissolved organic matter (IDOM) and metabolism over a 12-day culture. Acute exposure (days 0-4) induced species to resist stress via membrane lipid repair (S. obliquus) and enhanced signal transduction (Synechococcus sp.). Prolonged exposure (after day 4) presented reduced resistant levels, with these two algae exhibiting specific metabolic regulation-membrane lipid stabilization and optimized resource allocation, respectively. Divergent metabolic responses reflected species-specific differences driven by distinct cellular structures. Moreover, the transition from humic-dominant IDOM in the acute phase to protein-dominant IDOM during sustain exposure period reflected a strategic shift from rapid regulation to metabolic homeostasis, highlighting the potential of protein-like/humic-like ratio as a diagnostic proxy for algal physiological status under PVC-MP stress. This study better illustrates microalgal metabolic regulatory mechanisms on acute stress to prolonged bio-regulation under PVC-MP stress, providing clear evidence for evaluating the potential ecological impacts of MPs.
Adolescent idiopathic scoliosis (AIS) is associated with dysregulated bone remodelling, yet the molecular underpinnings remain unclear. To investigate site-specific osteoblast phenotypes at the spinal curve apex, we performed bulk RNA sequencing on primary matched osteoblasts isolated from the convex, concave, and non-curve regions of AIS patients. Principal component analysis revealed distinct transcriptional clustering by spinal site, independent of patient-specific factors. Differential expression analysis identified region-specific molecular profiles in convex and concave osteoblasts compared to non-curve controls, with the mTOR pathway being highlighted as one of the most dysregulated. Rapamycin, an mTOR inhibitor, reduced Alkaline phosphatase (ALP) activity, Osteoprotegerin (OPG) secretion, and mineralization, while modulating osteogenic gene expression, including sustained upregulation of RUNX2 and COL1A1. In AIS patient-derived osteoblasts, rapamycin elicited pronounced inhibition of mTOR signalling and osteogenic activity in convex cells compared to control. Convex osteoblasts also showed elevated mTOR expression but reduced downstream translation-related signalling, suggesting dysregulated or uncoupled mTOR activity. Notably, mTOR expression level correlated with curve severity, reinforcing the link between mTOR dysregulation and AIS pathology. These findings identify mTOR signalling as a key regulatory pathway in AIS osteoblast dysfunction and highlight rapamycin as a potential, though complex, therapeutic candidate.
Artificial intelligence (AI) has moved from proof-of-concept studies in dermatology to selective, real-world clinical use, particularly in image-based triage, lesion assessment, and workflow augmentation. Dermatology is uniquely suited to AI because much of diagnostic reasoning depends on visual information (clinical photos, dermoscopy, reflectance confocal microscopy, optical coherence tomography) plus context (history, distribution, symptoms, treatments, and risk factors). Yet translation into routine care depends less on eye-catching benchmark accuracy and more on careful validation, robust reference standards, fairness across skin tones and devices, usability within clinical workflows, and continuous post-deployment monitoring for performance and safety. This review summarizes leading diagnostic applications of AI in dermatology, provides a practical framework for clinical validation, and highlights real-world deployment patterns including teledermatology triage, melanoma risk workflows, inflammatory dermatoses severity scoring, and AI-assisted dermatopathology. We emphasize that "AI performance" is not a single number: the intended use (screening vs. diagnosis vs. referral prioritization), operating thresholds, prevalence, human-AI interaction, and downstream clinical actions determine real impact. Finally, we outline implementation considerations (governance, privacy, regulatory expectations, and monitoring) and propose practical steps for clinics and health systems seeking safe adoption.
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder caused by defective motile cilia, resulting in impaired mucociliary clearance, chronic respiratory disease, laterality defects and subfertility. Currently, no disease-modifying treatments exist. Targeting PCD at its root cause requires emerging genetic therapies, such as small molecules, oligonucleotides, mRNA therapy, gene replacement and genome editing. With over 52 implicated genes and numerous patient-specific variants, there is a need for robust preclinical models to evaluate and accelerate these approaches. This review examines human preclinical models that recapitulate patient-specific genotypes and phenotypes while providing sufficient scalability for screening and detailed efficacy assessment. The models should also resolve knowledge gaps, including which cells need targeting and at what stage of differentiation. Air-liquid interface cultures of primary human airway epithelial cells or induced pluripotent stem cells (iPSCs) represent the current practice, alongside three-dimensional organoids, spheroids and lung-on-a-chip platforms. To overcome the limited proliferative capacity of primary cells, strategies include BMI-1 or hTERT transduction, conditional reprogramming with Rho-associated kinase (ROCK) inhibitors and feeder layers, and differentiation of iPSCs. Patient-derived and CRISPR-edited models have been developed for multiple PCD genes. Outcome measures to confirm efficacy of the therapy include high-speed video microscopy for quantifying ciliary beat pattern, transmission electron microscopy for ultrastructural assessment, mucociliary clearance assays and deep molecular phenotyping. There is a need for field-wide standardisation through consensus protocols, core outcome sets, minimum reporting criteria, quality benchmarks and regulatory alignment to facilitate accelerated translation of preclinical findings to clinical therapeutics.
Intracellular organelles do not function in isolation but instead cooperate through organelle contact sites, where membranes closely appose without fusion to exchange information and metabolites. Among these interfaces, mitochondria-endoplasmic reticulum contact sites (MERCs) have emerged as central regulatory hubs involved not only in calcium and lipid exchange but also in mitochondrial dynamics, autophagy, stress responses, cell death, and metabolic regulation. In this review, the molecular basis of MERC formation is first organized from the perspectives of tethering, molecular transfer, and contact-site regulation, emphasizing that MERCs represent dynamic functional domains that are reorganized according to cellular conditions rather than static structures. Our recent findings are then introduced demonstrating that the mitochondrial outer membrane E3 ubiquitin ligase MITOL (also known as MARCHF5) selectively modulates substrate activity at MERCs and may contribute to mitochondrial iron supply and respiratory maintenance through regulation of the heme-degrading enzyme HMOX2. Because MERCs undergo rapid and reversible remodeling, quantitative analysis in living cells is essential. A split-luciferase-based reversible assay is presented as an example of an approach for real-time monitoring of MERC dynamics, revealing a stress-responsive increase in MERCs triggered by mitochondrial reactive oxygen species that is linked to the handling of lipid radicals. Finally, current methodologies for MERC analysis, including electron microscopy, super-resolution imaging, proximity sensors, and proximity labeling, are overviewed.
Misinformation influences cognition-shaping memory, beliefs, attitudes, reasoning, and decision-making. While intentionally disseminated misinformation (i.e., disinformation) has long served persuasive functions, its strategic use to generate epistemic uncertainty has grown in prominence. Such strategic manipulation by incentivised actors serves to construct 'alternative realities' that undermine shared truth and institutional trust. This review analyses recent evidence on the direct cognitive and behavioural impacts of misinformation, examines the transformative roles of social media and generative AI, and considers broader epistemological consequences, including the erosion of truth norms and implications for democratic discourse. Addressing these challenges requires coordinated individual and systemic interventions that integrate psychological, technological, educational, and regulatory approaches to strengthen epistemic resilience and safeguard evidence-informed public reasoning and decision-making.
Hesperidin is a bioactive flavonoid found in citrus fruits and has become a promising nutraceutical with multidimensional health benefits, such as anti-inflammatory, antioxidative, cardio-, neuroprotective, and metabolic-regulatory. However, poor bioavailability, variations in clinical efficacy, and limited standardized formulations are some of the challenges confronting this bioactive compound. Over the years, nanotechnology has remained a source of great developments in improving the absorption rate and specific delivery of hesperidin, therefore making it more therapeutic. Two of such recent developments are nano-encapsulation and phytosome-based delivery systems. In addition, emerging data have highlighted the importance of this seemingly mundane foodstuff in bridging the gut-brain axis, shaping the gut microbiome, and offering beneficial effects against chronic low-grade inflammation, as well as metabolic and neurodegenerative diseases. Nevertheless, additional phase 2 or 3 clinical trials should be performed to identify an optimal dose, safety in the long term, and synergy with other bioactive compounds. To enhance the preventive and therapeutic power of hesperidin, future studies should focus on individualized nutritional strategies, sustainable sources, and innovative, practical uses of functional foods. This review discusses the existing evidence on the mechanisms and the beneficial health effects of hesperidin, as well as providing future directions.
Flavonoids are polyphenolic secondary metabolites widely distributed in plants, exhibiting various biological activities such as antioxidant, anti-inflammatory, oestrogenic and metabolic regulatory effects. In recent years, their role in the regulation of female animal reproduction has attracted attention. This review summarises the structural characteristics, plant sources, forms of application and effects of flavonoids on reproductive function in female animals, with a focus on their roles in the hypothalamic-pituitary-varian axis, uterine receptivity and placental nutrient transport. Flavonoids primarily influence female reproductive function by regulating oestrogen receptor-related signalling, alleviating oxidative stress and inflammation, maintaining granulosa cell homeostasis, and promoting oocyte maturation and early embryonic development. There is already relatively direct production evidence regarding the improvement of reproductive performance in sows and placental function by certain isoflavonoids, whilst quercetin, luteolin and rutin, among others, are more commonly associated with ovarian protection, improved oocyte quality and the alleviation of damage. It should be noted that the effects of different flavonoid monomers or extracts are significantly influenced by animal species, dosage, timing of administration, physiological status and evaluation criteria. Current findings cannot be simply extrapolated to all female animal production practices; their safe dosages, critical administration windows and long-term efficacy still require further species-specific research for validation. This review indicates that flavonoids may serve as potential nutritional modulators for improving the reproductive microenvironment and alleviating reproduction-related damage, offering new insights into enhancing reproductive performance in female animals.
Reduction of DNA methylation has traditionally been associated with gene activation. Here, we show that DNA hypomethylation permits the binding of a transcriptional repressor, leading to gene silencing. In tomato, the SQUAMOSA PROMOTER BINDING PROTEIN-LIKE TF SlSPL-CNR exhibits methylation-sensitive DNA binding and preferentially occupies unmethylated GTACGG motifs. During fruit ripening, DEMETER-LIKE 2 (SlDML2)-mediated DNA demethylation at the alcohol acyltransferase 1 (SlAAT1) promoter allows SlSPL-CNR binding, which in turn represses SlAAT1 expression and thereby modulates the biosynthesis of ester metabolites-key components of fruit flavor. Structural analysis reveals that cytosine methylation introduces a steric clash with Gln94 in the SBP domain of SlSPL-CNR, explaining its methylation sensitivity. CRISPR knockout of SlSPL-CNR de-represses SlAAT1 and increases ester accumulation, confirming its inhibitory role. Importantly, this methylation-sensitive binding is conserved across SBP domain proteins from rice, maize, and tomato. Our findings reveal a mechanism in which DNA hypomethylation facilitates repressor recruitment, establishing a regulatory logic linking epigenetic dynamics to metabolic control in plants.