Search Results (4,222)

Crop losses driven by fungal pathogens remain a major constraint to global food production, reinforcing agriculture’s dependence on fungicide-based disease control. Soil acts as a long-term reservoir and key hotspot for the evolution and persistence of antifungal-resistant Fusarium. The intensive, prolonged use of overlapping single-site fungicides in agriculture strongly selects for both intrinsic and acquired resistance in soilborne Fusarium populations, contributing to major crop losses, food insecurity, and One Health concerns. This review synthesizes current knowledge on (i) target-site (CYP51, β-tubulin, cytochrome b, SDH, myosin-5) and non-target-site (ABC/MFS efflux, multidrug resistance, epigenetic regulation) resistance mechanisms across the genus Fusarium; (ii) the influence of management practices and fungicide characteristics and behaviour in soil in reshaping microbial communities and selecting for resistant Fusarium; (iii) the consequences for plant disease management and the limitations of practices like cultural and biological control; and (iv) innovative strategies for plant disease management, as well as the monitoring and detection of antifungal resistance in soils. These aspects show that soil reservoirs of antifungal-resistant Fusarium are compromising fungicide-based control and increasing risks across sectors, highlighting the urgent need for sustainable, multi-layered, integrated pest management strategies combined with robust, molecularly informed resistance monitoring. Full article

Fatty acids serve dual roles in cardiac physiology: as energy substrates and as precursors of bioactive lipid mediators (prostaglandins, leukotrienes, oxylipins) from n-3/n-6 PUFAs that regulate inflammation, thrombosis, and remodeling. Saturated, monounsaturated, and trans fatty acids modulate metabolism and membrane function, thereby shaping these pathways. Clinically, n-3 long-chain PUFAs (EPA and DHA) reduce cardiovascular mortality and aid postischemic remodeling; however, high doses increase the risk of atrial fibrillation. By contrast, trans and saturated fatty acids promote dyslipidemia, dysfunction, and higher rates of coronary artery disease and heart failure. Mechanistically, fatty acid uptake via FABPpm, CD36 (FAT), and FATPs, along with β-oxidation and PPAR signaling, regulates metabolism, while COX/LOX/CYP pathways generate eicosanoids and resolvins that influence inflammation and repair. This review synthesizes evidence on the roles of fatty acids and oxylipins in lipotoxicity, heart failure, ischemia–reperfusion, and arrhythmias, and evaluates dietary and supplemental interventions to optimize cardiac lipid metabolism, aligning with fatty acid signaling. Full article

Regulation of all-trans retinoic acid (ATRA) signaling is crucial to early embryonic development. Embryonic stem (ES) cell-derived gastruloids mimic normal development in response to the Wnt/β-catenin agonist CHIR9901, and this study has examined the importance of the activities of RAR (retinoic acid receptor) α and γ to gastruloid development. Expression of retinoic acid receptor (RAR)γ within developing gastruloids was spatially restricted to primitive cells that co-expressed ES cell and early progenitor cell markers, i.e., Nanog, Sox2, and Oct4. In contrast, RARα expression was ubiquitous. mRNAs for the key enzymes involved in ATRA synthesis (Aldh1a2) and degradation (Cyp26a1) were not seen in cells that expressed RARγ. Treatment of ES cell-derived gastruloids with physiologically relevant (10 nM) levels of ATRA or with a highly selective RARγ agonist blocked normal developmental processes, preventing symmetry-breaking and axial elongation. This was not seen following treatments with an RARα agonist, where there was a tendency for enhanced axial elongation. Brachyury (TBXT) immuno-positive cells localized in the posterior end of elongated gastruloids in control- and RARα agonist-treated cultures, with Sox2 immuno-positive cells seen more widely, whilst both TBXT and Sox2 immuno-positive cells were randomly distributed throughout ATRA- and RARγ agonist-treated gastruloids. Concurrent treatment of gastruloids with 10 nM ATRA and 100 nM of an RARγ antagonist partially abrogated the ATRA-mediated block to axial elongation. Conversely, 10 nM RARγ antagonist treatments were associated with the formation of multi-axis gastruloid elongations, with comparatively little effect seen after treatments with an RARα antagonist. These findings reveal that RARγ plays a crucial role in the development of embryonic tissues. Full article

Phellodendron amurense Rupr. is a native tree species in China, well known for its significant medicinal value. Its pharmacological activity mainly derives from the abundant isoquinoline alkaloids in its bark. Berberine serves as the key compound underlying the multiple pharmacological effects of P. amurense and exhibits organ-specific accumulation. However, the genetic mechanisms governing this organ-specific accumulation remain unclear. Genes encoding O-methyltransferase (OMT) and cytochrome P450 (CYP) may play an important role in this regulatory process. In this study, by integrating transcriptomic and metabolomic data from the leaves and stems of P. amurense plantlets, we identified core candidate genes and transcription factors (TFs) that regulate the differential biosynthesis of berberine between these two organs. The results showed that 37 metabolites were significantly upregulated in stems, including main medicinal components such as berberine and jatrorrhizine, while 8497 genes were differentially expressed between leaves and stems. Among these, downstream genes in the berberine biosynthesis pathway, including OMTs and CYPs, were predominantly highly expressed in stems. A co-expression regulatory network identified some TFs such as PaBES1, PaWRKY12/13, PaNAC5, and PaMYB12 as the key nodes regulating the differential biosynthesis of berberine. Phylogenetic analysis classified the 97 PaOMTs into four subgroups. Core candidate genes such as PaOMT7 and PaOMT9 were contained in subgroup IV, potentially contributing to the specific modification of characteristic alkaloids in P. amurense. This study reveals the transcriptional regulatory networks underlying the organ-specific accumulation of berberine in P. amurense plantlets, providing key targets and theoretical support for the targeted improvement and development of elite medicinal varieties. Full article

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality, frequently arising from chronic inflammatory states such as metabolic dysfunction-associated steatotic liver disease and cirrhosis. While extensive epidemiological data demonstrate a strong, dose-dependent inverse association between habitual coffee consumption and HCC incidence, the underlying molecular causality remains incompletely understood. In this comprehensive review, we elucidate the “Coffee Paradox” through the lens of nutriepigenomics. We demonstrate how coffee-derived bioactives—specifically chlorogenic acids, diterpenes, and microbially derived short-chain fatty acids—function as a coordinated epigenetic defense system. These compounds actively inhibit DNA methyltransferases, serve as endogenous histone deacetylase inhibitors via the gut–liver axis, and induce post-transcriptional, tumor-suppressive microRNA networks to halt oncogenic progression. However, to provide a critical and balanced perspective, we also address significant translational challenges. We evaluate conflicting null associations from recent Mendelian randomization studies and highlight the profound variability introduced by specific brewing methods, roasting profiles, and individual pharmacogenomics (e.g., CYP1A2 polymorphisms). Finally, we outline the future of precision hepatology, emphasizing the critical transition from observational epidemiology to clinical application via the utilization of circulating exosomal microRNAs as dynamic liquid biopsies and the development of standardized epi-nutraceuticals. Ultimately, this multi-layered epigenetic framework provides a robust foundation for integrating targeted dietary interventions into the primary prevention of HCC. Full article

Toxoplasma gondii, an obligate intracellular protozoan infecting approximately one-third of the global population, poses a significant yet underappreciated threat to reproductive health in both sexes. Although this parasite has long been linked to birth defects caused by infection during pregnancy, new research shows that it also reduces fertility in both sexes through different but related mechanisms. This review synthesizes knowledge on T. gondii-induced reproductive pathology across females and males, examining shared mechanistic themes while respecting tissue-specific differences, and evaluates emerging therapeutic strategies. In females, the parasite establishes persistent uterine reservoirs, triggers decidual immune dysregulation characterized by NK cell cytotoxicity, M1 macrophage polarization, Treg apoptosis, and inflammasome-mediated pyroptosis, while disrupting estrogen and progesterone signaling through both host receptor modulation and intrinsic parasite steroidogenic enzymes (TgCYP450mt, TgMAPR, Tg-HSD). In males, T. gondii breaches the blood–testis barrier, induces germ cell and Leydig cell apoptosis via ER stress and caspase pathways, impairs sperm quality parameters across acute and chronic infection, and disrupts the hypothalamic–pituitary–gonadal axis. Conserved molecular mechanisms—including NLRP3 inflammasome activation, PERK/eIF2α/ATF4/CHOP-mediated ER stress, and oxidative stress—operate in both reproductive tissues. The parasite’s intrinsic steroidogenic capability and bidirectional hormonal manipulation represent a paradigm shift in understanding host–parasite interactions. Conventional antiparasitics face limitations due to poor reproductive sanctuary penetration. Immunomodulatory approaches targeting Trem2, Tim-3, and the NLRP3 inflammasome show promise, along with natural products including Inonotus obliquus polysaccharide and ginseng polysaccharide. Nanomedicine platforms and mRNA vaccine candidates offer new directions for overcoming tissue barrier limitations. Toxoplasma gondii represents a fundamental threat to fertility and pregnancy outcomes rather than merely a risk for congenital infection. Integrated therapeutic strategies addressing direct parasitism, immunopathology, and endocrine disruption are needed. Longitudinal cohort studies, strain-specific mechanistic comparisons, and clinical trials of immunomodulatory adjuncts are urgently required. Full article

Globally, the invasive fall armyworm (Spodoptera frugiperda, FAW) has been characterized by the widespread development of tolerance to multiple insecticides, a process facilitated by extensive and prolonged exposure to these compounds. This study utilized RNA interference (RNAi) to explore the potential association of cytochrome P450 genes to spinetoram resistance in S. frugiperda, with the parallel aim of investigating nanocarrier-based P450-targeting formulations as synergistic agents for improved pest management. Bioassay results from Guangdong S. frugiperda populations revealed the highest tolerance in the Meizhou population (LC₅₀ = 0.673 µg/mL). Spinetoram exposure induced a 6.5 U/mL increase in larval P450 activity and triggered marked upregulation of CYP6AN4 (4.98-fold versus control), which exhibited concentration-dependent induction (2.52-fold under tested conditions). The LDH-dsCYP6AN4 + spinetoram formulation achieved 62.87% mortality, representing an 11.31% enhancement over the LDH + spinetoram group, and maintained robust synergy across diverse field populations. These phenotypic and molecular observations indicate that CYP6AN4 upregulation is closely correlated with the spinetoram response and may potentially contribute to altered insecticide susceptibility in field populations. Full article

Rapeseed (Brassica napus L.) is a globally important oilseed crop; however, its ‘double-low’ cultivars exhibit substantially reduced glucosinolate levels in vegetative tissues. To investigate whether UV-B radiation could be used to enhance glucosinolate accumulation, we systematically examined the modulation of glucosinolate profiles and associated biosynthetic pathways in leaves of the ‘double-low’ cultivar NY4 under white light (WL) supplemented with two UV-B intensities: low-intensity UV-B (UVBL, 0.1 W m⁻²) and high-intensity UV-B (UVBH, 0.4 W m⁻²). Rapeseed seedlings were treated for 21 days under a 16 h photoperiod, and leaf samples were collected at the end of the treatment period, with three biological replicates per condition. Compared with the WL control, UVBL significantly increased total glucosinolate content by 64.57%, driven predominantly by elevated accumulation of progoitrin and neoglucobrassicin. In contrast, UVBH reduced total glucosinolate levels but markedly elevated gluconasturtiin content. Transcriptome analysis revealed that UVBL upregulated key genes involved in glucosinolate biosynthesis (e.g., MAM, IPMDH, CYP79F1, and SOT17/18) and transcription factors (e.g., MYB28, MYB34, MYB51, and MYB122). Conversely, UVBH downregulated genes associated with side-chain elongation of aliphatic glucosinolates and secondary modification of indolic glucosinolate. Collectively, these results demonstrate that low-intensity UV-B radiation can effectively boost total glucosinolate content in rapeseed leaves via transcriptional reprogramming. Full article

We synthesized two vitamin D₃ analogues, 3 and 4, which have a shortened or elongated fluoro-side-chain based on 24,24-difluoro-25-hydroxyvitamin D₃ (5) using an efficient convergent approach and studied their preliminary biological activity. Both analogues exhibited greater resistance to CYP24A1-mediated metabolism than the natural 25-hydroxyvitamin D₃ (6), although their stability was lower than that of 5. Analogue 3 showed an approximately 100-fold lower human vitamin D receptor (hVDR)-binding affinity compared with 5 and 6. Despite this marked reduction in VDR-binding affinity, it demonstrated an approximately 1.5-fold increase in VDR-ligand binding domain (LBD) transcriptional activation of the natural ligand 6. In contrast, analogue 4 displayed moderate VDR-binding affinity and VDR-LBD transactivation compared with 5 and 6. We found that compound 3 is a unique vitamin D analogue with a fluorinated and shortened side-chain, exhibiting low binding affinity for hVDR but potent transcriptional activity through VDR-LBD with its long half-life; thus, 3 may serve as a basic structural skeleton for advancing medicinal chemistry and drug discovery. Full article

Non-heading Chinese cabbage (NHCC) is a highly economically valuable leafy vegetable widely grown in Asian regions. However, it undergoes rapid leaf yellowing and wilting during postharvest storage, which subsequently cause rapid quality decline and loss of nutritional components. Abscisic acid (ABA) promotes postharvest leaf senescence, while hydrogen-rich water (HRW) is widely used in postharvest preservation due to its excellent antioxidant properties; yet, the mechanism through which they interact to regulate postharvest senescence in NHCC remains unclear. Herein we found that exogenous HRW effectively delayed dark- and ABA-induced postharvest leaf senescence in NHCC, significantly maintained chlorophyll content, inhibited oxidative damage, and preserve nutritional components such as soluble sugars and vitamin C. The underlying mechanism was HRW inhibiting chlorophyll degradation by repressing the expression of chlorophyll catabolic genes like NYC1, NYE1, and PPH1. Meanwhile, HRW effectively lowered the accumulation of MDA and H₂O₂, elevated both the enzymatic activities and transcript abundance of SOD and CAT, and downregulated the transcript levels of RbohB, RbohC, RbohD, and RbohE, thereby maintaining reactive oxygen species (ROS) homeostasis. In addition, HRW negatively regulated ABA biosynthesis by inhibiting the transcript levels of ABA1, ABA2 and ABA3, while promoting the transcription of CYP707A1, CYP707A2 and CYP707A3. It also dampened the transcript abundance of ABA signaling components including PYL5, ABI1, and ABF3, thus blocking ABA signal transduction and alleviating its senescence-promoting effect. Collectively, this study confirms that HRW mitigates leaf senescence induced under dark and ABA conditions in NHCC via multiple synergistic pathways. Full article

Chinese tongue sole (Cynoglossus semilaevis), an economically important mariculture species in China, exhibits pronounced sexual dimorphism in growth, underscoring the importance of elucidating sex regulatory mechanisms for aquaculture development. Heterogeneous nuclear ribonucleoprotein K (hnrnpk) critically regulates mammalian reproductive development, yet its role in fish sex regulation remains elusive. Here, we systematically investigated the underlying function and mechanisms of hnrnpk in C. semilaevis through integrated molecular cloning, expression profiling, upstream regulatory analysis, functional assays, and transcriptome sequencing. We found that hnrnpk was highly expressed in the gonad and liver, with female-biased expression during gonadal development. Promoter activity assays revealed that sox2 and c-Jun enhanced hnrnpk transcription, whereas foxl2 and ar suppressed it. Additionally, hnrnpk was directly targeted by miR-460a-5p in C. semilaevis, revealing multi-level transcriptional and post-transcriptional regulation. Functional analyses showed that hnrnpk regulated cyp19a1a in a cell type-dependent and dose-sensitive manner: the expression of cyp19a1a was both upregulated in hnrnpk-knockdown ovarian cells and hnrnpk-overexpression testicular cells. Interestingly, foxl2 was upregulated in hnrnpk-knockdown ovarian cells but suppressed in hnrnpk-overexpression testicular cells, which showed the distinct regulation mechanisms in the different sexual programs. Transcriptomic analyses further revealed that several sex-related genes (sox9a with downregulation, etc.) were significantly regulated, and cell development and cycle pathways were dramatically enriched in functional enrichment analyses. This might indicate that hnrnpk overexpression drives C. semilaevis testis (CSTE) toward feminization reprogramming through sox9 switching and multi-pathway perturbations. Overall, our findings might reveal that hnrnpk, a female-biased gene regulated by miR-460a-5p and transcription factors, influences sex-related gene expression through sox9 switching. This study will offer new insights for C. semilaevis hnrnpk into sex determination and also provide a potential target for monosex breeding in aquaculture. Full article

Strong-flavor-type Baijiu, represented by Wuliangye—a renowned traditional Chinese alcoholic beverage brewed from five grains (sorghum, rice, glutinous rice, wheat, and corn)—is widely consumed and appreciated for its balanced taste and potential health benefits. While the volatile flavor compounds of Baijiu have been well studied, its bioactive components and their underlying mechanisms remain insufficiently explored. In this study, widely targeted metabolomics techniques were innovatively employed, and 2128 compounds were identified from 10 Wuliangye samples, of which 445 were predicted to constitute potential bioactive substances. Network pharmacology analysis further identified four key compounds, namely the four potential bioactive small molecules (fisetin, luteolin, norartocarpetin, and scutellarein), along with ten core targets that were key protein targets interacting with these compounds (SRC, PIK3R1, PTGS1, AKR1B1, STAT3, CYP3A4, ESR1, PIK3CA, PIK3CB, and ALOX15). GO and KEGG enrichment analyses indicated that these targets participated in diverse biological processes, while DO analysis revealed potential associations between these targets and specific diseases. Additionally, molecular docking confirmed the binding patterns between the identified compounds and their targets. Collectively, this study provides systematic chemical information and theoretical screening results for identifying potential bioactive components in strong-flavor-type Baijiu, which may facilitate further studies of their biological functions. Full article

Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine disorder in women of reproductive age, characterized by hyperandrogenism, insulin resistance, and ovarian dysfunction. Current therapies are often associated with adverse effects, highlighting the need for safer therapeutic alternatives. Peganum harmala (P. harmala), a medicinal plant rich in bioactive metabolites, was investigated through in silico approaches to identify compounds with predicted binding affinity for the androgen receptor (AR), steroid 17α-hydroxylase/17,20-lyase (CYP17A1), and glycogen synthase kinase-3 beta (GSK-3β). GC-MS analysis of P. harmala leaf essential oil collected in Riyadh, Saudi Arabia, identified 109 compounds, with terpenoids as the dominant class (21.89%). The major constituents were cis-chrysanthenyl acetate (3.48%), cis-β-damascenone (3.06%), farnesylacetone (1.44%), β-calacorene (1.36%), dihydroedulan II (1.04%), and trans-calamenene (0.46%). In silico ADMET evaluation indicated that most compounds complied with Lipinski’s rule of five and showed favorable predicted pharmacokinetic properties. Safety profiling suggested an overall acceptable toxicity profile, with minimal predicted CYP450 inhibition, except for L11, which showed broader inhibitory potential. Molecular docking showed that L15 (trans-calamenene), L14 (dihydroedulan II), L6 (β-calacorene), L3 (farnesylacetone), and L8 exhibited higher predicted binding affinity toward the androgen receptor; L3, L10 (cis-β-damascenone), and L16 (cis-chrysanthenyl acetate) interacted with CYP17A1, while L3, L9, and L6 exhibited higher affinity toward GSK-3β. Overall, these findings provide hypothesis-generating in silico predictions of ligand–target binding affinities and drug-likeness profiles. These computational findings highlight the importance of future experimental investigations to substantiate the biological activity, pharmacokinetic behavior, and safety profile of P. harmala constituents. Full article

Nosema ceranae is a common and highly contagious fungal pathogen that primarily infects the gut of adult honeybees, causing nosemosis. As a chronic disease of the digestive system, it poses a global threat to honeybee health and colony sustainability. This study aimed to investigate the inhibitory effects of different concentrations of Scutellaria baicalensis aqueous extract on N. ceranae in the intestines of infected Apis cerana through feeding experiments. In addition, the therapeutic efficacy of its major active component, baicalin, was evaluated, and its potential molecular mechanisms of action were explored. The results showed that, compared with the control group, administration of S. baicalensis aqueous extract at concentrations of 1 mg/mL, 5 mg/mL, and 10 mg/mL significantly reduced midgut spore loads (p < 0.05). Further experiments showed that a 0.5 mg/mL baicalin sucrose solution, prepared with 0.5% (v/v) DMSO as co-solvent, exhibited optimal solubility and significantly inhibited the proliferation of spores in the honeybee midgut. Transcriptomic analysis of A. cerana revealed varying numbers of significantly differentially expressed genes among the baicalin-treated (HG) group, the co-solvent control (DMSO) group, and the blank control (C) group. Four candidate DEGs associated with the effects of baicalin were further identified, namely LOC108003965, LOC108000905, LOC107996681, and CYP4G11. Gene Ontology enrichment analysis showed that, in the comparison between the HG group and the C group, these DEGs were significantly enriched in six functional categories: iron ion binding, phosphoric ester hydrolase activity, heme binding, tetrapyrrole binding, hydrolase activity (acting on ester bonds), and oxidoreductase activity (acting on paired donors, with incorporation or reduction of molecular oxygen). Collectively, these results demonstrate that S. baicalensis aqueous extract effectively inhibits the proliferation of N. ceranae within the host, and its active component, baicalin, exhibits a similar inhibitory effect. The present study proposes a novel strategy in which baicalin may enhance host endogenous chitinase-related activity to target and disrupt the spore wall, offering a new perspective for the prevention and control of honeybee nosemosis. Full article

Bietti crystalline dystrophy (BCD) is a hereditary retinal disease caused by loss-of-function mutations in the CYP4V2 gene. Gene replacement therapy using rAAV-hCYP4V2 represents a promising therapeutic strategy, requiring robust bioassays for product quality control. This study developed and validated a sensitive LC-MS/MS method for quantifying CYP4V2 enzyme activity. Lysates from HeLa-AAVR cells transduced with rAAV-hCYP4V2 (MOI = 3 × 10⁵) were used, with lauric acid as substrate supplemented with cytochrome P450 reductase, cytochrome b5, and NADPH. The ω-hydroxylated product (12-hydroxy lauric acid) was quantified using tolbutamide as an internal standard. Method validation followed ICH guidelines. Results demonstrated excellent specificity with negligible background in negative controls. Linearity was achieved over 0.5–100 ng/mL (R² > 0.99), with an average recovery of 100.6%. Intra-batch and inter-batch precision RSDs were <47.8% and <28.4%, respectively. Product stability was maintained for ≥4 weeks at −80°C. The method was successfully applied to three AAV serotypes (AAV2, AAV8, and AAV2/8), with all RSDs < 23.9%. This validated LC-MS/MS bioassay provides a crucial quality control tool for potency assessment, process development, batch release, and stability studies of rAAV-hCYP4V2 gene therapy products. Full article