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PubMed2024

Biochemical insights into the biodegradation mechanism of typical sulfonylureas herbicides and association with active enzymes and physiological response of fungal microbes: A multi-omics approach.

The extensive use of sulfonylurea herbicides has raised major concerns regarding their long-term soil residues and agroecological risks despite their role in agricultural protection. Microbial degradation is an important approach to remove sulfonylureas, whereas understanding the associated biodegradation mechanisms, enzymes, and physiological responses remains incomplete. Based on the rapid biodegradation of nicosulfuron by typical fungal isolate Talaromyces flavus LZM1, the dependency on cellular accumulation and environmental conditions, e.g. pH and nutrient supplies, was shown in the study. The biodegradation of nicosulfuron occurred intracellularly and followed the cascade of reactions including hydrolysis, Smile contraction rearrangement, hydroxylation, and opening of the pyrimidine ring. Besides 2-amino-4,6-dimethoxypyrimidine (ADMP) and 2-aminosulfonyl-N,N-dimethylnicotinamide (ASDM), numerous products and intermediates were newly identified and the structural forms of methoxypyrimidine and sulfonylurea bridge contraction rearrangement are predicted to be more toxic than nicosulfuron. The biodegradation should be enzymatically regulated by glycosylphosphatidylinositol transaminase (GPI-T) and P450s, which were manifested with the significant upregulation in proteomics. It is the first time that the hydrolysis of nicosulfuron into ADMP and ASDM have been associated with GPI-T. The integrated pathways of biodegradation were further elucidated through the involvement of various active enzymes. Except for the enzymatic catalysis, the physiological responses verified by metabolo-proteomics were critical not only to regulate material synthesis, uptake, utilization, and energy transfer but also to maintain antioxidant homeostasis, biodegradability, and tolerance of nicosulfuron by the differentially expressed metabolites, such as acetolactate synthase and 3-isopropylmalate dehydratase. The obtained results would help understand the biodegradation mechanism of sulfonylurea from chemicobiology and enzymology and promote the use of fungal biodegradation in pollution rehabilitation.

Herbicides↗

PubMed2026

Mikania micrantha invasion restructures rhizosphere nitrogen cycling through enzyme activation, microbial recruitment, and allelopathic regulation.

BACKGROUND: Plant invasions profoundly influence terrestrial ecosystems by reshaping nutrient cycling processes. However, the mechanisms through which invasive plants such as Mikania micrantha modulate soil nitrogen (N) cycling and microbial communities remain insufficiently explored. Moreover, comparative studies with indigenous congener are scarce, limiting insights into whether such effects reflect species-specific strategies or genus-wide traits. This study investigates how M. micrantha modulates nitrogen metabolic pathways and rhizosphere microecology using combined metagenomic and metabolomic analyses. RESULTS: Integrated analyses revealed that M. micrantha established a distinctive "high total nitrogen-low mineral nitrogen" profile in the rhizosphere soil. Metagenomic profiling showed consistent enrichment of key ammonium assimilation enzymes, including glutamine synthetase and glutamate dehydrogenase, promoting enhanced incorporation of NH₄⁺ into organic nitrogen pools. In contrast, genes encoding nitrate reductase and nitrate transporters were significantly lower in relative abundance, limiting nitrate assimilation. Mikania micrantha also selectively enriched nitrogen-fixing microbes (notably rhizobia genera) and plant growth-promoting rhizobacteria (PGPR), thereby enhancing biological nitrogen fixation capacity. Metabolomic analysis further identified several allelopathic compounds in invaded soils at higher relative abundance, particularly epicatechin, which exhibited inhibitory effects on nitrifying bacteria. Compared with the congener Mikania cordata, which exerted weaker impacts on soil nitrogen cycling and microbial assembly, M. micrantha deployed a more comprehensive strategy integrating biochemical, microbial, and metabolic regulation. CONCLUSIONS: These findings demonstrate that under greenhouse-controlled conditions, M. micrantha reconfigures rhizosphere nitrogen cycling through a multi-dimensional strategy that couples biochemical regulation, microbial recruitment, and metabolite-mediated interference, thereby suggesting a potential mechanism that may contribute to its ecological advantage in natural settings. Video Abstract.

Rhizosphere↗

PubMed2026

Physiological sub-typing of cold and freezing injury in Triticum turgidum subspecies with bioinformatic and expression characterization of glutathione reductase.

BACKGROUND: This study examined how different subspecies of Triticum turgidum (T. durum, T. polonicum, T. turanicum) respond to cold and freezing, assessing their water status, stress responses, and antioxidant system, with particular focus on the structure and function of glutathione reductase (TtGR). METHODS: TtGR genes were first identified from the T. turgidum genome using publicly available genomic resources such as Ensembl Plants. Promoter regions (~2 kb upstream) were analyzed to identify cis-regulatory elements using PlantCARE. Gene classification was performed based on predicted subcellular localization and conserved domain features. Plants were subjected to cold acclimation and freezing treatments, and physiological, biochemical, and enzymatic parameters were measured. RESULTS: Bioinformatics analyses identified four TtGR genes in the T. turgidum genome. The genes in two groups: cytosolic (Class I) and chloroplastic (Class II). Gene structure analysis showed a conserved exon-intron organization, while motif analysis confirmed the presence of Nicotinamide Adenine Dinucleotide Phosphate (NADPH)-binding and redox-active domains across all TtGR proteins. Several regulatory sequences in the promoters are involved in cold (DRE), abscisic acid (ABRE), and stress (STRE) responses, indicating that TtGR genes are dynamically regulated in response to environmental changes. Physiological analyses showed that freezing treatment reduces leaf water content in all genotypes, leading to turgor loss, hydrogen peroxide (H2O2) accumulation, and increased malondealdehyte (MDA) levels. However, tolerance mechanisms addressing water stress and membrane damage differ among genotypes. At the biochemical level, activation of the antioxidant defense system occurs in all genotypes. T. turanicum displays strong defense by significantly increasing enzyme activities, ensuring that the ascorbate-glutathione cycle continues under stress. By contrast, T. polonicum, although showing increased overall enzyme activities, experiences a dramatic drop in glutathione reductase (GR) activity at freezing temperatures, which restricts reduced glutathione (GSH) regeneration and creates a functional bottleneck in the antioxidant cycle. T. durum fails to sustain enzyme activities over the stress period, leading to an intermediate-sensitive response. Thus, whereas T. turanicum effectively maintains antioxidant function during freezing, T. polonicum and T. durum exhibit less efficient stress responses, either through enzymatic bottlenecks or a lack of sustained defense. CONCLUSIONS: One of the most striking findings of this study is the observed dissociation between TtGR gene expression levels and enzyme activities. Low temperature limits the link between transcription and enzyme function. The primary determinant of low-temperature tolerance in T. turgidum subspecies is the sustainability of GR enzyme activity and GSH regeneration under freezing conditions.

Triticum↗

PubMed2026

Functional Characterization of the Oat (Avena sativa L.) TCP Transcription Factor AsTCP38 Reveals Its Role in Low-Nitrogen Stress Tolerance.

Nitrogen limitation restricts plant growth, development, and yield in crops and forage species. Although TCP transcription factors are implicated in diverse abiotic-stress responses, the functions of most TCP genes in oat remain unclear. Here, we cloned and characterized the AsTCP38 gene, which is 1215 bp long and encodes a 405-amino-acid protein. The predicted protein contains a conserved TCP domain and shares its highest sequence similarity with Arabidopsis thaliana (A. thaliana) AtTCP15. The AsTCP38 protein localized to the nucleus, and promoter analysis identified cis-elements associated with light, hormone, and stress responses. We generated AsTCP38-overexpressing A. thaliana and wheat plants and screened an oat leaf yeast cDNA library for candidate interacting proteins. In these heterologous overexpression lines, AsTCP38 overexpression was associated with greater abscisic acid (ABA) sensitivity and improved seedling growth under low-nitrogen conditions. Changes in antioxidant-enzyme activities, nitrogen-metabolism-related enzyme activities, and endogenous hormone contents were also observed. Together, these findings suggest that AsTCP38 may participate in low-nitrogen responses and provide a basis for further functional studies in oat. Direct regulatory targets and the contribution of AsTCP38 to low-nitrogen adaptation in oat remain to be established.

Avena↗

PubMed2026

Fasting-refeeding regimes induce compensatory growth and muscle transcriptomic remodeling in juvenile Qihe gibel carp (Carassius gibelio var. Qihe).

Compensatory growth, an important adaptive response in fish, holds considerable potential for improving feeding efficiency in aquaculture. To identify an optimal fasting-refeeding strategy for juvenile Qihe gibel carp (Carassius gibelio var. Qihe) and to clarify the mechanisms underlying the compensatory growth, we divided two-month-old fish into four groups, namely S0 group (continuous feeding for 28 days), S2 group (4 cycles of 2-day fasting followed by 5-day refeeding), S4 group (fasting for 4 days followed by refeeding for 24 days), and S8 group (fasting for 8 days followed by refeeding for 20 days), then growth performance, muscle tissue morphology, biochemical responses, and muscle transcriptomic profiles under different feeding regimes were investigated. After a 28-day aquaculture experiment, fish in the S4 group exhibited significantly greater body length and weight than those in the S0, S2, and S8 groups, indicating over-compensatory growth. Histological analysis further showed that muscle growth in the S4 group was mainly associated with myofiber hyperplasia. Different feeding regimes also induced distinct changes in hepatic antioxidant and metabolic enzyme activities, as well as intestinal digestive enzyme activities. Transcriptome analysis revealed that the forkhead box O (FoxO) signaling pathway was significantly enriched during compensatory growth. Key genes, including serum/glucocorticoid regulated kinase 1 (sgk1) and insulin receptor substrate 1 (irs1), were predicted to play important roles in this process. Overall, these results indicate that fasting for 4 days followed by refeeding for 24 days (the S4 regime) is the optimal strategy for inducing compensatory growth in juvenile Qihe gibel carp. This study provides new insights into the morphological, physiological, and molecular basis of compensatory growth and offers a scientific foundation for developing efficient and sustainable feeding strategies for this species.

Animals↗

PubMed2026

Melatonin Levels in 89 Individuals With Smith Magenis Syndrome.

In patients with Smith-Magenis syndrome (SMS), an inverted circadian rhythm of melatonin (MT) contributes to the sleep disturbance. Standard treatment of sleep disturbance with MT often leads to extremely high daytime MT levels, resulting in even more sleep disorders. We therefore retrospectively evaluated the MT data of 89 SMS patients. Mean MT levels in participants on exogenous MT were significantly higher than in participants that did not use MT (p = < 0.0001). In 9 participants with very high MT levels, these dropped significantly after discontinuation of exogenous MT (p = 0.0037). In 12 participants, MT levels were significantly higher after MT therapy start compared to MT levels before MT start (p = 0.028). MT is catabolized principally by the CYP1A2 enzyme, with a half-life of about 40 min. CYP1A2 genotyping was performed in five participants with high MT levels during MT use. Although clinically suspected to be a poor CYP1A2 metabolizer, all five turned out to have haplotype CYP1A2*1F, which is associated with increased enzyme activity. This shows that genotyping of CYP1A2 is not suitable to estimate the level of CYP1A2 enzyme activity. When prescribing MT, it is strongly recommended to measure a MT level prior to treatment in order to determine the dose to be given. Checks of the MT level during treatment are necessary due to the frequent occurrence of poor CYP1A2 metabolism. Since CYP1A2 genotyping does not provide adequate information about the level of CYP1A2 enzyme activity, we propose a simple way to determine CYP1A2 phenotype.

Humans↗

PubMed2025

Epitalon increases telomere length in human cell lines through telomerase upregulation or ALT activity.

Epitalon, a naturally occurring tetrapeptide, is known for its anti-aging effects on mammalian cells. This happens through the induction of telomerase enzyme activity, resulting in the extension of telomere length. A strong link exists between telomere length and aging-related diseases. Therefore, telomeres are considered to be one of the biomarkers of aging, and increasing or maintaining telomere length may contribute to healthy aging and longevity. Epitalon has been the subject of several anti-aging studies however, quantitative data on the biomolecular pathway leading to telomere length increase, hTERT mRNA expression, telomerase enzyme activity, and ALT activation have not been extensively studied in different cell types. In this article, the breast cancer cell lines 21NT, BT474, and normal epithelial and fibroblast cells were treated with epitalon then DNA, RNA, and proteins were extracted. qPCR and Immunofluorescence analysis demonstrated dose-dependent telomere length extension in normal cells through hTERT and telomerase upregulation. In cancer cells, significant telomere length extension also occurred through ALT (Alternative Lengthening of Telomeres) activation. Only a minor increase in ALT activity was observed in Normal cells, thereby showing that it was specific to cancer cells. Our data suggests that epitalon can extend telomere length in normal healthy mammalian cells through the upregulation of hTERT mRNA expression and telomerase enzyme activity.

Humans↗

PubMed2026

Comparative Responses of Invasive and Native Plant Species to Combined Cd and Microplastic Pollution.

The co-occurrence of heavy metal contamination and biodegradable microplastic (polylactic acid, PLA) pollution poses increasing risks to terrestrial plant communities and soil functioning, yet species-specific responses to combined stress remain poorly understood. Cd and microplastics frequently co-occur in agricultural soils, where microplastics can alter cadmium mobility, bioavailability, and transport pathways, potentially modifying metal toxicity and plant stress responses compared with single-pollutant exposure. We investigated the responses of the invasive Bidens pilosa and the native Solanum nigrum grown in monoculture and mixed culture under combined cadmium (Cd) and biodegradable microplastic (PLA) stress by integrating plant growth, photosynthetic performance, oxidative physiology, and rhizosphere biochemical processes. Combined Cd-MP exposure markedly reduced plant growth, chlorophyll content (SPAD), photosystem II efficiency (Fv/Fm), nitrogen accumulation, biomass production, and rhizosphere enzyme activities associated with carbon, nitrogen, and phosphorus cycling. However, B. pilosa maintained greater physiological stability under stress, characterized by higher antioxidant enzyme activities (SOD, CAT, POD), lower reactive oxygen species (H2O2, O2˙-) accumulation, and reduced lipid peroxidation (MDA), whereas S. nigrum exhibited stronger oxidative damage and functional impairment. Multivariate analyses further revealed that root antioxidant capacity was closely associated with rhizosphere microbial enzyme activity, suggesting a root-centered regulatory mechanism linking plant stress tolerance to soil functioning. Overall, the invasive species showed greater tolerance to combined contamination and maintained relatively higher rhizosphere functional activity than the native species, indicating that multi-pollutant stress may alter competitive interactions between invasive and native plants in contaminated environments.

Cadmium↗

PubMed2025

Biosynthetic potential of the culturable foliar fungi associated with field-grown lettuce.

Fungal endophytes and epiphytes associated with plant leaves can play important ecological roles through the production of specialized metabolites encoded by biosynthetic gene clusters (BGCs). However, their functional capacity, especially in crops like lettuce (Lactuca sativa L.), remains poorly understood. We sequenced the genomes of nine fungal isolates, representing Fusarium sp., Fulvia sp., Alternaria alternata, and Alternaria postmessia, from leaves of lettuce grown under field conditions in Arizona, USA. We used antibiotics and secondary metabolite analysis shell (antiSMASH) and the database for automated carbohydrate-active enzyme annotation (dbCAN3), to predict BGCs and carbohydrate-active enzymes (CAZymes) for each strain, and then compared them to conspecific strains from other environments and substrates. Foliar lettuce-associated fungi featured 39-95 BGCs per genome, with substantial overlap between isolates occurring in association with lettuce leaves vs. from other substrates. Species identity was a significant determinant of BGC count, while host type, isolation source, and lifestyle were not. Several BGCs, including those for alternariol and 1,3,6,8-Tetrahydroxynaphthalene (T4HN), showed 100% similarity to characterized minimum information about a biosynthetic gene cluster (MIBiG) clusters based on antiSMASH predictions. Although analysis by biosynthetic gene similarity clustering and prospecting engine (BiG-SCAPE) identified gene cluster families (GCFs) across the dataset, these reference-matching clusters were not always grouped, reflecting methodological differences in how the tools assess similarity. Comparative CAZyme analysis in a focal species (Fulvia sp.) revealed higher gene counts in a foliar lettuce-derived isolate than in tomato (Solanum lycopersicum)-associated strains, challenging assumptions about host chemical complexity. These results highlight the importance of phylogenetic context in shaping fungal functional potential and suggest that selection on microbial traits in edible leafy crops may be more subtle and species-specific than previously assumed. KEY POINTS: • Lettuce-associated fungi feature diverse biosynthetic potential • Phylogeny predicts fungal BGC content more strongly than ecological lifestyle • Findings support genome-informed microbiome strategies for leafy crops.

Lactuca↗

PubMed2025

A multifunctional sesquiterpene synthase integrates with cytochrome P450s to reinforce the terpenoid defense network in maize.

Terpenoids, the largest and most structurally diverse class of plant natural products, play essential roles in maize defense and ecological interactions. In this study, we identified and functionally characterized a sesquiterpenoid-based defense pathway in maize centered on α-santalenoic acid, a pathogen-inducible sesquiterpenoid antibiotic. Using a combination of metabolite-based genome-wide association studies (mGWAS), linkage mapping, and heterologous expression assays, we identified ZmTPS9 as a multiproduct terpene synthase that primarily produces α-santalene and β-bisabolene. Sequence analysis and site-directed mutagenesis revealed that threonine at position 413 is critical for enzyme activity, with its deletion resulting in a complete loss of enzyme activity. The sesquiterpene hydrocarbons produced by ZmTPS9 are further oxidized by three cytochrome P450 monooxygenases, ZmCYP71Z16, ZmCYP71Z18, and ZmCYP71Z19, to yield antimicrobial metabolites including α-santalenoic acid, zealexin D1 (ZD1), and zealexin D2 (ZD2). Together, these findings demonstrate a convergent biosynthetic strategy in maize, where multiproduct terpene synthases and promiscuous P450s collaboratively generate a flexible and robust terpenoid defense network.

Zea mays↗

PubMed2026

The novel transcriptional activator Bhr1 combining NTPase and Zn(II)2Cys6 DNA-binding domains controls (hemi-)cellulase response to mannose-rich substrates in the white-rot fungus Dichomitus squalens.

The regulatory landscape responsible for lignocellulose degradation in white-rot basidiomycete fungi remains largely unexplored. In this study, we characterize a novel transcriptional activator, Bhr1, in the white-rot fungus Dichomitus squalens. Bhr1 exhibits an unusual domain architecture that combines a septin-like P-loop NTPase fold with Zn(II)2Cys6 DNA-binding domains and plays a critical role in activating (hemi-)cellulase enzyme production when D. squalens is exposed to mannose-rich substrates. Using CRISPR/Cas9-mediated gene editing, we generated a bhr1 disruption mutant that displayed distinct phenotypes and enzyme activity profiles on mannose and guar gum compared to the wild type. RNA sequencing data indicate that Bhr1 induces specific (hemi-)cellulase-encoding genes without altering the expression of genes encoding sugar transporters or sugar metabolic enzymes. Phylogenetic analyses show that Bhr1 is basidiomycete specific and largely restricted to saprotrophic and plant-associated Agaricomycetes fungi. Based on the domain architecture of Bhr1 and the effects of its disruption in D. squalens, our findings reveal a lineage-specific regulatory innovation in basidiomycetes that is distinct from those described in ascomycetes. Elucidating the function and evolutionary conservation of Bhr1 advances our understanding of lignocellulose degradation at the molecular level in basidiomycete fungi and may inform studies of their ecological adaptation and the development of biotechnological applications.IMPORTANCEUnderstanding the transcriptional regulatory mechanisms in white-rot fungi, such as Dichomitus squalens, is crucial for advancing our knowledge of lignocellulose degradation. This study identifies D. squalens Bhr1 as a key regulator of (hemi-)cellulase production on mannose-rich substrates and further distinguishes basidiomycete transcription factors involved in plant biomass degradation from their ascomycete counterparts. Our findings highlight the significance of lineage-specific regulators in facilitating adaptive enzyme production for efficient biomass utilization, which is critical to carbon cycling in terrestrial ecosystems. This work establishes a foundation for exploring novel regulatory strategies among wood-degrading fungi, potentially enabling targeted strain engineering in biotechnological applications.

Mannose↗

PubMed2025

HDAC6-dependent deacetylation of SAE2 enhances SUMO1 conjugation for mitotic integrity.

Mammalian cells express three conjugatable SUMO variants: SUMO1 and the closely related SUMO2 and SUMO3 (together referred to as SUMO2/3). While some substrates are modified by both, others show a clear preference, though the basis for this selectivity remains unclear. Here, we examine a modification of the catalytic component of the human SUMO activation enzyme, SAE2. We find that lysine 164 of SAE2 undergoes HDAC6-dependent deacetylation during mitosis. A non-deacetylatable acetyl-mimetic mutant, SAE2-K164Q, selectively enhances SUMO2 over SUMO1 activation and conjugation, and distinguishes between SUMO1 and SUMO2/3 based on differences in their C-terminal tails. Complementation of SAE2-deficient or inhibited cells with SAE2-K164Q suppresses mitotic SUMO1 conjugation and promotes multipolar spindle formation. We identify NuMA as a SUMO E1-dependent substrate and demonstrate that mitotic defects caused by SAE2-K164Q or HDAC6 inhibition are rescued by SUMO1 overexpression or expression of a GFP-SUMO1-NuMA-K1766R fusion. These results support a model in which SAE1:SAE2 deacetylation during early mitosis promotes SUMO1 conjugation to ensure mitotic fidelity, highlighting a regulatory role for the SUMO-activating enzyme in the selection of SUMO proteins.

Humans↗

PubMed2026

Heterologous expression of DobHLH25 from Dendrobium officinale enhances drought tolerance in Arabidopsis.

Drought stress severely constrains the growth, yield, and accumulation of bioactive compounds in Dendrobium officinale (D. officinale), a valuable medicinal orchid, and this challenge is exacerbated under simulated wild cultivation where plants are inevitably exposed to recurring water deficits. Basic helix-loop-helix (bHLH) transcription factors are well-established regulators of plant abiotic stress responses. However, the molecular mechanisms by which bHLH transcription factors respond to drought stress in this species remain largely unknown. In this study, a bHLH transcription factor gene, DobHLH25, was cloned from D. officinale. Phylogenetic analysis revealed that DobHLH25 shares the highest sequence identity with its ortholog in Dendrobium nobile. Additionally, subcellular localization analysis indicated that DobHLH25 is targeted to the nucleus and possesses a functional transcriptional activation domain. Expression pattern analysis showed that DobHLH25 is most abundantly expressed in old leaves, and its expression in roots, stems, and leaves is induced by polyethylene glycol treatments. Heterologous expression of DobHLH25 in Arabidopsis thaliana resulted in higher seed germination rates and longer root lengths under mannitol-induced osmotic stress compared to wild-type plants. Under drought stress, DobHLH25 heterologous expression lines exhibited higher survival rates, reduced leaf water loss, lower malondialdehyde accumulation, and increased proline content. Moreover, the activities of antioxidant enzymes such as superoxide dismutase and peroxidase were significantly enhanced, and the expression levels of multiple drought-responsive genes were markedly upregulated. Collectively, these findings suggest a correlation between DobHLH25 expression and plant drought tolerance, as evidenced by reduced oxidative damage, increased osmolyte accumulation, enhanced antioxidant enzyme activities, and upregulation of drought-responsive genes. Together, these results suggest that DobHLH25 plays a positive role in drought tolerance, and provides a basis for future dissection of its regulatory network in D. officinale.

Drought Resistance↗

PubMed2026

Integrated physiological and transcriptomic analyses reveal coordinated gill responses to heat stress in pikeperch (Sander lucioperca).

Climate change-driven warming of aquatic environments has made thermal stress an increasingly important factor influencing fish physiological homeostasis. Given their central roles in respiration and osmoregulation, gills are particularly responsive to variations in ambient temperature. Histological examination, physiological measurements, and transcriptome profiling were integrated to investigate the mechanisms associated with heat stress-induced gill injury in pikeperch (Sander lucioperca). Histological analysis revealed that exposure to 29 °C directly caused structural damage to the gills of pikeperch. Oxidative status was evaluated by measuring malondialdehyde (MDA) levels and the activities of antioxidant enzymes, including superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT). MDA accumulation was significantly enhanced under heat stress, while antioxidant enzyme activities (SOD, POD, and CAT) displayed a transient increase followed by a subsequent decline. Transcriptome profiling showed marked enrichment of the protein processing in endoplasmic reticulum pathway after heat stress, suggesting activation of endoplasmic reticulum (ER) stress in pikeperch gills. With increasing stress duration, the unfolded protein response (UPR) appeared unable to re-establish ER homeostasis, shifting ire1 and atf6 toward a pro-apoptotic state. Protein-protein interaction (PPI) analysis further highlighted hub genes potentially involved in heat stress-induced ER stress and apoptosis. TUNEL staining and western blotting collectively confirmed that heat stress triggered apoptosis in pikeperch gill tissue. Overall, this study provides new insights into the physiological and molecular responses of pikeperch gills to heat stress and enhances our understanding of thermal stress adaptation in cold-water aquaculture species under climate change.

Animals↗

PubMed2025

Pharmacogenomic Assessment of Genes Implicated in Thiopurine Metabolism and Toxicity in a UK Cohort of Pediatric Patients With Inflammatory Bowel Disease.

BACKGROUND: Thiopurine drugs are effective treatment options in inflammatory bowel disease and other conditions but discontinued in some patients due to toxicity. METHODS: We investigated thiopurine-induced toxicity in a pediatric inflammatory bowel disease cohort by utilizing exome sequencing data across a panel of 46 genes, including TPMT and NUDT15. RESULTS: The cohort included 487 patients with a median age of 13.1 years. Of the 396 patients exposed to thiopurines, myelosuppression was observed in 11%, gastroenterological intolerance in 11%, hepatotoxicity in 4.5%, pancreatitis in 1.8%, and "other" adverse effects in 2.8%. TPMT (thiopurine S-methyltransferase) enzyme activity was normal in 87.4%, intermediate 12.3%, and deficient in 0.2%; 26% of patients with intermediate activity developed toxicity to thiopurines. Routinely genotyped TPMT alleles associated with defective enzyme activity were identified in 28 (7%) patients: TPMT*3A in 4.5%, *3B in 1%, and *3C in 1.5%. Of these, only 6 (21%) patients developed toxic responses. Three rare TPMT alleles (*3D, *39, and *40) not assessed on routine genotyping were identified in 3 patients, who all developed toxic responses. The missense variant p.R139C (NUDT15*3 allele) was identified in 4 patients (azathioprine 1.6 mg/kg/d), but only 1 developed toxicity. One patient with an in-frame deletion variant p.G13del in NUDT15 developed myelosuppression at low doses. Per-gene deleteriousness score GenePy identified a significant association for toxicity in the AOX1 and DHFR genes. CONCLUSIONS: A significant association for toxicity was observed in the AOX1 and DHFR genes in individuals negative for the TPMT and NUDT15 variants. Patients harboring the NUDT15*3 allele, which is associated with myelosuppression, did not show an increased risk of toxicity.

Humans↗

PubMed2026

Quercetin, a flavonoid, suppresses viral proliferation by interfering with the ubiquitin transfer from E1 to E2 enzymes.

Quercetin is recognized for diverse pharmacological activities. However, the mechanism underlying its broad-antiviral effects has not been elucidated. Herein, we identified quercetin as a potent inhibitor of both double-stranded DNA virus Bombyx mori nucleopolyhedrovirus (BmNPV) and single-stranded RNA virus porcine reproductive and respiratory syndrome virus (PRRSV). Surface plasmon resonance (SPR) revealed that quercetin targets host ubiquitin-activating enzyme 1 (Uba1) homologs. Uba1 knockdown reduced viral proliferation and enhanced the antiviral effect of quercetin, whereas Uba1 overexpression functioned oppositely. Quercetin bound Uba1 homologs with high affinity. Notably, mutation of two binding residues, Q977 and G978, significantly disrupted the binding between BmUba1 and quercetin, and abolished quercetin's antiviral activity. Quercetin obstructed the transfer of ubiquitin from Uba1 to the E2 enzyme Ubc6, impairing the ubiquitination process. Similarly, quercetin inhibited PRRSV proliferation via targeting Uba1 in mammals. These findings elucidate the molecular mechanism underlying the pharmacological effects of quercetin, providing a theoretical basis for the development of novel antiviral agents against both DNA and RNA viruses.

Quercetin↗

PubMed2018

Carnation I locus contains two chalcone isomerase genes involved in orange flower coloration.

Carnations carrying a recessive I gene show accumulation of the yellow pigment chalcononaringenin 2'-glucoside (Ch2'G) in their flowers, whereas those with a dominant I gene do accumulation the red pigment, anthocyanin. Although this metabolic alternative at the I gene could explain yellow and red flower phenotypes, it does not explain the development of orange flower phenotypes which result from the simultaneous accumulation of both Ch2'G and anthocyanin. The carnation whole genome sequencing project recently revealed that two chalcone isomerase genes are present, one that is consistent with the I gene (Dca60979) and another (Dca60978) that had not been characterized. Here, we demonstrate that Dca60979 shows a high level of gene expression and strong enzyme activity in plants with a red flower phenotype; however, functional Dca60979 transcripts are not detected in plants with an orange flower phenotype because of a dTdic1 insertion event. Dca60978 was expressed at a low level and showed a low level of enzyme activity in plants, which could catalyze a part of chalcone to naringenin to advance anthocyanin synthesis but the other part remained to be catalyzed chalcone to Ch2'G by chalcone 2'-glucosyltransferase, resulting in accumulation of anthocyanin and Ch2'G simultaneously to give orange color.

I gene↗

PubMed2025

Identifying novel heterozygous PI4KA variants in fetal abnormalities.

BACKGROUND: The clinical manifestations of PI4KA-related disorders are characterized by considerable variability, predominantly featuring neurological impairments, gastrointestinal symptoms, and a combined immunodeficiency. The aim of this study was to delineate the novel spectrum of PI4KA variants detected prenatally and to assess their influence on fetal development. METHODS: A thorough fetal ultrasound screening was conducted, supplemented by both antenatal and post-abortion magnetic resonance imaging (MRI) studies. Novel PI4KA variants were detected through clinical Whole exon sequencing (WES) and validated by Sanger sequencing. The functional consequences of these variants were evaluated using bioinformatics tools. The effects of the identified variants on splicing were analyzed through minigene splicing assays. Subsequently, both wild-type and mutant PI4KA protein fragments were purified, and their enzymatic activities were quantitatively assessed. RESULTS: Ultrasound imaging, MRI scans revealed a dilated small intestine with an obstruction. Compound heterozygous variants (NM_058004.3: c.2802_2863-40del and c.2819 C > T, p.Ala940Val) were identified in the PI4KA of the affected fetus through clinical trio-WES. Both variants were predicted deleterious. The PI4KA variant c.2802_2863-40del resulted in the production of three distinct mRNA isoforms. The PI4KA variant c.2819 C > T (p.Ala940Val) significantly reduced the enzyme activity. CONCLUSIONS: This study extended the mutational spectrum of PI4KA and may provide guidance for genetic counseling. Functional studies confirmed that the identified variant induces alterations in RNA splicing and impairs enzyme activity.

Adult↗