Messenger RNA levels, crucial for cell survival and adaptation, are regulated through their degradation by ribonucleases (RNases). Although the molecular mechanisms of RNases in Escherichia coli are established, the broader effects of RNases on growth and metabolism remain unclear. Here, the roles of three RNases, E, II, and R, were examined individually and in combination in double and triple mutants. Growth behaviors and metabolic changes were analyzed on different carbon sources and under recombinant protein production conditions. C-terminal truncation of RNase E was unexpectedly found to have strong effects, promoting carbon-storage metabolism, thereby leading to glycogen accumulation, especially with glucose as a carbon source. Even more surprisingly, it accelerated growth on xylose. Synergistic interactions between the three RNases were also identified. Deleting RNase R amplified glycogen accumulation in the RNase E mutant, and further increased its growth rate. All three RNases were found to significantly contribute to acetate overflow regulation, with synergy between RNase E and R. Combined mutations had additional benefits under protein production conditions. Compared with the parental strain, the double mutant with both RNase E truncation and RNase II deletion produced up to twice as much recombinant protein, grew faster on xylose, and produced more glycogen on glucose. Overall, this work shows that RNase E, II, and R act both independently and synergistically in controlling E. coli growth and metabolism across carbon sources and bioproduction conditions. These findings highlight the strong relationship between RNA degradation and cell physiology and offer perspectives for engineering optimized microbial chassis in biotechnology. Messenger RNA degradation is a fundamental layer of gene regulation; however, its system-level impact on bacterial physiology remains poorly understood. Here, we show that RNase E, RNase II, and RNase R act both independently and synergistically to control Escherichia coli growth and metabolism across diverse carbon sources and bioproduction conditions. Unexpectedly, C-terminal truncation of RNase E, either alone or in combination with RNase II or RNase R, modulates glycogen and acetate metabolism and improves growth performance. Enhanced recombinant protein production was also observed, and the underlying mechanism was investigated. By directly linking the RNA degradation machinery to metabolic regulation and cellular performance, this work highlights RNases as powerful and underexploited targets for engineering improved microbial chassis for biotechnology.
Kashin-Beck disease (KBD) is an endemic osteoarthropathy characterized by chondrocyte death and extracellular matrix (ECM) degradation; however, the underlying molecular mechanisms remain poorly understood. This study aimed to explore whether glutathione peroxidase 6 (GPx6) is involved in regulating ferroptosis and matrix degradation in KBD cartilage injury. In articular cartilage from children with KBD, GPx6 expression was markedly reduced, particularly in the deep zone where chondrocyte death and matrix loss were most severe. Similarly, downregulation of GPx6 was observed in a T-2 toxin‑induced rat model and in C28/I2 chondrocytes, accompanied by decreased COL2A1 and ACAN levels and increased expression of MMP13 and ADAMTS4. Molecular docking indicates a potential interaction between T-2 toxin and GPx6. Gpx6 knockout mice exhibited signs of ECM degradation in articular cartilage, along with an enhanced susceptibility to T-2 toxin exposure. Mechanistically, Gpx6 deficiency led to elevated MDA levels, reduced SOD activity and GSH/GSSG ratio, as well as mitochondrial shrinkage, cristae loss, and lipid peroxidation. Knockdown of GPX6 suppressed the expression of SLC7A11, SLC3A2, and GPx4, while Ferrostatin‑1 partially reversed these ferroptosis‑related alterations but failed to restore GPx6 expression. Conversely, overexpression of GPX6 partially restored the function of the SLC7A11/GPx4 axis, improved redox balance, attenuated mitochondrial lipid peroxidation, and mitigated matrix degradation. Collectively, these findings suggest that downregulation of GPx6 may be closely associated with ferroptosis in KBD chondrocytes, and that GPx6 may serve as a potential upstream regulator of this process. Furthermore, dysregulation of the GPx6‑SLC7A11/GPx4 pathway may also be involved in the pathological process of cartilage injury in KBD.
Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries, with incidence rising in parallel with obesity, insulin resistance, and type 2 diabetes (T2DM). EC exhibits characteristic metabolic vulnerabilities, including hyperactive glycolysis, mitochondrial dysfunction, and PI3K/AKT/mTOR pathway activation, driven by unopposed estrogen stimulation and systemic metabolic dysregulation. Metformin, a first-line antidiabetic agent and mitochondrial complex I inhibitor, has emerged as a promising repurposed drug for EC prevention and treatment through dual mechanisms: direct tumor suppression via AMPK/mTOR, PI3K/Akt, Wnt/β-catenin, and endoplasmic reticulum stress pathways; and indirect metabolic microenvironment improvement via insulin sensitization, sex hormone-binding globulin upregulation, and immune microenvironment remodeling. This narrative review comprehensively summarizes available preclinical mechanistic insights and published clinical evidence across EC disease spectrum: chemoprevention in high-risk populations (obesity, PCOS), fertility-preserving treatment for early-stage disease, and combination strategies for advanced/recurrent EC. We synthesize existing data rather than adopting formal systematic review methodology with predefined database retrieval and PRISMA-compliant screening criteria. We critically analyze survival outcomes, response heterogeneity contingent upon diabetic status and molecular subtypes, and current bottlenecks in biomarker-guided patient selection. Furthermore, we propose translational strategies for precision application: LKB1/PTEN status-based patient stratification, innovative combinations with CDK4/6 inhibitors, mTOR inhibitors, and immune checkpoint inhibitors, and clinical pathway optimization. By bridging metabolic endocrinology and gynecologic oncology, the available data provide preliminary theoretical basis to explore future shift of metformin from empirical off-label reuse toward biomarker-guided individualized medication, which still needs large-scale prospective validation.
Methylated amines (MAs) are ubiquitous in the marine environment, constituting an important part of the marine dissolved organic nitrogen pool and contributing to the formation of cloud condensation nuclei in the marine atmosphere. The aerobic trimethylamine (TMA) oxidation pathway represents the primary route for TMA utilization in marine environments and has been characterized in the model marine Roseobacter group bacterium Ruegeria pomeroyi DSS-3. However, the regulatory mechanism underlying this pathway has remained unclear. Transcriptome analysis revealed coordinated induction of the entire pathway by all intermediate MAs. We identified a master regulator, TmaR, which is essential for the growth of R. pomeroyi DSS-3 on any MA. TmaR functions as an activator of tdm and its downstream enzymatic genes, and as a mild repressor of tmm. It regulates target gene transcription by directly binding to their promoter regions and responds to further catabolite(s) derived from MMA. Another regulator, TmoR, acts as a strong repressor of tmm by binding to its promoter. The tmaR gene is widely distributed among alpha- and gamma-proteobacteria, and in most cases, it is located within MA catabolic gene clusters. Together, these results identify a master regulator of TMA catabolism in globally abundant marine bacteria.IMPORTANCETrimethylamine (TMA) is a key marine nitrogen source; however, its catabolic regulation remains poorly understood. This study identifies TmaR as the master transcriptional regulator of the TMA catabolic pathway in abundant marine bacteria. TmaR is essential for growth on all methylated amines, directly activating downstream genes' transcription while repressing the initial tmm gene, and responds to downstream MMA catabolite(s). This coordinated regulation enables efficient nitrogen acquisition from mixed methylamine substrates, a common marine scenario. Homologs of TmaR are widespread among marine Alpha- and Gammaproteobacteria, indicating a conserved regulatory strategy for a globally significant biogeochemical process. Our findings provide crucial molecular insight into ocean nitrogen cycling.
Methylation of DNA, histones, and RNA is central to the regulation of circadian rhythms, yet the biochemical origin of the methyl groups driving these modifications has received comparatively little attention in circadian biology. This review explores the bidirectional crosstalk between the methyl cycle and the mammalian circadian clock. We describe how S-adenosylmethionine-dependent epigenetic and epitranscriptomic modifications constitute essential layers of circadian gene regulation, and how the clock orchestrates the rhythmic expression of one-carbon metabolism enzymes and oscillations in S-adenosylmethionine availability. The direct interaction between the S-adenosylhomocysteine hydrolase AHCY and the core clock component BMAL1 at circadian gene promoters emerges as a molecular nexus linking methyl group supply to clock-driven transcription. We further discuss how the methyl cycle occupies a privileged position within the circadian entrainment hierarchy, acting as both a target of nutritional zeitgebers in peripheral tissues and a potential source of metabolic feedback to the central pacemaker, and how dietary perturbation of the methyl cycle disrupts circadian rhythms. Finally, we discuss how this crosstalk is implicated in metabolic liver disease, cancer, neurological disorders, and aging. Together, these findings position the circadian clock as a sensitive readout of nutritional methyl metabolic status, with broad implications for chronobiology and nutrigenomics.
Copper is an essential micronutrient required for mitochondrial respiration, antioxidant defense, and metabolic homeostasis. Accumulating evidence demonstrates that dysregulated copper handling, including deficiency, redistribution, or overload, is a reproducible feature of multiple cardiometabolic disorders, including heart failure, diabetes mellitus, obesity, and NAFLD/MASLD. Human, animal, and cellular studies consistently implicate altered copper trafficking and compartmentalization in mitochondrial dysfunction, oxidative stress, and tissue remodeling across these conditions. The recent identification of cuproptosis, a copper-dependent form of regulated cell death characterized by mitochondrial copper binding to lipoylated tricarboxylic acid cycle enzymes, has expanded mechanistic understanding of copper toxicity in cancer. However, the defining molecular hallmarks of canonical cuproptosis, including lipoylated protein aggregation, iron-sulfur cluster loss, and respiration-dependent cell death, have not yet been demonstrated in vivo in cardiometabolic tissues. Accordingly, cuproptosis is discussed here as a testable mechanistic hypothesis rather than an established driver of cardiometabolic pathology. In this review, we synthesize current evidence for copper dysregulation in cardiometabolic disease and carefully distinguish established copper-dependent pathology from speculative cuproptotic mechanisms. We explicitly address the apparent paradox that the cardiac tissue context in cardiometabolic disease is dominated by a copper-deficient phenotype, which is the opposite of the mitochondrial copper-loading state required for canonical cuproptosis, and reconcile this through the concept of intracellular copper redistribution and tissue-selective susceptibility. We evaluate clinical and preclinical studies of copper-modulating therapies with attention to tissue specificity and safety, and we outline a framework for rigorously testing cuproptosis in vivo using convergent molecular, functional, and clinical criteria. Together, this review clarifies what is known about copper biology in metabolic disease and defines the experimental standards required to determine whether cuproptosis contributes to these conditions.
To date, findings have denoted that disrupted meal timing and eating during biologically inappropriate hours are associated with an increased risk of adverse cardiometabolic outcomes among shift workers. However, solid evidence remains lacking due to the small number of clinical studies and low methodological quality. This review investigated how an intervention targeting shift workers' meal timing affects cardiometabolic markers. The MEDLINE, Cochrane Library, Web of Science, Embase, CINAHL Complete, and Scopus were searched using a predefined search strategy. Only randomized controlled trials of adults aged ≥18 under a shift work environment were included. Four trials met the inclusion criteria. Three studies assigned fasting periods during the night shift, ranging between 19:45 and 06:30 h, and one study used 10-h self-selected Time-Restricted Eating (TRE). A 10 h self-selected TRE reported a significantly lower VLDL-C particle size compared with the control group. Four studies reporting fasting insulin levels and homeostatic model assessment of insulin resistance observed a significant change in one trial after an 8.5-h overnight fast. No studies pointed to significant changes in HDL-C. In the postprandial measurement, 10.75 h of night fasting showed significantly lower glucose AUC, non-esterified fatty acids AUC, and 2-h glucose than in the meal- and snack-at-night group. Body weight was slightly lower after a short overnight fast. The scarcity of trials investigating mealtime interventions and cardiometabolic markers among shift workers limits the generalizability of the findings and raises concerns regarding the robustness of the preliminary positive outcomes. Therefore, more trials with larger sample sizes and longer study durations are required, given the limited number of studies.
Water scarcity in arid and desert regions critically threatens agricultural sustainability. We report a cellulose-based superabsorbent hydrogel achieving an ultrahigh water absorption ratio exceeding 20,000 wt %, the highest among all reported cellulose hydrogel systems. It retains ∼82% of its swelling capacity after five wet-dry cycles, demonstrating outstanding recyclability. In desert sand at 40 °C, just 3 wt % hydrogel sustained over 10% residual moisture for 48 h without irrigation. Swelling followed a quasi-second-order model with dual-phase diffusion, enabling rapid hydration and controlled water release. Hydrogel-amended sand markedly enhanced Triticum aestivum seedling drought resilience, extending wilting time by 5-7 days. Biodegradable and recyclable, this hydrogel simultaneously boosts soil moisture retention, respiration rate, microbial activity, and crop stress tolerance, offering a powerful, sustainable strategy for agriculture and ecological restoration in water-limited regions.
Ferroptosis is a newly defined form of programmed cell death and is associated with the progression of colorectal cancer (CRC). Abnormal levels of N6-methyladenosine (m6A) modification are frequently identified in CRC, but its regulation of ferroptosis is still unclear. In this study, we report that the m6A modification modulates ferroptotic susceptibility to inhibit CRC progression by targeting m6A-YTHDF2-mediated regulation of MUC1 mRNA stability. CRC cell lines were treated with ferroptosis inducers, and m6A methylation assay kit and dot blot were employed to assess m6A methylation status. Transcriptomic sequencing and immunoprecipitation were employed to elucidate the molecular mechanisms by which m6A modification modulates ferroptotic susceptibility. The CRC mouse tumor models were used to validate the regulatory mechanisms of m6A methylation on ferroptosis in vivo. The CRC patient-derived organoid models (PDOs) were applied to determine the regulatory role of m6A methylation-mediated ferroptosis. Clinical CRC specimens were analyzed to evaluate the relationship between m6A modification and ferroptosis. The upregulation of METTL3 and downregulation of FTO enhanced m6A methylation levels, while disruption of m6A methylation conferred resistance to ferroptosis in CRC cells. Mechanistic investigations through transcriptome sequencing and bioinformatics identified MUC1 as a key target for m6A methylation regulation of ferroptosis. YTHDF2 promoted the decay of MUC1 mRNA by recognizing the m6A-binding site at A1078 within 3'UTR regions, which can inhibit the function of SLC7A11 and thereby enhance susceptibility to ferroptosis. Ferroptosis inducer erastin augmented YTHDF2-mediated ferroptotic susceptibility to inhibit the growth of CRC by suppressing MUC1/SLC7A11 signaling in PDOs. Clinically, YTHDF2 was negatively correlated with MUC1 expression in CRC specimens, which was associated with poor prognosis. Our findings unveil a crucial mechanism through which YTHDF2 facilitates ferroptotic susceptibility via MUC1 destabilization and subsequent SLC7A11 downregulation. These discoveries open up new possibilities for ferroptosis-regulated therapeutics by offering targets and approaches for the treatment of CRC.
High risk human papillomavirus (HPV) infection and genome integration with pronounced expression of the viral E6/E7 oncogenes is the major cause of cervical cancer. Emerging evidence suggests that HPV reprograms host metabolism to support viral persistence and cellular transformation. However, global HPV oncogene-induced lipidomic reprogramming remains poorly understood, particularly at early stages of HPV-induced transformation. We sought to define the regulation of lipid metabolism in squamous epithelia of transgenic mice expressing the HPV16 oncogene E6 alone or in conjunction with E7. Untargeted lipidomics was used to identify novel lipid biomarkers in the skin and female reproductive tract (FRT) of HPV16 E6 and E6/E7 transgenic compared to wild-type (WT) mice. To investigate enzymatic dysregulation of lipids by HPV oncogene expression, we employed Lipid Network Explorer (LINEX2), which analyzes lipidomics data through lipid enrichment analysis. We also used the Global Natural Product Social Molecular Networking (GNPS) platform to enhance lipid identification, exploring molecular networking to improve feature annotation. Our lipidomic analysis produced several new observations. First, E6 expression caused a consistent alteration of glycerophospholipids, with particularly significant substrate-product shifts in the phosphatidylcholine (PC) to lysophosphatidylcholine (LPC) pathway in the skin. Second, E6/E7 expression caused a dysregulation of glucosylceramide (GlcCer) biosynthesis. Third, both E6/E7 expressing skin and FRT tissues exhibited a redox imbalance and increased levels of oxidized lipids, including oxylipins and several oxidized PCs. These findings suggest that HPV oncoproteins drive lipid reprogramming, potentially contributing to early HPV-related tumorigenesis. These findings provide new insights into HPV‑induced lipid reprogramming and establish a framework for future studies examining the functional and clinical relevance of lipid alterations in HPV‑associated cancers.
Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease caused by dystrophin deficiency and characterized by progressive muscle wasting. DMD is frequently accompanied by obesity and insulin resistance (IR); however, their influence on disease progression remains unknown. Moreover, the extent to which these comorbidities may interact with glucocorticoids, a commonly used intervention, is also unknown. We hypothesized that a high-fat, high-sucrose diet (HFHSD) would cause IR and accelerate disease progression, and treatment with prednisolone (Pred) would mitigate these effects. To test this hypothesis, 6-week-old C57 and mdx mice were fed a control diet (CD) or a HFHSD for 19 weeks, with or without Pred. In C57 and mdx mice, the HFHSD increased body fat percentage and caused hyperglycaemia, glucose intolerance and IR, and, in mdx mice, Pred exacerbated HFHSD-mediated hyperglycaemia, glucose intolerance and IR. The HFHSD augmented diaphragm fatigue and blunted the beneficial effects of Pred on specific tension in mdx mice. In C57 and mdx mice, the HFHSD increased fatty infiltration in diaphragm, but trichrome staining revealed the HFHSD and/or Pred decreased disease-related fibrosis in mdx mice. Additionally, the HFHSD altered disease and/or Pred-mediated changes to proteins associated with lipid storage, inflammatory signalling, mitochondrial/metabolic regulation, and Sestrin signalling. These data indicate that in mdx mice, 19 weeks of a HFHSD independently impaired muscle function, altered muscle composition, and further compromised muscle cell health, and that its interaction with Pred prevented functional recovery and further exacerbated glycaemic dysregulation and cellular dysfunction. KEY POINTS: Obesity and insulin resistance (IR) are common comorbidities of Duchenne muscular dystrophy (DMD), yet their influence on dystrophic pathology remains unknown. Additionally, the extent that obesity/IR interact with glucocorticoids in dystrophic progression is unclear. To address this, mdx mice were fed a high-fat, high-sucrose diet (HFHSD) for 6 months, with and without glucocorticoid treatment, and outcomes related to muscle function, composition, and cell health were evaluated. A HFHSD decreased fatigue resistance, reduced fibrosis, increased fatty infiltration, and impaired cell health in dystrophic diaphragms. The addition of glucocorticoids to the HFHSD did not considerably improve most outcomes, suggesting that the diet may blunt some glucocorticoid-mediated benefits, but did increase specific tension, reduce fibrosis, and attenuate inflammatory signalling. These results demonstrate that a HFHSD impacts some parameters of dystrophic physiology and highlight the importance of considering systematic and muscle metabolism when implementing therapeutic strategies.
Estrogen-related receptor γ (ERRγ) is an orphan nuclear receptor whose molecular functions in transcriptional regulation remain incompletely understood. The androgen receptor (AR) is a ligand-dependent transcription factor that plays a pivotal role in prostate cancer by regulating gene expression through androgen-response elements. Its activity is tightly controlled by receptor conformation and coactivator recruitment. Although ERRγ has been implicated in the suppression of prostate cancer progression, whether it modulates AR signaling remains unclear. In this study, we examined the functional and molecular interplay between ERRγ and AR using a heterologous expression system in HeLa cells. We found that ERRγ suppresses AR-mediated transcriptional activation in a dose-dependent manner on ARE-containing promoters. Mechanistically, ERRγ interacted with ligand-activated AR in the nucleus and disrupted the intramolecular interaction between the N-terminal domain (NTD) and the C-terminal ligand-binding domain (LBD), which is required for full receptor activation. This interference did not affect AR nuclear translocation. Furthermore, ERRγ functionally competed with major transcriptional coactivators, including steroid receptor coactivators-3 (SRC-3) and p300, thereby attenuating coactivator-enhanced AR-dependent transcription. Collectively, these findings demonstrate that ERRγ functions as a novel corepressor of AR by destabilizing receptor conformation and blocking coactivator recruitment, providing new mechanistic insights into the regulation of AR-mediated transcription.
Hyperlipidemia (HYL) and hyperglycemia (HYG) directly drive pathological cardiac remodeling; however, the mechanisms by which these conditions differentially regulate profibrotic signaling and early stress‑response pathways in left ventricular (LV) myocardium remain poorly defined. This study investigated the expression and localization of galectin-3 (Gal-3), transforming growth factor-β1 (TGF-β1), and brain natriuretic peptide (BNP) in a Yucatan miniswine model of HYL and HYG. Female Yucatan miniswine were assigned to normal control, HYL (high-cholesterol diet), or HYG (high-fat/high-carbohydrate diet plus low dose streptozotocin) groups (n = 6/group) for 8-weeks, and LV tissue was assessed by histology, qRT-PCR, Western blot, and immunohistochemistry. Both metabolic conditions induced cardiomyocyte hypertrophy and interstitial fibrosis, with more diffuse collagen deposition in HYG myocardium. qRT-PCR demonstrated upregulation of Gal-3, TGF-β1, and BNP relative to controls, with transcript levels positively correlating with circulating glucose concentration. Western blot analysis showed relatively greater active TGF-β1 signal in HYL myocardium and greater latent precursor accumulation in HYG myocardium, suggesting condition-associated differences in TGF-β1 regulation. Immunohistochemistry demonstrated perivascular Gal-3 localization, cytoplasmic and perinuclear TGF-β1 immunoreactivity in cardiomyocytes, and BNP immunoreactivity predominantly within subendocardial Purkinje fibers, with increased staining intensity in metabolically stressed groups compared with controls. Collectively, these findings suggest that HYL and HYG are associated with overlapping but distinct patterns of Gal-3, TGF-β1, and BNP expression during metabolic cardiac remodeling. The Gal-3/TGF-β1 axis may represent a shared profibrotic pathway, whereas BNP may reflect a compensatory stress response whose functional significance requires further mechanistic validation.
Obstructive sleep apnea (OSA) is frequently complicated by hypertension, with approximately 60% of patients exhibiting both conditions. However, the epigenetic mechanisms underlying this comorbidity remain largely unexplored. N6-methyladenosine (m6A), the most abundant internal RNA modification, has emerged as a critical regulator of cardiovascular pathology, yet its role in OSA-associated hypertension (OSA-HTN) is unknown. Here, we investigated the contribution of m6A RNA methylation to OSA-HTN pathogenesis. In a chronic intermittent hypoxia (CIH) mouse model and hypoxia-stimulated aortic vascular smooth muscle cells (AVSMCs), we observed marked inflammatory injury, pyroptosis, and decreased expression of methyltransferase-like 3 (METTL3) along with global m6A levels. Overexpression of METTL3 significantly attenuated hypoxia-induced pyroptosis and inflammation by downregulating SRY-box transcription factor 4 (SOX4), a pro-inflammatory transcription factor. Mechanistically, CIH suppressed YTH N6-methyladenosine RNA-binding protein 2 (YTHDF2), an m6A reader that directly binds SOX4 mRNA, while METTL3-mediated m6A modification enhanced YTHDF2-dependent SOX4 mRNA degradation. Knockdown of YTHDF2 abolished the suppressive effect of METTL3 on SOX4 stability, confirming a METTL3-m6A-YTHDF2 regulatory axis. This METTL3-dependent regulation of YTHDF2-SOX4 interaction and SOX4 mRNA decay was also validated in mouse aortic endothelial cells. Furthermore, in vivo silencing of SOX4 alleviated CIH-induced pyroptosis and inflammation in cardiac and aortic tissues. Notably, pharmacological activation of METTL3 or METTL3 overexpression similarly attenuated CIH-induced cardiac and aortic tissue injury in OSA-HTN mice. In conclusion, our findings identify a novel METTL3-YTHDF2-SOX4 axis that governs hypoxia-induced pyroptosis and inflammation, providing new mechanistic insights into the epigenetic regulation of OSA-HTN and highlighting potential therapeutic targets.
Signal transducer and activator of transcription 5B (STAT5B) plays a critical role in milk protein synthesis in mammals. However, its transcriptional regulatory mechanisms in buffalo, particularly in Binglangjiang buffalo, a breed characterized by high milk protein content, remain largely unclear. The study isolated and identified the functional STAT5B transcript variant in lactating buffalo mammary gland tissues. Expression analysis revealed that STAT5B was significantly upregulated in lactating buffalo mammary epithelial cells (BuMECs) compared with non-lactating BuMECs, suggesting its potential involvement in lactation regulation. Subcellular localization analysis confirmed that STAT5B was distributed in both the nucleus and cytoplasm of BuMECs, providing a structural basis for its transcriptional regulatory function. Importantly, functional experiments identified a novel positive feedback loop between ELF5 and STAT5B, through which STAT5B promoted casein synthesis in BuMECs. The findings significantly expand our understanding of STAT5B-mediated transcriptional regulation in ruminants and enrich the molecular regulatory network of milk protein synthesis in buffalo. These findings provide important theoretical support and potential molecular targets for genetic improvement of milk protein content in the buffalo dairy industry. STAT5B is critical for buffalo milk protein synthesis, while its regulatory mechanism remained unknown. The study identified a functional STAT5B variant in lactating buffalo mammary glands that promotes casein synthesis and cell proliferation via JAK2-STAT5 and mTOR pathways, and uncovered a novel ELF5-STAT5B positive feedback loop. These findings provide a theoretical basis for enhancing buffalo milk quality and improving milk nutritional value to meet consumer demands.
Domestication has profoundly transformed human production and lifestyles. The Qingtian rice-fish co-culture system is the first globally important agricultural heritage system (GIAHS). PF-carp are a key species in the Qingtian rice-fish system and have been domesticated in rice paddies for more than a millennium, yet the mechanisms of their tolerance to high temperature conditions remain unresolved. In this study, 28℃ as the control group (C0), and two heat stress groups were established at 38℃ for 0 h (H0) and 24 h (H24). Brain tissues were sampled for physiological index measurements and transcriptomic analysis. Physiological analyses showed that the activities of SOD, CAT, and GSH-Px increased initially and then declined, whereas MDA levels exhibited a continuous increase. Transcriptome profiling identified 9,825 differentially expressed genes (DEGs). KEGG enrichment analysis of DEGs indicated that immune responses and metabolic regulation were consistently involved throughout the thermal adaptation process. During acute warming phase, pathways such as protein processing in the endoplasmic reticulum, FoxO signaling pathway and glycerophospholipid metabolism were enriched. Under prolonged high temperature exposure, cytokine-cytokine receptor interaction, PPAR signaling pathway and TGF-β signaling pathway were prominently enriched. Within these pathways, genes including grp94, hsp70, bip, nef, il-1r, tlr8, cctgα6, ccr4, cxcr3, and il-10 were significantly up-regulated (p < 0.05). These results indicate that PF-carp exhibit coordinated brain physiological and transcriptomic responses to high temperature exposure, involving protein quality control, immune signaling, and metabolic regulation. Collectively, our findings provide new insights into the mechanisms by which PF-carp adapt to thermal exposure and provide theoretical support for the breeding of heat tolerant fish.
Simultaneous detection of biologically relevant thiols and toxic heavy metal ions is important for biomedical analysis, food safety, and environmental monitoring. Cysteine (Cys) is a key sulfur-containing amino acid involved in redox regulation, whereas mercury(II) (Hg2⁺) is a highly toxic pollutant that binds strongly to thiol groups. This Hg2⁺-thiol interaction provides a chemical basis for sequential Cys/Hg2⁺ sensing. However, many nanozyme-based optical assays rely on H₂O₂-dependent peroxidase-like activity, and the instability of H₂O₂ can compromise assay reproducibility and practical use. Here, we synthesized a core-shell Fe₃C@NC nanozyme through a two-step hydrothermal-calcination strategy. Fe₃C nanoparticles were encapsulated within a nitrogen-doped carbon shell to support stable oxidase-like catalysis. Fe₃C@NC catalyzed the H₂O₂-independent oxidation of o-phenylenediamine to fluorescent 2,3-diaminophenazine using dissolved oxygen. This reaction was coupled with Cys-mediated signal inhibition and Hg2⁺-induced signal recovery to construct a sequential ON-OFF-ON dual-readout platform. Cys suppressed fluorescence by scavenging reactive oxygen species, whereas Hg2⁺ restored the signal through coordination with the thiol group of Cys. The fluorescence detection limits were 28 nM for Cys and 12 nM for Hg2⁺. Smartphone-assisted RGB analysis enabled portable visual quantification and showed good consistency with fluorescence measurements. The method was validated in human serum, milk, and environmental water samples, giving satisfactory recoveries and acceptable precision. This work presents an H₂O₂-free Fe₃C@NC nanozyme platform that links oxidase-like OPD oxidation with thiol-mediated signal regulation, providing a simple strategy for sensitive laboratory analysis and portable visual detection in complex samples.
Date fruit is a nutrient-dense and bioactive-rich fruit that has garnered attention for its dual role in athletic performance and sustainable nutrition. Naturally abundant in readily digestible carbohydrates, dietary fiber, essential minerals, vitamins, and polyphenolic compounds, dates provide rapid and sustained energy while supporting glycogen replenishment, oxidative stress mitigation, and metabolic regulation. These functional attributes make dates an ideal candidate for incorporation into sports nutrition products, such as energy bars and functional snacks, offering an alternative to refined carbohydrate supplements and synthetic formulations. The fortification of date-based products with plant proteins, cereals, nuts, seeds, or polyphenol-rich extracts further enhances protein quality, fiber content, antioxidant potential, and micronutrient density without compromising sustainability goals. Moreover, local sourcing, farm engagement, and community-supported agriculture provide educational, cultural, and ecological benefits, fostering mindful dietary behaviors and connecting athletes to their food systems. This review synthesizes recent advances on the chemical composition, functional properties, processing methods, and health-promoting effects of dates, highlighting their strategic potential to support both performance-driven sports nutrition and environmentally responsible diets. Future research should focus on quantifying the environmental impact of date-based functional foods, optimizing formulations for athlete recovery and performance, and translating these findings into practical dietary recommendations.
Cervical cancer continues to pose a considerable challenge to global health, necessitating innovative approaches for improved diagnostics and personalized treatment strategies. Prior investigations have suggested that plasma proteins may play a role in the pathogenesis of cervical cancer; however, these studies do not confirm a causal relationship. To address this gap, conducted a large-scale Mendelian randomization (MR) study of the plasma proteome. We performed a two-sample bidirectional Mendelian randomization analysis involving 4,907 plasma proteins, utilizing publicly accessible genome-wide association study (GWAS) summary statistics, to examine the causal association between the plasma proteome and the risk of cervical cancer. Analytical methods included inverse variance weighting (IVW), weighted median, MR-Egger regression, and simple and weighted models. Additionally, we performed sensitivity analyses to evaluate heterogeneity and horizontal pleiotropy through Cochran's Q test, MR-Egger intercept, MR-PRESSO test, and leave-one-out analysis. We also applied false discovery rate (FDR) correction to the results of all IVW methods to identify the plasma proteins most strongly associated with cervical cancer. Finally, we enriched the most relevant plasma protein genes using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses and GeneMANIA to identify disease-related pathways. According to the IVW method, seven plasma proteins are significantly associated with cervical cancer risk (P < 0.05). Specifically, six proteins demonstrated protective factors: DEFB135 (OR = 0.201, 95% CI = 0.082-0.492, P < 0.001), FGL2 (OR = 0.104, 95% CI = 0.032-0.338, P < 0.001), FTMT (OR = 0.612, 95% CI = 0.465-0.804, P < 0.001), PDIA4 (OR = 0.088, 95% CI = 0.026-0.295, P < 0.001), SPHK2 (OR = 0.102, 95% CI = 0.030-0.350, P < 0.001), and TMED2 (OR = 0.045, 95% CI = 0.008-0.246, P < 0.001). In contrast, RACGAP1 (OR = 1.755, 95% CI = 1.286-2.395, P < 0.001) was identified as a risk factor. Reverse MR analysis revealed no significant evidence of reverse causation (P > 0.05) between cervical cancer and these plasma proteins. Functional enrichment analysis identified several biologically relevant pathways potentially involved in cervical cancer pathogenesis, including the establishment of organelle localization, regulation of oxidoreductase activity, Ferroptosis, and Porphyrin metabolism. These findings suggest that DEFB135, FGL2, FTMT, PDIA4, SPHK2, and TMED2 may protect against cervical cancer, while RACGAP1 may represent a potential risk factor. The identified tumor markers provide mechanistic insights into the molecular basis of cervical cancer and warrant further investigation in functional studies.
Hepatocellular carcinoma (HCC) is a major health issue, but treatment options are limited. This study investigated the role of CCR4-NOT transcription complex subunit 9 (CNOT9) in the pathogenesis of HCC and its potential as a therapeutic target. Bioinformatics analysis was performed on RNA-seq data from the TCGA and GTEx databases to assess CNOT9 expression and prognostic significance. CNOT9 expression was validated in clinical samples and cell lines using qRT-PCR and Western blot. CNOT9 was knocked down in HCC cell lines, and its effects on proliferation, apoptosis, and cell cycle were investigated using functional assays (CCK-8, EdU, colony formation, and flow cytometry). The underlying molecular mechanisms were explored via RNA-seq and Western blot analysis of the AKT pathway and cell cycle regulators. Xenograft mouse models were used to confirm the oncogenic role of CNOT9 in vivo. CNOT9 mRNA and protein expression were upregulated in HCC patients and associated with poor prognosis. CNOT9 induces abnormal proliferation of HCC cells and G2/M phase cell cycle progression. Knocking down CNOT9 reduces cell proliferation, increases apoptosis, and causes cell arrest at the G2 phase. CNOT9 knockdown activates PTEN to inhibit the AKT pathway and suppresses the expression of cell cycle-related proteins p53, p21, CCNE1 and CDK2. CNOT9-deficient tumors exhibited reduced growth in mice, supporting its pro-oncogenic role. This study first elucidates the molecular mechanism by which CNOT9 drives HCC progression through post-transcriptional regulation of the PTEN/AKT/p53 axis, providing a theoretical basis for precision treatment strategies targeting CNOT9 or the PTEN/AKT/p53 pathway.