Search Results (28,802)

Background/Objectives: Both adiposity and nutritional–inflammatory status influence glucose metabolism; however, their longitudinal associations with glycemic changes in non-diabetic populations remain unclear. We examined the independent, interactive, and joint associations of body mass index (BMI) and prognostic nutritional index (PNI) with the 3-year change in HbA1c (ΔHbA1c). PNI, a composite marker of serum albumin and peripheral lymphocyte count, reflects both protein nutritional status and systemic immune competence. We hypothesized that BMI and PNI would each independently predict ΔHbA1c and that their joint profiling would identify higher-risk subgroups. Methods: A total of 9414 non-diabetic adults from the Shanghai Suburban Adult Cohort were included. Participants with diabetes at baseline (defined as fasting plasma glucose ≥ 7.0 mmol/L, 2-h post-load glucose ≥ 11.1 mmol/L, HbA1c ≥ 6.5%, or self-reported physician diagnosis of diabetes or use of glucose-lowering medications) were excluded. BMI was measured, and PNI was calculated as serum albumin + 5 × lymphocyte count. ΔHbA1c was assessed over a 3-year period. Multivariable linear regression, interaction testing, and joint stratification were performed. Covariate selection was guided by prior biological plausibility, and model adequacy was evaluated using the Akaike Information Criterion (AIC). Results: Both BMI (β = 0.013% per kg/m², 95% CI: 0.011–0.016, p < 0.001) and PNI (β = 0.002% per unit, 95% CI: 0.000–0.004, p = 0.019) were independently and positively associated with ΔHbA1c. No significant interaction was observed (p = 0.431). High BMI (≥24 kg/m²) was associated with glycemic worsening irrespective of PNI level (β ≈ 0.075%, p < 0.001). Among normal-weight individuals, higher PNI was associated with a modest increase in ΔHbA1c (β = 0.031%, p = 0.007). Conclusions: Although the absolute effect sizes were modest at the individual level, BMI was consistently and independently associated with glycemic deterioration therefore, even small per-unit increases may translate into meaningful risk at the population level given the high prevalence of overweight and obesity. PNI showed a small positive association, suggesting that in relatively healthy populations a higher PNI may partly capture subtle pro-glycemic factors—such as low-grade inflammation or higher protein intake—rather than representing unambiguous nutritional benefit. The absence of interaction suggests that BMI and PNI act through largely independent pathways. These findings extend prior evidence by demonstrating that PNI provides modest additional glycemic information beyond BMI in non-diabetic community-dwelling adults, particularly among those of normal weight. Full article

DNA methylation is a fundamental epigenetic modification that regulates gene expression, genome stability, and cell identity across vertebrate development. Disruption of DNA methylation homeostasis contributes to a wide spectrum of human diseases, including developmental disorders, neurological conditions, and cancer. Understanding how DNA methylation patterns are established, maintained, and dynamically remodeled during development is therefore essential for elucidating disease mechanisms and identifying therapeutic opportunities. The zebrafish (Danio rerio) has emerged as a powerful vertebrate model for investigating DNA methylation dynamics in vivo. Its external fertilization, optical transparency, rapid embryogenesis, and high fecundity enable direct observation and experimental manipulation of epigenetic processes at developmental stages that are difficult to access in mammalian systems. In addition, the core enzymatic machinery governing DNA methylation, including DNA methyltransferase (DNMT) and ten-eleven translocation (TET) protein families, is evolutionarily conserved between zebrafish and humans. In this review, we summarize current knowledge of the zebrafish methylome and the enzymatic regulators that control DNA methylation dynamics. We discuss how DNA methylation shapes early embryonic development, organogenesis, and cell fate decisions, and highlight insights gained from zebrafish models of human disease. Finally, we examine emerging technologies that are enabling increasingly precise interrogation of epigenetic regulation in vivo. Together, these advances position zebrafish as an important platform for bridging developmental epigenetics with human disease biology and therapeutic discovery. Full article

RNA viruses exhibit high mutation rates, necessitating antivirals targeting conserved infection mechanisms. In this study, viral hemorrhagic septicemia virus (VHSV), a non-human pathogenic negative-sense RNA virus, was used as a surrogate model to enable high-throughput antiviral screening under reduced biosafety conditions. A recombinant VHSV expressing enhanced green fluorescent protein was used to screen 17,265 compounds, 2000 plant extracts, and 100 marine extracts. Among the candidates, the leaf extract of Phellodendron amurense Rupr. (PL extract) exhibited antiviral activity with low cytotoxicity (selectivity index ≈ 10). The extract reduced viral infectivity in a dose-dependent manner and showed cross-activity against snakehead rhabdovirus. Mechanistic analyses indicated that the PL extract acts primarily at early stages of infection. Virucidal assays demonstrated direct, time-dependent inactivation of viral particles, while pre-treatment reduced host cell susceptibility. Time-of-addition experiments confirmed that antiviral activity was restricted to early infection, suggesting interference with viral attachment or entry rather than intracellular replication. Fractionation revealed that activity was associated with the non-polar n-hexane fraction, implicating lipophilic compounds that may disrupt viral envelope integrity or membrane interactions. These findings suggest that P. amurense leaf extract is a promising candidate for broad-spectrum antivirals targeting conserved entry processes in enveloped RNA viruses. Full article

Pathological cardiac hypertrophy is an important risk factor for cardiovascular disease. Ganoderic acid A (GAA), the primary bioactive constituent of Ganoderma lucidum (G. lucidum), is known for its stable chemical properties and diverse biological activities. It has been shown to confer protection against myocardial ischemia–reperfusion injury in rat models, potentially through modulating inflammatory responses and inhibiting protein expression linked to both NF-κB and apoptosis pathways. Nevertheless, the role of GAA in cardiac hypertrophy has not yet been fully elucidated. Using transverse aortic constriction (TAC)-induced cardiac hypertrophy in mice, we analyzed the degree of hypertrophy using echocardiography and at the pathology and molecular levels. Our results demonstrate that GAA effectively attenuates Ang II-induced cardiomyocyte hypertrophy in vitro and reduces pressure overload-induced cardiac hypertrophy in vivo. Further investigation revealed that GAA exerts its anti-hypertrophic effects by downregulating the mRNA expression of hypertrophic and fibrotic markers and attenuating inflammatory responses, and that the protective effects of GAA may involve NF-κB signaling. This study provides valuable theoretical support for the potential therapeutic application of GAA in treating pathological myocardial hypertrophy and heart failure. Full article

The continuous increase in atmospheric CO₂ concentration exacerbates global climate change, making carbon reduction an urgent global priority. Carbonic anhydrase (CA), a highly efficient biocatalyst that converts CO₂ into bicarbonate, demonstrates significant potential for carbon capture and resource utilization. However, the stability and catalytic efficiency of native CA in industrial environments are limited, particularly its poor thermal tolerance under flue gas conditions and its sensitivity to impurities, hindering its direct large-scale application. This review systematically summarizes recent advances in modifying microbial CA through protein engineering (e.g., directed evolution, rational design) and immobilization techniques, which have markedly enhanced its thermal stability, adaptability, and reusability. Among these, the integration of machine learning with high-throughput experimentation has emerged as a transformative strategy for CA engineering. Furthermore, we outline CA-driven pathways for CO₂ conversion into high-value chemicals and bioenergy. Finally, future prospects are discussed, including interdisciplinary integration, computational modeling coupled with experimental validation, and comprehensive life-cycle and techno-economic assessments, to facilitate the scaled application of engineered microbial CA in carbon neutrality pathways. Collectively, this review highlights the critical role of engineered CA in bridging biocatalysis with industrial carbon management, offering a viable and sustainable pathway toward carbon neutrality. Full article

Artificial intelligence has evolved to generative AI (GenAI), a paradigm shift that has shifted the emphasis away from the evaluation of existing patterns to the generation of novel biological and medical material. This study examines GenAI achievements in biosciences and medical fields the last five years in these fields using databases such as PubMed and Scopus. The paper highlights the recent evolution in biomedical research from virtual screening to de novo design. It illustrates how models like RFdiffusion and ProteinMPNN leverage “inverse folding” to assemble novel of proteins and drugs. Ultimately, these generative methods yield candidate with enhanced binding affinity and structural stability. For example, exploratory studies suggest GenAI has the potential to address inefficiencies via automatic documentation in the therapeutic sector, and it may enhance research capabilities by using Generative Adversarial Networks (GANs) and Variational Autoencoders (VAEs) to generate synthetic clinical trial data that preserves confidentiality. In addition, the review argues that though GenAI democratizes medical education through scalable simulations, it raises questions about long-term knowledge retention. Finally, GenAI also offers a transformative “write” capability for biology, but its responsible application will require addressing model “hallucinations” and building Explainable AI (XAI) and robust ethical frameworks. Full article

Ormosia macrocalyx grows in tropical forests and is endangered in Mexico. The species has ecological and economic importance. To evaluate the relationship between fruit length and seed number, Pearson correlation and principal component analysis were used. A linear mixed-effects model was also applied. Pearson correlation, principal components analysis (PCA) and a Linear Mixed-Effects Model (LMM) were performed on an exploratory basis. In addition, seed coat and cotyledon anatomy were examined, and histochemical tests for secondary metabolites were carried out. Two high correlations and two components were obtained from the PCA, and the LMM showed that fruit length influenced the number of seeds per fruit. In the seed coats, differentiated layers of macrosclereids and osteosclereids were identified, where the hilar region presented macrosclereids and a pyriform bar of tracheids, the reserved cotyledons showed double-walled cells and simple plasmodesmata, the histochemical analyses demonstrated the presence of cellulose, condensed tannins, lipids, alkaloids, and proteins, and no starch was present. This study provides the first description of seed coat and cotyledon anatomy in O. macrocalyx, as well as the first report of secondary metabolites in storage cotyledons. These results could be useful for further studies of this species. Full article

(1) Aim: The incidence of high-altitude pulmonary hypertension (HAPH) has risen in recent years and is expected to continue increasing; however, its diagnosis remains challenging. In this study, we employed proteomics and metabolomics to identify the proteins and metabolic biomarkers that contribute to the development of HAPH. (2) Methods: We applied integrated proteomics and metabolomics to match blood samples from 40 HAPH patients and 40 healthy controls in Yunnan’s high-altitude regions to characterize molecular profiles, identify biomarkers, and develop a predictive model. (3) Results: Proteomic analysis identified four proteins (A2IPH7, K1C14, PSME2, SERPINE2) commonly dysregulated in HAPH patients from two high-altitude regions. SERPINE2 was notably downregulated and showed a negative correlation with clinical severity, which was further validated in HAPH rat lung tissues and supported by UK Biobank data for idiopathic PAH. Concurrent metabolomics uncovered 11 shared metabolites, largely acyl fatty acids, enriched in pathways such as unsaturated fatty acid synthesis. Integration of these multi-omics data enabled the development of a robust predictive model. (4) Conclusion: Our study identified key protein and metabolic biomarkers involved in HAPH development, which were validated in animal models. Based on these findings, a predictive model was developed, highlighting SERPINE2 and 11 metabolites as promising targets for the prediction and prevention of HAPH. Full article

Chronic liver injury is characterized by sustained activation of transforming growth factor-β (TGF-β) signaling within the fibrotic microenvironment, yet the contribution of TGF-β-associated metabolic remodeling to hepatic stellate cell (HSC) activation remains incompletely understood. Here, we investigated whether TGF-β signaling is associated with lipid metabolic remodeling in HSCs and whether pirfenidone (PFD) interferes with this process. We found that TGF-β1 was spatially associated with lipid accumulation in fibrotic liver tissue and that TGF-β1/2 promoted HSC proliferation. In vitro, TGF-β1/2 coordinately upregulated sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FASN), accompanied by increased intracellular lipid accumulation and enhanced oleic acid (OA)-associated lipid responses. Low-dose OA further activated AKT/ERK/p70 S6K signaling in HSCs, whereas PFD attenuated these signaling events. In parallel, PFD suppressed TGF-β-associated lipid accumulation in vitro, reduced SREBP1/FASN expression in activated HSC-rich regions in vivo, and alleviated CCl₄-induced liver fibrosis. Together, these findings support a model in which TGF-β-associated lipogenic remodeling contributes to HSC activation and suggest that interference with this metabolic state may represent one component of the antifibrotic action of pirfenidone. Full article

Fibromyalgia, a syndrome characterized by hyperalgesia and ‘negative emotionality’, and major depressive disorder (MDD) demonstrate substantial overlaps in clinical, neurobiological, and therapeutic domains. Currently, treatment options for fibromyalgia remain limited; however, the epidemiology of this syndrome continues to grow worldwide. The use of animal models is indispensable for developing new treatment strategies for fibromyalgia. Meanwhile, the choice of animal paradigms is limited. Here, we used the ultrasound exposure of emotional stress on CBA, BALB/c, and C57BL/6 mouse strains to model this condition and to identify new molecular targets of fibromyalgia treatment. We exposed young male mice of three common strains to a three-week ultrasound stress (US) comprising emotionally negative and neutral frequencies of 20–25 kHz and 25–45 kHz, resulting in the development of altered pain sensitivity and signs of ‘negative emotionality’. Specifically, mice were studied for timid-like/aggressive behaviors and the tail flick response. Serum levels of corticosterone, cortisol, β-Endorphin, and brain-derived neurotrophic factor (BDNF), as well as brain gene expression of interleukin-33 (Il-33), Bdnf, and its receptor Trkb were investigated. Among the stressed mouse strains, C57BL/6 mice displayed augmented pain sensitivity, allodynia, and suppressed dominant behavior, whereas CBA and BALB/c mice demonstrated opposing changes. Glucocorticoid levels were increased in all stressed groups. Stressed C57BL/6 mice showed downregulated gene and protein expression of functionally inter-related BDNF and IL-33 molecules in the hippocampus, amygdala, and striatum, significantly correlating with behavioral outcomes, as well as lowered blood levels of β-Endorphin and elevated cortisol concentrations. Altogether, our study identified the BDNF/IL-33 regulatory pathway as a molecular correlate of fibromyalgia, and the use of US-exposed young C57BL/6 mice as a potential model that recapitulates this syndrome. Full article

Genomic selection (GS) may improve the adaptation of white lupin to drought or moderately calcareous soil, enabling to realize its potential as a high-protein crop. This study aimed to (a) verify breeders’ ability to identify the top-, mid-, and bottom-performing genotypes of published GS models of breeding lines and landrace genotypes for adaptation to drought and moderately calcareous soil; and (b) compare the top-performing materials produced by GS and phenotypic selection. Twelve selected genotypes were evaluated in four managed environments obtained through combining two soils (non-calcareous; moderately calcareous) with two water treatments (moderate terminal drought; moisture-favorable). GS based on the genotyping-by-sequencing of independent material was challenged by validation conditions that were partly different from the training ones and an imposed similarity of genomically predicted genotype phenology (to exploit drought resistance rather than drought escape). Grain yield reduction relative to favorable conditions averaged 19% for drought and 23% for calcareous soil. GS correctly identified the top-performing material for drought-prone or moderately calcareous soil, except for one model based on a small training set. The best GS lines performed comparably to the best phenotypically selected material. A higher harvest index was associated with better adaptation to drought and calcareous soil. Crossover genotype × water treatment interaction underpinned the selection for adaptation to drought. Full article

Neuronal ferroptosis is a key contributor to secondary brain injury following cerebral ischemia, yet the metabolic mechanisms governing this process remain poorly understood. Enriched environment (EE) is a housing paradigm that provides enhanced sensory, cognitive, and social stimulation through complex physical surroundings and increased opportunities for voluntary activity. Our preliminary data indicate that EE confers cerebroprotection against ischemia-induced ferroptosis; however, whether this effect is associated with glycogen metabolic regulation and the underlying molecular pathways has not been elucidated. This study aimed to determine whether EE may influence ferroptosis-associated pathways, potentially via Sirtuin 1 (SIRT1)/protein kinase B (AKT)/glycogen synthase kinase-3β (GSK3β)-related mechanisms of glycogen metabolism. Using a mouse model of middle cerebral artery occlusion (MCAO) and an oxygen–glucose deprivation/reoxygenation (OGD/R) cellular model, we performed behavioral assessments, molecular and biochemical analyses, and pharmacological interventions to elucidate mechanistic pathways. EE was associated with improved neurological outcomes and reduced infarct volume after ischemia. Mechanistically, EE appeared to activate the SIRT1/AKT pathway and increase the inhibitory phosphorylation of GSK3β and relieving its suppressive effect on glycogen synthase, which may underlie the observed increase in glycogen levels within ischemic brain tissue. Pharmacological inhibition of SIRT1 largely diminished these metabolic and neuroprotective benefits. Consistently, at the cellular level, SIRT1 overexpression contributed to the restoration of glycogen metabolism and robustly attenuated ferroptosis under ischemic conditions. Collectively, these findings suggest that EE may attenuate ferroptosis-related pathways possibly involving SIRT1/AKT/GSK3β-dependent glycogen metabolic remodeling, providing a novel metabolic perspective on EE-induced cerebroprotection and highlighting SIRT1-centered regulation of glycogen metabolism as a potential therapeutic target for ischemic stroke. Full article

IGF1 plays a critical role in cell proliferation and survival. Previous studies show that IGF1 binds to integrin αvβ3 and induces αvβ3-IGF1-IGF1R ternary complex formation. However, how IGF1 binding to αvβ3 leads to IGF1R activation is unclear. Previous studies showed that Gα13, a guanine nucleotide-binding protein of the G12 class of Gα proteins, binds to the integrin β3 tail through the EEE motif upon fibrinogen binding to integrin αIIbβ3 and induces RhoA activation. We discovered that the EEE/AAA mutation of the β3 tail inhibited IGF1-induced cell survival, suggesting that Gα13 binding to the β3 tail is required for IGF1 signaling. Since RhoA activation may not be directly involved in IGF1R activation, we studied if Gα13 binds to molecules other than RhoA. Since Gα13 binds to several cytoplasmic tyrosine kinases, we studied if Gα13 binds to the IGF1R kinase by a docking simulation. The simulation predicted that Gα13 binds to the IGF1R kinase through a new binding site. Mutating the predicted Gα13 binding site in the IGF1R kinase (residues 1020-1022) or the predicted IGF1R kinase binding site in Gα13 (residues 260-279) inhibited Gα13 binding to the IGF1R kinase, which is consistent with the docking model. Notably, the Gα13(260-279A) mutant inhibited IGF1-induced cell survival. We propose that IGF1 binding to αvβ3 induces Gα13 binding to the β3 tail and subsequent Gα13 binding to the IGF1R kinase, leading to IGF1R activation. Interestingly, Gα13(260-279A) mutation inhibited cell survival due to a constitutively active Gα13(Q226L) mutant. We propose that Gα13(Q226L) induces its effect by binding to the IGF1R kinase. We propose that the Gα13 binding site of the IGF1R kinase or the IGF1R binding site in Gα13 may be a novel therapeutic target. Full article

Background/Objectives: Curcumin (CUR) is a potent anticancer agent whose clinical application is hindered by its extremely poor aqueous solubility. This study reports the development of enzyme-responsive whey protein isolate (WPI) nanoparticles for CUR targeted delivery. Methods: To overcome the initial solubility barrier, CUR was first formulated as a solid dispersion with WPI using freeze-drying. This process resulted in a significant enhancement in aqueous solubility (up to 1478-fold), with CUR existing in molecular dispersion or in an amorphous state within the protein matrix as confirmed by Differential Scanning Calorimetry (DSC) and Fourier-transform infrared (FT-IR) spectroscopy. The solubilized CUR-WPI solid dispersion was subsequently used to generate nanoparticles via a thermal gelation method, avoiding the use of organic solvents or toxic chemical crosslinkers. Results: The resulting nanoparticles exhibited a high drug loading efficiency of 85%. In vitro release studies demonstrated minimal CUR release in physiological buffer (pH 7.4) over 24 h, whereas exposure to trypsin, a nonspecific serine protease used as an in vitro model for tumor-associated proteolytic activity, triggered rapid nanoparticle degradation and released 95% of CUR within 3 h. Conclusions: These findings suggest that WPI-based nanoparticles developed from solid dispersions offer a promising, biocompatible platform for the solubility enhancement and protease-triggered delivery of hydrophobic anticancer drugs. Full article

The plague, caused by Yersinia pestis, has resulted in significant mortality over the past century. Despite advances in antimicrobial therapy, plague remains a re-emerging infectious disease with ongoing outbreaks and increasing concerns regarding antimicrobial resistance. Today, plague cases are still being reported, and the loss of effectiveness of treatment methods remains a major challenge. Therefore, effective treatment strategies are needed. In this study, we aimed to develop aptamers specific to Yersinia outer protein M (YopM), a key immunosuppressive protein that is essential for virulence. Our goal was to develop an aptamer that binds to YopM and inhibits its interaction with the human DEAD-box helicase 3 (DDX3) protein. YopM-DDX3 protein interaction was targeted because of its key role in nucleocytoplasmic shuttling of YopM. To achieve this, we developed the YopM16 aptamer using magnetic bead-based (Systematic Evolution of Ligands by Exponential Enrichment) (SELEX). The selected YopM16 aptamer exhibited a half-maximal inhibitory concentration(IC₅₀) value of 103.3 ± 2 nM and effectively inhibited the interaction between YopM and DDX3. The inhibitory effect of the aptamer on protein interaction was confirmed using a pull-down assay and colorimetric test. Given that protein–protein interaction surfaces are considered undruggable, YopM16 is a promising inhibitor with the potential to serve as a molecular tool to investigate the virulence mechanism of YopM, as well as a novel antibacterial agent upon validation of its inhibition in cellular models. Full article