Search Results (21,467)

Type 2 diabetes mellitus (T2DM) accounts for over 90% of diabetes cases, and T2DM-related sarcopenia is a growing concern. Carnosine, abundant in human skeletal muscle, helps maintain muscle quality and function. This study investigated whether carnosine deficiency contributes to T2DM-related sarcopenia and whether exogenous carnosine supplementation alleviates muscle atrophy. A mouse model of T2DM sarcopenia was established using streptozotocin combined with a high-fat diet. LC-MS metabolomics revealed a significant reduction in carnosine content in the gastrocnemius muscle of model mice. A C2C12 myotube atrophy model was induced by high-glucose (HG), and qRT-PCR showed altered expression of carnosine metabolism-related enzymes, suggesting disrupted carnosine homeostasis under T2DM conditions. Mechanistic investigations using immunofluorescence, Western blotting, transcriptome sequencing, mitochondrial staining, and molecular docking indicated that carnosine may alleviate high-glucose-induced myotube atrophy through the PI3K/AMPK/PGC-1α signaling pathway. In vivo, carnosine supplementation increased the number of mitochondria and the proportion of slow muscle fibers in gastrocnemius muscle, ameliorating the atrophic phenotype. These findings suggest that carnosine has potential as a candidate for intervention in T2DM-related sarcopenia, though further validation of its direct molecular targets is required. Full article

Aberrant activation of c-MET signaling contributes to tumor progression and resistance to therapy in non-small-cell lung cancer (NSCLC), yet its therapeutic significance remains incompletely understood. In this study, we evaluated c-MET expression and its association with AKT activation and clinical outcomes using a tissue microarray cohort and publicly available datasets. c-MET overexpression was significantly associated with increased p-AKT expression and showed a trend toward poorer overall survival in the tissue microarray cohort, while analysis of the TCGA LUAD dataset confirmed a significant association with reduced survival (log-rank p = 0.0223; HR = 1.234, 95% CI: 1.029–1.480). Functional studies demonstrated that pharmacological inhibition of c-MET suppressed cell proliferation and induced caspase-dependent mitochondrial apoptosis in NSCLC cell lines. Mechanistically, c-MET inhibition resulted in AKT inactivation, identifying AKT as a key downstream mediator of c-MET signaling. Notably, combined inhibition of c-MET (PHA665752) and AKT (MK2206) exhibited strong synergistic effects, significantly enhancing apoptosis and reducing cell viability compared to single-agent treatments. These findings were further validated in vivo, where combination therapy markedly delayed tumor growth without significant toxicity. Collectively, our results highlight c-MET-driven AKT activation as a key oncogenic mechanism and support dual c-MET/AKT targeting as a promising therapeutic strategy for NSCLC. Full article

Invasive infections caused by Aspergillus flavus are more common in tropical and subtropical countries. The emergence of azole resistance in A. flavus complicates the management of aspergillosis, as azoles are the first-line and empirical therapy. The aim of this study was to investigate the molecular mechanisms underlying azole resistance in A. flavus, focusing on the cyp51C gene. We screened 34 molecularly confirmed A. flavus isolates obtained from patients with invasive aspergillosis for cyp51C gene expression by real-time RT-qPCR and for mutations by PCR sequencing. Molecular modeling and docking studies were performed using SWISS-MODEL, SwissDock, and I-TASSER software. Susceptibility testing revealed that 14.71% and 8.82% of isolates were resistant to itraconazole and posaconazole, respectively, with 5.88% exhibiting cross-resistance. The mRNA expression of cyp51C was upregulated (>2.5-fold) in five of the six resistant strains (83.33%). Hyperexpression of cyp51C was significantly more frequent among resistant isolates than among susceptible isolates (Fisher’s exact test, p = 0.014). Sequencing identified ten point mutations, including six synonymous and four non-synonymous substitutions. The non-synonymous mutations M54T and S240A were detected in the protein sequences of both resistant and susceptible isolates. Notably, D254N and I285V were observed exclusively in resistant isolates and in susceptible isolates with itraconazole MICs near the epidemiological threshold. Homology modeling and 3D structure prediction of the mutated Cyp51C protein demonstrated interactions with itraconazole, posaconazole, and voriconazole. Importantly, I-TASSER analysis indicated that the I285V substitution is located near the itraconazole binding site. Simultaneous overexpression of the cyp51A, cyp51B and cyp51C genes was observed in 33.33% of resistant isolates. These findings suggest that multiple target genes and mechanisms may act concurrently to confer azole resistance in A. flavus. Overall, this study supports the hypothesis that azole resistance in A. flavus is multifactorial and highlights the potential value of combining mutation analysis, gene expression profiling, and structural modeling for improved molecular surveillance and antifungal resistance monitoring. Full article

Pubertal initiation critically determines reproductive performance in female pigs. Histone H3 lysine 27 trimethylation (H3K27me3) has been implicated in ovarian development. However, its genome-wide regulatory landscape during the pubertal transition remains unexplored. Here, we obtained transcriptomes of GCs treated with the pharmacological H3K27me3 agonist GSK-J4 or H3K27me3 inhibitor EPZ005687. We found that H3K27me3 substantially remodels the transcriptomic landscape of porcine GCs, with differentially expressed genes significantly enriched in pathways governing cell proliferation and apoptosis. Mechanistically, H3K27me3 suppressed GC proliferation by downregulating the expression of PCNA and promoting apoptosis through upregulation of CASP3, thereby delaying pubertal initiation. Furthermore, genome-wide ChIP-seq analysis on porcine ovaries from pre-pubertal and in-pubertal gilts revealed higher H3K27me3 enrichment around transcription start sites in the In-puberty stage than in the Pre-puberty stage. Genes with promoters exhibiting reduced H3K27me3 occupancy during the pubertal transition were enriched in pathways related to sex differentiation and serine-type endopeptidase inhibitor activity. Notably, secretory leukocyte peptidase inhibitor (SLPI) was identified by ChIP-qPCR as a direct target repressed by H3K27me3. Functional validation demonstrated that SLPI promoted GC proliferation and inhibited GC apoptosis in vitro. Intraperitoneal injection of LV-Slpi or sh-Slpi into C57BL/6J mice showed that Slpi accelerated pubertal initiation of mice in vivo. Collectively, our findings confirmed that developmental stage-specific loss of H3K27me3 at the SLPI promoter derepressed SLPI transcription, which in turn promoted porcine GC proliferation, suppressed apoptosis, and facilitated pubertal initiation in mice. These results provided valuable insights into the epigenetic regulation of pubertal initiation in mammals. Full article

Background: Cytarabine (Ara-C) remains the cornerstone of remission-induction and consolidation chemotherapy for acute myeloid leukemia (AML) and related hematological malignancies. Despite more than six decades of clinical use, its multi-organ toxicity continues to be managed almost exclusively through dose attenuation and supportive care, with no approved upstream pharmacological prevention strategy available. Objectives: This scoping review aimed to systematically map the breadth and nature of pharmacological agents tested in vivo for their capacity to mitigate cytarabine-induced multi-organ toxicity, to characterize their mechanisms of action and organ targets, and to identify evidence gaps and agents with translational potential. Methods: The review was designed and reported in accordance with the PRISMA-ScR checklist. A structured electronic search was conducted across PubMed/MEDLINE, Scopus, Cochrane Library and Embase, and Web of Science from database inception to 15 July 2025. Eligible studies were restricted to full-text, peer-reviewed, English-language research involving in vivo mammalian models administered cytarabine as the principal toxin, with at least one pharmacological co-intervention and at least one quantitative or histopathological organ-injury outcome. Results: From 5701 retrieved records, 36 eligible in vivo mammalian studies (spanning 1964–2024) were identified. Included studies addressed neurotoxicity (n = 6), gastrointestinal mucositis (n = 9), ocular toxicity (n = 3), hepatotoxicity (n = 3), bone marrow suppression (n = 4), chemotherapy-induced alopecia (n = 5), and reproductive and developmental toxicity (n = 4). Five recurring mechanistic strategies were identified across the heterogeneous agents tested: redox buffering (N-acetylcysteine, α-lipoic acid, rutin, swertiamarin, α-tocopherol), mitochondrial preservation (betanin, thymoquinone, vitamin D, sodium zinc dihydrolipoylhistidinate [DHLHZn]), tissue-microenvironment reprogramming (apraglutide, BADGE, plerixafor, short-chain fatty acids, β-glucan), molecular antagonism (deoxycytidine, dCMP), and immunomodulation (lienal peptide, IL-1β, AHCC). Conclusions: This scoping review provides the first systematic cartography of pharmacological mitigation strategies for cytarabine-induced multi-organ toxicity. Five mechanistic pathways converge across eight organ systems, with apraglutide and N-acetylcysteine representing the most clinically translatable candidates. Plerixafor and PPARγ blockade by BADGE constitute high-priority candidates for bone marrow niche protection, while the deoxycytidine antagonism principle warrants formal pharmacokinetic evaluation. The complete absence of cardiotoxicity mitigation data defines the most critical gap for future research. Full article

Fasciolosis, caused by the liver fluke Fasciola gigantica, remains a major parasitic disease affecting livestock in tropical regions and results in substantial economic losses. Although anthelmintic drugs are widely used for disease control, increasing reports of drug resistance highlight the need for alternative strategies such as vaccination. In this study, a recombinant digestive protein-based chimeric antigen (rFgCHI-DP) composed of three F. gigantica antigens—cathepsin L1 (FgCL1), cathepsin B1 (FgCB1), and saposin-like protein 2 (FgSAP2)—was designed and expressed in Escherichia coli. The mature regions of these proteins were sequentially linked to form a single chimeric construct. The recombinant protein was successfully expressed and purified under denaturing conditions, producing a protein of approximately 62 kDa. To evaluate its immunogenicity, BALB/c mice were immunized with rFgCHI-DP formulated with Quil A adjuvant. Indirect ELISA revealed that immunization induced antigen-specific IgG responses. Antibody responses showed strong reactivity toward FgCL1 and FgCB1, whereas the response against FgSAP2 was comparatively lower. Western blot analysis further demonstrated that antibodies generated against rFgCHI-DP recognized native parasite antigens. Immunolocalization also revealed that the anti-rFgCHI-DP antibodies could detect targeted antigens in the cecal epithelium of the parasite. These findings indicate that the adult-stage chimeric protein rFgCHI-DP is immunogenic in mice and capable of inducing specific antibody responses against F. gigantica. The results support the potential of rFgCHI-DP as a candidate antigen for future fasciolosis vaccine development. Full article

The detection of bolt preload force is of vital importance for ensuring the structural reliability of equipment under extreme operating conditions. Traditional ultrasonic transducers based on bulk piezoelectric materials suffer from poor long-term coupling stability and high brittleness of the material, which limits their practical applications. In this work, AlN piezoelectric thin films were fabricated by RF magnetron sputtering, and the effects of RF power and target-to-substrate distance on film morphology, crystal structure, and ultrasonic response were investigated. The results show that increasing RF power increased the film thickness and deposition rate, reduced the detected O content on the film surface, and changed the XRD response. The film deposited at 900 W generated ultrasonic longitudinal wave echoes with a relatively high signal amplitude among the tested RF powers. Among the tested target-to-substrate distances, the film deposited at 60 mm showed a relatively higher deposition rate and generated an ultrasonic longitudinal wave echo with a relatively higher amplitude. The measured d₃₃ value of this film was approximately 4.8 pC/N. The AlN thin-film ultrasonic transducers prepared under the selected deposition conditions were directly deposited on bolts, and the effects of temperature and axial load were calibrated using the ultrasonic TOF measurement method. There was a linear correlation between the TOF and the temperature (R² > 99.99%), as well as between the TOF and the axial load. These results indicate that the deposited AlN thin-film transducer has potential for bolt preload measurement in wind turbine bolts. Full article

Oxidative stress has been recognized as a repeatedly validated pathophysiological factor in schizophrenia, but its mechanistic role and translational relevance remain incompletely defined. Prior work has advanced redox dysregulation, neuroinflammation, and NMDA receptor hypofunction as a putative central hub in schizophrenia. This narrative review proposes an evidence-weighted redox–mitochondria–immune framework that integrates peripheral biomarkers, magnetic resonance spectroscopy, postmortem findings, and preclinical mechanisms while explicitly distinguishing established observations from candidate pathways. Existing studies support increased oxidative damage and altered antioxidant buffering in schizophrenia, particularly involving the glutathione system. However, these abnormalities are neither uniform across disease stages nor equally represented across patient subgroups, and may be markedly prominent only in certain biological subgroups. Mechanistically, redox imbalance may interact with mitochondrial bioenergetic deficits and innate immune signaling; however, pathway-specific links such as cGAS-STING activation, nitrosative/peroxynitrite stress, and GPx4-ferroptosis should currently be treated as testable extensions rather than validated human mechanisms in schizophrenia. Importantly, the pathological consequences of oxidative stress are unlikely to be cell-type neutral. Parvalbumin-positive interneurons and oligodendrocyte lineage cells are more vulnerable because of their high metabolic load, limited antioxidant buffering capacity, and lipid/iron-related susceptibility, thereby providing a mechanistic bridge to excitation–inhibition imbalance, myelin abnormalities, and reduced circuit synchrony. Microglial redox–inflammatory signaling may further exacerbate these processes. On the basis of this framework, we argue that the key for future research is not to continue demonstrating the universality of oxidative stress, but to improve the translational efficiency. Biomarker-guided stratification, stage-sensitive study designs, and cell-type-informed therapeutic strategies may therefore provide a more productive path toward redox-targeted interventions in schizophrenia. Full article

The lipoate-protein ligase A (LplA) identified in Escherichia coli K-12 exhibits structural homomeric oligomerization and reversible lower critical solution temperature (LCST)-type phase separation in vitro. In this study, based on the ability of LplA to form condensates, it was utilized as a temperature-sensitive purification tag in the field of protein purification for the first time, and a novel and convenient one-step purification method was established. A universal vector was developed for the fusion expression of LplA and the target protein. The fusion protein forms condensates upon heating, separating from the solution, and redissolves in buffer at lower temperatures, enabling the purification of the target protein from cell lysates. Through exploration of phase separation temperatures, 30 °C was determined to be the optimal purification temperature. Subsequently, three enzymes of different molecular sizes (lipase EstA, endoglucanase BcsZ, and endoglucanase EglS) demonstrated the versatility of this condensate-based purification method. Furthermore, the specific activity and purification efficiency of the purified enzymes were comparable to those of enzymes purified by conventional affinity chromatography. This research contributes to the introduction of condensates into protein purification applications, offering potential support for the large-scale production and purification of functional proteins. Full article

Systemic arterial hypertension (SAH) is a multifaceted condition marked by sustained elevations in arterial blood pressure. Its occurrence is closely related to alterations in target organs, such as the liver. Non-pharmacological treatments have been proposed for these effects. Thus, the aim of this study was to investigate the effects of açaí supplementation and resistance training, applied individually or in combination, on blood pressure and liver structural parameters. An experimental, quantitative, and longitudinal study was conducted using young Wistar rats (~60 days old) and spontaneously hypertensive rat (SHR) strains. Fifty rats were divided into five experimental groups: Wistar Control (C), Hypertensive Control (H), Hypertensive Trained (HT), Hypertensive Açaí-Supplemented (HA), and Hypertensive Trained plus Açaí Supplementation (HAT). Each group consisted of ten animals. Subsequently, analyses were performed for the antioxidant capacity and proximate composition of the açaí pulp, systolic blood pressure assessment, and histological evaluation of the liver. The açaí used exhibited high antioxidant capacity. At the end of the experimental period, the trained groups increased their maximal load carried, along with a reduction in systolic blood pressure in all treated groups. Açaí supplementation resulted in lower relative liver mass compared with the H group. The hypertensive condition promoted extracellular matrix expansion and a reduction in hepatocyte proportion. Both interventions attenuated these effects, and the combined treatment (HAT) produced the greatest improvement, indicating an additive response. Hypertension also elevated hepatic glycogen concentration, and the treatments reduced this alteration. It is concluded that açaí supplementation and resistance training could promote positive adaptations in the liver of hypertensive animals. Full article

Cervical cancer is a malignant disease that affects women worldwide and is associated with both high incidence and a high mortality rate. miR-34 is a direct transcriptional-target of p53 and is downregulated in several types of cancers. 1,4-Naphthoquinones (NQs) have anticancer properties and have been used to modulate miR-34 expression. We tested (3-chloro-NQ-2-yl)-alanine (ANQCl), -methionine (MNQCl), -glycine (GNQCl), -phenylalanine (FNQCl), -asparagine (NNQCl), and (1,4-napthoquinon-2-yl)-asparagine (NNQ) in immortal and tumorigenic cells, both HPV-positive and -negative, simulating precancerous and cancerous status to observe the response of the p53-miR-34 system, migration and invasion. A dose–response was achieved to determine the IC50 of the compounds in SiHa, CaLo, C33-A and HaCaT cells. HaCaT cell migration inhibition was more potent than in SiHa, CaLo, and C33-A cells, while invasion hindrance was more evident in the tumorigenic SiHa, CaLo and C33-A. NNQCl, GNQCl, ANQCl and FNQCl compounds induced p53 overexpression in SiHa and CaLo cells. Compound ANQCl in SiHa and FNQCl in CaLo induced miR-34a overexpression, probably via p53. Migration and invasion of most compounds decreased independently of p53-miR-34. NQ-amino acids exert effect on cell proliferation, migration and invasion in cervical cancer cells, suggesting their potential use in the field of cancer treatment. Full article

Palmatine chloride (berbericinine, C₂₁H₂₂ClNO₄) is a protoberberine alkaloid found in several plants, including Rhizoma Coptidis, Cortex Phellodendri, Rhizoma Corydalis, Guduchi (Tinospora cordifolia), and Tinospora sagittata roots. Palmatine chloride (PA) is known as an inhibitor of dopamine generation. However, its effect on endoplasmic reticulum (ER) stress-related macrophage activation caused by endotoxin (lipopolysaccharide) is not yet well known. In this study, the effects of PA on pyroptotic responses of mouse macrophages (RAW 264.7) activated by endotoxin were investigated using Griess reagent assay for nitric oxide (NO) production, fluo-4 assay for cytosolic calcium release, dihydrorhodamine 123 assay for hydrogen peroxide production, multiple cytokine assay for cytokine production, real-time PCR for inflammatory gene transcriptions, and flow cytometry assay for p38 MAPK activation. Preliminary experiments using THP-1 human monocytic cells demonstrated that PA was not cytotoxic and significantly reduced basal NO production. Results revealed that PA significantly reduced excessive production levels of NO, hydrogen peroxide, pro-inflammatory cytokines (such as interleukin (IL)-6, CCL3 (MIP-1α), and CSF2 (GM-CSF)), and cytosolic calcium release in endotoxin-stimulated RAW 264.7, but significantly increased the production of anti-inflammatory cytokine IL-10. PA inhibited endotoxin-induced transcripts of Chop, Stat1, Fas, and c-Fos in activated RAW 264.7. It also decreased p38 MAPK phosphorylation and level of Fas in RAW 264.7 stimulated by endotoxin. To further interpret these findings, a network pharmacology-informed analysis based on large-scale literature mining was performed, supporting the multi-target regulatory role of PA in ER stress-related pathways. Briefly, PA exerts anti-inflammatory effects on endotoxin-stimulated RAW 264.7 via the calcium-CHOP pathway, consequently reducing endotoxin-induced production of pro-inflammatory mediators (NO, cytokines, etc.) and relieving ER stress-related pyroptotic cascade. Full article

Background: Colorectal cancer (CRC) prognosis, particularly in liver metastasis (CRLM), is influenced by histopathological and molecular factors. Methods: A narrative analysis of the specialized literature was conducted using databases such as PubMed, MEDLINE, Scopus, and Embase. The review focused on original articles published between 2005 and 2025. Results: Lymph node involvement is a critical prognostic factor, with lymph node-positive CRC correlating with increased risk of liver metastasis and significantly reduced survival rates. Poorly differentiated tumors (G3) exhibit a higher likelihood of metastasis, including liver involvement, and are associated with worse clinical outcomes. Vascular emboli and perineural invasion are indicative of hematogenous spread and higher metastatic potential, leading to poorer survival outcomes. Genetic mutations, such as KRAS, NRAS, and BRAF, are associated with therapy resistance, complicating treatment and highlighting the importance of personalized approaches. MSI-H and HER2 amplification further affect treatment response, with MSI-H tumors showing a favorable response to immunotherapy, while HER2-positive CRCs may benefit from targeted therapies. Tumor budding, high levels of which predict poor survival, is another key histopathological feature associated with aggressive metastatic behavior. Systemic inflammatory markers, such as the Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), and C-Reactive Protein-to-Albumin Ratio (CAR), offer prognostic insights into CRLM patient survival. Conclusions: Histopathological features, molecular alterations, and immune microenvironment factors significantly impact the prognosis of CRC with liver metastasis. The integration of molecular profiling, immunotherapy, and targeted therapies offers promise for improving treatment outcomes. Personalized treatment strategies, incorporating these factors, are essential for overcoming therapy resistance and improving survival in CRLM patients. Full article

Poultry meat producers face pressure to ensure both safety and efficiency as food systems expand in scale and complexity. However, existing diagnostic tools often force a trade-off between speed, accuracy, and cost, leaving limited options for real-time, on-site pathogen detection. This study evaluated the performance of a novel point-of-use rapid diagnostic tool combining filtration and lyophilized isothermal amplification for detecting and semi-quantifying Salmonella in chicken carcass rinse samples. Targeted DNA (invA) was amplified at 65 °C for 60 min, and fluorescence was measured over time. Salmonella was successfully detected in all spiked samples (1.0- to 7.5-log10 CFU/mL; n = 57). An association was observed between the isothermal detection speed data and Salmonella load in the sample (r² = 0.90; p < 0.001), particularly at concentrations ≥ 1.5-log10 CFU/mL. Repeatable data were obtained across three operators and samples of multiple origins (Georgia, Illinois, Nebraska; 0.16-log10; 95%CI: 0.11–0.21). Importantly, complete inclusivity for all tested Salmonella serotypes (n = 46/46) and exclusivity against non-target organisms (n = 0/37) was validated in this study. In conclusion, the technological combination of filtration and lyophilized isothermal amplification enabled the point-of-use detection and quantification of Salmonella in chicken carcass samples within 60 min and minimal lab infrastructure. Full article

Modern mineral exploration faces the pivotal challenge of detecting concealed mineral deposits in complex geology, as depleting outcropping ores have driven global exploration to depths where 1000 m deep mining is now commonplace. To address this, this study proposes Geo-U-Mamba, an unsupervised deep learning framework for gold mineral prospectivity mapping. The model integrates multi-source geoscientific data, encompassing geochemistry, remote sensing alteration indicators, topography, and structural distance fields. By incorporating a Mamba-driven four-directional cross-scan mechanism into a U-Net architecture, the framework effectively models the complex nonlinear mapping relationships between metallogenic elements and the geological environment. This approach recognizes gold geochemical anomalies with an 86.11% deposit capture rate, decoupling environmental noise by reconstructing the geochemical background field and extracting anomalies in combination with C-A fractal theory. When applied to China’s Hatu gold belt in Xinjiang, Geo-U-Mamba achieved an AUC of 0.83, consistently outperforming classical baselines such as CAE, U-Net, and ViT. Ultimately, the findings indicate that this framework provides a reliable and high-precision tool for modern mineral exploration, successfully separating mineralization signals from geological backgrounds in complex metallogenic belts to facilitate exploration targeting. Full article