Search Results (2,403)

The progressive failure of pancreatic beta-cells under chronic glucolipotoxicity drives the pathogenesis of type 2 diabetes mellitus (T2DM). This metabolic stress overwhelms the folding capacity of the endoplasmic reticulum (ER), hyperactivates the unfolded protein response (UPR), engages terminal pro-apoptotic signaling through C/EBP-homologous protein (CHOP), and promotes beta-cell dedifferentiation. In this systematic review and meta-analysis, registered with PROSPERO (CRD420261370436), we evaluated the preclinical efficacy of the low-molecular-weight chemical chaperones tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyrate (4-PBA) in preserving beta-cell exocytotic identity and mitigating ER stress. Following PRISMA 2020 guidelines, a systematic search of PubMed, Scopus, and Web of Science (January 2016–May 2026) identified four eligible experimental studies. Preclinical models (INS-1 and βTC-6 cell lines, Wistar rats, and C57BL/6 mice) exposed to a high-fat diet (HFD), a high-fat/high-fructose diet (HFHFD), cholesterol loading, or protein restriction followed by high-fat feeding showed impaired or dysregulated glucose-stimulated insulin secretion (GSIS) and upregulated ER-stress markers. Co-administration of TUDCA or 4-PBA moved secretory output toward the healthy-control phenotype in every model and reduced pro-apoptotic markers in the three models in which they were measured. A hierarchical Bayesian random-effects meta-analysis of the between-arm GSIS restoration ratio at stimulatory glucose yielded a pooled ratio of 1.85 (95% credible interval [CrI] 1.38 to 2.43), with the entire credible mass above the null (posterior probability of benefit 0.996). This estimate was stable across nine prior specifications for the between-study standard deviation and in every leave-one-out analysis, including exclusion of the single hypersecretion model (1.98, 95% CrI 1.09 to 3.18). Between-study variance was small but weakly identified from only four studies and is reported as exploratory. Pooling instead on the registered within-arm stimulation-index scale, a change in metric declared as a protocol deviation, gave 1.46 (95% CrI 0.73 to 2.58) with substantial heterogeneity (I² = 89.3%), so the evidence supports restoration of absolute glucose-stimulated insulin output rather than of fold glucose responsiveness. Because no source report documents blinding of outcome assessment, the pooled estimate should be read as an upper bound. In conclusion, TUDCA and 4-PBA act as chemical chaperones that alleviate ER stress and may prevent terminal UPR activation and preserve the beta-cell exocytotic machinery, positioning them as candidate disease-modifying agents that merit confirmatory clinical evaluation. Full article

Piscidins, fish-specific antimicrobial peptides (AMPs), play important roles in the innate immunity of fish against invading bacteria. In this study, a novel piscidin was identified in largemouth bass (Micropterus salmoides) (MSPiscidin-4), which contained an active peptide of 25 aa with an amphipathic helix possessing distinct hydrophobic and positively charged regions. MSPiscidin-4 belongs to the Group I piscidins as determined by sequence identity, homology modeling and phylogenetic tree analysis. MSPiscidin-4 was constitutively expressed in all seven selected tissues, with the highest transcript level in the gill and the lowest in the brain and spleen. Furthermore, MSPiscidin-4 was significantly up-regulated in spleen from 6 h to 24 h post-lipopolysaccharide (LPS) stimulation. A synthetic MSPiscidin-4 peptide was produced by the Fmoc solid-phase synthesis method and exhibited antibacterial activity against several aquatic bacterial strains, with the strongest against Aeromonas hydrophila, followed by Vibrio splendidus, Staphylococcus aureus, Edwardsiella tarda, and the weakest against E. coli and A. veronii. MSPiscidin-4 is the fourth piscidin reported in largemouth bass, showing distinct sequence identity (35.0–68.0% with previously reported MSPiscidins), physicochemical properties (net charge +5, pI 12.48), tissue distribution (highest expression in gill), and antibacterial potency (particularly strong against A. hydrophila). Our results enrich the piscidin components and deepen the understanding of piscidins against invading bacteria in largemouth bass. Full article

Background/Objectives: The domestic yak (Bos grunniens) is a livestock species of major relevance in high-altitude environments and an important model for studying adaptation and reproductive isolation within Bovini. Despite its close phylogenetic relationship with cattle (Bos taurus), yak × cattle hybrids show a marked sex-biased fertility pattern, with fertile females and generally sterile F1 males, suggesting that subtle chromosomal or genomic differences may underlie post-zygotic reproductive barriers. In this study, we performed a cytogenetic characterization of eight adult yak bulls imported and reared in Central Italy using conventional and molecular cytogenetic approaches. Results: GTG-, RBG-, RBA- and CBA-banding confirmed the yak diploid number as 2n = 60 and the fundamental number as NF = 62, with banding patterns highly comparable to the standardized cattle karyotype. CBA-banding showed an X chromosome lacking evident constitutive heterochromatin and a Y chromosome with distal C-positive blocks. Chromosome instability was low, with 3.75% abnormal metaphases, mainly represented by chromatid and iso-chromatid breaks, while the mean sister chromatid exchange (SCE) rate was 5.19 ± 2.14 per cell. Sequential Ag-NOR/RBA staining localized nucleolar organizer regions (NORs) at the telomeres of autosomes 2, 3, 4, 11 and 25, as in cattle. Zoo-FISH using bovine chromosome paints for X, Y, 5 and 15 showed complete hybridization to the corresponding yak chromosomes, and BAC-FISH mapped the Y-linked ZFY and SRY genes to positions homologous to those reported in cattle. A comparative bioinformatics analysis of available yak genome assemblies confirmed the overall genome-wide correspondence with cattle, while revealing chromosome orientation issues and small local inconsistencies that may be relevant for comparative mapping and probe design. Conclusions: Overall, at the resolution tested, these findings support broad macrostructural conservation of yak and cattle karyotypes and provide cytogenetic reference data for yak populations reared outside of their traditional range. The persistence of F1 male sterility despite this large-scale chromosomal conservation suggests that fine-scale sex chromosome differences, particularly involving pseudoautosomal regions, recombination boundaries, or heterochromatin organization, may deserve targeted investigation. Full article

Background/Objectives: Loss of phosphatase and tensin homolog (PTEN) activity is a frequent feature of non-small-cell lung cancer (NSCLC), and epigenetic repression may contribute to its reduced expression. This study investigated the effects of 5-aza-2′-deoxycytidine (5-aza-dC) on PTEN, DNA methyltransferase 1 (DNMT1), PTEN promoter methylation-specific amplification patterns, and miR-148a-3p expression in NSCLC models. Methods: Publicly available cancer-genomics datasets were analyzed to compare PTEN and DNMT1 transcript abundance and to assess the association between PTEN methylation and transcript abundance in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). A549 and H460 cells were exposed to 2.5 or 5 µM 5-aza-dC for 72 h. Reverse-transcription quantitative PCR (RT-qPCR), Western blotting, methylation-specific PCR (MSP-PCR), and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were used to evaluate RNA expression, protein abundance, methylation-specific amplification, and metabolic activity, respectively. Results: Bioinformatic analyses showed lower PTEN and higher DNMT1 expression in both NSCLC subtypes, together with inverse associations between PTEN methylation and transcript abundance. In both cell lines, 5-aza-dC reduced MTT metabolic activity and DNMT1 expression. PTEN mRNA and protein abundance increased significantly at 5 µM, whereas no significant changes were detected at 2.5 µM. MSP-PCR revealed persistent heterogeneous PTEN methylation-specific amplification patterns without clear evidence of progressive promoter demethylation. miR-148a-3p exhibited a biphasic response in A549 cells but remained unchanged in H460 cells. Conclusions: These findings support an association between 5-aza-dC exposure, increased PTEN expression, and reduced DNMT1 expression in NSCLC cells. Quantitative methylation analysis and mechanistic validation are required to clarify the contribution of miR-148a-3p to this regulatory association. Full article

Lonicera japonica Thunb. (honeysuckle), a traditional herb with “food-medicine homology” status in Chinese medicine, is valued for its antipyretic and detoxifying properties. This review systematically summarizes its chemical composition—over 507 identified compounds, including phenylpropanoids, flavonoids, triterpenoids, saponins, and the plant-specific miR2911—as well as its multi-target pharmacological mechanisms and emerging translational applications, with particular emphasis on the gut–brain axis-mediated neuroprotective effects. Despite low oral bioavailability, honeysuckle polysaccharides and chlorogenic acid have been shown to exert significant neuroprotection in Alzheimer’s disease models by modulating gut microbiota composition, increasing short-chain fatty acid production, and restoring intestinal barrier integrity—a mechanism that challenges conventional direct-action paradigms. We also outline the applications of honeysuckle in functional foods, pharmaceuticals, animal husbandry, and cosmetics, and propose future directions including precision fermentation and mechanism-driven clinical trials. By integrating phytochemistry, pharmacology, and biotechnology, this review provides a roadmap for the evidence-based development of honeysuckle as a precise medicinal and edible resource. Full article

The transition toward sustainable biorefinery processes requires efficient strategies for lignocellulosic biomass deconstruction and valorization. In this study, an integrated enzymatic system combining fungal holocellulases and laccases with a bacterial galactolipase was developed and evaluated. The consortium, composed of Trametes hirsuta GMA-01, Mycothermus thermophilus CBS 619.91, and Burkholderia lata BL02, was produced using agro-industrial substrates and applied to the hydrolysis of different lignocellulosic biomasses. The incorporation of galactolipase activity enhanced the saccharification yields for leaf-derived substrates, reaching up to 292.0 mg/g for spinach leaves and 236.0 mg/g for corn straw, compared to fungal systems alone. This effect is associated with the selective hydrolysis of membrane-associated galactolipids, improving substrate accessibility to holocellulolytic enzymes. Proteomic analysis confirmed the partial identification of the BL02 enzyme as an ester hydrolase, while structural modeling based on homologous Burkholderia lipases provided preliminary insights into features that may be compatible with the accommodation of bulky polar substrates. In addition, the enzyme catalyzed the synthesis of sugar fatty acid esters with conversion yields above 50% for glucose and xylose in binary solvent systems. These findings support the role of galactolipases as accessory enzymes and highlight their potential application in integrated and sustainable biorefinery processes. Full article

PARP1/2 inhibitors have received FDA approval for pancreatic cancer harboring BRCA1/2 mutations and homologous recombination (HR) deficiency; however, their limited indications restrict their broader clinical application. Previous studies have demonstrated that PARP7, a member of the PARP family, enhances tumor sensitivity to PARP1/2 inhibition. However, the mechanisms underlying their synergistic effects in pancreatic cancer remain unclear. Herein, we found that combined inhibition of PARP1/2 and PARP7 using Olaparib and XYL-1 significantly inhibited the proliferation of SW1990 and CFPAC cells compared with either single agent. Furthermore, XYL-1 and Olaparib cooperatively caused DNA damage and induced cell apoptosis in SW1990 cells. Consistently, combined treatment with XYL-1 and Olaparib significantly suppressed SW1990 tumor growth compared with single-agent treatment in mouse xenograft models, accompanied by elevated levels of phosphorylated H2AX in tumor tissues. Notably, bioinformatic analyses and mechanistic studies identified SCD1 and BRCA1 as key mediators of the synergistic antitumor effects of XYL-1 and Olaparib. More importantly, the combination of XYL-1 and Olaparib synergistically downregulated the expression of SCD1 and BRCA1, thereby impairing the HR-mediated DNA repair pathway. Collectively, these findings suggest that dual targeting of PARP7 and PARP1/2 may represent a promising therapeutic strategy for BRCA-proficient pancreatic cancer. Full article

Pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) are aggressive malignancies frequently driven by oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations associated with metabolic reprogramming and resistance to apoptosis. In this study, we evaluated the antitumor and anti-inflammatory activity of a Lepidium latifolium L.-derived formulation (CTP) enriched in glucosinolate hydrolysis products in KRAS-mutant colorectal and pancreatic cancer models. The formulation was designed to promote the generation of the epithionitrile 1-cyano-2,3-epithiopropane (CETP) through iron-dependent myrosinase-mediated sinigrin hydrolysis. CTP induced dose-dependent cytotoxicity and morphological alterations consistent with apoptosis in KRAS-mutant cancer cell lines. Treatment significantly reduced mitochondrial membrane potential, ATP production, oxygen consumption rate (OCR), and extracellular acidification rate (ECAR), indicating severe bioenergetic impairment. In parallel, CTP downregulated the metabolic and proliferative regulators C-myc, PKM2, GLUT1, and Cyclin E1. RNA-seq analysis revealed extensive transcriptional reprogramming associated with oxidative stress, metabolic adaptation, and cell-cycle regulation. In addition, CTP significantly suppressed nitric oxide, IL-6, and IL-8 production in LPS-stimulated RAW 264.7 macrophages. These findings demonstrate that glucosinolate-derived metabolites from L. latifolium interfere with metabolic and inflammatory pathways critical for KRAS-driven tumor survival and support the therapeutic potential of Brassicaceae-derived epithionitriles as multitarget anticancer agents. Full article

Climate change may substantially alter the habitat suitability and spatial stability of highland edible and medicinal plant resources. Argentina anserina (L.) Rydb. is an important wild resource plant in western China, but its potential distribution and future climate-change response in the three ethnic prefectures of Sichuan Province remain insufficiently understood. In this study, we used an ensemble species distribution modeling framework based on 31 spatially filtered occurrence records and 12 environmental predictors to evaluate the current and future habitat suitability of A. anserina under SSP126, SSP370, and SSP585 scenarios for the 2050s and 2090s. The ensemble model showed acceptable overall discrimination ability and was used to identify broad-scale suitability patterns. Mean diurnal range, precipitation of the driest quarter, isothermality, and topsoil pH were the main environmental predictors, indicating that thermal variability, dry-season moisture availability, and edaphic conditions jointly shaped habitat suitability. Under current conditions, the total suitable habitat area was predicted to be 15.57 × 10⁴ km², accounting for 57.2% of the study region, with high-suitability habitats mainly concentrated in the northern, northwestern, and central areas. Future projections suggested an overall decline in suitable habitats, especially in high-suitability areas, although the magnitude varied among scenarios and periods. Spatial change and centroid migration analyses indicated that future suitable habitats may undergo contraction and westward or northwestward redistribution rather than uniform expansion. Niche overlap analysis further showed moderate to relatively high overlap between current and future environmental spaces, suggesting partial niche stability with scenario-dependent shifts. Given the limited field-based occurrence records, these findings should be interpreted as broad-scale spatial guidance rather than precise local predictions. Full article

Chinese wolfberry (CW) is a medicinal-food homologous fruit. Key mineral elements are important indicators of the nutritional quality and geographical authenticity of CW. Rapid and non-destructive evaluation of key mineral elements remains challenging because inductively coupled plasma mass spectrometry (ICP-MS) is accurate but destructive and laboratory-dependent. In this study, 120 CW batches from Ningxia, Qinghai, Gansu, and Xinjiang were analyzed by combining ICP-MS reference measurements of Cu, Fe, Mn, and Zn with standardized RGB image features. Visible-color proxy curves were reconstructed from RGB/L*a*b* information and Gaussian fitting, and frequency-domain texture descriptors were extracted from Fourier-derived angle–energy curves. Multivariate analysis showed that mineral profiles, the 570–593 nm visible-color proxy band, and the 0–40° and 63–140° texture-angle ranges contributed to regional differentiation. A Dung Beetle Optimizer-radial basis function (DBO-RBF) regression model was then used for internal prediction of mineral element contents and compared with nine baseline regression algorithms. DBO-RBF achieved test-set R² values of 0.949, 0.965, 0.951, and 0.913 for Cu, Fe, Mn, and Zn, respectively, with corresponding test RPD values of 2.9017, 3.2419, 3.0175, and 2.8416. These results indicate that image-derived visible-color and texture features can provide useful screening information for mineral quality assessment in CW, offering a rapid, low-cost, and non-destructive approach for preliminary batch evaluation. Full article

Introduction: The development of bivalent mucosal vaccines capable of providing protection against both influenza and SARS-CoV-2 is a major public health focus. While most COVID-19 vaccines target the spike (S) protein, the highly conserved nucleocapsid (N) protein represents a strategic target for cross-reactive, cell-mediated immunity. This study evaluates Corfluvec, an intranasal vaccine candidate based on an attenuated NS1-truncated influenza vector expressing a fragment of the SARS-CoV-2 N protein. Methods: Protective efficacy, including viral load and pathomorphological changes in the lungs and vessels, was evaluated in Syrian hamsters challenged with high and low doses of SARS-CoV-2 (lineage B.1.1). Cross-protective efficacy against homologous and heterologous influenza A strains (H1N1pdm09, H3N2, and A/PR/8/1934) was tested in a lethal murine model. Additionally, immunogenicity of Corfluvec applied via human-compatible delivery device was tested in cynomolgus macaques (Macaca fascicularis). Results: In Syrian hamsters, vaccination significantly reduced viral loads in the lungs and nasal turbinates. Histopathological analysis revealed a preservation of lung vascular integrity: vaccinated animals showed stable CD31 expression and controlled Ki-67 proliferative activity, accompanied by a marked reduction in vasculitis and perivascular edema compared to placebo controls. In mice, the vaccine provided 100% protection against homologous and heterologous influenza virus challenges. In macaques, the two-dose intranasal immunization was well-tolerated and induced significant systemic IgG and mucosal sIgA responses, alongside robust N-specific IFNγ+ T-cell activation. Conclusions: Corfluvec is a promising bivalent vaccine candidate that provides dual protection against influenza and COVID-19. Its ability to limit viral shedding from the upper respiratory tract and to mitigate SARS-CoV-2-induced pulmonary pathology, contributing to the preservation of lung vascular integrity, underscores the utility of mucosal immunization with Corfluvec as a valuable intranasal complement to current systemic vaccination strategies. Full article

Sea anemone venom has attracted increasing attention in biomedical research due to its multifarious compounds with biological activities. Although the venom is predominantly made up of proteins, the diversity and complexity of these proteins remain poorly understood. In this work, the proteins derived from the tentacle and column of Heteractis magnifica were investigated by integrating transcriptomic and proteomic technologies. A total of 3573 protein sequences from transcriptome databases were identified and clustered into nine functional categories. We also performed proteomic analysis on the proteins identified in H. magnifica, and 339 proteins were found to be present in both datasets. Notably, a comprehensive analysis of six typical categories was implemented, and the representative proteins were explored in depth using multiple alignments, homology modeling and molecular docking. Meanwhile, a few low-copy but functionally intriguing proteins were discovered, highlighting the presence of unconventional components in sea anemone venom. This work provides the first holistic overview of the typical protein families and novel information on functional proteins from H. magnifica, contributing to a deeper understanding of sea anemone proteins and facilitating the discovery of potential proteins for marine drugs or biotechnological tools. Full article

SASH1 (SAM [sterile alpha motif] and SH3 [SRC-homology-3] domain-containing protein 1) is a multidomain scaffold implicated in pigmentation, innate immunity, receptor signaling, cytoskeletal dynamics, vascular biology, and tumor suppression. Although genetic and expression studies link SASH1 dysfunction to diverse diseases, a unifying mechanistic framework has remained elusive. Here, we synthesize current knowledge of SASH1 structure, interaction networks, and biological functions across cell types and disease contexts. SASH1 contains an intrinsically disordered SPIDER (SLy Proteins Associated Disordered Region), an SH3 domain, two SAM domains, and multiple linear motifs; together, these elements mediate interactions with EphA8 (ephrin type-A receptor 8), β-arrestin 1, TRAF6 (TNF receptor-associated factor 6), CRKL (CRK-like proto-oncogene), IQGAP1 (IQ-motif-containing GTPase-activating protein 1), cortactin, and TNKS2 (tankyrase-2). We propose that SASH1 functions as a context-dependent multi-docking scaffold that organizes signaling architecture. Its modular domains, intrinsically disordered regions, and dual SAM domains enable flexible, multivalent interactions with partners that can be grouped into three functional modules: receptor regulation, intracellular signaling, and cytoskeletal organization. Notably, many SASH1 partners are themselves scaffold or adaptor proteins, allowing integration into pre-existing networks in a hierarchical ‘scaffold-of-scaffolds’ manner. Through selective partner recruitment, SASH1 links cell-surface receptor inputs to downstream signaling pathways and cytoskeletal remodeling. This model provides a mechanistic framework for how SASH1 drives diverse, cell-type-specific outputs across physiology and disease, while revealing broader principles by which multidomain scaffolds encode cellular behavior. Full article

Background: Staphylococcus aureus, including methicillin-resistant lineages, is a leading cause of device- and catheter-related infection, and rising resistance motivates the search for antimicrobial peptides (AMPs) with strong anti-staphylococcal activity and low host toxicity. Machine learning can prioritize candidate peptides. However, the literature-derived AMP datasets are prone to homology-driven optimism, and computational studies frequently overstate their translational reach. Methods: We curated 4007 deduplicated S. aureus-active AMP records and 582 binary-labeled hemolysis records. Each peptide was encoded with a transparent 538-dimensional physicochemical and compositional feature vector. Five classifiers and five regressors were evaluated for four endpoints (potency classification, log₁₀ MIC regression, hemolysis classification, normalized hemolytic index) under both conventional random 5-fold cross-validation and homology-aware cross-validation, in which sequences were clustered by 3-mer similarity and whole clusters were confined to single folds. Class imbalance was handled by class weighting. Model behavior was interpreted with SHAP and Fisher-exact k-mer enrichment, and candidates were ranked by a multi-objective score that combines the independently trained heads. Results: Under homology-aware validation, performance was lower than under random splitting, as expected. Potency classification reached an AUROC of about 0.71 (Random Forest), compared with 0.797 under random cross-validation. Hemolysis classification remained strong at AUROC 0.90 (95% CI 0.88 to 0.93), which indicates that its high accuracy is not a homology leakage artifact. MIC regression was modest (homology-aware R² 0.17, Spearman ρ 0.39) and is therefore treated only as a rank-ordering signal. SHAP and k-mer analyses recovered interpretable structure–activity relationships. Net positive charge and amphipathicity drove potency, whereas bulk hydrophobicity drove hemolysis. Applying the pipeline to a generated pool prioritized 20 candidates. Nearest-neighbor analysis shows that these are close optimized variants of known potent scaffolds, with a median identity of 95% to a known peptide, rather than novel sequences. Conclusions: We present an interpretable, honestly benchmarked multi-objective pipeline that optimizes known anti-S. aureus AMP scaffolds toward lower predicted hemolysis. The prioritized peptides are computational hypotheses for future synthesis and experimental testing. Their low predicted hemolysis reflects a selection criterion rather than validated safety, and cross-species selectivity was not assessed. Full article

Sirtuins (SIRTs) are NAD⁺-dependent enzymes implicated in cancer and other diseases, but the high conservation of their catalytic sites complicates the development of isoform-selective inhibitors. BZD9L1 is a benzimidazole-based sirtuin inhibitor with previously reported activity against SIRT1 and SIRT2. However, its potential interactions with other human sirtuin isoforms remain incompletely characterized. Here, we applied a comparative structure-based modelling framework integrating homology modelling, molecular docking, and targeted experimental assessment to investigate plausible binding modes of BZD9L1 across human SIRT1–7. Docking predicted that BZD9L1 could occupy the ADP-ribose cofactor-binding region of all seven isoforms, with broadly conserved orientations but differences in the predicted interaction networks. Hydrogen-bonding and π-mediated contacts predominated in the selected SIRT1–3 poses, whereas hydrophobic contacts were more apparent in several selected SIRT4–7 poses. The modest differences in docking scores were interpreted qualitatively and do not establish differential binding affinities or isoform selectivity. In colorectal cancer cells, BZD9L1 treatment altered acetyl-SOD2 levels, consistent with altered SIRT3-associated deacetylation in a cellular context. In a separate cell-free enzymatic assay, no measurable SIRT5 inhibition was detected under the conditions tested. These complementary assays provided distinct, independently interpreted readouts of SIRT3-associated cellular activity and SIRT5 enzymatic activity. Collectively, this study provides testable structural hypotheses regarding BZD9L1 recognition by human sirtuins and identifies interaction features that may guide subsequent biochemical and structure-based investigations. Full article