Search Results (40,300)

MicroRNA (miRNA), as a key post-transcriptional regulatory factor, plays a crucial role in embryonic development. The coordination of endoderm cell convergence and cardiac precursor cell (CPC) migration is critical for cardiac tube fusion. Defects in endoderm can impair the normal migration of CPCs towards the midline, leading to cardia bifida. Although the role of the microRNA-183 family (miR-183, miR-96 and miR-182) in cardiovascular diseases has been reported, the mechanism by which they regulate early heart development remains unclear. In this study, we used zebrafish as a model to elucidate the roles of the microRNA-183 family in early heart development. miRNA mimics were injected into Tg (cmlc2: eGFP) and Tg (sox17: eGFP) transgenic embryos to overexpress the miR-183 family. The results showed that, at 36 hpf, single or co-injection of miR-183/96/182 mimics caused defects in endoderm convergence, with a hole in the endoderm, and a significant down-regulation of the endoderm marker gene sox32. Additionally, embryos with single or co-injection of miR-183/96/182 mimics exhibited cardia bifida and tail blisters, with significantly down-regulated expression levels of genes related to heart development, including cmlc2, vmhc, amhc, nppa, gata4, gata5, nkx2.5, bmp2b, and bmp4. The phenotype caused by overexpression of the miR-183 family is highly consistent with loss of the sphingosine 1-phosphate receptor S1Pr2. Bioinformatics analysis result found that miR-183 can bind to 3′-UTR of the s1pr2 to regulate its expression; overexpression of miR-183 led to a significant decrease in the expression of the s1pr2 gene. Dual luciferase assay results suggest that s1pr2 is a bona fide target of miR-183. In summary, the miR-183 family regulates endoderm convergence and cardiac precursor cell migration via the S1Pr2 signaling pathway. This study reveals that the miR-183 family is a key regulatory factor in endoderm convergence and cardiac precursor cell migration during the early zebrafish development, elucidating the molecular mechanisms underlying early cardiac precursor cell and endoderm cell movement. Full article

Ischemic heart disease remains the leading cause of death despite substantial advances in diagnosis, revascularization therapies, and risk-factor control. Beta-adrenergic receptor blockers (Beta-Blockers, BBs), long used to control heart rate, blood pressure, and reduce arrhythmic risk, may also confer cardioprotection through mechanisms beyond hemodynamic unloading. This review integrates an extensive range of preclinical, translational, and clinical studies to present a comprehensive overview of the cardioprotective effects of BBs in the context of myocardial ischemia and reperfusion injury. Mechanistic domains include modulation of redox homeostasis, attenuation of inflammation and neutrophil activation, preservation of mitochondrial integrity and anti-apoptotic signaling, improvement of endothelial function, and stabilization of calcium handling. Third-generation compounds, carvedilol and nebivolol, demonstrate additional antioxidant and vasodilatory benefits compared with first- and second-generation agents; however, no consistent class-wide effect exists across most pathways. The evidence base remains fragmented, often derived from agent- or context-specific studies in heterogeneous populations, with uncertainty surrounding optimal timing of intervention. By bridging mechanistic understanding with clinical outcomes, this review highlights the importance of standardized assessment of BB effects, the development of personalized treatment approaches, and the pursuit of future research to address ongoing translational gaps. Full article

Objectives: Shen-Ling-Bai-Zhu-San (SLBZS) is a classical traditional Chinese herbal formula with spleen-invigorating and dampness-resolving properties. Recent pharmacological studies suggest its potential to regulate immune and metabolic disorders. Type 2 diabetes mellitus (T2D) and ulcerative colitis (UC) often coexist as comorbidities characterized by chronic inflammation, microbial imbalance, and insulin dysregulation, yet effective therapies remain limited. This study aimed to investigate the molecular mechanisms through which SLBZS may benefit T2D–UC comorbidity. Methods: An integrative multi-omics strategy was applied, combining network pharmacology, structural bioinformatics, and ensemble molecular docking–dynamics simulations. These complementary approaches were used to identify SLBZS bioactive compounds, predict their putative targets, and examine their interactions with disease-related biological networks. Results: The analyses revealed that flavonoids in SLBZS act on the SLC6A14/PI3K–AKT signaling axis, thereby modulating immune responses and improving insulin sensitivity. In addition, SLBZS was predicted to regulate the NF-$\kappa$B/MAPK signaling pathways, key hubs linking inflammation and metabolic dysfunction in T2D–UC. These dual actions suggest that SLBZS can intervene in both inflammatory and metabolic processes. Conclusions: SLBZS demonstrates promising therapeutic potential for T2D–UC by targeting interconnected immune–metabolic networks. These findings not only provide mechanistic insights bridging traditional therapeutic concepts with modern pharmacology but also establish a theoretical basis for future experimental validation and clinical application. Full article

Postharvest fungal rot causes significant economic losses in the agroindustry. Current control methods involving the use of synthetic fungicides are becoming increasingly ineffective and pose environmental risks. This necessitates exploring sustainable alternatives, such as essential oils derived from medicinal plants, to achieve safer and effective disease control. This research examined the chemical composition and efficacy of essential oils from Aloysia citriodora, Aloysia polystachya and their compounds against the postharvest rot fungi Monilinia fructicola, Monilinia laxa, and Botrytis cinerea. The main compounds of essential oils were analyzed by GC/MS and revealed differences in their composition. A. citriodora is characterized by the presence of spathulenol and caryophyllene oxide. In contrast, A. polystachya is characterized by the predominance of carvone. The results show that the essential oil of A. citriodora and the compound farnesol are able to inhibit the three pathogens. Notably, against M. fructicola, the EC₅₀ values were 61.89 μg/mL and 72.18 μg/mL, respectively. Against B. cinerea, the EC₅₀ values were 85.34 μg/mL and 47.6 μg/mL. Molecular docking also showed that farnesol has affinity for the enzyme succinate dehydrogenase suggesting a possible mechanism of action. This compound and A. citriodora essential oil show potential in the control of phytopathogens. Full article

Autoimmune gastritis (AIG) is a chronic, organ-specific autoimmune disease characterized by progressive destruction of gastric parietal cells driven by autoreactive CD4⁺ T-cells, epithelial stress pathways, and microbial factors. Parietal cell loss results in achlorhydria, intrinsic factor deficiency, and vitamin B12 malabsorption, ultimately leading to pernicious anemia. Compensatory hypergastrinemia promotes enterochromaffin-like (ECL) cell hyperplasia and contributes to the development of type 1 gastric neuroendocrine neoplasms (gNENs). These clinical consequences are well recognized, yet the cellular and molecular mechanisms driving mucosal atrophy and neoplastic transformation remain incompletely defined. Recent advances highlight the role of endoplasmic reticulum stress, impaired autophagy, innate immune effectors, and dysbiosis in perpetuating inflammation and epithelial injury. The frequent coexistence of AIG with other autoimmune disorders further adds to its clinical complexity. Therapeutic options remain limited, spanning vitamin B12 replacement and endoscopic management to emerging targeted approaches. Netazepide, a gastrin/CCK2 receptor antagonist, is the only agent tested in clinical trials, whereas interventions targeting ER stress, autophagy, immune tolerance, or microbiome composition are still in the preclinical stage. Clarifying these mechanisms is crucial to improve biomarker development, optimize surveillance, and identify targeted therapies to prevent neoplastic transformation. Full article

This study investigated the protective effects of Gardenia jasminoides Ellis polysaccharides (GP) on lipopolysaccharide (LPS)-induced immunosuppression and oxidative stress in mice and explored how GP modulates macrophage polarization through the TLR4/NF-κB signaling axis. The results showed that GP notably restored thymus and spleen indices in LPS-treated mice, markedly decreased the serum concentrations of malondialdehyde, and enhanced superoxide dismutase activity and total antioxidant capacity. In RAW 264.7 macrophage cultures, GP displayed immunostimulatory effects by improving phagocytic activity, promoting NO synthesis, and enhancing the secretion of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α. These effects were observed in cells not pretreated with TAK-242 or PDTC; however, they were not observed in cells pretreated with these inhibitors. At 300 µg/mL concentration, GP markedly enhanced the transcriptional levels of iNOS and cytokine genes. Protein analysis revealed significant upregulation of TLR4, MyD88, TRAF6, NF-κB RelA/p65, and phosphorylated p65. Fluorescence imaging confirmed the nuclear translocation of p65. Collectively, these findings indicated that GP reversed systemic immunosuppression and oxidative stress, offering foundational insights for developing natural immune regulators. The observed immunomodulatory properties of GP are likely mediated through the TLR4/NF-κB signaling pathway. Full article

Starvation in horses presents critical welfare, economic, and management challenges with underlying molecular mechanisms of metabolic modification and recovery left poorly defined. Prolonged caloric deprivation induces significant systemic shifts in carbohydrate, protein, and lipid metabolism, reflected in coordinated changes in tissue-specific gene expression. This review synthesizes current knowledge on equine metabolic responses to starvation, emphasizing pathways found through RNA sequencing (RNA-seq) and real-time quantitative polymerase chain reaction (RT-qPCR) studies. Molecular investigations using RNA-seq and RT-qPCR have provided insight into transcriptional reprogramming during starvation and subsequent refeeding. Shifts in gene expression reflect the metabolic transition from carbohydrate dependence to lipid use, suppression of anabolic signaling, and activation of proteolytic pathways. However, interpretation of these data requires caution, as factors such as post-mortem interval, tissue handling, and euthanasia methods particularly the use of sodium barbiturates can influence transcript stability and abundance, potentially confounding results. The literature shows that starvation-induced molecular changes are not uniform across tissues, with skeletal muscle, liver, and adipose tissue showing distinct transcriptional signatures and variable recovery patterns during refeeding. Cross-species comparisons with hibernation, caloric restriction, and cachexia models provide context for understanding these changes, though equine-specific studies remain limited. Identified gaps include the scarcity of longitudinal data, inconsistent tissue sampling protocols, and lack of standardized reference genes for transcriptomic analyses in horses. Addressing these limitations will improve the accuracy of molecular evaluations and enhance our ability to predict recovery trajectories. A more comprehensive understanding of systemic and tissue-specific responses to starvation will inform evidence-based rehabilitation strategies, reduce the risk of refeeding syndrome, and improve survival and welfare outcomes for affected horses. Full article

To elucidate the molecular mechanisms underlying salt tolerance in rice (Oryza sativa L.), this study investigated differential transcriptional responses during the tillering stage. Salt-tolerant (N14) and salt-sensitive (N6) varieties were subjected to 0.3% and 0.6% NaCl treatments for 72 h, and their transcriptomes were analyzed via RNA-Seq. The results revealed distinct response strategies: 372 differentially expressed genes (DEGs) were identified in N14 and 393 in N6, with only 17 genes responding similarly. Gene Ontology (GO) analysis showed the tolerant N14 activated protein phosphorylation and lipid transport, primarily in the membrane and extracellular regions (e.g., ATP binding), whereas the sensitive N6 activated photosynthesis and protein folding, localized to chloroplasts and peroxisomes. KEGG analysis highlighted the activation of “Plant-pathogen interaction” in N14 versus “Metabolic pathways” in N6. Differential transcription factor activation was also observed, with N14 mobilizing 52 TFs (mainly WRKY and MYB) and N6 mobilizing 36 TFs (mainly MYB and b-ZIP). This study demonstrates that N14 and N6 utilize significantly different molecular pathways to cope with salinity, providing a crucial theoretical foundation for identifying novel salt tolerance genes and developing molecular breeding strategies. Full article

Melanoma is an aggressive malignancy with poor prognosis in advanced stages, and current therapeutic options provide only limited benefits, highlighting the need for novel treatments. Chetomin, a fungal metabolite isolated from Chaetomium cochliodes, has been reported to exhibit diverse biological activities, yet its effects on melanoma cells remain poorly understood. In this study, we evaluated the antitumor potential of chetomin using the human A375 melanoma cell line. Cell viability was assessed with MTT and CellTiter-Glo^® assays, which revealed a significant dose- and time-dependent reduction in proliferation following chetomin exposure. Apoptotic effects were confirmed through Annexin V staining, and immunocytochemical analysis demonstrated a concentration-dependent increase in cleaved PARP1, indicating activation of programmed cell death pathways. Collectively, these findings demonstrate that chetomin effectively inhibits melanoma cell growth and promotes apoptosis. The results suggest that chetomin represents a promising lead compound for melanoma therapy, warranting further investigation into its precise molecular mechanisms. Full article

Background: Most immunologically “cold” tumors do not respond durably to checkpoint blockade because tumor antigen (TA) release and presentation are insufficient to prime effective T-cell immunity. While prior work demonstrated synergy between cisplatin and a TLR7/8/9 agonist (CR108) in 4T1 tumors, the underlying mechanism—particularly whether chemotherapy functions as a broad antigen-releasing agent enabling TLR-driven immune amplification—remained undefined. Methods: Using murine models of breast (4T1), melanoma (B16-F10), and colorectal cancer (CT26), we tested multiple chemotherapeutic classes combined with CR108. We quantified intratumoral and systemic soluble TAs, antigen presentation and cross-priming by antigen-presenting cells, tumor-infiltrating lymphocytes, and cytokine production by flow cytometry/ICS. T-cell receptor β (TCRβ) repertoire dynamics in tumor-draining lymph nodes were profiled to assess amplitude and breadth. Tumor microenvironment remodeling was analyzed, and public datasets (e.g., TCGA basal-like breast cancer) were interrogated for expression of genes linked to TA generation/processing and peptide loading. Results: Using cisplatin + CR108 in 4T1 as a benchmark, we demonstrate that diverse chemotherapies—especially platinum agents—broadly increase the repertoire of soluble tumor antigens available for immune recognition. Across regimens, chemotherapy combined with CR108 increased T-cell recognition of candidate TAs and enhanced IFN-γ⁺ CD8⁺ responses, with platinum agents producing the largest expansions in soluble TAs. TCRβ sequencing revealed increased clonal amplitude without loss of repertoire breadth, indicating focused yet diverse antitumor T-cell expansion. Notably, therapeutic efficacy was not predicted by canonical damage-associated molecular pattern (DAMP) signatures but instead correlated with antigen availability and processing capacity. In human basal-like breast cancer, higher expression of genes involved in TA generation and antigen processing/presentation correlated with improved survival. Conclusions: Our findings establish an antigen-centric mechanism underlying chemo–TLR agonist synergy: chemotherapy liberates a broadened repertoire of tumor antigens, which CR108 then leverages via innate immune activation to drive potent, T-cell-mediated antitumor immunity. This framework for rational selection of chemotherapy partners for TLR7/8/9 agonism and support clinical evaluation to convert “cold” tumors into immunologically responsive disease. Full article

The ability of common carp to withstand both short-term and long-term oxygen deprivation has been well documented; however, the potential genetic mechanisms behind common carp’s hypoxia response remain unclear. Therefore, to understand the possible genetic foundation of their response to hypoxia, comparative genomic analyses were conducted among six common carp varieties: Color, Songpu, European, Yellow, Mirror, and Hebao common carps. We identified 118 single-copy orthologous positively selected genes (PSGs) (dN/dS > 1) in all common carps under study, with GO functions directly related to the cellular responses to hypoxia in Color and European common carp PSGs, such as oxygen transport activity, oxygen binding activity, respiratory burst activity, and superoxide anion production. The Bayes Empirical Bayes (BEB) technique identified possible amino acid substitutions in mitochondrial and hypoxic genes under positive selection. Exonic and intronic structural variations (SVs) were discovered in the CYGB2 hypoxia-related gene of Color and European common carps, as well as in several mitochondrial genes, including MRPL20, MRPL32, NSUN3, GUF1, TMEM17B, PDE12, ACAD6, and COX10 of Color, European, Songpu, Yellow, and Hebao common carps. Moreover, Color common carp and Songpu common carp were found to share the greatest percentage of collinear genes (49.8%), with seven Songpu common carp chromosomes (chr A2, chr A9, chr A13, chr B13, chr B15, chr B2, and chr B12) showing distinct translocation events with the corresponding chromosomes of Color common carp. Additionally, we found 570 translocation sites that contained 3572 translocation-related genes in Color common carp, some of which are directly relevant to mitochondrial and hypoxic GO functions and KEGG pathways. Our results offer strong genome-wide evidence of the possible evolutionary response of Cyprinus carpio to hypoxia, providing important insights into the potential molecular mechanisms that explain their survival in hypoxic environments and guiding future research into carp hypoxia tolerance. Full article

In recent years, the scientific community has increasingly delved into the study of the interaction between the nervous system and tumors, revealing that the nervous system not only regulates bodily functions under physiological conditions, but also assumes a vital part in the emergence and progression of tumors. Research has demonstrated that the extensive neural network directly regulates tumor progression and can influence tumors by modulating the tumor microenvironment and immune system. Moreover, tumors induce neural networks to provide favorable conditions for their proliferation and metastasis. In the above process, neurotransmitters play a vital role. They directly act or bind to their receptor, activating various classical signaling pathways, among which are PI3K/AKT, MEK/ERK, and WNT/β-catenin, to facilitate tumor advancement. Therefore, this study systematically reviews the regulatory mechanisms of neurotransmitters and their receptors in the advancement of cancer, along with the utilization of targeted drugs. At the same time, we also analyzed that targeting specific receptor subtypes may produce more significant therapeutic effects in different types of cancer. Additionally, this research further explores the limitations of neurotransmitter-based drugs currently used in clinical cancer treatment. In summary, the field of cancer neuroscience is rapidly advancing, constantly revealing the regulatory effects of neurotransmitters on tumor progression and their specific molecular mechanisms, providing broad application prospects for future clinical therapy. Full article

Diketopiperazines (DKPs) are biologically important cyclic dipeptides widespread in nature, associated primarily with microorganisms. This is the case for the 2,5-DKP derivative cyclo(L-Leu-L-Pro) (cLP), also known as gancidin W or PPDHMP, identified from a variety of bacteria and fungi, and occasionally found in food products. The present review retraces the discovery of cLP, its identification in living species, its chemical syntheses, and its biochemical properties. In bacteria, cLP is often associated with other DKPs to serve as a defense element against other microorganisms and/or as a regulator of bacterial growth. cLP plays a role in quorum-sensing and functions as an anticariogenic and antifungal agent. The antimicrobial mechanism of action and molecular targets of cLP are evoked. The interest in cLP for combatting certain parasitic diseases, such as malaria, and cancers is discussed. The capacity of cLP to interact with CD151 and to down-regulate the expression of this tetraspanin can be exploited to reduce tumor dissemination and metastases. The review sheds light on the pharmacology and specific properties of cyclo(L-Leu-L-Pro), which can be useful for the development of a novel therapeutic approach for different human pathologies. It is also of interest to help define the bioactivity and mechanisms of action of closely related DKP-based natural products. Full article

Ammonia–coal co-combustion has emerged as a promising strategy for reducing carbon emissions from coal utilization, although its underlying reaction mechanisms remain insufficiently understood. The Chemkin simulation of zero-dimensional homogeneous reaction model and entrained flow reaction model was employed here, and the ROP (rate of production) and sensitivity analysis was performed for analyzing in-depth reaction mechanisms. The nitrogen conversion pathways were revealed, and the mechanisms were simplified. Based on simplified mechanisms, molecular-level reaction pathways and thermochemical conversion networks of nitrogen-containing precursors were established. The results indicate that NO emissions peak at a 30% co-firing ratio, while N₂O formation increases steadily. The NH radical facilitates NO reduction to N₂O, with NH + NO → N₂O + H identified as the dominant pathway. Enhancing NNH formation and suppressing NCO intermediates are key to improving nitrogen conversion to N₂. This paper quantifies the correlation between NO_x precursors such as HCN and NH₃ and intermediates such as NCO and NNH during ammonia–coal co-firing and emphasizes the important role of N₂O. These insights offer a molecular-level foundation for designing advanced ammonia–coal co-combustion systems aimed at minimizing NO_x emissions. Full article

The widespread use of neonicotinoid insecticides has led to increasing resistance in non-target organisms, including the egg parasitoid Trichogramma dendrolimi, a crucial biological control agent. Film-residue bioassays on 17 geographic strains revealed striking inter-strain variability in susceptibility to imidacloprid, with mortality at a discriminating dose of 0.1 mg/L ranging from 25.7% to 87%. The most tolerant (FS) and least tolerant (HA) strains were subsequently selected for evaluation of biological parameters and comparative transcriptomics. Tolerant strains (FS) showed adaptive trade-offs: extended longevity (5.47 ± 0.57 d) and emergence (93.6 ± 1.9%), but reduced fecundity (54.6 ± 4.9 eggs) compared to HA. Transcriptome analysis revealed 2115 differentially expressed genes, with GO enrichment highlighting metabolic and detoxification pathways. KEGG analysis the most enriched pathways were “Protein digestion and absorption” and “Neuroactive ligand-receptor interaction”. RT-qPCR confirmed overexpression of CYP4C1, CYP6K1, and GstS1 in FS, indicating their potential roles in metabolic resistance if present. This study presents preliminary evidence of potential fitness trade-offs and molecular mechanisms that could underly imidacloprid resistance in T. dendrolimi, which may lead to important insights for resistance monitoring and more sustainable integrated pest management strategies. Full article