Search Results (42,445)

Background: Colorectal cancer (CRC) is a malignancy that ranks among the top three in terms of both global mortality and incidence. Although numerous studies have demonstrated that gut microbes are implicated in CRC pathogenesis, the precise mechanisms underlying host–microbiota metabolic crosstalk remain poorly understood. Objective: This study aims to identify and delineate key co-metabolites and their associated metabolic pathways that modulate the biomass of CRC-related gut bacteria within healthy individuals, through the construction of host–gut microbiota co-metabolic network models. We seek to elucidate the underlying mechanisms of metabolic interplay between the host and CRC-related gut microbiota, thereby offering novel perspectives on the microbial involvement in the initiation and progression of CRC. Methods: We coupled a colon tissue-specific host Genome-Scale Metabolic Model (GEM), which utilized transcriptomic data from healthy human colon tissues, with 12 CRC-associated pro-/anti-carcinogenic gut bacterial GEMs to construct a co-metabolic network. Through a comparative analysis of the network structure and systemic methods (including Flux Sampling and metabolic difference analysis), we simulated scenarios of constrained host co-metabolite supply. Finally, metabolic subsystem enrichment analysis was employed to elucidate the specific molecular mechanisms by which key co-metabolites affect microbial function. Results: The 17 key co-metabolites identified include chloride ions, zinc ions, and acetate. Among these, thirteen metabolites (e.g., ferric iron, succinate, and acetate) were confirmed by literature to be associated with CRC. All 17 key co-metabolites were found to significantly modulate the biomass of CRC-associated gut bacteria. These regulatory effects primarily influence microbial function through core pathways such as glycerophospholipid metabolism and folate metabolism. Conclusion: This research provides a systemic perspective for elucidating the mechanisms of host–gut microbiota metabolic interplay in CRC, thereby complementing the existing theoretical framework concerning microbial regulation by the host genetic background. Full article

Background: Advances in the understanding of molecular mechanisms of human diseases, along with the generation of large amounts of molecular datasets, have highlighted the variability between patients and the need to tailor therapies to individual characteristics. In particular, RNA-based therapies hold strong promise for new drug development, as they can be easily designed to target specific molecules. Gene and protein functions, however, operate within a highly interconnected network, and inhibiting a single function or repressing a single gene may lead to unexpected secondary effects. In this study, we focused on genes associated with Alzheimer’s disease, a progressive neurodegenerative disorder characterized by complex pathological processes leading to cognitive decline and dementia. Its hallmark features include the accumulation of extracellular amyloid-β plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. Methods: We built a protein interaction network subgraph seeded on five Alzheimer’s-associated genes, including tau and amyloid-β precursor, and integrated it with microRNAs in order to select regulated nodes, study the effects of their depletion on signaling pathways, and prioritize targets for microRNA-based therapeutic approaches. Results: We identified nine protein nodes as potential candidates (Pik3R1, Bace1, Traf6, Gsk3b, Akt1, Cdk2, Adam10, Mapk3 and Apoe) and performed in silico node depletion to simulate the effects of microRNA regulation. Conclusions: Despite intrinsic limitations of the approach, such as the incompleteness of the available information or possible false associations, the present work shows clear potential for drug design and target prioritization and underscores the need for reliable and comprehensive maps of interactions and pathways. Full article

Therapeutic peptides have emerged as promising tools in oncology due to their high specificity, favorable safety profile, and capacity to target molecular hallmarks of cancer. Their clinical translation, however, remains limited by poor stability, rapid proteolytic degradation, and inefficient biodistribution. Iron oxide nanoparticles (IONPs) offer a compelling solution to these challenges. Owing to their biocompatibility, magnetic properties, and ability to serve as both drug carriers and imaging agents, IONPs have become a versatile platform for precision nanomedicine. The integration of peptides with IONPs has generated a new class of hybrid systems that combine the biological accuracy of peptide ligands with the multifunctionality of magnetic nanomaterials. Peptide functionalization enables selective tumor targeting and deeper tissue penetration, while the IONP core supports controlled delivery, MRI-based tracking, and activation of therapeutic mechanisms such as magnetic hyperthermia. These hybrids also influence the tumor microenvironment (TME), facilitating stromal remodeling and improved drug accessibility. Importantly, the iron-driven redox chemistry inherent to IONPs can trigger regulated cell death pathways, including ferroptosis and autophagy, inhibiting opportunities to overcome resistance in aggressive or refractory tumors. As advances in peptide engineering, nanotechnology, and artificial intelligence accelerate design and optimization, peptide–IONP conjugates are poised for translational progress. Their combined targeting precision, imaging capability, and therapeutic versatility position them as promising candidates for next-generation cancer theranostics. Full article

Bovine leukemia virus (BLV) causes enzootic bovine leukosis (EBL), yet its pathogenic mechanisms remain largely unclear. In particular, the role of BLV genomic integration sites (IS(s)) in BLV-induced leukemogenesis has not been fully elucidated. Here, we identified a total of 235 ISs from 99 BLV-infected cattle with lymphoma, of which 4.3% and 46.8% were located within exon and intron, respectively, while no preferential integration into CpG islands or repetitive regions was observed. All identified ISs were distinct, and no identical sites were detected among the samples. We identified 246 genes related with these ISs and protein–protein interaction analysis of these genes demonstrated one “IS-Clustered genes” composed of 85 among 246 genes. This “IS-Clustered genes” contains 12 cancer genes (14.1%) with high significantly proportion. Notably, with 55 among 99 cattle tested (55.6%) harboring ISs within this cluster, suggesting its crucial involvement in BLV-induced pathogenesis. Furthermore, integrated analysis of known lymphoma- and IS-related genes and the 85 “IS-Clustered genes” showed that key genes formed a shared cluster, indicating a potential “common EBL-associated cluster.” These findings provide important insights into the role of BLV integration in EBL development and may contribute to elucidating its molecular mechanisms underlying onset of EBL. In addition, these findings may also aid in the development of therapeutic strategies and facilitate early diagnosis. Full article

Soybean (Glycine max L.) is an essential food and economic crop in China, yet its growth and yield are severely constrained by saline–alkali stress. A saline–alkali soil exacerbates root absorption barriers, leading to 30–50% yield losses. Understanding the mechanisms underlying alkali tolerance is therefore crucial for developing stress-resilient soybean varieties and improving the productivity of saline–alkali land. In our previous study, we evaluated 99 soybean germplasms from Northeast China and obtained the alkali-tolerant varieties HN48 and HN69, along with the alkali-sensitive varieties HNWD4 and HN83. In this study, fifteen-day-old soybean seedlings were subjected to (30 mM NaHCO₃) alkali stress for 72 h, and whole plants were sampled to assess their morphology and physiology, while leaf tissues were harvested for biochemical analysis. For transcriptomic analysis, soybean seedlings were exposed to alkali stress (50 mM NaHCO₃, pH 9.0) for 6 h, and leaf and root tissues were harvested for RNA sequencing. The results showed that alkali-tolerant varieties mitigated these effects by suppressing excessive ROS generation by 55–63%, decreasing malondialdehyde (MDA) accumulation by 37–39%, and increasing photosynthetic efficiency by 18.3%, as well as accumulating more osmoprotectants and activating antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) under alkaline stress. Transcriptome analysis showed that the alkali-tolerant variety HN69 exhibited cultivar-specific enrichment of metabolism cytochrome P450, estrogen signaling, and GnRH signaling pathways under alkali stress. These results collectively indicate that alkali-tolerant soybean varieties adapt to alkali stress through coordinated multi-pathway responses, with differential pathway enrichment potentially underlying the variation in alkali tolerance between cultivars. Overall, this study elucidates the physiological and molecular mechanisms of alkali tolerance in soybean, providing a theoretical foundation for breeding stress-tolerant germplasms. Full article

Background: Intrinsically disordered regions (IDRs) within proteins often act as pivotal linkage units for the interaction of functional domains. The p53 tumor suppressor protein contains intrinsically disordered N-terminal and C-terminal domains (NTD and CTD), playing crucial regulatory roles in cellular processes. Furthermore, experimental approaches have encountered challenges in elucidating the structural regulation by the IDRs. Methods: In this work, we employed microsecond-scale molecular dynamics simulations to explore the allosteric regulation mechanism of the p53 DNA binding domain (DBD) induced by the CTD and the DNA binding. Subsequently, we integrated dynamic cross-correlation analysis with binding free energy calculations to evaluate the interaction between the CTD and DNA. Results: The free energy landscapes (FELs) were utilized to identify the conformational ensemble of the p53 DBD. The FELs revealed that the CTD enhances the allosteric regulatory mechanisms. Conclusions: Firstly, the conformation of DBD changes on the S6-S7 loop and L1 upon DNA binding. Then the CTD directly interacts with DNA and further regulates the allosteric network (involving the S6-S7 loop, L1 loop, S4, S10, H1, and H3) to promote the binding of DBD to DNA. The allosteric mechanisms presented in this work will provide new insights into the functional mechanisms of the p53 CTD and inform the rational design of p53-targeted drugs. Full article

Molecular dynamics simulations were conducted at a cooling rate of 1.0 × 10¹¹ K/s to investigate the solidification mechanism of zirconium (Zr) under high pressure. Three distinct pressure-dependent regimes are identified: crystallization into a body-centered cubic (BCC) phase below 27.5 GPa, vitrification between 27.5 and 65 GPa, and crystallization into an A15 phase above 65 GPa. The volume change during crystallization is found to reverse at critical pressures of 5 and 103 GPa, and anomalous behavior is observed at the phase boundaries: at 27.5 and 65 GPa, the volume varies continuously despite a sharp drop in potential energy, whereas at 65 GPa, the volume decreases abruptly while the energy changes smoothly. Structural analysis indicates that evolution in the low-pressure regime is governed by atomic configurations extending to the second-neighbor shell, while at high pressures, nearest-neighbor interactions become dominant. This work clarifies the microstructure–pressure relationship during metallic solidification, providing insights into controlling phase transitions under extreme conditions. Full article

Scylla paramamosain is a commercially important crab species widely cultured in China. However, artificial breeding remains limited by the high mortality of ovigerous females and asynchronous embryo hatching. In vitro embryo hatching has emerged as a promising alternative, yet its practical feasibility and underlying molecular mechanisms have not been systematically investigated. In this study, we examined the developmental characteristics of S. paramamosain embryos under different temperature regimes and hatching modes, evaluated embryo viability following maternal death, and compared transcriptomic profiles of Zoea I larvae between in vitro and maternal hatching. Our results demonstrated that temperature had a pronounced effect on embryogenesis and survival, with 27–30 °C identified as the optimal range for development and hatching. Both low and high temperature extremes markedly reduced embryo survival. Developmental trajectories were largely comparable between in vitro and maternal hatching, confirming the reliability and feasibility of the in vitro approach. Embryos collected within 4 h after maternal death exhibited high hatching success, whereas those obtained after 8 h failed to hatch. Transcriptomic analysis revealed 3505 differentially expressed genes, including 1933 upregulated and 1572 downregulated, which were significantly enriched in pathways related to cell cycle regulation, energy metabolism, immune defense, and ion transport. These findings implied that in vitro embryos could maintain developmental competence by stabilizing genomic integrity, reallocating energy resources, and activating stress responsive mechanisms. This study provides the first comprehensive evidence supporting the feasibility of in vitro embryo hatching in S. paramamosain and offers practical insights for optimizing temperature regimes, improving the utilization of maternal resources, and advancing large scale seedstock production in Full article

Actinidia deliciosa is a globally important economic fruit crop, and its fruit quality and yield are profoundly influenced by light and environmental conditions. Sucrose phosphate synthase (SPS), a key rate-limiting enzyme in the sucrose biosynthesis pathway, plays a central role in regulating carbon metabolism and sucrose accumulation in plants. However, comprehensive studies of the SPS gene family in A. deliciosa are still lacking, particularly regarding its expression in response to different light qualities. In this study, genome-wide identification of the SPS gene family in A. deliciosa was conducted using bioinformatics approaches. A total of 31 SPS genes were identified and named AdSPS1 to AdSPS31 on the basis of their chromosomal positions. The encoded proteins were predicted to be acidic, hydrophilic, and primarily localized in the chloroplast. All the AdSPS proteins contained the conserved domains Sucrose_synth, Glyco_trans_1, and S6PP, indicating potential roles in sucrose metabolism. Phylogenetic analysis classified the 31 AdSPS members into three subfamilies, A, B, and C, comprising 20, 5, and 6 members, respectively. Collinearity analysis revealed extensive syntenic relationships among AdSPS genes across different chromosomes, suggesting that gene duplication events contributed to the expansion of this gene family. Promoter cis-acting element analysis revealed that light-responsive elements were the most abundant among all the detected elements in the upstream regions of the AdSPS genes, implying potential regulation by light signals. Different light qualities significantly affected the contents of sucrose, glucose, and fructose, as well as SPS activity in kiwifruit leaves, with the highest activity observed under the R3B1 (red–blue light 3:1) treatment. Spearman’s correlation analysis indicated that AdSPS3 was significantly negatively correlated with sucrose, fructose, glucose, and SPS activity, suggesting a potential role in negatively regulating sugar accumulation in kiwifruit leaves, whereas AdSPS12 showed positive correlations with these parameters, implying a role in promoting sucrose synthesis. To further explore the light response of the AdSPS genes, eight representative members were selected for qRT‒PCR analysis under red light, blue light, and combined red‒blue light treatments. These results demonstrated that light quality significantly influenced SPS gene expression. Specifically, AdSPS6 and AdSPS24 were highly responsive to R1B1 (1:1 red‒blue light), AdSPS9 was significantly upregulated under R6B1 (6:1 red‒blue light), AdSPS21 was strongly induced by blue light, and AdSPS12 expression was suppressed. This study systematically identified and analyzed the SPS gene family in A. deliciosa, revealing its structural characteristics and light-responsive expression patterns. These findings suggest that AdSPS genes may play important roles in light-regulated carbon metabolism. These results provide a theoretical foundation and valuable genetic resources for further elucidating the molecular mechanisms of sucrose metabolism and light signal transduction in kiwifruit. Full article

Acute Respiratory Distress Syndrome (ARDS) is a severe complication of acute lung injury (ALI) characterized by acute hypoxemic respiratory failure and diffuse alveolar damage, with a high mortality rate and a current lack of treatments beyond supportive care. Its complex pathophysiology involves immune cell activation, pro-inflammatory cytokine release, and disruption of the alveolar–capillary barrier, leading to pulmonary edema and fibrosis. This review explores the potential of small interfering RNA (siRNA) therapy as a novel pathogenetic treatment for ARDS. The mechanism of RNA interference is described, highlighting its high specificity for silencing target genes. The paper then evaluates various animal models used in ARDS preclinical research, noting the advantages of large animals (pigs) for their physiological similarity to humans and the suitability of rodents for studying long-term fibrotic stages. Finally, the review summarizes promising in vivo studies where siRNA-mediated knockdown of several genes (e.g., TIMP1, BTK, LCN2, HDAC7, CCL2, NOX4, TNFα and TLR4) significantly reduced inflammation, improved lung histology, and increased survival. The collective evidence underscores siRNA’s considerable potential for developing targeted therapies against ARDS, moving beyond symptomatic care to address the root molecular mechanisms of the disease. Full article

Androgen signaling is critical for male sex differentiation and proper penile development. Disruption of this pathway results in congenital malformations of the male external genitalia, such as hypospadias. Hypospadias is a malformation of the penis, where the urethral opening is located along the ventral shaft rather than the tip. Although the molecular link between androgen signaling, penile differentiation, and proper urethra closure has been established for over 70 years, most hypospadias cases do not have a defined etiology. To clarify how the androgen receptor contributes to human hypospadias, we conducted a quantitative meta-analysis comparing androgen receptor expression in hypospadias patients and healthy boys. Due to substantial heterogeneity and imprecision in both mRNA and protein assays, no consistent direction of androgen receptor expression could be demonstrated, suggesting that hypospadias etiology may be more complicated than just the sole expression of the androgen receptor. To contextualize these results, we complemented the meta-analysis with a mini-review summarizing the various mechanisms through which androgen receptors can be regulated in the developing penis. This review aims to provide a framework for future investigations of androgen signaling and urethral closure mechanisms during penile development. Full article

Preservation of spermatogonial cells is of critical importance for male patients undergoing gonadotoxic therapies. Testicular organoids generated by 3D polymeric scaffolds filled with decellularized extracellular matrix (dECM) have the potential to promote stem cell growth. We propose a protocol to produce dECM from porcine prepubertal tunica albuginea for use in polymeric scaffolds. Spectroscopic analysis, molecular biology techniques, and histo-morphological assessment were used to evaluate the morphology and mechano-chemistry of the dECM at each phase of the process. The results obtained from this study demonstrate that the protocol can produce a high-purity product without causing significant alterations to protein conformation. The dECM obtained was then employed in the creation of a 3D scaffold for the cultivation of testis organoids. This was achieved by utilizing a mixture of alginate (A) and chitosan (C), which are natural polymers with a high degree of biocompatibility, that have extensive application in the field of biomedicine. Scaffold characterization demonstrated that the presence of dECM affects the scaffold’s mechanical properties by tuning structural reorganization and reducing hygroscopicity. The cell viability assay demonstrates that the A/C scaffolds are non-cytotoxic after a pre-phase of immersion in the medium. Full article

Grafting is a pivotal horticultural technique for enhancing vegetable crop productivity; however, the specific molecular mechanisms governing rootstock-induced vigor remain insufficiently elucidated. This study deciphers how bottle gourd rootstock augments growth in melon scions through an integrated approach combining physiology, transcriptomics, phytohormone profiling, and functional genetics. Phenotypic analysis confirmed a significant increase in plant height, fresh weight, and stem diameter in heterografted scions compared to controls. Transcriptome sequencing of scion apices identified 663 core differentially expressed genes (DEGs) specifically modulated by the bottle gourd rootstock. These DEGs were prominently enriched in carbohydrate metabolism and plant hormone signal transduction pathways. Consistent with this, hormonal assays revealed a specific elevation in cytokinin and ethylene levels in the scion, accompanied by the upregulation of key pathway genes, including MELO3C016881 (LOG) and MELO3C007769 (ERF060). Crucially, virus-induced gene silencing of either gene completely abolished the rootstock-conferred growth advantage. Our findings preliminarily unveil the secret behind scion vigor, providing a foundational mechanistic framework for how rootstocks reprogram scion development. The identified genes, MELO3C016881 and MELO3C007769, offer direct molecular targets for the precision breeding of superior scions in melon. Full article

With the growing prominence of skin photodamage caused by ultraviolet (UV) radiation, the development of efficient and safe natural photoprotectants has become a major research focus. Ginsenoside Re (G-Re), a primary active component of ginseng (Panax ginseng C. A. Mey.), has attracted much attention due to its significant antioxidant and anti-inflammatory activities; however, its systemic role and mechanism in protecting against photodamage remain unclear. In this study, a UVB-induced rat photodamage model was established to evaluate the protective effect of ginsenoside Re through histopathological staining, biochemical assay, and immunohistochemical analysis. Furthermore, an integrated transcriptomic and metabolomic approach was applied to elucidate the molecular mechanism of G-Re protection and to establish the association between the photodamage phenotype, metabolic pathways, and gene functions. Following their identification via integrated multi-omics analysis, the key targets were subjected to verification via Western blotting. The results showed that G-Re could effectively alleviate UVB-induced pathological injury and reduce the level of oxidative stress and inflammatory factors, which could reverse regulate the abnormal expression of 265 differential genes and 30 metabolites. The glutathione metabolism pathway was proven as a key pathway mediating the protective effects of ginsenoside Re against skin photodamage via integrated analysis, WB verification, and molecular docking. The current study indicated that G-Re could be a promising natural sunscreen additive in cosmetical products. Full article

Quercetin (Q), a bioactive flavonoid, exerts potent antioxidant and redox-modulating effects by activating the nuclear factor erythroid 2-related factor 2/antioxidant response Element (Nrf2/ARE) pathway and upregulating endogenous antioxidant defenses, including enzymatic antioxidants such as superoxide dismutase (SOD) and catalase (CAT), as well as non-enzymatic glutathione (GSH) and lipid peroxidation (MDA). Gemcitabine (Gem), a widely used antimetabolite chemotherapeutic, often shows limited efficacy under hypoxic and oxidative stress conditions driven by hypoxia-inducible factor 1-alpha (HIF-1α) and vascular endothelial growth factor (VEGF)-mediated angiogenesis. This study investigated the redox-mediated synergistic effects of Q and Gem in MDA-MB-231 human breast cancer cells. Combination treatment significantly reduced cell viability beyond the expected Bliss value, indicating a synergistic interaction and enhanced apoptosis compared with single-agent treatments. Increased reactive oxygen species (ROS) production was accompanied by depletion of GSH and accumulation of MDA, establishing a pro-apoptotic oxidative stress environment. Q alone enhanced SOD and CAT activities, whereas the combination induced exhaustion of antioxidant defenses under oxidative load, reflecting a redox-adaptive response. Molecular analyses revealed downregulation of HIF-1α and VEGF, alongside upregulation of Bax and Caspase-3, confirming suppression of hypoxia-driven survival and activation of the intrinsic apoptotic pathway. Transcriptomic and enrichment analyses further identified modulation of oxidative stress- and apoptosis-related pathways, including phosphoinositide-3-kinase–protein kinase B/Akt (PI3K/Akt), HIF-1 and VEGF signaling. Collectively, these results indicate that Q potentiates Gem cytotoxicity via redox modulation, promoting controlled ROS elevation and apoptosis while suppressing hypoxia-induced survival mechanisms, highlighting the therapeutic potential of redox-based combination strategies against chemoresistant breast cancer. Full article