Search Results (1,375)

This study investigated the molecular mechanisms by which phthalates induce depression, utilizing network toxicology and molecular docking techniques. By integrating the TargeNet, SwissTargetPrediction, and PharmMapper databases, 658 potential target genes of phthalates were identified. Additionally, 5433 depression-related targets were retrieved from the GeneCards and OMIM databases. Comparative analysis revealed 360 common targets implicated in both phthalate action and depression. A Protein-Protein Interaction (PPI) network was constructed using the STRING database. Subsequently, the CytoHubba plugin (employing the MCC algorithm) within Cytoscape was used to screen the network, identifying the top 20 hub genes. These core genes include AKT1, CASP3, TNF, TP53, BCL2, and IL6, among others. Validation on the GEO dataset (GSE23848) revealed that the expression of multiple core genes was significantly upregulated in patients with depression (p < 0.05). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that phthalates mainly regulate biological processes such as extracellular stimulus response, lipopolysaccharide metabolism, and chemical synaptic transmission. Depression is mediated by the AGE-RAGE signaling pathway (a complication of diabetes), lipids and atherosclerosis, Endocrine resistance, and the PI3K-Akt signaling pathway. Molecular docking confirmed that phthalates have strong binding activity with key targets (CASP3, TNF, TP53, BCL2, IL6). These findings present a novel paradigm for evaluating the health risks posed by environmental pollutants. Full article

Hearing loss is often caused by genetic and environmental factors, with inherited mutations responsible for 50–60% of cases. The GJB2 gene, encoding connexin 26, is a major contributor to nonsyndromic sensorineural hearing loss (NSHL) due to its role in cellular communication critical for auditory function. In Taiwan, common deafness-associated genes include GJB2, SLC26A4, OTOF, MYO15A, and MTRNR1, which were similar to those found in other populations. The most common pathogenic genes is GJB2 mutations and the hearing level in children with GJB2 p.V37I/p.V37I or p.V37I/c.235delC was estimated to deteriorate at approximately 1 decibel hearing level (dB HL)/year. We found another common mutation in Taiwan Biobank, GJB2 p.I203T, which were identified in our data and individuals carrying this mutation experienced more severe hearing loss, suggesting a synergistic effect of these mutations on auditory impairment. We suggest GJB2 whole genetic screening is recommended for clinical management and prevention strategies in Taiwan. This study used data from the Taiwan Biobank to analyze allele frequencies of GJB2 gene variants. Predictive software (PolyPhen-2 version 2.2, SIFT for missense variants 6.2.1, MutationTaster Ensembl 112 and Alphamissense CC BY-NC-SA 4.0) assessed the pathogenicity of specific mutations. Additionally, 82 unrelated NSHL patients were screened for mutations in these genes using PCR and DNA sequencing. The study explored the correlation between genetic mutations and the severity of hearing loss in patients. Several common GJB2 mutation sites were identified from the Taiwan Biobank, including GJB2 p.V37I (7.7%), GJB2 p.I203T (6%), GJB2 p.V27I (31%), and GJB2 p.E114G (22%). Bioinformatics analysis classified GJB2 p.I203T as pathogenic, while GJB2 p.V27I and GJB2 p.E114G were considered polymorphisms. Patients with GJB2 p.I203T mutation experienced more severe hearing loss, emphasizing the potential interaction between the gene in auditory impairment. The mutation patterns of GJB2 in the Taiwanese population are similar to other East Asian regions. Although GJB2 mutations represent the predominant genetic cause of hereditary hearing loss, the corresponding mutant proteins exhibit detectable aggregation, particularly at cell–cell junctions, suggesting at least partial trafficking to the plasma membrane. Genetic screening for these mutations—especially GJB2 p.I203T (6%), GJB2 p.V27I (31%), and GJB2 p.E114G (22%)—is essential for the effective diagnosis and management of non-syndromic hearing loss (NSHL) in Taiwan. We found GJB2 p.I203T which were identified in our data and individuals carrying this mutation experienced more severe hearing loss, suggesting a synergistic effect of these mutations on auditory impairment. We suggest whole GJB2 gene sequencing in genetic screening is recommended for clinical management and prevention strategies in Taiwan. These findings have significant clinical and public health implications for the development of preventive and therapeutic strategies. Full article

Saline–alkaline water resources are globally widespread, and their rational development offers significant potential to alleviate freshwater scarcity. Saline–alkaline water aquaculture farming not only affects fish growth and survival but also impairs reproductive and developmental functions. Largemouth bass (Micropterus salmoides), an economically important fish, has demonstrated excellent high tolerance to such environments, in order to investigate the effects of alkaline water aquaculture environments on its growth performance, sex hormone levels, gonadal development, and molecular adaptation mechanisms. In this study, largemouth bass were chronically exposed to freshwater (0.55 mmol/L), low alkalinity (10 mmol/L), or high alkalinity (25 mmol/L) and cultured for 80 days. Alkalinity exposure more severely impacted the growth rate of females. High alkalinity significantly increased the hepatosomatic index and decreased the gonadosomatic index in both sexes; moreover, it induced oxidative stress in both sexes, evidenced by reduced superoxide dismutase (SOD), catalase (CAT), and total antioxidant capacity (TAOC) levels and elevated malondialdehyde (MDA) content. Furthermore, the levels of sex hormones Serum estradiol (E2), 11-ketotestosterone (11-KT), and testosterone were significantly reduced, accompanied by either an elevated ratio of primary oocytes and follicular atresia, or by reduced spermatogenesis. Apoptotic signals appeared in gonadal interstitial cells, with upregulated expression of genes P53, Bax, Casp3, and Casp8. Ultrastructural damage included fewer mitochondria and cristae blurring, further indicating tissue damage causing dysfunction. Transcriptome results showed that oxidative stress damage and energy metabolism imbalance caused by carbonate alkalinity were key to the delayed gonadal development, which was mainly manifested in enrichment of the ECM–receptor interaction and PI3K-Akt signaling pathways in females exposed to low alkalinity, and the GnRH secretion and chemokine signaling pathways in males. Glycosphingolipid biosynthesis and Ferroptosis pathway were enriched in females exposed to high alkalinity, and the Cortisol synthesis and secretion pathway were enriched in males. Overall, high-alkalinity exposure significantly delayed gonadal development in both sexes of largemouth bass, leading to reproductive impairment. Full article

Potato (Solanum tuberosum L.) is a globally significant staple crop that faces constant threats from Phytophthora infestans, the causative agent of late blight (LB). The battle between Phytophthora infestans and its host is driven by the molecular interplay of RXLR-encoded avirulence (PiAvr) effectors and nucleotide-binding leucine-rich repeat (NLR) immune receptors in potato. This review provides a comprehensive analysis of the structural characteristics, functional diversity, and evolutionary dynamics of RXLR effectors and the mechanisms by which NLR receptors recognize and respond to them. The study elaborates on both direct and indirect modes of effector recognition by NLRs, highlighting the gene-for-gene interactions that underlie resistance. Additionally, we discuss the molecular strategies employed by P. infestans to evade host immunity, including effector polymorphism, truncation, and transcriptional regulation. Advances in structural biology, functional genomics, and computational modeling have provided valuable insights into effector–receptor interactions, paving the way for innovative resistance breeding strategies. We also discuss the latest approaches to engineering durable resistance, including gene stacking, synthetic NLRs, and CRISPR-based modifications. Understanding these molecular mechanisms is critical for developing resistant potato cultivars and mitigating the devastating effects of LB. This review aims to bridge current knowledge gaps and guide future research efforts in plant immunity and disease management. Full article

This study aims to investigate the molecular mechanisms underlying germ cell tumors (GCTs), focusing specifically on seminomas and teratomas. By analyzing gene expression profiles and miRNA interactions, the goal is to identify key regulatory miRNAs and signaling pathways that differentiate these tumor types and could serve as important regulators for therapy development. Raw data for seminomas and teratomas were extracted from the GEO database, and gene hubs were identified using STRING and Gephi. Signaling pathways and functional annotations were analyzed using miRPathDB, while miRNA–gene interactions were explored via miRWalk. Hub miRNAs were filtered and confirmed using miRDB. This study highlights significant changes in gene expression diversity between tumor and normal gonadal tissues, providing insights into the molecular dynamics of seminomas and teratomas. Distinctions between seminomas and teratomas were identified, shifting the focus toward miRNAs to discover more precise and novel therapeutic approaches. The hub genes of seminomas and teratomas were identified separately. MiRNAs targeting these hub genes were also determined and confirmed. These miRNAs collectively influence essential oncogenic pathways—confirming hsa-miR-138-5p as a regulator of pathways such as Hippo signaling, transcriptional misregulation in cancer, and microRNA cancer signaling in seminomas, and hsa-miR-200b-3p as a regulator of p53 signaling, T cell receptor signaling, and pathways including PI3K/AKT, MAPK/ERK, and Wnt/β-catenin in teratomas—confirming their potential as promising candidates for subtype-specific therapeutic intervention. MiRNAs identified through bioinformatics analyses, and their predicted regulatory roles in key oncogenic pathways, represent potential therapeutic targets or regulators of biological processes. However, further experimental validation is needed to confirm these findings. Full article

Background: Melanoma, the deadliest human skin cancer, frequently harbors activating BRAF mutations, with V600E being the most prevalent. These alterations drive constitutive activation of the MAPK pathway, promoting uncontrolled cell proliferation, survival, and dissemination. The advent of BRAFi and MEKi has significantly improved outcomes in BRAF V600-mutant melanoma. However, therapeutic resistance remains a major clinical barrier. Methods: This review integrates recent findings from preclinical and clinical studies to delineate resistance mechanisms to BRAF-targeted therapy. It categorizes resistance into primary (intrinsic), adaptive, and acquired forms, and analyzes their molecular underpinnings, including genetic and epigenetic alterations, pathway reactivation, and microenvironmental interactions. Results: Primary resistance is linked to pre-existing genetic and epigenetic changes that activate alternative signaling pathways, such as PI3K-AKT. Adaptive and acquired resistance includes secondary BRAF mutations, pathway redundancy, phenotype switching, and immune and stromal interactions. High-throughput sequencing has revealed novel mutations, including NRAS, NF1, and PTEN alterations, that contribute to resistance. Discussion: Understanding the multifaceted nature of resistance is critical to improving outcomes in advanced melanoma. This review highlights emerging strategies to overcome resistance, including combinatorial therapies, metabolic targeting, and biomarker-driven approaches, aiming to inform future therapeutic development and precision oncology strategies. Full article

Background: Intramuscular fat (IMF) enhances marbling, improving meat quality and value. Transcriptome analysis enables the identification of genes and pathways involved in IMF deposition, supporting targeted breeding and nutritional strategies to improve beef quality. Methods: This study used RNA-Seq to compare gene expression in high- (Hereford; Her), moderate- (Holstein Friesian; Hf), and low-marbling (Limousine; Lim) Semitendinosus muscle. Using Illumina’s NovaSeqX Plus, sequencing data underwent quality control with FastQC to remove low-quality reads and adapters, followed by alignment to the bovine genome using HISAT2. Differential expression analysis was performed using DESeq2, and genes were filtered based on a threshold of p-value < 0.05 and |log2FC| > 0.5 to identify significantly regulated genes. Results: A total of 21,881 expressed genes were detected, with 3025 and 7407 significantly differentially expressed in Her and Hf vs. Lim, respectively (|log2FC| > 0.5, p < 0.05). Protein–protein interaction analysis revealed 20 hub genes, including SMAD3, SCD, PLIN2, SHH, SQLE, RXRA, NPPA, NR1H4, PRKCA, and IL10. Gene ontology and KEGG pathway analyses linked these genes to lipid metabolism and IMF-associated pathways, such as PPAR signaling, fatty acid metabolism, and PI3K–Akt signaling. Conclusions: These findings highlight RNA-Seq’s utility in uncovering the genetic basis of marbling and the importance of aligning beef production with consumer demands through genetic improvements. This study aimed to identify breed-independent molecular mechanisms of intramuscular fat deposition and shared metabolic processes in the Semitendinosus muscle to improve beef quality. Full article

Taxifolin is a natural flavonoid found in a variety of plants, including Siberian larch (Larix sibirica) and milk thistle (Silybum marianum), that has attracted attention for its multifaceted pharmacological properties, including cardioprotective effects. Through its antioxidant and anti-inflammatory activities, taxifolin has shown significant therapeutic potential in cardiovascular diseases such as atherosclerosis, myocardial ischemia, and diabetic cardiomyopathy. This review highlights the cardioprotective effects of taxifolin in preclinical models of atherosclerosis, ischemia/reperfusion injury, and diabetic cardiomyopathy. Taxifolin contributes to its cardioprotective effects through key mechanisms such as modulation of pathways such as PI3K/AKT and JAK2/STAT3, inhibition of NADPH oxidase, and modulation of nitric oxide production. Recent studies have shown that taxifolin can affect glucose metabolism by modulating sodium–glucose transporter (SGLT) expression, potentially enhancing the cardioprotective effects of SGLT2 inhibitors. Given the emerging role of SGLT2 inhibitors in the management of cardiovascular disease, further investigation of the interaction of this pathway with taxifolin may provide new therapeutic insights. Although taxifolin has multifaceted potential in the prevention and treatment of cardiovascular disease, further studies are needed to better understand its mechanisms and validate its efficacy in different disease stages. This review aims to provide a rationale for the clinical application of taxifolin-based cardiovascular therapies and suggest directions for future research. Full article

The Kazakh horse, one of China’s indigenous primitive breeds, is renowned for its remarkable adaptability and distinctive physiological traits. The ovary is a vital reproductive organ in female animals, responsible for oocyte production and hormone secretion. However, limited research has been conducted on gene expression profiles in the ovarian tissue of equine species. To address this gap, the present study performed transcriptomic sequencing on ovarian tissues from 12 Kazakh horses in different physiological states. A total of 979 differentially expressed mRNAs were identified, including 619 upregulated and 360 downregulated genes. Among these, key genes such as COL1A1, LHCGR, KISS1, NTRK2, COL1A2, and THBS4 were identified as differentially expressed. Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that 374 of these genes were primarily involved in ovarian steroidogenesis, the PI3K-Akt signaling pathway, and ECM-receptor interactions among 292 enriched pathways. This study provides a comprehensive transcriptomic profile of equine ovarian tissue, offering in-depth insights into differential gene expression and signal pathways associated with ovarian development in Kazakh horses, providing theoretical foundations and referential data for future research in equine ovarian development and reproductive studies. Full article

Cucurbitacin B (CuB), a tetracyclic triterpenoid compound isolated from Cucurbitaceae plants, exhibits inhibitory effects on various tumor cells (e.g., liver, gastric, and colorectal cancer cells). Since the 1970s–1980s, cucurbitacin tablets containing CuB have been used as an adjuvant therapy for chronic hepatitis and primary liver cancer. CuB exerts anticancer effects through multiple mechanisms: inducing apoptosis, cell cycle arrest (G2/M or S phase), autophagy, and cytoskeleton disruption; inhibiting migration, invasion, and angiogenesis (via VEGF/FAK/MMP-9 and Wnt/β-catenin pathways); regulating metabolic reprogramming and immune responses; inducing pyroptosis, ferroptosis, and epigenetic changes; and reversing tumor drug resistance. These effects are associated with signaling pathways like JAK/STAT, PI3K/Akt/mTOR, and FOXM1-KIF20A. To improve its application potential, strategies such as structural modification (e.g., NO donor conjugation), combination therapy (with gemcitabine or cisplatin), and nanomaterial-based delivery (e.g., liposomes and exosome-mimicking nanoparticles) have been developed to enhance efficacy, reduce toxicity, and improve bioavailability. CuB shows broad-spectrum anticancer activity, but further research is needed to clarify the mechanisms underlying its cell-specific sensitivity and interactions with the immune system. This review systematically summarizes the physicochemical properties, anticancer mechanisms, and strategies for applying CuB and suggests future research directions, providing references for scientific research and clinical translation. Full article

This paper addresses stability issues in modern power grids arising from extensive integration of power electronic converters, which introduce complex multi-time-scale interactions. A symbolic simplification method is proposed to accurately model grid-connected converter dynamics, significantly reducing computational complexity through transfer function approximations and yielding efficient reduced-order models. An impedance-based approach utilizing impedance ratio (IR) is developed for stability assessment under active-reactive (PQ) and active power-AC voltage (PV) control strategies. The impacts of Phase-Locked Loop (PLL) and proportional-integral (PI) controllers on system stability are analysed, with a particular focus on quantifying remote converter interactions and delineating stability boundaries across varying network strengths and configurations. Furthermore, time-scale separation effectively simplifies Multi-Voltage Source Converter (MVSC) systems by minimizing inner-loop dynamics. Validation is conducted through frequency response evaluations, IR characterizations, and eigenvalue analyses, demonstrating enhanced accuracy, particularly with the application of lead–lag compensators within the critical 50–250 Hz frequency band. Time-domain simulations further illustrate the adaptability of the proposed models and reduction methodology, providing an effective and computationally efficient tool for stability assessment in converter-dominated power networks. Full article

Osteosarcoma (OS) and extraskeletal osteosarcoma (EOS) in dogs exhibit histological similarities but differ in anatomical origin, which poses a challenge to diagnostic accuracy. We adopted a marker-first strategy to enhance molecular classification by selecting RUNX2, KPNA2, and SATB2, three validated immunohistochemical (IHC) markers, as primary targets. Bioinformatic screening identified the miR-30 family as the only miRNA group predicted to coordinately regulate RUNX2, KPNA2, and SATB2, justifying its prioritization for expression analysis. RT-qPCR on FFPE tissues from 14 OS, 19 EOS, and 10 healthy controls revealed that miR-30a was significantly downregulated in OS and inversely correlated with RUNX2 nuclear expression, confirmed by IHC. MiR-30e also showed high diagnostic accuracy, while miR-30b and miR-30c distinguished EOS from OS. Non-seed interaction modeling (i.e., outside the canonical “seed” region, spanning nucleotides 2–8 of the miRNA) suggested divergent regulatory affinities within the PI3K/AKT/RUNX2 axis among miR-30 family members. MiR-30a and miR-30e exhibited the highest diagnostic power (LR⁺ 7.7 and 6.8, respectively), supporting their role as biomarkers. These results highlight a miR–30–centered regulatory axis with relevance for diagnosis and molecular stratification of canine osteogenic tumors. Full article

Persistent RNA virus infections (PI) are often characterized by extended viral shedding and maintained cycles of inflammation. The innate immune Complement (C′) pathways can recognize acute infected (AI) cells and result in their lysis, but the relative sensitivity of PI cells to C′-directed killing is incompletely understood. Here, we extended our previous studies on the interactions of C′ with parainfluenza virus AI and PI A549 cells to two additional respiratory tract cell lines. AI Hep2 and H1975 cells infected with Parainfluenza virus 5 (PIV5) were found to be highly sensitive to C′ lysis. By contrast, PIV5 PI cells were highly resistant to killing by C″. Surface deposition of membrane attack complex (MAC) and C3 was also greatly reduced on the surface of PI cells compared to AI cells. PI cells had lower levels of surface viral glycoprotein expression compared to AI cells. Treatment of AI cells with ribavirin (RBV) showed a dose-dependent decrease in both viral glycoprotein expression and sensitivity to C′-mediated lysis. When surface viral glycoprotein levels were reduced in AI cells to those in PI cells, AI cells became similarly resistant to C′. While sialic acid levels on PI cell surfaces matched that of naïve cells, enzymatic removal of this sialic acid did not increase sensitivity to C′-mediated lysis. Despite their varying profiles of C′ activation and deposition, these studies indicate downregulation of viral gene expression as a common mechanism of C′ resistance across various parainfluenza virus PI cell lines. Full article

This study investigates key factors affecting the adsorption behavior of proteins on the multimodal chromatographic adsorbent Capto MMC, aiming to enhance selective protein separation strategies. Batch equilibrium experiments were conducted using six model proteins to explore the combined effects of pH, ionic strength, and the nature of salts (kosmotropic and chaotropic) on protein–ligand interactions. Given that the Capto MMC ligand supports multiple interaction modes beyond cation exchange, particular focus was placed on acidic proteins (pI 4–5), which exhibited binding even at moderately elevated pH values—conditions ineffective for conventional cation exchangers. Hydrophobic interactions were identified as critical for stable binding of proteins like BSA and fetuin, while hydrophilic proteins such as ovalbumin showed minimal adsorption. Chromatographic column experiments were performed to evaluate elution performance under various buffer conditions, revealing that prolonged adsorption phases can reduce recovery yields for proteins with less stable tertiary structures. The findings highlight how salt type, pH, and protein hydrophobicity interplay to modulate multimodal binding mechanisms, providing practical insights for the design of tailored purification protocols. Full article

Background: Hepatocellular carcinoma is one of the leading causes of cancer-related deaths worldwide. Its high recurrence rate and limited treatment options underscore the urgent need for the development of new and highly effective drugs. Methods: This study systematically explores the molecular mechanism of cinnamic acid against hepatocellular carcinoma through integrated machine learning prediction, network pharmacological analysis and in vitro experimental verification. Results: The prediction of anti-tumor activity based on the random forest model showed that cinnamic acid has significant anti-tumor potential (probability = 0.69). Network pharmacology screened 185 intersection targets of cinnamic acid and liver cancer, of which 39 core targets (such as PIK3R1, AKT1, MAPK1) were identified as key regulatory hubs through protein interaction network and topological analysis. Functional enrichment analysis showed that these targets were mainly enriched in the PI3K/AKT signaling pathway (p = 2.1 × 10⁻¹²), the cancer pathway (p = 3.8 × 10⁻¹⁰), and apoptosis-related biological processes. Molecular docking validation revealed that the binding energies of cinnamic acid with the 19 core targets were all below −5 kcal/mol, a threshold indicating strong binding affinity in molecular docking. The binding modes to PIK3R1 (−5.4 kcal/mol) and AKT1 (−5.1 kcal/mol) stabilized through hydrogen bonding. In vitro, cinnamic acid dose-dependently inhibited Hep3B proliferation/migration, induced apoptosis, downregulated PI3K, p-AKT, and Bcl-2, and upregulated Bax and Caspase-3/8. Conclusions: This study systematically reveals, for the first time, that the multi-target mechanism of cinnamic acid exerts anti-hepatic cancer effects by targeting the PI3K/AKT signaling pathway, supporting its potential as a natural anti-tumor drug. Full article