Search Results (4,646)

Efficient milk protein synthesis in dairy cows, particularly casein production, is crucial for milk quality but has low nitrogen conversion efficiency. This study aimed to determine whether an optimal ratio of glycine, asparagine, and phenylalanine could synergistically promote α-casein synthesis in bovine mammary epithelial cells (MAC-T) and to elucidate its mechanism via the PI3K-AKT-mTOR signaling pathway. Single-factor experiments and response surface central composite design were conducted to determine the optimal amino acid combination. α-Casein synthesis was measured by ELISA, gene expression by RT-qPCR, and protein phosphorylation by Western blot. A PI3K-specific inhibitor (LY294002) was used in a blocking experiment to validate the involvement of the PI3K-AKT-mTOR pathway. Results: The optimal ratio was 9.898 mmol/L glycine, 7.014 mmol/L asparagine, and 5.865 mmol/L phenylalanine (molar ratio 1.69:1.20:1.00). This combination significantly increased α-casein synthesis and secretion compared to any single amino acid (p < 0.01), demonstrating a synergistic effect. It also upregulated CSN1S1 and CSN1S2 expression and activated the PI3K-AKT-mTOR pathway at both transcriptional and translational levels. The addition of LY294002 completely abolished these effects, confirming the pathway’s crucial role. The optimal combination of glycine, asparagine, and phenylalanine synergistically enhances α-casein synthesis in MAC-T cells by activating the PI3K-AKT-mTOR pathway. These findings provide a theoretical basis for developing targeted amino acid supplementation strategies to improve milk protein production in dairy cows. Full article

Ovarian cancer (OVC) is a leading cause of gynecological cancer mortality due to late-stage diagnosis and chemoresistance. Among the multiple molecular mediators, oncogenic epidermal growth factor receptor (EGFR) signaling has emerged as a key regulator of tumor progression and drug resistance, ultimately governing cancer survival. Therefore, this review focused on the molecular mechanisms of aberrant EGFR signaling to promote chemoresistance in ovarian cancer through multiple interlinking pathways, including the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of the rapamycin (mTOR), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling cascades. These pathways act in concert to confer resistance, including proliferation, antiapoptotic effects, cancer stem cell maintenance, and facilitating epithelial-mesenchymal transition (EMT), which function together to decrease sensitivity towards platinum-based and taxane chemotherapies. Furthermore, we incorporate novel evidence regarding EGFR cross-talk with extracellular matrix (ECM) and metabolic reprogramming, especially their relevance to immune evasion mechanisms, hypoxia, and extracellular vesicles (EVs)-mediated signaling. In addition, we elaborated on the limitation of the current EGFR targeting therapy, which will be beneficial for further designing new combinatorial treatment approaches by using EGFR inhibitors with immunotherapy, nanocarriers, and microbiota modulators. Overall, this review highlights the updated role of EGFR signaling as a key regulator of chemoresistance in ovarian cancer, providing insights for developing targeted therapies to overcome drug resistance and improve patient survival. Full article

Muscle wasting associated with gastric cancer represents a complex, multifactorial systems disorder involving inflammatory, anabolic, mechanosensory, calcium-regulatory, mitochondrial, and proteostatic disruption. This review synthesizes current evidence regarding the cellular and physiological mechanisms involved in skeletal muscle dysfunction in gastric cancer and provides a unifying framework centered on loss of signaling coherence. Specifically, it examines IL-6/STAT3 and NF-κB inflammatory signaling, the myostatin–activin–ACVR2B–SMAD pathway, PI3K/Akt/mTOR signaling, mechanotransduction, excitation–metabolism coupling, calcium homeostasis, mitochondrial function, and proteostasis. Although individual components of these pathways have been implicated in muscle wasting associated with chronic disease, current evidence suggests that they interact through positive feedback loops. Inflammation, anabolic resistance, impaired force-to-signal conversion, mitochondrial stress, altered intracellular calcium homeostasis, and disrupted protein quality control may reinforce one another, contributing to metabolic, structural, and transcriptional instability. Within this context, muscle wasting reflects not only loss of muscle mass or strength, but also loss of functional integrity resulting from disrupted integration of mechanical, metabolic, inflammatory, and anabolic signals. Given the systemic nature of these effects, this review proposes kinesitherapy as a potentially useful nonpharmacological adjunctive strategy that may modulate inflammation, restore responsiveness to mechanical stimuli, support calcium homeostasis and mitochondrial function, improve anabolic sensitivity, and maintain protein quality control. Overall, this review presents a systems-biology model of gastric cancer-associated muscle wasting and supports further investigation of exercise-based therapies for this condition. Full article

Natural products like the isoprenylated flavonoid Kuwanon G (KWG), isolated primarily from Morus alba, offer promising pleiotropic effects against multifactorial diseases, overcoming the limitations of conventional single-target synthetic drugs. This study aims to systematically review the pharmacological activities of KWG and evaluate its underlying molecular mechanisms. A comprehensive literature review was integrated with network pharmacology, protein–protein interaction (PPI) profiling, and KEGG/GO pathway enrichment analyses to identify shared targets across different pathologies. Experimental data demonstrate that KWG exhibits antimicrobial, anti-inflammatory, antidiabetic, neuroprotective, anti-obesity, and anticancer properties. Bioinformatics analyses revealed that KWG exerts these effects by modulating core targets (e.g., TNF, IL-6, SRC, RELA) and key signaling pathways, including NF-κB, PI3K/AKT/mTOR, and Toll-like receptors, which govern inflammation, oxidative stress, and metabolic regulation. In conclusion, KWG is a potent, multi-target compound with significant therapeutic potential for managing chronic and infectious diseases. However, future structure–activity relationship studies and clinical trials are required to address its pharmacokinetic limitations, such as low bioavailability, to facilitate its clinical translation. Full article

Total RNA was isolated from sections of healthy testes and Leydig cell tumors of mixed-breed dogs using TMA Master II device. The RNA-seq libraries were sequenced on the Illumina platform. Following differential expression analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) were applied with quality control obtained using FastQC and Trimmomatic. This analysis revealed 1500 transcripts, including 982 upregulated and 168 downregulated genes. The results demonstrated that a significant proportion of these differentially expressed genes are directly involved in the control of sex steroid production (CYP11A1, STAR, and 3β-HSD3B1) or tube formation, angiogenesis, and extracellular matrix remodeling in interstitial cells (ESM1, FGG, and VEGFA). Moreover, we identified the upregulation of transcripts responsible for neurotransmitter or neuroendocrine signaling (SLC6A4, GRIN2C, GABRB3) and cholesterol metabolism and its regulation (GPX3, MSMO1, DHCR24). These genes were strongly associated with the phosphatidylinositol-3-kinase (PI3K)-Protein Kinase B (Akt) cascade and extracellular matrix interactions, features shared with various malignancies. Alterations in estrogen and relaxin signaling appear to be distinctive, understudied mechanisms specific to canine Leydig cell tumors. Concurrently, downregulated genes (e.g., DMRTC2, SEMA3C, ALOX12) were linked with cell differentiation, signaling and immunoregulatory pathway suppression involved in tumorigenesis. A complex transcriptomic profile of canine Leydig cell tumors was developed, revealing a conserved oncogenic core shared in some aspects with human malignancies alongside unique species-specific alterations. Findings seem to be useful for identifying novel diagnostic biomarkers and targeted therapies in veterinary oncology, establishing canine reproductive tissues as a valuable comparative biomedical model for research in human. Full article

Ebola virus disease (EVD) is characterized by immune dysregulation and damaging hyperinflammation. We aimed to characterize the signaling pathways and regulatory mechanisms dysregulated during EVD. To avoid hyperinflammation, innate immune signaling is regulated by post-translational modifications (PTMs), including protein phosphorylation. Here, we show that the protein tyrosine phosphatase nonreceptor type 13 (PTPN13) negatively regulates Interferon (IFN)-β while also positively regulating the neutrophil chemoattractant CXCL1. Using vectors encoding IRF3 with mutations on phosphorylation sites, we identified Y292 on IRF3 as a PTPN13 target of dephosphorylation. Knockout of PTPN13 increased IRF3 phosphorylation and expression of IFNβ and IFN-stimulated genes (ISGs) following poly(I:C) stimulation. Intriguingly, depletion of PTPN13 during Ebola virus (EBOV) infection resulted in decreased IFNβ and ISG induction at later time points post-infection, which correlated with increased viral titers. We identified PTPN13-mediated dephosphorylation of the viral protein VP35 as one potential mechanism inhibiting virus replication. Additionally, the induction of inflammatory chemokines, including CXCL1, decreased in PTPN13 knockout cells late during EBOV infection. These effects could be explained by increased phosphorylation of the regulatory p85 subunit of PI3K. Dephosphorylation of p85 promotes its degradation, subsequently enhancing PI3K kinase activity and downstream signaling via AKT. Together, our study suggests that PTPN13 is involved in immune regulation and efficient antiviral responses by dephosphorylation of IRF3, EBOV-VP35 and PI3K-p85. Full article

Xanthotoxin (8-methoxypsoralen) belongs to the group of naturally occurring furanocoumarin (furocoumarin) compounds and is a product of plant secondary metabolism. Analysis of the available literature indicates that xanthotoxin exhibits a broad spectrum of pharmacological activities, including anti-inflammatory, antioxidant, immunomodulatory, and antibacterial effects. Xanthotoxin has been shown to stimulate autophagy via inhibition of the AKT/mTOR pathway, as well as to block cell migration by modulating RIG-1 and NF-κB signaling. Moreover, its effects on JNK/MAPK, PI3K/AKT, Calcium–CaMYK/PYK2, and other signaling cascades have been confirmed. Among its most promising properties is the ability to inhibit ABC transporters, thereby preventing the reduction of chemotherapeutic agent concentrations within tumor cells and enhancing their intracellular accumulation. Thus, the aim of this study was to evaluate xanthotoxin as a potential anticancer agent. The literature review was based on publications indexed in Google Scholar, Scopus, Web of Science, and PubMed and published between 2010 and 2026. Studies describing the biological properties of xanthotoxin, its toxicity, anticancer mechanisms of action, and modulation of ABC transporters were included. This literature review summarizes the pharmacological profile of xanthotoxin, and its biological activities and therapeutic potential, as well as its antitumor effects in various cancer cell lines. The available evidence may provide a foundation for the future development of xanthotoxin as a lead compound for anticancer drug discovery. Full article

Background: Mitochondrial bioenergetic dysregulation disrupts immune−metabolic homeostasis and promotes pro−inflammatory microenvironments in osteoarthritis (OA) synovitis. However, the mechanistic contributions of mitochondrial energy metabolism to synovitis pathogenesis in OA remain poorly defined. Methods: We analyzed mitochondrial energy metabolism−related genes (MEMRGs) in OA synovitis by integrating transcriptomic data from OA synovial tissues (GSE55235, GSE55457). LASSO regression and maximal clique centrality (MCC) algorithms were applied to identify hub genes, and single−cell RNA sequencing (GSE152805) was used to examine cell−type−specific expression patterns. Functional validation was performed in IRS2−knockdown THP−1 macrophages. Results: We identified 22 mitochondrial energy metabolism−related differentially expressed genes (MEMR−DEGs), which were enriched in the AMPK signaling, glucagon signaling, and insulin signaling pathways. Four hub genes (FOXO3, FASN, PTGS2, IRS2) were identified, and their expression was negatively correlated with synovial macrophage infiltration. Single−cell RNA sequencing revealed that IRS2 was specifically upregulated in a synovial macrophage cluster. Functional studies in IRS2−knockdown THP−1 macrophages demonstrated that IRS2 deficiency impaired IL−4−induced M2 macrophage polarization and reduced mitochondrial membrane potential and ATP synthesis, which was mediated by the suppression of the AKT/FOXO1 signaling. Conclusions: IRS2 potentially influences mitochondrial energy metabolism, as evidenced by the maintenance of mitochondrial membrane potential and ATP synthesis, via the AKT/FOXO1 signaling pathways to maintain synovial macrophage M2 polarization homeostasis. These findings provide novel molecular targets for addressing immune−metabolic pathways in OA therapy. Full article

Global warming has increasingly positioned heat stress (HS) as a major threat to public health, as it can inflict damage on multiple organs including the kidneys, liver, and heart. However, effective targeted therapeutic strategies remain limited. This investigation employed an integrated approach combining Network pharmacology, in silico binding simulations, and cell-based assays to elucidate the cytoprotective properties and molecular basis of oxymatrine action under heat-stressed conditions. Network analysis identified 36 overlapping targets common to oxymatrine and the pathological processes of HS-related acute kidney injury (AKI), acute liver injury (ALI), and acute myocardial injury (AMI). These targets were strongly enriched in the PI3K-AKT signaling cascade. Molecular docking showed that oxymatrine binds tightly to key pathway proteins such as PIK3CA and GSK3B, with Vina scores below −8 kcal/mol. In 293T cells, the half-maximal cytotoxic concentration (CC₅₀) of oxymatrine exceeded 2000 μM. Under heat stress, oxymatrine (31.25–1000 μM) dose-dependently increased cell viability by about 30% and significantly lowered HSP90 and HSP70 expression. Similar protective effects were observed in H9C2 cardiomyocytes under heat stress. RT-qPCR further confirmed that oxymatrine reduced the transcript levels of PI3K-AKT pathway-related genes, including CASP3, EGFR, RXRα, and MMP9 in 293T cells. We also found 18 overlapping targets between oxymatrine and ferroptosis, most of which matched the core targets above. Molecular docking analysis predicted binding of oxymatrine to the ferroptosis regulator GPX4. Together, these results suggested that oxymatrine potentially alleviates HS injury by modulating the PI3K-AKT signaling pathway andregulating potential ferroptotic targets such as GPX4. Full article

As a traditional element of Chinese medicine, Hippocampus erectus is well known for promoting adolescent growth, yet its active fractions and underlying molecular mechanisms remain unclear. In this study, the aqueous extract of H. erectus was subjected to in vitro simulated gastrointestinal digestion and ultrafiltration to separate three molecular weight fractions (<10 kDa, 10–30 kDa, >30 kDa). Their chemical profiles were characterized, and osteogenic activities were systematically evaluated using cell assays, a juvenile rat model, and integrated transcriptomics and data-independent acquisition (DIA) proteomics. Results revealed that chemical profiling showed the >30 kDa fraction was mainly composed of hemocyanin subunits, and the 10–30 kDa fraction was enriched in growth-related amino acids and steroid derivatives; functionally, the 10–30 kDa fraction promoted preosteoblast proliferation and early differentiation via enhanced alkaline phosphatase (ALP) activity, while the >30 kDa fraction dominated late osteoblast maturation and mineralization. Both fractions significantly increased rat body and bone length by expanding growth plate proliferative zones and elevating serum insulin-like growth factor-1 (IGF-1)/bone morphogenetic protein-2 (BMP-2) levels. Transcriptomic and proteomic analyses identified vascular endothelial growth factor (VEGF), Wingless-related integration site (Wnt), phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt), and extracellular matrix (ECM)–receptor interaction as potential core regulatory pathways. Integrated multi-omics analysis further confirmed Frizzled-related protein B (Frzb) and AKT1 substrate 1 (Akt1s1) as candidate key regulatory targets enriched in the Wnt and adenosine monophosphate-activated protein kinase (AMPK) signaling pathways. These findings elucidate the multi-fraction, multi-pathway mechanism of H. erectus in promoting skeletal development, providing scientific evidence for its traditional use and a theoretical basis for growth-promoting functional food development. Full article

Junken meat sheep exhibit a characteristic postnatal coat-color transition, in which the initially black fleece gradually fades and develops into a white-trunk phenotype; however, the transcriptional basis of this developmental change in follicular pigment output remains unclear. In this study, three Junken meat sheep lambs showing a natural postnatal black-to-white coat-color transition were sampled longitudinally at the newborn black-fleece stage and the 179-day white-trunk stage, generating three matched biological pairs for RNA-seq analysis. Representative candidate genes were further validated by RT-qPCR. Differential expression analysis identified 1657, 400, and 1086 differentially expressed genes in the C11 vs. C1, C22 vs. C2, and C33 vs. C3 comparisons, respectively. Functional enrichment analysis indicated that these genes were mainly associated with tyrosine metabolism, ECM–receptor interaction, focal adhesion, Phosphoinositide 3-kinase-Akt signaling pathway (PI3K-Akt), arachidonic acid metabolism, estrogen signaling, and immune-related pathways. Integrated analysis of shared downregulated genes and expression patterns highlighted candidate genes related to pigmentation, the ECM/follicular microenvironment, and regulatory or metabolic processes. Pigmentation-related genes, including SOX10, TYR, TYRP1, PMEL, OCA2 and SLC45A2, were generally downregulated in 179-day white-trunk-stage skin, while changes in ECM- and metabolism-related genes suggested altered follicular microenvironmental regulation. These findings identify candidate transcriptional features associated with developmental coat-color fading in Junken meat sheep and support a follicular microenvironment–melanogenesis expression axis as a transcriptome-based framework for further investigation. Full article

Hair loss is closely associated with oxidative stress, which impairs the function of human follicle dermal papilla cells (HFDPCs) and disrupts hair follicle homeostasis. Current pharmacological treatments, such as minoxidil and finasteride, are effective but may cause adverse effects, highlighting the need for safer alternatives. In this study, we utilized a patented high-pressure processing method to produce black ginseng concentrate (BGC), which is significantly enriched with rare bioactive ginsenosides, including Rg3, Rg5, and Rk1, through optimized chemical transformation. We aimed to elucidate the protective effects of BGC against oxidative stress-induced damage in HFDPCs. BGC significantly reduced intracellular reactive oxygen species (ROS) levels. BGC also improved mitochondrial function, including an increased oxygen consumption rate (OCR). In addition, BGC activated hair growth-related signaling pathways by upregulating Wnt/β-catenin and increasing the phosphorylation levels of ERK and AKT. Collectively, these findings demonstrate that BGC protects HFDPCs from oxidative stress, improves mitochondrial function, and supports key signaling pathways associated with hair growth. This study suggests that BGC has potential as a natural agent for preventing oxidative stress-induced cellular dysfunction related to hair loss. Full article

Background/Objectives: Rumex obtusifolius L. (Polygonaceae) has been traditionally used to treat various disorders, including hepatic and gastrointestinal diseases. However, the phytochemical constituents of its roots and their potential protective effects against skeletal muscle atrophy remain poorly understood. This study aimed to isolate and characterize bioactive constituents from R. obtusifolius roots and evaluate their protective effects against dexamethasone (DEX)-induced muscle atrophy in C2C12 myotubes. Methods: LC–MS-guided phytochemical investigation of the ethanol extract of R. obtusifolius roots, followed by successive column chromatography and HPLC purification, resulted in the isolation of four naphthalene-type glycosides. Their structures were elucidated using 1D and 2D NMR spectroscopy, HR-ESIMS, and chemical transformation. The protective effects of compounds 1 and 4 against dexamethasone (DEX)-induced muscle atrophy were evaluated by assessing myotube morphology, myogenic and atrophy-related protein expression, and PI3K/Akt/mTOR signaling. Results: A new naphthalene malonylglucoside, nepodin-8-O-β-D-(6′-O-malonyl)-glucopyranoside (1), together with three known glycosides (2–4), was identified. Among the isolated compounds, compound 1 significantly attenuated DEX-induced muscle atrophy in a concentration-dependent manner by increasing myotube diameter and improving myotube morphology. It restored the expression of the myogenic markers MyoD and myogenin while suppressing the atrophy-related proteins MuRF1 and MAFBX. Furthermore, compound 1 reversed DEX-induced suppression of the PI3K/Akt/mTOR signaling pathway, indicating recovery of anabolic signaling. Conclusions: This study reports a new naphthalene malonylglucoside (1) from R. obtusifolius roots and demonstrates that compound 1 protects against DEX-induced skeletal muscle atrophy through restoration of myogenic differentiation and activation of the PI3K/Akt/mTOR pathway. These findings suggest that compound 1 is a promising natural lead compound for the development of therapeutics targeting muscle wasting disorders. Full article

Metformin is a cornerstone medication for type 2 diabetes and exhibits anti-tumor activities. Previous studies have demonstrated that metformin suppresses tumor progression by regulating multiple signaling pathways, including the AMPK, PI3K/AKT/mTOR, and JNK pathways. However, most previous studies have focused on its direct effects on tumor cells, with limited attention to its effects in the TME. The TME constitutes a multifaceted ecosystem that drives tumor development and therapeutic resistance via physical barrier formation, immune evasion, and abnormal angiogenesis. In this review, we systematically summarize the impact and underlying regulatory mechanisms of metformin on distinct components of the TME. In addition, we discuss the individual and combined roles of metformin in immunity and inflammation, as well as vascular, matrix, and metabolic regulation. By elucidating the mechanisms of metformin-mediated TME reprogramming, we aim to provide new perspectives for understanding its anti-tumor effects and facilitating its clinical translation in cancer therapy. Full article

Cisplatin (CP) chemotherapy is limited by nephrotoxicity, primarily involving tubular epithelial cell apoptosis. αB-crystallin (CryAB) is a small heat shock protein that plays a cytoprotective role in stressed kidneys but can also promote tumor progression. Its precise role and molecular mechanisms in CP-induced kidney injury remain largely unclear. This study highlighted the function of CryAB and its regulatory pathways in CP nephrotoxicity by employing in vitro models of rat renal tubular epithelial cells (NRK-52E) with CryAB gene knockdown/overexpression, and in vivo models of CryAB knockout/wild-type mice, followed by CP treatment. Apoptosis and key signaling pathways (NF-κB, MAPK, AKT) were evaluated in this study. The results indicated that CP treatment (20 µM) significantly upregulated CryAB expression in renal cells (p < 0.01) and triggered both apoptosis and MAPK activation. CryAB deficiency sensitized cells and mice to CP, exacerbating renal dysfunction, tubular injury, and apoptosis, as evidenced by increased Bax, cyt c release, and caspase-3 cleavage. Conversely, CryAB overexpression attenuated these effects. Furthermore, our findings suggest that the lack of CryAB favors the cytoplasmic retention of NF-κB, and that CryAB status can influence MAPK signaling, pointing to a potential regulatory loop. Additionally, CP-induced AKT phosphorylation was diminished in CryAB-deficient models. Therefore, CryAB may exert a cytoprotective role in CP nephrotoxicity, potentially mitigating tubular apoptosis by modulating the mitochondrial apoptotic pathway, supporting NF-κB-mediated survival signaling, and cross-talking with MAPK and AKT pathways. Our findings suggest that CryAB serves as an important regulator of renal cell fate and a potential therapeutic target for mitigating CP-induced kidney injury. Full article