HIF-1 Signaling Research Articles

Contribution of hypoxia-inducible factor 1alpha to pathogenesis of sarcomeric hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) caused by autosomal-dominant mutations in genes coding for structural sarcomeric proteins, is the most common inherited heart disease. HCM is associated with myocardial hypertrophy, fibrosis and ventricular dysfunction. Hypoxia-inducible transcription factor-1α (Hif-1α) is the central master regulators of cellular hypoxia response and associated with HCM. Yet its exact role remains to be elucidated. Therefore, the effect of a cardiomyocyte-specific Hif-1a knockout (cHif1aKO) was studied in an established α-MHC719/+ HCM mouse model that exhibits the classical features of human HCM. The results show that Hif-1α protein and HIF targets were upregulated in left ventricular tissue of α-MHC719/+ mice. Cardiomyocyte-specific abolishment of Hif-1a blunted the disease phenotype, as evidenced by decreased left ventricular wall thickness, reduced myocardial fibrosis, disordered SRX/DRX state and ROS production. cHif1aKO induced normalization of pro-hypertrophic and pro-fibrotic left ventricular remodeling signaling evidenced on whole transcriptome and proteomics analysis in α-MHC719/+ mice. Proteomics of serum samples from patients with early onset HCM revealed significant modulation of HIF. These results demonstrate that HIF signaling is involved in mouse and human HCM pathogenesis. Cardiomyocyte-specific knockout of Hif-1a attenuates disease phenotype in the mouse model. Targeting Hif-1α might serve as a therapeutic option to mitigate HCM disease progression.

Treatment of delayed fracture healing with Bushen Tiansui decoction: Analysis of active agents and targets using bioinformatics and network pharmacology analysis.

This study aims to utilize bioinformatics and network pharmacology to identify the active components of Bushen Tiansui decoction (BSTSD) and elucidate its molecular mechanisms and targets in promoting delayed fracture healing. Using various databases and tools, we identified 155 active compounds within BSTSD's herbal components. Key compounds such as eriodictyol and β-sitosterol were noted for their significant anti-inflammatory, antioxidant, and immunomodulatory effects, which are crucial for promoting fracture healing. Network analysis revealed compounds such as kaempferol and luteolin as having high centrality within the network, indicating their central role in the therapeutic effects of BSTSD. Gene ontology (GO) enrichment analysis highlighted that biological processes such as gland development and aging are vital for fracture healing. Cellular components like membrane rafts and microdomains are essential for maintaining cellular functions and signal transduction during bone repair. Molecular functions such as protein serine/threonine kinase activity play key roles in regulating bone cell proliferation, differentiation, and remodeling. KEGG pathway analysis identified critical pathways including prostate cancer, proteoglycans in cancer, lipid and atherosclerosis, EGFR tyrosine kinase inhibitor resistance, chemical carcinogenesis receptor activation, PI3K-Akt signaling pathway, hepatitis B, endocrine resistance, HIF-1 signaling pathway, and estrogen signaling pathway. Molecular docking results showed strong binding affinities between key compounds and target proteins, supporting the reliability of the network pharmacology predictions. This study provides a comprehensive understanding of the molecular mechanisms by which BSTSD promotes fracture healing, identifying active compounds and pathways that offer scientific bases for the clinical application of BSTSD and paving the way for further experimental validation and therapeutic development.

Meta-analysis of retinal transcriptome profiling studies in animal models of myopia

ObjectiveMyopia prevalence is increasing at alarming rates, yet the underlying mechanistic causes are not understood. Several studies have employed experimental animal models of myopia and transcriptome profiling to identify genes and pathways contributing to myopia. In this study, we determined the retinal transcriptome changes in response to form deprivation in mouse retinas. We then conducted a transcriptome meta-analysis incorporating all publicly available datasets and analyzed how the results related to the genes associated with refractive errors in human genome-wide association studies (GWAS).MethodsForm deprivation was induced in three male C57BL6/J mice from postnatal day 28 (P28) to P42. Retinal gene expression was analyzed with RNA sequencing, followed by differential gene expression analysis with DESeq2 and identification of associated pathways with the Kyoto Encyclopedia of Genes and Genomes (KEGG). A systematic search identified four similar retinal transcriptomics datasets in response to experimental myopia using chicks or mice. The five studies underwent transcriptome meta-analyses to determine retinal gene expression changes and associated pathways. The results were compared with genes associated with human myopia.ResultsDifferential gene expression analysis of form-deprived mouse retinas revealed 235 significantly altered transcripts, implicating the BMP2 signaling pathway and circadian rhythms, among others. Transcriptome-wide meta-analyses of experimental myopia datasets found 427 differentially expressed genes in the mouse model and 1,110 in the chick model, with limited gene overlap between species. Pathway analysis of these two gene sets implicated TGF-beta signaling and circadian rhythm pathways in both mouse and chick retinas. Some pathways associated only with mouse retinal changes included dopamine signaling and HIF-1 signaling pathway, whereas glucagon signaling was only associated with gene changes in chick retinas. The follistatin gene changed in both mouse and chick retinas and has also been implicated in human myopia. TGF-beta signaling pathway and circadian entrainment processes were associated with myopia in mice, chicks, and humans.ConclusionThis study highlights the power of combining datasets to enhance statistical power and identify robust gene expression changes across different experimental animal models and conditions. The data supports other experimental evidence that TGF-beta signaling pathway and circadian rhythms are involved in myopic eye growth.

Study on mechanism of Spatholobi Caulis in the treatment of the hand-foot skin reaction induced by targeted drug therapy based on network pharmacology and molecular docking: An observational study.

Based on network pharmacology and molecular docking methods, this study explored its active compounds and confirmed its potential mechanism of action against Hand-foot skin reaction induced by tumor-targeted drugs. Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and UniProt Database were used to obtain the active ingredients and target proteins of Spatholobi Caulis. All hand-foot skin reaction (HFSR)-related targets were obtained with the help of the Human Gene Database, Online Mendelian Inheritance in Humans (OMIM), DisGeNET and DrugBank databases. Cytoscape 3.7.1 software was used to construct the active ingredient-target visualization network of Spatholobi Caulis, and the common target network of Spatholobi Caulis and HFSR. And through the BisoGenet plug-in in Cytoscape, PPI network topology analysis was performed. The Metescape database and online mapping tool platform were used for Gene Ontology (GO) function and Kyoto Encyclopedia of Genes Genomes (KEGG) pathway enrichment analysis to identify the key pathways of Spatholobi Caulis. Finally, Autodock Vina software and PyMol 2.5 software were used for molecular docking verification. There were 24 active components of Spatholobi Caulis and 244 target genes, 1635 disease-related target genes, 51 common target genes of Spatholobi Caulis and Hand-foot skin reaction, and key targets included NTRK1, epidermal growth factor receptor (EGFR), APP, TP53, HSP90AB1, HSP90AA, CUL3, etc. GO functional analysis involved a total of 66 molecular functions, 39 cellular components, and 817 biological processes. KEGG pathway analysis found 154 related signaling pathways, mainly enriched in Pathways in cancer, Human cytomegalovirus infection, Kaposi arcoma-associated herpesvirus infection, panic cancer, EGFR tyrosine kinase inhibitor resistance, P13K-Akt signaling pathway, Proteoglycans in cancer, HIF-1 signaling pathway and Ras signaling pathway, etc. Molecular docking results showed that luteolin, the active component of Spatholobi Caulis, had a high affinity with EGFR. Medicagol, the active components of Spatholobi Caulis, is proved in the Hand-foot skin reaction induced by lung cancer targeted therapy by regulating multiple signaling pathways through EGFR. It is confirmed that the treatment of Hand-foot skin reaction has the characteristics of multi-component, multi-target and multi-pathway regulation.

Discovering the compatibility of Coptidis Rhizoma and Gardeniae Fructus in attenuating hepatotoxicity through the association rules analysis of related formula.

Gardenia jasminoides J. Ellis (Gardeniae Fructus, GF) is a widely used herbal medicine in many prescriptions. However, inappropriate application of GF may induce hepatotoxicity, which greatly challenges its clinical application. In the field of Traditional Chinese Medicine, the principle of "Compatibility for Toxicity Attenuation" is a pivotal concept. So far, the basis and mechanisms of compatibility with GF remain unclear. We aimed to investigate the toxicity attenuating effects and potential mechanisms of compatibility of Coptis chinensis Franch (Coptidis Rhizoma, CR) and GF in hepatotoxicity. Association rules analysis was performed in 817 GF-related formulas, and 49 associated items were selected, among which CR and GF were ranked in the top two. Network pharmacology was used to elucidate the potential mechanisms of combination of CR and GF in mitigating hepatotoxicity. Nine potential hepatotoxic components of GF and 14 active components of CR were focused on, and 9 common targets for CR and GF were identified. Further GO and KEGG analyses showed that the toxicity attenuating effect of CR on GF-induced hepatotoxicity may be closely correlated with inflammatory response, response to hypoxia, cancer signaling pathways, PI3K-Akt and HIF-1 signaling pathway. The in vitro results indicated that the combined use of CR and GF increased the viability of HepG2 cells. Furthermore, the in vivo data demonstrated that CR inhibited GF-induced increase in serum ALT and AST levels and pathological changes in the livers of KM mice. Besides, CR reduced the accumulation of ROS and MDA, inhibited the release of TNF-α and IL-6, while elevated GSH level in the mouse liver tissues. Finally, the molecular docking results indicated that the active components of CR had strong binding affinity with the monooxygenase cytochrome P450 3A4 (CYP3A4). CR combination restored the expression of CYP3A4 in the liver tissues of mice challenged with GF. Co-administration with CR effectively reduced GF-induced hepatotoxicity through alleviating oxidative damage, inflammatory response and enhancing CYP3A4 expression.

Differences in the composition of plasma metabolites and intestinal flora of piglets with different weaning weights revealed by untargeted metabolomics and 16S rRNA gene sequencing.

Piglets with different weaning body weights exhibit varying growth performance. This study explores the relationship between their plasma metabolites and gut microbiota to reveal differences in metabolic regulation and microbial composition. Plasma and colon content samples from piglets of different weaning weights were collected. Untargeted metabolomics, 16S rRNA gene sequencing, multivariate statistics, and bioinformatics were used to identify and compare metabolites. Six key findings emerged. First, 23 differential metabolites were found, with three upregulated in high-weight piglets and 20 downregulated in low-weight piglets. A total of 15 were lipids or lipid-like molecules. Second, metabolic pathway enrichment analysis indicated that the sphingolipid signaling pathway, HIF-1 signaling pathway, sphingolipid metabolism pathway, ascorbate and aldarate metabolism pathway, and glycine, serine, and threonine metabolism pathway were the most significantly affected pathways in the plasma of piglets with different weaning body weights. Third, alpha diversity was lower in low-weight weaned piglets. Fourth, Lactobacillus was 23.16% in high-weight piglets, higher than 19.62% in low-weight ones. Fifth, linear discriminant analysis effect size (LEfSe) analysis showed that Faecalibacterium is a biomarker for low-body-weight piglets and Oscillospira is a biomarker for high-body-weight piglets. Finally, Spearman correlation analysis indicated that Lactobacillus, Prevotella, Ruminococcus, and Oscillospira were negatively correlated with differential metabolites in plasma. The plasma metabolites and colon microbiota differed between piglets of different body weights. Lipid-related plasma metabolites contributed to weight variation, being lower in heavier piglets. The colonic microbiota, especially Oscillospira and Roseburia, exhibited strong correlations with these metabolites. © 2025 Society of Chemical Industry.

MicroRNA in pediatric pulmonary hypertension microRNA profiling to inform disease classification, severity, and treatment response in pediatric pulmonary hypertension.

Pediatric pulmonary hypertension is a heterogeneous disease associated with significant morbidity and mortality. MicroRNAs have been implicated as both pathologic drivers of disease and potential therapeutic targets in pediatric pulmonary hypertension. We sought to characterize the circulating microRNA profiles of a diverse array of pediatric patients with pulmonary hypertension using high-throughput sequencing technology. Peripheral blood samples were drawn from patients recruited at the time of a clinically indicated cardiac catheterization, and microRNA sequencing followed by differential expression and target/pathway enrichment analyses were performed. Among 63 pediatric patients with pulmonary hypertension, we identified specific microRNA signatures that uniquely classified patients by disease subtype, correlated with indicators of disease severity including invasive hemodynamic metrics, and changed over the course of treatment for pulmonary hypertension. These microRNA profiles include a number of specific microRNA molecules known to function in signaling pathways critical to pulmonary vascular biology and disease, including transforming growth factor-β (TGF-β), VEGF, PI3K/Akt, cGMP-PKG, and HIF-1 signaling. Circulating levels of miR-122-5p, miR-124-3p, miR-204-5p, and miR-9-5p decreased over the course of treatment in a subset of patients who had multiple samples drawn during the study period. Our findings support the further investigation of specific microRNAs as mechanistic mediators, biomarkers, and therapeutic targets in pulmonary hypertension.NEW & NOTEWORTHY We present novel insight into the circulating microRNA profiles of pediatric patients with pulmonary hypertension. Our findings support the utility of microRNAs as both useful biomarkers of disease severity and potential therapeutic targets in pediatric pulmonary hypertension.

Hypoxia inducible factor-dependent upregulation of Agrp in glomus type I cells of the carotid body.

Agouti-related peptide (AgRP) is a well-established potent orexigenic peptide primarily expressed in hypothalamic neurons. Nevertheless, the expression and functional significance of extrahypothalamic AgRP remain poorly understood. In this study, utilizing histological and molecular biology techniques, we have identified a significant expression of Agrp mRNA and AgRP peptide production in glomus type I cells within the mouse carotid body (CB). Furthermore, we have uncovered evidence supporting the expression of the AgRP receptor melanocortin receptor 3 (Mc3r) in adjacent sympathetic neurons, suggesting a potential local paracrine role for AgRP within the CB. Importantly, AgRP immunoreactivity was also identified in glomus type I cells of the human CB. Given the unexpected abundance of AgRP in glomus type I cells, a chemoreceptor cell specialized i.a. for oxygen sensing, we proceeded to investigate whether Agrp expression in the CB is regulated by hypoxemia and associated oxygen-sensing molecular mechanisms. Invitro luciferase assays reveal that hypoxia stimulates the human and mouse Agrp promoters in a Hypoxia Inducible Factor (HIF1/2)-dependent manner. Our invivo experiments further demonstrate that exposure to environmental hypoxia (10%) robustly induces Agrp expression in type I glomus cells of mice. Furthermore, these findings collectively highlight the hitherto unknown source of AgRP in murine and human type I glomus cells and underscore the direct control of Agrp transcription by HIF signaling.

Perfluorooctane sulfonate (PFOS) induced bone loss by inhibiting FoxO1-mediated defense against oxidative stress in osteoblast.

Exposure to perfluorooctane sulfonate (PFOS) has been associated with lower bone density and the occurrence of osteoporosis in human studies, but the effects and mechanisms of PFOS induces bone loss is not well understood. Our research is aimed at examining the effects of PFOS on osteoblastic activity and investigating the toxicological mechanisms of PFOS-induced bone loss. Cell proliferation, ALP activity, bone nodule formation, ROS levels, and cell apoptosis were assessed after treating osteoblasts with different concentrations of PFOS. Through transcriptome analysis, the differentially expressed genes (DEGs) were screened and the biofunctions were elucidated by Kyoto Encyclopedia of Genes and Genomes (KEGG) and The Gene Set Enrichment Analysis (GSEA). Vation of important genes and protein expression was accomplished using RT-PCR and Western blot methods, respectively. The results show that PFOS can reduce bone formation markers and improve oxidative stress and cell apoptosis. The DEGs in PFOS-treated groups were involved in multiple pathways, including FoxO, HIF-1, Rap1, Hippo, and sphingolipid signaling. FoxO1 was validated as the key gene which regulates osteogenic differentiation and redox status. Our findings suggest that PFOS reduces bone formation through FoxO1-mediated oxidative stress and apoptosis, as well as inhibition of the OPG/RANKL and FoxO1/β-catenin pathways. It will be beneficial for early intervention or treatment of PFOS-induced bone loss, highlighting the importance of regulatory measures to limit human exposure to PFOS.

MTOR/HIF-1α pathway-mediated glucose reprogramming and macrophage polarization by Sini decoction plus ginseng soup in ALF.

Acute liver failure (ALF) has a high mortality rate, and despite treatment advancements, long-term outcomes remain poor. This study explores the therapeutic targets and pathways of Sini Decoction plus Ginseng Soup (SNRS) in ALF using bioinformatics and network pharmacology, focusing on its impact on macrophage polarization through glucose metabolism reprogramming. The efficacy of SNRS was validated in an LPS/D-GalN-induced ALF model, and its optimal concentration was determined for in vitro macrophage intervention. Differentially expressed genes (DEGs) in HBV-induced and acetaminophen-induced ALF were identified from GEO datasets. The correlation between target gene expression and immune cell infiltration in ALF liver tissue was analyzed. AST, ALT, TNF-α, HMGB1, IL-1β, IL-6, and IL-10 levels were measured, and liver histopathology was assessed. Macrophage polarization was analyzed via immunofluorescence, flow cytometry, and Western blot. Glycolysis-related enzymes and metabolites, including HK2, PFK-1, PKM2, and LDHA, were quantified. Cellular ultrastructure was examined by transmission electron microscopy. Five key glycolysis-regulating genes (HK2, CDK1, SOD1, VEGFA, GOT1) were identified, with significant involvement in the HIF-1 signaling pathway. Immune infiltration was markedly higher in ALF liver tissue. SNRS improved survival, reduced ALT/AST levels, alleviated liver injury, and modulated macrophage polarization by decreasing CD86 and increasing CD163 expression. In vitro, SNRS inhibited LPS-induced inflammatory cytokine release, lactate production, p-mTOR/mTOR ratio, and HIF-1α expression. SNRS modulates macrophage polarization and glucose metabolism reprogramming via the mTOR/HIF-1α pathway, showing promise as a treatment for ALF.

Synergistic Anti-Inflammatory Effects of Dibenzoylmethane and Silibinin: Insights From LPS-Induced RAW 264.7 Cells and TPA-Induced Mouse Model.

Inflammation is an important predisposing factor for many chronic diseases. The dietary flavonoid silibinin (SB) has excellent anti-inflammatory properties in cells, but its low bioavailability in the blood compromises its therapeutic potential. This study aims to investigate the potential of dibenzoylmethane (DBM) to synergistically enhance the anti-inflammatory benefits of SB. The synergistic effects of DBM and SB in combination were evaluated in lipopolysaccharide (LPS)-induced RAW264.7 cells and 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced mice. In addition, a network pharmacology approach and molecular docking were used to explore the key targets and signaling pathways of DBM and SB in combination. The results showed that DBM and SB synergistically inhibited the production of nitric oxide (NO), reactive oxygen species (ROS), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) in a 1:1 concentration ratio. These two compounds may exert their synergistic effects by modulating the nuclear factor kappa-B (NF-κB) and HIF-1 signaling pathways, among others. Molecular docking revealed that both compounds exhibited high binding affinities to inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Compared with single-compound use, the two compounds in combination significantly reduced ear edema and inflammatory cell infiltration and inhibited the protein expression of iNOS and COX-2 in TPA-induced mice. This research provides a rationale for the combination of DBM and SB as an effective anti-inflammatory agent.

Exploring the mechanism of fibrates regulating HIF-1A in the treatment of ischemic stroke based on network pharmacology and molecular docking

Fibrates can prevent and treat ischemic stroke (IS), the occurrence and development of IS is closely related to hypoxia-inducible factor-1A (HIF-1A). However, the exact mechanism by which fibrates regulate HIF-1A to treat IS remains unclear. So network pharmacology and molecular docking were used to explore the mechanism by which fibrates regulate HIF-1A to treat IS, firstly, the structure of five fibrates were obtained by reviewing the literature and pharmacopoeia, then the potential targets of fibrates, IS, HIF1A and HIF1A-related genes were obtained through various databases, their common targets were obtained through Venny 2.1.0. The PPI network diagram of fibrates, IS and HIF1A-related genes was plotted by String and Cytoscape3.8.1. The GO functional analysis results and KEGG pathways of fibrates, IS, HIF1A and HIF1A related genes were obtained by Metascape. Finally, the molecular docking of fibrates and HIF1A was performed by AutoDock. The common targets of five fibrates and IS showed that only 3 fibrates contained HIF1A, GO functional analysis, KEGG pathway analysis and molecular docking showed that fibrates can better regulate HIF1A to treat IS, its main action pathways are pathways in cancer, lipid and atherosclerosis and HIF-1 signaling pathway.

A Study on the Function of Arginine in the Growth, Immunity, Antioxidant Activity, and Oxygen Carrying-Capacity of Juvenile Gibel Carp (Carassius auratus gibelio).

An eight-week trial was designed to study the effects of arginine (Arg) supplemented diets on the growth, immunity, antioxidant activity, and oxygen-carrying capacity of juvenile Gibel carp (Carassius auratus gibelio). A total of 300 fish (27.53 ± 0.03 g) were randomized into 15 equal groups and fed on diets with graded Arg levels: 0 (control), 0.2%, 0.4%, 0.6%, and 0.8% (w/w). The results showed that final body weight (FBW), weight gain rate (WGR), and specific growth rate (SGR) all increased and then declined with increasing levels of Arg supplementation, while feed conversion ratio (FCR) showed the opposite trend. In addition, the fish's whole-body crude protein and ash content had no remarkable difference at different levels of Arg addition (p > 0.05). Supplementation with 0.6% and 0.8% Arg significantly increased plasma alanine transaminase (ALT) activity (p < 0.05). The malondialdehyde (MDA) levels and superoxide dismutase (SOD) activities of the liver were not significantly different between the different levels of Arg supplementation (p > 0.05), while catalase (CAT) activity was significantly increased with 0.4% Arg supplementation levels (p < 0.05). The 0.8% Arg supplementation greatly increased the expression of hepatic-related genes to the Nrf2 signaling pathway, including sod and gpx (p < 0.05). However, the 0.8% Arg supplementation did not significantly increase the relative expression of genes related to the NF-κB signaling pathway, including il-1β, il-8, and tnf-α (p > 0.05). Similarly, the relative expression of hif-1 signaling pathway-related genes at 0.8% Arg supplementation was significantly elevated, including hif-1α, epo, and vegf (p < 0.05). Hence, Arg supplementation could promote growth and improve immune, antioxidant, and oxygen-carrying capacity in juvenile Gibel carp.

Xuebijing and somatostatin against acute pancreatitis: A systematic review and network pharmacology.

Acute pancreatitis (AP) is a common pancreatic disease. Xuebijing injection (XBJ) combined with somatostatin in the treatment of AP is frequently used in clinical practice. There is, however, a lack of high-quality evidence-based evidence and network pharmacology to regard the therapeutic efficacy and pharmacological mechanisms. The purpose of this study is to investigate the potential therapeutic targets and pharmacological mechanism of XBJ in AP using integrating evidence-based medicine and network pharmacology. PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, Weipu, and Wanfang databases were searched. Randomized controlled trials of XBJ combined with somatostatin (experimental group) versus somatostatin alone (control group) in the treatment of AP were collected. After extracting data from the literature that meets the inclusion criteria, and using the Cochrane Scale to evaluate the quality of the literature, we used Rev Man 5.3.0 statistical software to perform meta-analysis of the effective rate, the disappearance time of abdominal pain and bloating, the recovery of gastrointestinal motility, serum-related indicators, inflammatory factors, ventilator evacuation time, and hospitalization time. A network pharmacology is used to analyze the potential active ingredients and related crucial targets of the XBJ in the treatment of AP, and we explored key regulatory pathways and potential biomarkers related to XBJ for AP with integrated bioinformatics analysis. It was significant that the total effective rate in the study group was higher than that in the control group (P < .05). The time of recovery of gastrointestinal motility, serum-related indicators, inflammatory factors, ventilator withdrawal time, and hospitalization time were significantly lower than that of the control group. The differences were statistically significant (P < .05). Signal transducer and activator of transcription 3, tumor protein P53, interleukin 6, tumor necrosis factor, Jun Proto-Oncogene, SRC Proto-Oncogene, Heat Shock Protein 90 Alpha Family Class A Member 1, Vascular Endothelial Growth Factor A, Epidermal Growth Factor Receptor, and Mitogen-Activated Protein Kinase 1 were identified as the key hub of the protein-protein interaction network according to an analysis of network centrality. According to the Kyoto Encyclopedia of Genes and Genomes pathway analysis, the main pathways are involved in PI3K-Akt signaling pathway, HIF-1 signaling pathway, and tumor necrosis factor signaling pathway. The effectiveness of combination therapy of XBJ and somatostatin on AP is likely to be better than somatostatin. In addition, XBJ and somatostatin synergistically treated AP through a multi-pathway network.

Circulating small extracellular vesicles as blood-based biomarkers of muscle health in aging nonhuman primates.

Age-associated loss of muscle mass and function and subsequent mobility decline define poor health outcomes, reduced quality of life, and mortality risk. The rate and extent of aging-related muscle loss varies across older adults. It is challenging to understand the molecular pathogenesis of mobility decline, as anthropometric and imaging techniques, primarily used in muscle function assessment, do not offer much molecular information. Small extracellular vesicles (sEV) are lipid membrane-bound, nano-sized (≤ 200nm) vesicles which carry a wide array of biomolecules as their cargo. sEV contain cell/tissue-specific signatures on their surface and can be isolated from biofluids. These properties pose sEV as a minimally invasive means to monitor the functional and biological health of difficult-to-access tissues, establishing them as a promising liquid biopsy tool. Here, we first isolated skeletal muscle-derived sEV (sEVSKM) from the serum of vervet monkeys (16 to < 25years old) using alpha sarcoglycan (SGCA) as a muscle-specific sEV surface marker. sEVSKM were extensively characterized for size, concentration, purity, and specificity. Further, sEVSKM isolated from young (11-15years) and old (25-29years) monkeys' serum were characterized for oxidized proteins by mass spectrometry and miRNAs by small-RNAseq. Notably, the analysis of oxidized proteins indicated perturbation of metabolic pathways, actin cytoskeleton, muscle cytoskeleton regulation, and HIF-1 signaling in older monkeys. Furthermore, small-RNAseq analysis identified differential expression of several miRNAs regulating metabolic pathways, inflammation, and stress signaling. Altogether, these results suggest that it is feasible to isolate sEVSKM and use them to identify molecular biomarkers that reflect the physiological state of muscle tissue.

To explore the protective mechanism of promethazine against hippocampal neuron injury based on network pharmacology and experimental verification.

This study aims to investigate the effect of promethazine (PMZ) on hippocampal neuronal injury through network pharmacology and in vivo experiments. Network pharmacology: The intersection genes of PMZ and Alzheimer Disease (AD) were obtained, and the core genes of PMZ in AD were screened. The intersection genes were enriched by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. In the in vitro experiment, mouse hippocampal neurons (HT22) were divided into control, glutamate (GLU) model, and GLU + PMZ treatment groups. The control group was given a complete culture medium, the model group was given GLU for 24 hours, the treatment group was given PMZ pretreatment for 3 hours, and then GLU was administered for 24 hours. Cell viability was determined, cell morphology was observed by microscopy, reactive oxygen species levels and glutathione content were detected, and protein expression of P53, PTGS2, SLC7A11, and GPX4 was detected by western blotting. Network pharmacology: A total of 317 PMZ targets, 1934 AD genes, 125 intersection genes, and 18 core genes, including P53 and PTGS2. Gene Ontology enrichment analysis showed that the effect of PMZ on AD was mainly related to cell proliferation, inflammation, hypoxia, synaptic structure, plasma membrane, and oxidoreductase activity. Kyoto Encyclopedia of Genes and Genomes results showed neuroactive ligand-receptor interaction, cell senescence, cancer pathway, PI3K-AKT signal pathway, neurodegeneration, and HIF-1 signal pathway. In vitro experiments: PMZ improved the GLU-induced decrease in cell viability and morphological changes in hippocampal neurons. PMZ inhibited reactive oxygen species levels and increased glutathione content in injured hippocampal neurons. Up-regulated of P53, SLC7A11 and GPX4 expression, and inhibited expression of PTGS2. PMZ regulates the SLC7A11-GPX4 antioxidant system to protect hippocampal neurons from oxidative stress injury.

Integrated miRNA-seq and functional analyses reveal the regulatory role of sha-miR-92a_L + 2R + 4 via targeting vegfaa in rainbow trout (Oncorhynchus mykiss) responding to acute hypoxia and reoxygenation stress

BackgroundHypoxia negatively affects the behavior, growth, reproduction and survival of fish, causing serious economic losses to aquaculture. Rainbow trout (Oncorhynchus mykiss), an important economic fish worldwide, belongs to a hypoxia-sensitive fish species, however, little is known about the regulatory mechanism of microRNAs (miRNAs) under hypoxia stress.ResultsRainbow trout were subjected to hypoxia stress for 3 h (H3h_L), 12 h (H12h_L), 24 h (H24h_L) and 3 h reoxygenation (R3h_L) to systemically evaluate the changes of miRNA expression profiles in liver, and functions of sha-miR-92a_L + 2R + 4 were investigated. We found 17, 144, 57 and 55 differentially expressed (DE) miRNAs in the H3h_L vs. control (N_L), H12h_L vs. N_L, H24h_L vs. N_L and R3h_L vs. N_L comparisons, respectively. Enrichment analysis revealed that the targets of DE miRNAs were significantly enriched in HIF signaling pathway, VEGF signaling pathway, FoxO signaling pathway and glycolysis/gluconeogenesis. Through miRNA-mRNA interaction and weighted gene co-expression network analysis (WGCNA), five key DE miRNAs (sha-miR-92a_L + 2R + 4, ssa-miR-128-3p, ssa-miR-101b-3p_R + 1, ola-miR-199a-5p_R + 2 and tni-miR-199_1ss18CG) were identified, which can target at least two hypoxia-responsive genes, such as vegfaa, ho, glut1a and junb. Functional analysis found that sha-miR-92a_L + 2R + 4 directly regulated vegfaa expression by targeting its 3′-UTR, overexpression of sha-miR-92a_L + 2R + 4 significantly decreased vegfaa expression in rainbow trout liver cells, while opposite results were obtained after transfection of sha-miR-92a_L + 2R + 4 inhibitor. Furthermore, overexpressed sha-miR-92a_L + 2R + 4 promoted rainbow trout liver cell proliferation and inhibited apoptosis.ConclusionThis study deepens our understanding of the crucial roles of miRNAs under hypoxia stress in rainbow trout. These results can contribute to devise strategies for improving rainbow trout survival rate and aquaculture production during hypoxia stress and help speeding up the selective breeding of hypoxia-tolerant rainbow trout.

The impact of Benzophenone-3 on osteoarthritis pathogenesis: a network toxicology approach.

Arthritis is a degenerative joint disease influenced by various environmental factors, including exposure to Benzophenone-3 (BP3), a common UV filter. This study aims to elucidate the toxicological impact of BP3 on arthritis pathogenesis using network toxicology approaches. We integrated data from the Comparative Toxicogenomics Database (CTD) and Gene Expression Omnibus (GEO) to identify differentially expressed BP3-related toxicological targets in osteoarthritis (OA). Enrichment analyses were conducted to determine the implicated biological processes, cellular components, and molecular functions. Further, the involvement of the PI3K-Akt signaling pathway was investigated, along with correlations with immune cell infiltration and immune-related pathways. Molecular docking analysis was performed to examine BP3 interactions with key PI3K-Akt pathway proteins. A total of 74 differentially expressed BP3-related targets were identified. Enrichment analysis revealed significant pathways, including PI3K-Akt, MAPK, and HIF-1 signaling. The PI3K-Akt pathway showed notable dysregulation in OA, with reduced activity and differential expression of key genes such as ANGPT1, ITGA4, and PIK3R1. Correlation analysis indicated significant associations between PI3K-Akt pathway activity and various immune cell types and immune pathways. Molecular docking highlighted strong interactions between BP3 and proteins like AREG, suggesting potential disruptions in signaling processes. BP3 exposure significantly alters the expression of toxicological targets and disrupts the PI3KAkt signaling pathway, contributing to OA pathogenesis. These findings provide insights into the molecular mechanisms of BP3-induced OA and identify potential therapeutic targets for mitigating its effects.

Unifying Theory and Experiments: Multi-Target Pharmacology of Dajihan Pill Against Hyperlipidemia

Background: The increasing incidence of hyperlipidemia (HLP) is attributed to the imbalance in redox homeostasis, aberrant lipid metabolism, and the excessive intake of empty calories. Dajihan Pill (DJHP) is a Traditional Chinese Medicine (TCM) formula composed of Zingiberis Rhizoma (ZR), Piperis Longi Fructus (PLF), Alpiniae Officinarum Rhizome (AOR), and Cinnamomi Cortex (CC) in a ratio of 3:2:3:2. It exhibits a significant preventive effect on HLP. Certainly, the active components and the precise mechanism of action are not fully understood. Therefore, this study aims to elucidate the preventive and ameliorative mechanisms of DJHP against HLP by integrating network pharmacology, molecular docking, and experimental validation. Methods: Based on the pharmacological method, active ingredients in DJHP and targets were extracted from Traditional Chinese Medicine System Pharmacology (TCMSP) and UniProt. Then core compounds and targets were obtained by constructing “compounds-targets-disease” and proteinprotein interaction (PPI) network. Gene Ontology (GO) function analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) were employed to elucidate further the associated action mechanism. The molecular binding mechanisms between the core ingredients and targets were elucidated through molecular docking. Additionally, the antioxidant capacities of DJHP extracts were investigated by assessing their DPPH, hydroxyl, and ABTS radical scavenging activities. Results: A total of 45 active compounds and 258 targets were identified in DJHP. Network analysis indicated that quercetin, beta-sitosterol, kaempferol, and oleic acid might serve as core bioactive compounds. Seven core targets, including AKT1, INS, and TNF, were identified as potential preventive targets. GO analysis suggested the improvement of HLP by DJHP may be related to the lipid metabolic process, high-density lipoprotein particle, triglyceride binding, and inflammatory response. The KEGG analysis indicated TNF, HIF-1, and AMPK signaling pathways were involved. The observations of active compounds binding with core targets indicated an excellent combination. Additionally, antioxidant results showed that DJHP exhibited significant DPPH, hydroxyl, and ABTS radical scavenging activities. Conclusion: Theoretical and experimental investigations indicate that DJHP can effectively modulate various signaling pathways and enhance the redox system, thus mitigating HLP. Our work provided a basis for the pharmacological study of DJHP in preventing HLP and further research.

Serum proteome profiling of plateau acclimatization in men using Olink proteomics approach.

Plateau acclimatization involves adaptive changes in the body's neurohumoral regulation and metabolic processes due to hypoxic conditions at high altitudes. This study utilizes Olink targeted proteomics to analyze serum protein expression differences in Han Chinese individuals acclimatized for 6 months-1 year at 4500 and 5300 m altitudes, compared to those residing at sea level. The objective is to elucidate the proteins' roles in tissue and cellular adaptation to hypoxia. We identified 54 metabolism-related differentially expressed proteins (DEPs) in the serum of the high-altitude group versus the sea-level group, comprising 20 significantly upregulated and 34 downregulated proteins. Notably, 2 proteins were upregulated and 11 downregulated at both 4500 and 5300 m altitudes. The top three protein correlations among DEPs included CRKL with CA13, RNASE3 with NADK, and NADK with APEX1, alongside APLP1 with CTSH, CTSH with SOST, and CTSH with NT-proBNP in inverse correlations. KEGG enrichment analysis indicated significant DEP involvement in various metabolic pathways, particularly those associated with hypoxic cellular metabolism like glycolysis/gluconeogenesis and the HIF-1 signaling pathway. Correlation with clinical phenotypes showed positive associations of SOST, RNASE3, CA13, NADK, and CRKL with SaO2 and negative correlations with Hemoglobin and Hematocrit; ALDH1A1 positively correlated with Triglyceride; and SDC4 inversely correlated with Uric acid levels. This study provides insights into specific DEPs linked to metabolic adaptations in high-altitude acclimatized individuals, offering a foundation for understanding acclimatization mechanisms and potential therapeutic targets.