Search Results (67)

As high-quality sheep germplasm resources in China, Hu sheep are characterized by fast growth and development, high fecundity, and tolerance to drought and cold. Tibetan sheep, adapted to high-altitude environments, have developed strong environmental adaptability. To explore the differences in the interaction among rumen microbial flora, hepatic gluconeogenesis, and mitochondrial function between Tibetan sheep and Hu sheep in the Qinghai–Tibet Plateau, this study systematically compared and analyzed the rumen flora density, key enzyme activities related to hepatic gluconeogenesis and mitochondrial function, and the expression levels of related genes in Tibetan sheep and Hu sheep under identical feeding management conditions, followed by correlation analysis. The results showed that Hu sheep had significantly higher densities of Ruminobacteramylophilus (Ram) and Fibrobacter succinogenes (Fs) associated with starch and protein degradation (p < 0.01). The expression levels of Forkhead box O1 (FOXO1), pyruvate carboxylase (PC) activity, and adenosine triphosphate (ATP) content were also significantly higher than those in Tibetan sheep (p < 0.01). In contrast, Tibetan sheep had higher densities of Butyrivibrio fibrisolvens (Bf), Ruminococcus albus (Ra), Ruminococcus flavefaciens (Rf), etc., related to cellulose degradation (p < 0.01). The gluconeogenesis-related genes, Glucose-6-phosphatase catalytic subunit 1 (G6PC1) and phosphoenolpyruvate carboxykinase1 (PCK1), and the activities of phosphoenolpyruvate carboxykinase (PEPCK) and fructose-1,6-bisphosphatase (FBPase) were significantly higher in Tibetan sheep than in Hu sheep (p < 0.01). Mitochondrial function-related genes Mitofusin-1 (Mfn1), Mitofusin-2 (Mfn2), subunit 6 of ATP synthase (ATP6), cytochrome b (Cytb), etc., also showed significantly higher expression in Tibetan sheep (p < 0.01). While no significant differences were observed in the contents of citric acid (CA), pyruvic acid (PA), glucose (Glu), etc. (p > 0.05). Correlation analysis indicated that rumen flora was associated with the key enzyme activities and gene expressions of hepatic gluconeogenesis and mitochondrial function to varying degrees. In summary, Tibetan sheep exhibit strong fiber degradation capacity, the efficient utilization of gluconeogenic intermediates, and mitochondrial oxidative phosphorylation (OXPHOS) ability, forming adaptive strategies for high-altitude environments. By contrast, Hu sheep show efficient protein and starch degradation capacity, thereby enhancing the supply of gluconeogenic precursors. It is indicated that when introducing Hu sheep to high-altitude areas, dietary intervention can be used to regulate rumen microorganisms, such as increasing fiber-decomposing bacteria or enhancing mitochondrial oxidative capacity, to counteract metabolic limitations induced by hypoxia. Full article

The Tibetan goat (Capra hircus) exhibits remarkable adaptations to high-altitude hypoxia, yet the molecular mechanisms remain unclear. This study integrates RNA-seq, WGCNA, and machine learning to explore gene-environment interactions (G × E) in hypoxia adaptation. Fibroblasts from the Tibetan goat and Yunling goat were cultured under hypoxic (1% O₂) and normoxic (21% O₂) conditions, respectively. This identified 68 breed-specific (G), 100 oxygen-responsive (E), and 620 interaction-driven (I) Differentially Expressed Genes (DEGs). The notably higher number of interaction-driven DEGs compared to other effects highlights transcriptional plasticity. We defined two gene sets: Environmental Stress Genes (n = 632, E ∪ I) and Genetic Adaptation Genes (n = 659, G ∪ I). The former were significantly enriched in pathways related to oxidative stress defense and metabolic adaptation, while the latter showed prominent enrichment in pathways associated with vascular remodeling and transcriptional regulation. CTNNB1 emerged as a key regulatory factor in both gene sets, interacting with CASP3 and MMP2 to form the core of the protein–protein interaction (PPI) network. Machine learning identified MAP3K5, TGFBR2, RSPO1 and ITGB5 as critical genes. WGCNA identified key modules in hypoxia adaptation, where FOXO3, HEXIM1, and PPARD promote the stabilization of HIF-1α and metabolic adaptation through the HIF-1 signaling pathway and glycolysis. These findings underscore the pivotal role of gene–environment interactions in hypoxic adaptation, offering novel perspectives for both livestock breeding programs and biomedical research initiatives. Full article

Background: Crossbreeding strategies that combine the growth performance of Western pig breeds with the meat quality traits of Chinese indigenous breeds have garnered considerable interest. Duroc pigs are known for their high growth efficiency but have relatively low intramuscular fat (IMF) content. In contrast, native breeds like the Diannan Small-Eared pig exhibit superior pork quality with higher IMF levels. This study aimed to compare the muscle growth characteristics and molecular mechanisms between Duroc × Landrace × Yorkshire (DLY) and Duroc × Berkshire × Diannan Small-Eared (DBD) pigs. Methods: The longissimus dorsi tissue of 210-day-old DLY and DBD pigs was collected for analysis. HE staining assessed muscle fiber characteristics, IMF content was measured, and ELISA quantified muscle-derived growth and development-related factors. Transcriptome sequencing was conducted, followed by differential gene expression analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein–protein interaction (PPI) analyses. Functional validation of key genes was performed in C2C12 cells. Results: DBD pigs exhibited significantly larger muscle fiber diameter and higher IMF content compared to DLY pigs. IGF1 and GH levels were elevated in DBD pigs. Transcriptome analysis identified 185 upregulated and 102 downregulated genes, with enrichment in pathways including PI3K-Akt, MAPK, FoxO, and cGMP-PKG signaling. ACSL1 and FABP3 were functionally validated, showing promotion of differentiation and inhibition of proliferation in C2C12 cells. Conclusions: DBD pigs exhibit superior muscle growth traits and higher IMF content compared to DLY pigs. ACSL1 and FABP3 may serve as key regulators of muscle development in pigs. Full article

Queen bee acid (10-hydroxy-2-decenoic acid, QBA) is a biologically active compound known for its anti-aging effects, though its molecular mechanisms are not fully understood. This study employed network pharmacology and molecular docking to explore QBA’s anti-aging mechanisms. Target proteins of QBA were identified via PharmMapper, SwissTarget Prediction, and PubChem, while aging-related target genes were sourced from GeneCards, DisGeNET, and OMIM databases. Venny 2.1 identified 58 common target genes, and a protein–protein interaction (PPI) network was constructed using STRING database. Ten core target genes, including TNF, AKT1, INS, and STAT3, were analyzed for GO and KEGG pathway enrichment using DAVID. GO analysis yielded 154 entries, encompassing biological processes, molecular functions, and cellular components. KEGG pathway analysis identified 73 signaling pathways, including the FOXO signaling pathway and the lifespan regulation pathway. Molecular docking confirmed QBA’s strong binding to core target proteins via hydrogen bonds to at least three sites. Full article

Proteoglycan 4 (PRG4), also known as lubricin, plays a critical role in maintaining joint homeostasis by reducing friction between articular cartilage surfaces and preventing cartilage degradation. Its deficiency leads to early-onset osteoarthritis (OA), while overexpression can protect against cartilage degeneration. Beyond its lubricating properties, PRG4 exerts anti-inflammatory effects by interacting with Toll-like receptors, modulating inflammatory responses within the joint. The expression of Prg4 is regulated by various factors, including mechanical stimuli, inflammatory cytokines, transcription factors such as Creb5 and FoxO, and signaling pathways like TGF-β, EGFR, and Wnt/β-catenin. Therapeutic strategies targeting PRG4 in OA have shown promising results, including recombinant PRG4 protein injections, gene therapies, and small molecules that enhance endogenous Prg4 expression or mimic its function. Further research into the molecular mechanisms regulating Prg4 expression will be essential in developing more effective OA treatments. Understanding the interplay between Prg4 and other signaling pathways could reveal novel therapeutic targets. Additionally, advancements in gene therapy and biomaterials designed to deliver PRG4 in a controlled manner may hold potential for the long-term management of OA, improving patient outcomes and delaying disease progression. Full article

Background: Colorectal cancer (CRC) is one of the most prevalent cancers worldwide, and current treatments have significant side effects. Cannabidiol (CBD), a compound derived from Cannabis sativa, has demonstrated promising anticancer properties. However, further investigation is required to elucidate its underlying molecular mechanisms. Methods: Network pharmacology and molecular docking analysis approaches were utilized. Molecular targets of CBD and CRC-associated genes were identified using the Swiss Target Prediction, Malacards, and DisGeNet databases. Protein–protein interactions were analyzed using the STRING and Cytoscape. Ontology enrichment was conducted using ShinyGO, and gene expression and immune infiltration were evaluated with UALCAN and TISIDB. Results: We found 95 common genes between CRC and CBD targets. Six major genes (ANXA5, IGF1R, JAK2, MAPK8, MDM2, and PARP1) were particularly interesting due to their high connectivity and role in relevant metabolic pathways. The results of the molecular docking analysis indicated that CBD interacts favorably with these genes, modulating critical pathways such as RAS/MAPK and PI3K-AKT/FoxO, which are involved in cell proliferation, apoptosis, and cell cycle regulation. ANXA5 and JAK2 were identified as particularly relevant, as they correlated significantly with immune cell infiltration, suggesting a role in the immunoregulation of the tumor microenvironment. Conclusions: CBD has the potential to modulate key molecular processes in CRC through specific pathways and core genes, presenting itself as a possible complementary therapy to improve efficacy and reduce the adverse effects of conventional treatments. Full article

Stress is recognized as an adaptive response to potentially harmful environmental stimuli. The primary physiological adaptation to stress is an increase in circulating cortisol levels, which, in excess, can be transferred and incorporated into the oocytes of maturing females, affecting the embryonic developmental program. Additionally, maternal energy availability is an essential environmental factor that modulates this program. Based on this background, we investigated the effects of maternal cortisol on the development of the somatotropic axis in zebrafish offspring and juveniles. Zebrafish mothers were divided into two groups based on diet: Group 1 received a cortisol-enriched diet, to mimic maternal stress, while Group 2 (control) received a standard diet, for five days. On the third day after treatment, the control and treated females were bred with untreated males. Offspring were assessed at 0, 24, 48, 72, 96, 120, and 144 h post-fertilization (hpf). Morphological analyses were performed during embryonic development, including survival rate, body length, the presence of pericardial edema, and heartbeat. We examined the gene expression of key somatotropic axis components, including mtor, foxo3a, mafbx, murf1, mstna, gh, igf1, igf2a, igf2b, 11hsdb2, and fkbp5. The study demonstrated that cortisol-treated females significantly influenced offspring development, resulting in higher mortality rates and increased morphological abnormalities, particularly pericardial edema. Gene expression analysis revealed alterations in transcripts related to the somatotropic axis, especially genes involved in protein synthesis, with signs of accelerated growth in the first hour post-fertilization. At 30 days post-fertilization, juveniles from cortisol-treated females displayed a marked increase in muscle bundle size and cross-sectional diameter compared to the control group. Our findings provide valuable insights into the intricate interaction between maternal factors and the development of the somatotropic axis in offspring. Full article

Type 2 diabetes mellitus (T2DM) is an intricate disease correlated with many metabolic deregulations, including disordered glucose metabolism, oxidative stress, inflammation, and cellular apoptosis due to hepatic gluconeogenesis aberrations. However, there is no radical therapy to inhibit hepatic gluconeogenesis disturbances yet. We thus sought to probe the effectiveness and uncover the potential mechanism of quercetin (QCT) and silk sericin (SS) in mitigating hyperglycemia-induced hepatic gluconeogenesis disorder, which remains obscure. Administration of QCT and SS to diabetic male albino rats markedly restored the levels of glucose, insulin, advanced glycation end-products (AGEs), liver function enzymes, alpha-fetoprotein (AFP), globulin, and glycogen, in addition to hepatic carbohydrate metabolizing enzymes and gluconeogenesis in comparison with diabetic rats. Furthermore, treatment with QCT and SS modulated hepatic malondialdehyde (MD), reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), nitric oxide, tumor necrosis factor-alpha (TNF-α), and interleukin-1β (IL-1β), in addition to serum interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2), implying their effectiveness in safeguarding cells against oxidative impairment and inflammation. Remarkably, QCT and SS treatments led to the upregulation of expression of phosphatidylinositol 3-kinases (PI3K), phospho-Akt (p-Akt), and forkhead box-O1 (FOXO1) genes in hepatic tissues compared to diabetic rats, orchestrating these singling pathways for curtailing hyperglycemia and pernicious consequences in hepatic tissues. Importantly, immunohistochemical investigations exhibited downregulation of caspase-3 expression in rats treated with QCT and SS compared to diabetic animals. Beyond that, the histopathological results of hepatic tissues demonstrated notable correlations with biochemical findings. Interestingly, the in silico results supported the in vivo findings, showing notable binding affinities of QCT and SS to PI3K, GPx, and TNF-α proteins. These results imply that QCT and SS could mitigate oxidative stress and inflammation and regulate hepatic gluconeogenesis in diabetic rats. However, QCT revealed greater molecular interactions with the studied proteins than SS. Overall, our results emphasize that QCT and SS have significant therapeutic effects on attenuating hyperglycemia-induced hepatic gluconeogenesis, with QCT showing superior effectiveness. Full article

Adipose tissue plays an important role in pig production efficiency. Studies have shown that postnatal development has a vital impact on adipose tissue; however, the mechanisms behind pig adipose tissue early-life programming remain unknown. In this study, we analyzed the transcriptomes of the subcutaneous adipose tissue (SAT) of 1-day and 21-day old Laiwu piglets. The results showed that the SAT of Laiwu piglets significantly increased from 1-day to 21-day, and transcriptome analysis showed that there were 2352 and 2596 differentially expressed genes (DEGs) between 1-day and 21-day SAT in male and female piglets, respectively. Expression of genes in glycolysis, gluconeogenesis, and glycogen metabolism such as pyruvate kinase M1/2 (PKM), phosphoenolpyruvate carboxy kinase 1 (PCK1) and amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase (AGL) were significantly different between 1-day and 21-day SAT. Genes in lipid uptake, synthesis and lipolysis such as lipase E (LIPE), acetyl-CoA carboxylase alpha (ACACA), Stearoyl-CoA desaturase (SCD), and 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) were also differentially expressed. Functional analysis showed enrichment of DEGs in transcriptional regulation, protein metabolism and cellular signal transduction. The protein–protein interaction (PPI) networks of these DEGs were analyzed and potential hub genes in these pathways were identified, such as transcriptional factors forkhead box O4 (FOXO4), CCAAT enhancer binding protein beta (CEBPB) and CCAAT enhancer binding protein delta (CEBPD), signal kinases BUB1 mitotic checkpoint serine/threonine kinase (BUB1) and cyclin-dependent kinase 1 (CDK1), and proteostasis-related factors ubiquitin conjugating enzyme E2 C (UBE2C) and cathepsin D (CTSD). Moreover, we further analyzed the transcriptomes of SAT between genders and the results showed that there were 54 and 72 DEGs in 1-day and 21-day old SAT, respectively. Genes such as KDM5D and KDM6C showed gender-specific expression in 1-day and 21-day SAT. These results showed the significant changes in SAT between 1-day and 21-day in male and female Laiwu pigs, which would provide information to comprehensively understand the programming of adipose tissue early development and to regulate adipose tissue function. Full article

Monoamine oxidases (MAOs), mitochondrial enzymes that constantly produce hydrogen peroxide (H₂O₂) as a byproduct of their activity, have been recently acknowledged as contributors to oxidative stress in cardiometabolic pathologies. The present study aimed to assess whether MAOs are mediators of valvular oxidative stress and interact in vitro with angiotensin 2 (ANG2) to mimic the activation of the renin–angiotensin system. To this aim, valvular tissue samples were harvested from 30 patients diagnosed with severe primary mitral regurgitation and indication for surgical repair. Their reactive oxygen species (ROS) levels were assessed by means of a ferrous oxidation xylenol orange (FOX) assay, while MAO expression was assessed by immune fluorescence (protein) and qRT-PCR (mRNA). The experiments were performed using native valvular tissue acutely incubated or not with angiotensin 2 (ANG2), MAO inhibitors (MAOI) and the angiotensin receptor blocker, irbesartan (Irb). Correlations between oxidative stress and echocardiographic parameters were also analyzed. Ex vivo incubation with ANG2 increased MAO-A and -B expression and ROS generation. The level of valvular oxidative stress was negatively correlated with the left ventricular ejection fraction. MAOI and Irb reduced valvular H₂O_2. production. In conclusion, both MAO isoforms are expressed in pathological human mitral valves and contribute to local oxidative stress and ventricular functional impairment and can be modulated by the local renin–angiotensin system_. Full article

The goal of our study was to identify and assess the functionally significant SNPs with potentially important roles in the development of type 2 diabetes mellitus (T2DM) and/or their effect on individual response to antihyperglycemic medication with metformin. We applied a bioinformatics approach to identify the regulatory SNPs (rSNPs) associated with allele-asymmetric binding and expression events in our paired ChIP-seq and RNA-seq data for peripheral blood mononuclear cells (PBMCs) of nine healthy individuals. The rSNP outcomes were analyzed using public data from the GWAS (Genome-Wide Association Studies) and Genotype-Tissue Expression (GTEx). The differentially expressed genes (DEGs) between healthy and T2DM individuals (GSE221521), including metformin responders and non-responders (GSE153315), were searched for in GEO RNA-seq data. The DEGs harboring rSNPs were analyzed using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). We identified 14,796 rSNPs in the promoters of 5132 genes of human PBMCs. We found 4280 rSNPs to associate with both phenotypic traits (GWAS) and expression quantitative trait loci (eQTLs) from GTEx. Between T2DM patients and controls, 3810 rSNPs were detected in the promoters of 1284 DEGs. Based on the protein-protein interaction (PPI) network, we identified 31 upregulated hub genes, including the genes involved in inflammation, obesity, and insulin resistance. The top-ranked 10 enriched KEGG pathways for these hubs included insulin, AMPK, and FoxO signaling pathways. Between metformin responders and non-responders, 367 rSNPs were found in the promoters of 131 DEGs. Genes encoding transcription factors and transcription regulators were the most widely represented group and many were shown to be involved in the T2DM pathogenesis. We have formed a list of human rSNPs that add functional interpretation to the T2DM-association signals identified in GWAS. The results suggest candidate causal regulatory variants for T2DM, with strong enrichment in the pathways related to glucose metabolism, inflammation, and the effects of metformin. Full article

FoxO is a member of the evolutionary conserved family of transcription factors containing a Forkhead box, involved in many signaling pathways of physiological and pathological processes. In mammals, mutations or dysfunctions of the FoxO gene have been implicated in diverse diseases. FoxO homologs have been found in some invertebrates, including echinoderms. We have isolated the FoxO cDNA from the sea urchin Paracentrotus lividus (Pl-foxo) and characterized the corresponding gene and mRNA. In silico studies showed that secondary and tertiary structures of Pl-foxo protein corresponded to the vertebrate FoxO3 isoform, with highly conserved regions, especially in the DNA-binding domain. A phylogenetic analysis compared the Pl-foxo deduced protein with proteins from different animal species and confirmed its evolutionary conservation between vertebrates and invertebrates. The increased expression of Pl-foxo mRNA following the inhibition of the PI3K signaling pathway paralleled the upregulation of Pl-foxo target genes involved in apoptosis or cell-cycle arrest events (BI-1, Bax, MnSod). In silico studies comparing molecular data from sea urchins and other organisms predicted a network of Pl-foxo protein–protein interactions, as well as identified potential miRNAs involved in Pl-foxo gene regulation. Our data may provide new perspectives on the knowledge of the signaling pathways underlying sea urchin development. Full article

Muscle-enriched A-type lamin-interacting protein (MLIP) is an emerging protein involved in cellular homeostasis and stress adaptation. Eukaryotic cells regulate various cellular processes, including metabolism, DNA repair, and cell cycle progression, to maintain cellular homeostasis. Disruptions in this homeostasis can lead to diseases such as cancer, characterized by uncontrolled cell growth and division. This review aims to explore for the first time the unique role MLIP may play in cancer development and progression, given its interactions with the PI3K/Akt/mTOR pathway, p53, MAPK9, and FOXO transcription factors, all critical regulators of cellular homeostasis and tumor suppression. We discuss the current understanding of MLIP’s involvement in pro-survival pathways and its potential implications in cancer cells’ metabolic remodeling and dysregulated homeostasis. Additionally, we examine the potential of MLIP as a novel therapeutic target for cancer treatment. This review aims to shed light on MLIP’s potential impact on cancer biology and contribute to developing innovative therapeutic strategies. Full article

During the adaptive evolution of animals, the host and its gut microbiota co-adapt to different elevations. Currently, there are few reports on the rumen microbiota–hepato-intestinal axis of Tibetan sheep at different altitudes. Therefore, the purpose of this study was to explore the regulatory effect of rumen microorganism–volatile fatty acids (VFAs)–VFAs transporter gene interactions on the key enzymes and genes related to gluconeogenesis in Tibetan sheep. The rumen fermentation parameters, rumen microbial densities, liver gluconeogenesis activity and related genes were determined and analyzed using gas chromatography, RT-qPCR and other research methods. Correlation analysis revealed a reciprocal relationship among rumen microflora–VFAs-hepatic gluconeogenesis in Tibetan sheep at different altitudes. Among the microbiota, Ruminococcus flavefaciens (R. flavefaciens), Ruminococcus albus (R. albus), Fibrobactersuccinogenes and Ruminobacter amylophilus (R. amylophilus) were significantly correlated with propionic acid (p < 0.05), while propionic acid was significantly correlated with the transport genes monocarboxylate transporter 4 (MCT4) and anion exchanger 2 (AE2) (p < 0.05). Propionic acid was significantly correlated with key enzymes such as pyruvate carboxylase, phosphoenolpyruvic acid carboxylase and glucose (Glu) in the gluconeogenesis pathway (p < 0.05). Additionally, the expressions of these genes were significantly correlated with those of the related genes, namely, forkhead box protein O1 (FOXO1) and mitochondrial phosphoenolpyruvate carboxykinase 2 (PCK2) (p < 0.05). The results showed that rumen microbiota densities differed at different altitudes, and the metabolically produced VFA contents differed, which led to adaptive changes in the key enzyme activities of gluconeogenesis and the expressions of related genes. Full article

Muscle growth stands as a pivotal economic trait within pig production, governed by a complex interplay of multiple genes, each playing a role in its quantitative manifestation. Understanding the intricate regulatory mechanisms of porcine muscle development is crucial for enhancing both pork yield and quality. This study used the GSE99749 dataset downloaded from the GEO database, conducting a detailed analysis of the RNA-seq results from the longissimus dorsi muscle (LD) of Tibetan pigs (TP), Wujin pigs (WJ) and large white pigs (LW) at 60 days of gestation, representing diverse body sizes and growth rates. Comparative analyses between TPvsWJ and TPvsLW, along with differential gene expression (DEG) analysis, functional enrichment analysis, and protein–protein interaction (PPI) network analysis, revealed 1048 and 1157 significantly differentially expressed genes (p < 0.001) in TPvsWJ and TPvsLW, respectively. With stricter screening criteria, 37 DEGs were found to overlap between the 2 groups. PPI analysis identified MYL5, MYL4, and ACTC1 as the three core genes. This article focuses on exploring the MYL4 gene. Molecular-level experimental validation, through overexpression and interference of the MYL4 gene combined with EDU staining experiments, demonstrated that overexpression of MYL4 significantly promoted the proliferation of porcine skeletal muscle satellite cells (PSMSC), while interference with MYL4 inhibited their proliferation. Furthermore, by examining the effects of overexpressing and interfering with the MYL4 gene on the muscle hypertrophy marker Fst gene and the muscle degradation marker FOXO3 gene, the pivotal role of the MYL4 gene in promoting muscle growth and preventing muscle degradation was further confirmed. These findings offer a new perspective on the molecular mechanisms behind porcine muscle growth and development, furnishing valuable data and insights for muscle biology research. Full article