Search Results (113)

Maternal obesity programs the fetus for increased risk of chronic disease development in early life and adulthood. We hypothesized that maternal nutrient excess leads to fetal inflammation and impairs offspring skeletal muscle mitochondrial biogenesis in non-human primates. At least 12 months before pregnancy, female baboons were fed a normal chow (CTR, 12% energy fat) or a maternal nutrient excess (MNE, 45% energy fat, and ad libitum fructose sodas) diet, with the latter to induce obesity. After 165 days of gestation (0.9 G), offspring baboons were delivered by cesarean section, and the soleus muscle was collected (CTR n = 16, MNE n = 5). At conception, MNE mothers presented increased body fat and weighed more than controls. The soleus muscle of MNE fetuses exhibited increased levels of stress signaling associated with inflammation (TLR4, TNFα, NF-kB p65, and p38), concomitant with reduced expression of key regulators of mitochondrial biogenesis, including PGC1α, both at the protein and transcript levels, as well as downregulation of PPARGC1B, PPARA, PPARB, CREB1, NOS3, SIRT1, SIRT3. Decreased transcript levels of NRF1 were observed alongside diminished mitochondrial DNA copy number, mitochondrial fusion elements (MFN1, MFN2), cytochrome C protein levels, and cytochrome C oxidase subunits I and II transcripts (cox1 and cox2). MNE coupled to MO-induced stress signaling in fetal baboon soleus muscle is associated with impaired mitochondrial biogenesis and lower mitochondrial content, resembling the changes observed in metabolic dysfunctions, such as diabetes. The observed fetal alterations may have important implications for postnatal development and metabolism, potentially increasing the risk of early-onset metabolic disorders and other non-communicable diseases. Full article

This review aims to provide a comprehensive framework for implementing precision sports medicine, integrating genetics, pharmacogenomics, digital health solutions, and multi-omics data. Literature review was conducted using MEDLINE, EMBASE, Web of Science, and Cochrane Library databases (January 2018–April 2024), focusing on precision medicine applications in sports medicine, utilizing key terms including “precision medicine”, “sports medicine”, “genetics”, and “multi-omics”, with forward and backward citation tracking. The review identified key gene variants affecting athletic performance: endurance (AMPD1, PPARGC1A), power (ACTN3, NOS3), strength (PPARG), and injury susceptibility (COL5A1, MMP3), while also examining inherited conditions like cardiomyopathies (MYH7, MYBPC3). Pharmacogenomic guidelines were established for optimizing common sports medications, including NSAIDs (CYP2C9), opioids (CYP2D6), and cardiovascular drugs (SLCO1B1, CYP2C19). Digital health technologies, including wearables and predictive analytics, showed potential for enhanced athlete monitoring and injury prevention, while multi-omics approaches integrated various molecular data to understand exercise capacity and injury predisposition, enabling personalized assessments, training regimens, and therapeutic interventions based on individual biomolecular profiles. This review provides sports medicine professionals with a framework to deliver personalized care tailored to each athlete’s unique profile, promising optimized performance, reduced injury risks, and improved recovery outcomes. Full article

Background and Aims: In this research, we sought to enhance our comprehension of liver cancer’s genetic architecture by employing Mendelian randomization (MR) techniques to establish causative relationships between particular genetic variations and liver cancer susceptibility. Methods: We integrated data from the public databases with MR analysis to identify differentially expressed genes (DEGs) associated with Hepatocellular Carcinoma (HCC). We conducted functional enrichment analyses to determine the biological processes and signaling cascades associated with the identified DEGs. We also used the CIBERSORT deconvolution method to evaluate immune cell composition in HCC tissues, followed by correlation studies examining relationships between our key genes of interest and various immune cell populations. Additionally, we validated our findings using a rat model of HCC and clinical HCC samples. Results: We obtained two key genes, EHD4 and PPARGC1A, which co-regulated M0 macrophages, suggesting their role in macrophage polarization and tumor progression. In addition, PPARGC1A is associated with resting and activated mast cells, suggesting its involvement in regulating the tumor microenvironment. Detection of rat and clinical samples further confirmed the upregulation of these genes in HCC, supporting their potential as therapeutic targets. Conclusions: Our findings emphasize the significant involvement of EHD4 and PPARGC1A in HCC, specifically regarding their influence on tumor-associated macrophage polarization and broader immune microenvironment modulation. These findings offer new insights into the molecular mechanisms driving HCC and suggest that targeting these genes may provide novel strategies for personalized treatment. Full article

Objectives: Ritodrine, a tocolytic agent used to delay preterm labor, can cause several cardiovascular-associated adverse events (AEs). This study aimed to examine the relationship between gene polymorphisms in peroxisome proliferator-activated receptor gamma (PPARG) and PPARG coactivator-1α (PPARGC1A) and the occurrence of ritodrine-induced AEs. Additionally, a risk-scoring system was developed to identify patients at high risk of AEs. Methods: Patients aged 18 years or older who were administered ritodrine to manage preterm labor with intact membranes and uterine contractions occurring at 20–36 weeks of gestation were enrolled in this study. A total of 70 common PPARG and PPARGC1A variants (minor allele frequency ≥ 0.2) with low linkage disequilibrium (r² < 0.8) were selected from an Axiom™ Precision Medicine Research Array (AMPRA). Results: A total of 149 patients were included in the analysis. After adjusting for confounders (age, gestational age, and the maximum infusion rate), weight and rs2946385, rs35523565, and rs2240748 of PPARGC1A were identified as significant predictors associated with ritodrine-induced AEs. Based on the risk-scoring system, the predicted probabilities of AEs for patients with scores of 0, 1, 2, 3, 4, and 5 points were 4%, 9%, 18%, 35%, 55%, and 74%, respectively. The AUROC for the risk score predicting ritodrine-induced AEs was 0.729 (95% CI: 0.672–0.831, p < 0.001). Conclusions: This study indicates that ritodrine-induced AEs are related to PPARGC1A polymorphisms. A risk-scoring system based on genetic variants showed moderate predictive ability for ritodrine-induced AEs, suggesting potential utility in females with preterm labor. Full article

Consumers are increasingly demanding higher-quality mutton. Crossbreeding has been recognized as an effective means to improve meat quality. However, the phenomenon underlying these molecular system mechanisms remains largely unidentified. In this study, 48 male lambs aged 3 months were selected, including ♂ Hu sheep × ♀ Hu (HH, n = 16), ♂ Polled Dorset × ♀ Hu sheep F₁ hybrid lambs (DH, n = 16), and ♂ Southdown × ♀ Hu sheep (SH, n = 16) F₁ hybrid lambs, and raised in a single pen under the same nutritional and management conditions for 95 days. Then, seven sheep close to the average weight of the group were selected and fasted for 12 h prior to slaughter. By comparing the muscle fiber characteristics of the Longissimus dorsi of the three groups of sheep, and through transcriptomic and metabolomic analyses, we revealed molecular differences in the meat quality of Hu sheep crossbred with different parent breeds. The results of this study showed that muscle fiber diameter and cross-sectional area were significantly greater in the DH group than in the HH group, and collagen fiber content in the DH group was also significantly higher than in the HH group (p < 0.05). A total of 163 differential genes and 823 differential metabolites were identified in the three groups, most of which were related to muscle development and lipid metabolism. These included the AMPK signaling pathway, the PI3K-Akt signaling pathway, glycerophospholipid metabolism, and the related genes EFHB, PER3, and PPARGC1A. The results of this study offer valuable insights into the molecular mechanisms underlying the impact of crossbreeding on meat quality and provide a theoretical foundation for sheep crossbreed production. Full article

Background/Objectives: Since its emergence in 2020, researchers worldwide have been collaborating to better understand the SARS-CoV-2 disease’s pathophysiology. Disease severity can vary based on several factors, including comorbidities and genetic variations. Notably, recent studies have highlighted the role of genes associated with athletic performance, such as ACE, ACTN3, and PPARGC1A, in influencing muscle function, cardiovascular health, and the body’s metabolic response. Given that these genes also impact oxidative metabolism, inflammation, and respiratory efficiency, we hypothesized that they might play a critical role in the host’s response to SARS-CoV-2 infection. This study aimed to investigate the association between disease severity and genetic polymorphisms in these sport performance-related genes, specifically ACE rs4646994, ACTN3 rs1815739, and PPARGC1A rs8192678. Methods: A total of 422 COVID-19-positive patients were included in this study. The participants were divided into three groups: a severe group (77 patients) requiring intensive care unit (ICU) admission, a mild group (300 patients) exhibiting at least one symptom, and an asymptomatic control group. Genotyping was performed using restriction fragment length polymorphism PCR. Results: The D allele and DD genotype of ACE and the T allele and TT genotype of ACTN3 were found to confer protective effects against severe SARS-CoV-2 infection. Conversely, the PPARGC1A TC genotype and the ACE-PPARGC1A ins/ins + TC combined genotype were associated with increased disease severity (p < 0.05). Conclusions: Although vaccination has reduced the severity of SARS-CoV-2, the virus continues to impact human health. Inter-individual differences due to these genetic variations will broaden the horizon of knowledge on the pathophysiology of the disease. Full article

Brown adipose tissue (BAT) is a critical regulator of non-shivering thermogenesis and energy expenditure, offering significant potential for addressing obesity and associated metabolic disorders. Isoliquiritigenin (ISL), a natural flavonoid, has shown promising therapeutic effects in lipid metabolism-related diseases. This study aimed to explore the effects of ISL on lipid metabolism and obesity using a high-fat-diet (HFD)-induced obesity model in mice. Mice were subjected to an HFD and treated with ISL via gavage. The results demonstrated that ISL treatment significantly reduced HFD-induced weight gain and upregulated the expression of key thermogenic genes, suggesting enhanced BAT activity and thermogenesis. In vitro experiments using C3H10-T1/2 cells further supported these findings, as ISL treatment markedly increased the expression of UCP1 and PPARGC1a, which are critical regulators of thermogenesis. To elucidate the molecular mechanisms underlying ISL’s effects, we conducted a transcriptomic analysis of BAT from ISL-treated mice. Pathway enrichment analysis revealed that differentially expressed genes were predominantly associated with metabolic processes, including the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and fatty acid degradation. These pathways are integral to energy metabolism and thermogenesis, providing mechanistic insights into ISL’s anti-obesity effects. Additionally, ISL treatment significantly downregulated the expression of NNAT and SGK1, genes implicated in lipid metabolism and energy homeostasis. These findings suggest that ISL modulates BAT function by regulating the expression of these genes, thereby influencing lipid deposition and thermogenic capacity. In summary, this study suggests that ISL treatment has the potential to mitigate HFD-induced obesity by promoting BAT thermogenesis and modulating lipid metabolism. The molecular mechanisms involve the regulation of key metabolic pathways and genes, such as NNAT and SGK1, highlighting ISL’s potential as a therapeutic agent for obesity and related metabolic disorders. Full article

Breast, colon, and lung carcinomas are classified as aggressive tumors with poor relapse-free survival (RFS), progression-free survival (PF), and poor hazard ratios (HRs) despite extensive therapy. Therefore, it is essential to identify a gene expression signature that correlates with RFS/PF and HR status in order to predict treatment efficiency. RNA-binding proteins (RBPs) play critical roles in RNA metabolism, including RNA transcription, maturation, and post-translational regulation. However, their involvement in cancer is not yet fully understood. In this study, we used computational bioinformatics to classify the functions and correlations of RBPs in solid cancers. We aimed to identify molecular biomarkers that could help predict disease prognosis and improve the therapeutic efficiency in treated patients. Intersection analysis summarized more than 1659 RBPs across three recently updated RNA databases. Bioinformatics analysis showed that 58 RBPs were common in breast, colon, and lung cancers, with HR values < 1 and >1 and a significant Q-value < 0.0001. RBP gene clusters were identified based on RFS/PF, HR, p-value, and fold induction. To define union RBPs, common genes were subjected to hierarchical clustering and were classified into two groups. Poor survival was associated with high genes expression, including CDKN2A, MEX3A, RPL39L, VARS, GSPT1, SNRPE, SSR1, and TIA1 in breast and colon cancer but not with lung cancer; and poor survival was associated with low genes expression, including PPARGC1B, EIF4E3, and SMAD9 in breast, colon, and lung cancer. This study highlights the significant contribution of PPARGC1B, EIF4E3, and SMAD9 out of 11 RBP genes as prognostic predictors in patients with breast, colon, and lung cancers and their potential application in personalized therapy. Full article

Omega-3 (ω-3) polyunsaturated fatty acids in fish oil have been shown to prevent diet-induced obesity in lean mice and to promote heat production in adipose tissue. However, the effects of fish oil on obese animals remain unclear. This study investigated the effects of fish oil in obese mice. C57BL/6J mice were fed a lard-based high-fat diet (LD) for 8 weeks and then assigned to either a fish oil-based high-fat diet (FOD) or continued the LD for additional 8 weeks. A control group was fed a standard diet for 16 weeks. Mice fed the FOD showed weight loss, reduced adipose tissue mass, and lower plasma insulin and leptin levels compared to those fed the LD. Rectal temperatures were higher in the FOD and LD groups compared to the control group. Energy intake was lower in the FOD group than the LD group but similar to the control group. The FOD and LD groups exhibited increased expression of heat-producing genes such as Ppargc1a, Ucp1, Adrb3, and Ppara in brown adipose tissue but not in white adipose tissue. The FOD reduced food consumption and increased rectal temperature and heat-producing genes in brown adipose tissue. Fish oil may therefore be a potential therapeutic approach to obesity. Full article

Background/Objectives: The PPARGC1A gene, encoding the PGC-1α protein, is a critical regulator of energy metabolism, influencing mitochondrial biogenesis, fatty acid oxidation, and carbohydrate metabolism. This narrative review aims to evaluate the role of the PPARGC1A gene, with a specific focus on the c.1444G<A polymorphism (rs8192678), in sports performance, including its impact on aerobic capacity, muscle adaptation, and its potential implications for metabolic health. Methods: A comprehensive literature search was conducted using databases such as PubMed, Scopus, Science Direct, and Web of Science, following PRISMA guidelines. Studies investigating the rs8192678 polymorphism in athletes, its relationship with physical performance, and its broader metabolic effects were included. Data were synthesized qualitatively, and heterogeneity among findings was assessed. The rs8192678 polymorphism influences sports performance differently. Results: the G allele is associated with enhanced mitochondrial efficiency, higher aerobic capacity, and a greater proportion of fatigue-resistant type I muscle fibers, benefiting endurance sports like cycling and triathlon. Conversely, the A allele correlates with reduced mitochondrial biogenesis and oxidative capacity, potentially impairing endurance but showing possible utility in strength-based sports. Furthermore, the A allele is linked to increased risks of metabolic conditions, including type 2 diabetes and obesity. Discrepancies in results highlight the influence of genetic, environmental, and training interactions. Conclusions: the PPARGC1A rs8192678 polymorphism plays a significant role in athletic performance and metabolic regulation. While the G allele confers advantages in endurance sports, the A allele presents mixed implications for strength and metabolic health. These findings support the potential for genetic profiling in personalized training and health interventions but emphasize the need for further research to clarify genotype-environment interactions. Full article

Meat quality is a complex trait that exhibits significant variation across pig breeds, and the regulatory mechanisms governing pork meat quality are not fully elucidated. We compared the transcriptomics and metabolomics of the longissimus dorsi (LD) muscle between the Songliao Black Pig (SBP) and Large White × Landrace Pig (LWLDP) to investigate breed-specific differences in meat quality and underlying regulatory pathways. The results showed that SBP meat had a higher marbling score and backfat thickness, a richer color, a lower shear force, and reduced drip loss. Fatty acid (FA) analysis identified 15 significant FAs in the LWLDP, with docosahexaenoic acid (DHA) in the SBP, while amino acid (AA) analysis revealed no breed-based differences. Transcriptome analysis identified 134 upregulated and 362 downregulated genes in the SBP. Protein–protein interaction (PPI) network analysis found 25 key genes, which are associated with muscle development, fat deposition, and overall meat quality, while genes in the insulin signaling pathway, such as PPP1R3B, PPARGC1A, SOCS1, EIF4E, PRKAR2A, PRKAG2, and FASN, play a crucial role in balancing fat metabolism and catabolism. Metabolomic analysis identified 89 upregulated and 10 downregulated metabolites in the SBP, primarily involved in fructose and mannose metabolism, amino acid biosynthesis, nucleotide sugar metabolism, and glucagon signaling pathways. Gene–metabolite association analysis found that the PPP1R3B gene had a strong association with Thr-Leu, Maltol, D-myo-Inositol-4-phosphate, and Fructose-6-phosphate, while MYOG correlated with Mannose-6-phosphate, Fructose-1-phosphate, Mannose-1-phosphate, and Glucose-6-phosphate. In contrast, NR4A3 and PPARGC1A showed a strong negative correlation with most upregulated metabolites. In conclusion, this study identified functional genes, elucidated the mechanisms associated with meat quality traits, and identified gene–metabolite associations involved in energy metabolism, muscle development, and fat deposition, providing valuable insights into the molecular mechanisms that regulate meat quality between pig breeds. Full article

Ubiquitin-specific protease 2 (USP2) maintains mitochondrial integrity in culture myoblasts. In this study, we investigated the molecular mechanisms underlying the protective role of USP2 in mitochondria. The knockout (KO) of the Usp2 gene or the chemical inhibition of USP2 induced a robust accumulation of mitochondrial reactive oxygen species (ROS), accompanied by defects in mitochondrial membrane potential, in C2C12 myoblasts. ROS removal by N-acetyl-L-cysteine restored the mitochondrial dysfunction induced by USP2 deficiency. Comprehensive RT-qPCR screening and following protein analysis indicated that both the genetic and chemical inhibition of USP2 elicited a decrease in uncoupling protein 2 (UCP2) at mRNA and protein levels. Accordingly, the introduction of a Ucp2-expressing construct effectively recovered the mitochondrial membrane potential, entailing an increment in the intracellular ATP level in Usp2KO C2C12 cells. In contrast, USP2 deficiency also decreased peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) protein in C2C12 cells, while it upregulated Ppargc1a mRNA. Overexpression studies indicated that USP2 potentially stabilizes PGC1α in an isopeptidase-dependent manner. Given that PGC1α is an inducer of UCP2 in C2C12 cells, USP2 might ameliorate mitochondrial ROS by maintaining the PGC1α–UCP2 axis in myoblasts. Full article

Normotensive and hypertensive organisms respond differently to stress factors; however, the features of the central molecular genetic mechanisms underlying the reaction of the hypertensive organism to stress have not been fully established. In this study, we examined the transcriptome profiles of the hypothalamus of hypertensive ISIAH rats, modeling a stress-sensitive form of arterial hypertension, and normotensive WAG rats at rest and after exposure to a single short-term restraint stress. It was shown that oxidative phosphorylation is the most significantly enriched process among metabolic changes in the hypothalamus of rats of both strains when exposed to a single short-term restraint stress. The analysis revealed DEGs representing both a common response to oxidative stress for both rat strains and a strain-specific response to oxidative stress for hypertensive ISIAH rats. Among the genes of the common response to oxidative stress, the most significant changes in the transcription level were observed in Nos1, Ppargc1a, Abcc1, Srxn1, Cryab, Hspb1, and Fosl1, among which Abcc1 and Nos1 are associated with hypertension, and Fosl1 and Ppargc1a encode transcription factors. The response to oxidative stress specific to hypertensive rats is associated with the activation of the Fos gene. The DEG’s promoter region enrichment analysis allowed us to hypothesize that the response to oxidative stress may be mediated by the participation of the transcription factor CREB1 (Cyclic AMP-responsive element-binding protein 1) and the glucocorticoid receptor (NR3C1) under restraint stress in the hypothalamus of both rat strains. The results of the study revealed common and strain-specific features in the molecular mechanisms associated with oxidative phosphorylation and oxidative stress response in the hypothalamus of hypertensive ISIAH and normotensive WAG rats following a single short-term restraint stress. The obtained results expand the understanding of the most significant molecular targets for further research aimed at developing new therapeutic strategies for the prevention of the consequences of acute emotional stress, taking into account the hypertensive state of the patient. Full article

Background/Objectives: The global SARS-CoV-2 outbreak has escalated into a critical public health emergency, with the spike glycoprotein S1 subunit of SARS-CoV-2 (spike-S1) linked to inflammation in lung tissue and immune cells. Luteolin, a flavone with anti-inflammatory properties, shows promise, but research on its effectiveness against long-COVID-related inflammation and spike protein-induced responses remains limited. This study aims to elucidate the underlying mechanisms of inflammation in THP-1 cells induced by the spike-S1. Additionally, it seeks to assess the potential of luteolin in mitigating inflammatory responses induced by the spike-S1 in a THP-1 macrophage model. Methods: The gene expression profiles of spike-S1 in THP-1 cells were analyzed by transcriptome sequencing. The inhibitory effect of luteolin on ER stress and inflammation in spike-S1-induced THP-1 cells was investigated using Western blotting, RT-PCR, and ELISA. Results: The candidate genes (CAMK2A, SIGLEC7, PPARGC1B, SEC22B, USP28, IER2, and TIRAP) were upregulated in the spike-S1-induced THP-1 group compared to the control group. Among these, calcium/calmodulin-dependent protein kinase II alpha (CAMK2A) was identified as the most promising molecule in spike-S1-induced THP-1 cells. Our results indicate that the spike S1 significantly increased the expression of ER-stress markers at both gene and protein levels. Luteolin significantly reduced ER stress by decreasing the expression of ER-stress marker genes and ER-stress marker proteins (p < 0.01). Additionally, luteolin exhibited anti-inflammatory properties upon spike S1-induction in THP-1 cells by significantly suppressing IL-6, IL-8, and IL-1β cytokine secretion in a dose-dependent manner (p < 0.05). Furthermore, our results revealed that luteolin exhibited the downregulation of the MAPK pathway, as evidenced by modulating the phosphorylation of p-ERK1/2, p-JNK and p-p38 proteins (p < 0.05). Conclusions: The results from this study elucidate the mechanisms by which the spike S1 induces inflammation in THP-1 cells and supports the use of naturally occurring bioactive compounds, like luteolin, against inflammation-related SARS-CoV-2 infection. Full article

In this study, the expression profiles of miR-148a were constructed in eight different ovine tissues, including mammary gland tissue, during six different developmental periods. The effect of miR-148a on the viability, proliferation, and milk fat synthesis of ovine mammary epithelial cells (OMECs) was investigated, and the target relationship of miR-148a with two predicted target genes was verified. The expression of miR-148a exhibited obvious tissue-specific and temporal-specific patterns. miR-148a was expressed in all eight ovine tissues investigated, with the highest expression level in mammary gland tissue (p < 0.05). Additionally, miR-148a was expressed in ovine mammary gland tissue during each of the six developmental periods studied, with its highest level at peak lactation (p < 0.05). The overexpression of miR-148a increased the viability of OMECs, the number and percentage of Edu-labeled positive OMECs, and the expression levels of two cell-proliferation marker genes. miR-148a also increased the percentage of OMECs in the S phase. In contrast, transfection with an miR-148a inhibitor produced the opposite effect compared to the miR-148a mimic. These results indicate that miR-148a promotes the viability and proliferation of OMECs in Small-tailed Han sheep. The miR-148a mimic increased the triglyceride content by 37.78% (p < 0.01) and the expression levels of three milk fat synthesis marker genes in OMECs. However, the miR-148a inhibitor reduced the triglyceride level by 87.11% (p < 0.01). These results suggest that miR-148a promotes milk fat synthesis in OMECs. The dual-luciferase reporter assay showed that miR-148a reduced the luciferase activities of DNA methyltransferase 1 (DNMT1) and peroxisome proliferator-activated receptor gamma coactivator 1-A (PPARGC1A) in wild-type vectors, suggesting that they are target genes of miR-148a. The expression of miR-148a was highly negatively correlated with PPARGC1A (r = −0.789, p < 0.001) in ovine mammary gland tissue, while it had a moderate negative correlation with DNMT1 (r = −0.515, p = 0.029). This is the first study to reveal the molecular mechanisms of miR-148a underlying the viability, proliferation, and milk fat synthesis of OMECs in sheep. Full article