A detailed understanding of molecular responses to a hypertrophic stimulus in skeletal muscle leads to therapeutic advances aimed at promoting muscle mass. To decode the molecular factors regulating skeletal muscle mass, we utilized a 24-h time course of human muscle biopsies after a bout of resistance exercise. Our findings indicate: (1) the DNA methylome response at 30 min corresponds to upregulated genes at 3 h, (2) a burst of translation- and transcription-initiation factor-coding transcripts occurs between 3 and 8 h, (3) changes to global protein-coding gene expression peaks at 8 h, (4) ribosome-related genes dominate the mRNA landscape between 8 and 24 h, (5) methylation-regulated MYC is a highly influential transcription factor throughout recovery.
View Article and Find Full Text PDFSkeletal muscle atrophy is a morbidity and mortality risk factor that happens with disuse, chronic disease, and aging. The tissue remodeling that happens during recovery from atrophy or injury involves changes in different cell types such as muscle fibers, and satellite and immune cells. Here, we show that the previously uncharacterized gene and protein Zfp697 is a damage-induced regulator of muscle remodeling.
View Article and Find Full Text PDFMolecular control of recovery after exercise in muscle is temporally dynamic. A time course of biopsies around resistance exercise (RE) combined with -omics is necessary to better comprehend the molecular contributions of skeletal muscle adaptation in humans. Vastus lateralis biopsies before and 30 minutes, 3-, 8-, and 24-hours after acute RE were collected.
View Article and Find Full Text PDFUsing the licochalcone moiety as a lead compound scaffold, 16 novel imidazole-chalcone derivatives were designed and synthesized as microtubule protein polymerization inhibitors. The proliferation inhibitory activities of the derivatives against SiHa (human cervical squamous cell carcinoma), C-33A (human cervical cancer), HeLa (human cervical cancer), HeLa/DDP (cisplatin-resistant human cervical cancer), and H8 (human cervical epithelial immortalized) cells were evaluated. Compound 5a exhibited significant anticancer activity with IC values ranging from 2.
View Article and Find Full Text PDFObjective: Skeletal muscle plasticity and remodeling are critical for adapting tissue function to use, disuse, and regeneration. The aim of this study was to identify genes and molecular pathways that regulate the transition from atrophy to compensatory hypertrophy or recovery from injury. Here, we have used a mouse model of hindlimb unloading and reloading, which causes skeletal muscle atrophy, and compensatory regeneration and hypertrophy, respectively.
View Article and Find Full Text PDFThe causal relationships between plasma metabolites and cholelithiasis/cholecystitis risks remain elusive. Using two-sample Mendelian randomization, we found that genetic proxied plasma campesterol level showed negative correlation with the risk of both cholelithiasis and cholecystitis. Furthermore, the increased risk of cholelithiasis is correlating with the increased level of plasma campesterol.
View Article and Find Full Text PDFObjective: Several novel fluorinated chalcone derivatives were synthesized, and their anticervical cancer activity and mechanism of action were investigated using the parent nucleus of licorice chalcone as the lead compound backbone and MDM2-p53 as the target.
Methods: In this study, 16 novel chalcone derivatives (3a-3r) were designed and synthesized by molecular docking technology based on the licorice chalcone parent nucleus as the lead compound scaffold and the cancer apoptosis regulatory target MDM2-p53. The structures of these compounds were confirmed by H-NMR, C-NMR, and HR-ESI-MS.
In this study, a collection of newly developed α-methylchalcone derivatives were synthesized and assessed for their inhibitory potential against human cervical cancer cell lines (HeLa, SiHa, and C33A) as well as normal human cervical epithelial cells (H8). Notably, compound exhibited substantial inhibitory effects on both HeLa and HeLa/DDP cells while demonstrating lower toxicity toward H8 cells. Furthermore, the compound was found to induce apoptosis in both HeLa and HeLa/DDP cells while also inhibiting the G2/M phase, resulting in a decrease in the invasion and migration capabilities of these cells.
View Article and Find Full Text PDFMuscular atrophy is a mortality risk factor that happens with disuse, chronic disease, and aging. Recovery from atrophy requires changes in several cell types including muscle fibers, and satellite and immune cells. Here we show that Zfp697/ZNF697 is a damage-induced regulator of muscle regeneration, during which its expression is transiently elevated.
View Article and Find Full Text PDFThis study involved the design and synthesis of 21 new nitrogen-containing heterocyclic chalcone derivatives utilizing the active substructure splicing principle, with glycyrrhiza chalcone serving as the lead compound. The targets of these derivatives were VEGFR-2 and P-gp, and their efficacy against cervical cancer was evaluated. Following preliminary conformational analysis, compound ((E)-1-(2-hydroxy-5-((4-hydroxypiperidin-1-yl)methyl)-4-methoxyphenyl)-3-(4-((4-methylpiperidin-1-yl)methyl)phenyl)prop-2-en-1-one) exhibited significant antiproliferative activity against human cervical cancer cells (HeLa and SiHa) with IC values of 6.
View Article and Find Full Text PDFBackground: Blood metabolites are important to various aspects of our health. However, currently, there is little evidence about the role of circulating metabolites in the process of skin aging.
Objectives: To examine the potential effects of circulating metabolites on the process of skin aging.
Background: There is very limited evidence on the causal effects of blood metabolites on pancreatitis risks. To reveal the causal associations between plasma metabolites and pancreatitis risks, we performed two-sample Mendelian randomization (MR) and Bayesian model averaging (MR-BMA) analyses in European ancestry.
Methods: The summary-level statistics from two genome-wide association studies with 249 and 123 metabolic traits derived from two separate cohorts involving ~115,000 (UK Biobank) and ~25,000 individuals from European ancestry were used for the analyses.
Myc is a powerful transcription factor implicated in epigenetic reprogramming, cellular plasticity, and rapid growth as well as tumorigenesis. Cancer in skeletal muscle is extremely rare despite marked and sustained Myc induction during loading-induced hypertrophy. Here, we investigated global, actively transcribed, stable, and myonucleus-specific transcriptomes following an acute hypertrophic stimulus in mouse plantaris.
View Article and Find Full Text PDFBackground: Antioxidants, as scavengers of free radicals, have been proposed as potential targets for the prevention and treatment of rheumatoid arthritis (RA), however, the causal associations between antioxidants and RA are still in debate.
Objective: This study aims to evaluate this causal association with two-sample Mendelian randomization (MR) analysis.
Methods: Inverse-variance weighted was used as the major analysis method of MR.
Background And Aims: IL-1 and IL-18 play important roles in intestine barrier integrity maintenance and inflammatory response. However, their net effects on the risk of IBD are still inconclusive. Here, we used Mendelian randomization (MR) approaches to investigate the causal associations of IL-18 and IL-1Ra (receptor antagonist) on the risks of IBD and subtypes.
View Article and Find Full Text PDFBackground And Aims: Observational and Mendelian randomization (MR) studies have identified several modifiable risk factors of cholelithiasis. However, there is limited evidence about the causal effect of blood metabolites on the cholelithiasis risk.
Methods: To have a comprehensive understanding to causal relations between blood metabolites and cholelithiasis, for the primary discovery, we applied two MR methods to explore the associations between 249 circulating metabolites and cholelithiasis.
The role of obesity in the development of dorsopathies is still unclear. In this study, we assessed the associations between body mass index (BMI) and several dorsopathies including intervertebral disc degeneration (IVDD), low back pain (LBP), and sciatica by using the Mendelian randomization method. We also assessed the effect of several obesity-related traits on the same outcomes.
View Article and Find Full Text PDFPrevious observational studies indicated that the serum albumin levels and circulating metabolites are associated with a high risk of venous thromboembolism (VTE). However, whether these observations reflect causality remained unclear. Hence, we conducted a two-sample Mendelian randomization (MR) analysis to evaluate the causal associations of serum albumin and circulating metabolites with the risk of VTE.
View Article and Find Full Text PDFLeisure sedentary behavior, especially television watching, has been previously reported as associated with the risk of lung cancer in observational studies. This study aims to evaluate the causal association with two-sample Mendelian randomization (MR) analysis. Single nucleotide polymorphisms associated with leisure television watching, computer use, and driving were extracted from genome-wide association studies.
View Article and Find Full Text PDFThe hypoxia-inducible nuclear-encoded mitochondrial protein NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like 2 (NDUFA4L2) has been demonstrated to decrease oxidative phosphorylation and production of reactive oxygen species in neonatal cardiomyocytes, brain tissue and hypoxic domains of cancer cells. Prolonged local hypoxia can negatively affect skeletal muscle size and tissue oxidative capacity. Although skeletal muscle is a mitochondrial rich, oxygen sensitive tissue, the role of NDUFA4L2 in skeletal muscle has not previously been investigated.
View Article and Find Full Text PDFCircadian rhythms are generated by an autoregulatory feedback loop of transcriptional activators and repressors. Circadian rhythm disruption contributes to type 2 diabetes (T2D) pathogenesis. We elucidated whether altered circadian rhythmicity of clock genes is associated with metabolic dysfunction in T2D.
View Article and Find Full Text PDFEndurance exercise promotes skeletal muscle vascularization, oxidative metabolism, fiber-type switching, and neuromuscular junction integrity. Importantly, the metabolic and contractile properties of the muscle fiber must be coupled to the identity of the innervating motor neuron (MN). Here, we show that muscle-derived neurturin (NRTN) acts on muscle fibers and MNs to couple their characteristics.
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