Molecular and Cellular Biochemistry最新文献

This study aimed to examine the causal relationship between systolic blood pressure (SBP) and myocardial injury (MI), and to evaluate its prognostic implications for all-cause and cardiovascular mortality. A two-stage analytical approach was used. First, Mendelian randomization (MR) was conducted to assess the independent causal effects of SBP on six MI-related phenotypes, with adjustment for potential confounders, including lipid profiles, glycemic indices, and anthropometric traits. Second, data from 4459 participants in the National Health and Nutrition Examination Survey, with a follow-up period of up to 15 years, were analyzed. The dose-response relationship between SBP and MI was assessed using restricted cubic spline analysis. Thresholds based on sex-, age-, and comorbidities were identified using the Johnson-Neyman interaction model. MR analysis demonstrated a causal association between elevated SBP and increased risks of acute heart failure (odds ratio [OR] = 1.523), MI (OR = 1.014), and ischemic stroke (OR = 33.339). In the prospective group analysis, SBP ≥ 180 mmHg was associated with a 213.4% increased risk of MI (OR = 3.134, p = 0.003), and a graded increase in mortality was observed (hazard ratio [HR] = 2.783 for all-cause death; HR = 1.888 for cardiovascular death). Sex-stratified analysis demonstrated that the lowest MI risk occurred at SBP levels of 120-150 mmHg in men and extended to 162 mmHg in women. Among individuals aged ≥ 43 years, the risk of all-cause mortality significantly increased when SBP exceeded 135 mmHg (p < 0.001). A U-shaped relationship between SBP and mortality was observed in individuals aged ≥ 58 years with MI, with the lowest risk at 113 mmHg. Genetic and observational evidence support a causal role of elevated SBP in the development of MI. The findings demonstrate sex- and age-specific thresholds, along with a U-shaped mortality curve, providing a nuanced framework for individualized blood pressure management strategies.

This study employs an integrative approach combining single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and bulk RNA sequencing to investigate the complex cellular and molecular dynamics following myocardial infarction (MI). Quality control, batch correction, dimensionality reduction, clustering, and annotation were performed on scRNA and ST data. The Milo tool was used to analyze differential cell abundance. Developmental trajectory inference was conducted using the Monocle2 algorithm, and cell-cell communication was explored using CellPhoneDB and NicheNet. SCENIC analysis identified active transcription factors (TFs) in macrophage subtypes. Additionally, deconvolution was used to assess the spatial distribution of cell types. The functional roles of different myocardial regions were explored through cell communication patterns. Mouse MI and ischemia-reperfusion (I/R) models were established by ligating the left anterior descending (LAD) coronary artery. Molecular changes were analyzed using RT-qPCR, Western blot, immunohistochemistry and immunofluorescence. In vitro, AC16 cardiomyocytes (CMs) and THP-1-derived M2 macrophages were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) and co-culture experiments to study TREM2-mediated effects. Cell viability and apoptosis were assessed using CCK-8 and flow cytometry, respectively. The study identified dynamic changes in the proportions of immune cell types at different time points post-MI. ST revealed distinct immune cell infiltration patterns in the infarct, border, and remote zones, with macrophages progressively infiltrating the infarct region over time. Functional enrichment analysis highlighted key pathways involved in inflammation, cell proliferation, and extracellular matrix remodeling across different cardiac regions. The study also identified Trem2^high macrophages as key players in tissue repair. SCENIC analysis uncovered TFs regulating macrophage subtypes, emphasizing their roles in immune regulation and tissue reconstruction. Finally, cell-cell communication analysis revealed complex signaling networks influencing immune responses and tissue repair. Our results demonstrated that the expressions of Trem2 were significantly increased in the IZ groups in the MI and I/R model, and co-culture with TREM2-overexpressing M2 macrophages significantly enhanced the proliferative capacity and reduced apoptosis in AC16 CMs under OGD/R conditions, indicating a critical role of Trem2 in the I/R response and CMs survival. This comprehensive analysis provides a detailed map of the cellular and molecular landscape post-MI, highlighting the temporal and spatial dynamics of immune cells and their regulatory networks.

Glioma is a common malignant tumor in nervous system, but the treatment efficacy is still unsatisfactory. Licochalcone A (Lic-A) is a kind of flavonoid isolated from glycyrrhiza and shows anti-tumor effect. This study aimed to investigate anti-tumor efficacy of Lic-A on glioma using both in vivo and in vitro models. The in vitro results showed that Lic-A inhibited the growth, migration, and invasion of glioma cells in a dose-dependent way. Lic-A induced mitochondrial dysfunction by regulating Bcl-2 family and induced reactive oxygen species (ROS), while ROS inhibition enhanced the migration and invasion of glioma cells. Finally, animal experiments confirmed that Lic-A inhibited the growth of glioma in vivo. In conclusion, our results suggest that Lic-A can inhibit the migration and invasion of glioma cells while inducing apoptosis of glioma cells. The mechanism may be related to the activation of ATM/ATR pathway and the induction of oxidative stress.

Renal vascular endothelial barrier dysfunction plays an important role in the pathogenesis of diabetic nephropathy (DN). Reactive oxygen species (ROS) contribute to barrier dysfunction in various aspects of diabetes. Phosphofurin acidic cluster sorting protein 2 (PACS2) is related to the ROS production, but the specific signaling pathway in endothelial cells remains unclear. In this study, we explored the mechanistic function of PACS2 and its downstream PKCα/NOX4 signaling pathway in endothelial barrier damage in DN. A significant upregulation of PACS2 expression was observed in human umbilical vein endothelial cells treated with high glucose and palmitic acid and glomerular endothelial cells derived from STZ + HFD-induced DN mice. SiRNA-mediated silencing or knockdown of PACS2 reversed the impaired vascular barrier function in vivo and in vitro. Furthermore, the inhibition of PACS2 significantly downregulated the protein expression of PKCα and NOX4 protein and the production of ROS in endothelial cells. Collectively, our findings indicate that the PACS2/PKCα/NOX4 signaling pathway may participate in the pathogenesis of DN by regulating vascular endothelial barrier function.

Globally, liver cancer is reported to be the third leading cause of cancer-related mortality. The most common type of these cancers is hepatocellular carcinoma (HCC). Current preventive strategies, including lifestyle modifications, antiviral therapies, and surveillance, are limited in their effectiveness. Mitochondria play critical roles in regulating cellular metabolism, oxidative stress, and apoptosis. Mitochondrial dysfunction can accelerate HCC progression, particularly in patients with liver diseases such as metabolic-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatohepatitis (MASH). In this review, we discuss the mechanisms of mitochondrial dysfunction in HCC from a molecular point of view, including oxidative stress, mitophagy dysregulation, mitochondrial dynamics dysregulation, and mitochondrial DNA (mtDNA)-mediated dysregulation of innate immune responses. Additionally, we explore molecular-targeted therapies aimed at restoring mitochondrial function. Critical approaches include targeting reactive oxygen species pathways through agents such as iridium (III) complexes and Mito Rh S, which induce cancer cell death through apoptosis and ferroptosis. Other compounds, including dehydrocrenatidine, enhance oxidative phosphorylation and promote apoptosis. Inhibitors of dynamin-related protein 1 (Drp1) target mitochondrial fission to reduce tumor growth. Furthermore, mitophagy modulators, such as SIRT1 activators, improve mitochondrial quality control, minimize the negative effects of oxidative stress, and reduce cancer development. Clinical trials are ongoing for the mitochondrial enzyme-targeting agents CPI-613 and Gamitrinib, a heat shock protein-targeting agent, which have hence shown great promise for these therapies. With further investigation, mitochondrial-targeted interventions could be promising for preventing or reducing HCC incidence and recurrence, increasing long-term survival, and improving the quality of life of patients with advanced-stage disease.

Age-related reductions in skeletal muscle insulin responsiveness promote metabolic dysregulation and contribute to an elevated probability of type 2 diabetes onset. The malfunction of nutrient-responsive signaling routes, specifically AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR), constitutes a central component of this biological process. The integrated activity of these kinases in controlling energy dynamics, protein formation, and glucose processing is fundamental to ensure metabolic homeostasis in skeletal muscle tissue. Through its modulation of AMPK and mTOR pathways, exercise helps reinstate signaling equilibrium and supports better insulin efficacy in aging skeletal muscle. This review explores the molecular mechanisms by which different forms of exercise-endurance, resistance, and combined training-modulate the AMPK/mTOR axis in aging muscle. This analysis focuses on exercise-induced AMPK signaling as a catalyst for mitochondrial development, enhanced glucose processing, and intensified fatty acid breakdown, while also temporally coordinating mTOR activity to support muscle maintenance without exacerbating insulin resistance. By integrating insights from aging biology, exercise physiology, and molecular metabolism, this review highlights the therapeutic potential of targeting AMPK/mTOR signaling through physical activity to combat insulin resistance in the elderly.

Intermittent fasting (IF) and exercise can reverse the impaired glycolipid conversion ability caused by obesity. However, the effects of IF and exercise combination on glycolipid conversion ability in normal individuals remain to be determined. In this study, male KM mice were subjected to IF (including alternate-day fasting (ADF), time-restricted fasting (TRF)), treadmill exercise, and a combination of the two interventions for 6 weeks. The effects of two IF models combined exercise on glycolipid conversion in mice were investigated by detecting serum biochemical indexes, and the expressions of genes and proteins closely related to the glycolipid conversion pathway in liver, gastrocnemius, and inguinal adipose tissue. The results showed that IF combined with exercise significantly reduced fasting blood glucose, glycated serum protein and liver glycogen levels in mice. TRF combined with exercise significantly decreased triglyceride levels in serum, liver and gastrocnemius. IF combined with exercise activated the ChREBP or SREBP1/FASN pathways to enhance the transcriptional activation of the glucose-mediated adipogenesis pathway, and simultaneously promoted the expression of fatty acid oxidation proteins and reduced liver gluconeogenesis genes expression, collectively improving lipid metabolic efficiency. Furthermore, IF increased the expression of glycogen turnover-related protein PPP1R3C and adipose thermogenesis-related protein UCP1 in the inguinal adipose tissue, indicating enhanced glycogen flux coordination with adipose thermogenic activation. In conclusion, IF combined with exercise orchestrates the glycolipid conversion and substrate utilization.

Epigenetics studies heritable changes in gene expression without altering the DNA sequence and is involved in diverse biological processes. In male reproduction, Leydig cells, the main site of testosterone synthesis, play an important role in maintaining the reproductive process. However, the role of epigenetics in the mechanism of testosterone synthesis in Leydig cells is still not well understood. This review systematically describes how classic epigenetic modifications such as DNA methylation, RNA methylation, histone modification, and non-coding RNA regulate the testosterone synthesis process of Leydig cells in different species. Accumulating evidences revealed that epigenetics can regulate the process of testosterone synthesis in Leydig cells. In future, we aim to provide new ideas for male reproduction by investigating the relationship between testosterone synthesis mechanisms and epigenetics.