Journal of physiology and biochemistry最新文献

Reactive oxygen species (ROS) play a key role in the regulation of adipogenesis. The aim of our study was to investigate the effect of quercetin (QCT) supplement on obese adipose tissue metabolism of 30-week-old diabetic Zucker rats (ZDF), not well examined yet. QCT was administered orally at dose of 20 mg/kg body weight/day for 6 weeks. Adipocytes from subcutaneous adipose tissue (ScWAT) were isolated and their size was evaluated by light microscopy. Gene expression of adipogenic markers in subcutaneous and visceral adipose tissue was determined by real-time PCR and expression of proteins involved in lipid and glucose metabolism was determined in ScWAT by immunoblotting. Obese ZDF rats suffered from diabetes, hyperinsulinemia and had higher index HOMA-IR (Homeostatic Model Assessment for Insulin Resistance). Treatment with QCT had no significant impact on these metabolic disorders in genetic model of obesity and type 2 diabetes used in our study. Nevertheless, QCT reduced expression of inflammatory cytokine tumour necrosis factor alpha in ScWAT and also visceral adipose tissue and up-regulated expression of anti-inflammatory adiponectin in ScWAT. A shift in redox equilibrium was detected via inhibition of pro-oxidant genes by QCT. Furthermore, QCT reduced adipocyte size in ScWAT, down-regulated expression of fatty acid synthase and adipogenic markers, and moreover stimulated expression of proteolytic enzymes. These changes likely resulted in reduced fat deposition in ScWAT, which was reflected in the elevated circulated levels of free fatty acids in QCT-treated obese ZDF rats compared with obese untreated controls. This increase could, at least in part, explain why we did not observe an improvement in systemic metabolic health by QCT in our model. In conclusion, our study suggests that preventive treatment with QCT might be more effective than its administration in the stage of fully developed diabetes, and further research in this area is needed.

Long non-coding RNA rhabdomyosarcoma 2-associated transcript (RMST) has been found to exert effects on cardiovascular diseases. However, the research for probing its role in heart failure (HF) is limited. Our study intends to unravel the regulatory effects of RMST on HF via the microRNA (miR)-10b-5p/tumor necrosis factor receptor-associated factor 6 (TRAF6) axis. The mouse model of HF was induced by doxorubicin. The expression levels of RMST, miR-10b-5p and TRAF6 were detected. The virus carrying RMST, miR-10b-5p or TRAF6 vectors were injected into doxorubicin-induced HF mice to examine the cardiac function, inflammatory response, pathological changes and cell apoptosis in doxorubicin-induced HF mice. The target relationships among RMST, miR-10b-5p and TRAF6 were confirmed. RMST and TRAF6 were elevated and miR-10b-5p was reduced in doxorubicin-induced HF mice. RMST or TRAF6 silencing or miR-10b-5p overexpression could improve doxorubicin-induced cardiac dysfunction, and inflammatory response, and reduce cardiomyocyte apoptosis. Down-regulation of miR-10b-5p or overexpression of TRAF6 were both able to inverse the therapeutic effect of silencing RMST on doxorubicin-induced HF mice. RMST bound to miR-10b-5p that targeted TRAF6. RMST silencing could attenuate inflammatory response and cardiomyocyte apoptosis and upregulate cardiac function in mice with doxorubicin-induced HF by modulating the miR-10b-5p/TRAF6 axis. The study provides novel therapeutic targets for HF treatment.

There are only scarce recent reports about the role of growth differentiation factor 15 (GDF-15) and some more data about interleukin-6 (IL-6) in inflammatory bowel diseases (IBD). We assessed GDF-15 and IL-6 serum levels in patients with IBD and associations with their characteristics. We included 122 and 71 stored samples from patients with Crohn's disease (CD) and ulcerative colitis (UC), respectively, and regular follow-up and 44 samples from healthy controls. Data regarding epidemiologic and disease characteristics were recorded. In CD, both GDF-15 and IL-6 levels were higher in active disease or all patients than controls (P ≤ 0.020) as well as patients with elevated CRP (P ≤ 0.008), endoscopically active disease (P ≤ 0.017), age ≥ 40 years (P ≤ 0.005) and active smokers (P ≤ 0.050) and were positively correlated with hospitalization numbers (P ≤ 0.019). GDF-15 levels were also positively correlated with flares within year-1 (P < 0.001). In UC, both GDF-15 and IL-6 levels were higher in clinically active or all patients than controls (P < 0.001), but they shared no other association with patient characteristics except for positive correlation with CRP. Only IL-6 levels were higher in active than inactive UC either clinically (P = 0.047) or endoscopically (P < 0.001) and were positively correlated with stool calprotectin (P = 0.021). GDF-15 was positively correlated to IL-6 levels only in UC (r_s=0.591, P < 0.001) but not in CD. In conclusion, in CD, GDF-15 and IL-6 levels could constitute indexes of activity and even offer a prognostic index of disease progression. In UC, IL-6 could also represent an activity index, but the role of GDF-15 needs further evaluation.

The high mortality rate of hepatocellular carcinoma (HCC) is partly due to advanced diagnosis, emphasizing the need for effective predictive tools in HCC treatment. The aim of this study is to propose a novel prognostic model for HCC based on adenosine metabolizing genes and explore the potential relationship between them. Regression analysis was performed to identify differentially expressed genes associated with adenosine metabolism in HCC patients using RNA sequencing data obtained from a public database. Adenosine metabolism-related risk score (AMrisk) was derived using the least absolute shrinkage and selection operator (LASSO) Cox regression and verified using another database. Changes in adenosine metabolism in HCC were analyzed using functional enrichment analysis and multiple immune scores. The gene expression levels in patient samples were validated using quantitative reverse transcription polymerase chain reaction. Thirty adenosine metabolism-related differentially expressed genes were identified in HCC, and six genes (ADA, P2RY4, P2RY6, RPIA, SLC6A3, and VEGFA) were used to calculate the AMrisk score; the higher the risk scores, the lower the overall survival. Moreover, immune infiltration activation and immune checkpoints were considerably higher in the high-risk group. Additional in vitro experiments validated the enhanced expression of these six genes in HCC. The established predictive model demonstrated that adenosine metabolism-related genes was significantly associated with prognosis in HCC patients.

Macrophage is considered as a critical driving factor in the progression of atherosclerosis (AS), and epigenetic heterogeneity contributes important mechanisms in this process. Here, we identified that a histone demethylase jumonji domain-containing protein 1 C (JMJD1C) is a promising biomarker for atherosclerotic cerebral infarction through clinical analysis. Then, AOPE^-/- mice fed with a high fat diet and RAW264.7 cells induced by oxidized low-density lipoprotein (ox-LDL) were used as AS models to verify the function of JMJD1C in AS development in vivo and in vitro. JMJD1C knockdown significantly reduced plaque area, inflammation and endothelial damage in AS model mice, and also alleviated foam cell formation, inflammatory cytokines production and cell apoptosis in ox-LDL-treated RAW264.7 cells. Mechanistically, JMJD1C promoted the transcription of proprotein convertase subtilisin/kexin type 9 (PCSK9) through mediating H3 Lysine 9 demethylation. The effects of JMJD1C knockdown on ox-LDL-induced macrophages were blocked by PCSK9 overexpression. Altogether, our study proves that JMJD1C advances macrophage foam cell formation, inflammation and apoptosis to accelerate AS progression through H3 demethylation of PCSK9. The findings underscore the important role of JMJD1C-mediated histone modification in macrophage regulation and AS progression, which brings a new insight into the pathobiology of AS.

Exosomes are widely recognized for their roles in numerous biological processes and as intercellular communication mediators. Human cancerous and normal cells can both produce massive amounts of exosomes. They are extensively dispersed in tumor-modeling animals' pleural effusions, ascites, and plasma from people with cancer. Tumor cells interact with host cells by releasing exosomes, which allow them to interchange various biological components. Tumor growth, invasion, metastasis, and even tumorigenesis can all be facilitated by this delicate and complex system by modifying the nearby and remote surroundings. Due to the existence of significant levels of biomolecules like microRNA, exosomes can modulate the immune system's stimulation or repression, which in turn controls tumor growth. However, the role of microRNA in exosome-mediated communication between immunological and cancer cells is still poorly understood. This study aims to get the most recent information on the "yin and yang" of exosomal microRNA in the regulation of tumor immunity and immunotherapy, which will aid current cancer treatment and diagnostic techniques.

Acute kidney injury is a serious public health problem worldwide, being ischemia and reperfusion (I/R) the main lesion-aggravating factor that contributes to the evolution towards chronic kidney disease. Nonetheless, intervention approaches currently available are just considered palliative options. In order to offer an alternative treatment, it is important to understand key factors involved in the development of the disease including the rescue of the affected cells and/or the release of paracrine factors that are crucial for tissue repair. Bioactive lipids such as sphingosine 1-phosphate (S1P) have significant effects on the modulation of signaling pathways involved in tissue regeneration, such as cell survival, proliferation, differentiation, and migration. The main objective of this work was to explore the protective effect of S1P using human kidney proximal tubule cells submitted to a mimetic I/R lesion, via ATP depletion. We observed that the S1P pre-treatment increases cell survival by 50% and preserves the cell proliferation capacity of injured cells. We showed the presence of different bioactive lipids notably related to tissue repair but, more importantly, we noted that the pre-treatment with S1P attenuated the ischemia-induced effects in response to the injury, resulting in higher endogenous S1P production. All receptors but S1PR3 are present in these cells and the protective and proliferative effect of S1P/S1P receptors axis occur, at least in part, through the activation of the SAFE pathway. To our knowledge, this is the first time that S1PR4 and S1PR5 are referred in these cells and also the first indication of JAK2/STAT3 pathway involvement in S1P-mediated protection in an I/R renal model.

The gene inhibin subunit beta B (INHBB) encodes the inhibin βB subunit, which is involved in forming protein members of the transforming growth factor-β (TGF-β) superfamily. The TGF-β superfamily is extensively involved in cell proliferation, differentiation, adhesion, movement, metabolism, communication, and death. Activins and inhibins, which belong to the TGF-β superfamily, were first discovered in ovarian follicular fluid. They were initially described as regulators of pituitary follicle-stimulating hormone (FSH) secretion both in vivo and in vitro. Later studies found that INHBB is expressed not only in reproductive organs such as the ovary, uterus, and testis but also in numerous other organs, including the brain, spinal cord, liver, kidneys, and adrenal glands. This wide distribution implies its involvement in the normal physiological functions of various organs; however, the mechanisms underlying these functions have not yet been fully elucidated. Recent studies suggest that INHBB plays a significant, yet complex role in tumorigenesis. It appears to have dual effects, promoting tumor progression in some contexts while inhibiting it in others, although these roles are not yet fully understood. In this paper, we review the different expression patterns, functions, and mechanisms of INHBB in normal and tumor tissues to illustrate the research prospects of INHBB in tumor progression.

Spinal cord injury (SCI) represents a destructive pathological and neurological state. Methyltransferase-like 14 (Mettl14)-mediated m6A modification links to spinal cord injury (SCI), and we explored its mechanism. SCI mouse models were subjected to si-Mettl14 and si-negative control treatments and mouse behavior, pathological condition and apoptosis assessments. The oxygen/glucose deprivation (OGD)-induced spinal cord neuronal cell models were processed with si-Mettl14 and si-peroxisome proliferator-activated receptor γ (PPARγ) plasmids, and pcDNA3.1-YTHDF2 or synthetic dsDNA Poly(dA: dT), followed by viability and apoptosis evaluation by MTT and flow cytometry. Levels of Mettl14, PPARγ, and YTHDF2 mRNAs and proteins, AIM2 inflammasome activation-associated and pyroptosis marker proteins, PPARγ m6A methylation and pyroptosis-related inflammatory factors were determined by RT-qPCR, Western blot, Me-RIP and ELISA, with PPARγ mRNA stability and YTHDF2-PPARγ interaction assessed. Mettl14 and PPARγ m6A modification levels rose in SCI spinal cord tissues, while PPARγ levels dropped. Mettl14 knockdown dampened m6A modification, up-regulated PPARγ levels, weakened neuronal apoptosis, and ameliorated SCI in mice. OGD down-regulated PPARγ and accelerated OGD-induced neuronal apoptosis and pyroptosis via inducing Mettl14-mediated m6A modification. Mettl14 amplified PPARγ mRNA degradation and down-regulated PPARγ by mediating m6A methylation via the YTHDF2-dependent pathway. Mettl14 silencing-mediated PPARγ m6A methylation mitigated OGD-induced neuronal apoptosis and pyroptosis by inactivating AIM2 inflammasome. Mettl14 triggered activated AIM2 inflammasomes, promoted neuronal apoptosis and pyroptosis, and worsened SCI in SCI mice via mediating PPARγ m6A methylation. Mettl14 regulates AIM2 inflammasome activation, and redounds to spinal cord neuronal apoptosis and pyroptosis in SCI by mediating m6A methylation of PPARγ.

High-intensity intermittent training (HIIT) in a normobaric hypoxic environment enhances exercise capacity, possibly by increasing the mitochondrial content in skeletal muscle; however, the molecular mechanisms underlying these adaptations are not well understood. Therefore, we investigated whether HIIT under normobaric hypoxia can enhance the expression of proteins involved in mitochondrial biogenesis and dynamics in rat gastrocnemius muscle. Five-week-old male Wistar rats (n = 24) were randomly assigned to the following four groups: (1) sedentary under normoxia (20.9% O₂) (NS), (2) training under normoxia (NT), (3) sedentary under normobaric hypoxia (14.5% O₂) (HS), and (4) training under normobaric hypoxia (HT). The training groups in both conditions were engaged in HIIT on a treadmill five to six days per week for nine weeks. From the fourth week of the training period, the group assigned to hypoxic conditions was exposed to normobaric hypoxia. Forty-eight hours after completing the final training session, gastrocnemius muscles were surgically removed, and mitochondrial enzyme activity and mitochondrial biogenesis and dynamics regulatory protein levels were determined. Citrate synthase (CS) activity and mitochondrial oxygen phosphorylation (OXPHOS) subunits in the gastrocnemius muscle in the HT significantly exceeded those in the other three groups. Moreover, the levels of a master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and a mitochondrial fusion-related protein, optic atrophy 1 (OPA1), were significantly increased by HIIT under normobaric hypoxia. Our data indicates that HIIT and normobaric hypoxia increase the expression of mitochondrial biogenesis- and dynamics-related proteins in skeletal muscles.