Journal of physiology and biochemistry最新文献

Current study investigated the impact of maternal and postnatal overnutrition on phenotype of adipose, in relation to offspring thermogenesis and sex. Female C57BL/6 J mice were fed with CHOW or high fat diet (HFD) for 2 weeks before mating, throughout gestation and lactation. At weaning, pups were fed to 9 weeks old with CHOW or HFD, which resulted in four groups for each gender--male or female: CHOW-CHOW (CC), CHOW-HFD (CH), HFD-CHOW (HC), HFD-HFD (HH). Maternal and post-weaning HFD enhanced thermogenic factors such as Acox1, Dio2 and Cox8b in iBAT of male and female offspring, but increased SIRT1, PGC-1α and UCP1 only in female. However, Acox1, Dio2 and Cox8b mRNA expression and SIRT1, PGC-1α and UCP1 protein expression were only enhanced upon maternal and post-weaning HFD in sWAT and pWAT of female offspring. Increased metrnl expression in adipose were observed in sex- and depot-specific manner, while enhanced circulating metrnl level was only observed in male offspring undergoing maternal HFD. Palmitic acid changed metrnl expression during preadipocytes differentiation and siRNA-mediated knockdown of metrnl inhibited preadipocyte differentiation. Female offspring were more prone to resist adverse outcomes induced by maternal and post-weaning overnutrition, which probably related to metrnl expression and thermogenesis.

In eukaryotes such as humans, some non-coding single-stranded RNAs (ncRNAs) help to regulate the pre- and post-transcriptional expression of certain genes, which in turn control many important physiological processes, such as cell proliferation, distinctions, invasion, angiogenesis, and embryonic development. microRNA-126 is an important member of these miRNAs that can be directly or indirectly involved in the control of angiogenesis. Recently, numerous studies have expounded that microRNA-126 can inhibit or promote angiogenesis as well as attenuate inflammatory responses through complex molecular mechanisms. As such, it serves as a biomarker or potential therapeutic target for the prediction, diagnosis, and treatment of relevant diseases. In this review, we present the advancements in research regarding microRNA-126's role in the diagnosis and treatment of related diseases, aiming to provide innovative therapeutic options for the diagnosis and treatment of clinically relevant diseases.

The shed form of the Klotho protein (S-Klotho) is considered a biomarker of longevity, but it is still unknown whether the levels are related to heart rate (HR) and heart rate variability (HRV); both of them greatly influenced by the ageing process, physical fitness, exercise, and health status. This study aimed (i) to investigate the association between S-Klotho plasma levels with HR and HRV parameters and (ii) to examine the association of exercise-induced changes in S-Klotho and those obtained in HR and HRV parameters after a 12-week exercise intervention in sedentary middle-aged adults. Sixty-six sedentary middle-aged adults participated in this study (50% women; 45-65 years old). Participants were randomized into 4 groups: (a) a control group (no exercise), (b) a physical activity recommendation from the World Health Organization group, (c) a high-intensity interval training group, and (d) a high-intensity interval training group adding whole-body electromyostimulation. S-Klotho plasma levels, HR, and HRV parameters (SDNN, RMSSD, high frequency, stress score, and sympathetic/parasympathetic ratio) were measured. At baseline, S-Klotho plasma levels were not related to HR and HRV parameters. After the intervention, exercise-induced changes in S-Klotho plasma levels were positively associated with changes in SDNN (β=0.261; R²=0.102; p=0.014) and negatively related to changes in stress score and sympathetic/parasympathetic ratio (all β=-0.257; R² ranges between 0.092 and 0.131; all p<0.020). Our study suggests that higher S-Klotho plasma levels are related to increased vagal influence and reduced sympathetic tone in the autonomic nervous system in sedentary middle-aged adults after different training programs. ClinicalTrials.gov identifier: CT03334357.

The role of Peroxisome proliferator-activated receptor-gamma coactivator alpha (PGC-1α) in fat metabolism is not well known. In this study, we compared the mechanisms of muscle-specific PGC-1α overexpression and exercise-related adaptation-dependent fat metabolism. PGC-1α trained (PGC-1α Ex) and wild-trained (wt-ex) mice were trained for 10 weeks, five times a week at 30 min per day with 60 percent of their maximal running capacity. The PGC-1α overexpressed animals exhibited higher levels of Fibronectin type III domain-containing protein 5 (FNDC5), 5' adenosine monophosphate-activated protein kinase alpha (AMPK-α), the mammalian target of rapamycin (mTOR), Sirtuin 1 (SIRT1), Lon protease homolog 1 (LONP1), citrate synthase (CS), succinate dehydrogenase complex flavoprotein subunit A (SDHA), Mitofusin-1 (Mfn1), endothelial nitric oxide synthase (eNOS), Hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL), G protein-coupled receptor 41 (GPR41), and Phosphatidylcholine Cytidylyltransferase 2 (PCYT2), and lower levels of Sirtuin 3 (SIRT3) compared to wild-type animals. Exercise training increased the protein content levels of SIRT1, HSL, and ATGL in both the wt-ex and PGC-1α trained groups. PGC-1α has a complex role in cellular signaling, including the upregulation of lipid metabolism-associated proteins. Our data reveals that although exercise training mimics the effects of PGC-1α overexpression, it incorporates some PGC-1α-independent adaptive mechanisms in fat uptake and cell signaling.

Hepatocellular carcinoma (HCC) is a highly vascularized tumor, one of the most common and lethal cancer-related tumor deaths worldwide, with cell proliferation playing a key role. In this study our western blot results and data from TAGC demonstrate a strong association between Sorcin (SRI) overexpression and poor outcomes in HCC. Moreover, SRI overexpression was remarkably effective in promoting proliferation in vitro and increasing tumor growth in vivo, which were attenuated by knocking down SRI. Mechanistically, SRI regulated vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor B (VEGFB) through PI3K/Akt/FOXO1 signal pathway. Overall, our study indicates that SRI stimulates HCC growth by controlling VEGFA/B, which presents a fresh insight into the pathogenesis of hepatocarcinogenesis and a new therapeutic target for HCC.

Pyruvate kinase M2 (PKM2), a subtype of pyruvate kinase (PK), has been shown to play an important role in the development of cancer. It regulates the last step of glycolytic pathway. PKM2 has both pyruvate kinase and protein kinase activity, and the conversion of these two functions of PKM2 depends on the mutual change of dimer and tetramer. The dimerization of PKM2 can promote the proliferation and growth of tumor cells, so inhibiting the dimerization of PKM2 is essential to curing cancer. The aggregation of PKM2 is regulated by both endogenous and exogenous cofactors as well as post-translational modification (PTM). Although there are many studies on the different aggregation of PKM2 in the process of tumor development, there are few summaries in recent years. In this review, we first introduce the role of PKM2 in various biological processes of tumor growth. Then, we summarize the aggregation regulation mechanism of PKM2 by various endogenous cofactors such as Fructose-1, 6-diphosphate (FBP), various amino acids, and post-translational modification (PTMs). Finally, the related inhibitors and agonists of PKM2 are summarized to provide reference for regulating PKM2 aggregation in the treatment of cancer in the future.

Hypothermia is an essential environmental factor in gastrointestinal diseases, but the main molecular mechanisms of pathogenesis remain unclear. The current study sought to better understand how chronic cold stress affects gut damage and its underlying mechanisms. In this work, to establish chronic cold stress (CS)-induced intestinal injury model, mice were subjected to continuous cold exposure (4 °C) for 3 h per day for 3 weeks. Our results indicated that CS led to gut injury via inducing changes of heat shock proteins 70 (HSP70) and apoptosis-related (caspases-3, Bax and Bcl-2) proteins; enhancing expression of intestinal tight-related (ZO-1 and occludin) proteins; promoting releases of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), high mobility group box 1 (HMGB1), interleukin1β (IL-1β), IL-18 and IL-6 inflammatory mediators in the ileum; and altering gut microbial diversity. Furthermore, persistent cold exposure resulted in the cleavage of pyroptosis-related Gasdermin D (GSDMD) protein by regulating the NLRP3/ASC/caspase-1 and caspase-11 pathway, and activation of toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)-mediated nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, which are strongly associated with changes in gut microbiota diversity. Taken together, these investigations provide new insights into the increased risk of intestinal disorders at extremely low temperatures and establish a theoretical foundation for the advancement of novel pharmaceutical interventions targeting cold-related ailments.

Palmitic acid (PA), a saturated fatty acid enriched in high-fat diet, has been implicated in the development of skeletal muscle regeneration dysfunction. This study aimed to examine the effects and mechanisms of lactate (Lac) treatment on PA-induced impairment of C2C12 cell differentiation capacity. Furthermore, the involvement of voltage-gated calcium channels in this context was examined. In this study, Lac could improve the PA-induced impairment of differentiative capacity in C2C12 cells by affecting Myf5, MyoD and MyoG. In addition, Lac increases the inward flow of Ca²⁺, and promotes the depolarization of the cell membrane potential, thereby activating voltage-gated calcium channels during C2C12 cell differentiation. The enchancement of Lac on myoblast differentiative capacity was abolished after the addition of efonidipine (voltage-gated calcium channel inhibitors). Therefore, voltage-gated calcium channels play an important role in improving PA-induced skeletal muscle regeneration disorders by exercising blood Lac. Our study showed that Lac could rescue the PA-induced impairment of differentiative capacity in C2C12 cells by affecting Myf5, MyoD and MyoG through the activation of voltage-gated calcium channels.

Corticosterone (CORT) damages hippocampal neurons as well as induces neuroinflammation. The tricarboxylic acid cycle metabolite itaconate has an anti-inflammatory role. Necroptosis is a form of programmed cell death, also known as inflammatory cell death. Menin is a multifunctional scaffold protein, which deficiency aggravates neuroinflammation. In this study, we explored whether itaconate inhibits CORT-induced neuroinflammation as well as necroptosis and further investigated the mediatory role of Menin in this protective effect of itaconate by using an exposure of CORT to HT22 cells (a hippocampal neuronal cell line). The viability of HT22 cells was examined by the cell counting kit 8 (CCK-8). The morphology of HT22 cells was observed by transmission electron microscope (TEM). The expressions of necroptosis-related proteins (p-RIP1/RIP1, p-RIP3/RIP3, and p-MLKL/MLKL) were evaluated by western blotting. The contents of inflammatory factors were detected by an enzyme-linked immunosorbent assay (ELISA) kit. Our results showed that CORT increases the contents of pro-inflammatory factors (IL-1β, TNF-α) as well as decreases the contents of anti-inflammatory factors (IL-4, IL-10) in HT22 cells. We also found that CORT increases the expressions of necroptosis-related proteins (p-RIP1/RIP1, p-RIP3/RIP3, and p-MLKL/MLKL) and decreases the cell viability in HT22 cells, indicating that CORT induces necroptosis in HT22 cells. Itaconate improves CORT-induced neuroinflammation and necroptosis. Furthermore, itaconate upregulates the expression of Menin in CORT-exposed HT22 cells. Importantly, silencing Menin abolishes the antagonistic effect of itaconate on CORT-induced necroptosis and neuroinflammation. In brief, these results indicated that itaconate protects HT22 cells against CORT-induced neuroinflammation and necroptosis via upregulating Menin.

Previous studies in Western diet (WD)-fed male rats have highlighted a link between the stimulation of cardiac contractility, mitochondrial adaptations and a pro-inflammatory fatty acid profile of phospholipids in the heart. Our objectives were to determine (1) if WD-fed female Wistar rats and obese humans display a similar pro-inflammatory profile in their cardiac phospholipids and (2) if this lipid profile is associated with deleterious effects on the heart of the female rodents. Female Wistar rats were fed WD for 5 weeks or a laboratory chow as a control. Ionic homeostasis, redox status, inflammation markers, and fatty acid composition of phospholipids were analysed in the heart. WD increased the abdominal fat mass without modifying the body weight of female rats. As previously found in males, a WD induced a shift in membrane fatty acid composition toward a pro-inflammatory profile in the female rats, but not in obese humans. It was associated with an increased COX2 expression suggesting an increased pro-inflammatory eicosanoid production. Signs of increased intracellular calcium strongly supported a stimulation of cardiac contractility without any induction of apoptosis. The heart of WD-fed rats exhibited a hypoxic state as a higher HIF1-α expression was reported. The expressions of antioxidant enzymes were increased, but the redox reserves against reactive oxygen species were lowered. In conclusion, as previously observed in males, we suppose that cardiac abnormalities are magnified with severe obesity in female rats, leading to hypoxia and intense oxidative stress which could ultimately induce cell death and heart failure.