Journal of physiology and biochemistry最新文献

Phenolic compounds are a large class of phytochemicals with relevant physiological effects that are naturally found in plant-origin foods and derived products. Beneficial effects associated with polyphenol consumption are related to their ability to prevent and/or counteract disease features: they exert anti-inflammatory, antioxidant and anticancer effects, as well as protective actions against metabolic diseases. Phenolic compounds and their metabolites can modulate cell function by regulating gene expression. These effects are partially mediated through specific changes in epigenetic mechanisms such as DNA methylation, histone modifications and microRNA (miRNA) expression. Some polyphenols affect DNA methylation and are effective in counteracting deleterious actions induced by inflammatory/pro-oxidant factors, both in in vitro and in vivo settings. Specific mechanisms include modulation of methyl-transferases, whose levels are inhibited upon polyphenols treatment. Some polyphenols are histone deacetylase inhibitors, which prevent transcriptional repression and suppress tumor and inflammation genes by affecting selective regulation of miRNA expression. Their mostly recognized actions as anti-inflammatory and antioxidants seem to be partially mediated through regulation of individual miRNAs. Due to these actions, polyphenols and polyphenol-derived metabolites are under study in clinical and interventional trials for their benefits on inflammation and/or metabolic disorders. In conclusion, phenolic compounds might be an interesting approach to contribute to human homeostasis given their capacity to dynamically regulate epigenetic factors at cellular and systemic level. The present review aims to study available evidence regarding regulatory effects of polyphenols on gene expression, specifically mediated through epigenetic mechanisms.

Emerging evidence suggests that prolyl-4-hydroxylase α subunit 2 (P4HA2) plays critical roles in cancer progression through multiple mechanisms. Notably, P4HA2 has been implicated in modulating glycolytic pathways in malignancies. Phosphofructokinase (PFKP), a key glycolytic enzyme, exhibits significant overexpression in thyroid cancer. This study investigates the functional of P4HA2 in thyroid cancer and elucidates the P4HA2/PFKP axis in regulating cancer cell glycolysis. Bioinformatics analysis using GEPIA website revealed P4HA2 expression patterns in thyroid cancer samples. P4HA2 protein levels were detected in thyroid cancer cell lines by western blot assay. Functional characterization was performed through siRNA-mediated P4HA2 knockdown followed by evaluation of proliferative capacity, cell cycle progression, migratory/invasive potential, and glycolytic activity. Rescue experiments employing PFKP overexpression were conducted to delineate molecular interactions. Significant P4HA2 up-regulation was observed in thyroid cancer tissues and cell lines. P4HA2 silencing marked inhibited cellular proliferation, suppressed cell cycle regulators, and attenuated metastatic potential. Glycolytic parameters including glucose consumption, lactate production, and ATP synthesis were significantly compromised following P4HA2 knockdown. Mechanistically, P4HA2 depletion down-regulated PFKP expression, while PFKP overexpression partially rescued the oncogenic phenotype. Our data indicated that P4HA2 promoted cell proliferation, cell cycle, migration, invasion, glycolysis and tumor growth, suggesting that it might be a valuable therapeutic target for thyroid cancer.

The farnesoid X receptor (FXR), a nuclear receptor (NR), plays a key role in balancing bile acid (BA), lipid, and glucose metabolism. By partnering with the retinoid X receptor (RXR), FXR influences gene transcription critical to these metabolic pathways. It also interacts with other NRs, including the pregnane X receptor (PXR), liver X receptor (LXR), and vitamin D receptor (VDR), creating an intricate signalling network. FXR activation triggers the production of small heterodimer partner (SHP), which suppresses cholesterol 7 alpha-hydroxylase (CYP7A1), the enzyme controlling BA synthesis. It also regulates lipid metabolism by controlling sterol regulatory element-binding protein 1c (SREBP-1c) and affects glucose balance. LXR, activated by oxysterols, supports reverse cholesterol transport (RCT) by regulating the expression of adenosine triphosphate binding cassette A1 (ABCA1) and adenosine-binding cassette sub-family G member 1 (ABCG1). Since FXR affects LXR-regulated genes, it indirectly modulates cholesterol homeostasis. Meanwhile, PXR, a xenobiotic sensor responsive to diverse compounds, such as BAs, regulates genes involved in drug detoxification and transport. FXR activation enhances PXR expression, influencing BA metabolism and removal. VDR, which responds to vitamin D and specific BAs such as lithocholic acid, plays a role in calcium balance and xenobiotic processing. The interplay among these NRs underscores FXR's central role in metabolic regulation and its potential as a therapeutic target for metabolic disorders.

Interscapular brown adipose tissue (iBAT) whitening is characterized by thermogenic dysfunction and may aggravate the metabolic complications of obesity. Moreover, whitening is linked to multiple factors, including the overactivation of the classical renin-angiotensin system (RAS) arm. Thus, we aim to compare the impact of RAS modulation by enalapril and/or aerobic exercise training (AET) in obesity-induced iBAT whitening. C57BL/6 mice were fed a standard chow (SC) or high-fat (HF) diet for 16 weeks. After 8 weeks, the HF animals were subdivided (n = 10 for each group): HF, HF + Enalapril (HF-E), HF + Training (HF-T), and HF + Enalapril + Training (HF-ET). We evaluated: body mass (BM) gain, adiposity index, iBAT morphology, RAS components, and thermogenic markers in iBAT. The HF group exhibited increased body adiposity, iBAT mass, and lipid content, as evidenced by a collapse in iBAT thermogenic capacity and overactivation of the classical RAS arm (AT1R) compared to the SC group. All interventions reduced body adiposity and iBAT mass, improved thermogenic capacity (UCP1, Vegfa, and AMPK), and shifted iBAT RAS balance to the counter-regulatory arm (MasR and MrgD). HF-E improved iBAT morphology and brown adipogenesis (Prdm16 and Cidea) compared to the HF group. HF-T improved mitochondrial biogenesis (PGC1α and Tfam) compared to the HF group. HF-ET showed additional reduced body adiposity by sympathetic activation (β3-ar) and increased brown adipocyte competence (AMPK, Tfam, and Cidea) compared to SC and HF groups. We concluded that combined interventions (enalapril and AET) have an additional impact on iBAT whitening, enhancing brown morphology and thermogenic capacity in obese mice.

Curcumin, a polyphenol extracted from the plant turmeric rhizoma, is well known for its strong antioxidant capacity and beneficial effects on the treatment of obesity induced by a high-fat diet in mice. However, the exact mechanism of action by which it improves obesity remains elusive. The aim of this study was to investigate the effect of curcumin on the biological phenotype of HFD-induced obese mice, to determine the related metabolic pathways and to determine whether the intestinal flora is involved. C57BL/6 mice were fed HFD for 8 weeks and then gavaged with 200 mg/kg curcumin or the same volume of vehicle for 16 weeks. The body weight, blood glucose level, blood lipid level, insulin resistance and oxidative stress level of the mice were detected to determine the effect of the treatment on lipid metabolism. Liver transcriptome analysis combined with qPCR and cell experiments revealed that curcumin improves hepatic steatosis and insulin resistance in mice fed a high-fat diet by downregulating the JNK2/FOXO1/Bcl6 axis. Curcumin treatment can regulate the composition and structure of intestinal flora in high-fat diet-fed mice, and increase the relative abundance of beneficial bacteria such as Coriobacteriaceae, Mailhella, Faecalibaculum, Phocaeicola vulgatus, Parvibacter vulgatus, and Bacteroides intestinalis, which are associated with obesity and metabolic disorders, while reducing the relative abundance of harmful bacteria such as Alistipes, Oscillibacter, Lactobacillus johnsonii, and Acutalibacter muris. In conclusion, curcumin ameliorated hepatic steatosis and insulin resistance in HFD-fed mice by down-regulating hepatic JNK2/FOXO1/Bcl6 axis and altering the composition and structure of intestinal flora.

Previous studies have revealed that different intensities of exercise training have an impact on cognition. However, the cognitive effects of different intensities of exercise and its underlying mechanisms are not fully understood. The aim of this paper was to investigate the effects of different intensities of treadmill exercise on cognition in rats from the perspective of metabolomic analysis. In this study, ninety-six male rats were randomly divided into four groups: control group (CON group, n = 24), low-intensity running group (LIR group, n = 24), medium-intensity running group (MIR group, n = 24), and high-intensity running group (HIR group, n = 24). After 4 weeks of treadmill running, rats in the LIR group located the platform significantly faster than those in the CON(p = 0.027) and HIR(p = 0.011) groups. After 8 weeks of treadmill running, rats in the LIR and MIR groups also found the platform more quickly than those in CON group (p = 0.003 and p = 0.015, respectively). Additionally, rats in the MIR group showed significantly increased superoxide dismutase (SOD)/catalase (CAT) in the hippocampus compared with those exposed to HIR(p = 0.03), LIR(p = 0.0008), and CON(p = 0.0004). Metabolomic analysis revealed that, after 8 weeks of running, 14 metabolites with similar characteristics differed between the MIR and HIR groups compared to the CON group. The LIR group showed significant alterations in 12 key metabolites compared to the CON group. The LIR, MIR, and HIR groups also demonstrated significant changes in 3, 4, and 3 metabolic pathways respectively, when compared to the CON group. In conclusion, the above results indicate that LIR can effectively decrease fumarate accumulation, thereby enhancing the TCA cycle and brain energy metabolism which in turn improved cognitive function, while MIR can modify glutathione metabolism to alleviate oxidative stress (OS), supporting cognitive function.

The possible role of vitamin D (VD) in the pathogenesis of inflammatory bowel disease (IBD) and the associations between VD levels and IBD activity remain unclarified. We aimed to assess VD levels in IBD patients and their associations with IBD activity. We evaluated VD levels in Greek patients aged 18-75 years old with Crohn's disease (CD) or ulcerative colitis (UC). Patients were ineligible under the following conditions: history of enterectomy/right colectomy, receiving VD or agent(s) interfering with VD metabolism during the last three months and any comorbidities that influence VD levels. Epidemiologic characteristics, clinical course, laboratory investigations, endoscopic and histologic findings were recorded. In total, 122 patients with CD and 71 with UC were included. Most of them had low levels of VD (90% of CD and 91.5% of UC patients). Patients with clinically active CD or UC had lower levels of VD compared to those in remission (p = 0.009 and p = 0.033, respectively).CD patients with low levels of VD had higher CRP and stool calprotectin compared to those with normal levels of VD (P = 0.032 and P = 0.002, respectively). In UC, patients with pancolitis had lower VD levels compared to patients with proctitis (P = 0.036). In conclusion, the majority of Greek IBD patients have low levels of VD. Clinical activity is related to lower levels of VD. Low compared to normal levels of VD in CD patients are associated with higher CRP and calprotectin levels, so VD levels might serve as an activity marker.

Diabetic nephropathy is recognized as the predominant cause of end-stage renal disease worldwide. In reaction to metabolic stress, the peptide hormone spexin-14, is synthesized in both central and peripheral tissues. Its level is reduced in type II diabetes mellites and may play a role in glucose metabolism. However, in the context of DN, the mechanisms through which spexin exerts its effects remain largely unknown. This research employed a rat model of DN to explore the therapeutic potential and the underlying mechanisms associated with spexin treatment. For the development of this experimental model, rats were subjected to an eight-week regimen of a high-fat, high-fructose diet prior to receiving a single dose of streptozotocin (35 mg/kg body weight). Subsequently, spexin was administered subcutaneously on a daily basis for a duration of eight weeks at a dosage of 50 µg/kg body weight. The evaluation methods employed encompassed renal function assessments, macromorphological examinations, histopathological evaluations, and analyses of inflammatory and oxidative stress mediators. Additionally, immunohistochemical staining for NF-kB and E-cadherin, along with PCR analysis of mTOR, Bcl2, and Bax gene expressions in renal tissues, were conducted. Following the administration of spexin to the diabetic rats, there was a significant reduction in serum levels of glucose, urea, creatinine, and inflammatory cytokines (IL-1β, TNF-α), alongside a marked restoration of antioxidant enzyme activities. Furthermore, a significant decline in the levels of NF-κB, mTOR, and Bax was noted and accompanied with increased expressions of Bcl-2 and E-cadherin proteins. The observed improvements in histopathological changes significantly corroborated the biochemical results. In summary, spexin has proven to be effective in alleviating DN by its capacity to mitigate metabolic disturbances, oxidative stress, inflammation, and apoptosis.

Hepatocellular carcinoma (HCC) is known for its aggressive nature and high mortality rates. Circular RNAs (circRNAs) have emerged as critical regulators of cancer progression, yet the role of the circRNA cell division cycle and apoptosis regulator 1 (circCCAR1) in HCC is poorly understood. This study aims to explore the mechanism of circCCAR1 in HCC progression. We measured the expression of circCCAR1, miR-641, and motor protein kinesin family member 5B (KIF5B) in HCC cell lines and normal hepatic cells, revealing that circCCAR1 was significantly overexpressed in HCC. Mechanistic analyses showed that the RNA methyltransferase YTH domain-containing protein 1 (YTHDC1) recognized N6-methyladenosine (m6A) modifications on circCCAR1, facilitating its transport from the nucleus to the cytoplasm. In the cytoplasm, circCCAR1 acted as a molecular sponge to sequester miR-641, relieving miR-641-mediated inhibition of KIF5B mRNA. CircCCAR1 directly bound to the RNA-binding protein polypyrimidine tract-binding protein 1 (PTBP1), which stabilized KIF5B mRNA. Functional experiments demonstrated that silencing circCCAR1 suppressed HCC cell proliferation, induced apoptosis, and reduced tumor growth in a xenograft mouse model, effects that were partially reversed after KIF5B overexpression or miR-641 inhibition. In conclusion, YTHDC1 promotes the cytoplasmic translocation of m6A-modified circCCAR1 and circCCAR1 facilitates HCC progression through the miR-641/KIF5B axis.

Neutrophil extracellular traps (NETs), web-like complex structures secreted by neutrophils, have emerged as key players in the modulation of immune responses and the immunopathogenesis of immune disorders. Initially described for their antimicrobial function, NETs now play a part in the fundamental processes of cancer biology, including cancer initiation, metastatic dissemination, and immune evasion strategies. NETs hijack anti-tumor immunity by entrapping circulating cancer cells, fostering the growth of tumors, and reorganizing the tumor microenvironment such that it is pro-malignancy. Emerging evidence emphasizes the role of NETosis coupled with non-coding RNAs-long non-coding RNAs (lncRNAs) and microRNAs (miRNAs)-as key regulators of gene expression and controllers of processes vital for cancer growth, such as immune response and programmed cell death processes like apoptosis, necroptosis, pyroptosis, and ferroptosis. Aberrantly expressed non-coding RNAs have been attributed to immune dysregulation and excessive NET production, promoting tumor growth. NETs are also associated with a myriad of pathological conditions, such as autoimmune disorders, cystic fibrosis, sepsis, and thrombotic disorders. New therapeutic approaches-such as DNase therapy and PAD4 inhibitors-target NET production and their degradation to modify immune function and the efficiency of immunotherapies. Further clarification of the intricate interactions of NETosis, lncRNAs, and miRNAs has the potential to establish new strategies for the suppression of the growth of tumors and preventing immune evasion. This review seeks to elucidate the interactions between NETosis and the regulatory networks involving non-coding RNAs that significantly contribute to the immunopathogenesis of cancer.