Journal of Physiology and Pharmacology最新文献

The digestive system, comprising gastrointestinal (GI)-tract and connecting organs, such as liver or pancreas, has a wide autonomy in the human body due to the presence of specific nervous and endocrine systems of its own and can act voluntarily without stimulation from the rest of the body. This wide physiological autonomy of a digestive tract does not exclude connection with other organs and central as well as peripheral mechanisms controlling nervous and hormonal systems. The vagal nerve is a structure connecting GI-tract with brain centers. Both, the afferent and efferent components of the vagal nerve innervate the GI-tract and modify its functions. An example of stimulants affecting afferent fibers of vagal nerve are digestive hormones, such as cholecystokinin (CCK), because CCK is commonly recognized as the gut hormone that stimulates specific receptors located at the endings of vagal afferent fibers and promotes the vago-vagal reflex. Recent studies have documented that GI-tract is a source of abundant hormones regulating the hunger - satiety centers in the hypothalamus via afferent fibers of the vagal nerve, forming the brain-gut axis. In addition, local endocrine cells in the GI-tract can produce biogenic amines, such as serotonin or histamine which also can stimulate afferent component of this axis. The complexity of brain - gut axis is augmented by the participation of other factors, that can influence it, such as metabolites of gut microbiota, changes in the intestinal permeability, the proinflammatory cytokines and other immune responses, activity of the stress hormones, such as adrenaline, cortisol and aldosterone. In addition, the presence of the short chain fatty acids (SCFA) can modify the bidirectional brain-gut and gut-brain axes activity, indirectly, as nutrients for specific bacterial species, or directly, by stimulation of the specific receptors located within the GI wall. In this review, we focused on the brain-gut axis is involved in the strenghtening of the mucosal barrier via maintaining of oxidative balance. The main process reaction causing cellular destruction is lipid peroxidation. Lipid peroxides disrupt the structure of cellular lipids, making this barrier more permeable. Increased cellular permeability of GI-tract barrier contributes to the stimulation of the brain-gut axis. Pharmacological agents, affecting mucosal blood flow, such as cyclooxygenase (COX) products, COX inhibitors and pentoxifylline, are also able to modify functions of the brain-gut axis. We conclude that brain-gut axis plays a particularly important role in maintaining of mucosal barrier in GI-tract and alteration in its functions is implicated in pathogenesis of various diseases of the gut.

The optimal choice of general anesthesia technique for patients with obesity remains the subject of debate. At present, the anesthesia methods widely applied in clinical settings mainly consist of propofol-based intravenous anesthesia and sevoflurane-based inhalation anesthesia. For patients undergoing metabolic bariatric surgery, there is limited evaluation data concerning the overall recovery effect, and the conclusions are varied. This study aims to explore the difference between intravenous anesthesia and inhalation anesthesia in terms of the quality of early postoperative recovery in patients who undergo bariatric surgery. A total of 104 patients with obesity who underwent elective laparoscopic sleeve gastroplasty were randomly assigned two groups: the propofol (T) group and the sevoflurane (S) group. Five cases were excluded due to last-min changes in surgical plans, and finally 99 patients were included in the analysis (49 in Group S and 50 in Group P). In both groups, patients received propofol, remifentanil and rocuronium for induction. In Group P, anesthesia was maintained with intravenous propofol and remifentanil. In Group S, anesthesia was maintained with sevoflurane and remifentanil. The quality of recovery-40 (QoR-40) scale and the pain numerical rating scale (NRS), were used for evaluations before surgery and 24 and 48 h after surgery, and other relevant indicators were recorded. In results: compared with Group S, the QoR-40 score at 24 h in the Group P was significantly higher (161 and 150; P<0.001), indicating better recovery quality in the Group P than in the Group S. Among the five dimensions of the QoR-40, the Group P showed significantly better physical comfort, psychological support, and physical independence at 24 h postoperatively. No significant intergroup difference in QoR-40 scores was observed at 48 h postoperatively, and NRS scores were comparable between groups at both time points. The study results indicate that propofol intravenous anesthesia is associated with better recovery quality at 24 h after metabolic bariatric surgery, while the recovery difference between the two methods diminishes by 48 h.

The circular RNA collagen Vα1 chain (circCOL5A1) is highly expressed in renal cell carcinoma (RCC) and is a candidate marker, but the mechanism is unknown. According to bioinformatics, it is predicted to bind with miR-3940-3p, and karyopherin α2 (KPNA2), a carcinogenic molecule in RCC, could be its target gene. This study aims to clarify the mechanism of circCOL5A1 regulating KPNA2 on renal cell carcinoma (RCC) cells through miR-3940-3 p. circCOL5A1, miR-3940-3p and KPNA2 were detected by RT-qPCR, and epithelial-mesenchymal transition (EMT) markers were detected by Western blot. The characteristics of circCOL5A1 were verified by RNase R and actinomycin D experiments, and its subcellular localization was analyzed by PARIS kit. After transfection and intervention of 786-O cells, proliferation was assessed using Cell Counting Kit-8 (CCK-8) and colony formation experiments, migration and invasion were evaluated with scratch healing and Transwell assays, and apoptosis was measured through flow cytometry. Glucose uptake, lactic acid production, and ATP/ADP were measured by kits to evaluate glycolysis. The targeting relationship of circCOL5A1, miR-3940-3p and KPNA2 was verified by dual luciferase reporter gene assay and RNA immunoprecipitation (RIP) assay. In results: in RCC tissues/cells, circCOL5A1 and KPNA2 were significantly increased, and miR-3940-3p was significantly decreased (P<0.05). The stability of circCOL5A1 was higher than that of linear COL5A1, and it was mainly distributed in the cytoplasm (P<0.05). Silencing circCOL5A1 could inhibit the proliferation, migration and invasion of 786-O cells, promote apoptosis, down-regulate EMT markers (N-cadherin, Vimentin, Snail) and glycolysis (P<0.05), and up-regulate E-cadherin (P<0.05). CircCOL5A1 targeted miR-3940-3p, and miR-3940-3p targeted KPNA2 (P<0.05). miR-3940-3p inhibitor could reverse the effect of silencing circCOL5A1, and si-KPNA2 could reverse the effect of miR-3940-3p inhibitor (P<0.05). We concluded that the circCOL5A1/miR-3940-3p/KPNA2 axis was a key pathway for RCC progression. CircCOL5A1 promoted cell proliferation, migration, invasion, EMT and glycolysis by cytoplasmic adsorption of miR-3940-3p and up-regulation of KPNA2 in RCC. CircCOL5A1 is anticipated to be a promising molecular target for diagnosing and treating RCC.

This study was designrd to investigate the effect of curcumin on chondrosynovitis in knee osteoarthritis (KOA) rat models and to explore its mechanism of action. The damage of knee cartilage tissue was detected by haematoxylin and eosin (HE) staining, toluidine blue, safranin O-fast green and a scoring system by Mankin were used to assess the histopathological features of cartilage. Chondrocytic cells of apoptosis was visualized by TUNEL staining; inflammatory cytokines (interleukin-6, interleukin-1beta (IL-1β) and tumor necrosis factor alpha (TNF-α)) in the synovial fluid were examined by ELISA; immunohistochemistry (IHC) was used to detect cartilage oligomeric matrix protein (COMP) and fibroblast activation protein (FAP) expression was determined to evaluate cartilage damage and fibrosis. In comparison to the control group, rats induced by MIA demonstrated joint cartilage injury, chondrocyte apoptosis (P<0.001), and synovial inflammation (P<0.0001). However, when compared to the model group, curcumin administration significantly ameliorated cartilage damage, as evidenced by a reduction in Mankin score (P<0.0001), chondrocyte apoptosis (P<0.01), and levels of inflammatory factors (P<0.0001). In conclusion: monosodium iodoacetate (MIA) induction was employed to establish a KOA rat model. Treatment with curcumin improved synovial inflammation, reduced chondrocyte apoptosis, and decreased cartilage destruction in KOA rats.

Despite similar clinical effectiveness of tumor necrosis factor (TNF) inhibitors in the treatment of inflammatory joint diseases, they differ in effectiveness in other diseases and the exact mechanisms of their actions remain unclear. The aim of this study was to determine whether TNF inhibitors - etanercept and monoclonal antibodies affect intracellular cytokine production by T cell subsets. Anti-TNF-naive patients with inflammatory arthritis (rheumatoid arthritis or spondyloarthritis), characterized by high disease activity, were treated with TNF inhibitor - etanercept (14 patients) or monoclonal antibody (16 patients) for 12 weeks, while 11 patients received placebo. At baseline, 4, and 12 weeks after introducing anti-TNF treatment, intracellular production of TNF, interferon gamma (IFNγ), interleukin 17A (IL-17A), and IL-4 by T cell subsets was assessed using flow cytometry and analyzed by repeated measures two-way ANOVA. There were no differences in TNF, IFNγ, or IL-4-positive CD4, CD8, and CD3⁺CD4^-CD8^- (double negative, DN) cells between groups, neither while comparing effects of all TNF inhibitors jointly to placebo nor while analyzing effects in etanercept, monoclonal antibodies or placebo receiving groups. Similarly, there was no difference in IL-17A⁺CD4⁺ cells; however, a decrease in the percentage of IL-17A-positive DN T cells was observed in the etanercept-treated group (mean±SEM: 0.82±0.55, 0.41±0.16, 0.13±0.07) in comparison to placebo (0.23±0.10, 0.32±0.12, 0.49±0.15), (p=0.014), and an opposite; however, insignificant trend was observed in the monoclonal antibody-receiving group (0.41±0.13, 0.53±0.17, 0.82±0.3), (p=0.056 vs. etanercept). In summary, we ascertain that treatment with TNF inhibitors does not affect Th1, Th2, or Th17 responses. Etanercept and monoclonal antibodies differ in their effect on IL-17A+DN T cells.

Time-restricted feeding (TRF), a chrono-nutrition-based intervention, has shown promise in mitigating the adverse effects of high-fat diets (HFDs) on metabolic and hepatic health. This study evaluates the protective effects of TRF on hepatic gene expression, inflammatory markers, and serum adipocytokine levels in a rat model of HFD-induced hepatic steatosis. Forty male Wistar rats were divided into four groups: control, control + TRF, HFD, and HFD+TRF. The TRF was implemented as an 18-hour fasting period followed by a 6-hour feeding window for 12 weeks. Body composition, glucose homeostasis, lipid profiles, serum inflammatory markers, and adipocytokines (adiponectin, leptin, resistin) were measured. Hepatic oxidative stress markers (malodialdehyde, total antioxidant capacity) and gene expression of inflammatory mediators (nuclear factor-κB, tumor necrosis factor-α, interleukin-1β, interleukin-6, high-sensivity-C-reactive protein) were assessed. Histopathological analysis of liver tissue evaluated steatosis and p53 expression. TRF significantly reduced body weight in HFD-fed rats from 396.5±6.9 g to 350±6.4 g (p<0.0001). Homeostasis model assessment of insulin resistance (HOMA-IR) decreased from 2.03±0.06 to 0.72±0.05 (p<0.05), and hepatic malodialdehyde levels were reduced from 25 to 12.42 nmol/g (p<0.0001). TRF also downregulated inflammatory cytokines, including tumor necrosis factor-a and nuclear factor-κB, while increasing adiponectin levels and improving adiponectin/leptin and adiponectin/resistin ratios. Histological examination showed steatosis improved from grade 3 to grade 1 or 0. We found that RF effectively mitigates HFD-induced hepatic steatosis and metabolic dysfunction by reducing oxidative stress and inflammation and modulating adipocytokine balance. These findings highlight TRF's potential as a therapeutic strategy for managing hepatic and metabolic disorders.

Lower limb arterial disease is among the most common vascular disorders, with its incidence rising significantly in aging populations, thus posing a major social and healthcare challenge. Currently, L-arginine is considered by vascular surgery experts as a compound with therapeutic potential in intermittent claudication, though its clinical efficacy remains insufficiently confirmed. The aim of this study was to evaluate the efficacy and safety of oral L-arginine supplementation in patients with atherosclerotic lower limb ischemia, with particular regard to lipid metabolism disorders. A randomized study included 100 patients (62 men and 38 women) over 50 years of age with Fontaine stage II ischemia. The study group received oral L-arginine at a dose of 6 g/day for 30 and 60 days. Clinical parameters were assessed, including the ankle-brachial index (ABI) and pain-free walking distance (PFWD), along with oxidative stress markers (serum nitric oxide (NO) concentration, total antioxidant status (TAS)) and lipid profile (total, HDL, and LDL cholesterol, and triglycerides). In both study and control groups, subgroups with hypertriglyceridemia, hypercholesterolemia, and mixed hyperlipidemia were additionally identified. Evaluations were performed at baseline, day 30, and day 60. After 30 and 60 days, significant increases in NO and TAS levels (p<0.001), as well as extended PFWD (p<0.001), were observed across all subgroups receiving L-arginine compared with controls. No significant effects were observed on ABI (right or left) or on cholesterol and triglyceride concentrations. These findings support the potential role of L-arginine as a supportive therapy in the management of atherosclerotic complications, particularly by improving oxidative balance and exercise tolerance.

Endoglin is a transmembrane glycoprotein associated with endothelial dysfunction. Elevated serum levels of its soluble form (sENG) have been reported in conditions such as atherosclerosis and systemic inflammation. However, to the best of our knowledge, sENG level has not yet been evaluated in patients with Crohn's disease (CD). This study assessed serum sENG concentration and its association with clinical characteristics and various laboratory parameters in patients with active and inactive CD. A total of 48 patients with CD were enrolled in the study, 17 patients with inactive disease (Crohn's Disease Activity Index (CDAI) <150 points; median age: 34 years) and 31 patients with active disease (CDAI ≥150 points; median age: 36 years). Complete blood count, C-reactive protein (CRP), albumin, creatinine, ferritin, liver function tests, and sENG were measured. In our study, the serum level of sENG was significantly higher in patients with active CD compared to those with inactive disease (median, IQR, 0.63 (0.38-0.89) ng/ml vs 0.27 (0.2-0.48) ng/ml, p=0.004). No significant differences in sENG level was observed based on age at diagnosis, disease location, disease behavior, or current treatment. A significant negative correlation was found between sENG level and hemoglobin (r= -0,323, p=0.025), hematocrit (r= -0.286, p=0.049), and albumin concentrations (r= -0.386, p=0.011), while a positive correlation was observed with platelet count (r=0.302, p=0.037), CRP (r=0.316, p=0.028) and CDAI. A serum sENG concentration of 0.29 ng/ml was identified as the optimal predictive cutoff value for disease flare, with an area under the curve (AUC) of 0.748, sensitivity of 83.9%, and specificity of 64.7%. We found that serum level of sENG was significantly higher in patients with active CD and we conclude that SENG may serve as a potential marker of disease activity. However, further studies are needed to confirm this association.

Reduced sun exposure and inadequate dietary intake are major contributors to vitamin D deficiency in older adults. While vitamin D3 is well studied, the metabolic role of vitamin D2 (VD2) remains underexplored. This study investigated associations between serum VD2 and selected metabolic indices in an institutionalized elderly population. In our study 95 older adults (mean age: 63±14 years) were assessed for dietary intake, body composition, 25(OH)D, VD2, vitamin D receptor (VDR) protein, and hormones regulating energy homeostasis. Food intake was evaluated via a questionnaire and analyzed using dedicated software. Participants were overweight, with excessive caloric intake and insufficient protein and vitamin D consumption. Serum 25(OH)D concentrations indicated vitamin D deficiency (17.6±23.9 ng/mL). Serum VD2 showed significant positive correlations with insulin (r=0.87, p<0.001), adiponectin (r=0.41, p<0.001), leptin (r=0.22, p=0.034), and VDR (r=0.37, p<0.001), and a negative correlation with non-HDL cholesterol in women (r=-0.33, p=0.042). Principal component analysis (PCA) was used to reduce data dimensionality. In the full sample, two components were extracted. Multiple regression including age, gender, medication use, and PCA components showed that PC1 (with high loadings for insulin, leptin, adiponectin) and gender were significant predictors of VD2 levels, together explaining 41.6% of the variance. Among participants with HOMA-IR <2.5, indicating preserved insulin sensitivity, a single principal component - characterized by insulin, adiponectin, and leptin - explained 69.4% of the variance in VD2 levels. In conclusion, significant associations between VD2 and energy-regulating hormones suggest a potential physiological role for VD2 in metabolic homeostasis, particularly among individuals with preserved insulin sensitivity. The observed inverse relationship with non-HDL cholesterol in women additionally points to a possible involvement of VD2 in lipid metabolism. These findings underscore the importance of further investigation into the role of VD2 in endocrine and metabolic health among aging individuals.

Omentin-1 (ITLN1) is an adipokine involved in energy metabolism and insulin resistance; its expression has been demonstrated in the ovary, but its effect on ovarian endocrine function remains unknown. Therefore, this study aimed to determine the effect of ITLN1 alone or with follicle stimulating hormone (FSH) or luteinising hormone (LH) on secretion of progesterone (P⁴), testosterone (T), estradiol (E²); mRNA, protein expression of StAR, CYP11A1, HSD3B, CYP19A1; mRNA levels of receptors for gonadotropins and steroid hormones in ovarian follicle cells of normal weight Large White and fat Meishan pigs. Moreover, we studied the involvement of insulin receptor (INSR), extracellular signal-regulated kinase 1/2 (ERK1/2), protein kinase A (PKA) in ITLN1-mediated steroidogenesis. Ovarian follicle cells were treated with ITLN1 (10-100 ng/mL) alone or FSH/LH (100 ng/mL) preincubated or not with pharmacological inhibitors of INSR, ERK1/2, PKA to investigate the mechanism of ITLN1 action in ovarian cells. The concentration of steroids, mRNA and protein expression of steroidogenic markers were determined using ELISA, RT-qPCR or Western blotting. For E₂ secretion, StAR, HSD3B, CYP19A1 protein expression, all main effects of ITLN1 dose, breed, and their interactions were significant. When combined with FSH/LH, ITLN1 significantly influenced E₂, T secretion, CYP11A1 mRNA expression, StAR, CYP19A1 protein levels, with all main effects (FSH, LH, ITLN1 dose, breed) and interactions being significant. This suggests that ITLN1's impact on steroidogenesis is strongly dependent on breed, ITLN1 dose and hormonal context. Furthermore, the increase in E₂ synthesis indicates a potential role of ITLN1 in enhancing steroidogenesis, potentially via ERK1/2, PKA, and INSR pathways. Therefore, ITLN1 may play a role in the regulation of steroidogenesis in ovarian follicle cells.