Canadian journal of physiology and pharmacology最新文献

This work evaluated the combined effects of alpha-lipoic acid (ALA) and ischemic postconditioning (Post) on myocardial infarction and cell death in rats with chronic type-II diabetes following ischemia/reperfusion injury. The rats received a high-fat diet and were given one intraperitoneal injection of 35 mg/kg streptozotocin to induce chronic diabetes. They were then pretreated with ALA (100 mg/kg/day, orally) for 5 weeks before undergoing ischemia/reperfusion (I/R) insult. The hearts experienced 35 min regional ischemia through ligating the left anterior descending coronary artery, followed by 60 min reperfusion. The Post protocol involved 6 cycles of a 10/10 s algorithm, applied during the early stage of reperfusion. The use of Post alone did not significantly alter lactate dehydrogenase and infarct size levels, while ALA showed positive effects. Similar findings were observed for apoptotic changes with single treatments. However, the concurrent administration of ALA and Post significantly reduced the protein expressions of Bax, Bax/Bcl2, and cleaved caspase-3 while increasing Bcl2 expression. Additionally, the histopathological findings of the combined therapy were superior to those of single treatments. The concomitant use of ALA and Post effectively inhibited apoptosis, leading to cardiac recovery after I/R injury in diabetic conditions. This strategy could improve outcomes for preserving diabetic hearts following I/R insults.

This study hypothesized that acetate breaks the vicious cycle driving adipose-hepatic metabolic dysregulation in a rat model of polycystic ovarian syndrome (PCOS), possibly by suppression of nuclear factor-kappaB (NF-κB)/NOD-like receptor protein 3 (NLRP3) inflammasome. Female Wistar rats (8-week-old) were randomly allocated into four groups of n =6/group, which received vehicle, sodium acetate (200 mg), letrozole (1 mg/kg), and letrozole plus sodium acetate, respectively. The animals were treated by oral gavage, once daily for a period of 21 days. The PCOS animals were insulin-resistant, hyperandrogenic, and hypoestrogenic with decreased sex-hormone binding globulin. In addition, the hepatic tissue had increased lipid profile and decreased glycogen synthesis, while the adipose tissue showed decreased lipid profile with elevated glycogen synthesis. Besides, the results also showed increased malondialdehyde, γ-glutamyl transferase, lactate dehydrogenase, and inflammatory mediators with corresponding decrease in antioxidant defense in the hepatic and adipose tissues. Immunohistochemical evaluation also demonstrated severe expression with Bcl2-associated X protein/NLRP3 antibodies. Nonetheless, concomitant acetate supplementation attenuated these derangements. The present data collectively suggest that acetate ameliorates adipose-hepatic glycolipid dysregulation in experimental PCOS model by attenuating androgen excess and NF-κB/NLRP3 immunoreactivity.

Renovascular hypertension (RHV) is the cause of high blood pressure due to left renal ischemia, and obesity and hypertension cause an inflammatory response. This work analyzed the inflammatory and tissue repair profile in renal, hepatic, and cardiac tissues in an animal model of RVH associated with a high-fat diet and caloric restriction. The expressions of RORγ-t, IL-17, T-bet, and TNF-α decreased and IFN-γ increased in the right kidney. In relation to the left kidney, caloric restriction decreased the expression of IFN-γ. In the liver, caloric restriction decreased RORγ-t, IL-17, and T-bet. Hypertension associated with obesity decreased the expression of IFN-γ, while caloric restriction increased. In the right kidney, hypertension and obesity, associated or not with caloric restriction, increased the area of collagen fibers. In the heart and liver, caloric restriction reduced the area of collagen fibers. Caloric restriction increased vascular endothelial growth factor, reduced levels of growth transformation factor-β1 (TGF-β), and increased collagen I in the left kidney. Hypertension/obesity, submitted or not having caloric restriction, increased TGF-β in liver. The results suggest that caloric restriction has beneficial effects in lowering blood pressure and regulating tissue proinflammatory cytokines. However, there was no change in the structure and composition of tissue repair markers.

Vascular smooth muscle cells (VSMCs) phenotypic switching is identified as enhanced dedifferentiation, proliferation, and migration ability of VSMCs, in which microRNAs have been identified as important regulators of the process. The present study is aimed to explore the pathophysiological effect of miR-122 on VSMC phenotypic modulation. Here, the result showed that the decreased miR-122 expression was found in VSMCs subjected to platelet-derived growth factor-BB (PDGF-BB) treatment. Next, we investigated the response of miR-122 knockdown in VSMCs with PDGF-BB stimulation. MiR-122 silencing showed increased proliferation and migration capability, whereas attenuated the differentiation markers expression. The above results were reversed by miR-122 overexpression. Finally, we further demonstrated that FOXO3 was an important target for miR-122. Collectively, we demonstrated that miR-122 silencing promoted VSMC phenotypic modulation partially through upregulated FOXO3 expression that indicated miR-122 may be a novel therapeutic target for neointimal formation.

Ionizing radiation (IR) activates several signaling pathways. This study shows the impact of acute low-dose IR on crucial cytokines involved in cell-mediated immunity. The immunomodulatory effects of 0.25 and 0.5 Gray (Gy) gamma rays and standard immunomodulatory drugs (cyclophosphamide) on blood counts and significant pro-inflammatory cytokines implicated in various inflammatory conditions were tested in 20 rats. Examined was the effect of acute low doses on critical cytokines, which could be utilized as an alternative to current immunosuppressive drugs. One day post-irradiation, serum levels of interferon-gamma (INF-γ), tumor necrosis factor-alpha, and interleukin-2/1-beta were measured. A 0.25 Gy exposure did not affect the detected cytokines or blood cell count compared to the nonirradiated group. On the other hand, 0.5 Gy raises the majority of the immunologically examined cytokines except for INF-γ. Except for INF-γ, cyclophosphamide reduces all of the cytokines examined. As a result, low-dose IR has a less negative influence on essential inflammatory cytokines, permitting its use. More research is needed to determine how low amounts could be used in different immunological disorders.

The purpose of this study was to characterize the role of β₁-AR signaling and its cross-talk between cardiac renin-angiotensin system and thyroid-hormone-induced cardiac hypertrophy. T₃ was administered at 0.5 mg·kg^-1·day^-1 for 10 days in β1-KO_T3 and WT_T3 groups, while control groups received vehicle alone. Echocardiography and myocardial histology was performed; cardiac and serum ANGI/ANGII and ANP and cardiac levels of p-PKA, p-ERK1/2, p-p38-MAPK, p-AKT, p-4EBP1, and ACE were measured. WT_T3 showed decreased IVST_d and increased LVEDD versus WT_sal (p < 0.05). β1-KO_T3 exhibited lower LVEDD and higher relative IVST_d versus β1-KO_sal, the lowest levels of ejection fraction, and the highest levels of cardiomyocyte diameter (p < 0.05). Cardiac ANP levels decreased in WT_T3 versus β1-KO_T3 (p < 0.05). Cardiac ACE expression was increased in T₃-treated groups (p < 0.05). Phosphorylated-p38 MAPK levels were higher in WT_T3 versus WT_sal or β1-KO_T3, p-4EBP1 was elevated in β1-KO animals, and p-ERK1/2 was up-regulated in β1-KO_T3. These findings suggest that β₁-AR signaling is crucial for TiCH.

The effects of endothelin-1 (ET-1) on erythrocytes from sickle cell disease (SCD) patients have been described, but mechanisms of ET-1 regarding primary erythrocyte functions remain unknown. ET-1 is a vasoconstrictor peptide produced by endothelial cells, and the expression of ET-1 is increased in SCD. The present study used ex vivo experiments with sickle cell erythrocytes, ET-1, and bosentan, a dual antagonist of ET_A and ET_B receptors. We performed a hemoglobin S (HbS) polymerization assay with three concentrations of ET-1 (1, 20, and 50 pg/mL) and bosentan (100 nmol/L). ET-1 increased HbS polymerization at all concentrations, and this effect was suppressed by bosentan. For the deformability assay, red blood cells (RBCs) were incubated on a Sephacryl column with the same concentrations of ET-1 and bosentan. ET-1 decreased deformability, and this effect was reversed by bosentan. To observe erythrocyte adhesion, ET-1 and bosentan were incubated with RBCs in thrombospondin-coated 96-well plate, which demonstrated that ET-1 decreased adhesion but that bosentan enhanced adhesion. We also assessed erythrocyte apoptosis and observed decreased eryptosis induced by ET-1, and these effects were inhibited bosentan. Thus, these findings demonstrated that ET-1 modulates HbS polymerization, erythrocyte deformability, adhesion to thrombospondin, and eryptosis, and these effects were suppressed or enhanced by bosentan.