Abstract Background Physical exercise is the first-line intervention for prediabetes, and metformin is the most widely used oral insulin-sensitizing agent. Moreover, intermuscular adipose tissue (IMAT) directly affects insulin resistance by helping maintain glucose homeostasis. Here, we evaluated the effects of moderate aerobic exercise and/or metformin on histological IMAT parameters in non-streptozotocin-induced prediabetes. Methods Male Wistar rats with prediabetes fed a high-fat diet and high-sugar drinks were randomly assigned to high-fat diet (PRE), metformin (MET), moderate aerobic exercise (EXE), combined therapy (EMC), or EMC + compound-c (EMA) groups for 4 weeks. Multimodal magnetic resonance imaging (MRI) was then performed, and tissue-specific inflammation and energy and lipid metabolism were evaluated in IMAT. Results The EXE group had lower inflammatory factor levels, lipid metabolism, and mitochondrial oxidative stress, and shorter IMAT adipocyte diameters than the MET group. The MET group exhibited lower IL-1β and Plin5 expression than the PRE group. Furthermore, the IMAT of the EMC group had lower TNF-α and phosphorylated NF-κB levels and higher GLUT1 and GLUT4 expression than the PRE group. Multimodal MRI revealed significant changes in transverse-relaxation time 2, apparent diffusion coefficient, and fractional anisotropy values in the IMAT and muscles, as well as lower IMAT% values in the EXE and EMC groups than in the MET and PRE groups. Conclusion Moderate aerobic exercise training can effectively improve IMAT function and structure via the AMP-activated protein kinase pathway in prediabetes. Combining metformin with moderate aerobic exercise might elicit modest synergy, and metformin does not counterbalance the beneficial effects of exercise.
Objective: To evaluate the value of super microvascular imaging(SMI) for evaluating the effect of interventional therapy of liver cancer. Methods: A total of 30 patients with 40 leisions were enrolled in this study, from the tumor intervention department in the third affiliated hospital of suzhou university.This patients were underwent TACE, after the treatment 1 month, CDFI, SMI, and CT were study respectively. Using the continuity correction McNemar matching chi-square test, with P < 0.05 for the standard , CDFI and SMI shows the difference in monitoring the microvascular imaging in and around the tumors leisions. Results: A total of 30 patients, 12 cases were primary liver cancer (7 cases combined with liver cirrhosis), 18cases were metastatic liver cancer; 30 cases including 25 single and 5 multiple. Significant difference were found between CT and SMI in detecting blood flows inside the lesion (χ² = 8.642 9, P < 0.05), and were also found between CT and CDFI in detecting blood flows inside the lesion (χ² = 16.961 5, P < 0.05). The AUROC, sensitivity, specificity, accuracy, PPV and NPV of CDFI were 0.647, 29.4%、100%、29.4%、100%、20.0%, while in SMI were 0.809, 61.8%、100%、61.7%、100%、31.5%, respectively. Conclusions: SMI SMI can detect the microvascular inside the lesions. This new method was superior to CDFI, achieving the same effect as CT.目的： 探讨超微细彩色血管成像(SMI)技术评价肝癌介入治疗疗效的临床应用价值。 方法： 选取30例肝肿瘤患者共40个病灶，均经肝穿刺病理学证实，在给予肝动脉化疗栓塞术（TACE）后1个月，分析彩色多普勒血流成像（CDFI）、SMI及增强CT的影像学差异，并以增强CT作为金标准，比较同一病灶的血供情况。数据采用经过连续性校正的McNemar配对χ(2)检验，以P < 0.05为标准比较CDFI技术与SMI技术显示瘤体内部与周边血流信号能力的差异。 结果： 30例肝癌患者，原发性肝癌12例（合并肝硬化7例），转移性肝癌18例；共40个瘤体，单发25例，多发5例（15个病灶）。CDFI与SMI在显示肝癌介入治疗后病灶内部残留细微血管的能力差异有统计学意义(χ(2) = 16.961 5，P < 0.01)，SMI显示病灶内部血流信号的能力与增强CT间差异有统计学意义(χ(2) = 8.642 9，P < 0.05)，SMI显示病灶周边血流信号的能力与增强CT间差异无统计学意义(χ(2) = 2.285 7，P > 0.05)。CDFI显示肝癌病灶内部与周边血流信号的灵敏度与SMI显示肝癌病灶内部与周边血流信号的灵敏度分别为29.40%、67.60%和61.80%、82.30%，特异度分别为66.70%、66.70%和83.30%、83.30%，正确指数分别为35.00%、67.50%和65.00%、82.50%。 结论： SMI技术是一种新型的血流成像技术，可检测到肝癌病灶内部与周边细微的血流信号，明显优于CDFI，达到与增强CT相近似的效果，为临床评估肝癌TACE术后疗效提供了一种新的方法。.
Hyperglycemia impairs endothelium-dependent vasodilation. In this study, we examined the effect of high glucose (HG) on vascular smooth muscle function. Rat small coronary arteries were freshly isolated or incubated for 24 h with normal glucose (NG; 5.5 mmol/l) or HG (23 mmol/l). In freshly isolated arteries, dilation to isoproterenol (Iso) was reduced by 3 mmol/l 4-aminopyridine (4-AP; 44 ± 10% vs. 77 ± 4%; P < 0.05) and further reduced by 4-AP + iberiotoxin (IbTX; 100 nmol/l; 17 ± 2%). Dilation to forskolin was abolished by 4-AP (–3 ± 17 vs. 73 ± 9%). cAMP production was similar in NG and HG vessels. Dilations to Iso and forskolin were significantly reduced in HG arteries (Iso, 41 ± 5% vs. 70 ± 6%; forskolin, 40 ± 4% vs. 75 ± 4%) compared with NG arteries. A similar reduction was also observed to the dilation to papaverine. Endothelial denudation had no effect on Iso-induced dilation. In HG vessels, the reduced 4-AP-sensitive component of Iso-induced dilation was greater compared with the IbTX-sensitive component. Iso increased whole cell K + current in NG cells but had little effect in HG cells. Similarly, 4-AP-, but not IbTX-sensitive, K + currents were reduced in HG cells. These results suggest that HG impairs cAMP-mediated dilation primarily by reducing K v channel function. We speculate that in addition to the endothelial dysfunction, altered smooth muscle function may also contribute to the reduced coronary vasodilation in diabetes.
The A1166C polymorphism is located within the microRNA-155 binding site of the human angiotensin II (Ang II) type-1 receptor (AGTR1) gene. The C allele interferes with the base-pairing complementariness between AGTR1 mRNA and microRNA-155 and thereby increases AGTR1 protein expression in vitro. We hypothesized that left ventricular (LV) mass is associated with the AGTR1 A1166C polymorphism.Among 708 individuals (mean age, 49.4 years; 51.8% women) randomly recruited in a white European population, we measured LV structure by two-dimensional guided M-mode echocardiography, the AGTR1 A1166C polymorphism and the 24-h urinary aldosterone. We applied a mixed model to assess phenotype-genotype associations while adjusting for covariables and accounting for relatedness.The AA (49.1%), AC (42.8%), and CC (8.1%) genotypes were in Hardy-Weinberg equilibrium. Using a recessive model, CC homozygotes compared to A-allele carriers showed significant increases (P < 0.021) in LV mass index (+5.78 ± 2.25 g/m(2)), mean wall thickness (MWT) (+0.48 ± 0.15 mm), interventricular septum (IVS) (+0.60 ± 0.18 mm) and posterior wall thickness (PWT) (+0.34 ± 0.15 mm), but lower 24-h urinary aldosterone excretion (geometric mean, 22.4 vs. 19.0 nmol; P = 0.050). Sensitivity analyses in 552 participants untreated for hypertension were confirmatory.LV mass index is associated with the AGTR1 A1166C polymorphism. Further research should clarify to what extent this association might be mediated via different expression of AGTR1 as modulated by microRNA-155.
Abstract The mechanism of ketamine-induced neurotoxicity development remains elusive. Mitochondrial fusion/fission dynamics play a critical role in regulating neurogenesis. Therefore, this study was aimed to evaluate whether mitochondrial dynamics were involved in ketamine-induced impairment of neurogenesis in neonatal rats and long-term synaptic plasticity dysfunction. In the in vivo study, postnatal day 7 (PND-7) rats were intraperitoneally injected with 40 mg/kg ketamine four consecutive times at 1 h intervals. Our work revealed that ketamine induced mitochondrial fusion dysfunction in hippocampal NSCs by downregulating Mfn2 expression. In the in vitro study, ketamine treatment at 100 µM for 6 h significantly decreased the Mfn2 expression, and increased ROS generation, decreased mitochondrial membrane potential and ATP levels in cultured hippocampal NSCs. For the interventional study, lentivirus (LV) overexpressing Mfn2 (LV-Mfn2) or control LV vehicle was microinjected into the hippocampal dentate gyrus (DG) 4 days before ketamine administration. Targeted Mfn2 overexpression in the DG region could restore mitochondrial fusion in NSCs and reverse the inhibitory effect of ketamine on NSC proliferation and its faciliatory effect on neuronal differentiation. In addition, synaptic plasticity was evaluated by transmission electron microscopy, Golgi-Cox staining and long-term potentiation (LTP) recordings at 24 h after the end of the behavioral test. Our work revealed that preconditioning with LV-Mfn2 improved long-term cognitive dysfunction after repeated neonatal ketamine exposure by reversing the inhibitory effect of ketamine on synaptic plasticity in the hippocampal DG. The present findings demonstrated that Mfn2-mediated mitochondrial fusion dysfunction plays a critical role in the impairment of long-term neurocognitive function and synaptic plasticity caused by repeated neonatal ketamine exposure by interfering with hippocampal neurogenesis. Thus, Mfn2 might be a novel therapeutic target for the prevention of the developmental neurotoxicity of ketamine.
Objective
To explore the effects and mechanisms of prenatal hypoxia on vasomotor functions of fetal rats.
Methods
Sixteen pregnant Sprague-Dawley rats were randomly divided into two groups: control and hypoxia groups (eight in each group). Rats in the hypoxia group were provided with 10.5% of oxygen from gestation day 5 to 21, while those in the control group were exposed to normoxic condition. Fetuses were removed from the pregnant rats by cesarean section on gestational day 21. Fetal body weight, blood gas and electrolyte levels were measured. Thoracic aorta rings were separated from fetal rats and used in different vascular function tests. Effects of hypoxia during pregnancy on angiotensinⅡ (AngⅡ)-mediated vasoconstrictions and acetylcholine (Ach)-mediated vasodilatations in fetal thoracic aortas were measured. Changes in vasomotor functions were observed after both endothelial nitric oxide synthase (eNOS) inhibitor NG-nitro-L-arginine methyl ester (L-Name) and L-type calcium channel (LTCC) inhibitor nifedipine were administered. T-test and two-way analysis of variance were used for statistical analysis.
Results
(1) Compared with the control group, fetal body weight [(4.40±0.23) vs (3.33±0.42) g, t=2.871], blood partial pressure of oxygen [(50.64±2.17) vs (42.50±2.32) mmHg (1 mmHg=0.133 kPa), t=2.618] and blood oxygen saturation [(58.95±1.97)% vs (47.73±2.24)%, t=3.564] in the hypoxia group were significantly reduced (all P<0.05). (2) Compared with the control group, AngⅡ-mediated vasoconstrictions increased, but Ach-mediated vasodilatations in fetal thoracic aortas decreased in the hypoxia group (both P<0.05). L-Name induced stronger AngⅡ-mediated contractions in thoracic aortas in the control group than that in the hypoxia group (P<0.05). However, nifedipine decreased AngⅡ-induced contractions, especially in the hypoxia group (P<0.05).
Conclusions
Maternal hypoxia during pregnancy not only affects the growth and development of fetuses but also changes their blood vessel functions, which may be related to the change of LTCC and the impairment of eNOS.
Key words:
Fetal hypoxia; Birth weight; Fetal development; Vasoconstriction; Vasodilation
Scope High salt (HS) diets are related to cardiovascular diseases, and prenatal HS was suggested to increase risks of coronary artery diseases in the offspring. This study tested the hypothesis that prenatal HS may influence Adenosine‐induced vasodilatation via protein kinase A (PKA) pathway in coronary arteries. Methods and results Sprague–Dawley rats were fed with 8% salt diet for gestation, the control was fed with 0.3% salt diet. Coronary arteries from male adult offspring were tested for K + channels and Adenosine signal pathways. Adenosine‐mediated vasodilatation was reduced in coronary arteries in HS. There was no difference in gene expression of A 2A receptors between the two groups. After pretreatment with PKA inhibitor, vasodilatation to Adenosine was decreased to a smaller extent in HS than that in control. Forskolin (activator of adenylate cyclase)‐mediated vasodilatation was decreased in HS. Iberiotoxin (large‐conductance Ca 2+ ‐activated K + channel [BK channel] inhibitor) attenuated Forskolin‐induced vasodilatation in control, not in HS group. Currents of BK channels decreased in coronary artery smooth muscle cells, and PKA‐modulated BK channel functions were declined. Protein levels of BK β1 and PKA C‐subunits in coronary arteries of HS offspring were reduced. Conclusions Prenatal HS diets altered Adenosine‐mediated coronary artery vasodilatation in the offspring, which was linked to downregulation of cAMP/PKA/BK channel pathway.
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