Attenuation of beta2-adrenergic receptors and homocysteine metabolic enzymes cause diabetic cardiomyopathy

Although adrenergic receptors (AR) and hyperhomocysteinemia (HHcy) are implicated in heart failure, their role in diabetic cardiomyopathy is not completely understood. We tested the hypothesis that glucose mediated depletion of beta2-AR and HHcy impair contractile function of cardiomyocytes leading to diabetic cardiomyopathy. To prove the hypothesis, cardiac function was assessed in 12 week male diabetic Ins2+/− Akita and C57BL/6 J mice by echocardiography, pressure-volume loop, and contractile function of cardiomyocytes. The results revealed cardiac dysfunction in Akita. To investigate the mechanism, the levels of beta2-AR, GLUT4, sarcoplasmic reticulum calcium ATP-ase-isoform 2 (SERCA-2) and homocysteine (Hcy) metabolic enzymes-cystathionine beta synthase (CBS), cystathionine gamma lyase (CTH), and methyl tetrahydrofolate reductase (MTHFR) were determined in the heart. It revealed down-regulation of beta2-AR, GLUT4, SERCA-2, CBS, CTH, and MTHFR in Akita. Attenuation of beta2-AR in hyperglycemic condition was also confirmed in cardiomyocytes at in vitro level. Interestingly, the ex vivo treatment of cardiomyocytes with beta2-AR antagonist deteriorated whereas beta-AR agonist ameliorated contractile function. It points to the involvement of beta2-AR in diabetic cardiomyopathy. We conclude that degradation of beta2-AR and impairment of Hcy metabolism is implicated in diabetic cardiomyopathy.     

右美托咪定复合小剂量艾司氯胺酮对髋骨骨折老年患者术后早期认知功能和应激反应的影响

摘要 目的：探讨右美托咪定复合小剂量艾司氯胺酮对髋骨折老年患者术后早期认知功能和应激反应的影响。方法：选取110例髋骨骨折老年患者，按照随机数字表法分为观察组（采用右美托咪定复合小剂量艾司氯胺酮麻醉）55例与对照组（采用右美托咪定麻醉）55例。观察两组的血流动力学、疼痛程度、应激反应、认知功能以及不良反应。结果：在T1、T2、T3、T4点，观察组患者的舒张压（diastolic blood pressure，DBP）、收缩压（systolic blood pressure，SBP）、心率（heart rate，HR）均低于对照患者（P<0.05）。观察组术后6 h、12 h、24 h疼痛评分均显著低于对照组（P<0.05）。麻醉前，两组患者的应激反应比较无统计学意义（P>0.05）；术后6 h，观察组去甲肾上腺素、促肾上腺皮质激素和皮质醇低于对照组患者（P＜0.05）。观察组术后1 d认知功能评分高于对照组（P<0.05）。两组恶心、呕吐、低血压、头痛等不良反应发生率比较无统计学意义（P>0.05）。结论：右美托咪定复合小剂量艾司氯胺酮能够提高髋骨骨折老年患者术后早期认知功能，维持稳定血流动力学，减轻疼痛感，改善应激反应，安全性较高。     

慢性鼻窦炎患者嗅觉障碍的危险因素探讨及其对患者心理健康和生存质量的影响

摘要 目的：探讨慢性鼻窦炎患者嗅觉障碍的危险因素及其对患者心理健康和生存质量的影响。方法：选取2017年9月~2020年9月期间首都医科大学附属北京同仁医院收治的120例慢性鼻窦炎患者进行嗅觉功能测试。统计嗅觉功能障碍患者的发生率，并依据嗅觉功能测试情况将患者分为嗅觉障碍组（n=64）和嗅觉正常组（n=56）。对两组患者的基础资料、临床资料、心理健康状况和生存质量等进行比较分析，采用单因素分析慢性鼻窦炎患者嗅觉障碍发生的影响因素，多因素Logistic回归分析慢性鼻窦炎患者嗅觉障碍发生的危险因素。结果：经嗅觉功能测试结果统计，120例患者中有64例患者出现嗅觉功能障碍，嗅觉障碍患病率为53.33%，其中男性有36例（56.25%），女性有28例（43.75%）；嗅觉下降46例(38.33%)、失嗅18例(15.00%)。单因素分析显示：鼻内镜手术史、伴鼻息肉、哮喘病史、嗜酸粒细胞比例、鼻内镜Lund-Kennedy评分是慢性鼻窦炎嗅觉障碍发生的影响因素(均P<0.05)。多因素Logistic回归分析表明：鼻内镜手术史、伴鼻息肉、哮喘病史、嗜酸粒细胞比例>5%、鼻内镜Lund-Kennedy评分≥2分是慢性鼻窦炎嗅觉障碍发生的独立危险因素。嗅觉正常组的焦虑自评量表（SAS）、抑郁自评量表（SDS）评分均低于嗅觉障碍组（P<0.05）。嗅觉正常组生活质量简表（SF-36）各维度评分均高于嗅觉障碍组（P<0.05）。结论：慢性鼻窦炎患者的嗅觉障碍发生率较高，鼻内镜手术史、伴鼻息肉、哮喘病史、嗜酸粒细胞比例>5%、Lund-Kennedy评分≥2分是影响患者嗅觉障碍发生的危险因素。同时嗅觉障碍还会引起患者抑郁焦虑等不良情绪，降低患者的生活质量。     

The APPswe/PS1A246E mutations in an astrocytic cell line leads to increased vulnerability to oxygen and glucose deprivation,Ca2+ dysregulation,and mitochondrial abnormalities

Growing evidence suggests a close relationship between Alzheimer′s Disease (AD ) and cerebral hypoxia. Astrocytes play a key role in brain homeostasis and disease states, while some of the earliest changes in AD occur in astrocytes. We have therefore investigated whether mutations associated with AD increase astrocyte vulnerability to ischemia. Two astroglioma cell lines derived from APP_SWE /PS 1A246E (APP , amyloid precursor protein; PS 1, presenilin 1) transgenic mice and controls from normal mice were subjected to oxygen and glucose deprivation (OGD ), an in vitro model of ischemia. Cell death was increased in the APP_SWE /PS 1A246E line compared to the control. Increasing extracellular calcium concentration ([Ca²⁺]) exacerbated cell death in the mutant but not in the control cells. In order to explore cellular Ca²⁺ homeostasis, the cells were challenged with ATP or thapsigargin and [Ca²⁺] was measured by fluorescence microscopy. Changes in cytosolic Ca²⁺ concentration ([Ca²⁺]_c) were potentiated in the APP_SWE /PS 1A246E transgenic line. Mitochondrial function was also altered in the APP_SWE /PS 1A246E astroglioma cells; mitochondrial membrane potential and production of reactive oxygen species were increased, while mitochondrial basal respiratory rate and ATP production were decreased compared to control astroglioma cells. These results suggest that AD mutations in astrocytes make them more sensitive to ischemia; Ca²⁺ dysregulation and mitochondrial dysfunction may contribute to this increased vulnerability. Our results also highlight the role of astrocyte dyshomeostasis in the pathophysiology of neurodegenerative brain disorders.

     

PDGF-mediated PI3K/AKT/β-catenin signaling regulates gap junctions in corpus cavernosum smooth muscle cells

Erectile dysfunction (ED) is the most common sexual disorder that men report to healthcare providers. Gap junctions (GJs) are thought to be responsible for synchronous shrinkage of corpus cavernosum smooth muscle cells (CCSMCs), and play thus an important role in the maintenance of an erection. Hypoxia has been suggested as a pathological mechanism underlying ED. Here we demonstrate that hypoxia increased the expression of platelet-derived growth factor (PDGF) and the main GJ component connexin (Cx)43 in CCSMCs. Inhibiting PDGF receptor (PDGFR) activity decreased Cx43 expression. Treatment with different concentrations of PDGF increased the levels of phosphorylated protein kinase B (AKT), β-catenin, and Cx43, whereas inhibition of PDGFR or activation of phosphatidylinositol 3 kinase (PI3K)/AKT signaling altered β-catenin and Cx43 expression. Meanwhile, silencing β-catenin resulted in the downregulation of Cx43. These results demonstrate that PDGF secretion by CCSMCs and vascular endothelial cells is enhanced under hypoxic conditions, leading to increased Cx43 expression through PI3K/AKT/β-catenin signaling and ultimately affecting GJ function in ED. Thus, targeting this pathway is a potential therapeutic strategy for the treatment of ED.     

Rewiring of Glutamine Metabolism Is a Bioenergetic Adaptation of Human Cells with Mitochondrial DNA Mutations

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