Patients with Parkinson's disease(PD) have impaired insulin signaling in the brain. Incretin hormones, including glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic polypeptide(GIP), can re-sensiti...Patients with Parkinson's disease(PD) have impaired insulin signaling in the brain. Incretin hormones, including glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic polypeptide(GIP), can re-sensitize insulin signaling. In a recent phase II clinical trial, the first GLP-1 mimic, exendin-4, has shown reliable curative effect in patients with PD. DA-CH5 is a novel GLP-1/GIP receptor unimolecular coagonist with a novel peptide sequence added to cross the blood-brain barrier. Here we showed that both exendin-4 and DA-CH5 protected against 6-hydroxydopamine(6-OHDA) cytotoxicity, inhibited apoptosis, improved mitogenesis and induced autophagy flux in SH-SY5Y cells via activation of the insulin receptor substrate-1(IRS-1)/alpha serine/threonine-protein kinase(Akt)/c AMP response element-binding protein(CREB) pathway. We also found that DA-CH5(10 nmol/kg) daily intraperitoneal administration for 30 days post-lesion alleviated motor dysfunction in rats and prevented stereotactic unilateral administration of 6-OHDA induced dopaminergic neurons loss in the substantia nigra pars compacta. However, DA-CH5 showed curative effects in reducing the levels of α-synuclein and the levels of pro-inflammatory cytokines(tumor necrosis factor-α, interleukin-1β). It was also more effective than exendin-4 in inhibiting apoptotic process and protecting mitochondrial functions. In addition, insulin resistance was largely alleviated and the expression of autophagy-related proteins was upregulated in PD model rats after DA-CH5 treatment. These results in this study indicate DA-CH5 plays a therapeutic role in the 6-OHDAunilaterally lesioned PD rat model and is superior to GLP-1 analogue exendin-4. The study was approved by the Animal Ethics Committee of Shanxi Medical University of China.展开更多
目的:以硫酸葡聚糖5000(dextran sulfate sodium3%D S S)诱导建立溃疡性结肠炎(u n c r e a t i v e colitis,UC)模型,研究γ-氨基丁酸(γ-aminobutyric acid,GABA)对实验性UC大鼠结肠离体平滑肌的影响.方法:Wistar大鼠17只随机分为正常...目的:以硫酸葡聚糖5000(dextran sulfate sodium3%D S S)诱导建立溃疡性结肠炎(u n c r e a t i v e colitis,UC)模型,研究γ-氨基丁酸(γ-aminobutyric acid,GABA)对实验性UC大鼠结肠离体平滑肌的影响.方法:Wistar大鼠17只随机分为正常组(6只)和模型组(11只).正常组饮用蒸馏水,模型组饮用含3%DSS的蒸馏水,诱导建立大鼠UC模型每天观察大鼠体质量和大便性状,进行疾病活动指数(disease activity index,DAI)评分,9 d后模型组UC模型建立.所有大鼠处死后观察大体形态改变,并自病变严重部位取组织标本HE染色,镜下观察结肠的病理学改变.同时取大鼠结肠平滑肌,以离体结肠收缩张力变化为指标观察,观察GABA、GABA A受体激动剂蝇蕈醇和GABA A受体拮抗剂荷包牡丹碱、GABA B受体拮抗剂巴氯酚对大鼠离体结肠平滑肌的影响.结果:模型组大鼠第5天出现大便形状改变30%为大便松散不成型,70%出现腹泻,为黄色稀便,第7天左右40%左右大鼠出现明显血便,活动及进食明显减少,病理学检查正常组大鼠结肠无黏连,黏膜轻度充血,无溃疡形成,镜下组织结构可见,腺体排列基本整齐;模型组大鼠腺体数目减少,组织结构紊乱,黏膜糜烂,出血、坏死和大面积深层溃疡.与正常组相比,模型组大鼠DAI(3.83±2.74 vs1.23±1.62,P<0.05),组织病理学评分(2.52±1.36 v s 0.41±0.74,P<0.05)显著升高;与加GABA前比较,GABA对正常大鼠和UC大鼠离体结肠平滑肌自主收缩活动均有抑制作用(P<0.05),0.01 mmol/L GABA和100 mmol/L G A B A对正常大鼠离体结肠平滑肌抑制率分别为20.00%±0.02%和67.60%±0.03%,0.01 mmol/L GABA和100 mmol/L GABA对溃疡性结肠大鼠离体结肠平滑肌抑制率分别为19.50%±0.02%和64.50%±0.05%,但G A B A对正常大鼠和U C大鼠离体结肠平滑肌自主收缩活动抑制作用差异无统计学意义(P>0.05).与加药前比较,0.01 mmol/L GABA A受体拮抗剂荷包牡丹碱能使大鼠离体结肠平滑肌收缩张力增大(1.25 g±0.03 g vs 0.77 g±0.04 g,P<0.05);与加药前比较,0.01 mmol/L GABA A受体激动剂蝇蕈醇能显著抑制大鼠离体结肠平滑肌张力(0.38 g±0.03 g vs 0.75 g±0.06 g,P<0.05);与加药前比较,0.01 mmol/L GABA B受体拮抗剂巴氯酚能显著抑制大鼠离体结肠平滑肌张力(0.45 g±0.05 g vs 0.75 g±0.04 g,P<0.05).结论:D S S可成功诱导建立大鼠U C模型,GABA对UC大鼠离体结肠平滑肌收缩起抑制作用.大鼠离体结肠平滑肌中存在GABA A受体以及GABA B受体,GABA作用于GABA A受体起抑制收缩作用,GABA作用于GABA B受体起收缩增强作用.展开更多
Background: After years of predictable outcomes with limited tools to combat the ravages of proteinuric chronic kidney disease (CKD) associated with or without diabetes, exciting new options are available to slow the ...Background: After years of predictable outcomes with limited tools to combat the ravages of proteinuric chronic kidney disease (CKD) associated with or without diabetes, exciting new options are available to slow the progression of CKD. Purpose: Focusing on sodium-glucose co-transporter 2 inhibitors (SGLT2), angiotensin receptor blockers (ARB), angiotensin converting enzyme inhibitors (ACE I), and new mineralocorticoid antagonists (MRA), this review examines how these agents compliment the standard of care in an attempt to educate and stimulate broader use of these agents. Methods: Using the search terms “mineralocorticoid antagonist, sodium glucose co-transporter 2 inhibitors, proteinuria, albuminuria, and diabetic kidney disease,” five randomized controlled clinical trials were identified and then analyzed in the context of the results found from the Irbesartan Diabetic Nephropathy Trial (IDNT). Two trials using SGLT2 and 2 using MRA were reviewed. Results: In the 2 SGLT2 trials renal outcomes were reduced by 30% - 39% among patients with estimated GFR ranging from roughly 25 - 90 mL/min. In the 2 MRA trials, renal outcomes fell by 13% - 18% among patients with estimated GFR ranging from 25 - 90 mL/min. In the IDNT, renal outcomes fell by 19%. Trial duration ranged from 28 - 41 months, and in all trials, the IDNT, Ace inhibitors (ACE I) and ARBs use was uniform. There is small overlap in the 5 trials in which both MRA and SGLT2 agents were used. Conclusions: Over a wide range of renal function, both MRA and SGLT2 inhibitors demonstrate outstanding efficacy in diabetic and non-diabetic (SGLT2) proteinuric kidney disease. Compared to the prior standard of care, these agents dramatically improve outcomes.展开更多
基金supported by the Doctoral Start-Up Foundation of Shanxi Province of China,No. SD1817 (to QQJ)。
文摘Patients with Parkinson's disease(PD) have impaired insulin signaling in the brain. Incretin hormones, including glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic polypeptide(GIP), can re-sensitize insulin signaling. In a recent phase II clinical trial, the first GLP-1 mimic, exendin-4, has shown reliable curative effect in patients with PD. DA-CH5 is a novel GLP-1/GIP receptor unimolecular coagonist with a novel peptide sequence added to cross the blood-brain barrier. Here we showed that both exendin-4 and DA-CH5 protected against 6-hydroxydopamine(6-OHDA) cytotoxicity, inhibited apoptosis, improved mitogenesis and induced autophagy flux in SH-SY5Y cells via activation of the insulin receptor substrate-1(IRS-1)/alpha serine/threonine-protein kinase(Akt)/c AMP response element-binding protein(CREB) pathway. We also found that DA-CH5(10 nmol/kg) daily intraperitoneal administration for 30 days post-lesion alleviated motor dysfunction in rats and prevented stereotactic unilateral administration of 6-OHDA induced dopaminergic neurons loss in the substantia nigra pars compacta. However, DA-CH5 showed curative effects in reducing the levels of α-synuclein and the levels of pro-inflammatory cytokines(tumor necrosis factor-α, interleukin-1β). It was also more effective than exendin-4 in inhibiting apoptotic process and protecting mitochondrial functions. In addition, insulin resistance was largely alleviated and the expression of autophagy-related proteins was upregulated in PD model rats after DA-CH5 treatment. These results in this study indicate DA-CH5 plays a therapeutic role in the 6-OHDAunilaterally lesioned PD rat model and is superior to GLP-1 analogue exendin-4. The study was approved by the Animal Ethics Committee of Shanxi Medical University of China.
文摘目的:以硫酸葡聚糖5000(dextran sulfate sodium3%D S S)诱导建立溃疡性结肠炎(u n c r e a t i v e colitis,UC)模型,研究γ-氨基丁酸(γ-aminobutyric acid,GABA)对实验性UC大鼠结肠离体平滑肌的影响.方法:Wistar大鼠17只随机分为正常组(6只)和模型组(11只).正常组饮用蒸馏水,模型组饮用含3%DSS的蒸馏水,诱导建立大鼠UC模型每天观察大鼠体质量和大便性状,进行疾病活动指数(disease activity index,DAI)评分,9 d后模型组UC模型建立.所有大鼠处死后观察大体形态改变,并自病变严重部位取组织标本HE染色,镜下观察结肠的病理学改变.同时取大鼠结肠平滑肌,以离体结肠收缩张力变化为指标观察,观察GABA、GABA A受体激动剂蝇蕈醇和GABA A受体拮抗剂荷包牡丹碱、GABA B受体拮抗剂巴氯酚对大鼠离体结肠平滑肌的影响.结果:模型组大鼠第5天出现大便形状改变30%为大便松散不成型,70%出现腹泻,为黄色稀便,第7天左右40%左右大鼠出现明显血便,活动及进食明显减少,病理学检查正常组大鼠结肠无黏连,黏膜轻度充血,无溃疡形成,镜下组织结构可见,腺体排列基本整齐;模型组大鼠腺体数目减少,组织结构紊乱,黏膜糜烂,出血、坏死和大面积深层溃疡.与正常组相比,模型组大鼠DAI(3.83±2.74 vs1.23±1.62,P<0.05),组织病理学评分(2.52±1.36 v s 0.41±0.74,P<0.05)显著升高;与加GABA前比较,GABA对正常大鼠和UC大鼠离体结肠平滑肌自主收缩活动均有抑制作用(P<0.05),0.01 mmol/L GABA和100 mmol/L G A B A对正常大鼠离体结肠平滑肌抑制率分别为20.00%±0.02%和67.60%±0.03%,0.01 mmol/L GABA和100 mmol/L GABA对溃疡性结肠大鼠离体结肠平滑肌抑制率分别为19.50%±0.02%和64.50%±0.05%,但G A B A对正常大鼠和U C大鼠离体结肠平滑肌自主收缩活动抑制作用差异无统计学意义(P>0.05).与加药前比较,0.01 mmol/L GABA A受体拮抗剂荷包牡丹碱能使大鼠离体结肠平滑肌收缩张力增大(1.25 g±0.03 g vs 0.77 g±0.04 g,P<0.05);与加药前比较,0.01 mmol/L GABA A受体激动剂蝇蕈醇能显著抑制大鼠离体结肠平滑肌张力(0.38 g±0.03 g vs 0.75 g±0.06 g,P<0.05);与加药前比较,0.01 mmol/L GABA B受体拮抗剂巴氯酚能显著抑制大鼠离体结肠平滑肌张力(0.45 g±0.05 g vs 0.75 g±0.04 g,P<0.05).结论:D S S可成功诱导建立大鼠U C模型,GABA对UC大鼠离体结肠平滑肌收缩起抑制作用.大鼠离体结肠平滑肌中存在GABA A受体以及GABA B受体,GABA作用于GABA A受体起抑制收缩作用,GABA作用于GABA B受体起收缩增强作用.
文摘Background: After years of predictable outcomes with limited tools to combat the ravages of proteinuric chronic kidney disease (CKD) associated with or without diabetes, exciting new options are available to slow the progression of CKD. Purpose: Focusing on sodium-glucose co-transporter 2 inhibitors (SGLT2), angiotensin receptor blockers (ARB), angiotensin converting enzyme inhibitors (ACE I), and new mineralocorticoid antagonists (MRA), this review examines how these agents compliment the standard of care in an attempt to educate and stimulate broader use of these agents. Methods: Using the search terms “mineralocorticoid antagonist, sodium glucose co-transporter 2 inhibitors, proteinuria, albuminuria, and diabetic kidney disease,” five randomized controlled clinical trials were identified and then analyzed in the context of the results found from the Irbesartan Diabetic Nephropathy Trial (IDNT). Two trials using SGLT2 and 2 using MRA were reviewed. Results: In the 2 SGLT2 trials renal outcomes were reduced by 30% - 39% among patients with estimated GFR ranging from roughly 25 - 90 mL/min. In the 2 MRA trials, renal outcomes fell by 13% - 18% among patients with estimated GFR ranging from 25 - 90 mL/min. In the IDNT, renal outcomes fell by 19%. Trial duration ranged from 28 - 41 months, and in all trials, the IDNT, Ace inhibitors (ACE I) and ARBs use was uniform. There is small overlap in the 5 trials in which both MRA and SGLT2 agents were used. Conclusions: Over a wide range of renal function, both MRA and SGLT2 inhibitors demonstrate outstanding efficacy in diabetic and non-diabetic (SGLT2) proteinuric kidney disease. Compared to the prior standard of care, these agents dramatically improve outcomes.
