黄葵胶囊联合海昆肾喜治疗慢性肾病的临床研究

目的 探讨黄葵胶囊联合海昆肾喜治疗慢性肾病的有效性和安全性。方法 选取2015年1月-2018年1月中国人民解放军总医院收治的慢性肾病患者113例,随机分为对照组（56例）和治疗组（57例）。对照组患者口服海昆肾喜胶囊,2粒/次,3次/d。治疗组患者在对照组基础上口服黄葵胶囊,5粒/次,3次/d。两组均连续治疗3个月。观察两组患者临床疗效,同时比较治疗前后两组患者血肌酐（Scr）、尿素氮（BUN）、24 h尿蛋白定量（Upro）、肾小球滤过率评估值（eGFR）、白细胞介素-6（IL-6）、超敏C-反应蛋白（hs-CRP）和肿瘤坏死因子-α（TNF-α）水平。结果 治疗后,对照组和治疗组临床有效率分别为78.57%和92.98%,两组比较差异具有统计学意义（P<0.05）。治疗后,两组患者Scr、BUN、Upro、IL-6、hs-CRP和TNF-α水平显著降低,eGFR水平显著升高,同组治疗前后比较差异具有统计学意义（P<0.05）,且治疗组各指标明显优于对照组,两组比较差异具有统计学意义（P<0.05）。结论 黄葵胶囊联合海昆肾喜可有效改善患者的肾功能及机体炎性状态,疗效安全显著,具有一定的临床推广应用价值。     

海昆肾喜胶囊联合氢氯噻嗪治疗慢性肾功能衰竭的临床研究

目的探讨海昆肾喜胶囊联合氢氯噻嗪片治疗慢性肾功能衰竭的临床疗效。方法选取2014年6月—2018年6月在漯河市第三人民医院治疗的慢性肾功能衰竭患者82例,根据用药的差别分为对照组(41例)和治疗组(41例)。对照组口服氢氯噻嗪片,25 mg/次,1次/d;治疗组在对照组基础上口服海昆肾喜胶囊,0.44 g/次,3次/d。两组患者均治疗8周。观察两组患者临床疗效,同时比较治疗前后两组患者症候积分、SF-36量表、APACHEⅡ量表、肾功能和血清学指标。结果治疗后,对照组和治疗组临床有效率分别为73.17%和95.12%,两组比较差异具有统计学意义(P0.05)。治疗后,两组症状积分均显著降低(P0.05),且治疗组这些症候积分明显低于对照组(P0.05)。治疗后,两组SF-36量表显著升高(P0.05),APACHEⅡ量表积分明显降低(P0.05),且治疗组SF-36和APACHEⅡ量表明显好于对照组(P0.05)。治疗后,两组患者尿素氮(BUN)、血肌酐(SCr)、尿微量蛋白(U-MTB)明显降低(P0.05),GFR显著升高(P0.05),且治疗组肾功能明显好于对照组(P0.05)。治疗后,两组患者血清胱抑素C(CysC)、β2-微球蛋白(β2-MG)、可溶性fms样酪氨酸激酶受体1(s FIt-1)、组织金属蛋白酶抑制因子-1(TIMP-1)水平明显降低(P0.05),且治疗组这些血清学指标明显低于对照组(P0.05)。结论海昆肾喜胶囊联合氢氯噻嗪片治疗慢性肾功能衰竭可有效改善患者临床症状及肾功能,促进患者生活质量改善,具有一定的临床推广应用价值。     

拟人参皂苷-F11对SAMP8小鼠认知障碍的改善作用及机制

目的阿尔茨海默病(AD)是一种常见的、以认知障碍为主要症状的中枢神经系统退行性疾病。β-淀粉样蛋白(Aβ)聚集形成的淀粉样斑块(SP)和过度磷酸化的Tau蛋白引发的神经原纤维缠结(NFT)是AD临床上的主要病理特征。拟人参皂苷F11(PF11)是西洋参茎叶中分离提取的一种三萜皂苷化合物,本文通过自发快速老化(SAMP8)模型小鼠,从Aβ沉积和Tau过度磷酸化等方面,结合神经行为学、免疫组织化学和蛋白质免疫印迹等手段,进一步评价PF11对AD模型动物认知障碍的改善作用及潜在机制。方法灌胃给予6月龄雄性SAMP 8快速衰老小鼠PF11(2,8和32 mg·kg~(-1)),在给药3个月后进行行为学实验,并检测APP和β-分泌酶(BACE1)、晚期内含体Rab7和循环内含体Rab11的表达。结果灌胃给予PF11(8和32 mg·kg~(-1))3个月可以显著改善SAMP8小鼠的识别记忆和空间学习记忆障碍,显著增加SAMP8小鼠海马和皮质中突触后致密蛋白95的水平;显著降低SAMP8小鼠海马和皮质中胞浆淀粉样蛋白前体蛋白(APP)和β-分泌酶(BACE1)的水平,减少海马和皮质中APP与晚期内含体(LE)的共定位,从而降低脑内Aβ的沉积;PF11可以显著提高SAMP8小鼠海马和皮质中异常降低的亮氨酸羧甲基转移酶(LCMT-1)水平,增加甲基化蛋白磷酸酶2A(PP2A)的水平,从而减少过度磷酸化的Tau。结论 PF11能够明显改善SAMP8小鼠的认知障碍,其机制与抑制海马和皮质脑区中APP淀粉样剪切途径进而减少Aβ沉积,以及增加PP2A活力进而减少Tau蛋白的过度磷酸化相关。     

荭草苷对APP/PS1转基因痴呆小鼠认知功能和海马自噬的影响

目的探究荭草苷对APP/PS1转基因小鼠认知功能的影响及其可能的作用机制。方法实验动物分为3组:7月龄的转基因模型组(Tg)、荭草苷处理转基因组(Tg+Ori)、同月龄的野生型C57BL/6J小鼠作为非转基因对照组(NT),每组8只。Tg+Ori组连续30 d每天腹腔注射荭草苷(10 mg·kg~(-1)),NT和Tg组注射同等剂量的生理盐水。水迷宫实验检测学习记忆能力,免疫组化检测β淀粉样蛋白(Aβ),免疫印迹检测自噬相关蛋白。结果与NT组相比,Tg组小鼠学习记忆能力受损,海马出现大量Aβ斑块, LC3-Ⅱ、p62、Cathepsin D蛋白表达升高;与Tg组相比,Tg+Ori组小鼠学习记忆能力增强,海马Aβ斑块减少,LC3-Ⅱ、p6、Cathepsin D蛋白水平降低;组间Beclin-1蛋白水平无明显差异。结论荭草苷能够改善转基因小鼠认知功能,减少海马Aβ沉积,促进自噬溶酶体降解。     

海昆肾喜胶囊联合复方α-酮酸片治疗慢性肾功能衰竭的临床研究

目的探讨海昆肾喜胶囊联合复方α-酮酸片治疗慢性肾功能衰竭的临床效果。方法选取2016月3月—2019年4月天津市第一中心医院收治的90例慢性肾功能衰竭患者,随机分为对照组和治疗组,每组各45例。对照组口服复方α-酮酸片,4片/次,3次/d,用餐期间整片吞服。治疗组在对照组基础上口服海昆肾喜胶囊,2粒/次,3次/d。两组均连续治疗2个月。观察两组的临床疗效,比较两组治疗前后肾功能指标、EQ-5D评分、血清学指标的变化情况。结果治疗后,对照组和治疗组的总有效率分别是82.2%、95.6%,两组比较差异具有统计学意义(P0.05)。治疗后,两组血清肌酐(Cr)、尿素氮(BUN)水平均显著降低,而内生肌酐清除率(Ccr)和白蛋白(ALB)均显著高于治疗前,同组治疗前后比较差异有统计学意义(P0.05);治疗后,治疗组血清Cr、BUN水平低于对照组,而Ccr值和ALB高于对照组,两组比较差异有统计学意义(P0.05)。治疗后,两组EQ-5D健康效用值、EQ-VAS评分均较治疗前显著升高,同组治疗前后比较差异有统计学意义(P0.05);治疗后,治疗组EQ-5D健康效用值、EQ-VAS评分高于对照组,两组比较差异有统计学意义(P0.05)。治疗后,两组血清白介素(IL)-8、脂质过氧化物(LPO)及C-反应蛋白(CRP)水平均显著下降,而谷胱甘肽过氧化物酶(GSH-Px)水平均显著增高,同组治疗前后比较差异有统计学意义(P0.05);治疗后,治疗组IL-8、LPO及CRP水平显著低于对照组,而GSH-Px水平高于对照组,两组比较差异有统计学意义(P0.05)。结论海昆肾喜胶囊联合复方α-酮酸治疗慢性肾功能衰竭的整体疗效显著,能有效改善患者肾功能,抑制机体炎性反应和氧化应激,提高患者生命质量,具有一定的临床推广应用价值。     

天胡荽积雪草苷对SAMP8小鼠学习记忆功能的改善作用

目的观察天胡荽积雪草苷(asiaticoside from Hydrocotyle sibthorpioides,AHS)对快速老化模型SAMP8小鼠学习记忆功能的影响及其可能机制。方法选用6月龄SAMP8小鼠75只,随机分为SAMP8空白组、阳性药石杉碱甲对照组和AHS低、中、高剂量组,每组15只;另选用6月龄SAMR1小鼠15只作正常对照。各组分别灌胃相应药物3个月后,采用Morris水迷宫法检测小鼠的学习记忆能力,采用Western blot测定Aβ1-42蛋白和可塑性相关蛋白在海马组织的表达水平,采用实时荧光定量PCR测定Aβ相关基因的表达。结果 AHS能明显提高小鼠的学习记忆能力。其机制研究表明,AHS明显降低脑组织Aβ1-42蛋白的含量,抑制Aβ相关基因APP、BACE1和CatB的表达,但提高NEP和IDE的水平;另外,AHS能明显提高突触可塑性相关蛋白包括突触后密度蛋白-95、磷-N-甲基-D-天门冬氨酸受体1、磷酸-钙-钙调素依赖性蛋白激酶Ⅱ、磷酸蛋白激酶A Cβ亚基、蛋白激酶Cγ亚单位、磷酸化CREB和脑源性神经营养因子的表达。结论 AHS能明显改善学习记忆功能,其机制可能与降低脑组织Aβ的形成与沉积、提高突触可塑性相关蛋白的表达有关。     

伐尼克兰通过PKR/STAT3通路调节自噬功能改善术后认知功能障碍

目的探讨伐尼克兰是否可以通过PKR/STAT3通路调节自噬,改善术后认知功能障碍。方法♂C57BL/6J小鼠随机分对照组(CON组)、剖腹探查组(LAP组)、伐尼克兰+剖腹探查组(Var+LAP组)和伐尼克兰组(Var组)。Var+LAP组和Var组从术前1 d给予伐尼克兰灌胃,持续至术后d 13;另外两组用等量生理盐水灌胃。于剖腹探查后d 10～12行新物体识别实验和d 14行Y迷宫实验。取海马组织,Western blot检测AT8、LC3B、p-PKR和p-STAT3的表达;免疫荧光染色检测AT8、LC3B、PKR和STAT3的表达。结果与CON组比较,LAP组小鼠逃往安全区的错误次数增加、进洞潜伏期延长、辨别指数降低,AT8和p-PKR表达增加,LC3B和p-STAT3表达降低,PKR和STAT3共定位增加;与LAP组比较,Var+LAP组小鼠逃往安全区的错误次数减少、进洞潜伏期缩短、辨别指数增加,AT8和p-PKR表达降低,LC3B和p-STAT3表达增加,PKR和STAT3共定位减少。结论伐尼克兰通过PKR/STAT3通路调节自噬,减少tau的磷酸化,改善术后认知功能障碍。     

表没食子儿茶素没食子酸酯对APP/PS1转基因小鼠认知功能和海马自噬的影响

目的探讨表没食子儿茶素没食子酸酯(EGCG)对APP/PSl转基因小鼠海马神经元自噬的作用。方法8月龄APP/PSl转基因小鼠随机分为模型组(Tg)、EGCG低剂量组(Tg/EGCG-L)、高剂量组(Tg/EGCG-H),同月龄C57BL/6J小鼠作为对照组(NT)。采用Morris水迷宫检测各组小鼠学习、记忆能力;Western blot检测各组小鼠海马ULK1、P62、LC3Ⅱ/LC3Ⅰ的蛋白表达;免疫组织化学方法检测mTOR的表达;ELISA法检测Aβ1-42水平。结果与NT组比较,Tg组小鼠寻找平台的逃避潜伏期延长及穿越目的象限的次数减少(P<0.05),海马ULK1表达降低、P62、LC3Ⅱ/LC3Ⅰ、Aβ1-42表达升高(P<0.05),EGCG治疗组较Tg组各异常指标均明显改善(P<0.05)。结论EGCG可以改善APP/PSl小鼠空间学习记忆能力,其机制可能与提高海马神经元自噬活性,减少脑内Aβ沉积有关。     

8-氮鸟嘌呤通过Akt/mTORC1/ULK1诱导细胞自噬增强其在肝癌细胞中的耐药性

细胞自噬是真核生物中进化保守的对细胞内容物进行降解的生理过程,其利用溶酶体将细胞内物质降解再利用,在应激条件下可以促进癌细胞的存活.8-氮鸟嘌呤(8-azaguanine,8-AG)是一种嘌呤核苷酸生物合成的抑制剂,对多种肿瘤细胞具有抗肿瘤活性.然而,耐药性限制了8-AG作为抗癌药物的应用,其耐药性机制尚不清楚.本研究...     

益气养阴化浊通络方对高糖诱导小鼠肾足细胞自噬ATG5、Beclin-1及BNIP3表达的影响

目的:观察益气养阴化浊通络方对高糖诱导的小鼠肾足细胞自噬相关蛋白5(autophagy-related protein 5,ATG5)、B细胞淋巴瘤-2蛋白相互作用中心卷曲螺旋蛋白1(B-cell lymphoma-2-interacting myosin-like coiled-coil protein 1,Beclin-1)及B淋巴细胞瘤-2基因/腺病毒E1B相互作用蛋白3(B-cell lymphoma-2/adenovirus E1 B interacting protein 3,BNIP3)表达的影响，探讨其对自噬的作用。方法:选取Wistar大鼠，分别灌胃20,40,80 g·kg^-1益气养阴化浊通络方及生理盐水，制备低、中、高浓度含药血清和空白血清。体外培养小鼠肾足细胞，分为正常对照组、高糖组、益气养阴化浊通络方低、中、高剂量组和雷帕霉素组。CCK-8法检测细胞增殖，细胞划痕检测细胞迁移能力，qRT-PCR和Western blot检测微管相关蛋白1轻链3B(microtubule-associated protein 1 light chain 3...     

益脑胶囊治疗阿尔茨海默病大鼠模型病理改变的研究

目的观察益脑胶囊治疗AICl3鞘内注射对阿尔茨海默病（Alzheimer’s disease,AD）模型大鼠学习记忆功能及病理改变,探讨其对AD大鼠的治疗机制。方法SD大鼠鞘内注射AlCl3,5d后拔管,末次注药28d后采用一次性避暗回避实验及病理学观察判断造模成功,益脑胶囊灌胃6个月后处死3组大鼠观察海马CA1区、顶叶皮层神经元形态、分布及利用免疫组化及原位杂交技术观察β-AP、β-APP、tau蛋白的阳性表达改变。结果AD模型组在避暗回避实验中错误次数增多,潜伏期缩短,免疫组化染色及原位杂交后β—AP、β—APP、tau蛋白阳性表达明显增多,与对照组比较差异有统计学意义（P〈0．05）,治疗组与对照组比较差异无统计学意义（P〉0．05）。结论益脑胶囊中人参皂甙及五味子酚抗氧化损伤作用可能是改善AD大鼠学习、记忆能力及病理改变的机制之一。     

五味子乙素抑制M146L细胞Aβ42生成的机制研究

目的研究五味子乙素抑制M146L细胞Aβ₄₂生成的机制。方法体外培养高效表达Aβ42的M146L细胞株，分别加入不同浓度的五味子乙素(1.67，5.00和15.00 μg·mL^-1)、 β分泌酶抑制剂(S4562，100.00 μg·mL^-1)和γ分泌酶抑制剂(S2188，13.68 μg·mL^-1)。用CCK-8(cell counting kit-8)比色法检测不同处理对M146L细胞活性的影响；用ELISA法测定M146L细胞所分泌的Aβ₄₂的变化；用Western blotting检测APP的β分泌酶剪切产物C99蛋白的含量变化，结合用β和γ分泌酶活性试剂盒，检测五味子乙素对这两种酶活性的影响。结果不同处理因素对M146L细胞的存活率均无影响，不具有细胞毒作用。中、高剂量的五味子乙素均不同程度地抑制M146L细胞分泌Aβ₄₂及γ分泌酶的活性，但都不改变M146L细胞C99蛋白的含量及β分泌酶的活性。结论五味子乙素可抑制γ分泌酶活性，其降低Aβ₄₂生成是通过抑制γ分泌酶的活性来实现的。     

酸性寡糖对阿尔茨海默病模型小鼠脑内基因表达的影响

目的应用基因芯片检测酸性寡糖971对阿尔茨海默病(AD)模型小鼠脑内基因表达谱的影响。方法 Balb/c小鼠随机分为对照组、AD模型组(β-AP_25-35侧脑室注射)和971给药组，采用Morris水迷宫测试小鼠行为学改变；提取各组小鼠大脑皮层总RNA，与含有1 176个基因的cDNA表达谱芯片进行杂交。并用RT-PCR对其中5个基因表达进行验证。结果AD模型组寻找平台潜伏期比对照组显著延长，给予971可使其明显缩短。基因芯片结果显示，模型组与对照组存在表达差异的基因共有31个，其中上调19个，下调12个；给药组与模型组存在表达差异的基因共有17个，其中上调13个，下调4个。RT-PCR结果显示基因变化趋势与芯片结果相符。结论酸性寡糖971改善AD模型小鼠学习记忆功能可能与DNA损伤修复、神经生长、突触可塑性、免疫应答等相关基因的表达变化有一定关系。     

Probiotics modulate the microbiota–gut–brain axis and improve memory deficits in aged SAMP8 mice

ProBiotic-4 is a probiotic preparation composed of Bifidobacterium lactis, Lactobacillus casei, Bifidobacterium bifidum, and Lactobacillus acidophilus. This study aims to investigate the effects of ProBiotic-4 on the microbiota–gut–brain axis and cognitive deficits, and to explore the underlying molecular mechanism using senescence-accelerated mouse prone 8 (SAMP8) mice. ProBiotic-4 was orally administered to 9-month-old SAMP8 mice for 12 weeks. We observed that ProBiotic-4 significantly improved the memory deficits, cerebral neuronal and synaptic injuries, glial activation, and microbiota composition in the feces and brains of aged SAMP8 mice. ProBiotic-4 substantially attenuated aging-related disruption of the intestinal barrier and blood–brain barrier, decreased interleukin-6 and tumor necrosis factor-α at both mRNA and protein levels, reduced plasma and cerebral lipopolysaccharide (LPS) concentration, toll-like receptor 4 (TLR4) expression, and nuclear factor-κB (NF-κB) nuclear translocation in the brain. In addition, not only did ProBiotic-4 significantly decreased the levels of γ-H2AX, 8-hydroxydesoxyguanosine, and retinoic-acid-inducible gene-I (RIG-I), it also abrogated RIG-I multimerization in the brain. These findings suggest that targeting gut microbiota with probiotics may have a therapeutic potential for the deficits of the microbiota–gut–brain axis and cognitive function in aging, and that its mechanism is associated with inhibition of both TLR4-and RIG-I-mediated NF-κB signaling pathway and inflammatory responses.     

In vitro antiglycating effect and in vivo neuroprotective activity of Trigonelline in d-galactose induced cognitive impairment

Background

Alzheimer’s disease (AD) is characterized by amyloid beta (Aβ) plaques, neurofibrillary tangles (NFTs) and cognitive impairment. Literature cites the role of advanced glycation end products (AGEs) in AD due to increased cytotoxicity via oxidative stress. d-galactose (d-gal) induced amnesia stimulates Aβ overproduction via increased oxidative stress and AGEs. Trigonelline (TRG), a naturally occurring alkaloid has been reported to have neuroprotective and antidiabetic properties.

Dopamine D1 receptor agonist A-68930 ameliorates Aβ1-42-induced cognitive impairment and neuroinflammation in mice

Alzheimer's disease (AD) is an irreversible neurodegenerative disease characterized by progressive cognitive dysfunction and memory impairment. Dopamine is an important catecholaminergic neurotransmitter that controls movement, reward, motivation, and cognition. Recently, dopamine receptors were reported to regulate immune system in both periphery and central nervous system. However, whether dopamine D1 receptor (DRD1) activation could improve neuroinflammation in AD conditions remains unknown. The present study aimed to investigate the therapeutic effects and underlying mechanisms of a potent and selective DRD1 agonist A-68930 on Aβ_1-42-induced mice. Here we showed that intraperitoneal injection of A-68930 significantly ameliorated Aβ_1–42-induced cognitive dysfunction in mice. Moreover, both in vivo and in vitro data showed that A-68930-induced DRD1 activation significantly inhibited NLRP3 inflammasome-dependent neuroinflammation induced by Aβ_1–42, and this effect may be mediated by the activation of AMPK/autophagy signaling pathway, which enhanced NLRP3 inflammasome degradation and thus decreased the secretion of IL-1β and IL-18. The present study suggests that A-68930-induced DRD1 signaling efficiently alleviates Aβ_1–42-induced cognitive impairment and neuroinflammation in mice and BV2 cells, and DRD1 may become a promising therapeutic target for AD.     

Challenges and hopes for Alzheimer’s disease

Recent drug development efforts targeting Alzheimer’s disease (AD) have failed to produce effective disease-modifying agents for many reasons, including the substantial presymptomatic neuronal damage that is caused by the accumulation of the amyloid β (Aβ) peptide and tau protein abnormalities, deleterious adverse effects of drug candidates, and inadequate design of clinical trials. New molecular targets, biomarkers, and diagnostic techniques, as well as alternative nonpharmacological approaches, are sorely needed to detect and treat early pathological events. This article analyzes the successes and debacles of pharmaceutical endeavors to date, and highlights new technologies that may lead to the more effective diagnosis and treatment of the pathologies that underlie AD. The use of focused ultrasound, deep brain stimulation, stem cell therapy, and gene therapy, in parallel with pharmaceuticals and judicious lifestyle adjustments, holds promise for the deceleration, prevention, or cure of AD and other neurodegenerative disorders.     

Prophylactic neuroprotective efficiency of co-administration of Ginkgo biloba and Trifolium pretense against sodium arsenite-induced neurotoxicity and dementia in different regions of brain and spinal cord of rats

The present study was carried out to evaluate the potential protective role of co-administration of Ginkgo biloba, Trifolium pretenseagainst sodium arsenite-induced neurotoxicity in different parts of brain (Cerebral cortex, Hippocampus, striatum and Hind brain) and in the spinal cord of rats. Sodium arsenite caused impairment in the acquisition and learning in all the behavioral tasks and caused significant increase in tumor necrosis factor-α,thiobarbituric acid-reactive substances andlipid profile, while caused significant decrease in glutathione, total thiol content, total antioxidant capacity, acetylcholinesterase, monoamine oxidase and ATPases activities. These results were confirmed by histopathological, fluorescence and scanning electron microscopy examination of different regions of brain. From these results sodium arsenite-induced neurodegenerative disorder in different regions of brain and spinal cord and this could be mediated through modifying the intracellular brain ions homeostasis, cholinergic dysfunction and oxidative damage. The presence of Ginkgo biloba and/orTrifolium pretense with sodium arsenite minimized its neurological damages. It was pronounced that using Ginkgo biloba and Trifolium pretense in combination was more effective as protective agents compared to use eachone of them alone.