舒尼替尼和雷米普利联合用药在大鼠体内的药代动力学相互作用

初步考察舒尼替尼和雷米普利联合用药在大鼠体内的药代动力学相互作用。18只雄性SD大鼠随机分成3组,分别灌胃给予舒尼替尼、雷米普利、舒尼替尼合用雷米普利,连续给药10 d,分别于给药第1天和第10天后不同时间点采集血样,用LC-MS/MS测定雷米普利拉和舒尼替尼的血药浓度,并计算二者药代动力学参数。单剂量联合用药时,与单用雷米普利相比,合用舒尼替尼后,雷米普利拉t_max显著减小,t_1/2显著增加,AUC_0-∞没有显著性差异,表明其吸收加快,消除减慢,但整体吸收程度不变。多剂量给药后,联合用药组雷米普利拉CL显著降低、AUC_0-∞显著增大,表明联合用药导致雷米普利拉在大鼠体内消除减慢,并有明显的蓄积。单剂量和多剂量联合用药后舒尼替尼的药代动力学行为都没有发生显著变化。结果显示,舒尼替尼和雷米普利联合用药后会导致雷米普利拉消除减慢,并且单剂量联合用药后其吸收变快,多剂量联合用药后其在体内有明显蓄积,提示二者存在一定的药代动力学相互作用。     

中西医结合治疗肝硬化腹水疗效观察

[目的]探讨中西医结合方法治疗肝硬化（LC）腹水的疗效。[方法]LC腹水患者62例,对照组28例,采用西医治疗;治疗组34例,西医治疗联合中医药治疗,比较两组患者的腹水消退情况。[结果]治疗组与对照组腹水消退率比较无统计学差异（P〉0.05）;治疗组腹水消退时间明显短于对照组,差异具有统计学意义（P〈0.05）。[结论]中医药在LC腹水的患者治疗中,对腹水的消退疗效显著。     

Melatonin protects N2a against ischemia/reperfusion injury through autophagy enhancement

Researches have shown that melatonin is neuroprotectant in ischemia/reperfusion-mediated injury.Although melatonin is known as an effective antioxidant,the mechanism of the protection cannot be explained merely by antioxidation.This study was devoted to explore other existing mechanisms by investigating whether melatonin protects ischemia/reperfusion-injured neurons through elevating autophagy,since autophagy has been frequently suggested to play a crucial role in neuron survival.To find it out,an ischemia/...     

Targeting whole body metabolism and mitochondrial bioenergetics in the drug development for Alzheimer's disease

Aging is by far the most prominent risk factor for Alzheimer's disease (AD), and both aging and AD are associated with apparent metabolic alterations. As developing effective therapeutic interventions to treat AD is clearly in urgent need, the impact of modulating whole-body and intracellular metabolism in preclinical models and in human patients, on disease pathogenesis, have been explored. There is also an increasing awareness of differential risk and potential targeting strategies related to biological sex, microbiome, and circadian regulation. As a major part of intracellular metabolism, mitochondrial bioenergetics, mitochondrial quality-control mechanisms, and mitochondria-linked inflammatory responses have been considered for AD therapeutic interventions. This review summarizes and highlights these efforts.     

Histone deacetylase inhibitors inhibit cervical cancer growth through Parkin acetylation-mediated mitophagy

Parkin, an E3 ubiquitin ligase, plays a role in maintaining mitochondrial homeostasis through targeting damaged mitochondria for mitophagy. Accumulating evidence suggests that the acetylation modification of the key mitophagy machinery influences mitophagy level, but the underlying mechanism is poorly understood. Here, our study demonstrated that inhibition of histone deacetylase (HDAC) by treatment of HDACis activates mitophagy through mediating Parkin acetylation, leading to inhibition of cervical cancer cell proliferation. Bioinformatics analysis shows that Parkin expression is inversely correlated with HDAC2 expression in human cervical cancer, indicating the low acetylation level of Parkin. Using mass spectrometry, Parkin is identified to interact with two upstream molecules, acetylase acetyl-CoA acetyltransferase 1 (ACAT1) and deacetylase HDAC2. Under treatment of suberoylanilide hydroxamic acid (SAHA), Parkin is acetylated at lysine residues 129, 220 and 349, located in different domains of Parkin protein. In in vitro experiments, combined mutation of Parkin largely attenuate the interaction of Parkin with PTEN induced putative kinase 1 (PINK1) and the function of Parkin in mitophagy induction and tumor suppression. In tumor xenografts, the expression of mutant Parkin impairs the tumor suppressive effect of Parkin and decreases the anticancer activity of SAHA. Our results reveal an acetylation-dependent regulatory mechanism governing Parkin in mitophagy and cervical carcinogenesis, which offers a new mitophagy modulation strategy for cancer therapy.     

补肾固本方对大鼠骨质疏松模型中PI3K/AKT/mTOR信号通路表达的调控研究

目的观察补肾固本方对去卵巢骨质疏松(osteoporosis,OP)大鼠骨组织中PI3K/AKT/mTOR信号通路的影响,探讨补肾固本方干预OP的作用机制。方法将100只SD大鼠随机分为5组:正常组(C组)、模型组(M组)、补肾固本方组(B组)、补肾固本方+PI3k受体特异性阻断剂LY294002组(B+L组)、PI3k受体特异性阻断剂LY294002组(L组),除正常组外,其余4组建立去卵巢大鼠OP模型。药物连续干预12周后,采用ELISA方法检测血清中E2、BGP、ALP水平,实时荧光定量聚合酶链式反应(Real-time PCR)检测各组股骨组织中LC3、Beclin1、caspase-9 mRNA的表达情况,蛋白质印迹法(Western blot)检测各组股骨组织中PI3K、AKT、mTOR蛋白的表达。结果补肾固本方可显著增高OP大鼠血清E2水平,降低BGP、ALP水平,显著上调LC3、Beclin1表达水平,降低caspase-9、PI3K、p-AKT、mTOR的表达;而上述变化能够被PI3k受体特异性阻断剂LY294002所阻断,且其差异具有统计学意义(P0.05)。结论补肾固本方减少去卵巢后大鼠OP的发生,其机制可能与抑制PI3K/AKT/mTOR信号通路及其下游基因蛋白表达有关。     

难切性胆囊的腹腔镜治疗

目的 探讨胆囊壶腹结石嵌顿伴胆囊积脓的腹腔镜胆囊切除（LC）的可行性及手术方法。方法 76例急性胆囊炎伴胆囊壶腹结石嵌顿胆囊积脓患者行LC。手术中见胆囊管增粗34例,阶梯施夹法11例,大号钛夹法9例,套扎线法4例,HOO-M-LOK结扎11例;手术中取出胆囊管结石9例,处理胆囊床出血6例;6例行胆囊前壁切除手术。结果 76例中LC全部成功,手术后均放置引流,手术后2例出现胆漏,经放置的腹腔引流管治愈,全组病例无术后出血,内脏损伤和胆道损伤等并发症发生。结论急性胆囊炎伴胆囊壶腹结石嵌顿和胆囊积脓患者LC手术可行,可达到LC的良好效果,不是LC手术的禁忌症。     

丙戊酸钠诱导人结肠癌细胞HT-29自噬及其机制研究

目的对丙戊酸钠诱导人结肠癌细胞HT-29发生自噬性死亡的过程进行观察,并初步探讨其可能的机制。方法用不同浓度、不同作用时间的丙戊酸钠处理人结肠癌细胞系HT-29,用细胞计数试剂盒CCK8法观察其对细胞增殖的抑制作用,丹酰戊二胺染色法观察细胞自噬,荧光测试仪检测自噬水平,荧光定量PCR法检测以下基因表达水平的变化：微管相关蛋白轻链3Ⅱ（LC3-Ⅱ）、自噬相关基因Beclin-1、哺乳动物雷帕霉素靶蛋白（mTOR）、磷酸化蛋白激酶B（p-Akt）和磷酸化核糖体蛋白S6激酶（p-p70S6K）。结果随着丙戊酸钠处理浓度的递增及作用时间的延长,其对人结肠癌细胞HT-29的增殖抑制率逐渐提高,呈剂量依赖性及时间依赖性（P均﹤0.01）;同时,随着药物浓度的增加,细胞中自噬泡数量增多,荧光强度增强,与对照组比较,差异有统计学意义（P均〈0.05）。经丙戊酸钠处理后,自2 mmol/L浓度始,人结肠癌细胞系HT-29自噬相关基因LC3-Ⅱ和Beclin-1表达水平明显升高（P均〈0.01）,而mTOR、p-Akt和p-p70S6K表达水平明显降低（P均〈0.01）。结论丙戊酸钠可诱导结肠癌细胞发生自噬,其诱导结肠癌细胞发生自噬的机制可能与阻断mTOR-Akt信号转导通路及激活Beclin-1信号转导通路有关。     

Beclin1和LC3在膀胱尿路上皮癌中的表达及意义

目的探讨Beclin1和微管相关蛋白1轻链3( LC3)在膀胱尿路上皮癌中的表达及两者的相关性。方法通过免疫组化法检测56例膀胱尿路上皮癌和32例正常膀胱组织的Beclin1和LC3表达,对比表达的差异。结果膀胱尿路上皮组织 Beclin1阳性表达率为66.1%(37/56),显著低于正常膀胱组织的93.8%(30/32),差异有统计学意义(P<0.01),而癌组织中LC3阳性表达率为50%(28/56),亦显著低于正常膀胱组织87.5%(28/32),差异有统计学意义(P<0.01);Beclin1和 LC3表达均与患者临床分期有关( P <0.01),与患者年龄、性别及肿瘤生长方式不具有相关性(P>0.05);Beclin1和LC3在膀胱尿路上皮癌中的表达具有正相关性( P <0.01)。结论膀胱尿路上皮癌中 Beclin1和LC3阳性表达率低于正常膀胱组织,两者可能均与膀胱尿路上皮癌的发生发展有关。     

恩丹西酮与地塞米松预防性治疗腹腔镜胆囊切除术后恶心呕吐的临床观察

目的：探讨恩丹西酮与地塞米松预防性治疗腹腔镜胆囊切除术后恶心呕吐的比较。方法：89例择期腹腔镜胆囊切除术者随机为恩丹西酮、地塞米松和生理盐水组。麻醉诱导及维持方法相同，诱导时三组分别注射恩丹西酮8mg、地塞米松10mg及生理盐水5ml。术后观察病人24h恶心、呕吐情况。结果：恩丹西酮和地塞米松组与生理盐水组相比＊P＜0．01，恩丹西酮组与地塞米松组相比＃P＞0．05。结论：恩丹西酮与地塞米松均能有效防治腹腔镜胆囊切除术后恶心呕吐，但恩丹西酮价格昂贵，地塞米松则比较低廉，有推广使用价值。