氧化苦参碱的肾脏保护作用及其机制的研究进展

氧化苦参碱具有抗肾缺血再灌注损伤、抗内毒素性肾损伤、抗四氯化碳致慢性肾损伤、抗阿霉素肾病、抗输尿管梗阻大鼠肾间质纤维化和抗高糖、高脂诱导的肾脏纤维化的作用。氧化苦参碱肾脏保护作用的作用机制是抗氧化、抗炎、降血糖、调血脂作用,抑制活性氧(ROS)/TLR4、PERK/ATF4/CHOP、JAK2/STATs、TGF-β1/Smads和NF-κB/TNF-α信号通路,减轻肾损伤炎症反应和细胞外基质沉积,阻滞肾损伤和纤维化。     

苦参碱的心脏保护作用及其机制的研究进展

苦参碱对心脏具有正性肌力、负性频率和负性自律性的作用,因此具有广谱的抗心律失常作用。苦参碱对冠脉结扎缺血、缺血再灌注、异丙肾上腺素、高血脂、糖尿病和阿霉素引起的心肌损伤都有保护作用。苦参碱还能阻滞心肌肥大和纤维化的发生、发展。苦参碱保护心脏作用的基本机制是抗氧化、抗炎、降血糖、调血脂作用,由此抑制ROS/TLR4信号通路、PI3K/Akt信号通路和TGF-β诱导的PERK信号通路,激活Akt和STAT3信号通路和AMPKα/UCP2信号通路,上调JAK2/STAT3通路上的HSP70以及JNK、ASK1、e NOS和一氧化氮的表达,提高线粒体ATP酶活性,保护线粒体而减少心肌细胞凋亡、减轻心肌损伤和抑制胶原合成,从而抑制心肌肥大和纤维化。从抗各种心肌缺血性损伤、抗阿霉素诱导的心肌损伤、抗高糖性心肌损伤、抗心肌肥大和纤维化4个方面综述苦参碱的心脏保护作用及其机制。     

氧化苦参碱心脏保护作用的研究进展

氧化苦参碱对心脏具有正性肌力、负性频率和负性自律性的作用,因此具有广谱抗心律失常作用。氧化苦参碱对冠脉狭窄缺血、缺血再灌注以及异丙肾上腺素、阿霉素、感染和免疫引起的心肌损伤都有保护作用,并能阻滞心肌肥大和纤维化发生发展。氧化苦参碱心脏保护作用的基本机制是其抗氧化、抗炎和免疫抑制以及抑制盐皮质激素（醛固酮）受体的表达,产生心肌保护作用。即通过激活Nrf2/HO-1信号通路和抑制转化生长因子（TGF）-β1及I型TGF-β1受体的表达,从而抑制下游的JAK/STAT、MAPK/Smad2/3和Notch的信号通路的机制,减少心肌细胞凋亡,减轻心肌损伤和抑制胶原合成,产生抑制心肌肥大和纤维化的作用。     

肾脏纤维化相关细胞因子和信号通路

<正>肾脏纤维化是导致各种肾损伤的病因,是引起慢性肾脏病病情进展成终末期肾衰竭的病理损伤过程。各类原发,继发致肾损伤病因引起的慢性肾脏病,如肾病综合征、慢性肾小球肾炎、糖尿病肾病、高血压肾病等,病情进展成终末期肾衰竭,其实质就是肾脏固有细胞在炎症反应损伤之后,发生了纤维化和硬化。慢性肾脏纤维化的主要病理特征就是细胞外基质的过度沉积。肾脏纤维化的发生发展涉及多种信号通路和细胞因子。对这些细胞因子和信号通路的了解有助于以     

黄芪甲苷治疗肾脏疾病的研究进展

黄芪甲苷是中药黄芪的主要活性成分之一,研究证实具有抗氧化应激、抗炎、抗纤维化等作用,近年来研究发现黄芪甲苷与肾脏疾病的治疗关系密切,也与糖尿病肾病、慢性肾小球肾炎、高血压肾病、肾肿瘤、急性肾损伤等肾脏疾病具有相关性.本文简述黄芪甲苷与肾脏疾病的相关性.     

苦参碱防治高血糖、高血脂症及其并发症的药理机制研究进展

苦参碱可防治高糖、高脂引起的心血管并发症，脂肪肝并发症，糖尿病视网膜病变，糖尿病肾病以及肺、腹膜纤维化并发症。苦参碱防治这些并发症的药理机制可能是：（1）苦参碱的降血糖、调血脂及抗氧化作用，从源头上减少了氧化型低密度脂蛋白和晚期糖基化终末产物的生成；（2）苦参碱的抗氧化、抗炎和细胞保护作用可保护和修复β细胞，促进胰岛素合成与分泌，也可保护累及的心血管系统、肾脏、肝脏、肺和视网膜等其他器官，减轻胰岛素抵抗，提高胰岛素敏感性。因此，苦参碱有开发成为治疗代谢综合征新药的潜力。     

黄连素调节鞘氨醇激酶-1-磷酸鞘氨醇信号通路抗糖尿病小鼠肾损伤的研究

目的研究黄连素对四氧嘧啶诱导的糖尿病小鼠肾损伤的保护作用及其对糖尿病小鼠肾脏鞘氨醇激酶-1-磷酸鞘氨醇(SphK-S1P)信号通路的抑制效应。方法四氧嘧啶诱导的糖尿病小鼠采用黄连素(300 mg.kg-1.d-1)灌胃给药12周,正常组和糖尿病组小鼠给予同体积的溶媒。采用Re-al-time PCR技术检测肾组织中SphK1、TGF-β1、FN、ColⅣ的基因;Western blot法检测肾脏组织中SphK1、FN、ColⅣ的蛋白表达;LC-MS/MS检测肾脏组织中SphK1活性和S1P含量。结果黄连素明显抑制糖尿病小鼠血糖,肾重/体重比、血尿素氮、血肌酐和24 h尿蛋白异常增高;抑制肾脏肥大、纤维连接蛋白和Ⅳ型胶原积聚。此外,黄连素明显减少肾脏SphK1活性、mRNA和蛋白表达,降低S1P的生成。结论黄连素发挥抗糖尿病小鼠肾损伤的作用可能与抑制肾脏SphK-S1P信号通路的激活相关联。     

Wnt/β-catenin信号通路在急性肾损伤及慢性肾脏病中的作用

目的 Wnt信号通路参与生物胚胎发育、器官形成、组织再生等多种生理过程,是生物进化过程中高度保守的信号通路.在病理情况下,Wnt信号通路异常激活,参与多种疾病的病理过程并发挥不同作用.在急性肾损伤中,Wnt信号通路被激活,发挥肾脏保护作用,而在慢性肾脏疾病,Wnt信号通路可以促进肾脏纤维化及肾功能恶化的发生.本文就经典的wnt/β-catenin信号通路在急性肾损伤及慢性肾脏病中异常激活,发挥的不同作用及其机制进行综述.     

胰高糖素样肽-1类似物对糖尿病肾病的肾保护作用研究进展

胰高糖素样肽-1(GLP-1)类似物是目前用于治疗2型糖尿病较新的一类药物,动物模型和临床研究发现,GLP-1类似物对糖尿病肾病的肾功能也具有一定的保护作用,其机制主要来源于抑制细胞间黏附分子-1,减少巨噬细胞的滤过,抑制NF-κB活动以及抗炎和抗氧化等作用。此外,GLP-1还可以影响肾脏的水和电解质平衡。在安全性方面,尽管也有GLP-1类似物引起肾损伤的个案报道,但是多项研究结果表明,GLP-1类似物在轻中度的糖尿病肾病肾损伤患者中可以安全使用,但是对于重度肾损伤患者包括终末期肾病(ESRD)则不建议使用。     

氧化苦参碱抗慢性肝损伤的药理作用及其机制研究进展

氧化苦参碱具有抗高脂饮食性、CCl₄性、CCl₄/酒精性、二甲基亚硝胺性、半乳糖胺性、免疫性慢性肝损伤作用。氧化苦参碱是通过抗氧化、抗炎作用,减轻肝脏的氧化应激和炎症反应以及抑制成纤维细胞和肝星状细胞的活化以及细胞外基质生成,产生抗肝纤维化作用。氧化苦参碱还可通过促进胰岛素信号转导,改善胰岛素抵抗,抑制肝细胞吸收长链脂肪酸和脂肪酸合成并加速游离脂肪酸的β-氧化,产生抗脂肪肝作用。     

Affective and Anxiety Disorders and Alcohol and Drug Dependence:

Depression and anxiety frequently coexist in patients with substance use disorders. This clinically-oriented article examiens the relationship between these conditions and emphasizes data showing that substances of abuse can cause signs and symptoms of both depression and anxiety. These substance-related syndromes appear to have a different course and prognosis than uncomplicated, independent anxiety and major depressive disorders, and clinicians should consider the role of alcohol and other drugs in all patients presenting with these complaints. The authors will also outline an approach for diagnosing and managing patients with the combination of a substance use and depressive or anxiety disorder.     

Synthesis and anti-nociceptive and anti-inflammatory effects of gaultherin and its analogs

The synthesis of gaultherin (1) and its analogs was carried out to provide 11 glycosides under phase-transfer catalytic conditions. The activities of all synthesized compounds were evaluated by nitric oxide production inhibitory assay in vitro. Methyl 2-O-(4-O-β-d-galactopyranosyl)-β-d-glucopyranosylbenzoate (5f) showed significantly anti-nociceptive and anti-inflammatory effects by the evaluation in vivo. Structure–activity relationships within these compounds were discussed.     

Modelling and simulation of variability and uncertainty in toxicokinetics and pharmacokinetics

Two important methodological issues within the framework of the variability and uncertainty analysis of toxicokinetic and pharmacokinetic systems are discussed: (i) modelling and simulation of the existing physiologic variability in a population; and (ii) modelling and simulation of variability and uncertainty when there is insufficient or not well defined (e.g. small sample, semiquantitative, qualitative and vague) information available. Physiologically based pharmacokinetic models are especially suited for separating and characterising the physiologic variability from the overall variability and uncertainty in the system. Monte Carlo sampling should draw from multivariate distributions, which reflect all levels of existing dependencies in the intact organism. The population characteristics should be taken into account. A fuzzy simulation approach is proposed to model variability and uncertainty when there is semiquantitative, qualitative and vague information about the model parameters and their statistical distributions cannot be defined reliably.     

成骨细胞的功能与损伤和骨质疏松的防治

骨质疏松是一种全身性骨骼疾病,导致骨折风险增加。成人的骨量通过破骨细胞的骨吸收和成骨细胞的骨形成作用来维持动态平衡,治疗骨质疏松症的理想策略是抑制破骨细胞的骨吸收和/或增强成骨细胞的骨形成功能。目前针对保护成骨细胞及增强其功能的骨质疏松疗法相对较少。因此,本文针对成骨细胞相关功能蛋白、各种细胞损伤机制（内质网应激、氧化应激、机械过载、微小RNA和长链非编码RNA的影响等）及骨质疏松的治疗与预防作一综述,以期为针对增强成骨细胞功能的骨质疏松治疗策略提供新思路。     

Self-stimulation and amphetamine: Tolerance to d and l isomers and cross tolerance to cocaine and methylphenidate

The effects of the d and l isomers of amphetamine on self-stimulation responding were tested following acute and chronic administration. Tolerance and post-drug depression of responding occurred in tests with both isomers, indicating no role for p-hydroxynorephedrine (PHN) which is one of the metabolites of d-amphetamine. In the second experiment, d-amphetamine, methylphenidate and cocaine all produced quantitatively and qualitatively similar effects on self-stimulation responding following acute administration. Following chronic administration of d-amphetamine, animals showed tolerance to all three drugs, indicating cross-tolerance among them. These data are consistent with an hypothesis that tolerance and post-drug depression following chronic amphetamine treatment are the result of decreases in postsynaptic receptor sensitivity, which would lead to a decreased effectiveness of all three drugs, regardless of their pre-synaptic mechanisms.     

益生菌与肿瘤防治

益生菌广泛存在于自然界中,通过维持宿主体内菌群平衡、影响肠屏障功能和调节免疫应答等作用,提高宿主健康水平,被公认为"肠道健康卫士".一些益生菌可以增强机体的免疫功能,抑制致癌物质,影响肿瘤细胞的基因表达,对肿瘤具有拮抗作用.大量研究表明,益生菌在未来的肿瘤防治中有很好的应用和发展前景.     

Acamprosate and naltrexone treatment effects on ethanol and sucrose seeking and intake in ethanol-dependent and nondependent rats

Rationale  Two pharmacotherapies are approved for treating alcohol craving (acamprosate and naltrexone), but both have shown mixed findings in animals and humans. Objectives  The present experiments utilized a “reinforcer blocking” approach (i.e., rats were able to consume ethanol during treatment) to better understand the efficacy of these treatments for ethanol seeking and drinking using ethanol-dependent and nondependent rats. Materials and methods  In “nondependent” experiments, drugs (acamprosate 50, 100, and 200 mg/kg; naltrexone 0.1, 0.3, and 1.0 mg/kg) were administered over 3-week periods prior to operant sessions with a low response requirement to gain access to reinforcers for 20 min. For “dependent” experiments, rats were made dependent in vapor/inhalation chambers. Results  Acamprosate and naltrexone had similar effects on intake in nondependent and dependent rats; neither drug was selective for ethanol over sucrose drinking. In nondependent animals, naltrexone was more efficacious at more doses than acamprosate, and acamprosate’s effects were limited to a dose that also had adverse effects on body weight. Both pharmacotherapies showed more selectivity when examining reinforcer seeking. In nondependent rats, acamprosate and naltrexone had response-attenuating effects in ethanol, but not sucrose, groups. In dependent animals, acamprosate had selective effects limited to a decrease in sucrose seeking. Naltrexone, however, selectively decreased ethanol-seeking in nondependent rats. Conclusions  The naltrexone-induced decreases in seeking suggested a change in incentive motivation which was selective for ethanol in nondependent rats. The “nondependent” paradigm may model early stages of “problem drinking” in humans, and the findings suggest that naltrexone could be a good intervention for this level of alcohol abuse and relapse prevention.     

Antiinfective and encrustation-inhibiting materials--myth and facts

Catheters, urethral and ureteral stents and other urological implants are frequently affected by encrustration and infection due to their permanent contact with urine. Indwelling urinary catheters provide a haven for microorganisms and thus require extensive monitoring. Several surface modification techniques have been proposed to improve the performance of devices including the immobilization of biomolecules, the incorporation of hydrophilic grafts to reduce protein adsorption, the creation of hydrophobic surfaces, the creation of microdomains to regulate cellular and protein adhesion, new polymers and antimicrobial coatings. Physico-chemical explanation to elucidate the mechanism of such encrustation or infection inhibiting materials is still not available. Our series of experiments showed a marked decrease of silver-activity in biological fluids which corresponds with the controversial clinical results obtained with silver coated urinary catheters. Rifampicin/minocycline coated catheters had very low activity against Gram-negative rods, enterococci and Candida spp., the main causing organisms of urinary catheter infection. Surface engineered materials and antimicrobial drug delivery systems will be the next generation of sophisticated urinary catheters and stents, if both efficacy as well as efficiency has been proved clinically.     

Alprazolam and lorazepam single and multiple-dose effects on psychomotor skills and sleep

Summary The effects of alprazolam 0.5 mg and lorazepam 2 mg on cognitive and psychomotor skills were assessed in twelve normal volunteer subjects in a randomised, double-blind, crossover design. Single and multiple dose effects were monitored using a battery of tests comprising critical flicker fusion threshold (CFFT), choice reaction time (CRT), simulated car tracking, and subjective ratings of perceived sedation (LARS) and of sleep behaviour (LSEQ). Compared with placebo baseline scores, treatment with lorazepam 2 mg (both single and multiple doses) resulted in a widespread impairment of CRT, tracking accuracy, and CFFT. Single doses of alprazolam 0.5 mg reduced CFFT with respect to the placebo baseline. Single and multiple dose treatment with both drugs resulted in subjective reports of sedation, a reduction of sleep onset latency, and improved sleep quality. Only lorazepam 2 mg significantly disrupted the integrity of behaviour on waking from sleep. These results suggest important pharmacodynamic differences between the two drugs in the doses used.