NaCL, Sodium chloride

NaCl,氯化钠
  • 文章类型: Journal Article
    计算机辅助方法的使用继续推动各种疾病模型加速药物发现,有趣的是,允许特异性抑制致病靶标。氯化物细胞内通道蛋白4(CLIC4)是一类与肿瘤和血管生物学密切相关的新型细胞内离子通道。它调节细胞增殖,细胞凋亡和血管生成;并参与多种病理信号通路。然而,缺乏特异性抑制剂阻碍了其向转化研究的发展。这里,我们整合了结构生物信息学和实验研究方法,以发现和验证CLIC4的小分子抑制剂.通过高性能计算驱动的盲对接方法,从1615个食品和药物管理局(FDA)批准的药物库中鉴定出高亲和力变构结合剂,导致选择两性霉素B和雷帕霉素。NMR测定证实了两种药物的结合和构象破坏作用,同时它们还逆转了应激诱导的CLIC4的膜易位并抑制了内皮细胞迁移。结构和动力学模拟研究进一步表明,这些化合物的抑制机制取决于催化谷胱甘肽(GSH)样位点环和延伸的催化β环的变构调节,这可能引起对CLIC4催化活性的干扰。来自本研究的基于结构的见解为CLIC4的选择性靶向治疗相关病理提供了基础。
    The use of computer-aided methods have continued to propel accelerated drug discovery across various disease models, interestingly allowing the specific inhibition of pathogenic targets. Chloride Intracellular Channel Protein 4 (CLIC4) is a novel class of intracellular ion channel highly implicated in tumor and vascular biology. It regulates cell proliferation, apoptosis and angiogenesis; and is involved in multiple pathologic signaling pathways. Absence of specific inhibitors however impedes its advancement to translational research. Here, we integrate structural bioinformatics and experimental research approaches for the discovery and validation of small-molecule inhibitors of CLIC4. High-affinity allosteric binders were identified from a library of 1615 Food and Drug Administration (FDA)-approved drugs via a high-performance computing-powered blind-docking approach, resulting in the selection of amphotericin B and rapamycin. NMR assays confirmed the binding and conformational disruptive effects of both drugs while they also reversed stress-induced membrane translocation of CLIC4 and inhibited endothelial cell migration. Structural and dynamics simulation studies further revealed that the inhibitory mechanisms of these compounds were hinged on the allosteric modulation of the catalytic glutathione (GSH)-like site loop and the extended catalytic β loop which may elicit interference with the catalytic activities of CLIC4. Structure-based insights from this study provide the basis for the selective targeting of CLIC4 to treat the associated pathologies.
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  • 文章类型: Journal Article
    由于偏头痛的高患病率,对个人和社会造成了巨大的负担,严重残疾,和可观的经济成本。目前偏头痛的治疗方案仍然不足,对疼痛机制的不完全理解严重阻碍了新疗法的发展。颅脑膜的感觉神经支配现在被认为是偏头痛发生的关键因素。最近的研究大大提高了我们对驱动脑膜伤害感受神经元的一些过程的理解,这可以在治疗上有针对性地中止或预防偏头痛。在这篇综述中,我们将总结我们目前对一种偏头痛亚型-先兆偏头痛的头痛发生机制的理解。我们将专注于动物研究,解决皮质扩散抑制是一个关键的过程,驱动脑膜伤害感受的先兆偏头痛的概念,并讨论对一些拟议的潜在机制的最新见解。
    Migraine results in an enormous burden on individuals and societies due to its high prevalence, significant disability, and considerable economic costs. Current treatment options for migraine remain inadequate, and the development of novel therapies is severely hindered by the incomplete understanding of the mechanisms responsible for the pain. The sensory innervation of the cranial meninges is now considered a key player in migraine headache genesis. Recent studies have significantly advanced our understanding of some of the processes that drive meningeal nociceptive neurons, which may be targeted therapeutically to abort or prevent migraine pain. In this review we will summarize our current understanding of the mechanisms that contribute to the genesis of the headache in one migraine subtype - migraine with aura. We will focus on animal studies that address the notion that cortical spreading depression is a critical process that drives meningeal nociception in migraine with aura, and discuss recent insights into some of the proposed underlying mechanisms.
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  • 文章类型: Journal Article
    这项工作的目的是研究五种精油(EO)的保护作用;迷迭香,胸腺,牛至紧致Benth。,球桉树。和罗勒;抵抗酿酒酵母中过氧化氢诱导的氧化应激。通过气相色谱(GC)和气相色谱-质谱(GC/MS)分析E0的化学组成。评估了体外抗氧化活性,并研究了EO的保护作用。用不同浓度的EOs(6.25-25μg/ml)预处理酵母细胞1小时,然后用H2O2(2mM)再孵育1小时。细胞活力,抗氧化剂(过氧化氢酶,超氧化物歧化酶和谷胱甘肽还原酶)和代谢(琥珀酸脱氢酶)酶,以及脂质过氧化(LPO)和蛋白质羰基含量(PCO)的水平进行了评估。EO的化学组成在定性和定量上都显示出差异。的确,O.compactum主要含有香芹酚,O.basilicum主要由芳樟醇组成,T.vulgaris富含百里酚,R.officinalis具有较高的α-pine含量,对于E.globulus,桉树脑是主要化合物。罗勒的EO,发现牛至和百里香的总酚类化合物含量最高。此外,它们对酵母细胞抗H2O2诱导的氧化应激表现出最佳的保护作用。此外,以酵母培养基中EOs的剂量依赖性方式,处理过的细胞LPO水平较低,抗氧化和代谢酶活性低于仅暴露于H2O2的细胞。细胞活力也得到改善。似乎所研究的EOs是有效的天然抗氧化剂,可用于防止与氧化应激相关的损害和严重疾病。
    The purpose of this work was to investigate the protective effect of five essential oils (EOs); Rosmarinus officinalis, Thymus vulgaris, Origanum compactum Benth., Eucalyptus globulus Labill. and Ocimum basilicum L.; against oxidative stress induced by hydrogen peroxide in Saccharomyces cerevisiae. The chemical composition of the EOs was analyzed by gas chromatography (GC) and gas chromatography-mass spectrometry (GC/MS). The in vitro antioxidant activity was evaluated and the protective effect of EOs was investigated. Yeast cells were pretreated with different concentrations of EOs (6.25-25 µg/ml) for an hour then incubated with H2O2 (2 mM) for an additional hour. Cell viability, antioxidants (Catalase, Superoxide dismutase and Glutathione reductase) and metabolic (Succinate dehydrogenase) enzymes, as well as the level of lipid peroxidation (LPO) and protein carbonyl content (PCO) were evaluated. The chemical composition of EOs has shown the difference qualitatively and quantitatively. Indeed, O. compactum mainly contained Carvacrol, O. basilicum was mainly composed of Linalool, T. vulgaris was rich in thymol, R. officinalis had high α-Pinene amount and for E. globulus, eucalyptol was the major compound. The EOs of basil, oregano and thyme were found to possess the highest amount of total phenolic compounds. Moreover, they have shown the best protective effect on yeast cells against oxidative stress induced by H2O2. In addition, in a dose dependent manner of EOs in yeast medium, treated cells had lower levels of LPO, lower antioxidant and metabolic enzymes activity than cells exposed to H2O2 only. The cell viability was also improved. It seems that the studied EOs are efficient natural antioxidants, which can be exploited to protect against damages and serious diseases related to oxidative stress.
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  • 文章类型: Journal Article
    纯药物组装纳米药物(PDAN)目前正在深入研究,作为有前途的癌症治疗纳米平台。然而,较差的胶体稳定性和较少的肿瘤归巢能力仍然是阻碍其临床转化的关键问题。在这里,我们报道了一种用于光动力治疗(PDT)的纤芯匹配纳米组装体(PPa).发现纯PPa分子自组装成纳米颗粒(NP),和两亲性PEG聚合物(PPa-PEG2K)用于通过π-π堆积效应和PPa核与PPa-PEG2K壳之间的疏水相互作用实现核匹配的聚乙二醇化修饰。与具有相似分子量的PCL-PEG2K相比,PPa-PEG2K显著增加稳定性,延长体循环,提高PPa纳米组装的肿瘤归巢能力和ROS生成效率。因此,PPa/PPa-PEG2KNP在带有4T1乳腺肿瘤的BALB/c小鼠异种移植模型中发挥有效的抗肿瘤活性。一起,这种核匹配的纯光敏剂纳米组装体为开发成像引导的热不可知纳米药物提供了新的策略.
    Pure drug-assembled nanomedicines (PDANs) are currently under intensive investigation as promising nanoplatforms for cancer therapy. However, poor colloidal stability and less tumor-homing ability remain critical unresolved problems that impede their clinical translation. Herein, we report a core-matched nanoassembly of pyropheophorbide a (PPa) for photodynamic therapy (PDT). Pure PPa molecules are found to self-assemble into nanoparticles (NPs), and an amphiphilic PEG polymer (PPa-PEG2K) is utilized to achieve core-matched PEGylating modification via the π‒π stacking effect and hydrophobic interaction between the PPa core and the PPa-PEG2K shell. Compared to PCL-PEG2K with similar molecular weight, PPa-PEG2K significantly increases the stability, prolongs the systemic circulation and improves the tumor-homing ability and ROS generation efficiency of PPa-nanoassembly. As a result, PPa/PPa-PEG2K NPs exert potent antitumor activity in a 4T1 breast tumor-bearing BALB/c mouse xenograft model. Together, such a core-matched nanoassembly of pure photosensitizer provides a new strategy for the development of imaging-guided theragnostic nanomedicines.
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  • 文章类型: Journal Article
    高血压是心血管疾病的最大危险因素,全球死亡的主要原因。由于血压调节受到多个生理系统的影响,高血压不能归因于单一可识别的病因。对孟德尔型高血压的三十年研究涉及肾小管钠处理的改变,特别是远端卷积小管(DCT)-原生,噻嗪类敏感Na-Cl协同转运蛋白(NCC)。NCC功能的改变已显示出对血压调节的深远影响,如分别在Gordon和Gitelman综合征中NCC的过度激活和失活所示。实质性进展揭示了影响NCC表达和活性的多种因素。特别是,NCC活性受磷酸化/去磷酸化控制,NCC的表达受糖基化促进,并受泛素化的负调控。研究甚至发现小白蛋白是NCC的意想不到的调节剂。近年来,我们对NCC控制机制的理解有了相当大的进步,特别是通过含有无赖氨酸[K](WNK)及其下游靶激酶的途径,SPS/Ste20相关的富含脯氨酸-丙氨酸激酶(SPAK)和氧化应激反应1(OSR1),这导致了新的抑制分子的发现。这篇综述总结了目前报道的NCC的调节机制,并讨论了它们作为高血压治疗靶点的潜力。
    Hypertension is the largest risk factor for cardiovascular disease, the leading cause of mortality worldwide. As blood pressure regulation is influenced by multiple physiological systems, hypertension cannot be attributed to a single identifiable etiology. Three decades of research into Mendelian forms of hypertension implicated alterations in the renal tubular sodium handling, particularly the distal convoluted tubule (DCT)-native, thiazide-sensitive Na-Cl cotransporter (NCC). Altered functions of the NCC have shown to have profound effects on blood pressure regulation as illustrated by the over activation and inactivation of the NCC in Gordon\'s and Gitelman syndromes respectively. Substantial progress has uncovered multiple factors that affect the expression and activity of the NCC. In particular, NCC activity is controlled by phosphorylation/dephosphorylation, and NCC expression is facilitated by glycosylation and negatively regulated by ubiquitination. Studies have even found parvalbumin to be an unexpected regulator of the NCC. In recent years, there have been considerable advances in our understanding of NCC control mechanisms, particularly via the pathway containing the with-no-lysine [K] (WNK) and its downstream target kinases, SPS/Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress responsive 1 (OSR1), which has led to the discovery of novel inhibitory molecules. This review summarizes the currently reported regulatory mechanisms of the NCC and discusses their potential as therapeutic targets for treating hypertension.
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  • 文章类型: Journal Article
    马齿莲地上部分的煎剂和输液。,尤其是叶子和茎,被尼日利亚的传统医学从业者用来提高人类的生育能力。关于将这种植物用于所述目的及其功效的文献的匮乏促使了这项研究。研究了马齿轮轴亲脂性和亲水性叶提取物对发情周期的影响,白化病大鼠在发情周期和卵巢和子宫组织形态学的各个阶段的女性性激素。
    实验动物随机分为7组,每组5只大鼠。A组(对照组)接受0.5毫升20%吐温80(载体),B组,C&D分别接受125、250和500mg/kg的亲脂性提取物,F&G分别接受125、250和500mg/kg的亲水性提取物21天。每天评估发情周期。最后,收集血液样本(激素)和卵巢和子宫切片(组织结构)。
    两种提取物对发情周期均无明显影响(p>0.05),卵巢和子宫组织结构和女性性激素,除了在发情期,其中记录到LH和FSH显着降低(p<0.05)。本研究中使用的P.oleracea可能对女性生殖系统产生有害影响,如发情期激素的破坏所示。这可以构成反驳使用紫花苜蓿叶提取物增强生育力的基础,因为它已被证明会影响与卵泡发生有关的促性腺激素。
    UNASSIGNED: Decoctions and infusions from the aerial parts of Portulaca oleracea Linn., especially the leaves and stems, are used by traditional medicine practitioners in Nigeria to enhance fertility in humans. The scarcity of literature on the use of this plant for the said purpose as well as its efficacy prompted this research. Study investigated effect of lipophilic and hydrophilic leaf extracts of Portulaca oleracea on oestrous cycle, female sex hormones at various phases of oestrous cycle and ovarian and uterine histomorphology in albino rats.
    UNASSIGNED: Experimental animals were randomly divided into 7 groups of 5 rats each. Group A (control) received 0.5 ml 20% Tween 80 (vehicle), groups B, C & D received 125, 250 & 500 mg/kg of the lipophilic extract respectively and E, F & G received 125, 250 & 500 mg/kg of the hydrophilic extract respectively for 21 days. Oestrous cycle was assessed daily. At the end, blood samples (for hormones) and ovarian &uterine sections (histoarchitecture) were collected.
    UNASSIGNED: Both extracts had no significant (p > 0.05) effect on oestrous cycle, ovarian & uterine histoarchitecture and female sex hormones except at proestrus phase where significant (p < 0.05) decrease in LH and FSH was recorded. P.oleracea as used in this study may have deleterious effect on female reproductive system as shown by the disruption of the hormones at proestrus phase. This can form a basis to refute the use of P.oleracea leaf extracts in enhancing fertility as it has been shown to affect the gonadotropins involved in folliculogenesis.
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  • 文章类型: Journal Article
    桌上的橄榄,橄榄树(OleaeuropaeaL.)的产品,是地中海饮食的重要发酵产品。农艺因素,尤其是品种,成熟阶段和加工方法是影响食用橄榄营养和非营养成分及其感官特性的主要因素。该产品的重要营养价值是由于其丰富的单不饱和脂肪(MUFA),主要是油酸,纤维和维生素E以及几种植物化学物质的存在。其中,羟基酪醇(HT)是所有类型食用橄榄中存在的主要酚类化合物。体外有一种稀缺性,表橄榄的体内和人体研究。这篇综述全面关注了食用橄榄的营养成分和生物活性化合物含量以及健康益处。与它们的消费相关的可能的健康益处被认为主要与MUFA对心血管健康的影响有关。维生素E的抗氧化(AO)能力及其在保护机体免受氧化损伤中的作用以及HT的抗炎和AO活性。还讨论了多种因素对最终产品组成的影响以及通过降低其最终盐含量来生产食用橄榄的潜在创新。
    Table olives, a product of olive tree (Olea europaea L.), is an important fermented product of the Mediterranean Diet. Agronomical factors, particularly the cultivar, the ripening stage and the processing method employed are the main factors influencing the nutritional and non-nutritional composition of table olives and their organoleptic properties. The important nutritional value of this product is due to its richness in monounsaturated fat (MUFA), mainly oleic acid, fibre and vitamin E together with the presence of several phytochemicals. Among these, hydroxytyrosol (HT) is the major phenolic compound present in all types of table olives. There is a scarcity of in vitro, in vivo and human studies of table olives. This review focused comprehensively on the nutrients and bioactive compound content as well as the health benefits assigned to table olives. The possible health benefits associated with their consumption are thought to be primarily related to effects of MUFA on cardiovascular health, the antioxidant (AO) capacity of vitamin E and its role in protecting the body from oxidative damage and the anti-inflammatory and AO activities of HT. The influence of multiple factors on composition of the end product and the potential innovation in the production of table olives through the reduction of its final salt content was also discussed.
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  • 文章类型: Journal Article
    左甲丙嗪(LMP)是一种具有强烈镇痛和镇静特性的酚噻嗪类神经安定药,在儿科中越来越多地使用,并作为新生儿重症监护的辅助疗法进行讨论。基础研究指出了酚噻嗪的神经保护潜力,但LMP对发育中的大脑的影响目前尚不清楚。本研究的目的是评估LMP作为已建立的健康和受损发育小鼠脑的新生儿体外和体内模型的药理学策略。体外,用媒介物或增加剂量的LMP预处理保持未暴露或谷氨酸损伤的HT-22细胞,并测定细胞活力。在体内,LMP的效果首先在5天大的健康人群中进行评估,接受单次腹膜内注射媒介物或不同剂量的LMP的未受伤的CD-1小鼠幼崽。第二步,小鼠幼崽遭受兴奋性脑损伤,随后用媒介物或LMP治疗。终点包括体测量数据以及组织学和免疫组织化学分析。体外,高剂量的LMP显着降低了暴露原始细胞中的细胞活力,但在谷氨酸损伤的细胞中未受影响。在体内,在健康的小鼠幼崽和遭受兴奋性毒性损伤的实验动物中均未观察到LMP的特定毒性作用,但接受高剂量LMP治疗后,体重增加显著降低.此外,LMP未能在受损的发育中的大脑中产生神经保护作用。在新生儿重症监护病房中常规临床使用LMP之前,需要进行其他研究。
    Levomepromazine (LMP) is a phenothiazine neuroleptic drug with strong analgesic and sedative properties that is increasingly used off-label in pediatrics and is being discussed as an adjunct therapy in neonatal intensive care. Basic research points towards neuroprotective potential of phenothiazines, but LMP\'s effect on the developing brain is currently unknown. The aim of the present study was to assess LMP as a pharmacologic strategy in established neonatal in vitro and in vivo models of the healthy and injured developing mouse brain. In vitro, HT-22 cells kept exposure-naïve or injured by glutamate were pre-treated with vehicle or increasing doses of LMP and cell viability was determined. In vivo, LMP\'s effects were first assessed in 5-day-old healthy, uninjured CD-1 mouse pups receiving a single intraperitoneal injection of vehicle or different dosages of LMP. In a second step, mouse pups were subjected to excitotoxic brain injury and subsequently treated with vehicle or LMP. Endpoints included somatometric data as well as histological and immunohistochemical analyses. In vitro, cell viability in exposure-naïve cells was significantly reduced by high doses of LMP, but remained unaffected in glutamate-injured cells. In vivo, no specific toxic effects of LMP were observed neither in healthy mouse pups nor in experimental animals subjected to excitotoxic injury, but body weight gain was significantly lower following higher-dose LMP treatment. Also, LMP failed to produce a neuroprotective effect in the injured developing brain. Additional studies are required prior to a routine clinical use of LMP in neonatal intensive care units.
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  • 文章类型: Journal Article
    丰富,低价格和高度减少的性质使甘油成为生产减少的生物化学品和生物燃料的理想原料。大肠杆菌作为微生物细胞工厂的平台,由于其高生长速率(提供较高的代谢物生产率)和利用多种碳源的能力而备受关注。然而,使用大肠杆菌作为平台的缺点之一是其在厌氧条件下的混合代谢物形成。在本研究中,研究表明,野生型大肠杆菌可以从甘油中专门生产乙醇,而d-乳酸可以完全由葡萄糖通过pflA产生。Cra突变体,其中与野生型菌株相比,该突变体可以增加葡萄糖摄取速率。还显示,在pflA中生长速率显著降低。cra突变体用于由于氧化还原失衡而使用甘油作为碳源的情况。在一定程度上阐明了发酵特性背后的代谢调节机制。
    Abundant, low prices and a highly reduced nature make glycerol to be an ideal feedstock for the production of reduced biochemicals and biofuels. Escherichia coli has been paid much attention as the platform of microbial cell factories due to its high growth rate (giving higher metabolite production rate) and the capability of utilizing a wide range of carbon sources. However, one of the drawbacks of using E. coli as a platform is its mixed metabolite formation under anaerobic conditions. In the present study, it was shown that ethanol could be exclusively produced from glycerol by the wild type E. coli, while d-lactic acid could be exclusively produced from glucose by pflA.cra mutant, where the glucose uptake rate could be increased by this mutant as compared to the wild type strain. It was also shown that the growth rate is significantly reduced in pflA.cra mutant for the case of using glycerol as a carbon source due to redox imbalance. The metabolic regulation mechanisms behind the fermentation characteristic were clarified to some extent.
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  • 文章类型: Journal Article
    帕金森病(PD),进行性神经变性,其特征是黑质(SN)中多巴胺能神经元的丢失和运动协调的丢失。在细胞功能和信号传导中起调节作用的主要脂质如磷脂的代谢受损与PD的病理学有关。我们的目的是研究鱼藤酮注入大鼠半帕金森病的纹状体磷脂(PLs)。由于没有成本效益的PL模式,我们首次在PD模型中利用染料-脂质复合技术进行筛查,并对脑样本中失调的PL水平进行半定量(单独).大鼠分为2组:i.对照组和ii.ROT输注,其接受鱼藤酮的颅内注射(6μg/μl;流速0.2μl/min)。在14天的实验期结束时,对纹状体进行解剖以进行PLs分析。进行了基于染料的PL检测和PL的二维薄层色谱分析。磷脂酰胆碱(PC)可以检测染料-PL复合物,磷脂酰肌醇(PI),和脊髓磷脂(SM)(但不适用于磷脂酰乙醇胺-PE),使用染料即维多利亚蓝B,甲苯胺蓝和硫氰酸铁铵,分别。磷脂的二维分析证实了染料-PL复合物,并描绘了半定量评估的显着减少(p<0.05),在对照和半帕金森病大鼠的纹状体中。我们建议使用经HR-LCMS验证的简单染料检测,大鼠纹状体中的PLs水平较低,尤其是PI。这一发现意味着这些PLs(PC,PI和SM)主要是PI(p<0.001),在鱼藤酮输注偏侧帕金森病中,因此,值得进行更广泛但更简单的调查来检测和确定它们在帕金森病中的作用。
    Parkinson\'s disease (PD), a progressive neurodegeneration, is characterized by loss of dopaminergic neurons in the substantia nigra (SN) and loss of motor co-ordination. Impaired metabolism of major lipids such as phospholipids which play regulatory roles in cellular functions and signaling has been implicated in the pathology of PD. We aim to investigate the striatal phospholipids (PLs) in hemiparkinsonism infused by rotenone in rats. As there are no cost-effective modes of PL, we have utilized dye-lipid complex technique for the first time in PD models for screening and also for semi-quantifying (individually) the levels of the deregulated PL in brain samples. Rats were divided into 2 groups: i. control and ii. ROT-infused which received intracranial injection of Rotenone (6 μg/μl; flow rate 0.2 μl/min). At the end of experimental period of 14 days, the striatum was dissected out for the analyses of PLs. Dye-based detection of PL and two-dimensional thin-layer chromatographic analyses of PL were performed. Detection of dye-PL complex was possible for phosphatidyl choline (PC), phosphatidyl inositol (PI), and spingomyelin (SM) (but not for phosphatidyl ethanolamine-PE) using dyes viz victoria blue B, toluidine blue and ammonium ferrothiocyanate, respectively. Two-dimensional analyses of phospholipids confirmed the dye-PL complex and depicted significant reduction (p < 0.05) on semi-quantitative assessment, in the striatum of control and hemiparkinsonic rats. We suggest a low level of PLs esp of PI in striatum of rats using a simple dye-detection that was validated by HR-LCMS. The finding implies that a critical role is being played by these PLs (PC, PI and SM) mainly PI (p < 0.001), in rotenone infused hemiparkinsonism, thus deserving wider but simpler investigations to detect and identify their role in parkinsonism.
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