L-Arginine and Alzheimer's Disease

Alzheimer''s disease (AD), the most common form of dementia, is characterized by progressive neurodegeneration and loss of cognitive and memory functions. Although the exact causes of AD are still unclear, evidence suggests that atherosclerosis, redox stress, inflammation, neurotransmitter dysregulation, and impaired brain energy metabolism may all be associated with AD pathogenesis. Herein, we explore a possible role for L-arginine (L-arg) in AD, taking into consideration known functions for L-arg in atherosclerosis, redox stress and the inflammatory process, regulation of synaptic plasticity and neurogenesis, and modulation of glucose metabolism and insulin activity. L-arg, a precursor of nitric oxide and polyamine, exhibits multiple functions in human health and may play a prominent role in age-related degenerative diseases such as AD.     

Nanoparticle-based targeted drug delivery

Nanotechnology could be defined as the technology that has allowed for the control, manipulation, study, and manufacture of structures and devices in the “nanometer” size range. These nano-sized objects, e.g., “nanoparticles”, take on novel properties and functions that differ markedly from those seen from items made of identical materials. The small size, customized surface, improved solubility, and multi-functionality of nanoparticles will continue to open many doors and create new biomedical applications. Indeed, the novel properties of nanoparticles offer the ability to interact with complex cellular functions in new ways. This rapidly growing field requires cross-disciplinary research and provides opportunities to design and develop multifunctional devices that can target, diagnose, and treat devastating diseases such as cancer. This article presents an overview of nanotechnology for the biologist and discusses the attributes of our novel XPclad^© nanoparticle formulation that has shown efficacy in treating solid tumors, single dose vaccination, and oral delivery of therapeutic proteins.     

Dopamine D2-Receptor-Mediated Increase in Vascular and Endothelial NOS Activity Ameliorates Cerebral Vasospasm After Subarachnoid Hemorrhage In Vitro

Introduction  Cerebral vasospasm after subarachnoid hemorrhage (SAH) is a serious complication resulting in delayed neurological deficit, increased morbidity, mortality, longer hospital stays, and rehabilitation time. It afflicts approximately 35 per 100,000 Americans per year, and there is currently no effective therapy. We present in vitro data suggesting that increasing intrinsic nitric oxide relaxation pathways in vascular smooth muscle via dopaminergic agonism ameliorates cerebral vasospasm after SAH. Methods  Cerebrospinal fluid (CSF) from patients with cerebral vasospasm after SAH (CSF_V) was used to induce vasospasm in porcine carotid artery in vitro. Dopamine was added to test its ability to reverse spasm, and specific dopamine receptor antagonists were used to determine which receptor mediated the protection. Immunohistochemical techniques confirmed the presence of dopamine receptor subtypes and the involvement of NOS in the mechanism of dopamine protection. Results  Dopamine receptor 1, 2, and 3 subtypes are all present in porcine carotid artery. Dopamine significantly reversed spasm in vitro (67% relaxation), and this relaxation was prevented by Haloperidol, a D₂R antagonist (10% relaxation, P < 0.05), but not by D₁ or D₃-receptor antagonism. Both eNOS and iNOS expression were increased significantly in response to CSF_V alone, and this was significantly enhanced by addition of dopamine, and blocked by Haloperidol. Conclusion  Cerebral vasospasm is significantly reversed in a functional measure of vasospasm in vitro by dopamine, via a D₂R-mediated pathway. The increase in NOS protein seen in both the endothelium and vascular smooth muscle in response to CSF_V is enhanced by dopamine, also in a D₂R-dependent mechanism.     

Genetic variability of the fatty acid synthase pathway is not associated with prostate cancer risk in the European Prospective Investigation on Cancer (EPIC)

A western lifestyle, characterised by low rates of energy expenditure and a high-energy diet rich in animal protein, saturated fats and refined carbohydrates, is associated with high incidence of prostate cancer in men. A high-energy nutritional status results in insulin/IGF signalling in cells, which in turn stimulates synthesis of fatty acids. We investigated whether the genetic variability of the genes belonging to the fatty acid synthesis pathway is related to prostate cancer risk in 815 prostate cancer cases and 1266 controls from the European Prospective Investigation on Cancer (EPIC). Using a tagging approach and selecting 252 SNPs in 22 genes, we covered all the common genetic variation of this pathway. None of the SNPs reached statistical significance after adjusting for multiple comparisons. Common SNPs in the fatty acid synthase pathway are not major contributors to prostate cancer risk.     

Fatty Acid Synthase Inhibitors from Plants and Their Potential Application in the Prevention of Metabolic Syndrome

Fatty acid synthase (FAS) attracts more and more attention recently as a potential target for metabolic syndrome,such as cancer, obesity, diabetes and cerebrovascular disease. FAS inhibitors are widely existed in plants, consisting of diversiform compounds. These inhibitors exist not only in herbs also in many plant foods, such as teas, allium vegetables and some fruits. These effective components include gallated catechins, theaflavins,flavonoids, condensed and hydrolysable tannins, thioethers,pentacyclic triterpenes, stilbene derivatives, etc, and they target at the different domains of FAS, showing different inhibitory mechanisms. Interestingly, these FAS inhibitor-contained herbs and plant foods and their effective components are commonly related to the prevention of metabolic syndromes including fatreducing and depression of cancer. From biochemical angle,FAS can control the balance between energy provision and fat production. Some studies have shown that the effects of those effective components in plants on metabolic syndromes are mediated by inhibiting FAS. This suggests that FAS plays a critical role in the regulation of energy metabolism, and the FAS inhibitors from plants have significant potential application value in the treatment and prevention of metabolic syndromes.     

脂肪酸合成酶抑制剂胖大海提取物对营养性肥胖大鼠的减肥作用

目的研究胖大海提取物对营养性肥胖大鼠的减肥作用。方法利用高脂营养饲料制备大鼠肥胖模型,观察胖大海提取物10、30和100 mg/kg 3个不同剂量对肥胖大鼠的减肥效果及对肝脏脂肪酸合成酶的影响。于实验结束时测定体质量、机体脂肪、食物消耗量、血清生物化学指标及肝脏脂肪酸合成酶活性指标,实验持续45 d。结果胖大海提取物100 mg/kg组大鼠体脂显著低于模型对照组(P<0.05);实验期间各剂量组大鼠的食物消耗量均低于模型对照组,且100 mg/kg组与模型对照组相比差异有统计学意义(P<0.05)。给予胖大海提取物组大鼠肝脏脂肪酸合成酶(fatty acid synthase,FAS)活性低于模型对照组,其中胖大海提取物30和100 mg/kg,2组与模型对照组相比差异有统计学意义(P<0.05)。结论胖大海提取物可抑制脂肪酸合成酶活性,抑制肥胖大鼠摄食量。     

急性脑梗死患者血浆超敏C-反应蛋白、一氧化氮及一氧化氮合酶水平的变化及其相关性

目的探讨急性脑梗死患者血浆超敏C-反应蛋白(high sensitive C-reactive protein,hsCRP)、一氧化氮(nitric oxide,NO)和一氧化氮合酶(nitric oxide synthase,NOS)水平的变化及其与病情严重程度的关系。方法分别应用乳胶增强散射比浊法和分光光度法对183例急性脑梗死患者(起病24 h内)血浆hsCRP、NO和NOS水平进行测定,并与56例健康对照和32例腔隙性脑梗死患者结果进行比较,分析急性脑梗死患者hsCRP、NO和NOS水平与神经功能损害程度的关系。患者神经功能缺失程度根据NIHSS量表评定。结果腔隙性脑梗死组血浆hsCRP水平高于对照组(P<0.05),NO和NOS水平低于对照组(P<0.05)。急性脑梗死组血浆hsCRP、NO和NOS水平均高于对照组和腔梗组(P<0.01);不同神经功能缺失组血浆hsCRP和NOS水平明显高于对照组;中度组和重度组血浆NO水平明显高于对照组,轻度组与对照组血浆NO水平差异无统计学意义;不同神经功能缺失程度各组之间血浆hsCRP、NO和NOS水平的差异有统计学意义(除中度组与重度组hsCRP比较P<0.05外,其余各组间比较P<0.01);急性脑梗死患者血浆hsCRP水平与NO及NOS水平呈明显正相关(r分别为0.848,0.833,P<0.01);血浆NO水平与NOS水平呈明显正相关(r=0.899,P<0.01)。结论 ACI患者血浆hsCRP、NO和NOS水平均显著升高,并与脑梗死严重程度密切相关,三者联合检测更有利于ACI的诊断和病情判断。     

五味子乙素对染矽尘大鼠肺组织一氧化氮水平和诱导型一氧化氮合酶mRNA表达动态变化的影响

目的观察五味子乙素(Sch-B)对染矽尘大鼠肺组织一氧化氮(NO)水平和诱导型一氧化氮合酶(iNOS)mRNA动态变化的影响。方法将96只大鼠随机分为对照组、染矽尘组、Sch-B组,每组32只,气管暴露法建立大鼠矽肺模型,造模后d 1开始灌胃给予Sch-B治疗,药物治疗3 d、7 d、14 d和28 d后,HE染色检测肺组织病理改变;硝酸还原酶法测肺组织NO含量;RT-PCR检测肺组织iNOS mRNA的表达。结果 HE染色显示Sch-B组大鼠肺损伤较染矽尘组明显减轻。NO含量和iNOS mRNA表达在染尘后各个时间点均较相应的对照组明显升高(P<0.01),其中NO含量在d 7时达到高峰后开始下降,iNOS mRNA的峰值出现在d 14。五味子组与染矽尘组相比,各时间点NO含量均明显降低(P<0.05或P<0.01),而iNOS mRNA表达仅在d 3和d 7时降低明显(P<0.05)。结论染矽尘大鼠肺组织存在着NO含量和iNOS mRNA的动态变化。Sch-B能减轻染矽尘大鼠肺组织的纤维化程度,其机制可能与染尘初期Sch-B降低iNOS mRNA转录水平,抑制NO炎症介质的合成与释放有关。     

Suppressive effects of methoxyflavonoids isolated from Kaempferia parviflora on inducible nitric oxide synthase (iNOS) expression in RAW 264.7 cells

Ethnopharmacological relevance

The rhizomes of Kaempferia parviflora Wall. ex Baker have been traditionally used in Thailand to treat abscesses, gout, and peptic ulcers.

Aim

Previously, we reported that the chloroform fraction of a Kaempferia parviflora extract had an inhibitory effect on rat paw-edema. In the present study, we isolated the constituents of this fraction and investigated the anti-inflammatory mechanism against nitric oxide (NO) production, tumor necrosis factor-α (TNF-α) and the expression of inducible nitric oxide synthase (iNOS) as well as phosphorylated extracellular signal-regulated kinase (p-ERK), and phosphorylated c-Jun N-terminal kinase (p-JNK). In addition, effects of trimethylapigenin (4) on the enzyme activities of protein kinases possibly leading to iNOS expression were examined to clarify the targets.

Materials and methods

The chloroform fraction was isolated using silica gel column chromatography and HPLC. Isolated compounds were tested against NO and TNF-α using RAW264.7 cells. Cytotoxicity and iNOS, p-ERK and p-JNK expression were also examined.

Results

Three active components, 5,7-dimethoxyflavone (2), trimethylapigenin (4), and tetramethylluteolin (5), markedly inhibited the production of NO in lipopolysaccharide (LPS)-activated RAW264.7 cells. Compounds 2, 4, and 5 moderately inhibited production of TNF-α. Compounds 2, 4, and 5 strongly inhibited expression of iNOS mRNA and iNOS protein in a dose-dependent manner, but did not inhibit p-ERK or p-JNK protein expression. The most active compound, 4, did not inhibit the enzyme activity of inhibitor of κB kinases or mitogen-activated protein kinases, but inhibited that of spleen tyrosine kinase (SYK).

Conclusion

The mechanism responsible for the anti-inflammatory activity of methoxyflavonoids from the chloroform fraction of the rhizomes of Kaempferia parviflora is mainly the inhibition of iNOS expression, and the inhibition of SYK by 4 may be involved in the suppression of LPS-induced signaling in macrophages.