Current drug targets. CNS and neurological disorders最新文献_第8页

Central G-Protein Coupled Receptors (GPCR)s as molecular targets for the treatment of obesity: assets, liabilities and development status. 中心g蛋白偶联受体(GPCR)作为治疗肥胖的分子靶点:优势、劣势和发展现状

Current drug targets. CNS and neurological disorders Pub Date : 2004-10-01 DOI: 10.2174/1568007043337003

Keith J Miller, Brian J Murphy, Mary Ann Pelleymounter

引用次数: 16

Exercise in a pill: feasibility of energy expenditure targets. 药片运动:能量消耗目标的可行性。

Current drug targets. CNS and neurological disorders Pub Date : 2004-10-01 DOI: 10.2174/1568007043337076

J Himms-Hagen

{"title":"Exercise in a pill: feasibility of energy expenditure targets.","authors":"J Himms-Hagen","doi":"10.2174/1568007043337076","DOIUrl":"https://doi.org/10.2174/1568007043337076","url":null,"abstract":"The possibility of developing a pill to increase energy expenditure is explored by examining the metabolic processes involved. Such a pill should be targeted at organ systems involved in facultative thermogenesis. In rodents, these are brown adipose tissue (BAT) and skeletal muscle. Since BAT-mediated thermogenesis is not available in adult humans, emphasis here is on skeletal muscle. A hypothesis is presented based on three known facts: (1) plasticity of skeletal muscle, with interconversion of fiber types that differ in their fuel efficiency; (2) presence of thyroxine 5'-deiodinase type 2 (TD2) in human skeletal muscle; (3) gradual increase in thermogenesis that occurs during rehabilitation after starvation, probably in muscle. A low capacity thermogenic system, muscle efficiency thermogenesis (MET), is proposed to occur as adipose stores refill during the transition from famine to feasting to obesity. This system involves increased activity of TD2 and a T3-induced increase in proportion of type II fibers, less efficient at rest and during activity. The protective effect of this system is probably overwhelmed by long-term eating in excess of energy needs. Better understanding of the complex remodeling of differentiated muscle fibers in the conversions proposed and of the regulation of TD2 activity in human skeletal muscle may reveal targets for increasing energy expenditure in humans. In addition, the possibility of exploiting the plasticity of the adipose organ, with conversion of white adipocytes in white adipose tissue to atypical brown adipocytes and increasing thermogenesis in them is considered as another potential target for increasing energy expenditure in humans.","PeriodicalId":11063,"journal":{"name":"Current drug targets. CNS and neurological disorders","volume":"3 5","pages":"389-409"},"PeriodicalIF":0.0,"publicationDate":"2004-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24812952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 39

Gut hormones as peripheral anti obesity targets. 肠道激素作为外周抗肥胖靶点。

Current drug targets. CNS and neurological disorders Pub Date : 2004-10-01 DOI: 10.2174/1568007043336950

Caroline J Small, Stephen R Bloom

{"title":"Gut hormones as peripheral anti obesity targets.","authors":"Caroline J Small, Stephen R Bloom","doi":"10.2174/1568007043336950","DOIUrl":"https://doi.org/10.2174/1568007043336950","url":null,"abstract":"Many peptides are synthesised and released from the gastrointestinal tract. Whilst their roles in regulation of gastrointestinal function have been known for some time, it is now evident that they also influence eating behaviour and thus potential anti obesity targets. Peptide YY (PYY) is released post prandially from the gastrointestinal L-cells with glucagon-like peptide 1 (GLP-1) and oxyntomodulin. Following peripheral administration of PYY 3-36, the circulating form of PYY, to mouse, rat or human there is marked inhibition of food intake. PYY 3-36 is thought to mediate its actions through the NPY Y2 GPCR. Obese subjects have lower basal fasting PYY levels and have a smaller post prandial rise. However, obesity does not appear to be associated with resistance to PYY (as it is with leptin) and exogenous infusion of PYY 3-36 results in a reduction in food intake by 30% in an obese group and 31% in a lean group. GLP-1 or oxyntomodulin, products of the prepreglucagon gene, decrease food intake when administered either peripherally or directly into the CNS. In addition, both have been shown to decrease food intake in humans. These effects are thought to be mediated by the GLP-1 receptor. Ghrelin, a huger hormone produced by the stomach, increases in the circulation following a period of fasting. Administration of ghrelin either peripherally or directly into the CNS increases food intake and chronic administration leads to obesity. Further infusion into normal healthy volunteers increases both food intake and appetite. Ghrelin is thought to act through the growth hormone secretagogue receptor (GHS-R). Obesity is the current major cause of premature death in the UK, killing almost 1000 people a week. Worldwide its prevalence is accelerating. The administration of the naturally occurring gut hormone may offer a long-term therapeutic approach to weight control. Here we consider the therapeutic potential of some gut hormones, and the GPCR's through which they act, in the treatment of obesity.","PeriodicalId":11063,"journal":{"name":"Current drug targets. CNS and neurological disorders","volume":"3 5","pages":"379-88"},"PeriodicalIF":0.0,"publicationDate":"2004-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24812951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 27

Metabolic syndrome targets. 代谢综合征目标。

Current drug targets. CNS and neurological disorders Pub Date : 2004-10-01 DOI: 10.2174/1568007043337030

Steven R Smith

引用次数: 10

A perspective on the current strategies for the treatment of obesity. 肥胖症治疗的当前策略展望。

Current drug targets. CNS and neurological disorders Pub Date : 2004-10-01 DOI: 10.2174/1568007043336978

Steven V Joyal

{"title":"A perspective on the current strategies for the treatment of obesity.","authors":"Steven V Joyal","doi":"10.2174/1568007043336978","DOIUrl":"https://doi.org/10.2174/1568007043336978","url":null,"abstract":"The prevalence in obesity has increased dramatically over the past 30 years, more than double in the United States alone. Obesity is associated with an increased risk for type 2 diabetes mellitus, dyslipidemia, hypertension, biliary disease, obstructive sleep apnea, and certain types of cancer. The pathophysiology of obesity is complex, involving behavioral, environmental, and genetic factors. Current treatment options include behavior modification and lifestyle changes which incorporate weight-reducing diets and physical activity, FDA approved long-term anti-obesity pharmacological agents sibutramine and orlistat, non-FDA approved over-the-counter (OTC) supplements and nutriceuticals, and, when appropriate, bariatric surgery. Without adequate prevention and treatment of obesity, government agencies have suggested that the direct and indirect costs associated with obesity may overwhelm the healthcare system. This brief review explores the current data available on treatments for the obese patient including the relative merits of different types of macronutrient composition (e.g., low carbohydrate vs. high carbohydrate diets) of weight-reducing diets, the value of resistance/ strength training in physical activity programs designed for the obese patient, the safety and efficacy associated with OTC supplements and nutriceuticals for weight reduction (e.g., Ephedra, conjugated linoleic acid (CLA), Garcinia cambogia/ hydroxycitric acid (HCA), chromium, pyruvate), the safety and efficacy of FDA-approved long-term obesity treatments sibutramine and orlistat, and bariatric surgery.","PeriodicalId":11063,"journal":{"name":"Current drug targets. CNS and neurological disorders","volume":"3 5","pages":"341-56"},"PeriodicalIF":0.0,"publicationDate":"2004-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24812949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 35

The MAPK/JNK signalling pathway offers potential therapeutic targets for the prevention of acquired deafness. MAPK/JNK信号通路为预防获得性耳聋提供了潜在的治疗靶点。

Current drug targets. CNS and neurological disorders Pub Date : 2004-08-01 DOI: 10.2174/1568007043337166

A Zine, T R van de Water

{"title":"The MAPK/JNK signalling pathway offers potential therapeutic targets for the prevention of acquired deafness.","authors":"A Zine, T R van de Water","doi":"10.2174/1568007043337166","DOIUrl":"https://doi.org/10.2174/1568007043337166","url":null,"abstract":"The c-Jun N-terminal kinases (JNKs) are also called stress activated protein kinases (SAPKs) and are members of the family of mitogen activated protein kinases (MAPKs). While the functions of the JNKs under physiological conditions are diverse and not completely understood, there is increasing evidence that JNKs are potent effectors of apoptosis of oxidative stress-damaged cells in both the brain and the mammalian inner ear following a trauma. The activation of the inducible transcription factor c-Jun by N-terminal phosphorylation is a central event in JNK-mediated apoptosis of oxidative stress-damaged auditory hair cells following exposure to either acoustic trauma or a toxic level of an aminoglycoside antibiotic and also the apoptosis of auditory neurons as a consequence of a loss of the trophic support provided by the auditory hair cells. In this review, we summarise what is known about the expression and activation of G-proteins, JNKs, c-Jun and c-Fos under oxidative stress conditions within the mammalian cochlea. A particular focus is put on a new peptide conjugate that is a promising protective agent(s) and pharmacological strategies for preventing cochlear damage induced by both acoustic trauma and aminoglycoside ototoxic damage.","PeriodicalId":11063,"journal":{"name":"Current drug targets. CNS and neurological disorders","volume":"3 4","pages":"325-32"},"PeriodicalIF":0.0,"publicationDate":"2004-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24693241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 64

Cytokines in the central nervous system: targets for therapeutic intervention. 中枢神经系统中的细胞因子:治疗干预的靶点。

Current drug targets. CNS and neurological disorders Pub Date : 2004-08-01 DOI: 10.2174/1568007043337300

Bared Safieh-Garabedian, John J Haddad, Nayef E Saadé

引用次数: 21

Beyond estrogen: targeting gonadotropin hormones in the treatment of Alzheimer's disease. 超越雌激素:靶向促性腺激素治疗阿尔茨海默病。

Current drug targets. CNS and neurological disorders Pub Date : 2004-08-01 DOI: 10.2174/1568007043337265

Gemma Casadesus, Xiongwei Zhu, Craig S Atwood, Kate M Webber, George Perry, Richard L Bowen, Mark A Smith

{"title":"Beyond estrogen: targeting gonadotropin hormones in the treatment of Alzheimer's disease.","authors":"Gemma Casadesus, Xiongwei Zhu, Craig S Atwood, Kate M Webber, George Perry, Richard L Bowen, Mark A Smith","doi":"10.2174/1568007043337265","DOIUrl":"https://doi.org/10.2174/1568007043337265","url":null,"abstract":"Based on epidemiological and observational studies, estrogen and hormone-replacement therapy were until recently viewed as major factors in the prevention of Alzheimer's disease (AD). However, a recent randomized clinical trial revealed that hormone replacement therapy using estrogen plus progestin may actually exacerbate the incidence of dementia when administered to elderly women. These contradictory reports have cast grave doubt on the role of estrogen in disease pathogenesis and led us to consider an alternate hypothesis that would be consistent with both observations. Specifically, we suspect that hormones of the hypothalamic pituitary gonadal axis such as gonadotropins, that are regulated by estrogen (or in males by testosterone), are involved in the pathogenesis of Alzheimer's disease. One such gonadotropin, luteinizing hormone (LH), is significantly elevated in both the sera and brain tissue of patients with AD and leads to an increased production of amyloid-beta. Importantly, a key role in disease pathogenesis is further supported by the fact that the distribution of neuronal receptors for LH parallels those populations of neurons that degenerate during the course of the disease. That gonadotropins, not estrogen nor testosterone, mediate disease pathogenesis has led to a paradigm shift, not only for the treatment of AD but a wide variety of other age-related diseases. Therefore, the effects of agents that abolish LH, such as leuprolide acetate, which are currently being evaluated in Phase II clinical trials for the treatment of AD, are eagerly anticipated.","PeriodicalId":11063,"journal":{"name":"Current drug targets. CNS and neurological disorders","volume":"3 4","pages":"281-5"},"PeriodicalIF":0.0,"publicationDate":"2004-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24692835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 33

Mitochondria as therapeutic targets of estrogen action in the central nervous system. 线粒体作为雌激素在中枢神经系统中的治疗靶点。

Current drug targets. CNS and neurological disorders Pub Date : 2004-08-01 DOI: 10.2174/1568007043337193

Jon Nilsen, Roberta Diaz Brinton

{"title":"Mitochondria as therapeutic targets of estrogen action in the central nervous system.","authors":"Jon Nilsen, Roberta Diaz Brinton","doi":"10.2174/1568007043337193","DOIUrl":"https://doi.org/10.2174/1568007043337193","url":null,"abstract":"Neuron viability and defense against neurodegenerative disease can be achieved by targeting mitochondrial function to reduce oxidative stress, increase mitochondrial defense mechanisms, or promote energetic metabolism and Ca2+ homeostasis. Exposure to estrogen prior to contact with toxic agents can protect neurons against a wide range of degenerative insults. The proactive defense state induced by estrogen is mediated by complex mechanisms ranging from chemical to biochemical to genomic but which converge upon regulation of mitochondria function. Estrogen preserves ATP levels via increased/enhanced oxidative phosphorylation and reduced ATPase activity thereby increasing mitochondrial respiration efficiency, resulting in a lower oxidative load. In addition, estrogen increases antiapoptotic proteins, Bcl-2 and Bcl-xL, which prevents activation of the permeability transition pore protecting against estrogen-induced increase in mitochondrial Ca2+ sequestration. These effects are likely to be enhanced by antioxidant effects of estrogen, preventing the initiation of the deleterious \"mitochondrial spiral\". The extent to which each of these mechanisms contribute to the overall proactive defense state induced by estrogen remains to be determined. However, each aspect of the cascade appears to make a significant if not obligatory impact on the neuroprotective effects of estrogens. Moreover each component of the cascade is required for estrogen regulation of mitochondrial function. Mechanisms of estrogen action and results of the clinical efficacy of estrogen therapy for prevention or treatment of Alzheimer's disease are considered in the context of clinical use of estrogen therapy and the design of brain selective estrogens or NeuroSERMs.","PeriodicalId":11063,"journal":{"name":"Current drug targets. CNS and neurological disorders","volume":"3 4","pages":"297-313"},"PeriodicalIF":0.0,"publicationDate":"2004-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24693239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 156

Mechanosensitive ion channels as drug targets. 机械敏感离子通道作为药物靶点。

Current drug targets. CNS and neurological disorders Pub Date : 2004-08-01 DOI: 10.2174/1568007043337283

Philip A Gottlieb, Thomas M Suchyna, Lyle W Ostrow, Frederick Sachs

{"title":"Mechanosensitive ion channels as drug targets.","authors":"Philip A Gottlieb, Thomas M Suchyna, Lyle W Ostrow, Frederick Sachs","doi":"10.2174/1568007043337283","DOIUrl":"https://doi.org/10.2174/1568007043337283","url":null,"abstract":"Mechanically sensitive ion channels (MSCs) are ubiquitous. They exist as two major types: those in specialized receptors that require fibrous proteins to transmit forces to the channel, and those in non-specialized tissues that respond to stress in the lipid bilayer. While few MSCs have been cloned, the existing structures show no sequence or structural homology--an example of convergent evolution. The physiological function of MSCs in many tissues is not known, but they probably arose from the need for cell volume regulation. Recently, a peptide called GsMTx4 was isolated from tarantula venom and is the first specific reagent for mechanosensitive channels. GsMTx4 is a approximately 4 kD peptide with a hydrophobic face opposite a positively charged face. It is active in the D and L forms, and appears non-toxic to mice. GsMTx4 has shown physiological effects on cationic MSCs in heart, smooth muscle, astrocytes, and skeletal muscle. By itself, GsMTx4 can serve as a lead compound or as a potential drug. Its availability opens clinical horizons in the diagnosis and treatment of pathologies including cardiac arrhythmia, muscular dystrophy and glioma.","PeriodicalId":11063,"journal":{"name":"Current drug targets. CNS and neurological disorders","volume":"3 4","pages":"287-95"},"PeriodicalIF":0.0,"publicationDate":"2004-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24693238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 55