Current drug targets. Immune, endocrine and metabolic disorders最新文献_第4页

Modulation of cholesterol crystallization in bile. Implications for non-surgical treatment of cholesterol gallstone disease. 胆汁中胆固醇结晶的调节。非手术治疗胆固醇性胆结石的意义。

Current drug targets. Immune, endocrine and metabolic disorders Pub Date : 2005-06-01 DOI: 10.2174/1568008054064922

Piero Portincasa, Antonio Moschetta, Karel J van Erpecum, Michele Vacca, Michele Petruzzelli, Giuseppe Calamita, Giuliano Meyer, Giuseppe Palasciano

{"title":"Modulation of cholesterol crystallization in bile. Implications for non-surgical treatment of cholesterol gallstone disease.","authors":"Piero Portincasa, Antonio Moschetta, Karel J van Erpecum, Michele Vacca, Michele Petruzzelli, Giuseppe Calamita, Giuliano Meyer, Giuseppe Palasciano","doi":"10.2174/1568008054064922","DOIUrl":"https://doi.org/10.2174/1568008054064922","url":null,"abstract":"The first step in cholesterol gallstone disease is precipitation of cholesterol crystals in bile. In gallbladder bile. cholesterol is normally solubilized together with bile salts and phospholipids to form mixed micellar structures. When cholesterol in bile is in excess, vesicles (i.e. phospholipid-cholesterol globular structures: liquid crystals) form which become supersaturated in cholesterol. Early aggregation and precipitation of cholesterol molecules into submicroscopic nuclei occurs from these supersaturated vesicles. This crucial step is followed by precipitation and agglomeration of cholesterol crystals which then become visible at light microscopy. Here we describe the mechanism of cholesterol crystallization and its modulation in vivo and in vitro. Recent advances on the role of ursodeoxycholate as an agent preventing the precipitation of cholesterol crystals in bile will be highligthed.","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"5 2","pages":"177-84"},"PeriodicalIF":0.0,"publicationDate":"2005-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568008054064922","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25238809","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: 1

Effects of leptin on biliary lipids: potential consequences for gallstone formation and therapy in obesity. 瘦素对胆脂的影响:肥胖患者胆结石形成和治疗的潜在后果。

Current drug targets. Immune, endocrine and metabolic disorders Pub Date : 2005-06-01 DOI: 10.2174/1568008054064896

Nahum Méndez-Sánchez, Guadalope Ponciano-Rodrigoez, Norberto Chavez-Tapia, Misael Uribe

引用次数: 15

Assessment of modes of action and efficacy of plasma cholesterol-lowering drugs: measurement of cholesterol absorption, cholesterol synthesis and bile acid synthesis and turnover using novel stable isotope techniques. 血浆降胆固醇药物的作用方式和疗效评估:使用新型稳定同位素技术测量胆固醇吸收、胆固醇合成和胆汁酸合成和转化。

Current drug targets. Immune, endocrine and metabolic disorders Pub Date : 2005-06-01 DOI: 10.2174/1568008054064913

Frans Stellaard, Folkert Kuipers

{"title":"Assessment of modes of action and efficacy of plasma cholesterol-lowering drugs: measurement of cholesterol absorption, cholesterol synthesis and bile acid synthesis and turnover using novel stable isotope techniques.","authors":"Frans Stellaard, Folkert Kuipers","doi":"10.2174/1568008054064913","DOIUrl":"https://doi.org/10.2174/1568008054064913","url":null,"abstract":"Several processes are involved in control of plasma cholesterol levels, e.g., intestinal cholesterol absorption, endogenous cholesterol synthesis and transport and bile acid synthesis. Adaptation of either of these processes allows the body to adapt to changes in dietary cholesterol intake. Disturbances herein may lead to hypercholesterolemia and increase the risk for atherosclerosis. Several approaches are available for plasma-cholesterol lowering therapies, particularly aimed at reduction of low-density lipoprotein (LDL) cholesterol. Currently used therapies aim to decrease (hepatic) cholesterol synthesis, to inhibit cholesterol absorption or to stimulate bile acid synthesis. The latter can be achieved by reducing bile acid absorption to alleviate the negative feedback control exerted by bile acids circulating in the body. Approaches to directly stimulate bile acid synthesis may become available. Novel drugs should be tested on the efficiency to influence their actual targets. Several techniques are available to measure cholesterol absorption, cholesterol synthesis and bile acid synthesis and absorption in vivo in human subjects. The most reliable techniques are based on the use of stable isotopes and mass spectrometry. This paper provides a condensed background on physiological parameters that determine cholesterol homeostasis, and potential new mechanisms of drug action and focuses, especially, on new techniques to monitor the effects of drugs in humans.","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"5 2","pages":"209-18"},"PeriodicalIF":0.0,"publicationDate":"2005-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568008054064913","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24947825","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: 14

The mammalian innate immune system: potential targets for drug development. 哺乳动物先天免疫系统:药物开发的潜在靶点。

Current drug targets. Immune, endocrine and metabolic disorders Pub Date : 2005-06-01 DOI: 10.2174/1568008054064959

Thomas T Wheeler, Kylie A Hood

{"title":"The mammalian innate immune system: potential targets for drug development.","authors":"Thomas T Wheeler, Kylie A Hood","doi":"10.2174/1568008054064959","DOIUrl":"https://doi.org/10.2174/1568008054064959","url":null,"abstract":"The innate immune system is the oldest mammalian defence against invading micro-organisms and provides the first line of defence against them, however until recently a detailed understanding of its complexity has been lacking. This review describes recent advances that have been made in understanding the components of the innate immune system, including the pathogen sensing mechanisms, receptor and intracellular signalling pathways, linkage to the acquired immune system, and effectors of the innate immune response. These discoveries have created an opportunity for the development of novel drugs through the identification of targets for rational drug design. The opportunity for the development of novel anti-inflammatory and antimicrobial drugs through modulation of pro-inflammatory or antimicrobial signals within the innate immune system, are discussed. A more detailed understanding of the effectors of the innate immune system is providing an opportunity for the design of effector mimetics as novel antimicrobial drugs. The innate immune system is providing the basis for much-needed alternative approaches to controlling infection and inflammation in human medicine.","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"5 2","pages":"237-47"},"PeriodicalIF":0.0,"publicationDate":"2005-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568008054064959","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24947828","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: 4

Manipulation of biliary lipids by gene therapy: potential consequences for patients with progressive familial intrahepatic cholestasis. 基因治疗对胆脂的控制:对进行性家族性肝内胆汁淤积症患者的潜在影响。

Current drug targets. Immune, endocrine and metabolic disorders Pub Date : 2005-06-01 DOI: 10.2174/1568008054064878

Ronald P J Oude Elferink

引用次数: 5

CXCR3-binding chemokines: novel multifunctional therapeutic targets. 结合cxcr3的趋化因子:新的多功能治疗靶点。

Current drug targets. Immune, endocrine and metabolic disorders Pub Date : 2005-03-01 DOI: 10.2174/1568008053174723

E Lazzeri, P Romagnani

{"title":"CXCR3-binding chemokines: novel multifunctional therapeutic targets.","authors":"E Lazzeri, P Romagnani","doi":"10.2174/1568008053174723","DOIUrl":"https://doi.org/10.2174/1568008053174723","url":null,"abstract":"The goal to attenuate inflammation without inducing generalized immunosuppression has focused the attention on chemokines, a family of chemotactic peptides that regulate the leukocyte traffick into tissues. However, the development of drugs that block ckemokine activity may be hampered by the observation that some chemokines display pleiotropic biologic functions. For example, the chemokines CXCL9/Mig, CXCL10/IP-10, and CXCL11/I-TAC exhibit the ability to recruit different leukocytes subsets, the capacity to induce the proliferation of vascular pericytes as well as powerful anti-tumor effects, which are mediated by a common receptor, named CXCR3. Because of their pleiotropic biologic effects, these chemokines have been proposed as possible therapeutic targets in cancer, allograft rejection, glomerulonephritis, diabetes, multiple sclerosis, and autoimmune disorders of the thyroid. The chemokine CXCL4/PF4 shares several activities with CXCL9, CXCL10, and CXCL11, including angiostatic effects, although its specific receptor has remained unknown for a long time. Recently, we provided evidence that the different functions of CXCL9, CXCL10, and CXCL11 on distinct cell types can be at least partly explained by the interaction of these chemokines with two distinct receptors. Indeed, in addition to the classic form of CXCR3 receptor, which we have renamed as CXCR3-A, a novel CXCR3 receptor variant (CXCR3-B) was identified, that not only mediates the angiostatic activity of CXCR3 ligands, but also acts as functional receptor for CXCL4. In this review, we focus on the accumulating evidence demonstrating the pivotal role of CXCR3-binding chemokines in several human diseases. Studies based on CXCR3 targeting have shown its importance in different pathologic conditions and orally active small molecules capable of inhibiting this receptor are now being developed in order to be tested for their activity in humans.","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"5 1","pages":"109-18"},"PeriodicalIF":0.0,"publicationDate":"2005-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568008053174723","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25182664","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: 121

Signal transduction by IL-2 and its receptors as target in treatment of rheumatoid arthritis. IL-2及其受体在类风湿关节炎治疗中的信号转导作用。

Current drug targets. Immune, endocrine and metabolic disorders Pub Date : 2005-03-01 DOI: 10.2174/1568008053174741

V I Kozanidou, A D Theocharis, A Georgiadis, P V Voulgari, A A Drosos, N K Karamanos

{"title":"Signal transduction by IL-2 and its receptors as target in treatment of rheumatoid arthritis.","authors":"V I Kozanidou, A D Theocharis, A Georgiadis, P V Voulgari, A A Drosos, N K Karamanos","doi":"10.2174/1568008053174741","DOIUrl":"https://doi.org/10.2174/1568008053174741","url":null,"abstract":"Rheumatoid arthritis (RA) is a chronic and destructive arthropathy with systemic features, the etiopathogenesis of which remains unclear. It is characterized by relapsing and remitting inflammation and hyperplasia of synovial cells. Proinflammatory cytokines, such as interleukin-2 (IL-2), play an important role in maintaining cartilage damage and severe destruction of the joints due to an uncontrolled activation of cellular immunity. An imbalance between proinflammatory and anti-inflammatory mediators is likely to contribute to the chronicity of the disease. Therefore, insight into the activation state of T-cells in different stages of the disease may be important to understand pathogenetic mechanisms underlying RA and could be a lead for the design of future therapeutic strategies. Because of the central role of the IL-2/IL-2 receptor (IL-2R) system in mediation of the immune system, monitoring and manipulation of this system has important diagnostic and therapeutic implications. New approaches in RA therapy with anticytokine agents, which block cytokines and their receptors, are now used as antirheumatic drugs in clinical practice.","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"5 1","pages":"41-50"},"PeriodicalIF":0.0,"publicationDate":"2005-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568008053174741","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25014231","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: 11

Effects of endocrine disruptors on developmental and reproductive functions. 内分泌干扰物对发育和生殖功能的影响。

Current drug targets. Immune, endocrine and metabolic disorders Pub Date : 2005-03-01 DOI: 10.2174/1568008053174750

Tiziana A L Brevini, Simona Bertola Zanetto, Fabiana Cillo

{"title":"Effects of endocrine disruptors on developmental and reproductive functions.","authors":"Tiziana A L Brevini, Simona Bertola Zanetto, Fabiana Cillo","doi":"10.2174/1568008053174750","DOIUrl":"https://doi.org/10.2174/1568008053174750","url":null,"abstract":"Endocrine disruptors (EDs) are exogenous environmental molecules that may affect the synthesis, secretion, transport, metabolism, binding, action, and catabolism of natural hormones in the body. EDs may thus interact with the endocrine system of animals and humans and can exert this effect even when present in minute amounts. EDs have adverse impacts on a number of developmental functions in wildlife and humans. Critical periods of urogenital tract and nervous system development in-utero and during early post-natal life are especially sensitive to hormonal disruption. Furthermore a wide range of hormone-dependent organs (pituitary gland, hypothalamus, reproductive tract) are targets of EDs disrupting effects in adult subjects, possibly resulting in cell transformation and cancer. At present about 60 chemicals have been identified and characterized as EDs and belong to three main groups: (a) synthetic compounds utilized in industry, agriculture and consumer products; (b) synthetic molecules used as pharmaceutical drugs and (c) natural chemicals found in human and animal food (phytoestrogens). In the present review we will give special attention to the family of Polychlorinated biphenyls (also indicated as PCBs) because of their persistence in the environment, ability to concentrate up the food chain, continued detection in environmental matrices, and ability to be stored in the adipose tissue of animals as well as humans. The detrimental effects of these compounds, and of EDs more in general, on health and reproduction will be discussed, presenting experimental data aimed at understanding the molecular mechanisms involved in their action.","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"5 1","pages":"1-10"},"PeriodicalIF":0.0,"publicationDate":"2005-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568008053174750","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25014228","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: 67

Regulation of the steroidogenic acute regulatory protein expression: functional and physiological consequences. 类固醇急性调节蛋白表达的调控:功能和生理后果。

Current drug targets. Immune, endocrine and metabolic disorders Pub Date : 2005-03-01 DOI: 10.2174/1568008053174714

P R Manna, D M Stocco

{"title":"Regulation of the steroidogenic acute regulatory protein expression: functional and physiological consequences.","authors":"P R Manna, D M Stocco","doi":"10.2174/1568008053174714","DOIUrl":"https://doi.org/10.2174/1568008053174714","url":null,"abstract":"Steroid hormones are synthesized in steroidogenic cells of the adrenal, ovary, testis, placenta and brain and are essential for normal reproductive function and bodily homeostasis. The rate-limiting and regulated step in steroid biosynthesis is the intramitochondrial transport of cholesterol, a process that is mediated by the steroidogenic acute regulatory (StAR) protein. The importance of StAR has been illustrated by analyses of patients with lipoid congenital adrenal hyperplasia (lipoid CAH), an autosomal recessive disorder that markedly disrupts the synthesis of all gonadal and adrenal steroids. Molecular and physio-pathological analyses have demonstrated that alterations in the StAR gene are the only known cause of lipoid CAH. Furthermore, StAR knockout mice have been generated and display a phenotype that is essentially identical to the human condition. Recent advances in tissue-specific and hormone-induced expression of the StAR protein provide insights into a number of human endocrinological health issues including developmental and reproductive abnormalities. Several factors and processes have been demonstrated to influence StAR expression in steroidogenic cells and there is increasing evidence that a transcription factor-binding site-rich region present in the proximal region of the StAR promoter is highly instrumental in StAR gene expression. In this review we focus on the significant findings that have been made with regards to the regulation of StAR expression and also on the clinical and endocrinological consequences of a non-functioning StAR gene.","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"5 1","pages":"93-108"},"PeriodicalIF":0.0,"publicationDate":"2005-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568008053174714","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25182663","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: 136

Mitochondrial trifunctional protein defects: molecular basis and novel therapeutic approaches. 线粒体三功能蛋白缺陷:分子基础和新的治疗方法。

Current drug targets. Immune, endocrine and metabolic disorders Pub Date : 2005-03-01 DOI: 10.2174/1568008053174796

J Angdisen, V D G Moore, J M Cline, R M Payne, J A Ibdah

{"title":"Mitochondrial trifunctional protein defects: molecular basis and novel therapeutic approaches.","authors":"J Angdisen, V D G Moore, J M Cline, R M Payne, J A Ibdah","doi":"10.2174/1568008053174796","DOIUrl":"https://doi.org/10.2174/1568008053174796","url":null,"abstract":"Mitochondrial trifunctional protein (MTP) is a complex protein that catalyzes the last three steps of long chain fatty acid oxidation. MTP defects have emerged recently as important inborn errors of metabolism because of their clinical implications. These disorders are recessively inherited and display a spectrum of clinical phenotypes in affected children including hepatic dysfunction, cardiomyopathy, neuro-myopathy, and may cause sudden unexpected infant death if undiagnosed and untreated. Interestingly, mothers who carry fetuses with MTP defects develop life-threatening complications during pregnancy. Recently, we delineated disease-causing mutations in MTP and reported the molecular basis for the pediatric and fetal-maternal genotype-phenotype correlations. Current management of patients with MTP defects include long-term dietary therapy of fasting avoidance, low fat diet with the restriction of long chain fatty acid intake and substitution with medium chain fatty acids. The long-term outcome of patients treated by dietary modifications remains unknown. Thus, treatment that aims at correcting the metabolic defect remains the therapy of choice for this disorder. Currently, we are exploring the potential use of protein transfection domains (PTD) for treatment of these disorders. We have shown that the transactivator of transcription (TAT) peptide from the human immunodeficiency virus can deliver proteins to mitochondria. We have further developed methods to localize these proteins to mitochondria by including a mitochondrial targeting in the fusion protein construct. Finally, we have shown that the fusion protein can cross the placenta and was detectable in the fetus and newborn pups. The practical therapeutic implications of this novel approach will be discussed.","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"5 1","pages":"27-40"},"PeriodicalIF":0.0,"publicationDate":"2005-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568008053174796","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25014230","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: 28