Current drug targets. Immune, endocrine and metabolic disorders最新文献

{"title":"Chemokine-chemokine receptor network in immune cell trafficking.","authors":"Chang H Kim","doi":"10.2174/1568008043339712","DOIUrl":"https://doi.org/10.2174/1568008043339712","url":null,"abstract":"<p><p>Chemokines play critical roles in leukocyte trafficking in normal and inflammatory conditions. The primary roles of chemokines are to activate integrins for leukocyte adherence on endothelial cells and to induce chemotaxis of leukocytes in tissue microenvironments. Specificity in leukocyte migration is regulated at multiple levels. First, it is achieved through differential tissue expression of chemokines and adhesion molecules. Second, it is achieved by limited and differential expression of chemokine receptors by leukocyte subsets. Third, combinatorial expression of multiple chemokine receptors and adhesion molecules makes leukocyte migration more specific. Homing of leukocytes into various tissue sites (e.g. inflamed skin, small intestine, mucosal tissues, T cell areas vs. B cell follicles) requires different chemokines and chemokine receptors. Furthermore, distinct immune responses and diseases (e.g. Th1 vs. Th2 responses) involve different sets of chemokines and leukocyte subsets. This review examines the recent advances in research on chemokines and chemokine receptors in tissue-specific migration of immune cells, and discusses potential targets of intervention in chemokine-mediated leukocyte migration in normal and diseased conditions.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"4 4","pages":"343-61"},"PeriodicalIF":0.0,"publicationDate":"2004-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568008043339712","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24843144","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}

{"title":"Structure and function of HIV-1 auxiliary regulatory protein Vpr: novel clues to drug design.","authors":"L J Zhao,&nbsp;H Zhu","doi":"10.2174/1568008043339668","DOIUrl":"https://doi.org/10.2174/1568008043339668","url":null,"abstract":"<p><p>Vpr is a 96-amino acid auxiliary regulatory protein that is packaged in the HIV-1 virion. It enhances the nuclear transport of the pre-integration complex, and regulates cell cycle, transcription and apoptosis. These biological activities suggest strongly that Vpr interacts with cellular biochemical pathways to regulate HIV-1 replication and pathogenesis. The karyophilic property of Vpr appears to be due to direct interaction of Vpr with nuclear transport factors and residents of the nuclear pore complex, whereas transcriptional effects of Vpr may be exerted through direct and indirect mechanisms. Cell cycle arrest at the G2/M checkpoint by Vpr is correlated with the hyperphosphorylation of Cdc2. The pro-apoptotic activity of Vpr is dependent on the subtype of the HIV-1 isolate, and may be dramatically enhanced by a single L64P mutation. Mitochondria- and caspase-dependent mechanisms appear to mediate Vpr-induced apoptosis. Recent evidence suggests that Vpr interacts with a cellular ubiquitination machinery and promotes degradation of Vpr mutants carrying the L64P mutation. Vpr interaction with the ubiquitination machinery may contribute to the regulation of the HIV-1 life cycle at various stages. NMR studies of Vpr have shown a Vpr monomer with three helical domains arranged in a twisted-U shape. However, Vpr most likely exists as a trimer in vivo. Structural/functional domains have been tentatively mapped for Vpr induction of apoptosis and for Vpr interaction with the ubiquitination machinery. Structural refinement of Vpr, specially by crystallography of the potential Vpr trimer, should help design therapeutic approaches to specifically target Vpr.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"4 4","pages":"265-75"},"PeriodicalIF":0.0,"publicationDate":"2004-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568008043339668","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24842706","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}

{"title":"Targeting the Nef induced increase of HIV infectivity.","authors":"Maurizio Federico","doi":"10.2174/1568008043339730","DOIUrl":"https://doi.org/10.2174/1568008043339730","url":null,"abstract":"<p><p>Nef is a regulatory protein expressed exclusively by HIV-1/2 and SIV. It is critical for the optimal viral infectivity and for the destruction of the host immune system. This renders Nef a rather attractive therapeutic target. The most affordable point(s) of attack for effective anti-Nef therapeutic strategies can be individuated on the basis of a detailed knowledge of the mechanisms underlying the Nef induced enhancement of infectivity. However, the emerging picture still appears rather complex and not always coherent, so that additional, intensive endeavours in basic research are required for an effective exploitation of the Nef induced increase of infectivity as a therapeutic target.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"4 4","pages":"321-6"},"PeriodicalIF":0.0,"publicationDate":"2004-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24842712","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}

{"title":"New perspectives in the treatment of Cushing's syndrome.","authors":"M Labeur,&nbsp;E Arzt,&nbsp;G K Stalla,&nbsp;M Páez-Pereda","doi":"10.2174/1568008043339703","DOIUrl":"https://doi.org/10.2174/1568008043339703","url":null,"abstract":"<p><p>Regardless of etiology, all cases of endogenous Cushing's syndrome are due to increased production of cortisol by the adrenal gland. Most are caused by adrenocorticotrophic hormone (ACTH)-secreting pituitary adenomas. Alternatively, the glucocorticoid excess may be due to adrenal neoplasia or to ectopic ACTH-secreting tumors. Cushing's syndrome is characterized by endocrine and metabolic alterations such as truncal obesity, hypertension, weakness, amenorrhea, hyperglycemia, osteoporosis and depression. Unless treated, the disease is associated with high morbidity, and ultimately, mortality. Depending on the etiology of Cushing's syndrome two different treatment modalities are possible: reduction of pituitary ACTH production or reduction of adrenocortical cortisol secretion. In the absence of efficient drug therapy, transsphenoidal resection of the pituitary adenoma is the primary treatment of choice for the reduction of ACTH secretion. In the last years there was much progress in understanding the molecular mechanisms that control the function of the hypothalamic-pituitary-adrenal axis. Thus, new insights made it possible to identify potential drug targets for the treatment of Cushing's syndrome. The present article reviews different drug targets and therapeutic options including drugs that control the central ACTH regulation, e.g. by modulating signaling pathways and transcriptional regulation of ACTH biosynthesis, corticotrophin releasing hormone (CRH) or glucocorticoid receptor antagonists, inhibitors of glucocorticoid synthesis, ketoconazole, somatostatin and dopamine analogs. Some of these substances might be useful for the treatment of Cushing's syndrome.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"4 4","pages":"335-42"},"PeriodicalIF":0.0,"publicationDate":"2004-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24842714","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}

{"title":"Controlling HIV-1 Rev function.","authors":"Alan Cochrane","doi":"10.2174/1568008043339677","DOIUrl":"https://doi.org/10.2174/1568008043339677","url":null,"abstract":"<p><p>Although current therapies used in the treatment of HIV-1 infection have proven effective in reducing mortality due to the infection, the increase in drug resistant strains of the virus call for increased effort to explore and develop alternative treatment modalities. In this review, the various strategies to control HIV-1 replication through the disruption of Rev function are outlined. A wide range of methods have been developed including antisense DNA, ribozymes, decoy RNAs, transdominant proteins and suicide vectors targeted at disrupting Rev function. Although many of these methods have proven effective alone, it is hoped that a more robust antiviral response can be attained through combination of these strategies. As the methods of delivering these therapeutic agents matures through the development of lentiviral-based vectors, it is hoped that they will eventually reach the clinic where they may not only supplement the current treatment strategies but also provide resistance to those at high risk of infection or failing therapy.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"4 4","pages":"287-95"},"PeriodicalIF":0.0,"publicationDate":"2004-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568008043339677","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24842708","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}

{"title":"Recent advances in the understanding of HIV-1 Vpu accessory protein functions.","authors":"Julie Binette,&nbsp;Eric A Cohen","doi":"10.2174/1568008043339695","DOIUrl":"https://doi.org/10.2174/1568008043339695","url":null,"abstract":"<p><p>HIV-1 encodes a number of accessory proteins, which are not commonly found in other retroviruses. These proteins, which include Vif, Vpr, Vpu and Nef, act as multifunctional adapters capable of recruiting and modulating basic host cell processes to optimize wide-ranging aspects of viral replication. This review describes our current understanding of how the Vpu accessory protein functions to modulate HIV-1 particle release and CD4 receptor expression during HIV-1 infection and underlines the potential opportunities afforded by this viral protein for therapeutic intervention.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"4 4","pages":"297-307"},"PeriodicalIF":0.0,"publicationDate":"2004-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24842709","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}

{"title":"Preface [Hot Topic: Regulatory / Accessory HIV-1 Proteins (Guest Editor: Maurizio Federico)]","authors":"M. Federico","doi":"10.2174/1568008043339721","DOIUrl":"https://doi.org/10.2174/1568008043339721","url":null,"abstract":"","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"4 1","pages":"1-1"},"PeriodicalIF":0.0,"publicationDate":"2004-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67889756","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}

{"title":"Redifferentiation therapy in advanced thyroid cancer.","authors":"Bryan R Haugen","doi":"10.2174/1568008043339811","DOIUrl":"https://doi.org/10.2174/1568008043339811","url":null,"abstract":"<p><p>Thyroid cancer is a relatively common malignancy with an estimated prevalence of 250,000 in the U.S. A minority of patients have poorly differentiated thyroid carcinoma that is unresponsive to radioiodine therapy. Redifferentiation agents that 'reprogram' these tumors to concentrate radioiodine would be of great value in treating patients with advanced thyroid cancer. The retinoid isotretinoin is the most extensively studied of these agents. It appears that 20-40% of patients respond to isotretinoin treatment by concentration of radioiodine in metastatic tumors, but the clinical utility of this redifferentiation is still unclear. In vitro studies suggest that the retinoid receptors (RARbeta and RXRgamma) are required for this effect. Abnormal DNA methylation may be an early event in thyroid tumorigenesis and methylation of the sodium iodide symporter (NIS) may play a role in the loss of iodine concentration in these tumors. Inhibitors of methylation (5-azacytidine, phenylacetate and sodium butyrate) have been shown to increase NIS expression and iodine uptake in cell culture models, but published trials in humans are not yet available. Histone acetylation is required for efficient transcription of genes necessary for differentiated function. Proteins that cause histone deacetylation inhibit gene transcription and differentiated function. Inhibitors of histone deacetylation (depsipeptide, trichostatin A) have been shown to increase NIS expression and iodine uptake in poorly differentiated and undifferentiated cell lines. Phase II human trials are currently underway for depsipeptide. Finally, commonly used agents such as thiazolidinediones (diabetes) and HMG-CoA reductase inhibitors (hypercholesterolemia) have shown promise in preliminary in vitro studies in advanced thyroid cancer cell lines. Development of these and other novel agents for the treatment of advanced thyroid cancer is critical for us to treat an uncommon progression of a common malignancy.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"4 3","pages":"175-80"},"PeriodicalIF":0.0,"publicationDate":"2004-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24691558","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}

{"title":"Viral mediated gene therapy for the management of metastatic thyroid carcinoma.","authors":"Leslie J DeGroot,&nbsp;Rusheng Zhang","doi":"10.2174/1568008043339875","DOIUrl":"https://doi.org/10.2174/1568008043339875","url":null,"abstract":"<p><p>Thyroid cancers are of special interest in gene therapy, since it is possible to direct gene expression specifically to the thyroid derived cells by using promoters with limited expression, and secondly, because destruction of the normal tissue by introduction of a toxic gene would have no important adverse effect. A variety of methods for gene delivery are available. Adenovirus is a well studied and widely used vector and is useful for targeting genes because it infects many cell types, including differentiated thyroid cancer and medullary thyroid cancer cells. Strategies that have been employed successfully in animal models include adenoviral mediated expression of thymidine kinase under control of a thyroglobulin promoter, similarly expression of the cytokine IL-2, and perhaps most effectively, expression of IL-12. Combinations of vectors expressing thymidine kinase and IL-12 under control of a strong but non-tissue specific CMV promoter effectively destroy a model anaplastic thyroid tumor in Wistar rats. Replicating adenoviruses, in contrast to the non-replicating form commonly used, have also been used to infect tumor cells and express P-53 protein, leading to apoptosis of tumor cells. Medullary thyroid cancer provides a target much like differentiated thyroid cancer because it is possible to address gene expression specifically to the medullary thyroid cells by the use of a modified calcitonin promoter. Animal models of this tumor are available in a mouse and Wag/Rij rat model. In the latter system, treatment with adenoviruses expressing genes under control of the modified calcitonin promoter and expressing thymidine kinase or IL-12 leads to destruction of growing medullary thyroid cancer tumors, destroy distant tumors after injection in one tumor, and cause induction of long lasting immunity to subsequent tumor development in the animals. There are many ongoing studies of gene therapy in humans using various genes such as thymidine kinase, IL-2, and now IL-12. Although none of these trials to date shows complete eradication of metastatic tumors in humans, there are reports showing distinctly that the viral mediated gene therapy approach can effectively destroy human tumors after in vivo administration. Tumors that have been treated include melanomas, glioblastomas, breast tumors, and prostate carcinomas. In the latter studies, it has been possible to show objective responses documented by a fall in serum PSA levels of 50% or more that are sustained for prolonged periods. Gene therapy using the adenoviral vectors appears to be safe in studies reported so far. A problem is prior or induced immunity to adenoviral proteins, but direct injection of the vector into a tumor nodule largely circumvents this problem. New genes and new vectors under development will certainly lead to the established use of these methods in the therapy of human thyroid carcinomas in the near future.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"4 3","pages":"235-44"},"PeriodicalIF":0.0,"publicationDate":"2004-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24691563","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}

{"title":"Akt: a potential target for thyroid cancer therapy.","authors":"Faiza Kada,&nbsp;Motoyasu Saji,&nbsp;Matthew D Ringel","doi":"10.2174/1568008043339857","DOIUrl":"https://doi.org/10.2174/1568008043339857","url":null,"abstract":"<p><p>Thyroid cancer is a heterogeneous disorder characterized by gene mutations that activate signaling pathways, and also by abnormalities in tumor suppressor genes and cell cycle proteins. Activation of the Akt/PKB signaling pathway appears to be an important event in thyroid tumorigenesis and, perhaps, in tumor progression too. Akt is activated in Cowden's syndrome through inactivation of PTEN, a negative regulator of Akt. Cowden's syndrome is an autosomal dominant multiorgan hamartoma syndrome characterized by benign and malignant thyroid tumors, breast cancers, and colon cancers. In addition, the Akt pathway appears to be activated in a significant proportion of sporadic thyroid cancers through activation of growth factor pathways by thyroid oncogenes and/or receptor overexpression. Disruption of PI3-kinase activity pharmacologically or disruption of Akt signaling using dominant negative cDNA expression have demonstrated salutary effects on several cancer models in vitro. Therefore, Akt represents an attractive target for pharmaceutical development for a variety of malignancies, including thyroid cancer.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"4 3","pages":"181-5"},"PeriodicalIF":0.0,"publicationDate":"2004-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24691559","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}