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

{"title":"Determination of binding constant of DNA-binding drug to target DNA by surface plasmon resonance biosensor technology.","authors":"Liang-Ping Lin,&nbsp;Long-Sun Huang,&nbsp;Chii-Wann Lin,&nbsp;Chi-Kung Lee,&nbsp;Ji-Liang Chen,&nbsp;Su-Ming Hsu,&nbsp;Shiming Lin","doi":"10.2174/1568008053174697","DOIUrl":"https://doi.org/10.2174/1568008053174697","url":null,"abstract":"<p><p>The experimental determination of the binding constant of a drug for its target molecule is of considerable importance. It is a basic experimental parameter in a variety of studies, such as the prediction of drug efficiency, or in the pharmacokinetic drug interaction. DNA-binding drugs have been reported to be able to interfere in a sequence dependent manner with biological functions such as topoisomerase activity, restriction of enzyme cleavage of DNA, protein-DNA interactions and the activity of transcription factors, leading to alteration of gene expression. This effect could have important practical application in the experimental therapy of human pathologies, including neoplastic diseases and viral, or microbial infections. The assessment of the biological activity of DNA-binding drugs by polymerase chain reaction, footprinting, gel retardation and in vitro transcription studies was recently reported. However, most of these techniques are steady-state methodologies and therefore are not suitable for an easy determination of the binding activity of DNA-binding drugs to target DNA and the stability of drugs-DNA complexes. Direct real-time observation and measurement of the interaction between DNA-binding drug and target DNA sequence is a subject of interest for drug discovery and development. The recent development of biosensors, based on surface plasmon resonance (SPR) technology, enables monitoring of a variety of biospecific interactions of DNA-binding drugs with target DNA elements in real-time. The present review is designed to indicate the theoretical background of SPR-based biosensor technology as well as to present the great variety of measurements and modes of interaction kinetics that can be performed with these techniques. In addition, some of the most recent studies in determining the binding constant and stoichiometry of DNA-binding drugs to target DNA with SPR technology are reviewed and the available theoretical aspects necessary for the comprehension of the experiments are provided.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"5 1","pages":"61-72"},"PeriodicalIF":0.0,"publicationDate":"2005-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568008053174697","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25014233","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":"Therapeutic strategies to prevent neurodegeneration and promote regeneration in multiple sclerosis.","authors":"T Chitnis,&nbsp;J Imitola,&nbsp;S J Khoury","doi":"10.2174/1568008053174804","DOIUrl":"https://doi.org/10.2174/1568008053174804","url":null,"abstract":"<p><p>Multiple sclerosis (MS) is an immune-mediated demyelinating and degenerative disease of the central nervous system (CNS), with lesions predominantly occurring in the CNS white matter. The current treatment for MS relies on therapies that primarily target the peripheral immune response. However, it is clear that these strategies alone are insufficient for treating the chronic progressive disability that is the ultimate outcome of the disease. Axonal degeneration may be the primary determinant of fixed neurological deficits in MS. Here, we will discuss the contribution of axonal damage to MS pathogenesis, and potential cellular and molecular targets in the prevention of neurodegeneration. In addition, we will discuss potential molecular approaches to promote repair of CNS components in multiple sclerosis.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"5 1","pages":"11-26"},"PeriodicalIF":0.0,"publicationDate":"2005-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568008053174804","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25014229","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":"Reduction of hepatic glucose production as a therapeutic target in the treatment of diabetes.","authors":"Chaodong Wu,&nbsp;David A Okar,&nbsp;Johnthomas Kang,&nbsp;Alex J Lange","doi":"10.2174/1568008053174769","DOIUrl":"https://doi.org/10.2174/1568008053174769","url":null,"abstract":"<p><p>There has been an alarming increase in the population diagnosed with diabetes worldwide. Although there is an ongoing debate as to the role of liver in the pathogenesis of diabetes, reduction of hepatic glucose production has been targeted as a strategy for diabetes treatment. Indeed, reduction of hepatic glucose production can be achieved through modulation of both hepatic and extra-hepatic targets. This review describes the role of the liver in the control of glucose homeostasis. Gluconeogenesis and glycogenolysis are pathways for glucose production, whereas glycolysis and glycogenesis are pathways for glucose utilization/storage. At the biochemical and molecular level, the metabolic and regulatory enzymes integrate hormonal and nutritional signals and regulate glucose flux in the liver. Modulating either activities of or gene expression of these metabolic enzymes can control hepatic glucose production. Dysfunction of one or several enzyme(s) due to insulin deficiency or resistance results in increases in fluxes of glycogenolysis and gluconeogenesis and/or decreases in fluxes of glycolysis and glycogenesis, which thereby lead to glucose generation exceeding glucose consumption/disposal, as well as dysregulation of lipid metabolism. Activation of enzymes that promote glucose utilization/storage and/or inhibition of enzymes that reduce glucose generation achieve reduction of hepatic glucose production, and hence lower levels of plasma glucose in diabetes. This is also beneficial for the correction of dyslipidemia. Therefore, many enzymes are viable therapeutic targets for diabetes.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"5 1","pages":"51-9"},"PeriodicalIF":0.0,"publicationDate":"2005-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568008053174769","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25014232","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 approach to immunotherapy against organ-specific autoimmune diseases with T cell receptor and chemokine receptor DNA vaccines.","authors":"Yoh Matsumoto","doi":"10.2174/1568008053174732","DOIUrl":"https://doi.org/10.2174/1568008053174732","url":null,"abstract":"Organ-specific autoimmune diseases are characterized by the presence of relapse and remittance of the clinical signs, and last for a long period of time in most cases without an appropriate treatment. Immunopathologically, T cells that respond to organ-specific autoantigens play an important role in the development of inflammatory lesions in the target organ. These pathogenic T cells that had been activated by various stimuli including preceding infection infiltrate the target organ in an antigen-specific manner and break the homeostasis of the organ. Furthermore, they secrete a large number of pro-inflammatory cytokines and chemokines, which recruit by-stander inflammatory cells in the lesion. Although general immunosuppressive drugs such as corticosteroid and cyclosporine are effective in suppressing clinical signs and inflammation, immunospecific therapy is essential for the establishment of long-lasting remission or complete cure. In order to achieve effective immunospecific therapy, several groups have focused on two key molecules that are deeply involved in pathogenesis of autoimmune diseases. One is the T cell receptor (TCR) expressed on pathogenic T cells and the other is the cytokine and chemokine receptor expressed in the target organ. Another important aspect of this issue is the reagent that is used for the suppression of the function of the key molecules. So far, monoclonal antibodies, peptide vaccines and DNA vaccines are the major reagents used for immunosuppressive therapies. In the present review, I introduce the results of immunotherapy obtained in my laboratory using TCR-based and chemokine receptor (chemoR)-based DNA in experimental autoimmune encephalomyelitis (EAE) and myocarditis (EAC) and discuss its effectiveness and pathomechanisms of immunosuppression. First, we administered DNA vaccines encoding pathogenic TCR Vbeta8.2, 10 (to Lewis rats) and 15 (to DA rats) and observed that these vaccinations protected animals from the development of EAE. Similar results were obtained in EAC. Second, DNAs encoding several chemoRs were prepared and administered after the challenge to neutralize the function of chemokines that are highly upregulated in the lesions. It was demonstrated that these chemoR DNAs suppress the relapse of chronic relapsing EAE and block the progression of EAC to dilated cardiomyopathy (manuscripts submitted for publication). These findings clearly indicate that DNA vaccination can be a powerful tool for treatment of organ-specific autoimmune diseases.","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"5 1","pages":"73-7"},"PeriodicalIF":0.0,"publicationDate":"2005-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568008053174732","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25182661","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":"Signaling mechanism for the insulin-like effects of growth hormone--another example of a classical hormonal negative feedback loop.","authors":"Martin Ridderstråle","doi":"10.2174/1568008053174787","DOIUrl":"https://doi.org/10.2174/1568008053174787","url":null,"abstract":"<p><p>Growth hormone (GH) exerts many effects in addition to its ability to stimulate growth. The metabolic effects are either chronic diabetogenic or acute insulin-like. The latter effects are only seen in cells that have been deprived of the hormone for a few hours. After exposure to GH the ability of the cells to respond with insulin-like effects disappears within a couple of hours, a negative feedback loop, which is a part of the chronic effects of the hormone. The insulin-like effects are mediated by the cytosolic tyrosine kinase Janus kinase 2 (JAK2) upon GH-GH receptor interaction, resulting in tyrosine phosphorylation of downstream targets including the GH receptor itself and insulin receptor substrate-1 (IRS-1) and IRS-2. Analogous to the post-receptor events for insulin this results in recruitment of phosphatidylinositol-3 kinase (PI3-kinase) to the IRS-proteins. Downstream PI3-kinase protein kinase B/Akt participates in the activation of glucose transporters (GLUT4) and increased glucose uptake as well as activation of phosphodiesterase 3B and hydrolysis of cAMP leading to a net dephosphorylation of the hormone sensitive lipase and inhibition of lipolysis. Simultaneously, JAK2 phosphorylates STAT-family transcription factors that move into the nucleus and activate the transcription of, among others, genes coding for negatively regulatory proteins called Suppressors of cytokine signalling (SOCS). The turnover of SOCS is rapid and in their presence JAK2 will still activate STAT-proteins (and the diabetogenic effects), but no longer phosphorylate the IRS-proteins (and induce insulin-like effects), closing the loop of yet another classical hormonal negative feedback loop.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"5 1","pages":"79-92"},"PeriodicalIF":0.0,"publicationDate":"2005-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568008053174787","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25182662","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":"The HIV-1 Tat protein: a multifaceted target for novel therapeutic opportunities.","authors":"Mauro Giacca","doi":"10.2174/1568008043339767","DOIUrl":"https://doi.org/10.2174/1568008043339767","url":null,"abstract":"Transcription of the integrated HIV-1 proviral genome is an essential step in the retrovirus life cycle and thus an appealing target for chemotherapeutic intervention to restrict retroviral replication. A fundamental role in this process is exerted by the viral protein Tat, a powerful transactivator of viral gene expression. This protein binds a structured RNA sequence at the 5'-ends of all nascent viral mRNAs and promotes transcription by mediating the recruitment to the viral promoter of cellular factors required for chromatin remodelling and transcriptional processivity. In addition to these transcriptional activities, Tat is released from the cells and enters neighbouring cells when present in the extracellular environment, a process that is possibly involved in HIV disease pathogenesis. Given its pleiotropic functions, the protein represents a highly appealing target for drug development. Here I will summarise the known molecular mechanisms by which Tat exerts its activities and review the currently available compounds that interfere with the process of transcriptional activation of the HIV-1 provirus.","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"4 4","pages":"277-85"},"PeriodicalIF":0.0,"publicationDate":"2004-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24842707","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":"Functions of the HIV-1 Nef protein.","authors":"Andreas Baur","doi":"10.2174/1568008043339749","DOIUrl":"https://doi.org/10.2174/1568008043339749","url":null,"abstract":"<p><p>The Nef protein of the human immunodeficiency virus is as important for disease progression as it is perplexing in its number of target molecules and functions. In this chapter I will try to give an overview on the numerous functions of HIV from a molecular as well as functional point of view. Due to space restriction and for the sake of clarity I will not describe or list all the effects reported in the literature but rather concentrate on the most important aspects of Nef function.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"4 4","pages":"309-13"},"PeriodicalIF":0.0,"publicationDate":"2004-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24842710","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":"Therapeutic targeting of interactions between Nef and host cell proteins.","authors":"Kalle Saksela","doi":"10.2174/1568008043339776","DOIUrl":"https://doi.org/10.2174/1568008043339776","url":null,"abstract":"<p><p>Nef is a viral pathogenicity factor that has an important role in disease progression associated with HIV infection. Yet, no antiviral drugs capable of inhibiting of Nef are available or in clinical trials today. In this review the challenges and potential involved in pharmaceutical targeting of Nef are discussed in light of current understanding of the molecular mechanisms of Nef action, with a special emphasis on effector functions of Nef that are mediated via SH3 domain-directed interactions with host cell proteins.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"4 4","pages":"315-9"},"PeriodicalIF":0.0,"publicationDate":"2004-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24842711","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":"The impact of body mass index and type 2 diabetes on breast cancer: current therapeutic measures of prevention.","authors":"F Resta,&nbsp;V Triggiani,&nbsp;C Sabbà,&nbsp;B Licchelli,&nbsp;S Ghiyasaldin,&nbsp;A Liso,&nbsp;F Schittulli,&nbsp;M Quaranta,&nbsp;A Paradiso,&nbsp;E Tafaro,&nbsp;E Guastamacchia","doi":"10.2174/1568008043339686","DOIUrl":"https://doi.org/10.2174/1568008043339686","url":null,"abstract":"<p><p>Epidemiological data have suggested a possible relationship between obesity, diabetes mellitus and cancer risk, particularly breast cancer. We set out to investigate the effect of body mass index and diabetes mellitus on the presence of breast cancer in the Apulian population. We selected 1,663 women affected with primary breast cancer and 4,702 control patients. All patients with breast cancer underwent surgical excision of the tumor and their tumors were histologically confirmed. The prevalence of type 2 diabetes (8%) in the women affected by breast cancer was significantly higher than in the control group (5%) (p<0.05). The majority of the diabetic women affected by breast cancer had a BMI value >25, both in premenopause and in postmenopause. With respect to BMI, the non-diabetic patients with breast cancer in postmenopause showed the same pattern as the diabetic ones. Instead, among the women in premenopause a higher percentage (55%) of patients with a BMI <24.9 was found (p<0.01). In the Apulian population, the presence of both type 2 diabetes and elevated values of BMI (that is in a condition of hyperinsulinemia) were found to enhance the frequency of breast cancer.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"4 4","pages":"327-33"},"PeriodicalIF":0.0,"publicationDate":"2004-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24842713","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":"Blocking HIV-1 Vif restores a natural mechanism of intracellular antiviral defense.","authors":"Chiara Bovolenta","doi":"10.2174/1568008043339758","DOIUrl":"https://doi.org/10.2174/1568008043339758","url":null,"abstract":"<p><p>AIDS has become the greatest pandemic in the human history counting approximately 40 millions people worldwide. To purge HIV-1 infection, new therapeutic approaches need to be searched in alternative and/or in addition to the current pharmacological ones. Recently, several independent laboratories have unveiled a non-immune intracellular anti-HIV-1 defense strategy based on the cytidine deaminase APOBEC3G, which restricts HIV-1 production by directly mutating the proviral DNA in infected cells. To counteract this defense pathway, HIV-1 has developed an evasion strategy by acquiring the accessory protein Vif, which blocks the action of APOBEC3G by inducing its proteasome-mediated degradation.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"4 4","pages":"257-63"},"PeriodicalIF":0.0,"publicationDate":"2004-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24842749","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}