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

{"title":"Management of liver disease in thalassemia: main drug targets for a correct therapy.","authors":"G C Del Vecchio,&nbsp;A Nigro,&nbsp;P Giordano,&nbsp;D De Mattia","doi":"10.2174/156800805774912917","DOIUrl":"https://doi.org/10.2174/156800805774912917","url":null,"abstract":"<p><p>Liver disease is the second cause of mortality in thalassemia major. We present a review on the hepatic damage in thalassemic patients aimed at a knowledge of current preventive, diagnostic and therapeutic approaches, useful to guide in clinical judgment and treatment decisions. Transfusion related iron overload and hepatitis are the causes of liver damage in thalassemic patients. We examined means of primary prevention, anti-hepatitis vaccinations, blood donors screening; diagnostic tests for secondary prevention (computed tomography, magnetic resonance imaging, super conducting quantum interference device and biopsy) were also discussed about. A survey of treatment methods and strategies ( chelation therapy, antiviral treatments and liver and bone marrow transplantation) follows.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"5 4","pages":"373-8"},"PeriodicalIF":0.0,"publicationDate":"2005-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800805774912917","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25768655","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":"Failure of immune homeostasis -- the consequences of under and over reactivity.","authors":"B Crimeen-Irwin,&nbsp;K Scalzo,&nbsp;S Gloster,&nbsp;P L Mottram,&nbsp;M Plebanski","doi":"10.2174/156800805774912980","DOIUrl":"https://doi.org/10.2174/156800805774912980","url":null,"abstract":"<p><p>The immune system is a tightly regulated network that is able to maintain a balance of immune homeostasis under normal physiological conditions. Normally, when challenged with foreign antigen, specific appropriate responses are initiated that are aimed at restoring homeostasis. However under particular circumstances, this balance is not maintained and immune responses either under or over react. Cancer is an example of a situation where the immune response can be inefficient or unresponsive, resulting in uncontrolled growth of the cancer cells. Conversely, when the immune response over-reacts, this can result in conditions such as autoimmunity or pathology following infection. Many drug therapies have been developed that aim to alleviate or prevent such immune disorders and restore immune homeostasis. This review highlights recent advances in immunotherapies, with an emphasis on specific examples in the treatment of cancer, autoimmune disease (multiple sclerosis) and viral infection (respiratory syncytial virus).</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"5 4","pages":"413-22"},"PeriodicalIF":0.0,"publicationDate":"2005-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800805774912980","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25768658","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":"Boosting interleukin-10 production: therapeutic effects and mechanisms.","authors":"Xiaoxia Zhou,&nbsp;Peter Schmidtke,&nbsp;Fred Zepp,&nbsp;Claudius U Meyer","doi":"10.2174/156800805774912926","DOIUrl":"https://doi.org/10.2174/156800805774912926","url":null,"abstract":"<p><p>More than forty cytokines have been extensively researched on the molecular structure, cell signaling and transduction pathway. With respect to cytokine-regulating therapy in immunological imbalance however, the reported results are conflicting because of the pleiotropic functions and the intricate interactions of the cytokine network. In this review, we outline the observations on interleukin-10 (IL-10) upregulatory therapy. Despite varying opinions on its therapeutic effects for different disorders, IL-10 has been considered a potential anti-inflammatory cytokine. Numerous studies support the view that IL-10 shows a strong suppressive effect on Th1 lymphocytes, antigen presenting cells and the production of inflammatory mediators. It is also noticeable that recent research has revealed the relationship between IL-10 induced antigen specific regulatory CD4+ T cells and antigen specific immune tolerance. This specific regulation was mediated in part through IL-10 secretion, because anti-IL-10 treatment reverted the inhibitory effect of regulatory T cell clones. In different models, these cells were shown to inhibit both Th1 and Th2-type inflammatory responses through the secretion of IL-10. With the presence of IL-10, regulatory T cells may induce peripheral immune tolerance. Exogenous administration, transgenic expression and endogenous stimulative agents of IL-10 have been used for a variety of inflammatory diseases, autoimmune diseases and allograft rejection in patients and experimental models. A therapeutic intervention with drug inducing endogenous IL-10 may be more practical than an exogenous administration of IL-10 with transient effect. Although further investigation on gene regulation of IL-10 is necessary, increasing studies have been reported concerning the attempt to develop the agents, which could promote endogenous IL-10 production for the treatment of immunological disorders and inflammatory diseases. With some unclear mechanisms, these agents have strongly upregulated IL-10 production in vitro or in vivo. Reported IL-10 upregulatory agents have shown promising prospects for remission of autoimmune diseases and inflammatory diseases and have even induced antigen specific immune tolerance. It is interesting that the IL-10 upregulatory effect of several traditional immunosuppressive drugs has been detected, e.g. glucocorticoid, which is considered \"not more as an immunosuppressive drug but an immune modulating agent\". Approximately twenty IL-10 upregulatory agents as instances are described in the present review. In addition, their therapeutic effects in various diseases are discussed.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"5 4","pages":"465-75"},"PeriodicalIF":0.0,"publicationDate":"2005-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800805774912926","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25768599","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":"Molecular basis of therapeutic strategies for breast cancer.","authors":"Jing Huang,&nbsp;Xiaodong Li,&nbsp;Russell Hilf,&nbsp;Robert A Bambara,&nbsp;Mesut Muyan","doi":"10.2174/156800805774912944","DOIUrl":"https://doi.org/10.2174/156800805774912944","url":null,"abstract":"<p><p>The development of breast cancer is the consequence of uncontrolled growth and division of breast-ductal epithelial cells. While many factors contribute to its etiology, estrogen hormones within the context of many interrelated growth signaling pathways play critical roles for the initiation and development of breast cancer. The effects of estrogens are primarily mediated by the estrogen receptors (ERs) alpha and beta. ER mediates a complex array of genomic and non-genomic events that orchestrate cellular metabolism, mitogenesis, morphogenesis, motogenesis, and apoptosis. The current modalities for the treatment of breast cancer have centered on the development of agents with diverse pharmacology to reduce/ablate the circulating estrogens or to alter/prevent ER function. Approaches to perturb the estrogen environment are successful usually in the remission of established tumors. However, many breast tumors are not responsive or eventually develop resistance to endocrine therapies. Despite considerable effort, the mechanism for the non-responsiveness and acquisition of resistance remains unclear. The establishment of hormone responsiveness is one of the current approaches for the development of an effective therapeutic modality for de novo resistant breast tumors. Re-establishment of loss of ER synthesis/function, on the other hand, constitutes a primary therapeutic goal for acquired resistance neoplasms. We have recently engineered transregulatory proteins that specifically targeted and robustly regulated estrogen responsive genes independent of ligand, ER-subtype and cell-context. The targeted regulation of estrogen responsive gene networks by these designer transregulators could provide a basis for the development of novel approaches for experimental biology and medicine.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"5 4","pages":"379-96"},"PeriodicalIF":0.0,"publicationDate":"2005-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800805774912944","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25768656","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 new immunosuppression: intervention at the dendritic cell-T-cell interface.","authors":"A M Paterson,&nbsp;S F Yates,&nbsp;K F Nolan,&nbsp;H Waldmann","doi":"10.2174/156800805774912935","DOIUrl":"https://doi.org/10.2174/156800805774912935","url":null,"abstract":"<p><p>Dendritic cells (DCs) play an important role in initiating and directing T-cells towards immunity or tolerance. An important aim of emerging immunosuppressive strategies is to ensure that antigen is perceived in a 'tolerogenic context'. This would have obvious benefit in minimising the need for long-term drug maintenance in organ transplantation, hypersensitivity and autoimmune diseases. Here we review the biology of the interplay between the DC and T-cell, with a specific focus on therapeutic drugs targeting molecules that effect their interaction and function.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"5 4","pages":"397-411"},"PeriodicalIF":0.0,"publicationDate":"2005-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800805774912935","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25768657","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":"Augmenting T helper cell immunity in cancer.","authors":"K L Knutson,&nbsp;M L Disis","doi":"10.2174/156800805774913006","DOIUrl":"https://doi.org/10.2174/156800805774913006","url":null,"abstract":"<p><p>Cancer specific immunity elicited with vaccines has traditionally focused on the activation of the CD8 cytolytic T lymphocyte (CTL) often involving direct stimulation of immunity using HLA-class I binding peptide epitopes. Recently it has become clear that activation of the CTL immune effector arm alone is insufficient to mediate an anticancer response. A major problem is that CD8 T cells alone can not be sustained without the concomitant activation of CD4 T helper (Th) cells. In fact, it is now widely recognized that the Th cell regulates nearly all aspects of the adaptive immune response. In addition, Th cells can recruit the innate immune system during immune augmentation. Therefore, the focus of the immune response in cancer has shifted away from activating CTL immunity alone to activating Th cell immunity alone or concurrently with CTL. Evidence suggests that activating the Th cell is sufficient to get a complete adaptive immune response because, once activated, the Th cell will elicit endogenous CD8 T cell and humoral immunity. In this review, we discuss the role of the Th cell in the adaptive immune response to cancer, how peptides that are capable of activation of Th cells are identified, and the clinical translation of newly identified candidate Th cell peptide epitopes to human cancer specific vaccines. Over the next decade, studies should begin to further define how we can manipulate the Th immune effector arm to achieve effective antitumor immunity.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"5 4","pages":"365-71"},"PeriodicalIF":0.0,"publicationDate":"2005-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800805774913006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25768654","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":"Signal transducer and activator of transcription 5 (STAT5), a crucial regulator of immune and cancer cells.","authors":"Ilka Wittig,&nbsp;Bernd Groner","doi":"10.2174/156800805774912999","DOIUrl":"https://doi.org/10.2174/156800805774912999","url":null,"abstract":"<p><p>STAT5 belongs to a small family of transcription factors with dual functions. The seven signal transducers and activators of transcription (STAT) act as signaling components between the plasma membrane and the nucleus, and as transcription factors with specific DNA binding ability in the nucleus. STAT5 regulates the expression of genes, which determine important cellular phenotypes. It can promote proliferation and inhibit apoptosis, but is also involved in the regulation of differentiation between specific gene expression. STAT5 can also contribute to the transformed phenotype. In many leukemias and some solid tumors, STAT5 is constitutively activated through receptors or receptor associated tyrosine kinases and contributes to the survival and the proliferation of malignant cells. STAT5 activity appears to be limiting for these phenotypes. Inhibition of STAT5 in these tumor cells results in growth arrest and apoptosis. Targeting of STATs and other downstream mediators of oncogenic tyrosine kinases provides a promising strategy for tumor therapy, which might be refractory to resistance mechanisms incapacitating tyrosine kinase inhibitors. The well-studied steps in the activation of STAT5 and its roles in different subcellular compartments suggest original interference strategies, which could be used to inhibit its function. The challenge for drug developers will be the exploitation of defined protein-protein or protein-DNA interactions as targets of inhibition.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"5 4","pages":"449-63"},"PeriodicalIF":0.0,"publicationDate":"2005-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800805774912999","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25768598","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":"Amino Acid Transporter ATB0,+ as a delivery system for drugs and prodrugs.","authors":"M E Ganapathy,&nbsp;V Ganapathy","doi":"10.2174/156800805774912953","DOIUrl":"https://doi.org/10.2174/156800805774912953","url":null,"abstract":"<p><p>ATB(0,+) is a unique amino acid transporter because of its broad substrate specificity and concentrative ability. This transporter recognizes neutral as well as cationic amino acids. It is energized by Na(+) and Cl(-) gradients and membrane potential. Many of the amino acids and amino acid derivatives that are substrates for ATB(0,+) serve as therapeutic agents (e.g., D-serine, carnitine, and nitric oxide synthase inhibitors). Recent studies have shown that the potential of ATB(0,+) as a drug delivery system may be greater than previously envisaged. ATB(0,+) can transport antiviral drugs such as acyclovir and ganciclovir when they are covalently coupled to the side chain of anionic amino acids. Chemical modification of the carboxyl groups in the side chain of aspartate and glutamate with drugs converts these anionic amino acids into neutral amino acid derivatives. Therefore, the modified drugs are recognized by ATB(0,+). Interestingly, even when acyclovir and ganciclovir are coupled as esters with alpha-carboxyl group of neutral amino acids, the modified drugs are transported via ATB(0,+). Similarly, the hydroxyl group in the side chains of serine and threonine can also be used to covalently couple drugs for delivery into cells via ATB(0,+). This increases the potential for designing a wide variety of amino acid-based prodrugs that can utilize ATB(0,+) as drug delivery system. Furthermore, the transporter is expressed in the colon, lung, and eye, the tissues easily amenable for drug delivery. These findings argue strongly in support of ATB(0,+) as a potential delivery system for a wide variety of drugs and prodrugs.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"5 4","pages":"357-64"},"PeriodicalIF":0.0,"publicationDate":"2005-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800805774912953","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25768653","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":"Insulin regulation of PEPCK gene expression: a model for rapid and reversible modulation.","authors":"P G Quinn,&nbsp;D Yeagley","doi":"10.2174/156800805774912962","DOIUrl":"https://doi.org/10.2174/156800805774912962","url":null,"abstract":"<p><p>Insulin and glucagon regulate the expression and/or activity of a variety of proteins to maintain blood glucose within normal limits. A key target is the gene encoding phosphoenolpyruvate carboxykinase (PEPCK), which catalyzes the first committed step in hepatic gluconeogenesis. Acute regulation of PEPCK is achieved by modulating transcription of the gene, which is tightly regulated by cAMP (the mediator of glucagon and catecholamines), glucocorticoids and insulin. Normally, PEPCK expression is induced by glucagon, catecholamines and glucocorticoids during periods of fasting and in response to stress, but is dominantly inhibited by glucose-induced increases in insulin secretion upon feeding. The incomplete effectiveness of insulin action, whether due to intermittent insulin injection in type I diabetics or insulin resistance in type II diabetics, contributes to hyperglycemia and complications, resulting in damage to the eyes, nerves, kidneys and other organs over time. Thus, defining a molecular mechanism for insulin inhibition of PEPCK gene transcription has been a major goal of research in several labs, because it would allow the development of drugs to prevent episodic increases in circulating glucose in diabetics. Here, we review the main lines of investigation into this complex problem and the likely properties of an inhibitor. Any mechanism must account for the rapidity, specificity and dominance with which insulin is known to act in regulating PEPCK transcription. To date Foxo1 (FKHR) is the only transcription factor for which a complete path from the insulin receptor to gene regulation has been described. While this explains the regulation of some genes, such as IGFBP-1, Foxo1 appears not to play a requisite role in regulating PEPCK transcription. Investigation of cis-acting elements in the PEPCK promoter has shed considerable light on the mechanisms of activation by cAMP and glucocorticoids but has failed to identify a regulatory element that mediates insulin inhibition of transcription. This, together with evidence from analysis of the inducing mechanisms, has prompted us, and others, to investigate the possibility that insulin disrupts activation rather than independently promoting repression. Thus, we hypothesize that insulin-induced modification of a key transcription regulatory protein prevents an essential factor from participating in the induction process, leading to rapid but reversible inhibition, as is seen in animals. The ability to alter the sensitivity of a key transcription factor to improve insulin-regulated control of blood glucose would be a major improvement in the treatment of diabetes, a growing problem in the industrialized world.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"5 4","pages":"423-37"},"PeriodicalIF":0.0,"publicationDate":"2005-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800805774912962","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25768659","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":"Hormonal effects on drug metabolism through the CYP system: perspectives on their potential significance in the era of pharmacogenomics.","authors":"N J Sarlis,&nbsp;L Gourgiotis","doi":"10.2174/156800805774912971","DOIUrl":"https://doi.org/10.2174/156800805774912971","url":null,"abstract":"<p><p>Cytochrome P450 (CYP) is a group of enzymes that metabolize drugs to a more water-soluble form, rendering them available for renal excretion. The major site of CYP expression is the liver. Nearly 50% of all medications currently on the market are metabolized by the enzyme CYP3A4, while metabolism of another 35-40% occurs through enzymes CYP1A2, CYP2C19, CYP2D6, CYP3A5 CYP3A6, and CYP3A7. Here, we summarize the current knowledge of the effects of hormones on the CYP family. The term \"hormone\" is used in its broad sense and includes products of the major endocrine glands (i.e., thyroid, adrenals, gonads, pancreas) and compounds that are not classically considered hormones, such as neurogenic amines, cytokines, interleukins, and eicosanoids. In addition, we comment on the effects on CYP expression of states associated with profound hormonal changes, such as pregnancy, malnutrition, obesity, diabetes mellitus, systemic inflammation, and conditions of altered extracellular fluid volume or osmolality. Available data are limited and are derived primarily from in vitro and animal studies. Moreover, the picture is obscured by conflicting results among studies and the complexity of the regulation of the expression and activity of elements of the CYP system. While the clinical significance of hormonal effects on the CYP system remains to be determined, we anticipate that such effects will be most pertinent to drugs with a narrow therapeutic range. Further research is needed to determine the scope and significance of these effects in view of rapid advances in the field of pharmacogenomics and the ever-increasing number of drugs available for therapeutic use.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"5 4","pages":"439-48"},"PeriodicalIF":0.0,"publicationDate":"2005-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800805774912971","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25768660","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}