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

{"title":"Activins, myostatin and related TGF-beta family members as novel therapeutic targets for endocrine, metabolic and immune disorders.","authors":"Kunihiro Tsuchida","doi":"10.2174/1568008043339901","DOIUrl":"https://doi.org/10.2174/1568008043339901","url":null,"abstract":"<p><p>Activins and inhibins were first identified by virtue of their ability to regulate follicle-stimulating hormone (FSH) secretion from the anterior pituitary. Activins are also powerful regulators of gonadal functions. However, the physiological functions of activins are not restricted to reproductive tissues. Activins are involved in apoptosis of hepatocytes and B cells, fibrosis, inflammation and neurogenesis. Activins are regarded as novel drug targets since blocking activins would provide benefits by preventing apoptosis, fibrosis, inflammation and growth of several cancers. Activins are members of the transforming growth factor-beta (TGF-beta) family, which has numerous peptide growth and differentiation factors including activins, bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs) and TGF-betas. Among them, GDF8 is also known as myostatin and is structurally related to activins. Myostatin is specifically expressed in the skeletal muscle lineage and is a candidate for muscle chalone negatively regulating the growth of myoblasts. Myostatin is regarded as a good drug target since therapeutics that modulate skeletal muscle growth would be useful for disease conditions such as muscular dystrophy, sarcopenia, cachexia and even diabetes. Recent studies have revealed that activins and myostatin signal through activin type II receptors (ActRIIA and ActRIIB) and their activities are regulated by extracellular binding proteins, follistatins and follistatin-related gene (FLRG). Furthermore, signaling of activins, myostatin and related ligands is also controlled by intracellular receptor-interacting proteins by novel mechanisms. In this review, I would like to show the current progress in the field emphasizing the importance of activins and myostatin as novel drug targets for immune, endocrine and metabolic disorders.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"4 2","pages":"157-66"},"PeriodicalIF":0.0,"publicationDate":"2004-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568008043339901","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24551358","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":"Common and uncommon features of rheumatoid arthritis and chronic obstructive pulmonary disease: clues to a future therapy.","authors":"E Andreakos","doi":"10.2174/1568008043339910","DOIUrl":"https://doi.org/10.2174/1568008043339910","url":null,"abstract":"<p><p>Over the last decade it has become apparent that common pathogenic mechanisms are shared between many human chronic inflammatory diseases of unrelated pathology and manifestation. These mechanisms include common inflammatory networks that control tissue destructive and repair processes and their study is of major therapeutic potential as recently demonstrated for TNFalpha. Thus, early studies in rheumatoid arthritis defined TNFalpha as a major therapeutic target, the blockade of which was subsequently proved to be of great efficacy in the clinic. This paved the way for the successful blockade of TNFalpha in various other diseases including Crohn's disease, psoriasis, spondyloarthropathies and juvenile arthritis, although no similar networks with anti-TNFalpha at their apex had previously been demonstrated. In this article, we review the current knowledge of the pathogenic mechanisms involved in rheumatoid arthritis and chronic obstructive pulmonary disease with particular emphasis on the role of inflammatory cytokines, chemokines, and tissue degrading enzymes as revealed by studies in the laboratory and the clinic. Direct comparison of these mechanisms may provide clues for a future therapy for these painful and incurable diseases.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"4 2","pages":"85-92"},"PeriodicalIF":0.0,"publicationDate":"2004-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24550302","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":"Hyperferritinaemia without iron overload: pathogenic and therapeutic implications.","authors":"F Bertola,&nbsp;D Veneri,&nbsp;S Bosio,&nbsp;P Battaglia,&nbsp;A Disperati,&nbsp;R Schiavon","doi":"10.2174/1568008043339893","DOIUrl":"https://doi.org/10.2174/1568008043339893","url":null,"abstract":"<p><p>It is not unusual to meet increased levels of ferritinaemia in patients apparently healthy. Among other causes of hyperferritinaemia, recently was described the Hereditary Hyperferritinemia Cataract Syndrome, a genetic condition characterized by increased serum ferritin values without iron overload and bilateral nuclear cataract, both of early onset. It has been demonstrated that single or double point mutations or deletions in the stem-loop structure of the iron regulatory element (I.R.E.) located in the 5 untranslated regions of the ferritin L-subunit gene (19q13.1) are responsible for the upregulation of ferritin. This overexpression only for the L-chain gives rise to typical piles in several tissues. When this altered ferritin accumulates in lens it causes bilateral nuclear cataracts, that is the peculiar sign of this syndrome. It is essential to differentiate true iron overload from Hereditary Hyperferritinaemia Cataract Syndrome (H.H.C.S.), because these patients rapidly develop iron deficient anaemia when venosectioned. Here we describe a case report about a 40 years old healthy female blood donor who presented isolated hyperferritinaemia without iron overload, in the absence of concomitant pathologies. Anamnestic, biochemical, instrumental and clinical investigations led us to diagnose H.H.C.S., a pathology first described in 1995. From 1995 to date about 40 cases concerning patients showing the characteristics of this syndrome from Europe, USA, and Australia were described. Biochemical, genetical and clinical investigations led finally to understand every matter of this pathology, providing conclusive and exhaustive explanations.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"4 2","pages":"93-105"},"PeriodicalIF":0.0,"publicationDate":"2004-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24551352","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 implications of immune-endocrine interactions in the critically ill patients.","authors":"Reiner Oberbeck","doi":"10.2174/1568008043339884","DOIUrl":"https://doi.org/10.2174/1568008043339884","url":null,"abstract":"<p><p>The existence of an immune-endocrine interaction has been demonstrated decades ago. An immunomodulatory effect was reported for a wide range of hormones. The best known example for this interaction is the glucocorticoids released by the adrenal cortex. Apart of the glucocorticoids several hormones and neurotransmitters released by these systems are capable of altering immune functions. This includes the catecholamines epinephrine, norepinephrine and dopamine, the pituitary hormone prolactin, and the adrenal hormone dehydroepiandrosterone (DHEA). Several pathological states are paralleled by an activation of the endocrine system leading to an increased hormone release. In line with this an elevated release of catecholamines, of prolactin, and of DHEA has been demonstrated after major surgery, during systemic inflammation and following trauma hemorrhage. Furthermore, due to their pharmacologic properties several neurotransmitters are used as pharmaceutical agents to stabilize cardiovascular function or to prevent organ failure (e.g. epinephrine, norepinephrine, dopamine). Several pharmacological substances interact with the release of immunomodulatory hormones (e.g. metoclopramid and prolactin, dopamine and prolactin) and some hormones are available as over-the counter self medications like DHEA. Therefore, alterations of the serum concentrations of these hormones may affect the immunocompetence of the organism and may thereby affect the clinical course of critically ill patients. The clinical and pharmacological implications of this complex relationship between the endocrine and the immune system will be provided on the background of a review of the recent literature and of our research work.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"4 2","pages":"129-39"},"PeriodicalIF":0.0,"publicationDate":"2004-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568008043339884","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24551355","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":"Treatment of inflammatory and paraproteinemic neuropathies.","authors":"Salvatore Monaco,&nbsp;Emanuela Turri,&nbsp;Gianluigi Zanusso,&nbsp;Barbara Maistrello","doi":"10.2174/1568008043339947","DOIUrl":"https://doi.org/10.2174/1568008043339947","url":null,"abstract":"<p><p>Acquired demyelinating and inflammatory neuropathies encompass a number of acute and chronic autoimmune conditions characterized by variable degrees of clinical involvement. These disorders, including Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy (MMN), and paraprotein-associated neuropathy, have an overall annual incidence of 2-4/100,000 worldwide and are potentially treatable. Over the last few years, several investigations have helped clarify the pathogenesis of immune neuropathies and the definition of molecular targets involved in these diseases, thus providing firmer grounds for treatment with classical immunosuppressive drugs and new biological agents. In GBS and related variants, which are characterized by cellular inflammation and alterations of the blood-nerve barrier, randomized clinical trials show that plasma exchange (PE) and intravenous immunoglobulin (IVIg) are equally effective as disease-modifying treatments, although IVIg has been adopted as the favourite treatment in most centres. In CIDP, controlled clinical trials have established the efficacy of oral prednisone, PE and IVIg, with intermittent IVIg treatment or corticosteroids being usually preferred. Adding azathioprine can help keep lower the required dose of prednisone, while other immunosuppressive agents, such as cyclophosphamide and cyclosporin A may have side effects, limiting their use to selected cases. Currently, the efficacy of interferon beta and alfa is under evaluation. Controlled trials support the view that IVIg is the treatment of choice in MMN. Patients resistant to IVIg administration may benefit of treatments which deplete B cells, such as cyclophosphamide and rituximab. Demyelinating neuropathies associated with circulating paraproteins are clinically heterogeneous, depending on the reactivity and type of the monoclonal (M) protein. In many cases, neuropathies associated with IgM M proteins are not treated because of their slow progression. In patients with a disabling or rapid progression, small trials have shown short-term benefits from IVIg or PE. Recently, fludarabine and rituximab have been reported as beneficial in selected cases.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"4 2","pages":"141-8"},"PeriodicalIF":0.0,"publicationDate":"2004-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24551356","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":"DI-2-ethylhexyl phthalate and endocrine disruption: a review.","authors":"Giuseppe Latini,&nbsp;Alberto Verrotti,&nbsp;Claudio De Felice","doi":"10.2174/1568008043340017","DOIUrl":"https://doi.org/10.2174/1568008043340017","url":null,"abstract":"<p><p>Esters of o-phthalic acid are widely distributed in the ecosystem. The phthalate acid esters (PAE's) are used as plasticizers in enormous quantities for a variety of industrial uses in the formulation of plastics. They are also used as solvents in certain industrial processes and as vehicles for pesticides and have been described as being among the most abundant man-made environmental pollutants. Plasticizers have been shown to elute at a constant rate from plastic products to the environment. Increasing chemical use needs a better understanding of how these pollutants may affect human health. In particular, certain members of this chemical class, such as di-[2-ethylhexyl]-phthalate (DEHP), have been shown to cause reproductive and developmental toxicity and are suspected to be endocrine disruptors.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"4 1","pages":"37-40"},"PeriodicalIF":0.0,"publicationDate":"2004-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568008043340017","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40851430","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 utility of proteomic patterns for the diagnosis of cancer.","authors":"Thomas P Conrads,&nbsp;Timothy D Veenstra","doi":"10.2174/1568008043340062","DOIUrl":"https://doi.org/10.2174/1568008043340062","url":null,"abstract":"<p><p>The advent of proteomics has brought with it the hope of discovering novel biomarkers that can be used to diagnose diseases, predict susceptibility, and monitor progression. Much of this effort has focused on the mass spectral identification of the thousands of proteins that populate complex biosystems such as serum and tissues. A revolutionary approach termed proteomic pattern analysis has emerged as an effective method for the early diagnosis of diseases such as ovarian, breast, and prostate cancer. Proteomic pattern analysis relies on the pattern of proteins observed and does not rely on the identification of a traceable biomarker. Utilizing this technology, hundreds of clinical samples per day can be analyzed with the potential to be a novel, highly sensitive diagnostic tool for the early detection of diseases or as a predictor of response to therapy.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"4 1","pages":"41-50"},"PeriodicalIF":0.0,"publicationDate":"2004-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40851431","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":"Melatonin role in experimental arthritis.","authors":"Daniel P Cardinali,&nbsp;Ana P García,&nbsp;Pilar Cano,&nbsp;Ana I Esquifino","doi":"10.2174/1568008043340071","DOIUrl":"https://doi.org/10.2174/1568008043340071","url":null,"abstract":"<p><p>Our perception of the function of the pineal gland and its hormone melatonin has attained a new dimension during the last decade. Through melatonin, the pineal becomes a principal organ present in vertebrates involved in the control of rhythmic adaptations to daily and seasonal cycles. Melatonin is synthesized and secreted during the dark period of the light/dark cycle. The rhythmic nocturnal melatonin secretion is directly generated by the circadian clock and is entrained to a 24-hour period by the light-dark cycle. The periodic secretion of melatonin may be used as a circadian mediator to any system than can \"read\" the message. Melatonin acts as an arm of the circadian clock, giving a time-related signal to a number of body functions; one of them is the circadian organization of the immune response. This review discusses melatonin role in rheumatoid arthritis. Animal studies employing Freund's complete mycobacterial adjuvant (FCA) as a model of rheumatoid arthritis are described. Immune and neuroendocrine circadian rhythms were examined in FCA-injected rats, both in the preclinical phase of arthritis (2-3 days after FCA injection) as well as in the acute phase of the disease (18 days after FCA injection). In arthritic rats, the 24-h organization of immune and neuroendocrine responses becomes altered. Significant effects of immune response on diurnal rhythmicity of adenohypophysial and hypophysiotropic hormones occurred in arthritic rats. Melatonin treatment prevented alteration of 24-h rhythms of serum ACTH, prolactin and luteinizing hormone in rats injected with FCA. In addition, melatonin treatment prevented alteration of the 24-h variation in hypothalamic monoamine transmitter turnover during the preclinical phase of Freund's adjuvant arthritis in rats. A comparison between the inflammatory and immune responses elicited by physiological and pharmacological doses of melatonin in FCA arthritis is reported. Pinealectomized rats exhibited a significantly less pronounced inflammatory response, which was restored to normal by a low melatonin dose (0.3 microg/ml of drinking water), whereas a high melatonin dose (30 microg/ml) that resulted in a 50-60-fold increase in plasma melatonin, augmented the inflammatory and immune response. These results should be considered in the light of recent reports that rheumatoid arthritis patients have increased nocturnal plasma levels of melatonin and that their synovial macrophages respond to melatonin with an increased cytokine production.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"4 1","pages":"1-10"},"PeriodicalIF":0.0,"publicationDate":"2004-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568008043340071","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40850970","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":"CD26/dipeptidyl peptidase IV: a regulator of immune function and a potential molecular target for therapy.","authors":"Ugur Aytac,&nbsp;Nam H Dang","doi":"10.2174/1568008043340035","DOIUrl":"https://doi.org/10.2174/1568008043340035","url":null,"abstract":"<p><p>CD26 is a 110 kDa surface-bound ectopeptidase with intrinsic dipeptidyl peptidase IV (DPP IV) activity, which has multiple biological functions. In this review, we will focus specifically on work demonstrating that CD26 has a key role in immune function as a T cell activation molecule and a regulator of the functional effect of selected biological factors through its DPP IV enzyme activity. As further evidence of the important role played by this multifaceted molecule in immune regulation, we will also discuss experimental attempts from our laboratory and others to influence immune-mediated conditions through CD26 monoclonal antibodies and DPP IV activity with various agents, including anti-CD26 monoclonal antibodies and DPP IV chemical inhibitors. Of special significance from a clinical perspective is also CD26 effect on glucose metabolism through its DPP IV activity and its potential role as a therapeutic target in diabetes. In addition, we will review recent studies that describe the physical and functional interaction of CD26 with other essential cellular structures and the biological consequences of their association. In particular, we will present recent data from our laboratory that demonstrates the correlation between CD26, especially its DPP IV activity, and the key nuclear protein topoisomerase II alpha, an interaction that has important clinical implications. In summary, we will examine the biology of the multifaceted CD26/DPP IV molecule, focusing particularly on its function in immune regulation and its potential role as a molecular target for novel treatment modalities for a number of disease states, ranging from autoimmune diseases, diabetes to malignancies.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"4 1","pages":"11-8"},"PeriodicalIF":0.0,"publicationDate":"2004-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568008043340035","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40850971","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":"HDL and inflammation in atherosclerosis.","authors":"Lukas E Spieker,&nbsp;Frank Ruschitzka,&nbsp;Thomas F Lüscher,&nbsp;Georg Noll","doi":"10.2174/1568008043340044","DOIUrl":"https://doi.org/10.2174/1568008043340044","url":null,"abstract":"<p><p>Atherosclerotic vascular disease is among the most frequent causes of death worldwide. Current therapeutic strategies concentrate mainly on lowering of low-density lipoprotein (LDL) cholesterol and an impressive reduction in the risk for cardiovascular morbidity and mortality has been achieved. Inflammatory mechanisms are more and more recognized to play an important role in vascular disease as inflammatory markers correlate with prognosis in acute and chronic coronary artery disease. HDL cholesterol exerts anti-inflammatory effects on the vasculature. Moreover, HDL is an antioxidant, inhibits thrombogenesis, and has pro-fibrinolytic properties. Last but not least, HDL mediates reverse cholesterol transport. These pleiotropic effects make HDL an ideal therapeutic target for novel therapeutic strategies specifically aiming at HDL elevation for the prevention and treatment of atherosclerotic vascular disease.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"4 1","pages":"51-7"},"PeriodicalIF":0.0,"publicationDate":"2004-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40851432","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}