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

{"title":"Tissue-specific glucocorticoid reactivating enzyme, 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1)--a promising drug target for the treatment of metabolic syndrome.","authors":"Hiroaki Masuzaki,&nbsp;Jeffrey S Flier","doi":"10.2174/1568008033340135","DOIUrl":"https://doi.org/10.2174/1568008033340135","url":null,"abstract":"<p><p>Obesity is closely associated with the Metabolic Syndrome, which includes insulin resistance, glucose intolerance, dyslipidemia and hypertension. The best predictor of these morbidities is not the total body fat mass but the quantity of visceral (e.g. omental, mesenteric) fat. Glucocorticoids play a pivotal role in regulating fat metabolism, function and distribution. Indeed, patients with Cushing-s syndrome (a rare disease characterized by systemic glucocorticoid excess originating from the adrenal or pituitary tumors) or receiving glucocorticoid therapy develop reversible visceral fat obesity. The role of glucocorticoids in prevalent forms of human obesity, however, has remained obscure, because circulating glucocorticoid concentrations are not elevated in the majority of obese subjects. Glucocorticoid action on target tissue depends not only on circulating levels but also on intracellular concentration. Locally enhanced action of gluccorticoids in adipose tissue and skeletal muscle has been demonstrated in the Metabolic Syndrome. Evidence has accumulated that enzyme activity of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which regenerates active glucocorticoids from inactive forms and plays a central role in regulating intracellular glucocorticoid concentration, is commonly elevated in fat depots from obese individuals. This suggests a role for local glucocorticoid reactivation in obesity and the Metabolic Syndrome. 11beta-HSD1 knockout mice resist visceral fat accumulation and insulin resistance even on a high-fat diet. Furthermore, fat-specific 11beta-HSD1 transgenic mice, those have increased enzyme activity to a similar extent seen in obese humans, develop visceral obesity with insulin and leptin resistance, dyslipidemia and hypertension. In adipocytes, both antidiabetic PPARgamma agonists and LXRalpha agonists significantly reduce 11beta-HSD1 mRNA and enzyme activity, suggesting that suppression of 11beta-HSD1 in adipose tissue may be one of the mechanisms by which these drugs exert beneficial metabolic effects. Recently reported selective inhibitors of 11beta-HSD1 can ameliorate severe hyperglycemia in the genetically diabetic obese mice. In summary, 11beta-HSD1 is a promising pharmaceutical target for the treatment of the Metabolic Syndrome.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"3 4","pages":"255-62"},"PeriodicalIF":0.0,"publicationDate":"2003-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568008033340135","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24133529","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":"Physiological roles of glycogen synthase kinase-3: potential as a therapeutic target for diabetes and other disorders.","authors":"J R Woodgett","doi":"10.2174/1568008033340153","DOIUrl":"10.2174/1568008033340153","url":null,"abstract":"<p><p>Glycogen synthase kinase-3 (GSK-3) has perplexed signal transduction researchers since its detection in skeletal muscle 25 years ago. The enzyme confounds most of the rules normally associated with protein kinases in that it exhibits significant activity, even in resting, unstimulated cells. However, the protein is highly regulated and potently inactivated in response to signals such as insulin and polypeptide growth factors. The enzyme also displays a distinct and unusual preference for substrates that have been previously phosphorylated by other protein kinases which provides obvious opportunities for cross-talk. Its substrates are diverse and are predominantly regulatory molecules. The molecular cloning of the kinase revealed it to be encoded by two related but distinct genes. Moreover, the mammalian proteins showed remarkable similarity to a fruitfly protein isolated on the basis of its role in cell fate determination. From these humble beginnings, study of the enzyme has accrued further surprises such as its inhibition by lithium, its regulation by serine and tyrosine phosphorylation and its implication in several human disorders including Alzheimers disease, bipolar disorder, cancer and diabetes. Most recently, small molecule inhibitors of GSK-3 have been developed and assessed for therapeutic potential in several of models of pathophysiology. The question is whether modulation of such an \"involved\" enzyme could lead to selective restoration of defects without multiple unwanted side effects. This review summarizes current knowledge of GSK-3 with respect to its known functions, together with an assessment of its real-life potential as a drug target for chronic conditions such as type 2 diabetes.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"3 4","pages":"281-90"},"PeriodicalIF":0.0,"publicationDate":"2003-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490889/pdf/nihms1578.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24132292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preface [Hot topic: Diabetes (Guest Editor: Alex M. DePaoli)]","authors":"A. DePaoli","doi":"10.2174/1568008033340126","DOIUrl":"https://doi.org/10.2174/1568008033340126","url":null,"abstract":"","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"3 1","pages":"1-1"},"PeriodicalIF":0.0,"publicationDate":"2003-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67889743","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":"Thalidomide derived immunomodulatory drugs (IMiDs) as potential therapeutic agents.","authors":"J Blake Marriott,&nbsp;Keith Dredge,&nbsp;Angus G Dalgleish","doi":"10.2174/1568008033340207","DOIUrl":"https://doi.org/10.2174/1568008033340207","url":null,"abstract":"<p><p>Thalidomide is known to be effective in the treatment of a number of conditions, including leprosy and various cancers. The exact mechanisms of action remain unclear although these are known to include anti-tumour necrosis factor (TNF)-alpha, T cell costimulatory, anti-angiogenic and anti-tumour activities. However, thalidomide is being superceded by novel structural derivatives which have been designed to have improved immunomodulatory activity and side effect profiles. These are currently being characterised and some are entering the clinic in phase I/II studies. One novel group of structural analogues are classified as the Immunomodulatory Drugs (IMiDs). This review describes the emerging immunological, anti-angiogenic and direct anti-tumour properties of thalidomide and the characterisation and clinical application of its IMiD analogues. We describe the laboratory studies which have led to the characterisation and development of IMiDs into potentially clinically relevant drugs. Early trial data suggests that these compounds may themselves become established therapies, particularly in certain cancers. Furthermore, ongoing studies will determine how best to apply these compounds to the appropriate clinical settings. We will describe the various clinical studies of lead compounds that are in progress and speculate as to the potential and future development of these exciting compounds.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"3 3","pages":"181-6"},"PeriodicalIF":0.0,"publicationDate":"2003-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568008033340207","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22490596","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":"Induction of optimal immune responses against human immunodeficiency virus at mucosal portals of entry.","authors":"M Vajdy","doi":"10.2174/1568008033340225","DOIUrl":"https://doi.org/10.2174/1568008033340225","url":null,"abstract":"<p><p>Mucosal surfaces comprise the largest surface area of the human body and are the first line of defense against many pathogens. In fact, over 90% of common infectious disease pathogens in humans gain access to the host through mucosal membranes. A number of studies have demonstrated that mucosal immunizations induce local as well as systemic immunity. However, induction of mucosal responses by mucosal immunization is often hampered by a number of factors including degradation of vaccines at the site of delivery. Moreover, many pathogens, including the human immunodeficiency virus, HIV, primarily enter the host through a mucosal membrane after which they spread systemically. Thus, induction of optimal and protective immune responses are required at both mucosal and systemic sites. This review deals with current efforts on the induction of HIV-specific prophylactic humoral and/or cell mediated immunity in the female genital tract and rectal mucosa. The importance of the various routes of mucosal or systemic as well as combinations of mucosal and systemic immunizations through delivery of gene and protein based experimental vaccines will be reviewed. Furthermore, a summary of current and future therapeutic treatment targets will be presented.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"3 3","pages":"222-33"},"PeriodicalIF":0.0,"publicationDate":"2003-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568008033340225","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22490601","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":"Skin photoprotection by green tea: antioxidant and immunomodulatory effects.","authors":"Santosh K Katiyar","doi":"10.2174/1568008033340171","DOIUrl":"https://doi.org/10.2174/1568008033340171","url":null,"abstract":"<p><p>Because of a characteristic aroma and health benefits, green tea is consumed worldwide as a popular beverage. The epicatechin derivatives, commonly called polyphenols, present in green tea possess antioxidant, anti-inflammatory and anti-carcinogenic properties. The major and most highly chemopreventive constituent in green tea responsible for the biochemical or pharmacological effects is (-)-epigallocatechin-3-gallate (EGCG). Epidemiological, clinical and biological studies have implicated that solar ultraviolet (UV) light is a complete carcinogen and repeated exposure can lead to the development of various skin disorders including melanoma and nonmelanoma skin cancers. We and others have shown that topical treatment or oral consumption of green tea polyphenols (GTP) inhibit chemical carcinogen- or UV radiation-induced skin carcinogenesis in different laboratory animal models. Topical treatment of GTP and EGCG or oral consumption of GTP resulted in prevention of UVB-induced inflammatory responses, immunosuppression and oxidative stress, which are the biomarkers of several skin disease states. Topical application of GTP and EGCG prior to exposure of UVB protects against UVB-induced local as well as systemic immune suppression in laboratory animals, which was associated with the inhibition of UVB-induced infiltration of inflammatory leukocytes. Prevention of UVB-induced suppression of immune responses by EGCG was also associated with the reduction in immunosuppressive cytokine interleukin (IL)-10 production at UV irradiated skin and draining lymph nodes, whereas IL-12 production was significantly enhanced in draining lymph nodes. Antioxidant and anti-inflammatory effects of green tea were also observed in human skin. Treatment of EGCG to human skin resulted in the inhibition of UVB-induced erythema, oxidative stress and infiltration of inflammatory leukocytes. We also showed that treatment of GTP to human skin prevents UVB-induced cyclobutane pyrimidine dimers formation, which are considered to be mediators of UVB-induced immune suppression and skin cancer induction. The in vitro and in vivo animal and human studies suggest that green tea polyphenols are photoprotective in nature, and can be used as pharmacological agents for the prevention of solar UVB light-induced skin disorders including photoaging, melanoma and nonmelanoma skin cancers after more clinical trials in humans.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"3 3","pages":"234-42"},"PeriodicalIF":0.0,"publicationDate":"2003-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568008033340171","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22490602","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":"A discussion of natural rubber latex allergy with special reference to children: clinical considerations.","authors":"Nettis Eustachio,&nbsp;Colanardi Maria Cristina,&nbsp;Ferrannini Antonio,&nbsp;Tursi Alfredo","doi":"10.2174/1568008033340234","DOIUrl":"https://doi.org/10.2174/1568008033340234","url":null,"abstract":"<p><p>Latex allergy is an increasingly common condition, because the use of latex products is widespread. Three types of reactions can occur in persons using natural latex rubber products: 1) Irritant contact dermatitis, 2) Allergic contact dermatitis, 3) and Type I hypersensitivity. Children's subpopulations at particular risk include: atopics, individuals with spina bifida, or individuals who required frequent surgical instrumentations. An association between allergy to latex and allergy to various fruits and vegetables has been reported. Recently, an homology between latex allergens and mold allergens has been reported leading to postulate a possible existence of a \"latex-mold syndrome\". Diagnosis of allergy is based initially on history, skin prick test and search for specific serum IgE. Provocation tests may confirm the suspicion, although these are seldom performed on children because they are not easy to bear with. The most effective strategy to decrease the incidence of NRL (natural rubber latex) sensitization is avoidance; however, this is virtually impossible, given the large number of latex products we encounter since childhood. Studies of secondary prophylaxis among children demonstrate that notwithstanding recommendations, children could manifest yet adverse reactions to latex products and have detectable levels of anti latex IgE.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"3 3","pages":"171-80"},"PeriodicalIF":0.0,"publicationDate":"2003-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568008033340234","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22490628","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":"Breast cancer: biological characteristics in postmenopausal type 2 diabetic women. Identification of therapeutic targets.","authors":"E Guastamacchia,&nbsp;F Resta,&nbsp;A Mangia,&nbsp;F Schittulli,&nbsp;A Ciampolillo,&nbsp;V Triggiani,&nbsp;B Licchelli,&nbsp;A Paradiso,&nbsp;C Sabbà,&nbsp;E Tafaro","doi":"10.2174/1568008033340199","DOIUrl":"https://doi.org/10.2174/1568008033340199","url":null,"abstract":"<p><strong>Hypothesis: </strong>Epidemiological data have suggested a possible relationship between diabetes mellitus and cancer risk, particularly breast cancer. We set out to investigate the effect of diabetes mellitus on the expression of estrogen and progesteron receptors and on the proliferative activity of primary breast cancer.</p><p><strong>Methods: </strong>We selected 77 diabetic women and 578 control patients all in post-menopause and diagnosed with primary breast cancer. All patients underwent surgical excision of the tumor and on the specimens were performed an assessment of estrogen receptor and progesteron receptor and proliferative activity assay by (3)H-Thymidine incorporation.</p><p><strong>Results: </strong>Diabetic women showed a decreased proliferative activity, while having the same estrogen receptor and progesteron receptor status and mean cytoplasmic concentration of their receptors than control group. Insulin treated women had a lower proliferative activity than non-insulin treated ones.</p><p><strong>Conclusion: </strong>Hyperinsulinemia and hyperglicemia influence in negative way the proliferative activity of diabetic women, likely inducing the expression of transforming growth factor beta, despite the high serum levels of Insulin-like growth factor and estrogen.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"3 3","pages":"205-9"},"PeriodicalIF":0.0,"publicationDate":"2003-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22490599","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":"Fc receptors as potential targets for the treatment of allergy, autoimmune disease and cancer.","authors":"Toshiyuki Takai,&nbsp;Akira Nakamura,&nbsp;Kenichi Akiyama","doi":"10.2174/1568008033340180","DOIUrl":"https://doi.org/10.2174/1568008033340180","url":null,"abstract":"<p><p>The activation threshold of various cells in the immune system is tuned by immune inhibitory receptors. The inhibitory Fc receptor, FcgammaRIIB, is one of the critical elements for keeping immune cells silent. Murine models for allergic responses and autoimmune diseases illustrate the indispensable roles of FcgammaRIIB in the suppression of these immune disorders. On the contrary, activating-type Fc receptors are crucial for the onset and exacerbation of such diseases. In addition, recent reports have revealed the pivotal roles of Fc receptors in enhancing antigen presentation by dendritic cells, which leads to efficient major histocompatibility complex class I- and class II-restricted T cell activation. In this context, anti-cancer immunopotentiation could be augmented by targeting the tumor antigens to Fc receptors on dendritic cells. This review summarizes recent advances in Fc receptor biomedicine in light of exploiting them as potential therapeutic targets for allergy, autoimmune disease and cancer.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"3 3","pages":"187-97"},"PeriodicalIF":0.0,"publicationDate":"2003-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22490597","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":"Evidences for iNOS expression and nitric oxide production in the human macrophages.","authors":"M A Panaro,&nbsp;O Brandonisio,&nbsp;A Acquafredda,&nbsp;M Sisto,&nbsp;V Mitolo","doi":"10.2174/1568008033340216","DOIUrl":"https://doi.org/10.2174/1568008033340216","url":null,"abstract":"<p><p>Nitric oxide (NO) is a pleiotropic mediator of numerous biological processes, including smooth muscle relaxation, neurotransmission and defence against pathogens. In addition, NO is involved in the pathogenesis and control of inflammation, tumors, autoimmunity, and infectious and chronic degenerative diseases. NO, a highly reactive radical, is produced from L-arginine and oxygen by the enzyme NO synthase (NOS). Three NOS isoforms have been identified: two distinct NOS isoforms are constitutively expressed in cells, whereas a third isoform, inducible NOS (iNOS), is transcribed in response to specific stimuli. In particular, iNOS is responsible for the discontinuous synthesis of high amounts of NO and was originally characterized in murine macrophages after exposure to cytokines and/or microbial products. A wide range of microorganisms is sensibly inhibited in its development by NO, like fungi, bacteria, protozoa and viruses. Although NO production and its antimicrobial effect appear well established in rodent macrophages, the existence of L-arginine pathway in human mononuclear phagocytes has long been disputed. Recently, evidences showing the iNOS activity and NO production in other animal models, including humans, are now emerging, even if the NO induction has been more difficult to demonstrate. The present observations provide evidence for the occurrence of iNOS protein expression and NO production in human macrophages cultured in vitro.</p>","PeriodicalId":84524,"journal":{"name":"Current drug targets. Immune, endocrine and metabolic disorders","volume":"3 3","pages":"210-21"},"PeriodicalIF":0.0,"publicationDate":"2003-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568008033340216","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22490600","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}