Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Receptor tyrosine kinases (RTKs), such as the epidermal growth factor receptor (EGFR) and the platelet-derived growth factor receptor (PDGFR), are critically involved in the transduction of mitogenic signals across the plasma membrane and therefore in the regulation of cell growth and proliferation. Enhanced RTK activity is associated with proliferative diseases such as cancer, psoriasis and atherosclerosis, while decreased function may be associated for instance with diabetes. EGFR and PDGFR are selectively inhibited by analogues of the marine natural product aeroplysinin. The synthetic inhibitors display IC50 values in the low micromolar range and in contrast to the natural product show pronounced inhibitory activity in cultured cells in vivo. The mechanism of inhibition is likely based on a covalent modification of the target enzymes by reaction of epoxy ketone 8 with various nucleophiles.
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PMID:Synthesis and biological evaluation of aeroplysinin analogues: a new class of receptor tyrosine kinase inhibitors. 978 57

The etiology of chronic diseases of the ankle joint comprises a wide spectrum including chronic inflammatory processes and chronic degenerative, tumorous and neuropathic processes, as well as some specific syndromes based on chronic changes of the ankle joint. Of the inflammatory processes, chronic juvenile arthritis (JVC) is the most common disease. However, also Reiter disease, psoriasis or chronic monoarthritid diseases such as gout, as well as granulomatous diseases (tuberculosis, sarcoidosis) and fungal infections, may affect the ankle joint in a chronic course. Chronic degenerative changes are usually secondary due to abnormal positioning of the joint constituents or repetitive trauma. Neuropathic changes, as frequently seen in the course of diabetes, present with massive osseous destruction and malposition of the articular constituents. Chronic osseous as well as cartilaginous and synovial changes are seen in hemophilic patients. Chronic traumatic changes are represented by pigmented villonodular synovitis (PVNS), and chondromatosis, both with a predilection for the ankle joint. Due to the possibilities of magnetic resonance imaging (MRI), diagnosis of chronic ankle changes includes chronic ligamentous, tendinous and soft tissue changes. With the use of MRI, specific syndromes can be defined which particularly affect the ankle joint in a chronic way, such as the os trigonum syndrome, the anterolateral impingement syndrome and the sinus tarsi syndrome. Nevertheless, plain film radiographs are still the basic element of any investigation. MRI, however, can be potentially used as a second investigation, saving an unnecessary cascade of investigations with ultrasound and CT. The latter investigations are used only with very specific indications, for instance CT for subtle bone structures and sonography for a limited investigation of tendons or evaluation of fluid. Particularly due to the possibilities of MRI and the development of special gradient-echo imaging or high-resolution coils, the investigation of the ankle joint still offers a wide spectrum of innovation for the next years, which is particularly enforced by the increasing demand for specific diagnosis of chronic diseases in orthopedic medicine.
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PMID:[Chronic diseases of the ankle joint]. 1006 76

Inbred LEW/N rats are relatively susceptible, while histocompatible inbred F344/N rats are relatively resistant to development of a wide variety of inflammatory diseases in response to a range of pro-inflammatory stimuli. In a LEW/N vs. F344/N F2 intercross, we identified a quantitative trait locus (QTL) on Chr 10 that protects in a dominant fashion against the exudate volume component of innate inflammation in the F344/N rat, as well as a suggestive QTL on Chr 2 near the Fibrinogen cluster region. The exudate volume linkage region on Chr 10 may be similar to one of the multiple regions found to link to inflammatory arthritis phenotypes in other crosses. The suggestive linkage on Chr 2 has not been previously reported and does not seem to contribute to this phenotype in the same manner as the QTL on Chr 10. These findings are consistent with the hypothesis that the innate exudate volume trait is a sub-phenotype of more complex inflammatory phenotypes, such as arthritis, and genes within the Chr 10 linkage region could account for differences in this non-specific acute phase component of the inflammatory response. Since the rat Chr 10 exudate volume linkage region we have identified is syntenic with a region of human Chr 17 that has been shown to link to a variety of autoimmune/inflammatory diseases, including insulin-dependent diabetes mellitus, multiple sclerosis, and psoriasis, identification of genes within this linkage region will shed light on genes relevant to the earliest inflammatory component and to susceptibility and resistance to such human autoimmune/inflammatory diseases.
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PMID:Identification of a novel inflammation-protective locus in the Fischer rat. 1008 93

Psoriasis is an inflammatory skin disorder affecting approximately 3% of the population. Genetic studies published so far have shown a complex genetic inheritance with heterogeneity and a putative major susceptibility locus in the HLA region on chromosome 6. We have collected a large amount of material consisting mostly of small nuclear families in order to perform a genome-wide scan for psoriasis-associated genes. In order to focus the scan properly on possible candidate regions, we performed a cytogenetic analysis of 477 unrelated psoriatics. We divided our findings into sporadic, affecting a minor fraction of the cells, and constitutional, i.e. they were present in all cells examined. We found three cases of balanced translocation, all of which involved chromosome 11q. Two of these had a breakpoint in q12-13, whilst one involved the telomeric part of chromosome 11q. In order to characterise further the breakpoint on 11q12-13, we used bacterial artificial chromosomes (BACs) analysed by fluorescent in situ hybridisation (FISH). We were able to show that the persons had a close, but not identical breakpoints; they were separated by at least 5 cM. The major atopy locus is located in this region, as well as a locus for insulin-dependent diabetes mellitus, both being conditions with a pathogenetic mechanism involving antigen presentation.
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PMID:Cytogenetic analysis of 477 psoriatics revealed an increased frequency of aberrations involving chromosome region 11q. 1023 10

Retinoids mediate a number of physiological pathways through their effects on cellular growth and differentiation. Upon binding to retinoic acid receptors (RARs) and retinoid X receptors (RXRs), retinoids regulate cellular processes by directly modulating the expression of responsive genes. The wide-ranging effects of retinoid action are attributable to two main factors-the ubiquitous distribution of several subtypes and isoforms of RARs and RXRs, and the ability of these receptors to regulate numerous genes upon ligand activation. The broad range of effects mediated by retinoids means not only that they have many potential therapeutic applications but also that non-selective retinoids are associated with a high incidence of adverse effects. The design of retinoids that are receptor-selective and function-selective is a strategy that is proving successful in developing novel retinoids that offer not only good efficacy but also good tolerability. Tazarotene, a receptor-selective retinoid indicated for the topical treatment of psoriasis, is at the forefront of this new generation of retinoids. In the near future, other receptor-selective retinoids may prove useful for the treatment of other dermatological diseases, cancer, and diabetes.
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PMID:Novel retinoids with receptor selectivity and functional selectivity. 1073 Nov 29

The active vitamin D metabolite, 1,25-dihydroxyvitamin D3[1,25-(OH)2D3], exerts immunosuppressive activity. At a cellular and molecular level, the hormone preferentially targets helper T cell activity (Th1) by inhibiting the secretion of both IL-2 and IFN-gamma by Th1 and by suppressing the secretion pro-Th1 cytokine IL-12 by antigen-presenting cells. The active metabolite further inhibits class II antigen expression and enhances suppressor cell activity. In animal models of autoimmunity, 1,25-(OH)2D3 prevents the development of experimental autoimmune encephalomyelitis, reduces the incidence of diabetes, and attenuates murine lupus. The hormone also prolongs graft survival in animal models of transplantation. In humans, non-classical use of 1,25-(OH)2D3 has led to an anti-proliferative effect in psoriasis, antineoplastic effect in prostate cancer, and immunomodulatory effect in scleroderma. The development of less hypercalcemic analogs might open a new therapeutic area for vitamin D3.
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PMID:1,25-Dihydroxyvitamin D3--a hormone with immunomodulatory properties. 1076 31

The relationship between a history of selected medical conditions and risk of lymphomas was investigated in a hospital-based case-control study conducted in Northern Italy on 429 incident, histologically confirmed cases of non-Hodgkin's lymphoma (NHL), 158 cases of Hodgkin's disease (HD) and 1157 controls admitted to hospitals for acute conditions. The odds ratios (OR) for NHL were above unity in patients with a history of infectious mononucleosis (OR 2.9), herpes zoster (OR 1.8), pyelonephritis (OR 4.9), tuberculosis (OR 1.8), malaria (OR 1.9), any chronic bacterial diseases (OR 1.7), rheumatoid arthritis (OR 1.7) and psoriasis (OR 2.5). With reference to HD, the ORs were 4.0 for infectious mononucleosis, 2.9 for herpes zoster, 3.3 for pyelonephritis, 2.3 for tuberculosis, 1.4 for chronic bacterial diseases, 2.4 for rheumatoid arthritis, 2.7 for psoriasis and 2.1 for diabetes. The association of NHL and HD with herpes zoster was restricted to the first ten years since the onset of the disease. The relationships between NHL and mononucleosis (OR 12.9), malaria (OR 2.8) and psoriasis (OR 14.0) were stronger for cases aged > or = 60 years, and that with tuberculosis (OR 3.5) was stronger for younger cases. For HD, the positive association was stronger for cases aged > or = 40 years for herpes zoster (OR 3.8) and diabetes (OR 2.6). An increased risk of NHL was found in association with poliomyelitis (OR 1.6) (restricted to cases aged > or = 60 years, OR 4.0) and BCG immunizations (OR 1.6), but not with vaccination against smallpox, tetanus and diphtheria; increased risks of HD were found in relation to poliomyelitis and BCG immunization in cases aged > or = 40 years (OR respectively 2.5 and 2.1), or > or = 50 years (OR 4.3 and 2.2). Thus, our results confirm the association between a history of several chronic infectious and inflammatory diseases and the risk of NHL or HD, and are compatible with a role of chronic immunological alterations in the aetiology of lymphomas.
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PMID:Medical history and risk of Hodgkin's and non-Hodgkin's lymphomas. 1077 11

Essential fatty acids (EFAs) form an important component of cell membranes, are eicosanoid precursors and are therefore required for both the structure and function of every cell in the body. EFAs can modulate the activity of protein kinase C, T and B cell response, free radical generation and lipid peroxidation, lymphokine secretion and cell proliferation. EFAs also have anti-mutagenic, anti-bacterial, anti-fungal and anti-viral properties. EFAs and their metabolites lower serum cholesterol, triglycerides and blood pressure. EFAs appear to be of benefit in atopic eczema, premenstrual syndrome, psoriasis, auto-immune disorders especially rheumatoid arthritis and systemic lupus erythematosus, prevention of target organ damage in diabetes mellitus, peptic ulcer disease, ulcerative colitis, coronary heart disease and atherosclerosis. EFAs and their metabolites can selectively kill tumor cells both in vitro and in vivo without harming normal cells. In addition, EFAs seem to play a fundamental role in inflammation and immune response. In view of their actions and relative safety, it is anticipated that EFAs may be useful in the management of several diseases.
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PMID:Essential fatty acids in health and disease. 1077 63

Natural (all trans-retinoic acid, RA) and synthetic retinoids exhibit potent anti-proliferative, normalization of differentiation and anti-inflammatory activities which appear to account for their therapeutic effects in acne, psoriasis, photoaging, precancerous lesions and established cancers. Although RA has shown considerable promise in dermatologic indications, certain side effects have restricted its use as a choice of agent for chronic administration. Systematic synthesis of receptor-selective retinoids has resulted in two topical drugs, Tazorac/Zorac (tazarotene) and Differin (adapalene). Tazorac is indicated for psoriasis and acne and Differin gel for the treatment of acne. These drugs bind to the retinoic acid receptor (RAR) family members. Various RAR subtype-specific and function-selective retinoids have been synthesized. These retinoids, which are in various stages of pre-clinical development for the treatment of cancers, psoriasis and as an antidote to Accutane-mediated mucocutaneous toxicity, will also be discussed in this review. Discovery of another retinoid receptor, retinoid X receptor (RXR), revealed that RXR-specific retinoids already existed in retinoid chemical libraries. Structure activity relationship studies based upon binding and transactivation assays led to the synthesis of RXR-specific ligands with high affinities for RXR subtypes. These compounds were found to be effective in the treatment of hyperglycemia in animal models of type II diabetes. The discovery of novel retinoids along with an increased understanding of the biological functions and mechanisms of action of retinoid receptors are likely to result in improved treatments for existing responsive indications and identification of new retinoid therapeutic targets.
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PMID:Recent developments in receptor-selective retinoids. 1082 16

Viral superantigens bind several alleles and isotypes belonging to the MHC class II and subsequently activate particular T cell families via the variable portion of the beta chain of TCR. As a result, a superantigen bridges MHC and TCR molecules, leading to activation of T and B cells. The T expansion of various TCR V beta subsets is triggered on the basis of their V beta specificity, but not on their antigenic specificity. The best known superantigens are bacterial endotoxins produced by Staphylococcus aureus. However, viruses such as mouse mammary tumor or rabies viruses encode superantigens too. The ability of superantigens to break the barriers of MHC restriction and to activate large numbers of T and B cells has led to the hypothesis that superantigens may activate autoreactive T and B cells to initiate or worsen autoimmune diseases such as diabetes, multiple sclerosis, or psoriasis.
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PMID:[Viral superantigens]. 1098 4


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