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)

Excess levels of circulating amino acids (AAs) play a causal role in specific human pathologies, including obesity and type 2 diabetes. Moreover, obesity and diabetes are contributing factors in the development of cancer, with recent studies suggesting that this link is mediated in part by AA activation of mammalian target of rapamycin (mTOR) Complex 1. AAs appear to mediate this response through class III phosphatidylinositol 3-kinase (PI3K), or human vacuolar protein sorting 34 (hVps34), rather than through the canonical class I PI3K pathway used by growth factors and hormones. Here we show that AAs induce a rise in intracellular Ca(2+) ([Ca(2+)](i)), which triggers mTOR Complex 1 and hVps34 activation. We demonstrate that the rise in [Ca(2+)](i) increases the direct binding of Ca(2+)/calmodulin (CaM) to an evolutionarily conserved motif in hVps34 that is required for lipid kinase activity and increased mTOR Complex 1 signaling. These findings have important implications regarding the basic signaling mechanisms linking metabolic disorders with cancer progression.
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PMID:Amino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34. 1846 Mar 36

The Rho family GTPase Cdc42 regulates cytoskeletal organization and membrane trafficking in physiological processes such as cell proliferation, motility and polarity. Aberrant activation of Cdc42 results in pathogenesis, such as tumorigenesis and tumor progression, cardiovascular diseases, diabetes, and neuronal degenerative diseases. The activation of Cdc42 in response to upstream signals is mediated by guanine nucleotide exchange factors (GEFs), which converse GDP-bound inactive form to the GTP-bound active form of Cdc42. The activated Cdc42 transduces signals to downstream effectors and generates cellular effects. This review will discuss the molecular mechanism of activation of Cdc42 and postulate that signaling specificity of Cdc42 is conferred by the GEF/GTPase/Effector (GGE) complexes in response to external stimuli.
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PMID:Cellular signaling for activation of Rho GTPase Cdc42. 1855 78

The receptor for advanced glycation endproducts (RAGE) mediates responses to cell danger and stress. When bound by its many ligands (which include advanced glycation endproducts, certain members of the S100/calgranulin family, extracellular high-mobility group box 1, the integrin Mac-1, amyloid beta-peptide and fibrils), RAGE activates programs responsible for acute and chronic inflammation. RAGE is therefore also involved in cancer progression, diabetes, atherosclerosis, and Alzheimer's disease. RAGE has several isoforms deriving from alternative splicing, including a soluble form called endogenous secretory RAGE (esRAGE). We show here that most soluble RAGE, either produced by cell lines or present in human blood, is not recognized by an anti-esRAGE antibody. Cells transfected with the cDNA for full-length RAGE, and thus not expressing esRAGE, produce a form of soluble RAGE, cleaved RAGE (cRAGE) that derives from proteolytic cleavage of the membrane-bound molecules and acts as a decoy receptor. By screening chemical inhibitors and genetically modified mouse embryonic fibroblasts (MEFs), we identify the sheddase ADAM10 as a membrane protease responsible for RAGE cleavage. Binding of its ligand HMGB1 promotes RAGE shedding. Our data do not disprove the interpretation that high levels of soluble forms of RAGE protect against chronic inflammation, but rather suggest that they correlate with high levels of ongoing inflammation.
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PMID:A soluble form of the receptor for advanced glycation endproducts (RAGE) is produced by proteolytic cleavage of the membrane-bound form by the sheddase a disintegrin and metalloprotease 10 (ADAM10). 1860 87

Glycogen synthase kinase 3beta (GSK3beta), a multifunctional serine/threonine kinase found in all eukaryotes, had been initially identified as a key regulator of insulin-dependent glycogen synthesis. It is now known that GSK3beta functions in diverse cellular processes including proliferation, differentiation, motility and survival. Aberrant regulation of GSK3beta has been implicated in a range of human pathologies including non-insulin-dependent diabetes mellitus, cardiovascular disease, some neurodegenerative diseases, and bipolar disorder. As a consequence, the therapeutic potential of GSK3beta inhibitors has become an important area of investigation. However, GSK3beta also participates in neoplastic transformation and tumor development. The role of GSK3beta in tumorigenesis and cancer progression remains controversial; it may function as a "tumor suppressor" for certain types of tumors, but promotes growth and development for some others. GSK3beta also mediates drug sensitivity/resistance in cancer chemotherapy. Therefore, although GSK3beta is an attractive therapeutic target for a number of human diseases, its potential impact on tumorigenesis and cancer chemotherapy needs to be carefully evaluated. This mini-review discusses the role of GSK3beta in tumorigenesis/cancer progression as well as its modulation of cancer chemotherapy.
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PMID:Glycogen synthase kinase 3beta (GSK3beta) in tumorigenesis and cancer chemotherapy. 1860 91

Antitumor and immunosuppressant treatment-related neurotoxicity can determine nonspecific clinical syndromes. Exclusion of other possible causes, among which tumor progression, appearance of paraneoplastic disease, renal or hepatic failure, diabetes or hypertension, is relevant. We report clinical and neuroradiological features in five patients with neurotoxic syndromes due to chemotherapy/radiotherapy or immunosuppression in the context of neoplastic disease/organ transplantation. Acute neurological syndrome developed in three patients after methotrexate (MTX), cyclosporine A, and L-asparaginase therapy, respectively. MRI showed posterior reversible encephalopathy in two cases and venous thrombosis with intraparenchymal hematoma in the third patient. Late onset clinical syndrome occurred in the last two patients, treated with MTX or radiation therapy for breast cancer metastasis and pituitary adenoma. Neuroimaging showed brain diffuse abnormalities. Patients affected by tumors suffer from increased risk for treatment-related toxicities. Appearance or worsening of neurological signs and symptoms challenge the clinician to discriminate between CNS involvement by the tumor, toxicity of drugs, parane-oplastic disease and infections. MRI has a key role in differential diagnosis. Close interaction between the neurologist, the oncologist and the neuroradiologist leads to the optimal management of patients.
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PMID:Clinical and radiological features of brain neurotoxicity caused by antitumor and immunosuppressant treatments. 1861 59

The role of carbohydrate-related pathways in a wide range of clinically significant diseases has provided great impetus for researchers to characterise key proteins as targets for drug discovery. Carbohydrate-recognising proteins essential in the lifecycles of high health impact pathogens and diseases such as diabetes, cancer, autoimmunity, inflammation and in-born errors of metabolism continue to stimulate much interest in both structure elucidation and structure-based drug design. For example, advances in structure-based inhibitor design against the mycobacterial enzyme UDP-galactopyranose mutase offer new hope in next generation anti-tuberculosis chemotherapeutics. The appearance of H5N1 avian influenza virus has re-stimulated much research on influenza virus haemagglutinin and sialidase. These latest developments on influenza virus sialidase have provided new opportunity for the development of Group 1-specific anti-influenza drugs. The role of siglecs and galectins in a range of disease processes such as inflammation, apoptosis and cancer progression has also inspired significant structure-based inhibitor design research.
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PMID:Disease-associated carbohydrate-recognising proteins and structure-based inhibitor design. 1870 99

Molecular target therapy (MTT), using chemicals of low molecular weight, monoclonal antibodies, and/or polypeptides to interfere with specific signal pathways in cancer cells, causes inhibition of tumor progression. Clinical evidence has demonstrated that MTT has promising potential in not only killing tumors but also inducing tumor cells differentiate into normal cells, leading to cure of the patients. Furthermore, MTT leads to potent inhibition of oncogenic signals. The delay of tumor progression makes the patients "survival with tumor". Thus, in the future it is possible that cancer become a chronic disease much like diabetes and hypertension. This article reviewed the theory on molecular target therapy, its features and future direction.
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PMID:[Molecular target therapy: a milestone on the road for curing cancer]. 1871 Jun 9

PED/PEA-15 is a 15-kDa ubiquitously expressed protein implicated in a number of fundamental cellular functions, including apoptosis, proliferation, and glucose metabolism. PED/PEA-15 lacks enzymatic function and serves mainly as a molecular adaptor. PED/PEA-15 is an endogenous substrate for protein kinase C (PKC), calcium/calmodulin-dependent protein kinase II (CAM kinase II), and Akt. In particular, PKC phosphorylates PED/PEA-15 at Ser(104) and CAM kinase II or Akt at Ser(116), modifying its stability. Evidence obtained over the past 10 years has indicated that PED/PEA-15 regulates cell survival by interfering with both intrinsic and extrinsic apoptotic pathways. In addition, it may also control cell proliferation by interfering with ERK1/2-mediated pathways. Indeed, PED/PEA-15 has been identified as an ERK1/2 interactor, which modifies its subcellular localization and targeting to a specific subset of substrates. Increased PED/PEA-15 levels may affect tumorigenesis and cancer progression as well as sensitivity to anticancer agents. Moreover, PED/PEA-15 affects astrocyte motility and increases susceptibility to skin carcinogenesis in vivo. PED/PEA-15 expression is regulated at the transcriptional and the posttranslational levels. Increased PED/PEA-15 expression has been identified in individuals with type 2 diabetes early during the natural history of the disease. Evidence generated over the past 10 years indicated that this defect contributes to altering glucose tolerance by impairing insulin action and insulin secretion and might play a role in the development of diabetes-associated neurological disorders. Strategies are being devised to target key signaling events in PED/PEA-15 action aimed at improving glucose tolerance and at facilitating cancer cell death.
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PMID:Frontiers: PED/PEA-15, a multifunctional protein controlling cell survival and glucose metabolism. 1953 39

Hypoxia-inducible transcription factor (HIF) is the master regulator of hypoxia-inducible genes involved in the mediation of survival and adaptive responses to insufficient oxygen availability, such as genes involved in hematopoesis, angiogenesis, iron transport, glucose utilization, resistance to oxidative stress, cell proliferation, survival and apoptosis, extracellular matrix homeostasis, and tumor progression. The stability of the HIFalpha subunit is regulated by oxygen-dependent prolyl 4-hydroxylation catalyzed by the HIF prolyl 4-hydroxylases (P4Hs). The 4-hydroxyproline residues generated in normoxic conditions facilitate binding of HIFalpha to the von Hippel-Lindau E3 ubiquitin ligase complex resulting in the attachment of ubiquitin molecules and subsequent rapid proteasomal degradation of HIFalpha. In hypoxia this oxygen-requiring hydroxylation event is inhibited, HIFalpha escapes degradation and can translocate to the nucleus and form a functional dimer with HIFbeta that triggers the hypoxic response. HIF-P4Hs are considered as promising drug development targets in the treatment of diseases such as myocardial infarction, stroke, peripheral vascular disease, inflammation, diabetes and severe anemias. Studies with HIF-P4H inhibitors in various animal models and ongoing clinical trials support this hypothesis by demonstrating efficacy in many applications.
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PMID:HIF prolyl 4-hydroxylases and their potential as drug targets. 1967 Oct 43

Chlamydia trachomatis (CT) infection is one of the most common causes of reproductive tract diseases and infertility. CT-Hsp60 is synthesized during infection and is released in the bloodstream. As a consequence, immune cells will produce anti-CT-Hsp60 antibodies. Hsp60, a ubiquitous and evolutionarily conserved chaperonin, is normally sequestered inside the cell, particularly into mitochondria. However, upon cell stress, as well as during carcinogenesis, the chaperonin becomes exposed on the cell surface (sf-Hsp60) and/or is secreted from cells into the extracellular space and circulation. Reports in the literature on circulating Hsp and anti-Hsp antibodies are in many cases short on details about Hsp60 concentrations, and about the specificity spectra of the antibodies, their titers, and their true, direct, pathogenetic effects. Thus, more studies are still needed to obtain a definitive picture on these matters. Nevertheless, the information already available indicates that the concurrence of persistent CT infection and appearance of sf-Hsp60 can promote an autoimmune aggression towards stressed cells and the development of diseases such as autoimmune arthritis, multiple sclerosis, atherosclerosis, vasculitis, diabetes, and thyroiditis, among others. At the same time, immunocomplexes composed of anti-CT-Hsp60 antibodies and circulating Hsp60 (both CT and human) may form deposits in several anatomical locations, e.g., at the glomerular basal membrane. The opposite side of the coin is that pre-tumor and tumor cells with sf-Hsp60 can be destroyed with participation of the anti-Hsp60 antibody, thus stopping cancer progression before it is even noticed by the patient or physician.
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PMID:Chlamydia trachomatis infection and anti-Hsp60 immunity: the two sides of the coin. 1971 22


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