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)

We provide a global assessment, with detailed multi-scale data, of the ecological and toxicological effects generated by inorganic nitrogen pollution in aquatic ecosystems. Our synthesis of the published scientific literature shows three major environmental problems: (1) it can increase the concentration of hydrogen ions in freshwater ecosystems without much acid-neutralizing capacity, resulting in acidification of those systems; (2) it can stimulate or enhance the development, maintenance and proliferation of primary producers, resulting in eutrophication of aquatic ecosystems; (3) it can reach toxic levels that impair the ability of aquatic animals to survive, grow and reproduce. Inorganic nitrogen pollution of ground and surface waters can also induce adverse effects on human health and economy. Because reductions in SO2 emissions have reduced the atmospheric deposition of H2SO4 across large portions of North America and Europe, while emissions of NOx have gone unchecked, HNO3 is now playing an increasing role in the acidification of freshwater ecosystems. This acidification process has caused several adverse effects on primary and secondary producers, with significant biotic impoverishments, particularly concerning invertebrates and fishes, in many atmospherically acidified lakes and streams. The cultural eutrophication of freshwater, estuarine, and coastal marine ecosystems can cause ecological and toxicological effects that are either directly or indirectly related to the proliferation of primary producers. Extensive kills of both invertebrates and fishes are probably the most dramatic manifestation of hypoxia (or anoxia) in eutrophic and hypereutrophic aquatic ecosystems with low water turnover rates. The decline in dissolved oxygen concentrations can also promote the formation of reduced compounds, such as hydrogen sulphide, resulting in higher adverse (toxic) effects on aquatic animals. Additionally, the occurrence of toxic algae can significantly contribute to the extensive kills of aquatic animals. Cyanobacteria, dinoflagellates and diatoms appear to be major responsible that may be stimulated by inorganic nitrogen pollution. Among the different inorganic nitrogenous compounds (NH4+, NH3, NO2-, HNO2NO3-) that aquatic animals can take up directly from the ambient water, unionized ammonia is the most toxic, while ammonium and nitrate ions are the least toxic. In general, seawater animals seem to be more tolerant to the toxicity of inorganic nitrogenous compounds than freshwater animals, probably because of the ameliorating effect of water salinity (sodium, chloride, calcium and other ions) on the tolerance of aquatic animals. Ingested nitrites and nitrates from polluted drinking waters can induce methemoglobinemia in humans, particularly in young infants, by blocking the oxygen-carrying capacity of hemoglobin. Ingested nitrites and nitrates also have a potential role in developing cancers of the digestive tract through their contribution to the formation of nitrosamines. In addition, some scientific evidences suggest that ingested nitrites and nitrates might result in mutagenicity, teratogenicity and birth defects, contribute to the risks of non-Hodgkin's lymphoma and bladder and ovarian cancers, play a role in the etiology of insulin-dependent diabetes mellitus and in the development of thyroid hypertrophy, or cause spontaneous abortions and respiratory tract infections. Indirect health hazards can occur as a consequence of algal toxins, causing nausea, vomiting, diarrhoea, pneumonia, gastroenteritis, hepatoenteritis, muscular cramps, and several poisoning syndromes (paralytic shellfish poisoning, neurotoxic shellfish poisoning, amnesic shellfish poisoning). Other indirect health hazards can also come from the potential relationship between inorganic nitrogen pollution and human infectious diseases (malaria, cholera). Human sickness and death, extensive kills of aquatic animals, and other negative effects, can have elevated costs on human economy, with the recreation and tourism industry suffering the most important economic impacts, at least locally. It is concluded that levels of total nitrogen lower than 0.5-1.0 mg TN/L could prevent aquatic ecosystems (excluding those ecosystems with naturally high N levels) from developing acidification and eutrophication, at least by inorganic nitrogen pollution. Those relatively low TN levels could also protect aquatic animals against the toxicity of inorganic nitrogenous compounds since, in the absence of eutrophication, surface waters usually present relatively high concentrations of dissolved oxygen, most inorganic reactive nitrogen being in the form of nitrate. Additionally, human health and economy would be safer from the adverse effects of inorganic nitrogen pollution.
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PMID:Ecological and toxicological effects of inorganic nitrogen pollution in aquatic ecosystems: A global assessment. 1678 74

Oral tolerance has been applied successfully as a potential therapeutic strategy for preventing and treating autoimmune diseases including type 1 diabetes. In this paper we constructed an edible vaccine consisting of a fusion protein composed of cholera toxin B subunit (CTB) and insulin B chain (InsB) that was produced in silkworm larvae. The silkworm larvae produced this fusion protein at levels of up to 0.97mg/ml of hemolymph as the pentameric CTB-InsB form, which retained the GM1-ganglioside binding affinity and the native antigenicity of CTB. Non-obese diabetic mice fed hemolymph containing microgram quantities of the CTB-InsB fusion protein showed a prominent reduction in pancreatic islet inflammation and a delay in the development of diabetic symptoms. This study demonstrates that silkworm-produced CTB-InsB fusion protein can be used as an ideal oral protein vaccine for induction of immunological tolerance against autoimmune diabetes.
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PMID:Suppression of diabetes in non-obese diabetic (NOD) mice by oral administration of a cholera toxin B subunit-insulin B chain fusion protein vaccine produced in silkworm. 1711 87

Oral tolerance is classically defined as the suppression of immune responses to antigens (Ag) that have been administered previously by the oral route. Multiple mechanisms of tolerance are induced by oral Ag. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral Ag induces Th2 (IL-4/IL-10) and Th3 (TGF-beta) regulatory T cells (Tregs) plus CD4+CD25+ regulatory cells and LAP+T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-beta, cholera toxin B subunit (CTB), Flt-3 ligand, anti-CD40 ligand and continuous feeding of Ag. In addition to oral tolerance, nasal tolerance has also been shown to be effective in suppressing inflammatory conditions with the advantage of a lower dose requirement. Oral and nasal tolerance suppress several animal models of autoimmune diseases including experimental allergic encephalomyelitis (EAE), uveitis, thyroiditis, myasthenia, arthritis and diabetes in the nonobese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, colitis and stroke. Oral tolerance has been tested in human autoimmune diseases including MS, arthritis, uveitis and diabetes and in allergy, contact sensitivity to DNCB, nickel allergy. Positive results have been observed in phase II trials and new trials for arthritis, MS and diabetes are underway. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time and Ag-specific mechanism of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy and early therapy.
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PMID:Oral tolerance: therapeutic implications for autoimmune diseases. 1716 57

Secondary active glucose transport occurs by at least four members of the SLC5 gene family. This review considers the structure and function of two premier members, SGLT1 and SGLT2, and their role in intestinal glucose absorption and renal glucose reabsorption. Genetics disorders of SGLTs include Glucose-Galactose Malabsorption, and Familial Renal Glucosuria. SGLT1 plays a central role in Oral Rehydration Therapy used so effectively to treat secretory diarrhoea such as cholera. Increasing attention is being focused on SGLTs as drug targets for the therapy of diabetes.
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PMID:Active sugar transport in health and disease. 1722 66

It has been previously shown that diabetes-associated central nervous system abnormalities are characterized by progressive alterations of neurotransmission. In particular, recent studies from our group have demonstrated that more early diabetes is accompanied by the increased spontaneous serotonin release from isolated synaptic endings; however the mechanism is still not clear. The current study was undertaken to estimate the relative importance of membrane potential and extracellular Ca2+ in the serotonin secretion process in diabetes. With the premise that increased phosphorylation of target proteins may be responsible for the increase in transmitter release we tested whether cAMP/PKA-mediated phosphorylations as well as mono-ADP-ribosylation of effector proteins were implicated in diabetes-associated brain failures. In addition, the effects of nicotinamide, a multiple-action compound, were examined. It was shown that diabetes caused a significant increase in spontaneous release of [2-(14)C]serotonin that was accompanied by synaptic membranes depolarization. Omission of Ca2+ from the incubation medium largely inhibited serotonin release only in untreated diabetes. Exposure of diabetic synaptosomes to cAMP-dependent protein kinase inhibitor H89, similar to Ca2+ -free medium, downregulated serotonin release. The level of constitutively mono-ADP-ribosylated proteins of diabetic synaptosomes was elevated vs control. Protein mono-ADP-ribosylation induced by cholera toxin (CTX), activator of Gs-protein-coupled adenylyl cyclase, resulted in excessive 1.2-fold enhancement over basal level but to the less extent in diabetes as compared with that of control. Nevertheless, CTX as well as forskolin exerted more strong stimulating effect on serotonin release from diabetic synaptosomes as compared to control. H89 counteracted CTX-related action on this variable strongly suggesting that impaired serotonin release is, at least, dependent on Gs-protein-mediated phosphorylation. Nicotinamide treatment virtually normalized both protein mono-ADP-ribosylation and serotonin release as well as synaptosomal response to all stimuli used. The data suggest that alterations in protein mono-ADP-ribosylation may be involved as a possible mechanism responsible for the impaired neurotransmission in diabetes and nicotinamide may efficiently protect against ADP-ribosylationmediated abnormalities in brain function.
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PMID:[Mechanisms of diabetes-induced impairements of serotonin release from rat brain synaptosomes: effect of nicotinamide]. 1723 30

In autoimmune (type 1) diabetes, autoreactive lymphocytes destroy pancreatic beta-cells responsible for insulin synthesis. To assess the feasibility of gene therapy for type 1 diabetes, recombinant vaccinia virus (rVV) vectors were constructed expressing pancreatic islet autoantigens proinsulin (INS) and a 55-kDa immunogenic peptide from glutamic acid decarboxylase (GAD), and the immunomodulatory cytokine interleukin (IL)-10. To augment the beneficial effects of recombinant virus therapy, the INS and GAD genes were fused to the C terminus of the cholera toxin B subunit (CTB). Five-week-old non-obese diabetic (NOD) mice were injected once with rVV. Humoral antibody immune responses and hyperglycemia in the infected mice were analyzed. Only 20% of the mice inoculated with rVV expressing the CTB::INS fusion protein developed hyperglycemia, in comparison to 70% of the mice in the uninoculated animal group. Islets from pancreatic tissues isolated from euglycemic mice from this animal group showed no sign of inflammatory lymphocyte invasion. Inoculation with rVV producing CTB::GAD or IL-10 was somewhat less effective in reducing diabetes. Humoral antibody isotypes of hyperglycemic and euglycemic mice from all treated groups possessed similar IgG1/IgG2c antibody titer ratios from 19 to 32 wk after virus inoculation. In comparison with uninoculated mice, 11-wk-old NOD mice injected with virus expressing CTB::INS were delayed in diabetes onset by more than 4 wk. The experimental results demonstrate the feasibility of using rVV expressing CTB::INS fusion protein to generate significant protection and therapy against type 1 diabetes onset and progression.
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PMID:Suppression of hyperglycemia in NOD mice after inoculation with recombinant vaccinia viruses. 1728 79

Insulin peptide B:9-23 is a major autoantigen in type 1 diabetes that contains two distinct CD4 epitopes (B:9-16 and B:13-23). One of the two epitopes, B:13-23, overlaps with a CTL epitope (B:15-23). In this study, we report that the elimination of the CTL epitope from the B:9-23 peptide by amino acid substitution (with alanine) at positions B:16 and 19 (A16,19 altered peptide ligand) or truncation of the C-terminal amino acids from the peptide (B:9-21), neither of which stimulated the proliferation of insulin B:15-23 reactive CD8 T cells, provided significant intranasally induced suppression of diabetes when coadministered with a potent mucosal adjuvant cholera toxin (CT). Intranasal treatment with A16,19 resulted in the elimination of spontaneous insulin autoantibodies, significant inhibition of insulitis and remission from hyperglycemia, and prevented the progression to diabetes. Intranasal administration of native B:9-23/CT or B:11-23/CT resulted in a significant enhancement of insulin autoantibody expression and severity of insulitis and failed to prevent diabetes. Our present study indicates that elimination of the CTL epitope from the B:9-23 peptide was critically important for mucosally induced diabetes prevention. The A16,19 altered peptide ligand, but not other native insulin peptides, suppresses insulin autoantibodies associated with protection from and remission of diabetes.
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PMID:Altered B:9-23 insulin, when administered intranasally with cholera toxin adjuvant, suppresses the expression of insulin autoantibodies and prevents diabetes. 1767 66

Diets high in saturated fat, trans fat and glycaemic load and low in fibre and polyunsaturated fat are associated with a 25 to 50% increase in the risk of type 2 diabetes. However, obesity increases this risk by 500 to 1000%. Effects ascribed to dietary composition might therefore be due to unmeasured effects of body size. In clinical trials, a weight loss of 3-5 kg plus twice to min of walking per day reduced the incidence of diabetes by 58%. The size of this effect is remarkable. It points to the solution to the diabetes epidemic, which is to reconstruct cities so as to make people eat less and move more. There is an analogy here with the cholera epidemics, which also could be solved only by changing the urban environment.
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PMID:[The role of diet in the development of type 2 diabetes mellitus: calories play the leading role]. 1905 33

Treatment with anti-CD3 antibodies appears promising to preserve residual beta-cell function in recent onset type 1 diabetes although many patients had therapy related adverse events. Insulin is an important islet antigen and autoimmunity to insulin may be central to disease pathogenesis of type 1 diabetes in man and NOD mouse. Evidence is strongest for the NOD mouse model, where blocking immune responses to insulin by amino acid substitution at positions B: 16, prevents diabetes. Insulin can be used to immunologically prevent diabetes of NOD mice, however, insulin-based preventive immunoregulation of diabetes in man is not yet possible. Treatment of NOD mice with insulin B-chain peptide and poly I: C, a Toll-like receptor 3 ligand, induces the pathogenic T cells as well as regulatory T cells and recruits them into the islets. Intranasal treatment with insulin B-chain analogue peptide with amino acid substitutions at positions B: 16 and 19 prevented the progression to diabetes and induced remission from hyperglycemia when co-administered with a mucosal adjuvant cholera toxin. Thus, an antigenic peptide vaccination with an alternative adjuvant or route might induce antigen-specific regulatory cell populations rather than pathogenic T cells. We believe that such an improved antigen specific therapy could provide more efficient and safer disease suppression and remission for human type 1 diabetes.
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PMID:[Antigen specific treatment for the inhibition and remission of type 1 diabetes]. 1912 73

Induction of specific immunological unresponsiveness by oral autoantigens such as glutamic acid decarboxylase 65 (GAD65) is termed oral tolerance and may be a potential therapy for autoimmune diabetes. However, the requirement for large amounts of protein will limit clinical testing of autoantigens, which are difficult to produce. Mucosal adjuvants such as cholera toxin B subunit (CTB) may lower the level of autoantigens required. Here we describe cloning, expression, purification and identification study of the CTB and triple GAD(531-545) epitopes fusion gene. The fusion gene was ligated via a flexible hinge tetrapeptide and expressed as a soluble protein in Escherichia coli BL21 (DE3) driven by the T7 promoter. We purified the recombination protein from the cell lysate and obtained approximately 2.5mg of CTB-GAD((531-545)3) per liter of culture with greater than 90% purity by a Ni-NTA resin column. The bacteria produced this protein as the pentameric form, which retained the GM1-ganglioside binding affinity and the native antigenicity of CTB and GAD65. Further studies revealed that oral administration of bacterial CTB-GAD((531-545)3) fusion protein showed the prominent reduction in pancreatic islet inflammation in non-obese diabetic mice. The results presented here demonstrate that the bacteria bioreactor is an ideal production system for an oral protein vaccine designed to develop immunological tolerance against autoimmune diabetes.
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PMID:Cloning, expression, purification and characterization of the cholera toxin B subunit and triple glutamic acid decarboxylase epitopes fusion protein in Escherichia coli. 1936 33


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