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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vaccines are by definition prophylactic, but in recent years an interest has developed in therapeutic vaccines for infectious diseases such as AIDS and tuberculosis, as well as gastric ulcers, cancer (with different approaches to combat various types of malignancy) and autoimmune diseases (a definite success was the development of a vaccine against multiple sclerosis) and there are potential vaccines in development for myasthenia gravis, lupus and diabetes. Therapeutic vaccines are also being developed against cognitive diseases such as Alzheimer's disease, prion diseases and Huntington's disease. All of these efforts are based on the therapeutic vaccine being closely related chemically to the etiological agent that causes the disease.
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PMID:Therapeutic vaccines: realities of today and hopes for the future. 1211 Feb 43

Over 100 mutations of mitochondrial DNA (mtDNA) have been associated with human disease. The phenotypic manifestation of mtDNA mutations is extremely broad, from oligosymptomatic patients with isolated deafness, diabetes, ophthalmoplegia, etc., to complex encephalomyopathic disorders that may include dementia, seizures, ataxia, stroke-like episodes, etc. The genotype variants are also wide, with rearrangements (deletions, duplications) and point mutations affecting protein coding genes, tRNAs and rRNAs. There are some broad genotype/phenotype correlations but also substantial overlap. The pathogenetic mechanisms involved in the expression of mtDNA mutations are still not yet fully understood. More recently, mutations of nuclear genes encoding subunits of the respiratory chain, particularly those of complex I, have been identified. These predominantly, but not exclusively, involve infant onset disease with early death. Recently it has become clear that the function of the respiratory chain may be impaired by mutations affecting other mitochondrial proteins or as a secondary phenomenon to other intracellular biochemical derangements. Examples include Friedreich ataxia where a mutation of a nuclear encoded protein (frataxin), probably involved in iron homeostasis in mitochondria, results in severe deficiency of the respiratory chain in a pattern indicative of free radical mediated damage. Mutations of nuclear encoded proteins involved in cytochrome oxidase assembly and maintenance have been characterised and, as predicted, are associated with severe deficiency of cytochrome oxidase and, most frequently, Leigh syndrome. Defects of intracellular metabolism, with particularly excess-free radical generation including nitric oxide or peroxynitrite, may cause secondary damage to the respiratory chain. This is probably of relevance in Huntington disease, motor neuron disease (amyotrophic lateral sclerosis) and Wilson disease. These disorders seem to have defective oxidative phosphorylation as a common pathway in their pathogenesis and it may be that treatments designed to improve respiratory chain function may ameliorate the progression of these disorders.
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PMID:Primary and secondary defects of the mitochondrial respiratory chain. 1213 29

Chaperones are highly conserved proteins responsible for the preservation and repair of the correct conformation of cellular macromolecules, such as proteins, RNAs, etc. Environmental stress leads to chaperone (heat-shock protein, stress protein) induction reflecting the protective role of chaperones as a key factor for cell survival and in repairing cellular damage after stress. The present review summarizes our current knowledge about the chaperone-deficiency in the aging process, as well as the possible involvement of chaperones in neurodegenerative diseases, such as in Alzheimer's, Parkinson's, Huntington- and prion-related diseases. We also summarize a recent theory implying chaperones as "buffers" of variations in the human genome, which role probably increased during the last 200 years of successful medical practice minimizing natural selection. Chaperone-buffered, silent mutations may be activated during the aging process, which leads to the phenotypic exposure of previously hidden features and might contribute to the onset of polygenic diseases, such as atherosclerosis, cancer, diabetes and several neurodegenerative diseases.
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PMID:Chaperones and aging: role in neurodegeneration and in other civilizational diseases. 1221 25

Although all cells in the body require energy to survive and function properly, excessive calorie intake over long time periods can compromise cell function and promote disorders such as cardiovascular disease, type-2 diabetes and cancers. Accordingly, dietary restriction (DR; either caloric restriction or intermittent fasting, with maintained vitamin and mineral intake) can extend lifespan and can increase disease resistance. Recent studies have shown that DR can have profound effects on brain function and vulnerability to injury and disease. DR can protect neurons against degeneration in animal models of Alzheimer's, Parkinson's and Huntington's diseases and stroke. Moreover, DR can stimulate the production of new neurons from stem cells (neurogenesis) and can enhance synaptic plasticity, which may increase the ability of the brain to resist aging and restore function following injury. Interestingly, increasing the time interval between meals can have beneficial effects on the brain and overall health of mice that are independent of cumulative calorie intake. The beneficial effects of DR, particularly those of intermittent fasting, appear to be the result of a cellular stress response that stimulates the production of proteins that enhance neuronal plasticity and resistance to oxidative and metabolic insults; they include neurotrophic factors such as brain-derived neurotrophic factor (BDNF), protein chaperones such as heat-shock proteins, and mitochondrial uncoupling proteins. Some beneficial effects of DR can be achieved by administering hormones that suppress appetite (leptin and ciliary neurotrophic factor) or by supplementing the diet with 2-deoxy-d-glucose, which may act as a calorie restriction mimetic. The profound influences of the quantity and timing of food intake on neuronal function and vulnerability to disease have revealed novel molecular and cellular mechanisms whereby diet affects the nervous system, and are leading to novel preventative and therapeutic approaches for neurodegenerative disorders.
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PMID:Meal size and frequency affect neuronal plasticity and vulnerability to disease: cellular and molecular mechanisms. 1255 61

In a transgenic mouse model of the neurodegenerative disorder Huntington's disease (HD), age-dependent neurologic defects are accompanied by progressive alterations in glucose tolerance that culminate in the development of diabetes mellitus and insulin deficiency. Pancreatic islets from HD transgenic mice express reduced levels of the pancreatic islet hormones insulin, somatostatin, and glucagon and exhibit intrinsic defects in insulin production. Intranuclear inclusions accumulate with aging in transgenic pancreatic islets, concomitant with the decline in glucose tolerance. HD transgenic mice develop an age-dependent reduction of insulin mRNA expression and diminished expression of key regulators of insulin gene transcription, including the pancreatic homeoprotein PDX-1, E2A proteins, and the coactivators CBP and p300. Disrupted expression of a subset of transcription factors in pancreatic beta cells by a polyglutamine expansion tract in the huntingtin protein selectively impairs insulin gene expression to result in insulin deficiency and diabetes. Selective dysregulation of gene expression in triplet repeat disorders provides a mechanism for pleiotropic cellular dysfunction that restricts the toxicity of ubiquitously expressed proteins to highly specialized subpopulations of cells.
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PMID:Huntington's disease of the endocrine pancreas: insulin deficiency and diabetes mellitus due to impaired insulin gene expression. 1258 50

Immunization against extracellular neurotoxic proteins has shown promise in the treatment of several neurodegenerative disorders. We sought to determine whether immunization against mutant huntingtin, the intracellular protein that causes Huntington's disease (HD), could slow disease progression in the HD mouse model HDR6/2. DNA vaccination was used to present the mutant intracellular antigen to the immune system in a physiological context. Assay of a peripheral biomarker, pancreatic insufficiency, was used as an initial test of efficacy. DNA vaccination with a 5' fragment of the HD cDNA prevented development of the HDR6/2 diabetic phenotype. Insulin staining demonstrated that HDR6/2 diabetes may be caused by a severe pancreatic insulin deficiency. Immunoresponsive HDR6/2 mice showed increased insulin staining more closely resembling wild-type levels. These observations suggest that DNA vaccination against toxic intracellular proteins may be therapeutic.
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PMID:DNA vaccination against mutant huntingtin ameliorates the HDR6/2 diabetic phenotype. 1271 97

Gene transfer technology has many potential applications in medicine. Phase I and phase II gene-based clinical trials have been conducted for the treatment of cancer, monogenic disorders, some neurodegenerative illnesses, cardiopathies and infectious diseases. A phase I gene therapy clinical trial has recently been approved for the treatment of Parkinson's disease, while preclinical studies are in progress to develop gene-based interventions for the treatment of Alzheimer's disease and Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, and diabetes type 1 and type 2. A number of gene transfer models have been generated for gene therapy and genetic immunization programs. Vector design is addressing several pressing issues in the matter of gene delivery improvement, stabilization of transgene expression and safety. This is necessary in order to achieve efficient gene-based therapeutic interventions. Indeed, considerable progress has been reported in the field of vector design, which has produced some encouraging results in clinical trials and preclinical studies. However, vector design should be further developed to allow for the successful application of gene transfer technology in therapy. This review summarizes the latest achievements and controversies in clinical trials and preclinical studies in the field of gene therapy.
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PMID:Gene transfer in experimental medicine. 1294 57

Locomotor activity in Drosophila, as in other organisms, is an important trait since it is at the basis of almost all behaviours. Indeed, the locomotor centre is implicated in all complex behaviours consisting of a change in the position of the animal with respect to its environment. Despite its importance, locomotor activity itself has received sparse attention for the following two reasons: first, until recently, the study of locomotor activity has lacked a well automated and standardised paradigm which is necessary for a detailed description. Second, locomotor activity is complicated by many factors (genetic, feeding, temperature), and as such is rather difficult to study. With recent technological developments, locomotor activity is now more accessible to automated paradigms. These have permitted us to reveal that locomotor activity is a very complex and rich behaviour that follows strict rules, harbours an organised (fractal-like) structure, and consequently might adhere to highly organised neurophysiological processes. Undoubtedly, locomotor activity has now reached a scientific maturity that allows it to be studied with the panoply of neuroethological approaches, in particular genetic, to unravel its mechanisms and neural circuitry. Consequently, we propose that locomotor activity can now represent a relevant biomarker to study various model diseases such as addiction, Parkinson, Alzheimer, Huntington, and diabetes.
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PMID:Locomotor activity: a complex behavioural trait to unravel. 1455 49

Gene transfer to the nervous system is an attractive option to treat a wide variety of neurological insults. The expression of trophic factor and/or antiapoptotic genes may be beneficial in halting the slow neurodegeneration in such conditions as Parkinson's disease (4,5), the rapid neuronal cell death following trauma to the brain or spinal cord (6,7), or in treating peripheral neuropathies associated with diabetes or use of chemotherapeutic agents (8,9). Introduction of dominant-negative mutant genes or antisense RNA to treat diseases such as Huntington's disease, or transfer of genes to replace lost or mutated endogenous proteins to treat disorders such as lysosomal storage diseases, may prove useful. In addition, gene transfer to overexpress endogenous antinociceptive proteins has great potential in pain management. The problem faced by all of these applications is finding a suitable methodology that will facilitate the transfer of exogenous genes to the appropriate nerve cells; virusbased vectors have proven quite efficient in transferring genes to many different cell types.
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PMID:Delivery of herpes simplex virus-based vectors to the nervous system. 1497 Jun 1

More than 20 syndromes among the significant and increasing number of degenerative diseases of neuronal tissues are known to be associated with diabetes mellitus, increased insulin resistance and obesity, disturbed insulin sensitivity, and excessive or impaired insulin secretion. This review briefly presents such syndromes, including Alzheimer disease, ataxia-telangiectasia, Down syndrome/trisomy 21, Friedreich ataxia, Huntington disease, several disorders of mitochondria, myotonic dystrophy, Parkinson disease, Prader-Willi syndrome, Werner syndrome, Wolfram syndrome, mitochondrial disorders affecting oxidative phosphorylation, and vitamin B(1) deficiency/inherited thiamine-responsive megaloblastic anemia syndrome as well as their respective relationship to malignancies, cancer, and aging and the nature of their inheritance (including triplet repeat expansions), genetic loci, and corresponding functional biochemistry. Discussed in further detail are disturbances of glucose metabolism including impaired glucose tolerance and both insulin-dependent and non-insulin-dependent diabetes caused by neurodegeneration in humans and mice, sometimes accompanied by degeneration of pancreatic beta-cells. Concordant mouse models obtained by targeted disruption (knock-out), knock-in, or transgenic overexpression of the respective transgene are also described. Preliminary conclusions suggest that many of the diabetogenic neurodegenerative disorders are related to alterations in oxidative phosphorylation (OXPHOS) and mitochondrial nutrient metabolism, which coincide with aberrant protein precipitation in the majority of affected individuals.
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PMID:Neurodegenerative disorders associated with diabetes mellitus. 1517 61


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