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Novel Methods of Type 1 Diabetes Treatment

Abstract: Type 1 diabetes is an autoimmune disease characterized by the cell-mediated destruction of insulin-producing β-cells, leading to impaired glucose homeostasis, insulin insufficiency, and other complications. Although classic genetic studies have linked numerous genes to the susceptibility of developing diabetes, the mechanisms by which they influence the disease course remain poorly understood. Epigenetics, inheritable changes in gene expression that occur without accompanying genetic mutation, can both serve as a link between the environment and genetic causes of disease and help explain some of the observed vagaries of diabetes. Elucidation of the epigenetic landscape as it relates to putative treatment modalities is highly warranted. Drugs with histone deacetylase activity are in clinical trials for cancer and certain inflammatory diseases with high safety profiles and they hold similar promise for amelioration of type 1 diabetes with diminished secondary complications. Full-fledged studies on the epigenetics of type 1 diabetes are highly likely to provide novel tools for the manipulation of the disease in the years to come. In this review, epigenetic regulation mediated by small molecular inhibitors of histone deacetylases and their potential for preventing diabetes are discussed. Insights into the nature of the genetic mechanisms unraveled by these studies are also highlighted. ... Read more

Antidiabetic Drugs and Their Potential Role in Treating Mild Cognitive Impairment and Alzheimer's Disease

Abstract: The incidence of both diabetes mellitus (DM) and dementia increases with aging and the incidence of dementia are higher in people with diabetes. Epidemiological and pathological data suggest that DM contributes to mild cognitive impairment (MCI) and dementia. DM seems to be an independent risk factor for MCI and Alzheimer's disease (AD) and is associated with more rapid cognitive decline. Recent evidence points out that insulin affects central nervous system functions, and can modulate cognitive functions. Impaired insulin signaling and insulin resistance in brain have been found to play an important role in the pathogenesis of AD. Human studies have shown that some oral antidiabetic medications can improve cognition in patients with MCI and AD. Intranasal insulin has also been shown to improve memory and cognitive abilities in MCI and AD patients. While it remains unclear whether management of diabetes will reduce the incidence of MCI and AD, emerging evidence suggests that diabetes therapies may improve cognitive function. ... Read more

Adipose Tissue Inflammation in Obesity and Metabolic Syndrome

Abstract: Metabolic syndrome is a major risk factor for cardiovascular and metabolic diseases. Playing a central role in the development of metabolic syndrome and in its clinical consequences is visceral obesity. Adipose tissue is now considered to be an active endocrine organ that secretes various humoral factors (adipokines), and its shift to production of proinflammatory cytokines in obesity likely contributes to the low-level systemic inflammation that is seen in metabolic syndrome-associated chronic pathologies such as atherosclerosis. Recent studies have shown that obesity induces chronic local inflammation in adipose tissue, and that cells of the innate immune system, particularly macrophages, are crucially involved in adipose inflammation and systemic metabolic abnormalities. Moreover, we and others recently revealed that T cells are key regulators of adipose inflammation, and that the adaptive immune system is also crucially important. In mouse models modulation of T cell function ameliorated not only adipose inflammation but also systemic insulin resistance induced by obesity. Thus clarification of the inflammatory processes ongoing in obese adipose tissue would seem essential for the understanding of metabolic syndrome and for developing novel therapeutic strategies to treat it. ... Read more

Statins Lower Heart Disease Complications Among Diabetic Patients

A recent large clinical trial study concluded that cholesterol lowering statin drugs should be taken by diabetic patients to prevent heart disease complications regardless of their initial cholesterol levels (International Statin Study Group, Lancet 361:2005-2016, June 14, 2003). 5,963 UK adults with diabetes and 14,573 with occlusive arterial disease but no diagnosed diabetes were randomized into the treatment group who received Merck’s Zocor (simvastatin) 40 mg daily and the control group who received the placebo, for 5 years. In the three subgroups of patients evaluated: the diabetic patients with occlusive artery disease, diabetic patients who do not have occlusive artery ... Read more

The Heat Shock Response: Its Role in Pathogenesis of Type 2 Diabetes and Its Complications, and Implications for Therapeutic Intervention

Abstract: The heat shock response (HSR) is an evolutionarily conserved mechanism that cells and organisms utilize to protect themselves from the damaging effects of stress. Induction of HSR involves a complex multi-step process in which heat shock factor-1 (HSF-1), the key modulator of HSR, is activated, leading to the induction of a variety of heat shock genes. There is evidence that the HSR is defective in diabetes, which makes the tissues vulnerable to stress-induced pathological changes. Consistent with this observation, induction of HSR by either non-pharmacological methods such as hyperthermia or by pharmacological inducers has beneficial effects in managing insulin resistance and hyperglycemia, as well as secondary complications of diabetes, such as cardiovascular disease, nephropathy, neuropathy, and retinopathy as well as wound healing. This review summarizes what is currently known about the role of the HSR in diabetes and therapeutic implications of enhancing HSR in the management of diabetes and its associated complications, focusing on small molecule mediated therapeutics. ... Read more

Gene Therapy for Obesity: Progress and Prospects

Abstract: Advances in understanding the molecular basis of obesity and obesity-associated diseases have made gene therapy a vital approach in coping with this world-wide epidemic. Gene therapy for obesity aims to increase or decrease gene product in favor of lipolysis and energy expenditure, leading toward fat reduction and loss of body weight. It involves successful delivery and expression of therapeutic genes in appropriate cells. The ultimate goal of gene therapy is to restore and maintain energy homeostasis. Here we summarize progress made in recent years in identifying genes responsible for obesity and present examples where the gene therapy approach has been applied to treating or preventing obesity. Discussion on advantages and limitations of gene therapy strategies employed is provided. The intent of this review is to inspire further studies toward the development of new strategies for successful treatment of obesity and obesity-associated diseases. ... Read more

Advances in the Pharmacotherapy of Patients with Acromegaly

Abstract: Acromegaly is a disease characterized by growth hormone (GH) excess originating, in approximately 95% of cases, from a somatotroph pituitary adenoma. Symptomatology and clinical features are due to GH and insulin-like growth factor 1 excess; unfortunately, for most patients diagnosis is delayed by several years. Acromegaly patients' morbidity and mortality are higher than those of the normal population. However, with adequate biochemical control mortality rates can be restored to normal. Tumor size and location, symptoms, comorbidities, and lastly, but not least, patient preference, are all important aspects in treatment decision making, and treatment approach should be individualized. Current therapy includes medical, surgical, and radiation. This review focuses on recent significant developments in medical therapy. There are three major therapeutic drug classes: somatostatin receptor ligands (SRLs), which represent the mainstay of medical therapy, GH receptor blockers, and dopamine agonists. Multi-ligand receptor SRLs such as pasireotide, should increase therapeutic choices for acromegaly patients currently uncontrolled on available SRLs. Furthermore, significant research has been focused in the development of novel delivery modalities (e.g., oral and long acting subcutaneous administration). ... Read more

Epigenetic Silencing of RASSF10 Promotes Tumor Growth in Esophageal Squamous Cell Carcinoma

Abstract: Esophageal squamous cell carcinoma (ESCC) is one of the most malignant diseases and the five year survival rate remains less than 10%. RASSF10 is a newly identified member of the Ras-association family, but the regulation and the function of RASSF10 in ESCC remain unclear. Research methodologies such as methylation specific PCR (MSP), semi-quantitative RT-PCR, immunohistochemistry, Sodium bisulfite sequencing, and colony formation assay were utilized in this investigation. Loss of RASSF10 expression was found in KYSE150 cells and reduced expression was found in KYSE70 and KYSE180 cells. Expression of RASSF10 was found in KYSE140, KYSE450, KYSE510, TE1, TE3, and TE8 cell lines. Complete methylation was found in KYSE30 and KYSE150 cells, partial methylation was found in KYSE70, KYSE180, KYSE510, and TE1, and unmethylation was found in KYSE140, KYSE450, TE3, and TE8. Re-expression or increased expression was induced by 5-Aza-dC treatment. RASSF10 was methylated in 44.3% primary esophageal squamous cell carcinoma. RASSF10 inhibits cell proliferation and induces G2/M phase arrest in esophageal cancer cells. In conclusion: RASSF10 was frequently methylated in human esophageal squamous cell carcinoma and expression of RASSF10 was regulated by promoter region hypermethylation. RASSF10 may serve as a tumor suppressor of esophageal cancer. ... Read more

Mesenchymal Stem Cell-Based Therapy for Type 1 Diabetes

Abstract: Diabetes has increasingly become a worldwide health problem, causing huge burden on healthcare system and economy. Type 1 diabetes (T1D), traditionally termed "juvenile diabetes" because of an early onset age, is affecting 5~10% of total diabetic population. Insulin injection, the predominant treatment for T1D, is effective to ameliorate the hyperglycemia but incompetent to relieve the autoimmunity and to regenerate lost islets. Islet transplantation, an experimental treatment for T1D, also suffers from limited supply of human islets and poor immunosuppression. The recent progress in regenerative medicine, especially stem cell therapy, has suggested several novel and potential cures for T1D. Mesenchymal stem cell (MSC) based cell therapy is among one of them. MSCs are a type of adult stem cells residing in bone marrow, adipose tissue, umbilical cord blood, and many other tissues. MSCs, with self-renewal potential and transdifferentiation capability, can be expanded in vitro and directed to various cell lineages with relatively less efforts. MSCs have well-characterized hypoimmunogenicity and immunomodulatory effect. All these features make MSCs attractive for treating T1D. Here, we review the properties of MSCs and some of the recent progress using MSCs as a new therapeutic in the treatment of T1D. We also discuss the strength and limitations of using MSC therapy in human trials. ... Read more

Epigenetic Changes Associated with Neoplasms of the Exocrine and Endocrine Pancreas

Abstract: Early detection and multi-modality curative treatment for pancreatic cancer remain unsatisfactory due to the insufficient understanding of the mechanisms underlying tumor progression. Epigenetic events, including aberrant methylation of tumor suppressor gene promoter regions, may contribute to tumorigenesis involving both the exocrine and endocrine pancreas. Methylation changes of specific gene promoter regions were examined in 48 resected neoplasms of the exocrine and endocrine pancreas, which were obtained as paraffin-embedded tissue samples. The pancreatic neoplasms included acinar cell carcinoma (n=12), adenocarcinoma (n=18), and islet cell tumors (n=18). DNA methylation was determined with a nested methylation-specific PCR (MSP) technique incorporating an initial bisulfite modification of tumor DNA for the promoter regions associated with 14 tumor suppressor genes. In decreasing order, the 6 most frequently methylated genes were: APC 50%, BRCA1 46%, p16INK4a 35%, p15INK4b 35%, RARβ 35%, and p73 33%. Overall, 94% of the tumors had methylation of at least one gene, and methylation of two or more genes was present in 69% of pancreatic tumors. Pancreatic adenocarcinomas had patterns of gene methylation that differed from pancreatic endocrine tumors. These differences were most notable for the APC and hMLH1 genes. ... Read more

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