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The Relationship Between In Utero Conditions and Adult Health and Disease


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

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

Epigenetic Silencing of CXCL14 Induced Colorectal Cancer Migration and Invasion

Abstract:

To explore epigenetic regulation and the impact of chemokine CXCL14 on colorectal cancer, 7 colorectal cancer cell lines, 107 cases of primary colorectal cancer, and 10 cases of normal colorectal mucosa were evaluated in this study. Methylation specific PCR (MSP), semi-quantitative reverse-transcription PCR (RT-PCR), cell proliferation assay, colony formation, and transwell assay were performed for the evaluation. Complete methylation and loss of CXCL14 expression were found in 5 colorectal cancer cell lines. Partial methylation and weak expression were found in two cell lines. CXCL14 was methylated in 79.4% (85/107) of primary human colorectal cancer. No methylation was found in 10 cases of normal colorectal mucosa. Restoration of CXCL14 expression was induced by the 5-aza-2'-deoxycytidine (DAC) treatment. The cell viability was reduced and colony formation was inhibited by restoration of CXCL14 expression in HCT116 cells, a colorectal cancer cell line. The number of invasive and migration cells was reduced by CXCL14. The expression of MMP-2, Vimentin, and NF-κB was suppressed, and the expression of E-cadherin and IκB-α was induced by CXCL14. In conclusion, CXCL14 is frequently methylated in human colorectal cancer and promoter region hypermethylation silenced CXCL14 expression in colorectal cancer cells. Restoration of CXCL14 expression suppressed colorectal cancer proliferation. CXCL14 inhibits colorectal cancer migration, invasion, and epithelial-to-mesenchymal transition (EMT) by suppressing NF-κB signaling.

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Novel Biomarkers, Dysregulated Epigenetics, and Therapy in Cutaneous T-cell Lymphoma

Abstract: Cutaneous T cell lymphomas (CTCL) are a diverse group of lymphoid malignancies that develop in the skin. The most common variants are mycosis fungoides (MF) and Sezary syndrome (SS). These skin lymphomas can be challenging to differentiate from non-malignant inflammatory skin disorders such as psoriasis or nummular eczema, thus the identification of biomarkers is important in early diagnosis and treatment. Gene expression analysis has identified novel genes that are expressed in MF/SS that may improve diagnosis of MF/SS. Although the catalog of biomarker genes remains incomplete, a mechanism playing a role in the increased expression of biomarkers in MF/SS includes epigenetic changes. This is supported by the efficacy of evolving therapeutic strategies that modulate gene regulation, such as HDAC inhibitors and methylation inhibitors in the treatment of this group of cancers. ... Read more

RNA Interference and Personalized Cancer Therapy

Abstract: Despite billions of dollars allocated to cancer research, cancer remains the number 2 cause of death in the United States with less than 50% of advanced cancer patients living one year following standard treatment. Cancer is a complex disease both intrinsically and in relation to its host environment. From a molecular standpoint no two cancers are the same despite histotypic similarity. As evidenced by the recent advances in molecular biology, treatment for advanced cancer is headed towards specific targeting of vulnerable signaling nodes within the reconfigured pathways created by "omic" rewiring. With advancements in proteo-genomics and the capacity of bioinformatics, complex tumor biology can now be more effectively and rapidly analyzed to discover the vulnerable high information transfer nodes within individual tumors. RNA interference (RNAi) technology, with its capability to knock down the expression of targeted genes (the vulnerable nodes), is moving into the clinic to target these nodes, which are integral to tumor maintenance, with a low risk of side-effects and to block intrinsic immunosuppressors thereby priming the tumor for immune attack. An RNAi based sequential approach, a so called "one-two punch," is being advocated comprising tumor volume reduction (ideally to minimal residual disease status) effected by integrated multi-target knockdown followed by immune activation. Examples and recent developments are provided to illustrate this highly powerful approach heralding the future of personalized cancer therapy. ... Read more

Rheumatoid Arthritis and Alzheimer's Disease: Genetic and Epigenetic Links in Inflammatory Regulation

Abstract: Controversial data are available about the relationship between Alzheimer's disease (AD) and rheumatoid arthritis (RA). An inverse relationship between AD and RA, due to different factors, was previously described. Similarly to RA, AD pathogenesis is multifactorial and different findings support the inflammatory pathogenetic hypothesis. Several inflammatory mediators are involved in the disease onset and progression regulated by genetic and epigenetic mechanisms. Among them, inteleukin-6 (IL-6) and interleukin-1 (IL-1) as pro-inflammatory soluble factors produced by monocytes-macrophages and tumor necrosis factor alpha (TNF-α) produced by activated macrophages and mononuclear cells represent key molecules in the induction and maintenance of chronic inflammation in RA. In particular a link with the T allele of the SNP 3953 T/C in the IL-1 gene and an overexpression of miR-146a appears to be common to both RA and AD. In this review we will discuss the genetic and epigenetic regulation of the inflammatory cascade in RA and AD to find out the possible links between RA and AD onset. ... Read more

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