Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is growing evidence that many aspects of our lifestyle and the environment we now live in contribute to the development of disease. The luminal digestive tract is a clear target of the influence of dietary components, alcohol, microbial organisms, and other ingested materials. External factors including obesity, lack of physical exercise, and tobacco consumption also impact diseases of the luminal gastrointestinal (GI) tract. A growing understanding of the microbiome which forms an integral part of the human organism indicates that this is another important external force that impacts human health and disease. The luminal GI tract conditions that arise, at least in part, from these external factors range from malignancies (squamous cell esophageal cancer, Barrett's esophagus and associated esophageal adenocarcinoma, gastric cancer, and colorectal cancer), idiopathic inflammatory disorders such as inflammatory bowel diseases, and post-infectious syndromes including post-infectious irritable bowel syndrome, post-infectious dyspepsia and other functional GI disorders. Of particular interest, given their increase in prevalence in much of the world, are immune-mediated conditions in which food antigens are the driving force behind disease development. These entities include celiac disease, eosinophilic esophagitis, and food allergies. Celiac disease is a prime example of a condition mediated by dietary factors whose pathogenesis has only recently been determined, providing opportunities for developing treatment options beyond the gluten-free diet. While a genetic basis for this disease clearly exists, it is believed that environmental factors such as an increase in gluten in the human diet account for its rising prevalence, now roughly 1% of genetically susceptible populations in all continents. Proposed therapeutic strategies span from preventing disease by modulating the time of gluten introduction in infants, to reducing exposure to gluten by developing strains of wheat with lower levels of gluten, degrading ingested gluten peptides within the intestinal lumen via endopeptidases or modulating uptake of these peptides across intestinal tight junctions. Other novel treatments in development focus on interfering with the immune events that lead to disease once gluten accesses the lamina propria including altering the immune milieu from a Th1-predominant response via hookworm infection, inhibiting tissue transglutaminase, and blocking antigen presentation and/or T-cell responses to gluten peptides. While new treatment options for celiac disease reflect the complex interaction of diet, genetic factors and the host immune response, the implications for treatment of many conditions of the large and small intestine that arise from environmental and lifestyle are as basic as ensuring adequate nutrition, regular exercise and cessation of tobacco use. Much more needs to be learned about the microbiome, dietary and other factors and their interaction with the human host in order to develop potential new treatment strategies for diseases that result from the environment and lifestyle.
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PMID:Environmental and lifestyle influences on disorders of the large and small intestine: implications for treatment. 2173 92

Factor XIII-A (FXIII-A) transglutaminase (TG) was recently identified as a potential causative obesity gene in human white adipose tissue (WAT). Here, we have examined the role of TG activity and the role of protein crosslinking in adipogenesis. Mouse WAT and preadipocytes showed abundant TG activity arising from FXIII-A. FXIII-A was localized to the cell surface and acted as a negative regulator of adipogenesis by promoting assembly of fibronectin (FN) from plasma into preadipocyte extracellular matrix. This modulated cytoskeletal dynamics and maintained the preadipocyte state. FXIII-A-assembled plasma FN (pFN) matrix promoted preadipocyte proliferation and potentiated the proproliferative effects of insulin (INS) while suppressing the prodifferentiating INS signaling. FXIII-A-deficient mouse embryonic fibroblasts showed increased lipid accumulation and decreased proliferation as well as decreased pFN assembly into extracellular matrix. Thus, FXIII-A serves as a preadipocyte-bound proliferation/differentiation switch that mediates effects of hepatocyte-produced circulating pFN.
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PMID:Factor XIII-A transglutaminase acts as a switch between preadipocyte proliferation and differentiation. 2514 79

F13A1 gene, which encodes for Factor XIII-A blood clotting factor and a transglutaminase enzyme, was recently identified as a potential causative gene for obesity in humans. In our previous in vitro work, we showed that FXIII-A regulates preadipocyte differentiation and modulates insulin signaling via promoting plasma fibronectin assembly into the extracellular matrix. To understand the role of FXIII-A in whole body energy metabolism, here we have characterized the metabolic phenotype of F13a1-/- mice. F13a1-/- and F13a1+/+ type mice were fed chow or obesogenic, high fat diet for 20 weeks. Weight gain, total fat mass and fat pad mass, glucose handling, insulin sensitivity, energy expenditure and, morphological and biochemical analysis of adipose tissue was performed. We show that mice lacking FXIII-A gain weight on obesogenic diet, similarly as wild type mice, but exhibit a number of features of metabolically healthy obesity such as protection from developing diet-induced insulin resistance and hyperinsulinemia. Mice also show normal fasting glucose levels, larger adipocytes, decreased extracellular matrix accumulation and inflammation of adipose tissue, as well as decreased circulating triglycerides. This study reveals that FXIII-A transglutaminase can regulate whole body insulin sensitivity and may have a role in the development of diet-induced metabolic disturbances.
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PMID:Factor XIII-A transglutaminase deficient mice show signs of metabolically healthy obesity on high fat diet. 2775 18

The prevalence of type 2 diabetes mellitus (T2DM) has quadrupled within three decades since 1980, affecting 422 million adults in 2016. It remains one of the most common noncommunicable chronic diseases and the underlying risk factor for cardiovascular diseases worldwide. There are different underlying mechanisms that play a role in the development of pathologies associated with the disease such as hyperglycaemia, oxidative stress, obesity, inflammation and hypercoagulation; each of which are interlinked. Hyperglycaemia, oxidative stress and obesity play a huge role in the activation of inflammation and coagulation. Activation of inflammatory pathways increases the production of thrombin which predisposes the development of thrombotic related diseases. One of the factors that contribute to the increase of thrombin is the impairment of the fibrinolysis process due to decreased expression of tissue-plasminogen activator (tPA) by increased levels of plasminogen activator inhibitor-1 (PAI-1). Coagulation factor XIII (FXIII), a transglutaminase that is composed of subunits A and B (FXIII-A2B2), is essential for the last step of fibrin clot formation in the coagulation pathway. Genetic variation of FXIII-A in the form of single nucleotide polymorphisms (SNPs) alters the activity of FXIII, altering clot properties which influence disease outcomes. This review discusses the link between underlying mechanisms of T2DM, well known FXIII-A variants and coagulation.
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PMID:Coagulopathy in Type 2 Diabetes Mellitus: Pathological Mechanisms and the Role of Factor XIII-A Single Nucleotide Polymorphisms. 3070 22

Functional group modification is one of the main strategies used in drug discovery and development. Despite the controversy of being identified for many years as a biologically hazardous functional group, the introduction of an epoxide function in a structural backbone is still one of the possible modifications being implemented in drug design. In this manner, it is our intention to prove with this work that epoxides can have significant interest in medicinal chemistry, not only as anticancer agents, but also as important drugs for other pathologies. Thus, this revision paper aims to highlight the biological activity and the proposed mechanisms of action of several epoxide-containing molecules either in preclinical studies or in clinical development or even in clinical use. An overview of the chemistry of epoxides is also reported. Some of the conclusions are that effectively most of the epoxide-containing molecules referred in this work were being studied or are in the market as anticancer drugs. However, some of them in preclinical studies, were also associated with other different activities such as anti-malarial, anti-arthritic, insecticidal, antithrombotic, and selective inhibitory activity of FXIII-A (a transglutaminase). As for the epoxide-containing molecules in clinical trials, some of them are being tested for obesity and schizophrenia. Finally, drugs containing epoxide groups already in the market are mostly used for the treatment of different types of cancer, such as breast cancer and multiple myeloma. Other diseases for which the referred drugs are being used include heart failure, infections and gastrointestinal disturbs. In summary, epoxides can be a suitable option in drug design, particularly in the design of anticancer agents, and deserve to be better explored. However, and despite the promising results, it is imperative to explore the mechanisms of action of these compounds in order to have a better picture of their efficiency and safety.
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PMID:Epoxide containing molecules: A good or a bad drug design approach. 3252 52

Background The coexistence of celiac disease (CD) and obesity/overweight is not unusual. Objective We investigate the prevalence and clinical presentation of CD, detected by screening, among children with excessive weight gain. Methods We enrolled 200 children referred for overweight/obesity to our outpatient clinic. Medical history during pregnancy and childhood and lifestyle variables were recorded. Patients were screened for CD with total immunoglobulin A (IgA), IgA anti-transglutaminase (tTG-IgA) and IgA anti-endomysial antibodies (EMA-IgA). In subjects with positive autoantibodies, esophagogastroduodenoscopy (EGDS) was performed and genetic testing for HLA DQ2 and/or DQ8 haplotypes was tested. Results CD positive antibodies (tTg-IgA and EMA-IgA) were detected in eight patients (4%); in all subjects CD diagnosis was confirmed by HLA-DQ2 and/or DQ8 compatibility and EGDS. No association between CD and medical history during pregnancy and childhood or lifestyle variables was noted; however, a dietary difference was identified with those testing positive for CD also reporting a lower weekly consumption of fruits and vegetables (p=0.04). Headache was reported more frequently in patients with than without CD (p=0.04). Familiar positivity for autoimmune diseases was revealed in CD patients (p=0.01). Conclusion CD should be considered in children with excessive weight gain. Familial predisposition to other autoimmune diseases may represent a risk factor for development of CD. Even though the relationship between headache and CD is not well defined, the patients with headache of unknown origin should be screened for CD.
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PMID:Screening for celiac disease among children with overweight and obesity: toward exploring celiac iceberg. 3265 77