Translational research : the journal of laboratory and clinical medicine
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Tunneling nanotubes (TnTs) represent a novel mechanism by which intercellular components such as proteins, Golgi vesicles, and mitochondria can be transferred from cell to cell in the complex tumor microenvironment. Here, we report data showing that microRNAs (miRNAs) are transferred through TnTs in osteosarcoma (OS) and ovarian cancer as in vitro model systems. miRNA array analysis demonstrated significant upregulation of miR-19a in OS tumors resected from human patients, and differential expression of miR-199a in ovarian cancer cell lines resistant or sensitive to platinum chemotherapy. K7M2 murine OS cells were transfected with miR-19a and cultured with nontransfected K7M2 cells in low-serum, hyperglycemic medium for up to 72 hours to induce TnT formation. miRNA transfer via TnTs was detected by time-lapse microscopic imaging. miR-19a was also transported via TnTs connecting transfected K7M2 cells and nontransfected stromal MC3T3 murine osteoblast cells. ⋯ To quantify TnT-mediated transport of miRNAs, we used modified Boyden chambers to separate miR-19a-transfected K7M2 cells (top chamber) and DiI-labeled MC3T3 cells (bottom chamber) compared with open culture of these cells. Fluorescence-activated cell sorting analysis of cells collected after 48 hours of culture indicated that miR-19a-positive MC3T3 cells were 3-fold higher in open culture; this finding suggests that miR-19a transfer occurred via TnTs, exclusive of other forms of cell-cell communication. These studies demonstrate that TnTs mediate direct transfer of genetic material between tumor and stromal cells.
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Intermittent fasting (IF) regimens have gained considerable popularity in recent years, as some people find these diets easier to follow than traditional calorie restriction (CR) approaches. IF involves restricting energy intake on 1-3 d/wk, and eating freely on the nonrestriction days. Alternate day fasting (ADF) is a subclass of IF, which consists of a "fast day" (75% energy restriction) alternating with a "feed day" (ad libitum food consumption). ⋯ Results reveal superior decreases in body weight by CR vs IF/ADF regimens, yet comparable reductions in visceral fat mass, fasting insulin, and insulin resistance. None of the interventions produced clinically meaningful reductions in glucose concentrations. Taken together, these preliminary findings show promise for the use of IF and ADF as alternatives to CR for weight loss and type 2 diabetes risk reduction in overweight and obese populations, but more research is required before solid conclusions can be reached.
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Cardiac fibrosis is strongly associated with obesity and metabolic dysfunction and may contribute to the increased incidence of heart failure, atrial arrhythmias, and sudden cardiac death in obese subjects. This review discusses the evidence linking obesity and myocardial fibrosis in animal models and human patients, focusing on the fundamental pathophysiological alterations that may trigger fibrogenic signaling, the cellular effectors of fibrosis, and the molecular signals that may regulate the fibrotic response. Obesity is associated with a wide range of pathophysiological alterations (such as pressure and volume overload, metabolic dysregulation, neurohumoral activation, and systemic inflammation); their relative role in mediating cardiac fibrosis is poorly defined. ⋯ Activation of the renin-angiotensin-aldosterone system, induction of transforming growth factor β, oxidative stress, advanced glycation end-products, endothelin 1, Rho-kinase signaling, leptin-mediated actions, and upregulation of matricellular proteins (such as thrombospondin 1) may play a role in the development of fibrosis in models of obesity and metabolic dysfunction. Moreover, experimental evidence suggests that obesity and insulin resistance profoundly affect the fibrotic and remodeling response after cardiac injury. Understanding the pathways implicated in obesity-associated fibrosis may lead to the development of novel therapies to prevent heart failure and attenuate postinfarction cardiac remodeling in patients with obesity.
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Review
Obesity and heart failure: epidemiology, pathophysiology, clinical manifestations, and management.
Obesity is a risk factor for heart failure (HF) in both men and women. The mortality risk of overweight and class I and II obese adults with HF is lower than that of normal weight or underweight adults with HF of comparable severity, a phenomenon referred to as the obesity paradox. ⋯ The resultant syndrome is known as obesity cardiomyopathy. Substantial weight loss in severely obese persons is capable of reversing most obesity-related abnormalities of cardiac performance and morphology and improving the clinical manifestations of obesity cardiomyopathy.
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The increasing prevalence of nonalcoholic fatty liver disease (NAFLD) parallels the rise of obesity and its complications. NAFLD is a common cause of cirrhosis and a leading indication for liver transplant. Genetic susceptibility, dietary composition, and exercise habits influence the development of NAFLD, and insulin resistance results in widespread metabolic perturbations with a net effect of triglyceride accumulation in the liver. ⋯ Treatments targeting the pathophysiological mechanisms of NAFLD exist, but carry some potential risk and are not universally effective. Weight loss and lifestyle changes remain the most effective and safest approach, but sustainable change is difficult for most patients to achieve. Future work will continue to focus on developing effective and safe interventions to prevent the development of advanced liver disease, whereas efforts in the public health domain continue to combat obesity.