Host-derived MMP-9 expression, most likely in tumor-infiltrating macrophages, appears to play a critical role in angiogenesis and progressive growth of human ovarian tumors in mice.

Metabolism transfers energy from substrates to ATP. As a "metabolic omnivore," the normal heart adapts to changes in the environment by switching from one substrate to another. We propose that this flexibility is lost in the maladapted, diseased heart. Both adaptation and maladaptation are the results of metabolic signals that regulate transcription of key cardiac regulatory genes. We propose that metabolic remodeling precedes, initiates, and sustains functional and structural remodeling. The process of metabolic remodeling then becomes a target for pharmacological intervention restoring metabolic flexibility and normal contractile function of the heart.

Clinicaltrials.gov: NCT01279265 and NCT01849991.

It is suggested that insulin resistance and metabolic maladaptation of the heart are causes of contractile dysfunction. We tested the hypothesis whether systemic PPAR␥ activation, by changing the metabolic profile in a model of insulin resistance and type 2 diabetes (the ZDF rat) in vivo, improves contractile function of the heart in vitro. Male Zucker diabetic fatty (ZDF) and Zucker lean (ZL) rats, at 53-56 days of age, were treated with either GI-262570 (a nonthiazolidinedione PPAR␥ agonist; A) or vehicle (V) for 1 wk. Agonist treatment resulted in correction of hyperglycemia and dyslipidemia, as well as in reduced hyperinsulinemia. The accumulation of triacylglycerols in the myocardium, characteristic of the ZDF rat, disappeared with treatment. Cardiac power and rates of glucose oxidation in the isolated working heart were significantly reduced in ZDF-V rats, but both parameters increased to nondiabetic levels with agonist treatment. In ZDF-V hearts, transcript levels of PPAR␣-regulated genes and of myosin heavy chain-␤ were upregulated, whereas GLUT4 was downregulated compared with ZL. Agonist treatment of ZDF rats reduced PPAR␣-regulated genes and increased transcripts of GLUT4 and GLUT1. In conclusion, by changing the metabolic profile, reducing myocardial lipid accumulation, and promoting the downregulation of PPAR␣-regulated genes, PPAR␥ activation leads to an increased capacity of the myocardium to oxidize glucose and to a tighter coupling of oxidative metabolism and contraction in the setting of insulin resistance and type 2 diabetes.peroxisome proliferator-activated receptor-␥; Zucker diabetic fatty rat; diabetes mellitus; obesity; insulin; myocardial contraction; metabolism DIABETES MELLITUS ADVERSELY AFFECTS the cardiovascular system both at the level of the vasculature and at the level of the myocardium (45). Diabetes is considered an independent risk factor for heart failure (27), because abnormal ventricular function occurs in diabetic patients independently of clinically overt vascular disease (17, 32). Alterations in protein synthesis, calcium handling, and contractile proteins have all been implicated as key contributors to the development of cardiac dysfunction in diabetes (13,20). Changes in gene expression, energy substrate metabolism, and ultrastructure occur early in the course of the disease (45). Although the exact mechanism for the pathogenesis of diabetic cardiomyopathy is not understood, some of the first changes appear to be at the level of myocardial energy substrate metabolism (4, 36).Diabetes is as much a disease of dysregulated fatty acid metabolism as it is of dysregulated glucose metabolism (31). High rates of fatty acid uptake in the diabetic myocardium result in the accumulation of myocardial lipid and lipid intermediates, mitochondrial/peroxisomal generation of reactive oxygen species, and excessive oxygen consumption (18,50,52). These findings contrast with the metabolic characteristics of the normal heart.The normal heart readily adapts to changes in the environment by sw...

BackgroundThere are few carefully-designed studies investigating the safety of individual probiotics approved under Investigational New Drug policies.ObjectivesThe primary aim of this prospective, double-blind placebo-controlled trial was to investigate if daily treatment of adults with Lactobacillus reuteri DSM 17938 (LR) for 2 months is safe and well-tolerated. Our secondary aim was to determine if LR treatment has immune effects as determined by regulatory T cell percentages, expression of toll-like receptors (TLR)-2 and −4 on circulating peripheral blood mononuclear cells (PMBCs), cytokine expression by stimulated PBMC, and intestinal inflammation as measured by fecal calprotectin.MethodsForty healthy adults were randomized to a daily dose of 5×108 CFUs of LR (n = 30) or placebo (n = 10) for 2 months. Participants completed a daily diary card and had 7 clinic visits during treatment and observation.ResultsThere were no severe adverse events (SAEs) and no significant differences in adverse events (AEs). There were no differences in PBMC subclasses, TLRs, or cytokine expression after treatment. The probiotic-treated group had a significantly higher fecal calprotectin level than the placebo group after 2 months of treatment: 50 µg/g (IQR 24–127 µg/g) vs. 17 µg/g (IQR 11–26 µg/g), p = 0.03, although values remained in the normal clinical range (0–162.9 µg/g). LR vials retained >108 CFUs viable organisms/ml.ConclusionsLR is safe and well tolerated in adults, without significant changes in immunologic markers. There was a small but significant increase in fecal calprotectin, perhaps indicating some element of immune recognition at the intestinal level.Trial RegistrationClinical Trials.gov NCT00922727