Description: Background and Purpose— Prolonged ischemia causes blood–brain barrier (BBB) damage and increases the incidence of neurovasculature complications secondary to reperfusion. Therefore, targeting ischemic BBB damage pathogenesis is critical to reducing neurovasculature complications and expanding the therapeutic time window of tissue-type plasminogen activator (tPA) thrombolysis. This study investigates whether increasing cerebral tissue P O 2 through normobaric hyperoxia (NBO) treatment will slow the progression of BBB damage and, thus, improve the outcome of delayed tPA treatment after cerebral ischemia. Methods— Rats were exposed to NBO (100% O 2 ) or normoxia (21% O 2 ) during 3-, 5-, or, 7-hour middle cerebral artery occlusion. Fifteen minutes before reperfusion, tPA was continuously infused to rats for 30 minutes. Neurological score, mortality rate, and BBB permeability were determined. Matrix metalloproteinase-9 was measured by gelatin zymography and tight junction proteins (occludin and cluadin-5) by Western blot in the isolated cerebral microvessels. Results— NBO slowed the progression of ischemic BBB damage pathogenesis, evidenced by reduced Evan blue leakage, smaller edema, and hemorrhagic volume in NBO-treated rats. NBO treatment reduced matrix metalloproteinase-9 induction and the loss of tight junction proteins in ischemic cerebral microvessels. NBO-afforded BBB protection was maintained during tPA reperfusion, resulting in improved neurological functions, significant reductions in brain edema, hemorrhagic volume, and mortality rate, even when tPA was given after prolonged ischemia (7 hours). Conclusions— Early NBO treatment slows ischemic BBB damage pathogenesis and significantly improves the outcome of delayed tPA treatment, providing new evidence supporting NBO as an effective adjunctive therapy to extend the time window of tPA thrombolysis for ischemic stroke.

Description: Rationale: The effectiveness of transplanted bone marrow mesenchymal stem cells (MSCs) for cardiac repair has been limited; thus, strategies for optimizing stem-cell–based myocardial therapy are needed. Objective: The present study was designed to test our central hypothesis that hypoxia-preconditioned MSCs (HP-MSCs) are more effective than MSCs cultured under ambient oxygen levels for the treatment of myocardial injury in a large-scale (N=49), long-term (9 months), nonhuman primate (Cynomolgous monkeys) investigation. Methods and Results: MSCs were engineered to express green fluorescent protein, cultured under ambient oxygen or 0.5% oxygen (HP-MSCs) for 24 hours and then tested in the infarcted hearts of Cynomolgus monkeys (1 x 10 7 cells per heart). Hypoxia preconditioning increased the expression of several prosurvival/proangiogenic factors in cultured MSCs, and measurements of infarct size and left-ventricular function at day 90 after myocardial infarction were significantly more improved in monkeys treated with HP-MSCs than in monkeys treated with the control vehicle; functional improvements in normal cultured bone marrow mesenchymal stem cells–treated monkeys were not significant. HP-MSCs transplantation was also associated with increases in cardiomyocyte proliferation, vascular density, myocardial glucose uptake, and engraftment of the transplanted cells and with declines in endogenous cell apoptosis, but did not increase the occurrence of arrhythmogenic complications. Conclusions: Hypoxia preconditioning improved the effectiveness of MSCs transplantation for the treatment of myocardial infarction in nonhuman primates without increasing the occurrence of arrhythmogenic complications, which suggests that future clinical trials of HP-MSCs transplantation are warranted.

Description: Neuropeptide Y (NPY) is implicated in the regulation of blood pressure (BP), and NPY pathways in the hypothalamus are sensitive to dietary fat. We evaluated the potential effect of a functional variant rs16147 located in the NPY gene promoter region on the association between 2-year diet intervention and change in multiple BP measures in the randomized Preventing Overweight Using Novel Dietary Strategies Trial. The NPY rs16147 was genotyped in 723 obese adults who were randomly assigned to 1 of 4 diets differing in the target percentages of energy derived from fat, protein, and carbohydrate. The changes of 4 BP phenotypes, including systolic BP, diastolic BP, pulse pressure, and mean arterial pressure, during 2-year diet intervention were analyzed. In the total participants and participants with hypertension, we observed significant and consistent interactions between rs16147 genotype and dietary fat intake on changes in multiple BP phenotypes at 2 years (all P for interactions 〈0.05). The risk allele (C allele) was associated with a greater reduction of BP phenotypes in response to low-fat diet, whereas an opposite genetic effect was observed in response to high-fat diet. In addition, the C allele was related to greater changes in 4 BP phenotypes in hypertensive compared with nonhypertensive participants. Our data suggest that NPY rs16147 may modulate the association between dietary fat intake and changes in BP phenotypes, and the C allele exerts a long-term beneficial effect on lowering BP in response to low-fat diet in obese and hypertensive subjects.

Description: Background— Circulating branched-chain amino acids and aromatic amino acids were recently related to insulin resistance and diabetes mellitus in prospective cohorts. We tested the effects of a genetic determinant of branched-chain amino acid/aromatic amino acid ratio on changes in body weight and insulin resistance in a 2-year diet intervention trial. Methods and Results— We genotyped the branched-chain amino acid/aromatic amino acid ratio—associated variant rs1440581 near the PPM1K gene in 734 overweight or obese adults who were assigned to 1 of 4 diets varying in macronutrient content. At 6 months, dietary fat significantly modified genetic effects on changes in weight, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) after adjustment for the confounders (all P for interaction ≤0.006). Further adjustment for weight change did not appreciably change the interactions for fasting insulin and HOMA-IR. In the high-fat diet group, the C allele was related to less weight loss and smaller decreases in serum insulin and HOMA-IR (all P ≤ 0.02 in an additive pattern), whereas an opposite genotype effect on changes in insulin and HOMA-IR was observed in the low-fat diet group ( P =0.02 and P =0.04, respectively). At 2 years, the gene-diet interactions remained significant for weight loss ( P =0.008) but became null for changes in serum insulin and HOMA-IR resulting from weight regain. Conclusions— Individuals carrying the C allele of the branched-chain amino acid/aromatic amino acid ratio—associated variant rs1440581 may benefit less in weight loss and improvement of insulin sensitivity than those without this allele when undertaking an energy-restricted high-fat diet. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00072995.