WE, Tseng MT, Tyagi SC. Mitochondrial matrix metalloproteinase activation decreases myocyte contractility in hyperhomocysteinemia. myocyte N-methyl-D-aspartate receptor-1 (NMDA-R1) activation induces mitochondrial dysfunction. Matrix metalloproteinase protease (MMP) induction is a negative regulator of mitochondrial function. Elevated levels of homocysteine [hyperhomocysteinemia (HHCY)] activate latent MMPs and causes myocardial contractile abnormalities. HHCY is associated with mitochondrial dysfunction. We tested the hypothesis that HHCY activates myocyte mitochondrial MMP (mtMMP), induces mitochondrial permeability transition (MPT), and causes contractile dysfunction by agonizing NMDA-R1. The C57BL/6J mice were administered homocystinemia (1.8 g/l) in drinking water to induce HHCY. NMDA-R1 expression was detected by Western blot and confocal microscopy. Localization of MMP-9 in the mitochondria was determined using confocal microscopy. Ultrastructural analysis of the isolated myocyte was determined by electron microscopy. Mitochondrial permeability was measured by a decrease in light absorbance at 540 nm using the spectrophotometer. The effect of MK-801 (NMDA-R1 inhibitor), GM-6001 (MMP inhibitor), and cyclosporine A (MPT inhibitor) on myocyte contractility and calcium transients was evaluated using the IonOptix video edge track detection system and fura 2-AM. Our results demonstrate that HHCY activated the mtMMP-9 and caused MPT by agonizing NMDA-R1. A significant decrease in percent cell shortening, maximal rate of contraction (ϪdL/dt), and maximal rate of relaxation (ϩdL/dt) was observed in HHCY. The decay of calcium transient amplitude was faster in the wild type compared with HHCY. Furthermore, the HHCY-induced decrease in percent cell shortening, ϪdL/dt, and ϩdL/dt was attenuated in the mice treated with MK-801, GM-6001, and cyclosporin A. We conclude that HHCY activates mtMMP-9 and induces MPT, leading to myocyte mechanical dysfunction by agonizing NMDA-R1. myocyte; calcium; mitochondrial permeability; N-methyl-D-aspartate receptor-1; arrhythmogenesis THE PATHOPHYSIOLOGY of chronic heart failure (CHF) involves abnormalities in systolic and/or diastolic function and increases the propensity for reentry arrhythmias (30, 6). Continued elevation of cardiac sympathetic drive contributes to myocardial toxicity, leading to the decline in cardiac contractility (29). Recent observations suggest an increase in glutamatergic activity on sympathetic regulation, due to the upregulation of hypothalamic N-methyl-D-aspartate receptor-1 subunits (NMDA-R1) during CHF (16). Ischemia-and reperfusion-induced arrhythmias are sensitive to NMDA-R1 blockade (8).Hyperhomocysteinemia (HHCY) is a graded risk factor for CHF (12, 7) and for sudden cardiac death (SCD) resulting from coronary fibrous plaques (4, 1, 5). Homocysteinemia (HCY) induces interstitial cardiac fibrosis leading to systolic/diastolic dysfunction (13). The antagonist to the NMDA-R protects against HCY-induced oxidative damage in neurons (10) and protects against...
Background: Several drugs are used for the management of hypertension. Among these drugs, calcium channel blockers (CCBs) are the most potent and generally used drug. Gingival enlargement is a recognized outcome of the administration of CCBs. Other drugs which cause gingival enlargement are antiepileptic drugs (phenytoin) and immunosuppressants (cyclosporine). The role of bacterial plaque in the overall pathogenesis of drug-induced gingival enlargement is not clear as some studies indicate that plaque is a prerequisite for gingival enlargement, whereas others suggest that the presence of plaque is a result of its accumulation caused by the enlarged gingiva. Aim: The aim of this study is to find the association of local factors with CCBs-induced gingival enlargement. Conclusion:The observations made in this report support that the presence of local factors augments the degree of the gingival enlargement present. Significance: As the prevalence of CCB use is relatively high in the population, especially among patients with cardiovascular disease, it is important that medical professionals are aware of the association between drug-induced gingival enlargement and local factors so that they can emphasize thorough home care and professional cleaning in the treatment of drug-induced gingival enlargement.
INTRODUCTION Brain fog has been extensively studied in patients with inflammatory bowel disease (IBD). Probiotics have been shown to increase the incidence of brain fog in patients independently. There is a high prevalence of probiotic consumption in patients with IBD in clinical practice, whether by a physician or not. We aimed to study if there was an association between brain fog and IBD patients who took probiotics and those who did not. METHODS We conducted a cross-sectional study of patients visiting IBD clinic. Patients over the age of 18 with a biopsy-proven diagnosis of inflammatory bowel disease, without any known pre-existing psychiatric illness or current use of opioid medications were included. They were divided into 2 groups: those with history of probiotic use and those without. Patients were given a questionnaire that included details about symptoms of brain fog. Groups were analyzed by chi-square for differences in baseline demographics, and Mann Whitney U test with repeated measures to compare outcomes between groups. A p value < 0.05 was considered statistically significant. RESULTS Of the 66 patients included (mean age 44±2 years), 35 (53%) were female and 59 (89.4%) were Caucasian. Among these patients, 31.8% (n=21) were on probiotics as dietary supplement with majority (67%, n= 14) taking probiotics for over a year. Overall, there was trend for an association between probiotic use and brain fog in all patients (p=0.080) but no statistical significance was attained. However, brain fog was significantly associated with probiotic use among Caucasian patients (p=0.044). Furthermore, there was a statistically significant association between brain fog and male patients using probiotics (p=0.004). Duration of probiotic use was also associated with brain fog (p=0.038). CONCLUSION Consumption of probiotics was independently associated with brain fog in men, as well as Caucasian patients with IBD respectively. Future prospective studies are warranted to examine causal relationship between probiotics and IBD-associated brain fog to guide prescription of probiotic supplements for IBD.
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