Methylglyoxal Induces Apoptosis Mediated by Reactive Oxygen Species in Bovine Retinal Pericytes

One of the histopathologic hallmarks of early diabetic retinopathy is the loss of pericytes. Evidences suggest that the pericyte loss in vivo is mediated by apoptosis. However, the underlying cause of pericyte apoptosis is not fully understood. This study investigated the influence of methylglyoxal (MGO), a reactive α-dicarbonyl compound of glucose metabolism, on apoptotic cell death in bovine retinal pericytes. Analysis of internucleosomal DNA fragmentation by ELISA showed that MGO (200 to 800 µM) induced apoptosis in a concentration-dependent manner. Intracellular reactive oxygen species were generated earlier and the antioxidant, N-acetyl cysteine, inhibited the MGO-induced apoptosis. NF-κB activation and increased caspase-3 activity were detected. Apoptosis was also inhibited by the caspase-3 inhibitor, Z-DEVD-fmk, or the NF-κB inhibitor, pyrrolidine dithiocarbamate. These data suggest that elevated MGO levels observed in diabetes may cause apoptosis in bovine retinal pericytes through an oxidative stress mechanism and suggests that the nuclear activation of NF-κB are involved in the apoptotic process

Nutritional Status and Cardiac Autophagy

Autophagy is necessary for the degradation of long-lasting proteins and nonfunctional organelles, and is activated to promote cellular survival. However, overactivation of autophagy may deplete essential molecules and organelles responsible for cellular survival. Lifelong calorie restriction by 40% has been shown to increase the cardiac expression of autophagic markers, which suggests that it may have a cardioprotective effect by decreasing oxidative damage brought on by aging and cardiovascular diseases. Although cardiac autophagy is critical to regulating protein quality and maintaining cellular function and survival, increased or excessive autophagy may have deleterious effects on the heart under some circumstances, including pressure overload-induced heart failure. The importance of autophagy has been shown in nutrient supply and preservation of energy in times of limitation, such as ischemia. Some studies have suggested that a transition from obesity to metabolic syndrome may involve progressive changes in myocardial inflammation, mitochondrial dysfunction, fibrosis, apoptosis, and myocardial autophagy

Peroxisome Proliferator-Activated Receptors and the Heart: Lessons from the Past and Future Directions

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear family of ligand activated transcriptional factors and comprise three different isoforms, PPAR-α, PPAR-β/δ, and PPAR-γ. The main role of PPARs is to regulate the expression of genes involved in lipid and glucose metabolism. Several studies have demonstrated that PPAR agonists improve dyslipidemia and glucose control in animals, supporting their potential as a promising therapeutic option to treat diabetes and dyslipidemia. However, substantial differences exist in the therapeutic or adverse effects of specific drug candidates, and clinical studies have yielded inconsistent data on their cardioprotective effects. This review summarizes the current knowledge regarding the molecular function of PPARs and the mechanisms of the PPAR regulation by posttranslational modification in the heart. We also describe the results and lessons learned from important clinical trials on PPAR agonists and discuss the potential future directions for this class of drugs

Roles of NAD(P)H:quinone Oxidoreductase 1 in Diverse Diseases

NAD(P)H:quinone oxidoreductase (NQO) is an antioxidant flavoprotein that catalyzes the reduction of highly reactive quinone metabolites by employing NAD(P)H as an electron donor. There are two NQO enzymes—NQO1 and NQO2—in mammalian systems. In particular, NQO1 exerts many biological activities, including antioxidant activities, anti-inflammatory effects, and interactions with tumor suppressors. Moreover, several recent studies have revealed the promising roles of NQO1 in protecting against cardiovascular damage and related diseases, such as dyslipidemia, atherosclerosis, insulin resistance, and metabolic syndrome. In this review, we discuss recent developments in the molecular regulation and biochemical properties of NQO1, and describe the potential beneficial roles of NQO1 in diseases associated with oxidative stress

Effects of telmisartan on fat distribution: a meta-analysis of randomized controlled trials

<p><b>Objectives</b>: Several meta-analyses have confirmed the positive metabolic effects of telmisartan, an angiotensin II receptor blocker that can also act as a partial peroxisome proliferator-activated receptor-γ agonist, compared to those of other angiotensin II receptor blockers. These effects include decreased fasting glucose, glycosylated hemoglobin, interleukin-6, and tumor necrosis factor-α levels. However, no systemic analysis of telmisartan’s effects on body fat distribution has been performed. We performed a meta-analysis of randomized controlled telmisartan trials to investigate its effects on body weight, fat distribution, and visceral adipose reduction. <b>Research design and methods</b>: A literature search was performed using Embase, MEDLINE, and the Cochrane Library between January 1966 and November 2013. Randomized controlled trials in English and meeting the following criterion were included: random assignment of hypertensive participants with overweight/obesity, metabolic syndrome, or glucose intolerance to telmisartan or control therapy group. <b>Results</b>: Of 651 potentially relevant reports, 15 satisfied the inclusion criterion. While visceral fat area was significantly lower in the telmisartan group than in the control group (weighted mean difference = −18.13 cm², 95% C.I. = −27.16 to −9.11, <i>P_χ</i>² = 0.19, <i>I</i>² = 41%), subcutaneous fat area was similar (weighted mean difference =2.94 cm², 95% C.I. = −13.01 to 18.89, <i>P_χ</i>² = 0.30, <i>I</i>² = 17%). Total cholesterol levels were significantly different between the groups (standardized mean difference = −0.24, 95% C.I. = −0.45 to −0.03, <i>P_χ</i>² = 0.0002, <i>I</i>² = 67%). <b>Limitations</b>: Limitations include: (1) limited number of studies, especially those evaluating fat distribution; (2) different imaging modalities to assess visceral fat area (V.F.A.) and subcutaneous fat area (S.F.A.); (3) observed heterogeneity. <b>Conclusion</b>: The findings suggest that telmisartan affected fat distribution, inducing visceral fat reduction, and thus could be useful in hypertensive patients with obesity/overweight, metabolic syndrome, or glucose intolerance.</p

MTD-mediated parkin delivery to the brain.

<p>(<b>A–B</b>) Immunoblotting of parkin proteins in the cerebellum. Sagittal sections through the cerebellum were immunostatined with anti-parkin (<b>A</b>) or anti-MTD10 (<b>B</b>) antibody 2 hrs after IP injection of 200 µg of diluent alone or His-tagged parkin proteins without (HP) or with the MTD13 or MTD10 sequences (HPM₁₃ or PM₁₀) (<b>C–D</b>) Western blot analysis of brain parkin. Lysates were prepared from brain samples 2 hrs (<b>C</b>) and 30 hrs (<b>D</b>) after IV administration of diluent alone or 200 µg His-tagged parkin proteins without (HP) or with the MTD01 (HPM₀₁) or MTD13 (HPM₁₃) sequences (<b>C</b>) or with untagged parkin protein containing MTD10 (PM₁₀) (<b>D</b>) and analyzed by western blotting using anti-parkin and anti-β-actin antibodies.</p

Cell-Permeable Parkin Proteins Suppress Parkinson Disease-Associated Phenotypes in Cultured Cells and Animals

<div><p>Parkinson’s disease (PD) is a neurodegenerative disorder of complex etiology characterized by the selective loss of dopaminergic neurons, particularly in the substantia nigra. Parkin, a tightly regulated E3 ubiquitin ligase, promotes the survival of dopaminergic neurons in both PD and Parkinsonian syndromes induced by acute exposures to neurotoxic agents. The present study assessed the potential of cell-permeable parkin (CP-Parkin) as a neuroprotective agent. Cellular uptake and tissue penetration of recombinant, enzymatically active parkin was markedly enhanced by the addition of a hydrophobic macromolecule transduction domain (MTD). The resulting CP-Parkin proteins (HPM₁₃ and PM₁₀) suppressed dopaminergic neuronal toxicity in cells and mice exposed to 6-hydroxydopamine (6-OHDH) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These included enhanced survival and dopamine expression in cultured CATH.a and SH-SY5Y neuronal cells; and protection against MPTP-induced damage in mice, notably preservation of tyrosine hydroxylase-positive cells with enhanced dopamine expression in the striatum and midbrain, and preservation of gross motor function. These results demonstrate that CP-Parkin proteins can compensate for intrinsic limitations in the parkin response and provide a therapeutic strategy to augment parkin activity in vivo.</p></div

CP-Parkin stimulates dopamine expression in MPTP-lesioned mice.

<p>(<b>A</b>) Experimental design. 8-week-old C57BL/6 female mice received three doses of MPTP on days 1 and 2 and were injected IP on days 3 through 7 with diluent alone, or with 10 mg/kg of parkin proteins (IP) with (HPM₁₃ and PM₁₀) or without (HP) a MTD sequence. Urine and brain dopamine levels, gross motor function and brain lesions (TH immunostaining) were analyzed on subsequent days as indicated. (<b>B</b>) Dopamine levels in the urine of MPTP-lesioned mice. Urine dopamine levels in MPTP-lesioned mice were measured by ELISA 1, 2, 4, 6 and 8 hrs after HP and HPM₁₃ protein treatment. Values from 5 mice are presented as means ± S.D. Experimental differences between groups were assessed by a Student’s two-paired <i>t</i>-test (*<i>p</i><0.005). (<b>C</b>) Striatal dopamine levels in MPTP-lesioned mice. Dopamine levels in striatal biopsies were determined by ELISA in lesioned mice without protein treatment or after daily treatments with PM₁₀ as shown in panel A. Dopamine levels in groups of 5 mice are presented as means ± S.D. Experimental differences between groups were assessed by a Student’s two-paired <i>t</i>-test (*<i>p</i><0.01 and **<i>p</i><0.05).</p