Analysis of proteome-wide degradation dynamics in ALS SOD1 iPSC-derived patient neurons reveals disrupted VCP homeostasis.

Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS) through gain-of-function effects, yet the mechanisms by which misfolded mutant SOD1 (mutSOD1) protein impairs human motor neurons (MNs) remain unclear. Here, we use induced-pluripotent-stem-cell-derived MNs coupled to metabolic stable isotope labeling and mass spectrometry to investigate proteome-wide degradation dynamics. We find several proteins, including the ALS-causal valosin-containing protein (VCP), which predominantly acts in proteasome degradation and autophagy, that degrade slower in mutSOD1 relative to isogenic control MNs. The interactome of VCP is altered in mutSOD1 MNs in vitro, while VCP selectively accumulates in the affected motor cortex of ALS-SOD1 patients. Overexpression of VCP rescues mutSOD1 toxicity in MNs in vitro and in a C. elegans model in vivo, in part due to its ability to modulate the degradation of insoluble mutSOD1. Our results demonstrate that VCP contributes to mutSOD1-dependent degeneration, link two distinct ALS-causal genes, and highlight selective protein degradation impairment in ALS pathophysiology.

Neurons undergo pathogenic metabolic reprogramming in models of familial ALS.

OBJECTIVES: Normal cellular function requires a rate of ATP production sufficient to meet demand. In most neurodegenerative diseases (including Amyotrophic Lateral Sclerosis [ALS]), mitochondrial dysfunction is postulated raising the possibility of impaired ATP production and a need for compensatory maneuvers to sustain the ATP production/demand balance. We investigated intermediary metabolism of neurons expressing familial ALS (fALS) genes and interrogated the functional consequences of glycolysis genes in fitness assays and neuronal survival. METHODS: We created a pure neuronal model system for isotopologue investigations of fuel utilization. In a yeast platform we studied the functional contributions of glycolysis genes in a growth fitness assay iafter expressing of a fALS gene. RESULTS: We find in our rodent models of fALS, a reduction in neuronal lactate production with maintained or enhanced activity of the neuronal citric acid cycle. This rewiring of metabolism is associated with normal ATP levels, bioenergetics, and redox status, thus supporting the notion that gross mitochondrial function is not compromised in neurons soon after expressing fALS genes. Genetic loss-of-function manipulation of individual steps in the glycolysis and the pentose phosphate pathway blunt the negative phenotypes seen in various fALS models. CONCLUSIONS: We propose that neurons adjust fuel utilization in the setting of neurodegenerative disease-associated alteration in mitochondrial function in a baleful manner and targeting this process can be healthful.

Induced Abortion: a Systematic Review and Meta-analysis.

BACKGROUND: Induced abortion accounts for 1 in 8 of approximately 600000 maternal deaths that occur annually worldwide. Induced abortion rate can be considered as one of the indicators for assessing availability of the appropriate reproductive health plans for women and identifying needs for appropriate related health policies and programs. MATERIAL AND METHODS: Researchers searched Pubmed, Google Scholar, CINAHL, Embase, PsycINFO, Cochrane, Iranian Scientific Information Database (SID), Iranian biomedical journals (Iranmedex), and Iranian Research Institute of Information and Documentation (Irandoc) between January 2000 and June 2013, which reported induced abortion. Search terms from two categories including abortion and termination of pregnancy were compiled. The search terms were "induced abortion", "illegal abortion", "illegal abortion", "unsafe abortion", and "criminal abortion". The search was also conducted with "induced termination of pregnancy", "illegal termination of pregnancy", "illegal termination of pregnancy", "unsafe termination of pregnancy" and "criminal termination of pregnancy". Meta-analysis was carried out by using OpenMeta software. Induced abortion rates were calculated based on the random effect model. RESULTS: Overall induced abortion rate was obtained 58.1 per 1000 women (95%CI: 55.16-61.04). In continental level, rate of induced abortion was 14 per 1000 women (95%CI: 11-16). Nation-wide and local rates were obtained 67.27 per 1000 women (95% CI: 60.02-74.23) and 148.92 (95% CI: 140.06-157.79) respectively. DISCUSSION AND CONCLUSION: Induced abortion is a major public health problem that occurs worldwide whether under the legal restriction or freedom, and it remains as reproductive health concern globally. To eliminate the need for induced abortion is at the core of any effort for preventing this issue. Option with the highest priority is to prevent unwanted pregnancies through promoting reproductive health plans for women of reproductive age. In case the prevention strategies fail, universal provision of safe abortion services should be put in place.

AMPK activation by metformin inhibits local innate immune responses in the isolated rat heart by suppression of TLR 4-related pathway.

Toll like receptors (TLRs) are key players in the innate immune responses. The energy sensing enzyme, AMPK, has been implicated in the modulation of immunity. The present study investigated whether AMPK activation by metformin could contribute to the regulation of immune responses in the isolated heart via suppression of TLR4 activity, independent of circulatory immunity. Isolated Wistar rat hearts were perfused with Krebs-Henseleit buffer in the absence or presence of lipopolysaccharide (LPS; 0.2µM), LPS+metformin (10mM), and LPS+metformin+compound C (10µM). Following measurement of hemodynamic parameters, TLR4-activation related changes and TLR4 mRNA level in the heart was examined by western blotting and real-time PCR. The activation of AMPK was evaluated by measuring the ratio of p-AMPKα and p-ACC to their non-phosphorylated forms. The effluent and cardiac levels of TNF-α and IL6 were assayed by ELISA. LPS profoundly increased the levels of TLR4 mRNA, MyD88 (TLR4 adaptor protein), and NF-κB and also the release of TNF-α and IL6 from the heart. The enhancement in the TLR4 activity was associated with a significant depression of myocardial function. Metformin clearly augmented the phosphorylation of both AMPKα and ACC and in addition to improvement of cardiac performance, markedly suppressed the TLR4 activity. Antagonizing AMPK by compound C which is a selective inhibitor of AMPK pathway, considerably reversed the protective effects of metformin against the TLR4-related activity. The results of the study demonstrated the importance of TLR4-involved local immune responses in the LPS-induced myocardial dysfunction and indicated a clear link between AMPK and TLR4.

Cardioprotective Effects of Essential Oil of Lavandula angustifolia on Isoproterenol-induced Acute Myocardial Infarction in Rat.

Myocardial infarction (MI) is a common presentation of the ischemic heart disease. Lavandula angustifolia is an herbaceous plant with antioxidative effects. This study was designed to investigate the cardioprotective effects of lavandula angustifolia essential oil against isoproterenol-induced MI in rats. The dried sample was subjected to hydrodistillation by using a Clevenger and the oils were dried over anhydrous Na2SO4. Male Wistar rats were assigned to 6 groups of control, sham, isoproterenol and treatment with 5, 10, 20 mg/Kg of the essential oil. MI was induced by subcutaneous injection of Isoproterenol (100 mg/Kg) for 3 consecutive days at an interval of 24 h. The essential oil was given intraperitoneally every 24 h started at MI induction. Following anesthesia, hemodynamic parameters were measured. After sacrificing the animals, the hearts were removed to measure the heart to body weight ratio and histopathological examination. Myeloperoxidase (MPO) and Malondialdehyde (MDA) were measured in heart tissues for evaluating the activity of neutrophils and lipid peroxidation, respectively. The essential oil amended ECG pattern by suppressing ST-segment elevation and increasing R-amplitude. 10 mg/Kg of the essential oil significantly decreased heart to body weight ratio (P<0.001) and the elevation of MDA and MPO in myocardium, it also increased dp/dtmax from 2793 ± 210 to 4488 ± 253 mmHg/sec (P<0.001), and 20 mg/Kg of it significantly lowered LVEDP from 14 ± 3.43 to 4.3 ± 0.83 mmHg (P<0.001).The results demonstrated that L. angustifolia protects myocardium against isoproterenol-induced MI that it could be related to its antioxidant properties.

Tacrolimus ameliorates functional disturbances and oxidative stress in isoproterenol-induced myocardial infarction.

BACKGROUND: The inflammatory responses play a major role in the pathogenesis of acute myocardial infarction (MI). Early inhibition of inflammation may improve post MI cardiac function. The aim of this study was to investigate the effects of tacrolimus on cardiac function, hemodynamic parameters as well as histopathologic and electrocardiographic changes in isoproterenol-induced myocardial infarction. METHODS: Male Wistar rats were randomly divided into six groups of control, isoproterenol alone, tacrolimus alone, and isoproterenol plus tacrolimus (0.5, 1 and 2 mg/kg). Isoproterenol (100 mg/kg) was injected subcutaneously for two consecutive days to induce myocardial infarction, and simultaneously tacrolimus was administered orally twice a day for three days. RESULTS AND CONCLUSIONS: Administration of isoproterenol resulted in myocardial edema and necrosis as well as a marked reduction in the left ventricular systolic pressure (LVSP), left ventricular contractility (LVdP/dtmax) and relaxation (LVdP/dtmin) along with a severe elevation in left ventricular end-diastolic pressure (LVEDP). Isoproterenol also elevated the ST-segment and suppressed the R-amplitude and R-R interval on ECG. It was found that all doses of tacrolimus could amend the ECG pattern and ameliorated the isoproterenol induced disturbances in cardiac function. Acute and short term treatment with tacrolimus at dose of 2 mg/kg significantly (P < 0.001) improved LVdP/dtmax from 2712 ± 82 in myocardial infarcted rats to 4592 ± 149 mmHg/sec. Similarly, tacrolimus lowered LVEDP from 17.6 ± 0.68 in MI group to the value of 5.6 ± 0.22 mmHg (P < 0.001). Furthermore, tacrolimus was found to reduce malondialdehyde concentration in serum and myocardium by 50-70% (P < 0.001).

Ambivalent effects of atorvastatin on angiogenesis, epidermal cell proliferation and tumorgenesis in animal models.

BACKGROUND: A growing body of preclinical data indicates that statins may possess antineoplastic properties; however, some studies have raised the possibility that statins may also have carcinogenic potential. METHODS: An air pouch model was used for angiogenesis. Single or multiple applications of croton oil on the back of Swiss albino mice with or without initiation by dimethylbenz(a)antheracene (DMBA) were used to evaluate the skin tumorgenesis, ultrastructural and histological alterations. RESULTS: Atorvastatin (orally, 10 mg/kg/day) produced a significant (P<0.05) reduction in angiogenesis. Concurrent administration of mevalonate reversed the anti-angiogenic effect of atorvastatin. However, local injection of atorvastatin (200 µg) into the pouches induced a significant (P<0.5) increase in angiogenesis that was not reversed by co-administration of mevalonate. The disturbance of cell polarity, inflammatory response, thickness of epidermal layer, and mitotic index induced by croton oil were inhibited markedly and dose-dependently (P<0.001) by pre-treatment with atorvastatin. In spite of the strong anti-inflammatory and anti-proliferative effects of atorvastatin on epidermal cell proliferation, it was identified that the same doses of atorvastatin in DMBA-initiated and croton oil-promoted skin tumorgenesis in mice increased the incidence of tumors and their conversion into malignant carcinoma. CONCLUSION: The reasons for these discrepancies remain unclear, and could be related to ambivalent effects of atorvastatin on angiogenesis or to specific differences in the experimental conditions. It is suggested that the pro-angiogenic effect of the drug, which could be responsible for promotion of skin tumors, is independent of the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibition that can be mediated directly by atorvastatin.