Influence of Lactate Accumulation on Calcium Content of Ischemic and Postischemic Brain

In this study, the cerebral hemisphere content of calcium as well as selected parameters of oxidative metabolism and electrophysiological function were assessed in normoglycemic and hyperglycemic rats that were exposed to ischemia produced by electrocautery of the vertebral arteries and reversible occlusion of the carotid arteries. In hyperglycemic animals, 0.5 h of ischemia was associated with large accumulations of lactate (27 mmol/kg), whereas normoglycemic animals showed lesser lactate accumulation (17 mmol/kg). At this sampling time (0.5 h of ischemia), both groups of ischemic animals showed tissue calcium contents that were unchanged from preischemic control levels. In normoglycemic animals, release of the carotid clamps and recirculation for 1.5–24 h was associated with normalization of lactate, ATP and phosphocreatine, clinical behavior, and EEC During this 24 h of recirculation, cerebral calcium levels showed no changes. Hyperglycemic ischemic animals recirculated for 1.5–24 h showed a persistent lactic acidosis, depressed ATP and phosphocreatine, gross EEG abnormalities, seizures, and a high mortality rate. Again, during this 24 h period, cerebral calcium content showed no changes from preischemic control or from the matched saline-treated group. These data suggest that significant accumulation of calcium in brain tissue is not an early event in ischemic-hyperglycemic brain damage, and thus does not provide support for a role of calcium in the production of this form of ischemic damage.

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Abstract 276: Systemic Delivery of Microrna-146a Improves Endothelial Function and Ameliorates Atherosclerosis in Apolipoprotein E-deficient Mice

Circulation Research ◽

10.1161/res.117.suppl_1.276 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Shuangtao Ma ◽

Xiao Yu Tian ◽

Chaofeng Mu ◽

Haifa Shen ◽

Yunrong Zhang ◽

...

Keyword(s):

Endothelial Function ◽

Apolipoprotein E ◽

Carotid Arteries ◽

Treated Group ◽

Vehicle Group ◽

Early Event ◽

Aortic Tissue ◽

Systemic Delivery ◽

Plaque Area ◽

Deficient Mice

Rationale: Endothelial inflammation is an early event in the development of atherosclerosis. The microRNA (miR)-146a showed anti-inflammatory effects in cultured endothelial cells. In this study, we investigated the therapeutic role of miR-146a in endothelial function and atherosclerosis in apolipoprotein E (ApoE)-deficient mice. Methods and Results: The miR-146a was packaged into a multistage vector (MSV) that was conjugated with an E-selectin-targeting thioaptamer (ESTA) to form an ESTA-MSV microparticle. The ApoE-deficient mice were fed with Western diet and injected through tail vein with 15μg of miR-146a loaded ESTA-MSV microparticles or vehicle vectors biweekly for 12 weeks. The expressions of miR-146a in aortic tissue was increased by five times at two weeks after injection. However, the expressions of miR-146a in heart, lung, liver, spleen, kidney, and skeletal muscle were not increased. The acetylcholine-induced endothelium-dependent relaxations in both carotid arteries and aortas were significantly improved in mice from miR-146a treated group compared with vehicle group. In addition, the endothelium-dependent contractions of carotid arteries were also improved by miR-146a treatment. The en face oil red O staining of whole aortas showed the plaque area was decreased in miR-146a-treated mice. Application of miR-146a also decreased the plaque size, macrophages, and T-lymphocytes, but increased the collagen deposition and vascular smooth muscle cells in the sections of aortic roots. The PCR results showed that expressions of chemokine (C-C motif) ligand (CCL)-2, CCL-5, and CCL-8 were decreased by miR-146a. Conclusions: E-selectin-targeting delivery of miR-146a improves endothelial function and inhibits atherosclerosis.

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Tryptophan-Niacin Metabolism in Rat with Puromycin Aminonucleoside-Induced Nephrosis

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831.76.1.28 ◽

2006 ◽

Vol 76 (1) ◽

pp. 28-33 ◽

Cited By ~ 7

Author(s):

Yukari Egashira ◽

Shin Nagaki ◽

Hiroo Sanada

Keyword(s):

Body Weight ◽

Urinary Excretion ◽

Enzyme Activities ◽

Treated Group ◽

Control Group ◽

Puromycin Aminonucleoside ◽

Low Level ◽

Key Enzyme

We investigated the change of tryptophan-niacin metabolism in rats with puromycin aminonucleoside PAN-induced nephrosis, the mechanisms responsible for their change of urinary excretion of nicotinamide and its metabolites, and the role of the kidney in tryptophan-niacin conversion. PAN-treated rats were intraperitoneally injected once with a 1.0% (w/v) solution of PAN at a dose of 100 mg/kg body weight. The collection of 24-hour urine was conducted 8 days after PAN injection. Daily urinary excretion of nicotinamide and its metabolites, liver and blood NAD, and key enzyme activities of tryptophan-niacin metabolism were determined. In PAN-treated rats, the sum of urinary excretion of nicotinamide and its metabolites was significantly lower compared with controls. The kidneyα-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) activity in the PAN-treated group was significantly decreased by 50%, compared with the control group. Although kidney ACMSD activity was reduced, the conversion of tryptophan to niacin tended to be lower in the PAN-treated rats. A decrease in urinary excretion of niacin and the conversion of tryptophan to niacin in nephrotic rats may contribute to a low level of blood tryptophan. The role of kidney ACMSD activity may be minimal concerning tryptophan-niacin conversion under this experimental condition.

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Role of Quercetin in Mitigation of Lindane Induced Toxicity in Terms of Oxidative Responses and Metabolic Status in Mice Brain

Current Bioactive Compounds ◽

10.2174/1573407216999201123193457 ◽

2020 ◽

Vol 16 ◽

Author(s):

Anupama Sharma ◽

Renu Bist ◽

Hemant Pareek

Keyword(s):

Citrate Synthase ◽

Thiobarbituric Acid ◽

Tca Cycle ◽

Treated Group ◽

Protein Carbonyl ◽

Protein Carbonyl Content ◽

Mice Brain ◽

The Brain ◽

Oxidative Responses

Background:: Current study evaluated the protective potential of quercetin against lindane induced toxicity in mice brain. For investigation, mice were allocated into four groups; First group was control. Second group was administered with oral dose of lindane (25 mg/kg bw) for 4 consecutive days. Third group was exposed to quercetin (40 mg/kg bw) and in fourth group, quercetin was administered 1 hour prior to the exposure of lindane. Objective:: Two major objectives were decided for study. First was to create lesions in the brain by lindane and; second was to evaluate the neuroprotective potential of quercetin. Methods:: To study oxidative responses, level of thiobarbituric acid reactive substances (TBARS), protein carbonyl content (PCC), reduced glutathione (GSH), superoxide dismutase (SOD), Catalase (CAT), and glutathione peroxidase (GPx) were measured in brain homogenates. Three key step regulating enzymes of tricarboxylic acid (TCA) cycle viz citrate synthase (CS), pyruvate dehydrogenase (PDH) and fumarase were also assayed. Results:: Lindane treatment significantly enhanced the levels of TBARS (P<0.001),PCC (P<0.001), GPx (P<0.001), SOD (P<0.05), PDH (P<0.05) and fumarase (P<0.001) in brains of mice compared to control. Meanwhile, it alleviated GSH, CAT and CS (P<0.05) activity. Conclusion:: Pretreatment with quercetin in lindane treated group not only restored, previously altered biochemical parameters after lindane treatment and also significantly improved them too which suggests that quercetin is not only invulnerable rather neuroprotective against lindane intoxication.

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The signaling role of extracellular ATP in co-culture of Shiraia sp. S9 and Pseudomonas fulva SB1 for enhancing hypocrellin A production

Microbial Cell Factories ◽

10.1186/s12934-021-01637-9 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Xin Ping Li ◽

Lu Lu Zhou ◽

Yan Hua Guo ◽

Jian Wen Wang

Keyword(s):

Atp Release ◽

Specific Inhibitor ◽

Extracellular Atp ◽

Oxidase Inhibitor ◽

Disulfonic Acid ◽

Early Event ◽

Fungal Metabolites ◽

Extracellular Signaling ◽

Hypocrellin A

Abstract Background Adenosine 5′-triphosphate (ATP) plays both a central role as an intracellular energy source, and a crucial extracellular signaling role in diverse physiological processes of animals and plants. However, there are less reports concerning the signaling role of microbial extracellular ATP (eATP). Hypocrellins are effective anticancer photodynamic therapy (PDT) agents from bambusicolous Shiraia fungi. The co-culture of Shiraia sp. S9 and a bacterium Pseudomonas fulva SB1 isolated from Shiraia fruiting bodies was established for enhanced hypocrellin A (HA) production. The signaling roles of eATP to mediate hypocrellin biosynthesis were investigated in the co-culture. Results The co-culture induced release of eATP at 378 nM to the medium around 4 h. The eATP release was interdependent on cytosolic Ca2+ concentration and reactive oxygen species (ROS) production, respectively. The eATP production could be suppressed by the Ca2+ chelator EGTA or abolished by the channel blocker La3+, ROS scavenger vitamin C and NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI). The bacterium-induced H2O2 production was strongly inhibited by reactive blue (RB), a specific inhibitor of membrane purinoceptors, but dependent on the induced Ca2+ influx in the co-culture. On the other hand, the application of exogenous ATP (exATP) at 10–300 µM to Shiraia cultures also promoted fungal conidiation and HA production, both of which were blocked effectively by the purinoceptor inhibitors pyridoxalphosphate-6-azophenyl-2′, 4′-disulfonic acid (PPADS) and RB, and ATP hydrolase apyrase. Both the induced expression of HA biosynthetic genes and HA accumulation were inhibited significantly under the blocking of the eATP or Ca2+ signaling, and the scavenge of ROS in the co-culture. Conclusions Our results indicate that eATP release is an early event during the intimate bacterial–fungal interaction and eATP plays a signaling role in the bacterial elicitation on fungal metabolites. Ca2+ and ROS are closely linked for activation of the induced ATP release and its signal transduction. This is the first report on eATP production in the fungal–bacterial co-culture and its involvement in the induced biosynthesis of fungal metabolites. Graphic abstract

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Endovascular Considerations in Traumatic Injury of the Carotid and Vertebral Arteries

Seminars in Interventional Radiology ◽

10.1055/s-0041-1724008 ◽

2021 ◽

Vol 38 (01) ◽

pp. 053-063

Author(s):

Ananth K. Vellimana ◽

Jayson Lavie ◽

Arindam Rano Chatterjee

Keyword(s):

Natural History ◽

Clinical Presentation ◽

Traumatic Injury ◽

Classification Systems ◽

Endovascular Techniques ◽

Traumatic Injuries ◽

Cerebrovascular Injury ◽

Vertebral Arteries ◽

Carotid And Vertebral Arteries

AbstractCervical carotid and vertebral artery traumatic injuries can have a devastating natural history. This article reviews the epidemiology, mechanisms of injury, clinical presentation, and classification systems pertinent to consideration of endovascular treatment. The growing role of modern endovascular techniques for the treatment of these diseases is presented to equip endovascular surgeons with a framework for critically assessing patients presenting with traumatic cervical cerebrovascular injury.

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INSIGHTS INTO THE ROLE OF MORUS ALBA IN REVERSING OBESITY-ASSOCIATED HEPATIC STEATOSIS AND RELATED METABOLIC DISORDER IN RATS

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2016.v9s2.13674 ◽

2016 ◽

pp. 231

Author(s):

Hanaa H. Ahmed ◽

Fatehya M Metwally ◽

Hend Rashad ◽

Asmaa M Zaazaa

Keyword(s):

Insulin Resistance ◽

Hepatic Steatosis ◽

Metabolic Disorder ◽

Ethanolic Extract ◽

Treated Group ◽

Morus Alba ◽

The Other ◽

Obese Group ◽

Control Group

ABSTRACT Objective: The goal of the present study was to examine the viability of Morus alba (M. alba) ethanolic extract in repression of obesity-associated hepatic steatosis and related metabolic disorder; dyslipidemia, hyperinsulinemia, and glycemic status. Methods: Adult female albino rats were randomly assigned into four groups, eight rats each as follows: Group (1) control group received standard rodent diet for 24 weeks. The other three groups administered high cholesterol diet for 12 weeks and served as obese group, M. alba-treated group, and simvastatin-treated group. Results: The current results showed an increment in thoracic circumference (TCX) and abdominal circumferences (AC) as well as body mass index (BMI) in obese group. In addition, dyslipidemia, hyperinsulinemia, hyperglycemia, and insulin resistance have been elucidated in obese group. Moreover, hepatic malondialdehyde (MDA), nitric oxide (NO), serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin values were significantly increased in obese groups versus control group. On the other hand, administration of ethanolic extract of Morus alba or simvastatin could significantly lessen BMI and in addition to improve dyslipidemia in obese group. Glucose, insulin levels, and insulin resistance value in serum samples demonstrated a significant reduction in obese group upon treatment with M. alba ethanolic extract or simvastatin. Furthermore, noticeable depletion in hepatic MDA, NO contents, serum ALT, AST activities, and serum bilirubin level was recorded as a result of treatment with either ethanolic extract of M. alba or simvastatin. Histopathological examination of liver tissue showed ballooning degeneration in the hepatocytes (hepatic steatosis) associated with inflammatory cells penetration in portal zone in obese group. Meanwhile, the treatment of obese groups with ethanolic extract of M. alba or simvastatin was found to restore the structural organization of the liver. Conclusion: The present findings provide a novel aspect for understanding of the role of M. alba against obesity-associated liver diseases and related metabolic disorder. The mechanisms underlying these effects seem to depend on the hypolipidemic potential, anti-inflammatory property, and antioxidant activity of its phytochemicals. Keywords: Obesity, Morus alba, Dyslipidemia, Hyperinsulinemia, Hyperglycemia, Hepatic steatosis.

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Investigating New Therapeutic Strategies Targeting Hyperinsulinemia's Mitogenic Effects in a Female Mouse Breast Cancer Model

Endocrinology ◽

10.1210/en.2012-2263 ◽

2013 ◽

Vol 154 (5) ◽

pp. 1701-1710 ◽

Cited By ~ 21

Author(s):

Ran Rostoker ◽

Keren Bitton-Worms ◽

Avishay Caspi ◽

Zila Shen-Orr ◽

Derek LeRoith

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Breast Tumor ◽

Experimental Studies ◽

Tumor Development ◽

Treated Group ◽

Tumor Growth Rate ◽

Breast Cancer Patients ◽

Mitogenic Effect

Abstract Epidemiological and experimental studies have identified hyperinsulinemia as an important risk factor for breast cancer induction and for the poor prognosis in breast cancer patients with obesity and type 2 diabetes. Recently it was demonstrated that both the insulin receptor (IR) and the IGF-IR mediate hyperinsulinemia's mitogenic effect in several breast cancer models. Although IGF-IR has been intensively investigated, and anti-IGF-IR therapies are now in advanced clinical trials, the role of the IR in mediating hyperinsulinemia's mitogenic effect remains to be clarified. Here we aimed to explore the potential of IR inhibition compared to dual IR/IGF-IR blockade on breast tumor growth. To initiate breast tumors, we inoculated the mammary carcinoma Mvt-1 cell line into the inguinal mammary fat pad of the hyperinsulinemic MKR female mice, and to study the role of IR, we treated the mice bearing tumors with the recently reported high-affinity IR antagonist-S961, in addition to the well-documented IGF-IR inhibitor picropodophyllin (PPP). Although reducing IR activation, with resultant severe hyperglycemia and hyperinsulinemia, S961-treated mice had significantly larger tumors compared to the vehicle-treated group. This effect maybe secondary to the severe hyperinsulinemia mediated via the IGF-1 receptor. In contrast, PPP by partially inhibiting both IR and IGF-IR activity reduced tumor growth rate with only mild metabolic consequences. We conclude that targeting (even partially) both IR and IGF-IRs impairs hyperinsulinemia's effects in breast tumor development while simultaneously sparing the metabolic abnormalities observed when targeting IR alone with virtual complete inhibition.

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Role of iPLA2 and store-operated channels in agonist-induced Ca2+ influx and constriction in cerebral, mesenteric, and carotid arteries

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01148.2007 ◽

2008 ◽

Vol 294 (3) ◽

pp. H1183-H1187 ◽

Cited By ~ 39

Author(s):

Kristen M. Park ◽

Mario Trucillo ◽

Nicolas Serban ◽

Richard A. Cohen ◽

Victoria M. Bolotina

Keyword(s):

Carotid Arteries ◽

Cerebral Arteries ◽

Present Evidence ◽

Voltage Gated ◽

Functional Inhibition ◽

Intracellular Ca ◽

Dependent Pathway ◽

Secondary Activation

Store-operated channels (SOC) and store-operated Ca2+ entry are known to play a major role in agonist-induced constriction of smooth muscle cells (SMC) in conduit vessels. In microvessels the role of SOC remains uncertain, in as much as voltage-gated L-type Ca2+ (CaL2+) channels are thought to be fully responsible for agonist-induced Ca2+ influx and vasoconstriction. We present evidence that SOC and their activation via a Ca2+-independent phospholipase A2 (iPLA2)-mediated pathway play a crucial role in agonist-induced constriction of cerebral, mesenteric, and carotid arteries. Intracellular Ca2+ in SMC and intraluminal diameter were measured simultaneously in intact pressurized vessels in vitro. We demonstrated that 1) Ca2+ and contractile responses to phenylephrine (PE) in cerebral and carotid arteries were equally abolished by nimodipine (a CaL2+ inhibitor) and 2-aminoethyl diphenylborinate (an inhibitor of SOC), suggesting that SOC and CaL2+ channels may be involved in agonist-induced constriction of cerebral arteries, and 2) functional inhibition of iPLA2β totally inhibited PE-induced Ca2+ influx and constriction in cerebral, mesenteric, and carotid arteries, whereas K+-induced Ca2+ influx and vasoconstriction mediated by CaL2+ channels were not affected. Thus iPLA2-dependent activation of SOC is crucial for agonist-induced Ca2+ influx and vasoconstriction in cerebral, mesenteric, and carotid arteries. We propose that, on PE-induced depletion of Ca2+ stores, nonselective SOC are activated via an iPLA2-dependent pathway and may produce a depolarization of SMC, which could trigger a secondary activation of CaL2+ channels and lead to Ca2+ entry and vasoconstriction.

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Protective effects of histamine on Gq-mediated relaxation in regenerated endothelium

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00733.2013 ◽

2014 ◽

Vol 306 (2) ◽

pp. H286-H290 ◽

Cited By ~ 4

Author(s):

Calvin K. Chan ◽

Song Yan Liao ◽

Yue Lin Zhang ◽

Aimin Xu ◽

Hung Fat Tse ◽

...

Keyword(s):

Area Under The Curve ◽

Treated Group ◽

Control Group ◽

Protective Effects ◽

Treatment Control ◽

Porcine Coronary Artery ◽

Endogenous Histamine ◽

Coronary Endothelium ◽

Treatment Control Group

In the porcine coronary artery, regenerated endothelium is dysfunctional as regards the responses to endothelium-dependent agonists. The current study aimed to determine the possible involvement of histamine in such dysfunction. Pigs were treated chronically with pyrilamine (H1 receptor inhibitor, 2 mg·kg−1·day−1) with part of their coronary endothelium and allowed to regenerate for 28 days after balloon denudation. The results showed a reduction in relaxation to bradykinin (Gq protein dependent) only in the pyrilamine-treated group (area under the curve, 269.7 ± 13.4 vs. 142.0 ± 31.0, native endothelium vs. regenerated endothelium) but not in the control group (253.0 ± 22.1 vs. 231.9 ± 29.5, native endothelium vs. regenerated endothelium). The differences in the relaxation to serotonin (Gi protein dependent) between native and regenerated endothelium were not affected by the pyrilamine treatment (control group, 106.3 ± 17.0 vs. 55.61 ± 12.7; and pyrilamine group, 106.0 ± 8.20 vs. 49.30 ± 6.31, native endothelium vs. regenerated endothelium). These findings indicate that during regeneration of the endothelium, the activation of H1 receptors by endogenous histamine may be required to maintain the endothelium-dependent Gq protein-mediated relaxation to bradykinin, suggesting a beneficial role of the monoamine in the process of endothelial regeneration.

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