Neuronal NMDA receptor (NMDAR) activation leads to the formation of superoxide, which normally acts in cell signaling. With extensive NMDAR activation, the resulting superoxide production leads to neuronal death. It is widely held that NMDA-induced superoxide production originates from the mitochondria, but definitive evidence for this is lacking. We evaluated the role of the cytoplasmic enzyme NADPH oxidase in NMDA-induced superoxide production. Neurons in culture and in mouse hippocampus responded to NMDA with a rapid increase in superoxide production, followed by neuronal death. These events were blocked by the NADPH oxidase inhibitor apocynin and in neurons lacking the p47 phox subunit, which is required for NADPH oxidase assembly. Superoxide production was also blocked by inhibiting the hexose monophosphate shunt, which regenerates the NADPH substrate, and by inhibiting protein kinase C zeta, which activates the NADPH oxidase complex. These findings identify NADPH oxidase as the primary source of NMDA-induced superoxide production.Activation of the neuronal NMDAR initiates several downstream events, including cation influx, activation of nitric oxide synthase and formation of superoxide [1][2][3] . Superoxide functions as an inter-cellular messenger in long-term potentiation 4,5 and participates in redox inhibition of NMDAR channel function 6 ; however, superoxide can also promote neuronal death when NMDAR activation is sustained 1,7 . Notably, the primary source of superoxide induced by NMDAR activation remains unresolved.Initial studies suggested a mechanism in which Ca 2+ influx through NMDAR channels leads to mitochondrial depolarization 8,9 and subsequent mitochondrial production of superoxide 10,11 . However, a biochemical mechanism linking these events has not been identified and evidence supporting mitochondria as the primary source of neuronal superoxide production remains indirect 12,13 . Calcium was shown to induce superoxide production in isolated © 2009 Nature America, Inc. All rights reserved.Correspondence should be addressed to R.A.S. (Raymond.swanson@ucsf.edu). AUTHOR CONTRIBUTIONS A.M.B. carried out the cell culture studies and data analysis and prepared the manuscript drafts. S.W.S. supervised the mouse surgical studies and analyzed these data. S.J.W. performed mouse surgery studies and mouse brain histology. P.N. maintained the Sod2 + mouse colony and prepared the Sod2 + cell cultures. T.M.K. and Y.E. assisted with the p47 phox translocation studies and data analysis. H.L. assisted in the analysis of the cell culture ethidium fluorescence results. P.H.C. assisted with the studies involving Sod2 + neurons. R.A.S. organized the studies and prepared the final manuscript.Note: Supplementary information is available on the Nature Neuroscience website. 14 , but more recent studies indicate that this effect is highly dependent on experimental conditions, especially the presence of bovine serum albumin in the medium and succinate as a metabolic substrate 13 . The important question is w...

No abstract

Background: Little is known regarding health outcomes associated with isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH), or systolic and diastolic hypertension (SDH) among young adults with stage 1 hypertension, defined using the 2017 American College of Cardiology/American Heart Association blood pressure (BP) guideline. Methods: From a nationwide health screening database, we included 6 424 090 participants, aged 20 to 39 years, who were not taking antihypertensive medication at the baseline examination in 2003 to 2007. Participants were categorized as having normal BP (untreated systolic BP [SBP] <120/diastolic BP [DBP] <80 mm Hg; n=2 665 310); elevated BP (SBP 120–129/DBP <80 mm Hg; n=705 344); stage 1 IDH (SBP <130/DBP 80–89 mm Hg; n=1 271 505); stage 1 ISH (SBP 130–139/DBP <80 mm Hg; n=255 588); stage 1 SDH (SBP 130–139/DBP 80–89 mm Hg; n=711 503); and stage 2 hypertension (SBP ≥140, DBP ≥90 mm Hg; n=814 840). The primary outcome was composite cardiovascular disease (CVD) events, including myocardial infarction, stroke, heart failure, and CVD-related death. Results: The median age of the participants was 30 years and 60.9% were male. Over a median follow-up of 13.2 years, 44 070 new CVD events occurred. With normal BP as the reference, multivariable-adjusted hazard ratios (95% CIs) for CVD events were 1.14 (1.09–1.18) for elevated BP, 1.32 (1.28–1.36) for stage 1 IDH, 1.36 (1.29–1.43) for stage 1 ISH, 1.67 (1.61–1.72) for stage 1 SDH, and 2.40 (2.33–2.47) for stage 2 hypertension. Conclusions: Among young adults, stage 1 ISH, IDH, and SDH were all associated with higher CVD risks than normal BP. The CVD risks of stage 1 ISH and IDH were similar to each other but lower than the risk of stage 1 SDH. Categorizing young adults with stage 1 hypertension further into stage 1 ISH, IDH, and SDH may improve risk stratification for identifying high-risk individuals.

Background The Korean Society of Hypertension has published the Korea Hypertension Fact Sheet 2020 to provide an overview of the magnitude and management status of hypertension and their recent trends. Methods The Fact Sheets were based on the analyses of Korean adults aged 20 years or older of the 2007–2018 Korea National Health and Nutrition Examination Survey (KNHANES) and the 2002–2018 National Health Insurance Big Data (NHI-BD). Results Currently, the population average of systolic/diastolic blood pressure was 118/76 mmHg in Korean adults aged 20 years or older showing little change in the recent decade. However, the number of people with hypertension increased steadily, exceeding 12.0 million. Indeed, the number of people diagnosed with hypertension increased from 3.0 million in 2002 to 9.7 million in 2018. During the same period, the number of people using antihypertensive medication increased from 2.5 million to 9.0 million, and the number of people adherent to treatment increased from 0.6 million to 6.5 million. Hypertension awareness, treatment, and control rates increased rapidly until 2007, but showed plateaued thereafter. In 2018, the awareness, treatment, and control rates of hypertension among all adults were 67, 63, and 47%, respectively. However, the awareness and treatment rates were only 17 and 14% among adults aged 20 to 39 years old with hypertension. Among patients treated for hypertension, 61% of them were also using glucose-lowering or lipid-lowering drugs. Among antihypertensive prescriptions, 41% of the patients received monotherapy, 43% received dual therapy, and 16% received triple or more therapy. The most commonly prescribed antihypertensive medication was angiotensin receptor blockers, followed by calcium channel blockers and diuretics. Conclusion To achieve further improvement in management of hypertension, we need to encourage awareness and treatment in young adults. It is required to develop tailored prevention and management strategies that are appropriate for and inclusive of various demographics.

Pyruvate, a key intermediate in glucose metabolism, was explored as a potential treatment in models of experimental stroke and inflammation. Pyruvate was administered to rodents after the onset of middle cerebral artery occlusion (MCAO). Since the extent of inflammation is often proportional to the size of the infarct, we also studied a group of animals given lipopolysaccharide (LPS) to cause brain inflammation without cell death. Following MCAO, pyruvate did not affect physiological parameters but significantly reduced infarct volume, improved behavioral tests and reduced numbers of neutrophils, microglial and NF-kB activation. Animals given LPS showed increased microglial and NF-kB activation which was almost completely abolished by pyruvate. Lactate, a major metabolite of pyruvate, was increased after pyruvate administration. However, administration of lactate itself did not have any anti-inflammatory effects. Pyruvate protects against ischemia possibly by blocking inflammation, but lactate itself does not appear to explain pyruvate's anti-inflammatory properties.

Protection by mild hypothermia has previously been associated with better mitochondrial preservation and suppression of the intrinsic apoptotic pathway. It is also known that the brain may undergo apoptotic death via extrinsic, or receptor‐mediated pathways, such as that triggered by Fas/FasL. Male Sprague‐Dawley rats subjected to 2 h middle cerebral artery occlusion with 2 h intraischemic mild hypothermia (33°C) were assayed for Fas, FasL and caspase‐8 expression. Ischemia increased Fas, but decreased FasL by ∼ 50–60% at 6 and 24 h post‐insult. Mild hypothermia significantly reduced expression of Fas and processed caspase‐8 both by ∼ 50%, but prevented ischemia‐induced FasL decreases. Fractionation revealed that soluble/shed FasL (sFasL) was decreased by hypothermia, while membrane‐bound FasL (mFasL) increased. To more directly assess the significance of the Fas/FasL pathway in ischemic stroke, primary neuron cultures were exposed to oxygen glucose deprivation. Since FasL is cleaved by matrix metalloproteinases (MMPs), and mild hypothermia decreases MMP expression, treatment with a pan‐MMP inhibitor also decreased sFasL. Thus, mild hypothermia is associated with reduced Fas expression and caspase‐8 activation. Hypothermia prevented total FasL decreases, and most of it remained membrane‐bound. These findings reveal new observations regarding the effect of mild hypothermia on the Fas/FasL and MMP systems.

Background The Korean Society of Hypertension has published the Korea Hypertension Fact Sheet 2021 to provide an overview of the magnitude and management status of hypertension and their recent trends. Methods The Fact Sheets were based on the analyses of Korean adults aged 20 years or older of the 1998–2019 Korea National Health and Nutrition Examination Survey and the 2002–2019 National Health Insurance Big Data. Results Currently, the population average of systolic/diastolic blood pressure was 119/76 mmHg in Korean adults aged 20 years or older showing little change in the recent decade. It is estimated that 28% of the adult population aged 20 or older (33% of adults aged 30 or older) have hypertension. The estimated number of people with hypertension was 6.30 million for men and 5.77 million for women, and 1.96 million for men and 2.99 million for women among the population aged 65 or older. The number of people diagnosed with hypertension increased from 3.0 million in 2002 to 10.1 million in 2019. During the same period, the number of people using antihypertensive medication increased from 2.5 million to 9.5 million, and the number of people adherent to treatment increased from 0.6 million to 6.9 million. Among antihypertensive prescriptions, 40.6% of the patients received monotherapy, 43.4% received dual therapy, and 16.0% received triple or more therapy. The most commonly prescribed antihypertensive medication was angiotensin receptor blockers (ARB), followed by calcium channel blockers (CCB) and diuretics. In young women, angiotensin-converting enzyme inhibitors (ACEi), ARB and CCB are less frequently prescribed than in men, but 59.5% of hypertensive women aged 20–39 are prescribed ACEi or ARBs. Hypertensive disorders during pregnancy have been increasing over the past 10 years. In 2019, 5.4% of women who gave birth were diagnosed with chronic hypertension and 3.1% with pregnancy-induced hypertension. Conclusions To achieve further improvement in management of hypertension, we need to encourage awareness and treatment in young adults. It is required to develop tailored prevention and management strategies that are appropriate for and inclusive of various demographics.

No abstract