There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality.

Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

I and i

[신간의 별자리x] 우리/미술, 그리고 ‘슬픔의 박물관’

https://staff.blog.ui.ac.id/hsuryadi/files/2012/02/ROS_RNS.pdf

Free radicals and antioxidants in normal physiological functions and human disease

For a long time, superoxide generation by an NADPH oxidase was considered as an oddity only found in professional phagocytes. Over the last years, six homologs of the cytochrome subunit of the phag...

/pdf/the-nox-family-of-ros-generating-nadph-oxidases-physiology-zjc88zvh59.pdf

The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology

The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.

/pdf/nitric-oxide-and-peroxynitrite-in-health-and-disease-3uuuqgfdcz.pdf

Nitric Oxide and Peroxynitrite in Health and Disease

Abstract Alcohol consumption is a leading risk factor and increases the risk of liver diseases, cancers, tuberculosis, and injuries. The relationship between alcohol use and cardiovascular risk is complex. While it is well established that heavy alcohol use and binge drinking harm cardiovascular health, the effect of light-to-moderate alcohol consumption remains controversial. Observational studies have repeatedly confirmed the U- or J-shaped relationship between alcohol consumption and cardiovascular disease risk, with the lowest risk observed in the light-to-moderate drinking group. However, the protective effect of low-level alcohol has been challenged by recent genetic epidemiological studies with Mendelian randomization. Such studies have their own limitations, and the application of this methodology in studying alcohol has been questioned. Results from the latest Global Burden of Diseases, Injuries, and Risk Factors Study suggest that the impact of alcohol consumption on health depends on the age structure and the distribution of disease burden and underlying causes in a given population. For young adults, even small amounts of alcohol cause heath loss. For older adults facing a high burden of cardiovascular diseases, light-to-moderate alcohol consumption may improve cardiovascular health outcomes. Mechanistically, all types of alcoholic beverages, including wine, spirits, and beer, have been shown to increase the levels of high-density lipoprotein cholesterol and adiponectin, and reduce the level of fibrinogen. Nonalcoholic components of wine, especially polyphenolic compounds like resveratrol, may additionally enhance endothelial nitric oxide production, and provide antioxidant and anti-inflammatory effects. 

/pdf/alcohol-and-the-vasculature-a-love-hate-relationship-nhmu6lti.pdf

Alcohol and the vasculature: a love-hate relationship?

Endothelium-derived nitric oxide (NO) generated by endothelial NO synthase (eNOS) is a key regulator of endothelial function. Vascular NO induces vasodilation, inhibits platelet aggregation and adhesion, prevents oxidative modification of LDL cholesterol, limits vascular smooth-muscle-cell proliferation, and decreases the expression of proinflammatory genes that promote the development of atherosclerosis. In the presence of cardiac risk factors or cardiovascular disease, endothelial function is impaired. A growing amount of evidence indicates that oxidative stress – an imbalance between endogenous reactive oxygen species (ROS) and antioxidants in favor of the former – contributes markedly to endothelial dysfunction. A crucial aspect of endothelial dysfunction is the reduced bioactivity of NO. A dominant mechanism reducing bioavailability of vascular NO relates to its rapid oxidative inactivation by the ROS superoxide anion. In addition, evidence indicates that persisting oxidative stress renders eNOS dysfunctional, such that it ceases to produce NO and produces superoxide instead. In recent years, we have identified a number of compounds that can revert these events and improve the bioavailability of NO [1-3]. Below we describe the effects of trans-resveratrol as an example.

Trans-resveratrol, a naturally occurring phytoalexin found in grapes and wine, is likely to contribute to the potential of red wine in preventing human cardiovascular disease. We have published previously, that resveratrol upregulates eNOS expression and enhances eNOS activity [5,4]). In addition to its (moderate) direct antioxidant effect, we have found that resveratrol regulates gene expression of pro- and antioxidative enzymes in the cardiovascular system.

Resveratrol is an activator of sirtuin 1 (SIRT1) [6], a NAD+-dependent histone deacetylase. SIRT1 facilitates the formation of heterochromatin, the more tightly packed form of chromatin associated with histone hypoacetylation and gene repression. Multiple non-histone targets have also been described for SIRT1. These include some transcription factors or cofactors such as the tumor suppressor p53, the forkhead box class O (FOXO) transcription factors, nuclear factor κB (NF-κB), and peroxisome proliferator-activated receptor-γ co-activator 1α (PGC-1α) [7]. Recent studies point to SIRT1 as a key regulator of angiogenesis, vascular tone and endothelial function.

Incubation of human umbilical vein endothelial cells (HUVEC) and HUVEC-derived EA.hy 926 cells with resveratrol resulted in a concentration- and time-dependent upregulation of superoxide dismutases (SOD)1, 2 and 3. SIRT1 inhibition with sirtinol or knockdown of SIRT1 by sRNAi markedly reduced the upregulation of SOD1 and 2 with little effect on SOD3. Also glutathione peroxidase 1 (GPx1) and catalase were upregulated by resveratrol. Sirtinol and SIRT1 knockdown prevented the effect on GPx1, but had no significant effect on the enhancement of catalase. The same resveratrol regimen downregulated the expression of NADPH oxidase Nox4, which occurred independently of SIRT1. (6R)-5,6,7,8-tetrahydro-L-biopterin (BH4) is an essential cofactor of eNOS. BH4 is sensitive to oxidation and diminished in oxidative stress. BH4 is synthesized from guanosine 5'-triphosphate (GTP) via a de novo pathway by the rate-limiting enzyme GTP cyclohydrolase I (GCH1). Treatment of EA.hy 926 cells with resveratrol enhanced the expression of GCH1, which was reversed by sirtinol or knockdown of SIRT1 by siRNA.

Atherosclerotic apolipoprotein E knockout (ApoE-KO) mice were treated with resveratrol (30 or 100 mg/kg/day for 7 days via gavage). Resveratrol treatment significantly reduced the levels of superoxide in the heart, which was associated with an upregulation of SOD1-3, GPx1, and catalase. In parallel, mRNA expression of NADPH oxidase subunits Nox2 and Nox4 were reduced. Resveratrol also inhibited the translocation of p47phox and Rac1 and decreased the activity of the NADPH oxidase complex in heart membrane fractions. The cardiac content of malondialdehyde, an indicator of lipid peroxidation and a biomarker for oxidative stress, was reduced by resveratrol treatment. Resveratrol also reduced 3-nitrotyrosine levels in the heart. ApoE-KO mice are an animal model of oxidative stress, and eNOS was found in an uncoupled state, producing superoxide instead of NO. This was probably due to a relative deficiency of BH4. Treatment of ApoE-KO mice with resveratrol enhanced the expression of GCH1 and significantly increased BH4 levels in the heart. This was associated with reduced superoxide production by eNOS.

These data demonstrate that resveratrol protects against vascular oxidative stress in vitro and in vivo, by changing the expression pattern of pro- and antioxidative genes in an advantageous manner. The data also indicate that many of these effects are mediated by SIRT1, thereby identifying SIRT1 as a key regulator of cardiovascular oxidative stress.

/pdf/molecular-mechanisms-underlying-pharmacological-stimulation-2ovsjwjm4e.pdf

Molecular mechanisms underlying pharmacological stimulation of eNOS expression and eNOS activity

Oral treatment of apolipoprotein E-knockout (ApoE-KO) mice with the putative sirtuin 1 (SIRT1) activator resveratrol led to a reduction of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in the heart. In contrast, the SIRT1 inhibitor EX527 enhanced the superoxide production in isolated human polymorphonuclear granulocytes. In human monocytic THP-1 cells, phorbol ester-stimulated superoxide production was enhanced by inhibitors of histone deacetylases (HDACs; including quisinostat, trichostatin A (TSA), PCI34051, and tubastatin A) and decreased by inhibitors of histone acetyltransferases [such as garcinol, curcumin, and histone acetyltransferase (HAT) Inhibitor II]. These results indicate that protein acetylation and deacetylation may represent crucial mechanisms regulating NADPH oxidase-mediated superoxide production. In cell-free systems, incubation of recombinant Rac1 with SIRT1 resulted in decreased Rac1 acetylation. Mass spectrometry analyses identified lysine 166 (K166) in Rac1 as a residue targeted by SIRT1. Deacetylation of Rac1 by SIRT1 markedly reduced the interaction of Rac1 with p67phox in in vitro assays. Computational modeling analyses revealed that K166 deacetylation of Rac1 led to a 5-fold reduction in its binding affinity to guanosine-5'-triphosphate, and a 21-fold decrease in its binding potential to p67phox. The latter is crucial for Rac1-mediated recruitment of p67phox to the membrane and for p67phox activation. In conclusion, both SIRT1 and non-sirtuin deacetylases play a role in regulating NADPH oxidase activity. Rac1 can be directly deacetylated by SIRT1 in a cell-free system, leading to an inhibition of Rac1-p67phox interaction. The downstream targets of non-sirtuin deacetylases are still unknown. The in vivo significance of these findings needs to be investigated in future studies.

/pdf/regulation-of-nadph-oxidase-mediated-superoxide-production-32vrmt7hbr.pdf

Regulation of NADPH Oxidase-Mediated Superoxide Production by Acetylation and Deacetylation.

http://link.springer.com/content/pdf/10.1007/978-3-8274-2887-5_18.pdf

Resveratrol und Gesundheit

The invention relates to the use of one or more than one of the compounds of
the general formula (I)
 
wherein R 1 and R 2 may be identical or different and, each independently of
each other, represent hydrogen, hydroxy, amino, C 1 to C 10 alkyl, C 1 to C 10 alkoxy
or C 1 to C 10 alkylamino, or R 1 and R 2 , together with the carbon atom in
position 4 of the pyrrolidinone ring, form a five- to ten-membered saturated or
unsaturated ring which, besides the carbon atoms, may have up to 2 heteroatoms
selected from oxygen, sulfur and nitrogen atoms, and which ring may
be unsubstituted or substituted by up to 3 substituents selected from hydroxy
groups, amino groups, C 1 to C 4 alkyl radicals, C 1 to C 4 alkoxy radicals and C 1 
to C 4 alkylamino radicals, with the proviso that R 1 and R 2 are not both hydrogen;
R 3 , R 4 , R 5 and R 6 may be identical or different and, each independently
of each other, represent hydrogen, halogen, hydroxy, amino, C 1 to C 10 alkyl,
C 1 to C 10 alkoxy, C 1 to C 10 alkylamino of C 6 to C 10 aryl; and R 7 represents hydrogen,
C 1 to C 10 alkyl or C 1 to C 10 acyl, and pharmaceutically acceptable
salts thereof and/or prodrugs thereof for the manufacture of a medicament
having an oxidation stress protection-promoting effect on mammalian cells.

Huige Li

Papers

Alcohol and the vasculature: a love-hate relationship?

Molecular mechanisms underlying pharmacological stimulation of eNOS expression and eNOS activity

Regulation of NADPH Oxidase-Mediated Superoxide Production by Acetylation and Deacetylation.

Resveratrol und Gesundheit

2-pyrrolidone derivatives and their use in protecting mammalian cells against oxidation stress