A large number of changes, distant from the site or sites of inflammation and involving many organ systems, may accompany inflammation. In 1930 interest was focused on these changes by the discovery of C-reactive protein (so named because it reacted with the pneumococcal C-polysaccharide) in the plasma of patients during the acute phase of pneumococcal pneumonia.1 Accordingly, these systemic changes have since been referred to as the acute-phase response,2 even though they accompany both acute and chronic inflammatory disorders. New acute-phase phenomena continue to be recognized, and the mechanisms mediating them are becoming better understood. This review summarizes much of . . .

Acute-Phase Proteins and Other Systemic Responses to Inflammation

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.

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Nitric Oxide and Peroxynitrite in Health and Disease

Beckman, Kenneth B., and Bruce N. Ames. The Free Radical Theory of Aging Matures. Physiol. Rev. 78: 547–581, 1998. — The free radical theory of aging, conceived in 1956, has turned 40 and is rapidl...

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The Free Radical Theory of Aging Matures

Oxidative stress has been implicated in the progression of Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Oxygen is vital for life but is also potentially dangerous, and a complex system of checks and balances exists for utilizing this essential element. Oxidative stress is the result of an imbalance in pro-oxidant/antioxidant homeostasis that leads to the generation of toxic reactive oxygen species. The systems in place to cope with the biochemistry of oxygen are complex, and many questions about the mechanisms of oxygen regulation remain unanswered. However, this same complexity provides a number of therapeutic targets, and different strategies, including novel metal-protein attenuating compounds, aimed at a variety of targets have shown promise in clinical studies.

Neurodegenerative diseases and oxidative stress.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(05)71142-9.pdf

Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.

Oxidative damage in Alzheimer's

Alzheimer's disease (AD) is characterized by the deposition of amyloid plaques in the parenchyma and vasculature of the brain. Although previous analytical studies have provided much information about the composition and structure of synthetic amyloid-beta fibrils, there is, surprisingly, a dearth of data on intact amyloid plaques from AD brain. Therefore, to elucidate the structure and detailed composition of isolated amyloid plaque cores, we utilized a high-resolution, nondestructive technique, Raman microscopy. The data are of very high quality and contain detailed information about protein composition and conformation, about post-translational modification, and about the chemistry of metal binding sites. Remarkably, spectra obtained for senile plaque (SP) cores isolated from AD brain are essentially identical both within and among brains. The Raman data show for the first time that the SP cores are composed largely of amyloid-beta and confirm inferences from X-ray studies that the structure is beta-sheet with the additional possibility that this may be present as a parallel beta-helix. Raman bands characteristic of methionine sulfoxide show that extensive methionine oxidation has occurred in the intact plaques. The Raman spectra also demonstrate that Zn(II) and Cu(II) are coordinated to histidine residues in the SP cores, at the side chains' N(tau) and N(pi) atoms, respectively. Treatment of the senile plaques with the chelator ethylenediaminetetraacetate reverses Cu binding to SP histidines and leads to a broadening of amide features, indicating a "loosening" of the beta-structure. Our results indicate that Abeta in vivo is a metalloprotein, and the loosening of the structure following chelation treatment suggests a possible means for the solubilization of amyloid deposits. The results also reveal a direct chemical basis for oxidative damage caused by amyloid-beta protein in AD.

Metal Binding and Oxidation of Amyloid-β within Isolated Senile Plaque Cores: Raman Microscopic Evidence†

The application of Raman spectroscopy to characterize natively unfolded proteins has been underdeveloped, even though it has significant technical advantages. We propose that a simple three-component band fitting of the amide I region can assist in the conformational characterization of the ensemble of structures present in natively unfolded proteins. The Raman spectra of α-synuclein, a prototypical natively unfolded protein, were obtained in the presence and absence of methanol, sodium dodecyl sulfate (SDS), and hexafluoro-2-propanol (HFIP). Consistent with previous CD studies, the secondary structure becomes largely α-helical in HFIP and SDS and predominantly β-sheet in 25% methanol in water. In SDS, an increase in α-helical conformation is indicated by the predominant Raman amide I marker band at 1654 cm-1 and the typical double minimum in the CD spectrum. In 25% HFIP the amide I Raman marker band appears at 1653 cm-1 with a peak width at half-height of ∼33 cm-1, and in 25% methanol the amide I Raman b...

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Raman Spectroscopic Characterization of Secondary Structure in Natively Unfolded Proteins: α-Synuclein

https://case.edu/artsci/chem/faculty/zagorski/group/pubs/pub54.pdf

Secondary Structure of α-Synuclein Oligomers: Characterization by Raman and Atomic Force Microscopy

https://escholarship.org/content/qt49p301zw/qt49p301zw.pdf?t=lnqzc4

3-Nitropropionic Acid Is a Suicide Inhibitor of Mitochondrial Respiration That, upon Oxidation by Complex II, Forms a Covalent Adduct with a Catalytic Base Arginine in the Active Site of the Enzyme

Vernon E. Anderson

Papers

Oxidative damage in Alzheimer's

Metal Binding and Oxidation of Amyloid-β within Isolated Senile Plaque Cores: Raman Microscopic Evidence†

Raman Spectroscopic Characterization of Secondary Structure in Natively Unfolded Proteins: α-Synuclein

Secondary Structure of α-Synuclein Oligomers: Characterization by Raman and Atomic Force Microscopy

3-Nitropropionic Acid Is a Suicide Inhibitor of Mitochondrial Respiration That, upon Oxidation by Complex II, Forms a Covalent Adduct with a Catalytic Base Arginine in the Active Site of the Enzyme