scholarly journals Initiation and Prevention of Biological Damage by Radiation-Generated Protein Radicals

2021 ◽  
Vol 23 (1) ◽  
pp. 396
Author(s):  
Janusz M. Gebicki ◽  
Thomas Nauser
Keyword(s):  
Biological Damage ◽  
Physiological Conditions ◽  
Repair Protein ◽  
Endogenous Antioxidants ◽  
The Common ◽  
Promising Development ◽  
Ionizing Radiations ◽  
Protein Radicals ◽  
Protein Reaction ◽  
Hydroxyl Free Radicals

Ionizing radiations cause chemical damage to proteins. In aerobic aqueous solutions, the damage is commonly mediated by the hydroxyl free radicals generated from water, resulting in formation of protein radicals. Protein damage is especially significant in biological systems, because proteins are the most abundant targets of the radiation-generated radicals, the hydroxyl radical-protein reaction is fast, and the damage usually results in loss of their biological function. Under physiological conditions, proteins are initially oxidized to carbon-centered radicals, which can propagate the damage to other molecules. The most effective endogenous antioxidants, ascorbate, GSH, and urate, are unable to prevent all of the damage under the common condition of oxidative stress. In a promising development, recent work demonstrates the potential of polyphenols, their metabolites, and other aromatic compounds to repair protein radicals by the fast formation of less damaging radical adducts, thus potentially preventing the formation of a cascade of new reactive species.

Targeting G-quadruplexes in the rhinovirus genome by Pyridostatin inhibits uncoating 3 and highlights a critical role for sodium ions.

2021 ◽  
Author(s):  
Antonio Real-Hohn ◽  
Martin Groznica ◽  
Georg Kontaxis ◽  
Rong Zhu ◽  
Otávio Chaves ◽  
...  
Keyword(s):  
Common Cold ◽  
Critical Role ◽  
Sodium Ions ◽  
Structural Elements ◽  
Temperature Dependent ◽  
Physiological Conditions ◽  
Metastable Structures ◽  
G Quadruplex ◽  
The Common ◽  
Secondary Structural Elements

Abstract The ~ 2.4 µm long rhinovirus ss(+)RNA genome consists of roughly 7,200 nucleotides. It is tightly folded to fit into the ~ 22 nm diameter void in the protein capsid. In addition to previously predicted secondary structural elements in the RNA, using the QGRS mapper, we revealed the presence of multiple quadruplex forming G-rich sequences (QGRS) in the RV-A, B, and C clades, with four of them being exquisitely conserved. The biophysical analyses of ribooligonucleotides corresponding to selected QGRS demonstrate G-quadruplex (GQ) formation in each instance and resulted in discovering another example of an unconventional, two-layer zero-nucleotide loop RNA GQ stable at physiological conditions. By exploiting the temperature-dependent viral breathing to allow diffusion of small compounds into the virion, we demonstrate that the GQ-binding compounds PhenDC3 and pyridostatin (PDS) uniquely interfere with viral uncoating. Remarkably, this inhibition was entirely prevented in the presence of K+ but not Na+, despite the higher GQ stabilising effect of K+. Based on virus thermostability studies combined with ultrastructural imaging of isolated viral RNA, we propose a mechanism where Na+ keeps the encapsidated genome loose, allowing its penetration by PDS to promote the transition of QGRS sequestered in alternative metastable structures into GQs. The resulting conformational change then materialises in a severely compromised RNA release from the proteinaceous shell. Targeting extracellularly circulating RVs with GQ-stabilisers might thus become a novel way of combating the common cold.

Effects of methionine on endogenous antioxidants in the heart

1999 ◽  
Vol 277 (6) ◽  
pp. H2124-H2128 ◽  
Author(s):  
Charita K. Seneviratne ◽  
Timao Li ◽  
Neelam Khaper ◽  
Pawan K. Singal
Keyword(s):  
Antioxidant Enzyme Activities ◽  
Mrna Levels ◽  
Sod Activity ◽  
Time Points ◽  
Physiological Conditions ◽  
Control Value ◽  
Beneficial Effects ◽  
Different Types ◽  
Endogenous Antioxidants ◽  
Gshpx Activity

The deficiency of methionine, an essential amino acid, is associated with cardiovascular lesions. Because different types of cardiac pathologies are caused by a decrease in antioxidants, we examined the effects of methionine on myocardial antioxidant enzymes in hemodynamically assessed rats that were treated with methionine (10 mg/ml) in drinking water for 12, 24, and 48 h. Glutathione peroxidase (GSHPx) activity was significantly increased to 150.5 ± 12.2 and 191.7 ± 13.7% of the control value at 12 and 24 h, respectively, followed by a decline to 120 ± 24.6% at 48 h. The mRNA levels of GSHPx at these time points were 151.2 ± 12.0, 218.7 ± 35.3, and 173.5 ± 25.2%, respectively. Superoxide dismutase (SOD) activity was 144.3 ± 3.7, 114.3 ± 10.1, and 143.1 ± 11.2% at 12, 24, and 48 h, respectively. Catalase (Cat) activity was 272.4 ± 5.4, 237.8 ± 16.6, and 224.1 ± 17.3% of the control value. The expression of Cat and SOD mRNA was unchanged at 12, 24, and 48 h. The lipid peroxidation was decreased by 24.4 ± 11.2, 54.9 ± 0.1, and 6.4 ± 2.1% at 12, 24, and 48 h, respectively. Methionine had no effect on the ventricular or aortic pressures, heart rate, and myocardial glutathione levels at any of the time points. The study shows that methionine has a significant effect on the myocardial antioxidant enzyme activities, and only changes in GSHPx enzyme activity correlated with the mRNA changes. These antioxidant changes may have a role in the beneficial effects of methionine in pathological rather than physiological conditions.

Alternative splicing and exon duplication generates 10 unique porcine 5-HT4 receptor splice variants including a functional homofusion variant

2008 ◽  
Vol 34 (1) ◽  
pp. 22-33 ◽  
Author(s):  
Joris H. De Maeyer ◽  
Jeroen Aerssens ◽  
Peter Verhasselt ◽  
Romain A. Lefebvre
Keyword(s):  
Alternative Splicing ◽  
Molecular Level ◽  
Splice Variants ◽  
Laboratory Animals ◽  
Genomic Context ◽  
Common Region ◽  
Porcine Tissue ◽  
Physiological Conditions ◽  
Exon Duplication ◽  
The Common

5-HT4 receptors are present in human and porcine atrial myocytes while they are absent from the hearts of small laboratory animals. The pig is therefore the only available nonprimate animal model in which to study cardiac 5-HT4 receptor function under physiological conditions. While several human splice variants of the 5-HT4 receptor have been described, the splicing behavior of this receptor in porcine tissue is currently unknown. Here we report on the identification of nine novel COOH-terminal splice variants of the porcine 5-HT4 receptor, which were named 5-HT4(b2, j, k, l, m, o, p, q, r). The internal h-variant was found in combination with several COOH-terminal exons. In addition, splice variants were found that comprised duplicated exons fused to the common region of the 5-HT4 receptor, thereby providing evidence for a duplication of the porcine HTR4 gene. One of these variants putatively encoded a nine transmembrane-spanning domain homofusion receptor, 5-HT4(9TM); also the other variants with a duplicated region might translate into functional, transcriptionally fused dimeric 5-HT4 receptor variants. The elucidation of the genomic context confirmed that the variants were not genomic artefacts but originated from alternative splicing. This was further corroborated by a functional analysis of the variants 5-HT4(a), 5-HT4(r), and 5-HT4(9TM). To our knowledge, our data are the first to report on a functional GPCR with more than seven predicted transmembrane domains. These findings urge for caution when interpreting data on 5-HT4 receptor-related pharmacology obtained in the pig; validation at the molecular level might be needed before extrapolating results to human.

Substrate specificity of human ABCC4 (MRP4)-mediated cotransport of bile acids and reduced glutathione

2006 ◽  
Vol 290 (4) ◽  
pp. G640-G649 ◽  
Author(s):  
Maria Rius ◽  
Johanna Hummel-Eisenbeiss ◽  
Alan F. Hofmann ◽  
Dietrich Keppler
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Reduced Glutathione ◽  
Membrane Vesicles ◽  
Multidrug Resistance Protein ◽  
Bile Salt Export Pump ◽  
Physiological Conditions ◽  
Resistance Protein ◽  
The Common ◽  
Inside Out

The multidrug resistance protein ABCC4 (MRP4), a member of the ATP-binding cassette superfamily, mediates ATP-dependent unidirectional efflux of organic anions out of cells. Previous studies showed that human ABCC4 is localized to the sinusoidal membrane of hepatocytes and mediates, among other substrates, the cotransport of reduced glutathione (GSH) with bile acids. In the present study, using inside-out membrane vesicles, we demonstrated that human ABCC4 in the presence of physiological concentrations of GSH has a high affinity for the taurine and glycine conjugates of the common natural bile acids as well as the unconjugated bile acid cholate. Chenodeoxycholyltaurine and chenodeoxycholylglycine were the GSH cosubstrates with the highest affinities for ABCC4, with Km values of 3.6 and 5.9 μM, respectively. Ursodeoxycholyltaurine and ursodeoxycholylglycine were cotransported together with GSH by ABCC4 with Km values of 7.8 and 12.5 μM, respectively, but no transport of ursodeoxycholate and deoxycholate was observed. The simultaneous transport of labeled GSH and cholyltaurine or cholylglycine was demonstrated in double-labeled cotransport experiments with a bile acid-to-GSH ratio of ∼1:22. Km values of the bile acids for ABCC4 were in a range similar to those reported for the canalicular bile salt export pump ABCB11. Under physiological conditions, the sinusoidal ABCC4 may compete with canalicular ABCB11 for bile acids and thereby play a key role in determining the hepatocyte concentration of bile acids. In cholestatic conditions, ABCC4 may become a key pathway for efflux of bile acids from hepatocytes into blood.

scholarly journals BIOLOGICAL DAMAGE IN MATURE AND IMMATURE GERM CELLS OF DROSOPHILA VIRILIS WITH IONIZING RADIATIONS

Genetics ◽  
1959 ◽  
Vol 44 (6) ◽  
pp. 979-999
Author(s):  
Mary L Alexander ◽  
Janet Bergendahl ◽  
Madeleine Brittain
Keyword(s):  
Germ Cells ◽  
Drosophila Virilis ◽  
Biological Damage ◽  
Ionizing Radiations

scholarly journals Targeting G-quadruplexes in the rhinovirus genome by Pyridostatin inhibits uncoating and highlights a critical role for sodium ions.

2021 ◽  
Author(s):  
Antonio Real-Hohn ◽  
Martin Groznica ◽  
Georg Kontaxis ◽  
Rong Zhu ◽  
Otávio Chaves ◽  
...  
Keyword(s):  
Common Cold ◽  
Critical Role ◽  
Sodium Ions ◽  
Structural Elements ◽  
Temperature Dependent ◽  
Physiological Conditions ◽  
Metastable Structures ◽  
G Quadruplex ◽  
The Common ◽  
Secondary Structural Elements

Abstract The ~ 2.4 µm long rhinovirus ss(+)RNA genome consists of roughly 7,200 nucleotides. It is tightly folded to fit into the ~ 22 nm diameter void in the protein capsid. In addition to previously predicted secondary structural elements in the RNA, using the QGRS mapper, we revealed the presence of multiple quadruplex forming G-rich sequences (QGRS) in the RV-A, B, and C clades, with four of them being exquisitely conserved. The biophysical analyses of ribooligonucleotides corresponding to selected QGRS demonstrate G-quadruplex (GQ) formation in each instance and resulted in discovering another example of an unconventional, two-layer zero-nucleotide loop RNA GQ stable at physiological conditions. By exploiting the temperature-dependent viral breathing to allow diffusion of small compounds into the virion, we demonstrate that the GQ-binding compounds PhenDC3 and pyridostatin (PDS) uniquely interfere with viral uncoating. Remarkably, this inhibition was entirely prevented in the presence of K+ but not Na+, despite the higher GQ stabilising effect of K+. Based on virus thermostability studies combined with ultrastructural imaging of isolated viral RNA, we propose a mechanism where Na+ keeps the encapsidated genome loose, allowing its penetration by PDS to promote the transition of QGRS sequestered in alternative metastable structures into GQs. The resulting conformational change then materialises in a severely compromised RNA release from the proteinaceous shell. Targeting extracellularly circulating RVs with GQ-stabilisers might thus become a novel way of combating the common cold.

scholarly journals Crosslinking of DNA and proteins induced by protein hydroperoxides

1999 ◽  
Vol 338 (3) ◽  
pp. 629-636 ◽  
Author(s):  
Silvia GEBICKI ◽  
Janusz M. GEBICKI
Keyword(s):  
Free Radicals ◽  
Oxygen Species ◽  
Metal Chelators ◽  
Strand Breaks ◽  
Biological Damage ◽  
Vigorous Agitation ◽  
Ionic Detergents ◽  
Living Organisms ◽  
Dna Strand ◽  
Hydroxyl Free Radicals

Exposure of DNA to several proteins peroxidized by radiation-generated hydroxyl free radicals resulted in formation of crosslinks between the macromolecules, detected by retardation and broadening of DNA bands in agarose gels. This technique proved suitable for the study of crosslinking of DNA with peroxidized BSA, insulin, apotransferrin and α casein, but not with several other proteins, including histones. The crosslinking depended on the presence of intact hydroperoxide groups on the protein, on their number, and on the duration of the interaction with DNA. All DNA samples tested, pBR322, pGEM, λ/HindIII and pUC18, formed crosslinks with the peroxidized BSA. Sodium chloride and formate prevented the crosslinking if present during incubation of the peroxidized protein and DNA, but had no effect once the crosslinks had formed. The gel shift of the crosslinked DNA was reversed by proteolysis, indicating that the DNA mobility change was due to attachment of protein and that the crosslinking did not induce DNA strand breaks. The metal chelators Desferal and neocuproine reduced the extent of the crosslinking, but did not prevent it. Scavengers of free radicals did not inhibit the crosslink formation. The DNA–protein complex was not disrupted by vigorous agitation, by filtration or by non-ionic detergents. These observations show that the crosslinking of DNA with proteins mediated by protein hydroperoxides is spontaneous and probably covalent, and that it may be assisted by transition metals. It is suggested that formation of such crosslinks in living organisms could account for some of the well-documented forms of biological damage induced by reactive oxygen species-induced oxidative stress.

scholarly journals Glutathione in Brain Disorders and Aging

Molecules ◽  
2022 ◽  
Vol 27 (1) ◽  
pp. 324
Author(s):  
Igor Y. Iskusnykh ◽  
Anastasia A. Zakharova ◽  
Dhruba Pathak
Keyword(s):  
Neurological Disorders ◽  
Metabolic Pathways ◽  
Neurological Diseases ◽  
Signaling Cascades ◽  
Reduced Form ◽  
Brain Disorders ◽  
Cellular Homeostasis ◽  
Physiological Conditions ◽  
The Common ◽  
The Brain

Glutathione is a remarkably functional molecule with diverse features, which include being an antioxidant, a regulator of DNA synthesis and repair, a protector of thiol groups in proteins, a stabilizer of cell membranes, and a detoxifier of xenobiotics. Glutathione exists in two states—oxidized and reduced. Under normal physiological conditions of cellular homeostasis, glutathione remains primarily in its reduced form. However, many metabolic pathways involve oxidization of glutathione, resulting in an imbalance in cellular homeostasis. Impairment of glutathione function in the brain is linked to loss of neurons during the aging process or as the result of neurological diseases such as Huntington’s disease, Parkinson’s disease, stroke, and Alzheimer’s disease. The exact mechanisms through which glutathione regulates brain metabolism are not well understood. In this review, we will highlight the common signaling cascades that regulate glutathione in neurons and glia, its functions as a neuronal regulator in homeostasis and metabolism, and finally a mechanistic recapitulation of glutathione signaling. Together, these will put glutathione’s role in normal aging and neurological disorders development into perspective.

scholarly journals About the perverted light reaction of the pupils

2020 ◽  
Vol V (3) ◽  
pp. 138-159
Author(s):  
V. Bekhterev
Keyword(s):  
Oculomotor Nerve ◽  
Paradoxical Reaction ◽  
Upper Eyelid ◽  
Light Reaction ◽  
Accessory Muscle ◽  
Physiological Conditions ◽  
Lumbar Muscle ◽  
The Common ◽  
Normal Light

In view of the special interest of our case, we will enter here into consideration of the anatomical and physiological side of the normal light reaction and try to explain the peculiar symptom observed in the patient, which is called the perverted or paradoxical reaction of the pupils. As is known, the common oculomotor nerve innervates the muscle that lifts the upper eyelid, the four external ocular muscles: the internal, upper and lower rectus, lower oblique and two internal muscles of the eye the orbicular muscle of the pupil and the lumbar muscle, there are probably only seven muscles. The physiological conditions of the movement of the eye muscles convince us that not all of them have a separate movement. Excluding the lower oblique, which plays the role of an accessory muscle, and the orbicular muscle of the pupil, which is not rapidly contracting together with the lumbar muscle, all other muscles are so adapted to isolated movements that, it would seem, one could expect the corresponding differentiation in their nuclei.

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