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10 pages, 2063 KiB

Open AccessArticle

Transmission Electron Microscopy Study of Mitochondria in Aging Brain Synapses

by Vladyslava Rybka, Yuichiro J. Suzuki, Alexander S. Gavrish, Vyacheslav A. Dibrova, Sergiy G. Gychka and Nataliia V. Shults

Antioxidants 2019, 8(6), 171; https://doi.org/10.3390/antiox8060171 - 11 Jun 2019

Cited by 26 | Viewed by 6141

Abstract

The brain is sensitive to aging-related morphological changes, where many neurodegenerative diseases manifest accompanied by a reduction in memory. The hippocampus is especially vulnerable to damage at an early stage of aging. The present transmission electron microscopy study examined the synapses and synaptic [...] Read more.

The brain is sensitive to aging-related morphological changes, where many neurodegenerative diseases manifest accompanied by a reduction in memory. The hippocampus is especially vulnerable to damage at an early stage of aging. The present transmission electron microscopy study examined the synapses and synaptic mitochondria of the CA1 region of the hippocampal layer in young-adult and old rats by means of a computer-assisted image analysis technique. Comparing young-adult (10 months of age) and old (22 months) male Fischer (CDF) rats, the total numerical density of synapses was significantly lower in aged rats than in the young adults. This age-related synaptic loss involved degenerative changes in the synaptic architectonic organization, including damage to mitochondria in both pre- and post-synaptic compartments. The number of asymmetric synapses with concave curvature decreased with age, while the number of asymmetric synapses with flat and convex curvatures increased. Old rats had a greater number of damaged mitochondria in their synapses, and most of this was type II and type III mitochondrial structural damage. These results demonstrate age-dependent changes in the morphology of synaptic mitochondria that may underlie declines in age-related synaptic function and may couple to age-dependent loss of synapses. Full article

(This article belongs to the Special Issue Novel Aspects of Redox, Antioxidant and Mitochondrial Signaling)

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15 pages, 2561 KiB

Open AccessArticle

Protein Redox State Monitoring Studies of Thiol Reactivity

by Yuichiro J. Suzuki, Lucia Marcocci, Takashi Shimomura, Yuki Tatenaka, Yuya Ohuchi and Tinatin I. Brelidze

Antioxidants 2019, 8(5), 143; https://doi.org/10.3390/antiox8050143 - 22 May 2019

Cited by 6 | Viewed by 4370

Abstract

Protein cysteine thiol status is a major determinant of oxidative stress and oxidant signaling. The -SulfoBiotics- Protein Redox State Monitoring Kit provides a unique opportunity to investigate protein thiol states. This system adds a 15-kDa Protein-SHifter to reduced cysteine residues, and [...] Read more.

Protein cysteine thiol status is a major determinant of oxidative stress and oxidant signaling. The -SulfoBiotics- Protein Redox State Monitoring Kit provides a unique opportunity to investigate protein thiol states. This system adds a 15-kDa Protein-SHifter to reduced cysteine residues, and this molecular mass shift can be detected by gel electrophoresis. Even in biological samples, Protein-SHifter Plus allows the thiol states of specific proteins to be studied using Western blotting. Peroxiredoxin 6 (Prx6) is a unique one-cysteine peroxiredoxin that scavenges peroxides by utilizing conserved Cysteine-47. Human Prx6 also contains an additional non-conserved cysteine residue, while rat Prx6 only has the catalytic cysteine. In cultured cells, cysteine residues of Prx6 were found to be predominantly fully reduced. The treatment of human cells with hydrogen peroxide (H₂O₂) formed Prx6 with one cysteine reduced. Since catalytic cysteine becomes oxidized in rat cells by the same H₂O₂ treatment and treating denatured human Prx6 with H₂O₂ results in the oxidation of both cysteines, non-conserved cysteine may not be accessible to H₂O₂ in human cells. We also found that untreated cells contained Prx6 multimers bound through disulfide bonds. Surprisingly, treating cells with H₂O₂ eliminated these Prx6 multimers. In contrast, treating cell lysates with H₂O₂ promoted the formation of Prx6 multimers. Similarly, treating purified preparations of the recombinant cyclic nucleotide-binding domain of the human hyperpolarization-activated cyclic nucleotide-modulated channels with H₂O₂ promoted the formation of multimers. These studies revealed that the cellular environment defines the susceptibility of protein cysteines to H₂O₂ and determines whether H₂O₂ acts as a facilitator or a disrupter of disulfide bonds. Full article

(This article belongs to the Special Issue Novel Aspects of Redox, Antioxidant and Mitochondrial Signaling)

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10 pages, 1603 KiB

Open AccessArticle

Metabolomics Studies to Assess Biological Functions of Vitamin E Nicotinate

by Lucia Marcocci and Yuichiro J. Suzuki

Antioxidants 2019, 8(5), 127; https://doi.org/10.3390/antiox8050127 - 11 May 2019

Cited by 6 | Viewed by 3307

Abstract

Vitamin E nicotinate (tocopherol nicotinate, tocopheryl nicotinate; TN) is an ester of two vitamins, tocopherol (vitamin E) and niacin (vitamin B3), in which niacin is linked to the hydroxyl group of active vitamin E. This vitamin E ester can be chemically synthesized and [...] Read more.

Vitamin E nicotinate (tocopherol nicotinate, tocopheryl nicotinate; TN) is an ester of two vitamins, tocopherol (vitamin E) and niacin (vitamin B3), in which niacin is linked to the hydroxyl group of active vitamin E. This vitamin E ester can be chemically synthesized and is used for supplementation. However, whether TN is formed in the biological system was unclear. Our laboratory previously detected TN in rat heart tissues, and its level was 30-fold lower in a failing heart (Wang et al., PLoS ONE 2017, 12, e0176887). The rat diet used in these experiments contained vitamin E acetate (tocopherol acetate; TA) and niacin separately, but not in the form of TN. Since only TN, but not other forms of vitamin E, was decreased in heart failure, the TN structure may elicit biologic functions independent of serving as a source of active vitamin E antioxidant. To test this hypothesis, the present study performed metabolomics to compare effects of TN on cultured cells to those of TA plus niacin added separately (TA + N). Human vascular smooth muscle cells were treated with TN or with TA + N (100 μM) for 10 min. Metabolite profiles showed that TN and TA + N influenced the cells differentially. TN effectively upregulated various primary fatty acid amides including arachidonoylethanoamine (anandamide/virodhamine) and palmitamide. TN also activated mitogen-activated protein kinases. These results suggest a new biological function of TN to elicit cell signaling. Full article

(This article belongs to the Special Issue Novel Aspects of Redox, Antioxidant and Mitochondrial Signaling)

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10 pages, 1215 KiB

Open AccessArticle

Effects of Bcl-2/Bcl-x_L Inhibitors on Pulmonary Artery Smooth Muscle Cells

by Vladyslava Rybka, Yuichiro J. Suzuki and Nataliia V. Shults

Antioxidants 2018, 7(11), 150; https://doi.org/10.3390/antiox7110150 - 26 Oct 2018

Cited by 12 | Viewed by 3496

Abstract

Pulmonary arterial hypertension (PAH) is a fatal disease without satisfactory therapeutic options. By the time patients are diagnosed with this disease, the remodeling of pulmonary arteries has already developed due to the abnormal growth of pulmonary vascular cells. Therefore, agents that reduce excess [...] Read more.

Pulmonary arterial hypertension (PAH) is a fatal disease without satisfactory therapeutic options. By the time patients are diagnosed with this disease, the remodeling of pulmonary arteries has already developed due to the abnormal growth of pulmonary vascular cells. Therefore, agents that reduce excess pulmonary vascular cells have therapeutic potential. Bcl-2 is known to function in an antioxidant pathway to prevent apoptosis. The present study examined the effects of inhibitors of the anti-apoptotic proteins Bcl-2 and Bcl-x_L. ABT-263 (Navitoclax), ABT-199 (Venetoclax), ABT-737, and Obatoclax, which all promoted the death of cultured human pulmonary artery smooth muscle cells. Further examinations using ABT-263 showed that Bcl-2/Bcl-x_L inhibition indeed promoted apoptotic programmed cell death. ABT-263-induced cell death was inhibited by antioxidants. ABT-263 also promoted autophagy; however, the inhibition of autophagy did not suppress ABT-263-induced cell death. This is in contrast to other previously studied drugs, including anthracyclines and proteasome inhibitors, which were found to mediate autophagy to induce cell death. The administration of ABT-263 to rats with PAH in vivo resulted in the reversal of pulmonary vascular remodeling. Thus, promoting apoptosis by inhibiting anti-apoptotic Bcl-2 and Bcl-x_L effectively kills pulmonary vascular smooth muscle cells and reverses pulmonary vascular remodeling. Full article

(This article belongs to the Special Issue Novel Aspects of Redox, Antioxidant and Mitochondrial Signaling)

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Review

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9 pages, 3037 KiB

Open AccessReview

Antioxidant Regulation of Cell Reprogramming

by Yuichiro J. Suzuki and Nataliia V. Shults

Antioxidants 2019, 8(8), 323; https://doi.org/10.3390/antiox8080323 - 20 Aug 2019

Cited by 8 | Viewed by 4014

Abstract

Discovery of induced pluripotent stem cells (iPSCs) has revolutionized regeneration biology, providing further mechanistic insights and possible therapeutic applications. The original discovery by Yamanaka and co-workers showed that the expression of four transcription factors in fibroblasts resulted in the generation of iPSCs that [...] Read more.

Discovery of induced pluripotent stem cells (iPSCs) has revolutionized regeneration biology, providing further mechanistic insights and possible therapeutic applications. The original discovery by Yamanaka and co-workers showed that the expression of four transcription factors in fibroblasts resulted in the generation of iPSCs that can be differentiated into various cell types. This technology should be particularly useful for restoring cells with limited proliferative capacities such as adult heart muscle cells and neurons, in order to treat diseases affecting these cell types. More recently, iPSCs-mediated cell reprogramming has advanced to new technologies including direct reprogramming and pharmacological reprogramming. Direct reprogramming allows for the conversion of fibroblasts into cardiomyocytes, neurons or other cells by expressing multiple cell type-specific transcription factors without going through the production of iPSCs. Both iPSC-mediated reprogramming as well as direct reprogramming can also be promoted by a combination of small molecules, opening up a possibility for pharmacological therapies to induce cell reprogramming. However, all of these processes have been shown to be affected by reactive oxygen species that reduce the efficacies of reprogramming fibroblasts into iPSCs, differentiating iPSCs into target cells, as well as direct reprogramming. Accordingly, antioxidants have been shown to support these reprogramming processes and this review article summarizes these findings. It should be noted however, that the actions of antioxidants to support cell reprogramming may be through their ROS inhibiting abilities, but could also be due to mechanisms that are independent of classical antioxidant actions. Full article

(This article belongs to the Special Issue Novel Aspects of Redox, Antioxidant and Mitochondrial Signaling)

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13 pages, 1007 KiB

Open AccessReview

Juglone in Oxidative Stress and Cell Signaling

by Taseer Ahmad and Yuichiro J. Suzuki

Antioxidants 2019, 8(4), 91; https://doi.org/10.3390/antiox8040091 - 05 Apr 2019

Cited by 90 | Viewed by 10251

Abstract

Juglone (5-hydroxyl-1,4-naphthoquinone) is a phenolic compound found in walnuts. Because of the antioxidant capacities of phenolic compounds, juglone may serve to combat oxidative stress, thereby protecting against the development of various diseases and aging processes. However, being a quinone molecule, juglone could also [...] Read more.

Juglone (5-hydroxyl-1,4-naphthoquinone) is a phenolic compound found in walnuts. Because of the antioxidant capacities of phenolic compounds, juglone may serve to combat oxidative stress, thereby protecting against the development of various diseases and aging processes. However, being a quinone molecule, juglone could also act as a redox cycling agent and produce reactive oxygen species. Such prooxidant properties of juglone may confer health effects, such as by killing cancer cells. Further, recent studies revealed that juglone influences cell signaling. Notably, juglone is an inhibitor of Pin1 (peptidyl-prolyl cis/trans isomerase) that could regulate phosphorylation of Tau, implicating potential effects of juglone in Alzheimer’s disease. Juglone also activates mitogen-activated protein kinases that could promote cell survival, thereby protecting against conditions such as cardiac injury. This review describes recent advances in the understanding of the effects and roles of juglone in oxidative stress and cell signaling. Full article

(This article belongs to the Special Issue Novel Aspects of Redox, Antioxidant and Mitochondrial Signaling)

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7 pages, 971 KiB

Open AccessReview

Oxidant-Mediated Protein Amino Acid Conversion

by Yuichiro J. Suzuki

Antioxidants 2019, 8(2), 50; https://doi.org/10.3390/antiox8020050 - 25 Feb 2019

Cited by 13 | Viewed by 5417

Abstract

Biological oxidation plays important roles in the pathogenesis of various diseases and aging. Carbonylation is one mode of protein oxidation. It has been reported that amino acids that are susceptible to carbonylation are arginine (Arg), proline (Pro), lysine, and threonine residues. The carbonylation [...] Read more.

Biological oxidation plays important roles in the pathogenesis of various diseases and aging. Carbonylation is one mode of protein oxidation. It has been reported that amino acids that are susceptible to carbonylation are arginine (Arg), proline (Pro), lysine, and threonine residues. The carbonylation product of both Arg and Pro residues is glutamyl semialdehyde. While chemically the oxidation reactions of neither Pro to glutamyl semialdehyde nor Arg to glutamyl semialdehyde are reversible, experimental results from our laboratory suggest that the biological system may drive the reduction of glutamyl semialdehyde to Pro in the protein structure. Further, glutamyl semialdehyde can be oxidized to become glutamic acid (Glu). Therefore, I hypothesize that biological oxidation post-translationally converts Arg to Pro, Arg to Glu, and Pro to Glu within the protein structure. Our mass spectrometry experiments provided evidence that, in human cells, 5–10% of peroxiredoxin 6 protein molecules have Pro-45 replaced by Glu. This concept of protein amino acid conversion challenges the dogma that amino acid sequences are strictly defined by nucleic acid sequences. I propose that, in the biological system, amino acid replacements can occur post-translationally through redox regulation, and protein molecules with non-DNA coding sequences confer functions. Full article

(This article belongs to the Special Issue Novel Aspects of Redox, Antioxidant and Mitochondrial Signaling)

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9 pages, 999 KiB

Open AccessReview

Redox Biology of Right-Sided Heart Failure

by Nataliia V. Shults, Oleksiy Melnyk, Dante I. Suzuki and Yuichiro J. Suzuki

Antioxidants 2018, 7(8), 106; https://doi.org/10.3390/antiox7080106 - 08 Aug 2018

Cited by 14 | Viewed by 4027

Abstract

Right-sided heart failure is the major cause of death among patients who suffer from various forms of pulmonary hypertension and congenital heart disease. The right ventricle (RV) and left ventricle (LV) originate from different progenitor cells and function against very different blood pressures. [...] Read more.

Right-sided heart failure is the major cause of death among patients who suffer from various forms of pulmonary hypertension and congenital heart disease. The right ventricle (RV) and left ventricle (LV) originate from different progenitor cells and function against very different blood pressures. However, differences between the RV and LV formed after birth have not been well defined. Work from our laboratory and others has accumulated evidence that redox signaling, oxidative stress and antioxidant regulation are important components that define the RV/LV differences. The present article summarizes the progress in understanding the roles of redox biology in the RV chamber-specificity. Understanding the mechanisms of RV/LV differences should help develop selective therapeutic strategies to help patients who are susceptible to and suffering from right-sided heart failure. Modulations of redox biology may provide effective therapeutic avenues for these conditions. Full article

(This article belongs to the Special Issue Novel Aspects of Redox, Antioxidant and Mitochondrial Signaling)

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