New Insights into the Chemical and Biochemical Basis of the “Yang-Invigorating” Action of Chinese Yang-Tonic Herbs

In the practice of traditional Chinese medicine, many Yang-tonic herbs have been used for retarding the decline in bodily function and delaying the onset of age-related diseases. Our earlier studies have demonstrated that Yang-invigorating herbs/formulations protect against oxidative injury in various organs and also extend the median lifespan in mice. This lifespan extension was associated with an upregulation of cellular antioxidant status including that of mitochondria whose functional capacity is also increased by “Yang-invigorating” herbs/formulations. In this paper, we propose that triterpenes and phytosterols, which are ubiquitously found in Yang-tonic herbs, may be the chemical entities responsible for enhancing mitochondrial functional and antioxidant capacity and thus the “Yang-invigorating” action. The biochemical mechanism underlying this “Yang-invigorating” action may involve a sustained production of low levels of mitochondrial reactive oxygen species (ROS) secondary to an increased activity of the electron transport chain, with the possible involvement of mitochondrial uncoupling. The increase in mitochondrial functional capacity can retard the decline in bodily function during aging, whereas the mitochondrial ROS production is instrumental in eliciting a glutathione antioxidant response via redox-sensitive signaling pathways, which can delay the onset of age-related diseases.

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Internet Navigation Skills for Financial Management: Associations with Age, Neurocognitive Performance, and Functional Capacity

10.31234/osf.io/q46r8 ◽

2020 ◽

Author(s):

Samina Rahman ◽

Victoria Kordovski ◽

Savanna Tierney ◽

Steven Paul Woods

Keyword(s):

Older Adults ◽

Functional Capacity ◽

Financial Management ◽

Internet Banking ◽

Online Banking ◽

Neurocognitive Performance ◽

Younger Adults ◽

Neurocognitive Functions ◽

Age Related ◽

Use Factors

Objective: Online banking is becoming increasingly common among older adults, whomay experience difficulties effectively navigating this instrumental technology. Thisstudy examined age effects on a performance-based Internet banking task and itsassociation with neurocognitive ability and functional capacity in older and youngeradults. Method: Thirty-five older adults and 50 younger adults completed anexperimenter-controlled online banking measure in which they independentlyperformed a series of naturalistic financial tasks (e.g., account transfers, bill paying).Participants also completed a standardized battery of neuropsychological tests andmeasures of functional capacity. Results: Older adults were markedly slower and lessaccurate in completing the Internet-based banking task, which was not confounded byother demographic, mood, or computer use factors. Higher scores on measures ofneurocognition and financial functional capacity were both strongly associated withhigher Internet-based banking task accuracy scores and quicker completion times inthe older, but not the younger adults. Conclusions: Findings suggest that older adultsexperience difficultly quickly and accurately navigating online banking platforms, whichmay be partly related to age-related declines in neurocognitive functions and basicfinancial capacity. Future studies might examine whether neurocognitive approaches toremediation and compensation can be used to improve online banking capacity inolder adults.

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Rapamycin reverses age-related increases in mitochondrial ROS production at complex I, oxidative stress, accumulation of mtDNA fragments inside nuclear DNA, and lipofuscin level, and increases autophagy, in the liver of middle-aged mice

Experimental Gerontology ◽

10.1016/j.exger.2016.08.002 ◽

2016 ◽

Vol 83 ◽

pp. 130-138 ◽

Cited By ~ 39

Author(s):

V. Martínez-Cisuelo ◽

J. Gómez ◽

I. García-Junceda ◽

A. Naudí ◽

R. Cabré ◽

...

Keyword(s):

Oxidative Stress ◽

Complex I ◽

Nuclear Dna ◽

Ros Production ◽

Middle Aged ◽

Aged Mice ◽

Age Related ◽

Mitochondrial Ros ◽

Stress Accumulation

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Biochemical Basis for Increased Activity of Ebola Glycoprotein in the 2013–16 Epidemic

Cell Host & Microbe ◽

10.1016/j.chom.2017.02.002 ◽

2017 ◽

Vol 21 (3) ◽

pp. 367-375 ◽

Cited By ~ 26

Author(s):

May K. Wang ◽

Sun-Young Lim ◽

Soo Mi Lee ◽

James M. Cunningham

Keyword(s):

Biochemical Basis ◽

Increased Activity

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Urea Memory: Transient Cell Exposure to Urea Causes Persistent Mitochondrial ROS Production and Endothelial Dysfunction

Toxins ◽

10.3390/toxins10100410 ◽

2018 ◽

Vol 10 (10) ◽

pp. 410 ◽

Cited By ~ 2

Author(s):

Maria d’Apolito ◽

Anna Colia ◽

Enrica Manca ◽

Massimo Pettoello-Mantovani ◽

Michele Sacco ◽

...

Keyword(s):

Fusion Proteins ◽

Copy Number ◽

Electron Transport Chain ◽

Mitochondrial Fission ◽

Functional Decline ◽

Cell Types ◽

Mtdna Copy Number ◽

Mitochondrial Ros ◽

Transport Chain ◽

Arterial Endothelial Cells

Urea at post-dialysis levels induces increased ROS in a number of cell types. The aim of this study was to determine whether urea-induced production of ROS remains elevated after urea is no longer present, and, if it does, to characterize its origin and effects. Human arterial endothelial cells were incubated with 20 mM urea for two days, and then cells were incubated for an additional two days in medium alone. Maximal ROS levels induced by initial urea continued at the same level despite urea being absent. These effects were prevented by either MnSOD expression or by Nox1/4 inhibition with GKT13781. Sustained urea-induced ROS caused a persistent reduction in mtDNA copy number and electron transport chain transcripts, a reduction in transcription of mitochondrial fusion proteins, an increase in mitochondrial fission proteins, and persistent expression of endothelial inflammatory markers. The SOD-catalase mimetic MnTBAP reversed each of these. These results suggest that persistent increases in ROS after cells are no long exposed to urea may play a major role in continued kidney damage and functional decline despite reduction of urea levels after dialysis.

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From Flies to Men: ROS and the NADPH Oxidase in Phagocytes

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.628991 ◽

2021 ◽

Vol 9 ◽

Author(s):

Zohreh Mansoori Moghadam ◽

Philipp Henneke ◽

Julia Kolter

Keyword(s):

Defense Mechanisms ◽

Phagocytic Cells ◽

Mitochondrial Ros ◽

Transport Chain ◽

A Cell ◽

Health And Disease ◽

Ros Formation ◽

Immunological Process ◽

Lower Complexity ◽

Bacteria And Fungi

The cellular formation of reactive oxygen species (ROS) represents an evolutionary ancient antimicrobial defense system against microorganisms. The NADPH oxidases (NOX), which are predominantly localized to endosomes, and the electron transport chain in mitochondria are the major sources of ROS. Like any powerful immunological process, ROS formation has costs, in particular collateral tissue damage of the host. Moreover, microorganisms have developed defense mechanisms against ROS, an example for an arms race between species. Thus, although NOX orthologs have been identified in organisms as diverse as plants, fruit flies, rodents, and humans, ROS functions have developed and diversified to affect a multitude of cellular properties, i.e., far beyond direct antimicrobial activity. Here, we focus on the development of NOX in phagocytic cells, where the so-called respiratory burst in phagolysosomes contributes to the elimination of ingested microorganisms. Yet, NOX participates in cellular signaling in a cell-intrinsic and -extrinsic manner, e.g., via the release of ROS into the extracellular space. Accordingly, in humans, the inherited deficiency of NOX components is characterized by infections with bacteria and fungi and a seemingly independently dysregulated inflammatory response. Since ROS have both antimicrobial and immunomodulatory properties, their tight regulation in space and time is required for an efficient and well-balanced immune response, which allows for the reestablishment of tissue homeostasis. In addition, distinct NOX homologs expressed by non-phagocytic cells and mitochondrial ROS are interlinked with phagocytic NOX functions and thus affect the overall redox state of the tissue and the cellular activity in a complex fashion. Overall, the systematic and comparative analysis of cellular ROS functions in organisms of lower complexity provides clues for understanding the contribution of ROS and ROS deficiency to human health and disease.

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Nrf2 Is an Attractive Therapeutic Target for Retinal Diseases

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/7469326 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 26

Author(s):

Yasuhiro Nakagami

Keyword(s):

Oxidative Stress ◽

Neuronal Degeneration ◽

Antioxidant Response ◽

Related Factor ◽

Retinal Diseases ◽

Age Related ◽

Nrf2 Signaling Pathway ◽

Genes Encoding ◽

Antioxidant Response Elements ◽

Nrf2 Activator

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that binds to antioxidant response elements located in the promoter region of genes encoding many antioxidant enzymes and phase II detoxifying enzymes. Activation of Nrf2 functions is one of the critical defensive mechanisms against oxidative stress in many species. The retina is constantly exposed to reactive oxygen species, and oxidative stress is a major contributor to age-related macular diseases. Moreover, the resulting inflammation and neuronal degeneration are also related to other retinal diseases. The well-known Nrf2 activators, bardoxolone methyl and its derivatives, have been the subject of a number of clinical trials, including those aimed at treating chronic kidney disease, pulmonary arterial hypertension, and mitochondrial myopathies. Recent studies suggest that Nrf2 activation protects the retina from retinal diseases. In particular, this is supported by the finding that Nrf2 knockout mice display age-related retinal degeneration. Moreover, the concept has been validated by the efficacy of Nrf2 activators in a number of retinal pathological models. We have also recently succeeded in generating a novel Nrf2 activator, RS9, using a biotransformation technique. This review discusses current links between retinal diseases and Nrf2 and the possibility of treating retinal diseases by activating the Nrf2 signaling pathway.

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Abstract 241: Acetylomic and Metabolomic Alterations in Aged Hearts: Role for Silent Information Regulator (SIRT) 3

Circulation Research ◽

10.1161/res.117.suppl_1.241 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Jimmy Zhang ◽

William R Urciuoli ◽

Paul S Brookes ◽

George A Porter ◽

Sergiy M Nadtochiy

Keyword(s):

Metabolic Pathways ◽

Carbon Flux ◽

Tca Cycle ◽

Adult Group ◽

Protein Levels ◽

Mitochondrial Alterations ◽

Age Related ◽

Transport Chain ◽

Tca Cycle Intermediates ◽

Substantial Decline

Introduction: SIRT3 is a mitochondrial metabolic regulator, and a decline in function of SIRT3 may play a role in age-related mitochondrial alterations. The aim of this study was to investigate the possible down-regulation of SIRT3 activity in aged hearts, and to identify which metabolic pathways in aged hearts may be impaired due to SIRT3 dysfunction. Methods: Mitochondria were isolated from WT adult (7 mo.), SIRT3 -/- adult (7 mo.) and WT aged (18 mo.) hearts. Acetylated proteins in mitochondrial samples were identified using 2D gels and mass spectrometry. Metabolite concentrations and carbon fluxes through core metabolic pathways were determined using 13 C-labeled substrates and LC-MS/MS. Results: Mitochondrial acetylation patterns in the SIRT3 -/- adult group matched those found in the WT aged group; the level of acetylation was significantly higher than in WT adult. While the SIRT3 -/- samples exhibited zero SIRT3 protein content, no difference in SIRT3 protein level was seen between adult and aged WT hearts. Mechanistically, this suggests that alterations in mitochondrial acetylation during aging were not caused by lower SIRT3 protein levels, but rather by a lower SIRT3 enzymatic activity. Furthermore, aged myocardium exhibited 40% lower NAD + levels, which may underlie compromised SIRT3 activity. ATP levels were decreased in both SIRT3 -/- and WT aged hearts, suggesting possible defects in energy metabolism. Using metabolomics, we demonstrated that alterations of TCA cycle intermediates were similar in SIRT3 -/- and WT aged hearts (relative to WT adult), and included a substantial decline of carbon flux through α-ketoglutarate and malate. Furthermore, regulation of energy production might also be impaired at the level of the electron transport chain, where Complex I was significantly inhibited in both SIRT3 deficient and aged hearts. Conclusions: Collectively these data suggested that acetylomic and metabolomic fingerprints observed in SIRT3 -/- hearts were recapitulated in aged hearts.

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Upregulation of G protein-linked receptor kinases with advancing age in rat aorta

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2001.280.3.r897 ◽

2001 ◽

Vol 280 (3) ◽

pp. R897-R903 ◽

Cited By ~ 16

Author(s):

William E. Schutzer ◽

John F. Reed ◽

Michael Bliziotes ◽

Scott L. Mader

Keyword(s):

G Protein ◽

Rat Aorta ◽

Aortic Tissue ◽

Fischer 344 Rats ◽

Membrane Expression ◽

Fischer 344 ◽

Age Related ◽

Protein Receptor ◽

Receptor Kinases ◽

Increased Activity

The age-related decline in β-adrenergic receptor (β-AR)-mediated vasorelaxation is associated with desensitization of β-ARs without significant downregulation. The primary mode of this homologous β-AR desensitization, in general, is via G protein receptor kinases (GRK). Therefore, we hypothesize that age-related changes in GRKs are causative to this etiology in rat aorta. Herein, we investigate the activity and cellular distribution (cytoplasmic vs. membrane) of several GRK isoforms and β-arrestin proteins. GRK activity was assessed in extracts from aortic tissue of 6-wk, 6-mo, 12-mo, and 24-mo-old male Fischer-344 rats using a rhodopsin phosphorylation assay. We also performed immunoblots on lysates from aorta with specific antibodies to GRK-2, -3, -5, and β-arrestin-1. Results show an age-related increase in GRK activity. Furthermore, expression of GRK-2 (cytoplasmic and membrane), GRK-3 (cytoplasmic and membrane), and β-arrestin (soluble) increased with advancing age, whereas GRK-5 (membrane) expression remained unchanged. These results suggest that age is associated with increased activity and expression of specific GRKs. This increase likely results in enhanced phosphorylation and desensitization of β-ARs. These biochemical changes are consistent with observed aging physiology.

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The origin of intermuscular adipose tissue and its pathophysiological implications

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00229.2009 ◽

2009 ◽

Vol 297 (5) ◽

pp. E987-E998 ◽

Cited By ~ 153

Author(s):

Roberto Vettor ◽

Gabriella Milan ◽

Chiara Franzin ◽

Marta Sanna ◽

Paolo De Coppi ◽

...

Keyword(s):

Adipose Tissue ◽

Metabolic Diseases ◽

High Plasma ◽

Stem Cell Population ◽

Phenotypic Switch ◽

Mesenchymal Progenitors ◽

Intermuscular Adipose Tissue ◽

Pathological Conditions ◽

Age Related ◽

Mitochondrial Ros

The intermuscular adipose tissue (IMAT) is a depot of adipocytes located between muscle bundles. Several investigations have recently been carried out to define the phenotype, the functional characteristics, and the origin of the adipocytes present in this depot. Among the different mechanisms that could be responsible for the accumulation of fat in this site, the dysdifferentiation of muscle-derived stem cells or other mesenchymal progenitors has been postulated, turning them into cells with an adipocyte phenotype. In particular, muscle satellite cells (SCs), a heterogeneous stem cell population characterized by plasticity and self-renewal that allow muscular growth and regeneration, can acquire features of adipocytes, including the abilities to express adipocyte-specific genes and accumulate lipids. Failure to express the transcription factors that direct mesenchymal precursors into fully differentiated functionally specialized cells may be responsible for their phenotypic switch into the adipogenic lineage. We proved that human SCs also possess a clear adipogenic potential that could explain the presence of mature adipocytes within skeletal muscle. This occurs under some pathological conditions (i.e., primary myodystrophies, obesity, hyperglycemia, high plasma free fatty acids, hypoxia, etc.) or as a consequence of thiazolidinedione treatment or simply because of a sedentary lifestyle or during aging. Several pathways and factors (PPARs, WNT growth factors, myokines, GEF-GAP-Rho, p66shc, mitochondrial ROS production, PKCβ) could be implicated in the adipogenic conversion of SCs. The understanding of the molecular pathways that regulate muscle-to-fat conversion and SC behavior could explain the increase in IMAT depots that characterize many metabolic diseases and age-related sarcopenia.

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