Biomedical subjects

Kyung Jin Jung

Publications and source records attributed to Kyung Jin Jung.

At least 19 recordsLinked to original sources

PubMed2006

Modulation of the age-related nuclear factor-kappaB (NF-kappaB) pathway by hesperetin.

Nuclear factor-kappaB (NF-kappaB), a redox-sensitive transcription factor, plays an important role in the aging process. Thus, developing and identifying specific components that modulate NF-kappaB without adverse side-effects would be of major importance. Hesperetin, a flavanone abundant in citrus fruits, has a variety of pharmacological properties being antioxidant, cholesterol-lowering, and anti-inflammatory. In this study, we investigated how hesperetin fed to 6- and 24-month-old rats modulates NF-kappaB in their kidneys. Results showed that hesperetin suppressed NF-kappaB activation and related gene expressions. An even more interesting finding is that hesperetin suppressed NF-kappaB through four signal transduction pathways, NIK/IKK, ERK, p38, and JNK. Further evidence showed the remarkable efficacy of hesperetin to suppress the translocation of Trx/Ref-1, indicating its beneficial effect on the redox status. The most significant findings of the current study report new information on the use of hesperetin as a potential anti-aging agent.

Aging↗

PubMed2006

SMP30 deficiency causes increased oxidative stress in brain.

Senescence marker protein 30 (SMP30), an important aging marker molecule, has been identified functionally as a calcium regulatory protein. Recent evidence showed its new assumed role as an effective anti-oxidative property. However, the role of SMP30 in the brain has not been explored. To delineate its role in the brain, we utilized SMP30 knock-out (SMP30 KO) mice in the current study. We focused on the oxidative status of the brain by examining selected oxidative markers in brains of SMP30 KO mice. Results showed that the generation of reactive species (RS) and NADPH oxidase activities were significantly elevated in SMP30 deficient brain. The increased oxidative status in these mice was further confirmed by increased oxidatively modified proteins such as dityrosine formation and carbonylation in the cortex of SMP30 KO mice. Moreover, SMP30 deficient brain showed the increased Mac-1 protein and myeloperoxidase (MPO) activity in the brain, supporting the putative anti-oxidative action of SMP30. Interestingly, the activities of major antioxidant enzymes, superoxide dismutase, catalase and reduced glutathione peroxidase in the brain were not affected by SMP30 depletion. Our results documented that brain SMP30 has a protective action against oxidative damage, without influencing antioxidant enzyme status.

Animals↗

PubMed2006

Upregulation of aortic adhesion molecules during aging.

To investigate effects of aging on adhesion molecules (AMs), the present study assessed the expressions of aortic P-selectin and vascular adhesion molecule-1 (VCAM-1) in young (6-month-old) and old (24-month-old) Fischer 344 rats fed ad libitum (AL) or calorie-restricted diets. Results showed increased levels of aortic P-selectin and VCAM-1 in the old AL rats, causing excessive leukocyte infiltration as indicated by enhanced myeloperoxidase level. These elevations were parallel to increased oxidative stress including lipid peroxides during aging. Then involvement of redox-sensitive transcription factor nuclear factor-kappaB was analyzed, and greater activation of nuclear factor-kappaB-inducing kinase (NIK)/IkappaB kinase (IKK)/Inhibitor of kappaB (IkappaB) pathway in aorta from old AL rats was found. Further, in cultured endothelial cells challenged by various oxidative stimuli, the induced redox imbalance triggered overexpression and promoter activities of P-selectin and VCAM-1. Our study documented that aortic upregulated AMs with age are closely related to activation of NIK/IKK/IkappaB/nuclear factor-kappaB pathway brought on by oxidative stress.

Aging↗

PubMed2005

Effect of short-term, low dose aspirin supplementation on the activation of pro-inflammatory NF-kappaB in aged rats.

The basis of our recently proposed "molecular inflammation theory of aging" is that activated inflammatory transcription factors, including versatile NF-kappaB, occur widespread in the organism during aging. NF-kappaB plays a key role in pro-inflammatory gene expression, such as cyclooxygenase (COX). Aspirin is one of the most commonly used non-steroidal anti-inflammatory drugs because of its ability to inhibit COX activity. Thus, in the present study, we investigated the effect of short-term, low dose aspirin intake on the modulation of pro-inflammatory NF-kappaB activation in old rats. To conduct the study, 24-month-old Fischer 344 rats were supplemented with low dose aspirin (0.015%) for 10 days. Biochemical analyses showed suppressed reactive species (RS) and COX-2 activity. The data also showed that NF-kappaB activation and its associated gene expressions, such as COX-2, iNOS, VCAM-1 and ICAM-1, were all suppressed by the low dose aspirin supplementation through the inhibition of phosphorylation and degradation of IkappaBalpha via the NIK/IKK pathway. Our molecular exploration further revealed that aspirin's suppressive action of NF-kappaB was mediated by its ability to inhibit the nuclear translocation of cytosolic thioredoxin and redox factor-1. These findings showed for the first time that in aged rat short-term low dose dietary aspirin feeding modulates the molecular signal transduction involved in the inflammatory process.

Aging↗

PubMed2005

The effect of age and calorie restriction on HIF-1-responsive genes in aged liver.

Hypoxia inducible factor-1 (HIF-1) regulates transactivation of several genes in response to hypoxia condition. We explore hepatic HIF-1 responsive gene regulation during aging and the age-related changes of the HIF-1 related gene activation in young and old rats. Results indicate that the aging process induces the activation of HIF-1alpha, which is accompanied by increased HIF-1 DNA binding. This increased binding activity is accompanied by the increase of HIF-1-dependent genes, heme oxygenase-1 (HO-1), vascular endothelial growth factor (VEGF), erythropoietin (EPO), and inducible nitric oxide synthase (iNOS), which all showed remarkable up-regulation during aging process. In contrast, the increased HIF-1 related gene expression was effectively blunted by the anti-oxidative action of calorie restriction in aged rat liver. We propose that age-related HIF-1 binding activity may well be influenced by the increased pro-oxidative conditions of aged animals, which up-regulate HIF-1-dependent gene expression.

Aging↗

PubMed2005

cDNA representational difference analysis used in the identification of genes related to the aging process in rat kidney.

Aging is a complex physiological process by which the functions of many organ systems deteriorate. Growing evidence shows that age-related changes and damage are causally related to oxidative stress and inflammatory responses from reactive species. The aim of this study was to identify differentially expressed genes in old and young kidneys of Fisher 344 male rats during the aging process using complementary DNA representational difference analysis (cDNA RDA). cDNA RDA is a subtractive technique for identifying a focused set of differentially expressed genes. The distinctive advantage of this technique is its capability of detecting differences in gene expressions at less than one copy per cell and identifying genes not previously described in the database. Reverse transcription-polymerase chain reaction with specific primers was applied to confirm the differences found by RDA. Twenty-one putative differentially expressed genes were identified. Sixteen genes were up-regulated during aging and were associated with stress-response and inflammatory reactions, while five genes were down-regulated. These data suggested that the inflammatory process is a plausible cause of the aging process.

Age Factors↗

PubMed2005

Betaine suppresses proinflammatory signaling during aging: the involvement of nuclear factor-kappaB via nuclear factor-inducing kinase/IkappaB kinase and mitogen-activated protein kinases.

Betaine is an important human nutrient obtained from various foods. In the present study, we assessed the anti-inflammatory effect of betaine on nuclear factor-kappaB (NF-kappaB) during aging. Sprague-Dawley (SD) rats, ages 7 and 21 months, were used in this study. The older rats were fed betaine. To elucidate the effect of betaine on oxidative stress-induced NF-kappaB and its signaling pathway at molecular levels, YPEN-1 cells were used. Results showed that betaine suppressed NF-kappaB and its related gene expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), vascular cell adhesion molecule-1 (VCAM-1), and intracellular cell adhesion molecule-1 (ICAM-1) in aged kidney. Furthermore, betaine attenuated oxidative stress-induced NF-kappaB via nuclear factor-inducing kinase/IkappaB kinase (NIK/IKK) and mitogen-activated protein kinases (MAPKs) in the YPEN-1 cells. On the basis of these results, we concluded that betaine suppressed the age-related NF-kappaB activities associated with upregulated NIK/IKK and MAPKs that were induced by oxidative stress. Thus, betaine might be useful as a preventive agent against the activation of NF-kappaB induced during inflammation and aging.

Aging↗

PubMed2004

NF-kappaB activation mechanism of 4-hydroxyhexenal via NIK/IKK and p38 MAPK pathway.

4-Hydroxyhexenal (HHE) is known to affect redox balance during aging, included are vascular dysfunctions. To better understand vascular abnormality through the molecular alterations resulting from HHE accumulation in aging processes, we set out to determine whether up-regulation of mitogen-activated protein kinase (MAPK) by HHE is mediated through nuclear factor kappa B (NF-kappaB) activation in endothelial cells. HHE induced NF-kappaB activation by inhibitor of kappaB (IkappaB) phosphorylation via the IkappaB kinase (IKK)/NF-kappaB inducing kinase (NIK) pathway. HHE increased the activity of p38 MAPK and extracellular signal regulated kinase (ERK), but not c-jun NH(2)-terminal kinase, indicating that p38 MAPK and ERK are closely involved in HHE-induced NF-kappaB transactivation. Pretreatment with ERK inhibitor PD98059, and p38 MAPK inhibitor SB203580, attenuated the induction of p65 translocation, IkappaB phosphorylation, and NF-kappaB luciferase activity. These findings strongly suggest that HHE induces NF-kappaB activation through IKK/NIK pathway and/or p38 MAPK and ERK activation associated with oxidative stress in endothelial cells.

Aldehydes↗

PubMed2004

Age-associated increase in oxidative stress and nuclear factor kappaB activation are attenuated in rat liver by regular exercise.

The combined effects of aging and regular physical exercise was investigated on the production of reactive oxygen species (ROS), lipid peroxidation, glutathione status, and the activity of nuclear factor-kappaB (NF-kappaB) in rat liver. A group of 24 male F344 rats was divided into the following categories: adult control (18 months), adult exercised (18 months), and aged control (28 months) and aged exercised (28 months). The ROS formation increased as a function of age and exercise training decreased the rate of ROS formation in the two age groups. Significant positive correlation was found between ROS production and lipid peroxidation (LIPOX). The reduced glutathione (GSH) level was higher and the oxidized glutathione (GSSG) level lower in exercised groups compared with the sedentary controls (P<0.05). An age-associated increase in NF-kappaB activity was attenuated by the regular exercise. The content of p50 and p65 subunits of NF-kappaB increased with age and decreased with exercise training. The content of inhibitory factor-kappaB was inversely related to NF-kappaB activation. Regular exercise-induced adaptive responses, including attenuation of an increase in ROS production, LIPOX level, NF-kappaB activation, and reduced GSH/GSSG ratio, appear to be capable, even in old age, of reducing increases in inflammatory and other detrimental consequences that are often associated with advancing age.

Aging↗

PubMed2004

Proteomic analysis of post-mitochondrial fractions of young and old rat kidney.

Proteomic analysis is defined as the characterization of the entire set of proteins encoded by a genome. Two-dimensional (2D) electrophoresis and matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) are key technologies used in proteomic analysis to gain information about protein expression profiles and post-translational modifications. Knowledge about aging processes can be gained by recognizing changes in protein expression. Thus, to better understand the aging process through protein profiling, post-mitochondrial (PM) fractions of young (13-month) and old (31-month) male Fischer 344 rat kidney were differentially analyzed by 2D. We detected a total number of 380 spots on 2D gel images. Among them, 167 spots showed 2-fold significant alterations (p<0.05) between young and old PM fractions. Further, 103 proteins were identified by MALDI-TOF MS. The PM fraction of aged rat kidney showed increases in antioxidative and proteolytic proteins and decreases in cytoskeletal proteins. In addition, we found age-related changes in transport and homeostasis proteins. Thus, our results demonstrated that proteomic analysis can be effectively applied to the assessment of the age status of protein expression, and thereby provide valuable information on age-related changes of proteome.

Aging↗

PubMed2004

Modulation of gene expression of SMP-30 by LPS and calorie restriction during aging process.

Senescence marker protein-30 (SMP-30) has been proposed as an important aging marker and is now functionally identified as a Ca2+ binding protein. SMP-30 has been shown to blunt cell death caused by intracellular Ca2+ accumulation by enhancing plasma membrane Ca(2+)-pumping activity. Although SMP-30 is reported decrease during aging, at present, neither has the mechanism underlying this decrease been fully defined, nor have the mechanisms related to the modulation of SMP-30 been extensively explored. In the current study, we used the well-known anti-aging action of the calorie restriction (CR) paradigm to explore age-related changes in SMP-30 gene expression. The thrust of our investigation was based on CR's ability to defend against age-related oxidative stress and the inflammatory process. The kidney and liver from Fischer 344 rats at 6, 12, 18 and 24 months of age were utilized for this study. The rats were divided into two groups, ad libitum (AL)-fed and 40% restricted CR. Results showed that SMP-30 expression declined with age and that this decline was clearly blunted by CR. To correlate changes between SMP-30 gene expression and the oxidative status, SMP-30 expression and the production of reactive oxygen species (ROS) during aging and free-radical generating lipopolysaccharide (LPS) were monitored. Our data showed that the down-regulation of SMP-30 was accompanied by increased ROS generation and LPS-induced ROS. The potent anti-aging and anti-oxidative action of CR effectively suppressed the age-related down-regulation of SMP-30 by ROS reduction.

Aging↗

PubMed2004

Suppression of apoptosis by calorie restriction in aged kidney.

Programmed cell death by apoptosis is regarded as an organism's protective mechanism against the accumulation of defective cells. Apoptotic activity is shown to be elevated in most aged tissues, and its intracellular regulation is intricately manipulated by mitochondria. In this study, to determine the progression of apoptosis during aging, we investigated the expression of several key apoptosis-related markers in kidney of 12- and 24-month-old rats. Mitochondrial damage was detected by lipid peroxidation and Western blot analysis in several target apoptotic proteins in aged rat kidney. Our results showed that the expression levels of a pro-apoptotic Bax protein, was significantly enhanced at the age of 24 months, while an anti-apoptotic protein, Bcl-2, was reduced in the aged rat kidney. We also found that the cytosolic cytochrome c level was significantly increased in the aged kidney. However, these age-related changes were reversed by calorie restriction (CR), exhibiting its modulatory action on apoptotic activity. Furthermore, caspase-3 activation was markedly increased in kidney of 24-month-old rats fed ad libitum (AL), as indicated by the cleaved, active form of caspase-3 (17-19 kDa), which we found was replaced with the procaspase (32 kDa) in the CR rats of both age groups. We also found that a cleaved active form (85 kDa) of poly (ADP-ribose) polymerase (116 kDa inactivated form), which serves as a nuclear substrate for active caspase-3, was increased in aged AL kidney and was blunted by CR. In addition, to investigate the oxidative status in aged kidney, we measured and compared the malondialdehyde (MDA) and 4-hydroxynonenal (HNE) levels in aged AL and CR rat kidneys. Our results showed increased MDA and HNE levels in aged AL rats, while these levels were markedly lower in CR rats, even at 24 months. These results indicate that the kidneys of rats fed ad libitum are under the influence of high oxidative stress compared to CR rats. Thus, our present data strongly suggest that the apoptotic activity observed in the aged kidney is likely modulated by the age-related oxidative status, and reversed by CR as a result of its anti-oxidative and anti-aging actions.

Aging↗

PubMed2004

Hesperetin: a potent antioxidant against peroxynitrite.

Peroxynitrite (ONOO-) is a reactive oxidant formed from superoxide (*O2(-)) and nitric oxide (*NO), that can oxidize several cellular components, including essential protein, non-protein thiols, DNA, low-density lipoproteins (LDL), and membrane phospholipids. ONOO- has contributed to the pathogenesis of diseases such as stroke, heart disease, Alzheimer's disease, and atherosclerosis. Because of the lack of endogenous enzymes to thwart ONOO- activation, developing a specific ONOO- scavenger is remarkably important. In this study, the ability of hesperetin (3',5,7-trihydroxy-4-methoxyflavanone) to scavenge ONOO- and to protect cells against ONOO- and ROS was investigated. The data gained show that hesperetin can efficiently scavenge authentic ONOO- . In spectrophotometric analysis, the data revealed that hesperetin led to declined ONOO- -mediated nitration of tyrosine through electron donation. Hesperetin exhibited significant inhibition on the nitration of bovine serum albumin (BSA) by ONOO- in a dose-dependent manner. Hesperetin also manifested cytoprotection from cell damage induced by ONOO- and ROS. The present study suggests that hesperetin is a powerful ONOO- scavenger and promotes cellular defense activity in the protection against ONOO- involved diseases.

Animals↗

PubMed2003

Alteration of soluble adhesion molecules during aging and their modulation by calorie restriction.

To investigate the status of soluble adhesion molecules (sAMs) during aging, the present study determined protein levels of several major sAMs in serum samples obtained from rats at different ages. These sAMs include E-selectin, P-selectin, vascular cell adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1). Fischer 344 rats, ages 6, 12, 18, and 24 months, fed ad libitum (AL) and calorie restricted (CR) diets were used in this study. Analysis by Western blotting showed that the levels of all sAMs studied increased during aging in AL rats, but were effectively blunted in the CR rats. Total reactive oxygen species/reactive nitrogen species (ROS/RNS) levels were measured by fluorescent probe 2',7'-dichlorofluorescin diacetate. Increased ROS/RNS levels were found to coincide with increased levels of superoxide-generating xanthine oxidase in serum during aging, but were found suppressed by CR. Increases in sAMs levels were duplicated in another experiment in which young (13-month-old) and old (31-month-old) rats were injected with proinflammatory lipopolysaccharide. These findings suggest that the altered expressions of sAMs may be due to increased oxidative stress with advanced age and that these increases were prevented by CR through its antioxidative action.

Aging↗

PubMed2003

Modulation of glutathione and thioredoxin systems by calorie restriction during the aging process.

Accumulating evidence strongly suggests that oxidative stress underlies aging processes and that calorie restriction (CR) retards aging processes, leading to an extended lifespan for various organisms. Recent studies revealed that the anti-aging action of CR depends on its anti-oxidative mechanism. However, at present, the status of glutathione (GSH) and thioredoxin (Trx) system, two major thiol redox systems in animal cells during aging and its modulation by CR has not fully been explored. The purpose of this study is two-fold: one, to determine whether these two systems in rat kidney are altered as a consequence of aging; two, to determine whether these systems can be modulated by anti-oxidative CR. The results of our study showed that GSH and GSH-related enzyme activities decreased with age in ad libitum (AL)-fed rats, while CR rats consistently showed resistance to decreases in these activities. Data from the present data further showed that while Trx and Trx reductase (TrxR) in cytoplasm decrease with age in AL-fed rats, CR prevents these decreases. In contrast, we also found that the nuclear translocation of the redox regulators, Trx and Ref-1, increase with age, which was suppressed in CR rats. Therefore, increases in nuclear Trx and Ref-1 during aging may result in the up-regulation of redox-sensitive transcription factors, such as NF-kappaB or AP-1, via the interaction of Ref-1 and Trx in a redox-dependent manner. Our conclusion is that a redox imbalance occurs during aging and that redox changes are minimized through the anti-oxidative action of CR.

Aging↗

PubMed2002

Modulation of redox-sensitive transcription factors by calorie restriction during aging.

Oxidative stress is considered to be a major cause of aging and many age-related diseases. Calorie restriction (CR) is known to retard deleterious, age-related processes. Recent studies document that CR retards the aging process by regulating the redox environment through its anti-oxidative properties. Among the key cellular components exquisitely sensitive to redox status are transcriptions factors such as nuclear factor kappa B (NF-kappaB), activator protein-1 (AP-1), and hypoxia inducible factor-1 (HIF-1). Based on available findings and our recent supporting evidence, we proposed to use a new term, 'molecular inflammation' to emphasize the importance of molecular reaction mechanisms distinct from chronic and fully expressed inflammatory phenomena. Currently, limited information is available on the age-related and dietary modulations of these factors. In this review, we place a major focus on the age effects of NF-kappaB, AP-1, and HIF-1 regulation, and further delineate how age-related changes are modulated by CR. Age-related increases in redox-sensitive NF-kappaB, AP-1, and HIF-1 binding activities are concluded to be associated with increased ROS and CR to modulate their activations by suppressing oxidative stress. Data on cellular regulation provide better molecular insights into the mechanisms underlying cellular redox maintenance, which may be the cross-talk between normal aging and age-associated pathogenic processes.

Aging↗

PubMedDate not supplied

Influence of aging and calorie restriction on MAPKs activity in rat kidney.

Mitogen-activated protein kinases (MAPK), which include the extracellular signal-related kinases (ERK), the c-Jun N-terminal kinases (JNK), and the p38 MAPK, are important regulatory proteins by which a wide variety of extracellular signals are transduced into intracellular sites. Recent studies reported that mitogenic signal transduction in various cell types are exquisitely sensitive to reactive oxygen species (ROS) and the celluar redox status. In the present study, we investigated the activation of MAPK activity by aging and calorie restriction (CR) in rat kidneys isolated from Fischer 344 rats, ages 6, 12, 18, and 24 months fed ad libitum (AL) and CR diets. Results showed that the aging process strongly enhanced all three of the MAPK activities studied, ERK, JNK, and p38 MAPK, in parallel to increased ROS status. In contrast, we observed CR to markedly suppress the age-related activation of MAPKs. Based on these data, we concluded that an age-related increase in MAPK activity is associated with increased ROS, which was effectively suppressed by the anti-oxidative action of CR.

Active Transport, Cell Nucleus↗

PubMedDate not supplied

The molecular inflammatory process in aging.

Emerging pathological evidence indicates that major chronic aging-related diseases such as atherosclerosis, arthritis, dementia, osteoporosis, and cardiovascular diseases, are inflammation-related. In this review, inflammation is examined as a possible underlying basis for the molecular alterations that link aging and age-related pathological processes. A proposal for the molecular inflammation hypothesis of the aging views the redox derangement that occurs during aging as the major factor for increased risk for age-related inflammation. Accumulated data strongly indicate the activation of redox-sensitive transcription factors and dysregulated gene expression under the age-related oxidative stress seems to be the major culprits. Key players involved in the inflammatory process are the age-related upregulation of NF-kappaB, IL-1beta, IL-6, TNFalpha, cyclooxygenase-2, adhesion molecules, and inducible NO synthase. Furthermore, data are presented on the molecular events involved in age-related NF-kappaB activation and phosphorylation by IkappaB kinase/NIK and MAPKs. Experimental data on anti-aging calorie restriction (CR) for its antiinflammatory efficacy by suppressing the upregulated proinflammatory mediators will be reviewed. Also, the involvement of another super family of transcription factors, PPARs (PPARalpha, gamma) as regulators of proinflammatory responses and NF-kappaB signaling pathway is described as well as a discussion on the physiological significance of a well-maintained balance between NF-kappaB and PPARs.

Aging↗