Biomedical subjects

Byung Pal Yu

Publications and source records attributed to Byung Pal Yu.

At least 19 recordsLinked to original sources

PubMed2006

Short-term feeding of baicalin inhibits age-associated NF-kappaB activation.

Baicalin is a flavonoid isolated from Scutellaria baicalensis and is known to affect multiple biological functions, including the inhibition of aldose reductase, HIV infection, and nitric oxide producing activity. Oxidative stress is considered a major cause of aging and various age-related diseases, and among the key cellular components exquisitely sensitive to oxidative stress is the transcription factor, nuclear factor-kappaB (NF-kappaB). In the present study, we attempted to elucidate the mechanisms underlying the suppression of age-related NF-kappaB activation by baicalin in kidney tissue from old rats. Results showed NF-kappaB activation and the upregulation of NF-kappaB targeting genes, hemoxygenase-1, inducible nitric oxide synthase (iNOS), and COX-2 with age. In contrast, the increased expression of these NF-kappaB targeting genes was effectively inhibited by baicalin. Baicalin was shown to inhibit the NF-kappaB cascade via three signal transduction pathways, NIK/IKK, extracellular signal-regulated kinase (ERK), and p38 mitogen-activated protein kinase (MAPK). Our results clearly indicated the anti-oxidative effects of baicalin on age-related redox imbalance. Thus, the significance of the current study is the new information revealing the anti-oxidative properties of baicalin and the role it plays in the regulation of age-related alterations.

Aging↗

PubMed2006

Amelioration of age-related inflammation and oxidative stress by PPARgamma activator: suppression of NF-kappaB by 2,4-thiazolidinedione.

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of transcription factors and are key regulators in various pathophysiological processes related to energy metabolism including lipid and carbohydrate metabolism and inflammation. PPARgamma signaling pathways are reported to exert anti-inflammatory effects by inhibition of NF-kappaB. We previously reported that age-related oxidative stress and inflammatory reactions cause reduced PPARgamma during the aging process. In present study, we investigated the action of 2,4-thiazolidinedione (2,4-TZD), a well-known PPARgamma activator, on aging process using kidneys from Fischer 344 rats, young (9-month-old), old (22-month-old) and old-2,4-TZD fed (4 mg/kg for 10 days). The results showed that the 2,4-TZD treatment brought about several major changes, decrease of: (1) age-related oxidative stress; (2) p65 translocation and NF-kappaB binding activity; (3) NF-kappaB-regulated gene expression, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and inflammatory mediators such as interleukin-1beta (IL-1beta), IL-6, adhesion molecules, VCAM-1 and P-selectin; and (4) age-related disturbance of the redox-status. Therefore, we concluded that 2,4-TZD exerted significant anti-oxidative and anti-inflammatory effects in aged rats, most likely by its ability to attenuate oxidative stress. We propose that 2,4-TZD or other potent PPARgamma activators may be useful in the therapy against age-related inflammation.

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

Adaptive mechanisms to oxidative stress during aging.

Whether or not oxidative stress is the cause of the aging process, as proposed by the oxidative stress theory of aging remains unknown; but accumulated evidence overwhelmingly identifies increased oxidative stress with age as a source of damage to cellular structure and function. From an evolutionary perspective, the utilization of oxygen as a life supporting means makes oxidative stress an inescapable part of an organism's biological system. The inseparability of oxidative stress from the biological system can be viewed as an adaptive response that all aerobic organisms undergo to ward-off the potentially harmful effects of oxygen and its derivatives, including free radicals. The organism's adaptive mechanisms include an intricate network of defenses that regulate and guard against any over-acting oxidative reactions to ensure its survival. This review discusses and illustrates several adaptive responses at various levels (from gene regulation to physical exercise) that organisms use as part of their survival strategy.

Aging↗

PubMed2006

Why calorie restriction would work for human longevity.

Experimentally imposed calorie restriction (CR) is shown to result in the most reproducible endpoint of lifespan extension in all animals models tested. In this presentation, the question of CR's effect on human longevity is reviewed by discussing data pertinent to the putative efficacy of CR on humans. Arguments are presented in support of this possibility based on CR's unique abilities to retard biological functional declines and to deter pathological processes, both of which are major targets of deleterious oxidative stress. To delineate the cellular and molecular mechanisms of CR's efficacy on human longevity, this review elaborates on the modulation of CR on the inflammatory process, a common risk factor for many chronic diseases. Discussions also include evidence from human data on the effect of CR in the loss of body weight, known to suppress inflammatory cytokines, subsequently leading to the reduction of chronic diseases known to compromise the functional longevity of humans.

Aging↗

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↗

PubMed2006

Proteomic analysis of nitrated and 4-hydroxy-2-nonenal-modified serum proteins during aging.

Using proteomic techniques, we investigated peroxynitrite (ONOO-) and 4-hydroxy-2-nonenal (HNE) modified serum proteins from young and old Fischer 344 rats. Two-dimensional gel electrophoresis/western blot analysis of nitrotyrosine and HNE-histidine revealed that serum proteins were differentially modified by ONOO- and HNE. Among them, 16 of the modified proteins, identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS), are involved in blood coagulation, lipid transport, blood pressure regulation, and protease inhibition. Furthermore, nitration and HNE adduction were found to increase with age, lending support to the oxidative stress hypothesis of aging. Our data showed that proteomic techniques can be valuable tools in the study of protein profiling modifications during aging.

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

Membrane alteration as a basis of aging and the protective effects of calorie restriction.

As has been experimentally determined, oxidative modification to biological systems can be extensive, although the identification and stochiometric relation of the reactive species that cause these alterations have not been fully elucidated. In this review, arguments are presented to support the notion that the combined effects of membrane lipid peroxidation and its by-products, reactive aldehydes are likely responsible for membrane-associated functional declines during aging. As evidence for a systemic response to overall oxidative stress, the molecular inflammation hypothesis of aging is discussed by considering that the activation of inflammatory genes act as a bridge linking normal aging to pathological processes.

Aging↗

PubMed2005

Activation mechanisms of endothelial NF-kappaB, IKK, and MAP kinase by tert-butyl hydroperoxide.

Lipid peroxidation plays a major role in vascular dysfunction and age-related cardiovascular diseases. A major product of lipid peroxidation, tert-butyl hydroperoxide (t-BHP), has been reported to modulate vascular reactivity and cellular signaling. To better understand vascular abnormality, we set out to delineate the activation mechanism of nuclear factor kappa B (NF-kappaB) by t-BHP and the regulation of MAPK in endothelial cells. The results showed that t-BHP induces NF-kappaB activation by an inhibitor of kappaB (IkappaB) phosphorylation through IkappaB kinase (IKK) activation. Our data from this t-BHP study also showed increased p38 MAP kinase and ERK activity; however, interestingly, t-BHP showed no influence on JNK. Pretreatment with the p38 MAP kinase inhibitor, SB203580 and the ERK1/2 inhibitor, PD98059, prevented t-BHP-induced increases in p65 translocation, NF-kappaB luciferase activity, and phospho-IKKalpha/beta. Data suggested that t-BHP induces NF-kappaB activation through the IKK pathway, which involves p38 MAPK and ERK activation. This study illustrates a role of t-BHP in NF-kappaB activation and MAPK related-signaling pathways. The t-BHP-induced activation of NF-kappaB and MAPK could be a major player in vascular dysfunctions, as seen in oxidative stressed responses and the vascular inflammatory process.

Animals↗

PubMed2005

Aging effect on myeloperoxidase in rat kidney and its modulation by calorie restriction.

Myeloperoxidase (MPO), a heme protein existing in neutrophil and monocyte, is implicated in various stages of inflammatory conditions with the production of a variety of potent oxidants. To investigate the extent of the involvement of MPO in aging, we measured MPO activities in kidney of rats at different ages maintained with an ad libitum (AL) or a calorie restriction (CR) dietary regimen. Results showed that the MPO activities increased during aging in AL rats, but were significantly attenuated by CR. This result was consistent with altered protein level of MPO during aging. In addition, we were able to detect dityrosine that is a stable end MPO-oxidation product. The amount of dityrosine increased in old AL, but not in old CR rats. To examine the source responsible for increased MPO activity during aging for leukocyte recruitment and infiltration, the levels of vascular cell adhesion molecule (VCAM-1) protein were measured. The level of VCAM-1 showed age-dependent increase in AL rats, which was correlated with higher activity of MPO in old AL rats. Furthermore, we have found that LPS-induced inflammation increased the activity and protein levels of MPO, and VCAM-1 expression in young rat kidneys. These findings suggest that increased MPO activity with aging may related to increased recruitment of inflammatory cells, contributing to protein oxidation accumulation in the aging process. We propose that age-related alterations of MPO, dityrosine, and VCAM were modulated by CR through its anti-inflammatory action.

Aging↗

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

Activation of cyclooxygenases by H2O2 and t-butylhydroperoxide in aged rat lung.

The arachidonate cascade is important for the generation of reactive species (RS), and cyclooxygenase (COX) is a key enzyme of this cascade. Tissues of 24-month-old rat lung showed a 2-fold increase in RS, malondialdehyde and thromboxane B2 than those of 6-month-old rat. We found that the effects of 50 microM H2O2 and 200 microM t-butylhydroperoxide (t-BHP) specify on COX activity, and that their effects increased cytosolic COX activity in a concentration-dependent manner (1-50 microM) in 24-month-old rat. Our results suggested that COX activators such as t-BHP and H2O2, which are located in cytosol, are essential for the activation of COX in aged lung.

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↗