• The Korean Journal of Physiology and Pharmacology
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• v.21 no.3
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• pp.293-300
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• 2017

Prostaglandin $D_2$ ($PGD_2$) may act against myocardial ischemia-reperfusion (I/R) injury and play an anti-inflammatory role in the heart. Although the effect of $PGD_2$ in regulation of ANP secretion of the atrium was reported, the mechanisms involved are not clearly identified. The aim of the present study was to investigate whether $PGD_2$ can regulate ANP secretion in the isolated perfused beating rat atrium, and its underlying mechanisms. $PGD_2$ (0.1 to $10{\mu}M$) significantly increased atrial ANP secretion concomitantly with positive inotropy in a dose-dependent manner. Effects of $PGD_2$ on atrial ANP secretion and mechanical dynamics were abolished by AH-6809 ($1.0{\mu}M$) and AL-8810 ($1.0{\mu}M$), $PGD_2$ and prostaglandin $F2{\alpha}$ ($PGF2{\alpha}$) receptor antagonists, respectively. Moreover, $PGD_2$ clearly upregulated atrial peroxisome proliferator-activated receptor gamma ($PPAR{\gamma}$) and the $PGD_2$ metabolite 15-deoxy-${\Delta}12$, 14-$PGJ_2$ (15d-$PGJ_2$, $0.1{\mu}M$) dramatically increased atrial ANP secretion. Increased ANP secretions induced by $PGD_2$ and 15d-$PGJ_2$ were completely blocked by the $PPAR{\gamma}$ antagonist GW9662 ($0.1{\mu}M$). PD98059 ($10.0{\mu}M$) and LY294002 ($1.0{\mu}M$), antagonists of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signaling, respectively, significantly attenuated the increase of atrial ANP secretion by $PGD_2$. These results indicated that $PGD_2$ stimulated atrial ANP secretion and promoted positive inotropy by activating $PPAR{\gamma}$ in beating rat atria. MAPK/ERK and PI3K/Akt signaling pathways were each partially involved in regulating $PGD_2$-induced atrial ANP secretion.

• The Korean Journal of Physiology and Pharmacology
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• v.15 no.4
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• pp.189-194
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• 2011

ATP-sensitive $K^+$ channels ($K_{ATP}$) are major component of preventing ischemia-reperfusion injury. However, there is little information regarding to the expressional difference of $K_{ATP}$ and its function between left and right ventricles. In this study, we measured the lactate dehydrogenase release of rabbit heart slices in vitro and determined the difference of the $K_{ATP}$ expression at the both ventricles by measuring the level of $K_{ATP}$-forming Kir6.2 (OcKir6.2) mRNA using in situ hybridization. The hearts were preconditioned with 15 min hypoxia and reoxygenated for 15 min before a hypoxic period of 60 min, followed by reoxygenation for 180 min. With hypoxic preconditioning (100% $N_2$) with 15 min, left ventricles (LV) showed higher release of LDH comparing with right ventricles (RV). Adding $K_{ATP}$ blocker glibenclamide ($10{\mu}M$) prior to a hypoxic period of 60 min, hypoxic preconditioning effect of RV was more abolished than LV. With in situ hybridization, the optical density of OcKir6.2 was higher in RV. Therefore, we suggest that different $K_{ATP}$ expression between LV and RV is responsible for the different response to hypoxia and hypoxic preconditioning of rabbit hearts.

• The Korean Journal of Physiology and Pharmacology
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• v.11 no.2
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• pp.57-64
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• 2007

Ischemic preconditioning (IPC) is known to protect the heart against ischemia/reperfusion (IR)-induced injuries, and regional differences in the mitochondrial antioxidant state during IR or IPC may promote the death or survival of viable and infarcted cardiac tissues under oxidative stress. To date, however, the interplay between the mitochondrial antioxidant enzyme system and the level of reactive oxygen species (ROS) in the body has not yet been resolved. In the present study, we examined the effects of IR- and IPC-induced oxidative stresses on mitochondrial function in viable and infarcted cardiac tissues. Our results showed that the mitochondria from viable areas in the IR-induced group were swollen and fused, whereas those in the infarcted area were heavily damaged. IPC protected the mitochondria, thus reducing cardiac injury. We also found that the activity of the mitochondrial antioxidant enzyme system, which includes manganese superoxide dismutase (Mn-SOD), was enhanced in the viable areas compared to the infarcted areas in proportion with decreasing levels of ROS and mitochondrial DNA (mtDNA) damage. These changes were also present between the IPC and IR groups. Regional differences in Mn-SOD expression were shown to be related to a reduction in mtDNA damage as well as to the release of mitochondrial cytochrome c (Cyt c). To the best of our knowledge, this might be the first study to explore the regional mitochondrial changes during IPC. The present findings are expected to help elucidate the molecular mechanism involved in IPC and helpful in the development of new clinical strategies against ischemic heart disease.

• Proceedings of the SCSK Conference
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• 2003.09a
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• pp.13-34
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• 2003

Fructose-1, 6-diphosphate (FOP), a glycolytic metabolite is reported to ameliorate inflammation and inhibit the nitric oxide production in murine macrophages stimulated with endotoxin. It is also reported that FOP has cytoprotective effects against hypoxia or ischemia/reperfusion injury in brain and heart. In this study, we examined whether FDP has protective effects on UV-induced oxidative damage in skin cell culture system and human skin in vivo. FDP had a protective role in UVB-induced LDH release and ROS accumulation in HaCaT although it did not show direct radical scavenging effect in the experiment using 1, 1-diphenyl-2-picrylhydrazyl (DPPH). FDP also preserved cellular GSH content after UV irradiation in HaCaT and normal human fibroblast culture system. Cellular oxidative stress induces multiple downstream signaling pathways that regulate expression of multiple gene including MMP-1 and collagen, we examined the effects of FDP on UV-induced alteration of these protein expression in fibroblast culture and human skin in vivo. The increased MMP-1 expression in fibroblast and human skin by UV irradiation was significantly decreased by FDP. FDP also prevented the UV-induced decrease of collagen expression in fibroblast and human skin. Moreover, the decreasing the intracellular levels of reducing equivalents in human fibroblast by glutathione (GSH) depletion lowered the UVA dose threshold for reduction of procollagen expression, indicating that the differences of glutathione contents define the susceptibility of fibroblasts towards UV-induced reduction of procollagen expression. FDP also preserved cellular GSH content after UV irradiation, indicating that FDP has protective effects on UV-induced reduction of procollagen expression, which are possibly through maintaining intracellular reducing equivalent. Based on these premises, we examined the effect of daily use of a moisturizer containing FDP on facial wrinkle in comparison with vehicle moisturizer lacking FDP. In the clinical study, FDP significantly decreased facial wrinkle compared with vehicle alone after 6 months of use. Our results suggest that FDP has anti-aging effects in skin by increasing cellular antioxidant system and preventing oxidative signal and inflammatory reaction. Therefore FDP may be useful anti-aging agent for cosmetic purpose.

• Archives of Pharmacal Research
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• v.28 no.1
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• pp.61-67
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• 2005

We evaluated the antiplatelet effects of two classes of ATP-sensitive potassium channel openers $(K_{ATP}\;openers)$ on washed human platelets, and the study's emphasis was on the role of mitochondrial $K_{ATP}$ in platelet aggregation. Collagen-induced platelet aggregation was inhibited in a dose dependent manner by lemakalim and SKP-450, which are potent cardio-nonselective $K_{ATP}$ openers, and also by cardioselective BMS-180448 and BMS-191095 $(IC_{50}\;:\;1,130,\;>\;1,500,\;305.3\;and\;63.9\;{\mu}M,\;respectively)$, but a significantly greater potency was noted for the cardioselective $K_{ATP}$ openers. The latter two $K_{ATP}$ openers also inhibited platelet aggregation induced by thrombin, another important blood-borne platelet activator, with similar rank order of potency $(IC_{50}\;:\;498.0\;and\;104.8{\mu}M\; for\;BMS-180448\;and\;BMS-191095,\;respectively)$. The inhibitory effects of BMS-191095 on collagen-induced platelet aggregation were significantly blocked by a 30-min pretreatment of platelets with glyburide $(1{\mu}M)$ or sodium 5-hydroxyde­canoate$(5-HD,\;100{\mu}M)$, a nonselective and selective mitochondrial $K_{ATP}$ antagonist, respectively, at similar magnitudes; this indicates the role of mitochondrial $K_{ATP}$ in the antiplatelet activity of BMS-191095. However, glyburide and 5-HD had no effect when they were added to the platelet cuvette immediately prior to the addition of BMS-191095. These findings indicate that cardioselective mitochondrial $K_{ATP}$ openers like BMS-191095 are able to exert cardioprotective effects in cardiac ischemia/reperfusion injury via dual mechanisms directed at the inhibition of platelet aggregation and the protection of cardiomyocytes, and both these mechanisms are mediated by mitochondrial$K_{ATP}$.

• The Korean Journal of Physiology and Pharmacology
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• v.20 no.4
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• pp.333-340
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• 2016

Edaravone, a synthetic-free radical scavenger, has been reported to reduce ischemia-reperfusion-induced renal injury by improving tubular cell function, and lowering serum creatinine and renal vascular resistance. The present study investigated the effect of edaravone in diabetes mellitus-induced nephropathy in rats. A single administration of streptozotocin (STZ, 55 mg/kg, i .p.) was employed to induce diabetes mellitus in rats. The STZ-administered diabetic rats were allowed for 10 weeks to develop nephropathy. Mean body weight, lipid alteration, renal functional and histopathology were analysed. Diabetic rats developed nephropathy as evidenced by a significant increase in serum creatinine and urea, and marked renal histopathological abnormalities like glomerulosclerosis and tubular cell degeneration. The kidney weight to body weight ratio was increased. Moreover, diabetic rats showed lipid alteration as evidenced by a significant increase in serum triglycerides and decrease in serum high-density lipoproteins. Edaravone (10 mg/kg, i .p., last 4-weeks) treatment markedly prevented the development of nephropathy in diabetic rats by reducing serum creatinine and urea and preventing renal structural abnormalities. In addition, its treatment, without significantly altering the elevated glucose level in diabetic rats, prevented diabetes mellitus-induced lipid alteration by reducing serum triglycerides and increasing serum high-density lipoproteins. Interestingly, the renoprotective effect of edaravone was comparable to that of lisinopril (5 mg/kg, p.o, 4 weeks, standard drug). Edaravone prevented renal structural and functional abnormalities and lipid alteration associated with experimental diabetes mellitus. Edaravone has a potential to prevent nephropathy without showing an anti-diabetic action, implicating its direct renoprotection in diabetic rats.

• Archives of Pharmacal Research
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• v.28 no.11
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• pp.1287-1292
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• 2005

KR-33028 (N-[4-cyano-benzo[b]thiophene-2-carbonyl]guanidine) is a new cardioprotective agent for preventing ischemia-reperfusion injury. This study was performed to identify the metabolic pathway of KR-33028 in human liver microsomes and to compare its metabolism with that of cryopreserved human hepatocytes. Human liver microsomal incubation of KR-33028 in the presence of NADPH and UDPGA resulted in the formation of four metabolites, M1, M2, M3, and M4. M1 and M2 were identified as 5-hydroxy-KR-33028 and 7-hydroxy-KR-33028, respectively, on the basis of LC/MS/MS analysis with the synthesized authentic standard. M3 and M4 were suggested to be dihydroxy-KR-33028 and hydroxy-KR-33028-glucuronide, respectively. Metabolism of KR-33028 in cryopreserved human hepatocytes resulted in the formation of M1, M2, and M4. These data show a good correlation between major metabolites formed in human liver microsomes and cryopreserved human hepatocytes. In addition, KR­33028 was found to inhibit moderately the metabolism of CYP1A2 substrates. Based on the results obtained metabolic pathway of KR-33028 is proposed.

• Journal of the Society of Cosmetic Scientists of Korea
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• v.30 no.2
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• pp.247-251
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• 2004

UV radiation exerts various influences in the skin, including photoaging and inflammation (1). The MMPs (Matrix metalloproteinases), which are induced by UV irradiation, can degrade matrix proteins, and these results in a collagen deficiency in photodamaged skin that leads to skin wrinkling. It has been known that the production of PGE$_2$ stimulates MMPs expression, and inhibits procollagen (2). Thus, it is possible that the induction of MMPs and the inhibition of matrix protein synthesis by UV -induced PGE$_2$ may play some role in UV-induced collagen deficiency in photoaged skin. Fructose-1,6-diphosphate (FDP), a glycolytic metabolite, is reported to have cytoprotective effects against ischemia and postischemic reperfusion injury of brain and heart, presumably by augmenting anaerobic carbohydrate metabolism (3). And also, FDP significantly prevent skin aging by decreasing facial winkle compared with vehicle alone after 6 months of use. We studied the mechanism of anti-aging effect of FDP on UVB-irradiated HaCaT keratinocyte model. FDP has protective role in UVB injured keratinocyte by attenuating prostaglandin E$_2$ (PGE$_2$) production and COX-2 expression. And FDP also suppressed UVB-induced MMP-2 expression. Further, to delineate the inhibition of UVB-induced COX-2 and MMPs expression with cell signaling pathways, treatment of FDP to HaCaT keratinocytes resulted in marked inhibition of UVB-induced phosphorylation of ERK1/2, JNK. It also prevents UV induced NFB translocation, which are activated by cellular inflammatory signal. Our results indicate that FDP has protecting effects in UV-injured skin aging by decreasing UVB-induced COX-2 and MMPs expression, which are possibly through blocking UVB-induced signal cascades.

• Journal of Life Science
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• v.28 no.12
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• pp.1545-1553
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• 2018

The International Society of Rare Sugars (ISRS) defines rare sugars as monosaccharides and their derivatives that rarely occur in nature. Rare sugars have recently received much attention because of their many uses including low-calorie sweeteners, bulking agents, and antioxidants, and their various applications including as immunosuppressants in allogeneic rat liver transplantation, as potential inhibitors of various glycosidases and microbial growth, in ischemia-reperfusion injury repair in the rat liver, and in segmented neutrophil production without detrimental clinical effects. Because they rarely exist in nature, the production of rare sugars has been regarded as one of the most important research areas and, generally, they are produced by chemical synthesis. However, the production of rare sugars by bioconversion using enzymes from microorganisms has been receiving increased attention as an environmentally friendly alternative production method. In particular, D-allulose, D-allose, and D-tagatose are of interest as low-calorie sweeteners in various industries. To date, D-tagatose 3-epimerase, D-psicose 3-epimerase, and D-allulose 3-epimerase have been reported as D-allulose bioconversion enzymes, and L-rhamnose isomerase, Galactose 6-phosphate isomerase, and Ribose 5-phosphate isomerase have been identified as D-allose production enzymes. Elsewhere, D-tagatose has been produced by L-arabinose isomerase from various microorganisms. In this study, we report the production of D-allulose, D-allose, and D-tagatose by microorganism enzymes.

• Journal of Chest Surgery
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• v.34 no.7
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• pp.524-533
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• 2001

Background: Hyperoxemic cardiopulmonary bypass (CPB) has been recognized as a safe technique and is widely used in cardiac surgery. However, hyperoxemic CPB may produce higher toxic oxygen species and cause more severe oxidative stress and ischemia/reperfusion injury than normoxemic CPB. This study was undertaken to compare inflammatory responses and myocardial injury between normoxemic and hyperoxemic CPB and to examine the beneficial effect of normoxemic CPB. Material and method: Thirty adult patients scheduled for elective cardiac surgery were randomly divided into normoxic group (n=15), who received normoxemic CPB (about Pa $O_{2}$ 120 mmHg), and hyperoxic group (n=15), who received hyperoxemic CPB (about Pa $O_{2}$ 400 mmHg). Myeloperoxidase (MPO), malondialdehyde (MDA), adenosine monophosphate (AMP), and troponin-T (TnT) concentrations in coronary sinus blood were determined at pre- and post-CPB. Total leukocyte and neutrophil counts in arterial blood were measured at the before, during, and after CPB. Lactate concentration in mixed venous blood was analyzed during CPB, and cardiac index (Cl) and pulmonary vascular