• The Korean Journal of Physiology and Pharmacology
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• v.13 no.4
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• pp.309-313
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• 2009

Spontaneous hypertensive rats (SHR) are an established model of genetic hypertension. Vascular smooth muscle cells (VSMC) from SHR proliferate faster than those of control rats (Wistar-Kyoto rats; WKY). We tested the hypothesis that induction of heme oxygenase (HO)-1 induced by aprotinin inhibits VSMC proliferation through cell cycle arrest in hypertensive rats. Aprotinin treatment inhibited VSMC proliferation in SHR more than in normotensive rats. These inhibitory effects were associated with cell cycle arrest in the G1 phase. Tin protoporphyrin IX (SnPPIX) reversed the anti-proliferative effect of aprotinin in VSMC from SHR. The level of cyclin D was higher in VSMC of SHR than those of WKY. Aprotinin treatment downregulated the cell cycle regulator, cyclin D, but upregulated the cyclin-dependent kinase inhibitor, p21, in VSMC of SHR. Aprotinin induced HO-1 in VSMC of SHR, but not in those of control rats. Furthermore, aprotinin-induced HO-1 inhibited VSMC proliferation of SHR. Consistently, VSMC proliferation in SHR was significantly inhibited by transfection with the HO-1 gene. These results indicate that induction of HO-1 by aprotinin inhibits VSMC proliferation through cell cycle arrest in hypertensive rats.

• Archives of Pharmacal Research
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• v.25 no.3
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• pp.343-348
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• 2002

Carbon monoxide (CO) are produced by heme oxygenase (HO), and HO was detected in hypothalamus. However, the roles of CO produced in hypothalamus was not fully elucidated. So, we tested the effects of CO on body temperature because preoptic-anterior hypothalamus was known as the presumptive primary fever-producing site. CO-saturated aCSF ($4{\;}{\mu}l$, i.c.v.) and hemin ($10{\;}{\mu}g$, i.c.v.) elicited marked febrile response. Pretreatment with indomethacin completely inhibited CO- and hemin-induced fever. Zinc protoporphyrin-IX ($10{\;}{\mu}g$, i.c.v.) or ODQ ($50{\;}{\mu}g$, i.c.v.) partially reduced hemin-induced febrile response. Dibutyryl-cGMP ($100{\;}{\mu}g$, i.c.v.) produced profound febrile response and this febrile response was attenuated by indomethacin. These results indicate that endogenous CO may have a role as a pyrogenic mediator in CNS and CO-mediated pyresis is dependent on prostaglandin production and partially on activation of soluble guanylate cyclase.

• Bulletin of the Korean Chemical Society
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• v.30 no.1
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• pp.177-182
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• 2009

We present the geminate rebinding kinetics measurements of CO to 2-methylimidazole (2-MeIm) bound ferrous protoporphyrin- IX (FePPIX) in alkaline glycerol/water mixtures at 293 K after photolysis. The kinetics was probed by monitoring the CO stretching mode using femtosecond vibrational spectroscopy. When 2-MeIm is used in excess, heme dimers that typically form in low viscosity solutions disappear as the viscosity of the solvent increases. Heme aggregates formed in low viscosity solutions turn monomeric as more 2-MeIm is added, suggesting that 6-coordinated heme, including a strong proximal histidine tends to be in the monomeric form. The vibrational band of CO in the 2-MeIM-FePPIX-CO is well described by a single Gaussian function centered at 1958 $cm^-1$ and 28 $cm^-1$ full width at half maximum. The efficiency and rate of the geminate rebinding of CO to the heme increase with viscosity of the solvent, suggesting that retention of the dissociated CO near the heme, for a longer period by the viscous solvent media, accelerates rebinding.

• Journal of Society of Preventive Korean Medicine
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• v.12 no.3
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• pp.67-80
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• 2008

The pathobiologic process of arterial stenosis following balloon angioplasty continues to be an enigmatic problem in clinical settings. This study investigates the ability of demethoxycurcumin, a curcuminoid isolated from Radix Curcumae, to attenuate balloon injury-induced neointima(NI) formation in the rat carotid artery. It was found that demethoxycurcumin induced inducible heme oxygenase(HO-1) expression and inhibited dose-dependently cellular proliferation in rat vascular smooth muscle cells. Perivascular application of demethoxycurcumin immediately following injury significantly reduced NI area and NI thickness 2 weeks post-injury. Interestingly, treatment with tin-protoporphyrin IX, a HO inhibitor, reversed the effects of demethoxycurcumin on NI formation. These results implicate demethoxycurcumin as a potent new therapeutic agent that is capable of reducing post-angioplasty arterial stenosis through induction of the HO-1 expression.

• The Korean Journal of Physiology and Pharmacology
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• v.13 no.2
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• pp.123-129
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• 2009

Aprotinin is used clinically in cardiopulmonary bypass surgery to reduce transfusion requirements and the inflammatory response. The mechanism of action for the anti-inflammatory effects of aprotinin is still unclear. We examined our hypothesis whether inhibitory effects of aprotinin on cytokine-induced inducible nitric oxide synthase (iNOS) expression (IL-$l\beta$ plus TNF-$\alpha$), reactive oxygen species (ROS) generation, and vascular smooth muscle cell (VSMC) proliferation were due to HO-l induction in rat VSMCs. Aprotinin induced HO-l protein expression in a dose-dependent manner, which was potentiated during inflammatory condition. Aprotinin reduced cytokine mixture (CM)-induced iNOS expression in a dose dependent manner. Furthermore, aprotinin reduced CM-induced ROS generation, cell proliferation, and phosphorylation of JNK but not of P38 and ERK1/2 kinases. Aprotinin effects were reversed by pre-treatment with the HO-l inhibitor, tin protoporphyrin IX (SnPPIX). HO-l is therefore closely involved in inflammatory-stimulated VSMC proliferation through the regulation of ROS generation and JNK phosphorylation. Our results suggest a new molecular basis for aprotinin anti-inflammatory properties.

• Journal of Gastric Cancer
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• v.20 no.4
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• pp.355-375
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• 2020

Selective accumulation of a photosensitizer and the subsequent response in only the light-irradiated target are advantages of photodynamic diagnosis and therapy. The limited depth of the therapeutic effect is a positive characteristic when treating surface malignancies, such as peritoneal carcinomatosis. For photodynamic diagnosis (PDD), adjunctive use of aminolevulinic acid- protoporphyrin IX-guided fluorescence imaging detects cancer nodules, which would have been missed during assessment using white light visualization only. Furthermore, since few side effects have been reported, this has the potential to become a vital component of diagnostic laparoscopy. A variety of photosensitizers have been examined for photodynamic therapy (PDT), and treatment protocols are heterogeneous in terms of photosensitizer type and dose, photosensitizer-light time interval, and light source wavelength, dose, and dose rate. Although several studies have suggested that PDT has favorable effects in peritoneal carcinomatosis, clinical trials in more homogenous patient groups are required to identify the true benefits. In addition, major complications, such as bowel perforation and capillary leak syndrome, need to be reduced. In the long term, PDD and PDT are likely to be successful therapeutic options for patients with peritoneal carcinomatosis, with several options to optimize the photosensitizer and light delivery parameters to improve safety and efficacy.

• Asian-Australasian Journal of Animal Sciences
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• v.29 no.11
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• pp.1664-1674
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• 2016

This research analyzed the effect of ${\beta}$-glucan that is expected to alleviate the production of the inflammatory mediator in macrophagocytes, which are processed by the lipopolysaccharide (LPS) of Escherichia. The incubated layer was used for a nitric oxide (NO) analysis. The DNA-binding activation of the small unit of nuclear factor-${\kappa}B$ was measured using the enzyme-linked immunosorbent assay-based kit. In the RAW264.7 cells that were vitalized by Escherichia coli (E. coli) LPS, the ${\beta}$-glucan inhibited both the combatant and rendering phases of the inducible NO synthase (iNOS)-derived NO. ${\beta}$-Glucan increased the expression of the heme oxygenase-1 (HO-1) in the cells that were stimulated by E. coli LPS, and the HO-1 activation was inhibited by the tin protoporphyrin IX (SnPP). This shows that the NO production induced by LPS is related to the inhibition effect of ${\beta}$-glucan. The phosphorylation of c-Jun N-terminal kinases (JNK) and the p38 induced by the LPS were not influenced by the ${\beta}$-glucan, and the inhibitory ${\kappa}B-{\alpha}$ ($I{\kappa}B-{\alpha}$) decomposition was not influenced either. Instead, ${\beta}$-glucan remarkably inhibited the phosphorylation of the signal transducer and activator of transcription-1 (STAT1) that was induced by the E. coli LPS. Overall, the ${\beta}$-glucan inhibited the production of NO in macrophagocytes that was vitalized by the E. coli LPS through the HO-1 induction and the STAT1 pathways inhibition in this research. As the host immune response control by ${\beta}$-glucan weakens the progress of the inflammatory disease, ${\beta}$-glucan can be used as an effective immunomodulator.

• BMB Reports
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• v.41 no.2
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• pp.164-169
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• 2008

The tumor suppressor gene p53 regulates apoptotic cell death and the cell cycle. In this study, we investigated the role of p53 in nitric oxide (NO)-induced apoptosis in vascular smooth muscle cells (VSMCs). We found that the NO donor S-nitroso-N-acetyl-penicillamine (SNAP) increased apoptotic cell death in p53-deficient VSMCs compared with wild-type cells. The heme oxygen-ase (HO) inhibitor tin protoporphyrin IX reduced the resistance of wild-type VSMCs to SNAP-induced cell death. SNAP promoted HO-1 expression in both cell types. HO-2 protein was increased only in wild-type VSMCs following SNAP treatment; however, similar levels of HO-2 mRNA were detected in both cell types. SNAP significantly increased the levels of non-heme-iron and dinitrosyl iron-sulfur clusters in wild-type VSMCs compared with p53-deficient VSMCs. Moreover, pretreatment with FeSO4 and the carbon monoxide donor CORM-2, but not biliverdin, significantly protected p53-deficient cells from SNAP-induced cell death compared with normal cells. These results suggest that wild-type VSMCs are more resistant to NO-mediated apoptosis than p53-deficient VSMCs through p53-dependent up-regulation of HO-2.

• BMB Reports
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• v.46 no.8
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• pp.410-415
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• 2013

Adhesion molecules such as ICAM-1 are important in the infiltration of leukocytes into the site of inflammation. In this study, we investigated the inhibitory effects of curcumin on ICAM-1 expression and monocyte adhesiveness as well as its underlying action mechanism in the TNF-${\alpha}$-stimulated keratinocytes. Curcumin induced expression of heme oxygenase-1 (HO-1) in the human keratinocyte cell line HaCaT. In addition, curcumin induced Nrf2 activation in dose- and time-dependent manners in the HaCaT cells. Curcumin suppressed TNF-${\alpha}$-induced ICAM-1 expression and subsequent monocyte adhesion, which were reversed by the addition of tin protoporphyrin IX (SnPP), a specific inhibitor of HO-1, or HO-1 knockdown using siRNA. Furthermore, Nrf2 knockdown using siRNA reversed the inhibitory effect of curcumin on the TNF-${\alpha}$-induced ICAM-1 expression and adhesion of monocytes to keratinocytes. These results suggest that curcumin may exert its anti-inflammatory activity by suppressing the TNF-${\alpha}$-induced ICAM-1 expression and subsequent monocyte adhesion via expression of HO-1 in the keratinocytes.

• Proceedings of the Korean Institute of Information and Commucation Sciences Conference
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• 2015.10a
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• pp.958-960
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• 2015

Sickle cells possess a unique combination of traits that may enable their use as models for novel synthetic tumor targeting controlled release drug carriers with the ability to treat disseminated tumors in advanced metastatic disease. In this study, we assess the ability of light-activated release sickle cells to enhance tumor delivery of the fluorescent dye calcein by delayed photolysis controlled release compared to free systemic administration of calcein. Sickle cells from mouse models of the disease were shown to preferentially accumulate in tumors compared to adjacent tissue, in 4T1 tumors in mice on a time scale about 12 hours. Sickle cells photosensitized with protoporphyrin IX achieved delayed release of 50% of contents 8-16 hours after photoactivation, which was deemed useful for in vivo delivery of cargo to tumors given the tumor accumulation time of the sickle cells. Sickle cells may be useful as a model for new synthetic drug carrier particles with delayed photolysis controlled release properties.