• The Korean Journal of Physiology and Pharmacology
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• 제5권1호
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• pp.41-46
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• 2001

To investigate the mutual relationship between angiotensin II (Ang II) and nitric oxide (NO) in paraventricular nucleus (PVN), Ang II receptor type Ia $(AT_{1A}),$ type Ib $(AT_{1B}),$ endothelial constitutive nitric oxide synthase (ecNOS), and neuronal constitutive nitric oxide synthase (ncNOS) mRNA levels of rat PVN were measured after unilateral carotid artery ligation. $AT_{1A}$ and $AT_{1B}$ mRNA levels were markedly elevated 6 hrs after unilateral carotid artery ligation. Losartan injection $(10\;{\mu}g/0.3\;{\mu}l)$ into the PVN augmented of the increment of $AT_{1A}$ and $AT_{1B}$ mRNAs It also increased ecNOS gene expression. In addition, $AT_{1B}$ mRNA levels increased after N-nitro-L-arginine methyl ester (L-NAME) injection $(50\;{\mu}g/0.3\;{\mu}l)$ into the PVN. These results suggest that Ang II and NO in the rat PVN may interplay, at least in part, through regulation of gene expression of ecNOS and $AT_{1B},$ respectively.

• Restorative Dentistry and Endodontics
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• 제27권5호
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• pp.543-551
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• 2002

Nitric oxide (NO) is a small molecule (mol. wt. 30 Da) and oxidative free radical. It is uncharged and can therefore diffuse freely within and between cells across membrane. Such characteristics make it a biologically important messenger in physiologic processes such as neurotransmission and the control of vascular tone. NO is also highly toxic and is known to acts as a mediator of cytotoxicity during host defense. NO is synthesized by nitric oxide synthase (NOS) through L-arginine/nitric oxide pathway which is a dioxygenation process. NO synthesis involves several participants, three co-substrates, five electrons, five co-factors and two prosthetic groups. Under normal condition, low levels of NO are synthesized by type I and III NOS for a short period of time and mediates many physiologic processes. Under condition of oxidant stress, high levels of NO are synthesized by type II NOS and inhibits a variety of metabolic processes and can also cause direct damage to DNA. Such interaction result in cytostasis, energy depletion and ultimately cell death. NO has the potential to interact with a variety of intercellular targets producing diverse array of metabolic effects. It is known that NO is involved in hemodynamic regulation, neurogenic inflammation, re-innervation, management of dentin hypersensitivity on teeth. Under basal condition of pulpal blood flow, NO provides constant vasodilator tone acting against sympathetic vasoconstriction. Substance P, a well known vasodilator, was reported to be mediated partly by NO, while calcitonin-gene related peptide has provided no evidence of its relation with NO. This review describes the roles of NO in dental pulp in addition to the known general roles of it.

• The Korean Journal of Pain
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• 제33권1호
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• pp.30-39
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• 2020

Background: This study examined the effects of gabexate mesilate on spinal nerve ligation (SNL)-induced neuropathic pain. To confirm the involvement of gabexate mesilate on neuroinflammation, we focused on the activation of nuclear factor-κB (NF-κB) and consequent the expression of proinflammatory cytokines and inducible nitric oxide synthase (iNOS). Methods: Male Sprague-Dawley rats were used for the study. After randomization into three groups: the sham-operation group, vehicle-treated group (administered normal saline as a control), and the gabexate group (administered gabexate mesilate 20 mg/kg), SNL was performed. At the 3rd day, mechanical allodynia was confirmed using von Frey filaments, and drugs were administered intraperitoneally daily according to the group. The paw withdrawal threshold (PWT) was examined on the 3rd, 7th, and 14th day. The expressions of p65 subunit of NF-κB, interleukin (IL)-1, IL-6, tumor necrosis factor-α, and iNOS were evaluated on the 7th and 14th day following SNL. Results: The PWT was significantly higher in the gabexate group compared with the vehicle-treated group (P < 0.05). The expressions of p65, proinflammatory cytokines, and iNOS significantly decreased in the gabexate group compared with the vehicle-treated group (P < 0.05) on the 7th day. On the 14th day, the expressions of p65 and iNOS showed lower levels, but those of the proinflammatory cytokines showed no significant differences. Conclusions: Gabexate mesilate increased PWT after SNL and attenuate the progress of mechanical allodynia. These results seem to be involved with the antiinflammatory effect of gabexate mesilate via inhibition of NF-κB, proinflammatory cytokines, and nitric oxide.

• 한방비만학회지
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• 제23권1호
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• pp.1-9
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• 2023

Objectives: Noni fruit juice (NFJ) is liquor extracted from Morinda citrifolia (noni) fruit and has been used as an herbal remedy in many countries. However, the NFJ's anti-adipogenic and anti-inflammatory effects on adipocytes are poorly understood. The purpose of this study was to explore the commercially standardized NFJ effects on lipid accumulation throughout 3T3-L1 preadipocytes differentiation and interleukin-1β (IL-1β)-mediated inducible nitric oxide synthase (iNOS) expression in 3T3-L1 preadipocytes. Methods: Cellular lipid accumulation and triglyceride (TG) content in differentiating 3T3-L1 preadipocytes were assessed subsequently via the Oil Red O staining and AdipoRed assay. MTS assay was used to examine NFJ cytotoxicity in (differentiating) 3T3-L1 preadipocytes. Immunoblotting and reverse transcriptase polymerase chain reaction analysis were used to measure the expression levels of target protein and mRNA in (differentiating) 3T3-L1 preadipocytes, respectively. Results: NFJ treatment at 150 μL/mL led to a substantial reduction of fat accumulation and TG content during 3T3-L1 adipogenesis with no discernable impact on the cell viability. Of note, while NFJ treatment (150 μL/mL) largely inhibited the CCAAT/enhancer-binding protein-α (C/EBP-α) and peroxisome proliferator-activated receptor-β (PPAR-β) protein expressions, it did not influence PPAR-γ in differentiating 3T3-L1 preadipocytes. Of interest, treatment with IL-1β at 20 ng/mL for 4 hours elicited in firm induction of iNOS mRNA expression in 3T3-L1 preadipocytes. However, NFJ treatment at 100 or 200 μL/mL greatly attenuated the IL-1β-induced iNOS mRNA expression in 3T3-L1 preadipocytes. Conclusions: NFJ has anti-adipogenic and anti-inflammatory effects on (differentiating) 3T3-L1 preadipocytes which are in part intervened via control of the expression of C/EBP-α, PPAR-β, and iNOS.

• Journal of Acupuncture Research
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• 제29권1호
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• pp.75-87
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• 2012

Objectives : The purpose of this study is to inquire into the effect of different concentrations of bee venom pharmacopuncture to inhibit genesis of pro-inflammatory cytokines and to inhibit nuclear factor (NF)-${\kappa}B$ activation on type II collagen induced arthritis. Methods : The experiment was divided into category of the normal group (NOR)-no treated group, control group (CON)-CIA (collagen induced arthritis) induced group, and 4,000 : 1 bee venom group (BV-L)- 4000:1 bee venom pharmacopuncture treated group after CIA, and 2000:1 bee venom group (BV-H)- 2,000 : 1 Bee venom pharmacopuncture treated group after CIA. RA was induced in the mice via injecting $50{\mu}{\ell}$ C II mixed CFA. The bee venom pharmacopuncture was applied on $ST_{35}$ for 19 days from the 3rd day of RA inducement. To research the effect on the expression of IKK ($I{\kappa}B$ kinase), iNOS (inducible nitric oxide synthase) & COX-2 (cyclooxygenase-2) mRNA, RT-PCR was performed on synovial membrane cells from the knee joint of CIA mice. Results : The PMA-induced $I{\kappa}B$ kinase (IKK), inducible nitric oxide synthase (iNOS) and cyclooxygenase -2 (COX-2) mRNA expression were dose-dependantly decreased in bee venom treated with synoviocytes. In mice treated with bee venom pharmacopuncture, foot thickness and the damage of synovial membranes of the joint was lessened, and the activation of RA-related pro-inflammatory cytokines such as MIF, TNF-${\alpha}$ and MMP-9 was significantly decreased. The activation of iNOS and COX-2 was suppressed by the inhibition of NF-${\kappa}B$. In addition, each data was shown that 2,000 : 1 bee venom pharmacopuncture was more effective than 4,000 : 1 bee venom pharmacopuncture. Conclusions : It is speculated that bee venom pharmacopuncture has the therapeutic effect of palliating the damage of the synovial membrane and inflammation on RA by suppressing of NF-${\kappa}B$ activation.

• Childhood Kidney Diseases
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• 제15권2호
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• pp.125-137
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• 2011

목적: 일반적으로 남자는 여자에 비해 만성 신장병의 발병이 많고 말기 신부전으로의 진행이 더 흔한 것으로 알려져 있다. 본 연구는 일측성 요관 폐쇄를 가진 생쥐에서 신섬유화에 대한 성별과 성호르몬의 효과를 규명하기 위해 시행되었다. 방법: 일측성 완전 요관 폐쇄 7일째 암컷과 수컷 생쥐의 신장에서 ${\alpha}$-smooth muscle actin (${\alpha}$-SMA)의 발현을 측정한 후, 암컷 생쥐에서 난소를 제거하거나 제거 후 다시 $17{\beta}$-estradiol을 보충하여 나타나는 신섬유화 정도를 비교 분석하였다. 결과:일측성 요관 폐쇄를 가진 암컷 신장의 ${\alpha}$-SMA의 발현이 수컷 신장에 비해 현저히 낮았다. 난소 제거와 $17{\beta}$-estradiol의 보충은 일측성 요관 폐쇄를 가진 암컷 신장의 안지오텐신 II 1형 수용체의 발현에는 의미 있는 영향을 주지 않았지만, 안지오텐신 II 2형 수용체의 발현은 정상 암컷과 난소 제거 후 $17{\beta}$-estradiol를 보충한 암컷에서 현저히 증가되었다. 또한, inducible nitric oxide synthase (iNOS) 역시 유사한 변화를 보였다. 결론 : 여성은 폐쇄성 요로병증에서 신섬유화에 대한 저항성과 연관이 있으며 이러한 성별의 차이는 $17{\beta}$-estradiol에 의한 안지오텐신 II 2형 수용체와 iNOS의 발현 증가와 연관이 있을 것으로 사료된다.

• 한국수산과학회지
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• 제55권6호
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• pp.867-874
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• 2022

Osteoarthritis (OA) is an inflammatory disease due to wear caused by the continuous use of cartilage. Although many drugs for treating OA are being studied, they have side effects, such as digestive disorders and cardiovascular diseases. Glucosamine, a drug derived from natural products, is known to be less effective. Therefore, the marine organism, Sargassum fulvellum, was studied to determine whether it contains substances with a chondroprotective effect on the inflammatory response of chondrocytes induced by interleukin-1β (IL-1β). A 30% ethanol extract of S. fulvellum (SF30%EtOH) has therapeutic and few side effects. We first confirmed the presence of nitric oxide (NO) and the expression of inducible nitric oxide synthase (iNOS), which is expressed during inflammatory reactions. We then examined the expression of collagen type II, which is the main component of the extracellular matrix and cartilage. Finally, the expression of extracellular matrix degrading enzymes, MMPs and ADAMTS-4 and -5, was confirmed. The results showed that SF30%EtOH reduced the expression levels of NO, iNOS, MMPs, and ADAMT-4 and -5, and increased the expression level of collagen type II in chondrocytes induced with IL-1β. Therefore, SF30%EtOH has a chondroprotective effect against inflammation, indicating its potential use for the prevention and treatment of OA.

• Journal of Ginseng Research
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• 제35권2호
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• pp.200-208
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• 2011

Ginsenoside (G) $Rp_1$ is a ginseng saponin derivative with anti-cancer and anti-inflammatory activities. In this study, we examined the mechanism by which G-$Rp_1$ inhibits inflammatory responses of cells. We did this using a strategy in which DNA constructs containing cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) promoters were transfected into HEK293 cells. G-$Rp_1$ strongly inhibited the promoter activities of COX-2 and iNOS; it also inhibited lipopolysaccharide induced upregulation of COX-2 and iNOS mRNA levels in RAW264.7 cells. In HEK293 cells G-$Rp_1$ did not suppress TANK binding kinase 1-, Toll-interleukin-1 receptor-domain-containing adapter-inducing interferon-${\beta}$ (TRIF)-, TRIF-related adaptor molecule (TRAM)-, or activation of interferon regulatory factor (IRF)-3 and nuclear factor (NF)-${\kappa}$B by the myeloid differentiation primary response gene (MyD88)-induced. However, G-$Rp_1$ strongly suppressed NF-${\kappa}$B activation induced by I${\kappa}$B kinase (IKK)${\beta}$ in HEK293 cells. Consistent with these results, G-$Rp_1$ substantially inhibited IKK${\beta}$-induced phosphorylation of $I{\kappa}B{\alpha}$ and p65. These results suggest that G-$Rp_1$ is a novel anti-inflammatory ginsenoside analog that can be used to treat IKK${\beta}$/NF-${\kappa}$B-mediated inflammatory diseases.

• BMB Reports
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• 제54권10호
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• pp.516-521
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• 2021

Although arginase primarily participates in the last reaction of the urea cycle, we have previously demonstrated that arginase II is an important cytosolic calcium regulator through spermine production in a p32-dependent manner. Here, we demonstrated that rhaponticin (RPT) is a novel medicinal-plant arginase inhibitor and investigated its mechanism of action on Ca²⁺-dependent endothelial nitric oxide synthase (eNOS) activation. RPT was uncompetitively inhibited for both arginases I and II prepared from mouse liver and kidney. It also inhibited arginase activity in both aorta and human umbilical vein endothelial cells (HUVECs). Using both microscope and FACS analyses, RPT treatments induced increases in cytosolic Ca²⁺ levels using Fluo-4 AM as a calcium indicator. Increased cytosolic Ca²⁺ elicited the phosphorylations of both CaMKII and eNOS Ser1177 in a time-dependent manner. RPT incubations also increased intracellular L-arginine (L-Arg) levels and activated the CaMKII/AMPK/Akt/eNOS signaling cascade in HUVECs. Treatment of L-Arg and ABH, arginase inhibitor, increased intracellular Ca²⁺ concentrations and activated CaMKII-dependent eNOS activation in ECs of WT mice, but, the effects were not observed in ECs of inositol triphosphate receptor type 1 knockout (IP3R1^-/-) mice. In the aortic endothelium of WT mice, RPT also augmented nitric oxide (NO) production and attenuated reactive oxygen species (ROS) generation. In a vascular tension assay using RPT-treated aortic tissue, cumulative vasorelaxant responses to acetylcholine (Ach) were enhanced, and phenylephrine (PE)-dependent vasoconstrictive responses were retarded, although sodium nitroprusside and KCl responses were not different. In this study, we present a novel mechanism for RPT, as an arginase inhibitor, to increase cytosolic Ca²⁺ concentration in a L-Arg-dependent manner and enhance endothelial function through eNOS activation.

• The Korean Journal of Physiology and Pharmacology
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• 제21권3호
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• pp.353-360
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• 2017

Several human diseases have been associated with mitochondrial voltage-dependent anion channel-1 (VDAC1) due to its role in calcium ion transportation and apoptosis. Recent studies suggest that VDAC1 may interact with endothelium-dependent nitric oxide synthase (eNOS). Decreased VDAC1 expression may limit the physical interaction between VDAC1 and eNOS and thus impair nitric oxide production, leading to cardiovascular diseases, including pulmonary arterial hypertension (PAH). In this report, we conducted meta-analysis of genome-wide expression data to identify VDAC1 influenced genes implicated in PAH pathobiology. First, we identified the genes differentially expressed between wild-type and Vdac1 knockout mouse embryonic fibroblasts in hypoxic conditions. These genes were deemed to be influenced by VDAC1 deficiency. Gene ontology analysis indicates that the VDAC1 influenced genes are significantly associated with PAH pathobiology. Second, a molecular signature derived from the VDAC1 influenced genes was developed. We suggest that, VDAC1 has a protective role in PAH and the gene expression signature of VDAC1 influenced genes can be used to i) predict severity of pulmonary hypertension secondary to pulmonary diseases, ii) differentiate idiopathic pulmonary artery hypertension (IPAH) patients from controls, and iii) differentiate IPAH from connective tissue disease associated PAH.