• The Korean Journal of Physiology and Pharmacology
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• v.23 no.6
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• pp.501-508
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• 2019

Rosmarinic acid (RA) is a natural polyphenolic compound that exists in many medicinal species of Boraginaceae and Lamiaceae. The previous studies have revealed that RA had therapeutic effects on hepatocellular carcinoma (HCC) in the H22-xenograft models by inhibiting the inflammatory cytokines and $NF-{\kappa}B$ p65 pathway in the tumor microenvironment. However, its molecular mechanisms of immunoregulation and pro-apoptotic effect in HCC have not been fully explored. In the present study, RA at 75, 150, and 300 mg/kg was given to H22 tumor-bearing mice via gavage once a day for 10 days. The results showed that RA can effectively inhibit the tumor growth through regulating the ratio of $CD4^+/CD8^+$ and the secretion of interleukin (IL)-2 and interferon-${\gamma}$, inhibiting the expressions of IL-6, IL-10 and signal transducer and activator of transcription 3, thereby up-regulating Bax and Caspase-3 and down-regulating Bcl-2. The underlying mechanisms involved regulation of immune response and induction of HCC cell apoptosis. These results may provide a more comprehensive perspective to clarify the anti-tumor mechanism of RA in HCC.

• Journal of Trauma and Injury
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• v.25 no.1
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• pp.17-24
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• 2012

Purpose: This study was performed to investigate whether therapeutic hypercapnia could attenuate systemic inflammatory responses in hemorrhagic shock in rats. Methods: Male Sprague-Dawley rats were mechanically ventilated and underwent pressure-controlled (mean arterial pressure: $38{\pm}1$ mmHg) hemorrhagic shock. At 10 minutes after the induction of hemorrhagic shock, the rats were divided into the normocapnia ($PaCO_2$=35-45 mmHg, n=10) and the hypercapnia ($PaCO_2$=60-70 mmHg) groups. The $PaCO_2$ concentration was adjusted by using the concentration of inhaled $CO_2$ gas. After 90 minutes of hemorrhagic shock, rats were resuscitated with shed blood for 10 minutes and were observed for 2 hours. The mean arterial pressure (MAP) and the heart rate were monitored continuously, and the results of arterial blood gas analyses, as well as the plasma concentrations of interleukin (IL)-6, IL-10, and nitrite/nitrate were compared between the normocapnia and the hypercapnia groups. Results: The MAP and the heart rate were not different between the two groups. The plasma concentration of IL-6 was significantly lower in the hypercapnia group than in the normocapnia group (p<0.05). The IL-10 concentration was not different and the IL-6 to IL-10 ratio was significantly lower in the hypercapnia group compared to the normocapnia group. The plasma nitrite/nitrate concentration of the hypercapnia group was lower than that of the normocapnia group. Conclusion: Therapeutic hypercapnia attenuates systemic inflammatory responses in hemorrhagic shock.

• The Korean Journal of Physiology and Pharmacology
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• v.9 no.1
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• pp.23-27
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• 2005

The present study was performed to investigate the effects of intra-articular injection of interleukin-1${\beta}$ (IL-1${\beta}$) on the formalin-induced temporomandibular joint (TMJ) pain. Under anesthesia, a 30-gauge needle was introduced into the right TMJ region for injection of formalin. Microinjection of 50 ${\mu}l$ of 5% formalin significantly produced noxious scratching behavioral response, and the scratching behavior lasted for 40 min. Although the responses produced by formalin injection were divided into two phases, the response of 1st phase did not significantly differ from the scratching behavior response in the saline-treated group. We examined the effects of intra-articular injection of IL-1${\beta}$ on the number of noxious behavioral responses produced by 50${\mu}l$ of 5% formalin injection. Intra-articular injection of 100 pg and 1 ng of IL-1${\beta}$ significantly increased the number of behavioral responses of the 2nd phase, while 10 pg of IL-1${\beta}$ did not change the formalin-induced behavioral responses. To investigate whether IL-1 receptor was involved in the intra-articular administration of IL-1${\beta}$-induced hyperalgesic response, IL-1 receptor antagonist (IL- ra, 50 ng) was administrated together with IL-1${\beta}$ injection. IL-1${\beta}$ receptor antagonist blocked IL-1${\beta}$- induced hyperalgesic response in the TMJ formalin test. These results suggest that intra-articular injection of IL-1${\beta}$ facilitated the transmission of nociceptive information in the TMJ area.

• The Korea Journal of Herbology
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• v.28 no.1
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• pp.33-42
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• 2013

Objective : Morus alba Linne Root Bark (MRAL) is a medicinal herb in Korean Medicine, known for its anti-inflammatory and anti-allergic properties. However, its mechanisms of action and the cellular targets have not yet been found and the study was developed to investigate the allergic suppressive effect of MRAL. The purpose of this study is to investigate the allergic suppressive effects of MRAL on activation of MC/9 mast cells. Methods : Cytotoxic activity of MRAL (50, 100, 200, 400 ${\mu}g/mL$) on MC/9 mast cells measured using EZ-Cytox cell viability assay kit (WST reagent). The levels of interleukin-5 (IL-5), IL-13 and IL-4, IL-5, IL-6, IL-13 mRNA expression were measured by enzyme-linked immunosorbent assay (ELISA) and real-time PCR respectively. The expression of transcription factors such as GATA-1, GATA-2, NFAT, AP-1 and NF-${\kappa}B$ p65 DNA binding activity were measured by western blot and electrophoresis mobility shift assay (EMSA). Results : Our results indicated that MRAL (50 ${\mu}g/mL$, 100 ${\mu}g/mL$) significantly inhibited PMA/Ionomycin-induced production of IL-5 and IL-13 and the expression of IL-4, IL-5, IL-6 and IL-13 mRNA in MC/9 mast cells. Moreover, MRAL (50 ${\mu}g/mL$, 100 ${\mu}g/mL$) inhibited PMA/Ionomycin-induced GATA-1, GATA-2, NFAT-1, NFAT-2, c-Fos protein expression and NF-${\kappa}B$ p65 DNA binding activity in MC/9 mast cells. Conclusions : In conclusion, we suspect the anti-allergenic activities of MRAL, may be related to the regulation of transcription factors GATA-1, GATA-2, NFAT-1, NFAT-2, c-Fos and NF-${\kappa}B$ p65 DNA binding assay causing inhibition of Th2 cytokines IL-5 and IL-13 in mast cells.

• Environmental Analysis Health and Toxicology
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• v.17 no.4
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• pp.325-332
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• 2002

A helper T(Th)1-mediated response is known to enhance cell -mediated immunity, while a Th2-mediated response is associated with the humoral immunity that if elevated IgE levels and eosinophilia. Prostaglandin (PG)E$_2$results in the decreased capability of Iymphocytes to produce Thl cytokines, with a shift toward a Th2 cytokine response. Chlorpyrifos (CPF) has been reported to impair the blastogenesis and response of T Iymphocytes. CPF also induces delayed febrile effects, which results from the activation of COX -PGE$_2$pathway. The purpose of this study is to determine the effort of CPF on the in vitro production of Th cytokines and the role of PGE$_2$on the CPF-induced production of Th cytokines. Splenocytes obtained from male BALB/c mice were pretreated with CPF(0.1, 1, 10 and 100$\mu$M) in the presence of absence of indomethacin or PGE$_2$for 12 h and then were incubated with concanavalin (Con) A for 48 h. These results showed that CPF remarkedly reduced the production of splenic interleukin (IL)-2 and interferon (IFN)-γ in a dose-dependent manner. CPF significantly increased the splenic IL-4 production at low doses (0.1 and 1$\mu$M) but did not affect at high doses (10 and 100 $\mu$M). Indomethacin reduced the CPF-decreased production of IL-2 and IFN-γ in a dose -dependent manner and significantly attenuated the production of IL-4 increased by CPF 0.1 $\mu$M. High dose of CPF significantly reduced the PGE$_2$-decreased production of IL-2 and IFN-γ, while the PGE$_2$- induced production of IL-4 was significantly enhanced by CPF 1 $\mu$M. These findings suggest that CPF nay down-regulate the immune response of Th 1 type by the suppressed production of IL-2 and IFN-γ, with a shift toward a Th2 cytokine response. The CPF-decreased production of Thl cytokines may not be mediated by endogenous PGE$_2$. Also, CPF may attenuate the exogenous PGE$_2$-decreased Th 1 immune response in a dose--dependent manner but may affect dose-independently the PGE$_2$-induced Th2 immune response.

• IMMUNE NETWORK
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• v.20 no.3
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• pp.27.1-27.11
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• 2020

Although various studies on predictive markers in the use of PD-1/PD-L1 inhibitors are in progress, only PD-L1 expression levels in tumor tissues are currently used. In the present study, we investigated whether baseline serum levels of IL-6 can predict the treatment response of patients with advanced non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 inhibitors. In our cohort of 125 NSCLC patients, the objective response rate (ORR) and disease control rate (DCR) were significantly higher in those with low IL-6 (<13.1 pg/ml) than those with high IL-6 (ORR 33.9% vs. 11.1%, p=0.003; DCR 80.6% vs. 34.9%, p<0.001). The median progression-free survival was 6.3 months (95% confidence interval [CI], 3.9-8.7) in the low IL-6 group, significantly longer than in the high IL-6 group (1.9 months, 95% CI, 1.6-2.2, p<0.001). The median overall survival in the low IL-6 group was significantly longer than in the high IL-6 group (not reached vs. 7.4 months, 95% CI, 4.8-10.0). Thus, baseline serum IL-6 levels could be a potential biomarker for predicting the efficacy and survival benefit of PD-1/PD-L1 inhibitors in NSCLC.

• Journal of Pharmacopuncture
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• v.5 no.1 s.8
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• pp.91-103
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• 2002

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. characterized by leukocyte infiltration, a chronic inflammation of the joint, a pannus formation and the extensive destruction of the 3Iticular caJ1ilage and bone. Several proinflammatory cytokines such as tumor necrosis factor-${\alpa}$(TNF-${\alpa}$), interleukin-1${\beta}$ (IL-1${\beta}$) and interleukin 6 (IL-6) have been implicated in the pathological mechanisms of synovial tissue proliferation, joint destruction and programmed cell death in rheumatoid joint. In the Korean traditional medicine, Hominis placenta (HP) as an herbal solution of herb-acupuncture has been widely used to treat the inflammatory diseases including RA. In order to study the medicinal effect of HP herb-acupuncture on rheumatoid joint, an adjuvant-induced arthritis (AlA) was generated by the injection of 1.5 mg uf Mycobactelium tuberculusis. emulsified in squalene, 10 the base of the tail of Sprague-Dawley(SD) rats. After onset stage of polyarthritis, HP was daily injected to the Zusanti (ST36) acupuncture points in both of rat lags and the expression pattems of cytokines such as TNF-{\alpa}$, IL-1${\beta}$, and 1L-6 at the knee joint were analyzed using immunostaining and RT-PCR. The HP herb-acupuncture was found to be effective to alleviate the arthritic symptums in adjuvant-induced arthritic rats as regards the joint appearance and the expression profiles of inflammatory cytokines. In conclusion, therapeutic effects of HP herb-acupuncture on the rat with AlA might be related to anti inflammatory activities of the hurb-acupuncture.

• The Korean Journal of Physiology and Pharmacology
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• v.2 no.4
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• pp.435-441
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• 1998

We examined effects of interleukin $1{\alpha}$ ($IL1{\alpha}$) and phorbol 12, 13 dibutyrate (PDB), an activator of protein kinase C, on mRNA for Prostaglandin H synthase (PGHS) and prostanoid production in cultured ovine meningeal fibroblasts. Immuno- and morphologically-identified fibroblasts were derived from cerebral cortex and white matter from fetal lambs (approximately 120 days gestation) and grown to confluence on glass coverslips in 12 well plates. Levels of prostaglandin $F_{2{\alpha}}$ and the stable hydrolysis product of prostacyclin (i.e., $6-keto-PGF_{1{\alpha}}$) were determined using enzyme immunoassay. Relative amounts of mRNA were determined by in situ hybridization using ovine cDNA for PGHS1. $IL1{\alpha}$ (10 ng/ml) increased mRNA levels over baseline by $62{\pm}19%$ (p＜0.05) at 60 min., $37{\pm}12%$ (NS) at 120 min., and $36{\pm}18%$ (NS) at 240 min (n=12). Levels of $6-keto-PGF_{1{\alpha}}$ were $148{\pm}18%$ pg/ml during baseline, $246{\pm}41%$ pg/ml at 60 min., $248{\pm}40%$ pg/ml at 120 min., and $259{\pm}62%$ pg/ml at 240 min (all p＜0.05) (n=12). $PGF_{2{\alpha}}$ was increased although it wasn't statistically significant. However, $IL1{\alpha}$ decreased $PGE_2$ level significantly (all p＜0.05). PDB $(10^{-6}M)$ increased mRNA levels over baseline by $25{\pm}6%$ after 30 min., $40{\pm}6%$ after 60 min., and $20{\pm}8%$ after 90 min. (n=9) (all p＜0.05). Levels of $6-keto-PGF_{1{\alpha}}$ were $200{\pm}43%$ pg/ml during baseline, $202{\pm}43%$ pg/ml after 30 min. (NS), $268{\pm}58%$ pg/ml after 60 min. (p＜0.05), and $296{\pm}60%$ pg/ml after 90 min. (p＜0.05) (n=9). Levels of $PGF_{2{\alpha}}$ were $178{\pm}26%$ pg/ml during baseline, $300{\pm}30%$ pg/ml after 30 min., $299{\pm}35%$ pg/ml after 60 min., and $355{\pm}32%$ pg/ml after 90 min (all p＜0.05) (n=6). Actinomycin-D (1 mg/ml) prevented increases in mRNA, $6-keto-PGF_{1{\alpha}}$, and $PGF_{2{\alpha}}$ at 60 min. for both $IL1{\alpha}$ and PDB. We conclude that cerebral fibroblasts are avid producers of prostanoids, and that enhanced production of PGHS is responsible for augmented $PGF_{2{\alpha}}$ and prostacyclin production in the presence of an activator of protein kinase C and for decreased $PGE_2$ and increased prostacyclin production in the presence of $IL1{\alpha}$.

• Journal of Korean Medicine Rehabilitation
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• v.26 no.3
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• pp.31-49
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• 2016

Objectives The study was designed to evaluate the healing effects of Joaguihwan (JGH) extract on Anti-oxidation, Anti-inflammatory in RAW 264.7 Cells and factors related with bone metabolism in skull fractured Rat. Methods The fracture healing effect of JGH was measured by scavenging activities of1,1-diphenyl-2-picryl-hydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid (ABTS) and nitric oxide (NO) in RAW 264.7 cells. The inhibitory effect against the production of inflammatory mediators including interleukin-$1{\beta}$ (IL-$1{\beta}$), interleukin-6 (IL-6), tumor necosis factors-${\alpha}$ (TNF-${\alpha}$) expression was inhibited in RAW 264.7 cells was experimented using JGH. The effects of JGH on healing fractured rats was measured by osteocalcin, calcitonin, CTXII, TGF-${\beta}$, BMP-2, Insulin, ALP in the serum. and was checked every 3 weeks from 0 week to 6week using x-ray. Results 1. DPPH free radica and ABTS scavenging activity of JGH were increased according to concentration of JGH in RAW 264.7 Cells. 2. In the experiment, NO, IL-$1{\beta}$, IL-6, TNF-${\alpha}$ all showed decrease, in general. Especially NO and IL-$1{\beta}$ showed significantly decrease at a concentration of 10, 100 (${\mu}g/ml$). 3. In the production of osteocalcin in the serum, JGH 200, 400 mg/kg experimental group showed significant increased effect at 2 weeks. 4. In the production of calcitonin in the serum. JGH 200 mg/kg experimental group showed significant increased effect at 4, 6 weeks. JGH 400 mg/kg experimental group showed significant increased effect at 2, 4, 6 weeks. 5. In the production of CTX, TGF-${\beta}$, BMP-2 in the serum, experimental group showed increased effect. but no significant effect. 6. In the production of insulin in the serum. JGH 200, 400 mg/kg experimental group showed significant decrease effect at 2, 4, 6 weeks. 7. In the production of ALP in the serum. JGH 200 mg/kg experimental group showed significant increased effect at 2, 4, 6 weeks. JGH 400 mg/kg experimental group showed significant increased effect at 4, 6 weeks. 8. In the change of X-ray, the experimental group showed better healing effects on skull fractured rats than control group. Conclusions From above results, JGH showed healing effect on Anti-oxidation, Anti-inflammatory in RAW 264.7 Cells, factors related with bone metabolism in the serum of skull fractured rat and x-ray, which is expected to be applied in clinics.

• The Journal of Korean Medicine
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• v.35 no.4
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• pp.1-9
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• 2014

Objectives: This study was designed to find the effect of Phragmitis Rhizoma (PR) herbal-acupuncture solution on the inflammatory cytokine and chemokine secretion in human mast cell (HMC) and human alveolar epithelial cell 549 (A549) lines. Methods: Histamine levels in HMC after PR herbal-acupuncture solution treatment were measured with ELISA. Other cytokines and chemokines levels such as interleukin 8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), and chemokine (C-C motif) ligand 5 (Ccl5, RANTES) in A549 were measured with flow cytometry CBA system. Results: In the PR herbal-acupuncture solution treatment group, the expression of histamine, IL-8, MPC-1, Ccl5, and RANTES decreased significantly. Conclusions: The results support that PR herbal-acupuncture solution had a suppressive effect on cytokine-induced inflammation.