• Herbal Formula Science
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• v.28 no.1
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• pp.63-70
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• 2020

Objectives : The purpose of this study was to investigate the anti-cancer effects of 18α-Glycyrrhetinic acid (18α-GA), a hydrolyzed metabolite of glycyrrhizin, in AGS human gastric adenocarcinoma cells. Methods : We used human gastric adenocarcinoma cell line, AGS cells. We examined cell death by MTT assay and caspase 3 and 9 assay with 18α-GA. To examine the inhibitory effects of 18α-GA, sub-G1 analysis was done the AGS cells after 24 hours with 18α-GA. Also, to investigate the inhibitory mechanisms of 18α-GA, mitogen-activated protein kinase pathways and reactive oxygen species (ROS) generation were examined. Results : 1. 18α-GA inhibited the growth of AGS cells in a dose-dependent fashion. 2. Sub-G1 fractions were significantly and dose-dependently increased by 18α-GA. 3. 18α-GA increased the caspase 3 and 9 activities in AGS cells. 4. 18α-GA inhibited proliferation of AGS cells via the modulation of c‑Jun N‑terminal kinase (JNK) signaling pathways, which results in the induction of apoptosis. 5. 18α-GA enhanced ROS accumulation in AGS cells. Conclusions : Our findings provide insight into unraveling the effects of 18α-GA in human gastric adenocarcinoma cells and developing therapeutic agents against gastric cancer.

• IMMUNE NETWORK
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• v.10 no.6
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• pp.212-218
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• 2010

Backgroud: The stem bark of Kalopanax pictus (KP) has been used in traditional medicine to treat rheumatoidal arthritis, neurotic pain and diabetes mellitus in China and Korea. In this study, the mechanism responsible for anti-inflammatory effects of KP was investigated. Methods: We examined the effects of KP on NO production, nitric oxide synthase (iNOS) and HO-1 expression, NF-${\kappa}B$, Nrf2 and MAPK activation in mouse peritoneal macrophages. Results: The aqueous extract of KP inhibited LPS-induced NO secretion as well as inducible iNOS expression, without affecting cell viability. KP suppressed LPS-induced NF-${\kappa}B$ activation, phosphorylation and degradation of $I{\kappa}B-{\alpha}$, phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK). Furthermore, KP induced HO-1 expression and Nrf2 nuclear translocation. Conclusion: These results suggest that KP has the inhibitory effects on LPS-induced NO production in macrophages through NF-${\kappa}B$ suppression and HO-1 induction.

• Journal of Physiology & Pathology in Korean Medicine
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• v.28 no.1
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• pp.45-52
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• 2014

Hoesaeng-san is known to be effective for treating diarrhea and vomiting. However the therapeutic mechanism of Hoesaeng-san is still not well understood. The aim of the present study was to demonstrate the effects of Hoesaeng-san ethanol extract (HSSEE) on the expression of pro-inflammatory cytokines, as well as to elucidate its mechanism of action in the human mast cell line (HMC-1). Mast Cell were stimulated with phorbol 12-myristate 13-acetate (PMA) plus A23187 in the presence or absence of HSSEE. To study the possible effects of HSSEE, ELISA, RT-PCR, Western blot analysis were used in this study. HSSEE significantly inhibited the PMA plus A23187-induction of inflammatory cytokines such as tumor necrosis factor (TNF)-${\alpha}$, interleukin (IL)-6 and IL-8. In activated HMC-1 cells, phosphorylation of extra-signal response kinase (ERK) 1/2 and c-jun n-terminal kinase (JNK)1/2 decreased after treatment with HSSEE. Moreover HSSEE inhibited PMA plus A23187-induced nuclear factor (NF)-${\kappa}B$ activation and $I{\kappa}B$ degradation. HSSEE suppressed the expression of TNF-${\alpha}$, IL-6, IL-8 through a decrease in the ERK 1/2 and JNK 1/2, as well as activation of NF-${\kappa}B$. These results indicated that HSSEE exerted a regulatory effect on inflammatory reactions mediated by mast cells.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2004.04a
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• pp.3-10
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• 2004

Oxidative stress is a constant threat to all living organisms and an immense repertoire of cellular defense systems is being employed by most pro- and eukaryotic systems to eliminate or to attenuate oxidative stress. Ischemia and reperfusion is characterized by both a significant oxidative stress and characteristic changes in the antioxidant defense. Heme oxigenase-l (HO-l) is up-regulated by various stimuli including oxidative stress so that it is thought to participate in general cellular defense mechanisms against ischemic injury in mammalian cells. Higenamine, an active ingredient of Aconite tuber, has been shown to have antioxidant activity along with inhibitory action of inducible nitric oxide synthase (iNOS) expression in various cells. In the present study, we investigated whether higenamine and related analogs protect cells from oxidative cellular injuries by modulating antioxidant enzymes, such as HO-l, MnSOD etc. R-form of YS-51 was the most potent inducer of HO-l in bovine endothelial cells, which inhibited apoptotic cell death by H$_2$O$_2$. HO-1 induction by YS 51 was mediated by PI3 kinase activation in which PKA- as well as PKG pathway is considered as important regulators. YS-51 also induced Mn-SOD mRNA expression by activating c-jun N-terminal kinase in endothelial cells and Hela cells. In ROS 17/2.1 cells, higenamine and enetiomers of related compounds inhibited iNOS expression by cytokine mixtures. Taken together, higenamine and related compounds can be developed as possible protective agents from oxidative cell injury or death.

• IMMUNE NETWORK
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• v.14 no.6
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• pp.307-320
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• 2014

Mycobacterium scrofulaceum is an environmental and slow-growing atypical mycobacterium. Emerging evidence suggests that M. scrofulaceum infection is associated with cervical lymphadenitis in children and pulmonary or systemic infections in immunocompromised adults. However, the nature of host innate immune responses to M. scrofulaceum remains unclear. In this study, we examined the innate immune responses in murine bone marrow-derived macrophages (BMDMs) infected with different M. scrofulaceum strains including ATCC type strains and two clinically isolated strains (rough and smooth types). All three strains resulted in the production of proinflammatory cytokines in BMDMs mediated through toll-like receptor-2 and the adaptor MyD88. Activation of MAPKs (extracellular signal-regulated kinase 1/2, and p38, and c-Jun N-terminal kinase) and nuclear receptor (NF)-${\kappa}B$ together with intracellular reactive oxygen species generation were required for the expression of proinflammatory cytokines in BMDMs. In addition, the rough morphotypes of M. scrofulaceum clinical strains induced higher levels of proinflammatory cytokines, MAPK and NF-${\kappa}B$ activation, and ROS production than other strains. When mice were infected with different M. scrofulaceum strains, those infected with the rough strain showed the greatest hepatosplenomegaly, granulomatous lesions, and immune cell infiltration in the lungs. Notably, the bacterial load was higher in mice infected with rough colonies than in mice infected with ATCC or smooth strains. Collectively, these data indicate that rough M. scrofulaceum induces higher inflammatory responses and virulence than ATCC or smooth strains.

• Preventive Nutrition and Food Science
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• v.15 no.3
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• pp.206-212
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• 2010

Codium fragile (CF) is an edible green alga consumed as a traditional food source in Korea. In this study, the ethanol extract of CF was evaluated to determine if it has anti-inflammatory activity. Lipopolysaccharide (LPS), a toxin from bacteria, is a potent inducer of inflammatory cytokines, such as tumor necrosis factor (TNF)-$\alpha$ and interleukin (IL)-6. Therefore, we studied whether CF extracts have an anti-inflammatory effect in LPS-induced murine macrophage cell lines (RAW 264.7). In the present study, IL-6 production was measured using an enzyme-linked immunosorbent assay (ELISA), prostaglandin $E_2$($PGE_2$) production was measured using the EIA kit, and cyclooxygenase (COX)-2 and mitogen-activated protein kinase (MAPK) activation were determined by Western blot analysis. IL-6 mRNA, COX-2 mRNA and iNOS mRNA expression were measured using reverse transcription-polymerase chain reaction (RT-PCR). The results indicated that CF extracts inhibit LPS-induced IL-6, NO and PGE2 production in a dose-dependent manner, as well as expression of iNOS and COX-2. CF extracts significantly inhibited LPS-induced c-Jun N-terminal kinase (JNK) 1/2 phosphorylation. Taken together, these findings may help elucidate the mechanism by which CF modulates RAW 264.7 cell activation under inflammatory conditions.

• Biomolecules & Therapeutics
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• v.28 no.5
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• pp.423-430
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• 2020

Telmisartan is an angiotensin-II receptor blocker and acts as a selective modulator of peroxisome proliferator-activated receptor gamma (PPARγ). Several studies have demonstrated that telmisartan ameliorates depression and memory dysfunction and reduces brain inflammation. We hypothesized that the beneficial effects of telmisartan on brain could be due to modulation of the blood-brain barrier (BBB) function. Here, we examined the effect of telmisartan on tumor necrosis factor alpha (TNF-α)-induced expression of intercellular adhesion molecule 1 (ICAM-1) which plays an important role in leukocyte transcytosis through the BBB. Telmisartan blocked TNF-α-induced ICAM-1 expression and leukocyte adhesion in U87MG human glioma cells but showed no effect on human brain microvascular endothelial cells. In U87MG cells, a PPAR antagonist, GW9662 did not block the effect of telmisartan on ICAM1 expression but rather potentiated. Moreover, GW9662 caused no change in TNF-α-induced ICAM-1 expression, suggesting no implication of PPARγ in the telmisartan effect. Further studies showed that telmisartan blocked TNF-α-induced activation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and nuclear factorkappa B (NF-κB). In contrast, inhibitors of JNK, ERK1/2 and NF-κB but not p38, blocked ICAM-1 expression induced by TNF-α. Thus, our findings suggest that the beneficial effect of telmisartan is likely due to the reduction of astrocytic ICAM1 expression and leukocytes adhesion to astrocytes, and that this response was mediated by the inhibition of JNK/ERK1/2/NF-κB activation and in the PPAR-independent manner. In conclusion, this study enhances our understanding of the mechanism by which telmisartan exerts the beneficial brain function.

• The Journal of Korean Obstetrics and Gynecology
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• v.21 no.4
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• pp.36-48
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• 2008

Purpose: The purpose of this study is to investigate anti-inflammatory effect and immune responses of aqueous extract from Fructus Chaenomelis (FC). Methods: We studied anti-inflammatory effect by means of examining the production of NO(nitric oxide) and expressions of pro-inflammatory cytokine (TNF-$\alpha$(tumor necrosis factor-alpha), IL(Interleukin)-6, IL-12) in the LPS-induced peritoneal macrophages of mice. Also, The western blot analysis has been done to look into the mechanism of anti-inflammatory effect. Results: 1. The FC extract did not have any cytotoxicity in the peritoneal macrophages. 2. The FC extract inhibits the productions of NO, IL-6. IL-12 in the LPS-stimulated peritoneal macrophages of mice, but not of TNF-$\alpha$. 3. The FC extract inhibits the activation of NF-${\kappa}B$(nuclear factor-kappa B) by keeping $I{\kappa}B-\alpha$(inhibitory kappa B-alpha) from degradating, but not of MAPKs(mitogen-activated protein kinases) such as ERK(extracelluar signa 1-regulated kinase), JNK(c-Jun N-terminal kinase), p38. Conclusion: These results show that FC extract inhibits the production of pro-inflammatory cytokines such as IL-6. IL-12. NO by inhibiting NF-${\kappa}B$ activation in the peritoneal macrophages of mice. In conclusion, this experiment suggests that FC extract may be effective for the treatment of acute and chronic inflammation including genitourinary infection.

• Korean Journal of Clinical Laboratory Science
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• v.54 no.3
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• pp.201-208
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• 2022

Neuroinflammation is defined as a neurological inflammation within the brain and the spinal cord. In neuroinflammation, microglia are the tissue-resident macrophages of the central nervous system, which act as the first line of defense against harmful pathogens. Dexmedetomidine (Dex) has an anti-inflammatory effect in many neurological conditions. Additionally, the microRNA-30a-5p (miR-30a-5p) mimic has been proven to be effective in macrophages in inflammatory conditions. This study aimed to investigate the synergistic anti-inflammatory effects of both miR-30a-5p and Dex in lipopolysaccharide (LPS)-induced BV2 cells. This study showed that miR-30a-5p and Dex decreased nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) translocation in LPS-induced BV2 cells. MiR-30a-5p and Dex alleviated tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), LPS-induced phosphorylation c-Jun N-terminal kinases (JNK), extracellular signal-regulated kinase (ERK) and p38. Also, the expression of the NOD-like receptor pyrin domain containing 3 inflammasome (NLRP3), cleaved caspase-1, and ASC was inhibited. Furthermore, LPS-stimulated nitric oxide (NO) production, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) expression were attenuated by Dex and miR-30a-5p. Our results indicate that a combination of Dex and miR-30a-5p, attenuates NF-κB activation, the mitogen-activated protein kinase (MAPK) signaling pathway, and inflammatory mediators involved in LPS-induced inflammation and inhibits the activation of the NLRP3 inflammasome in LPS-activated BV2 cells.

• BMB Reports
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• v.55 no.9
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• pp.447-452
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• 2022

Neurogenic differentiation 1 (NeuroD1) is an essential transcription factor for neuronal differentiation, maturation, and survival, and is associated with inflammation in lipopolysaccharide (LPS)-induced glial cells; however, the concrete mechanisms are still ambiguous. Therefore, we investigated whether NeuroD1-targeting miRNAs affect inflammation and neuronal apoptosis, as well as the underlying mechanism. First, we confirmed that miR-30a-5p and miR-153-3p, which target NeuroD1, reduced NeuroD1 expression in microglia and astrocytes. In LPS-induced microglia, miR-30a-5p and miR-153-3p suppressed pro-inflammatory cytokines, reactive oxygen species, the phosphorylation of c-Jun N-terminal kinase, extracellular-signal-regulated kinase (ERK), and p38, and the expression of cyclooxygenase and inducible nitric oxide synthase (iNOS) via the NF-κB pathway. Moreover, miR-30a-5p and miR-153-3p inhibited the expression of NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasomes, NLRP3, cleaved caspase-1, and IL-1β, which are involved in the innate immune response. In LPS-induced astrocytes, miR-30a-5p and miR-153-3p reduced ERK phosphorylation and iNOS expression via the STAT-3 pathway. Notably, miR-30a-5p exerted greater anti-inflammatory effects than miR-153-3p. Together, these results indicate that miR-30a-5p and miR-153-3p inhibit MAPK/NF-κB pathway in microglia as well as ERK/STAT-3 pathway in astrocytes to reduce LPS-induced neuronal apoptosis. This study highlights the importance of NeuroD1 in microglia and astrocytes neuroinflammation and suggests that it can be regulated by miR-30a-5p and miR-153-3p.