• Journal of Microbiology and Biotechnology
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• v.28 no.4
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• pp.542-550
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• 2018

Heat shock protein 90 (Hsp90) is treated as a molecular therapeutic target for the prevention and treatment of cancer. Geldanamycin (GA) was the first identified natural Hsp90 inhibitor, but hepatotoxicity has limited its clinical application. Nevertheless, a new GA analog (WK-88-1) with the non-benzoquinone skeleton, obtained from genetically engineered Streptomyces hygroscopicus, was found to have anticancer activity against two human breast cancer cell lines. WK-88-1 produced concentration-dependent inhibition of cell proliferation, cell cycle arrest, and apoptosis in estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 cell lines. Detailed analysis showed that WK-88-1 downregulated some key cell cycle molecules (CDK1 and cyclin B1) and lead to $G_2/M$ cell cycle arrest. Further studies also showed that WK-88-1 could induce human breast cancer cell apoptosis by downregulating Hsp90 client proteins (Akt, p-Akt, IKK, c-Raf, and Bcl-2), decreasing the ATP level, increasing reactive oxygen species production, and lowering the mitochondrial membrane potential. Meanwhile, we discovered that WK-88-1 significantly decreased the levels of Her-2 and $ER-{\alpha}$ in MCF-7 cells but not in MDA-MB-231 cells. In addition, WK-88-1 significantly increased caspase-3, -8, and -9 activities and the cleavage of PARP in a concentration-dependent manner (with the exception of caspase-3 and PARP in MCF-7 cells). Taken together, our preliminary results suggest that WK-88-1 has the potential to play a role in breast cancer therapy.

• BMB Reports
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• v.51 no.6
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• pp.308-313
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• 2018

Small-molecule inhibitors are widely used to treat a variety of inflammatory diseases. In this study, we found a novel anti-inflammatory compound, 1-[(2R,4S)-2-methyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-1-yl]prop-2-en-1-one (MPQP). It showed strong anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. These effects were exerted through the inhibition of the production of NO and pro-inflammatory cytokines, such as interleukin (IL)-6, $IL-1{\beta}$, and tumor necrosis $factor-{\alpha}$ ($TNF-{\alpha}$). Furthermore, MPQP decreased the expression levels of inducible NO synthase (iNOS) and cyclooxygenase 2 (COX-2). Additionally, it mediated the inhibition of the phosphorylation of p38, c-Jun N-terminal kinase (JNK), the inhibitor of ${\kappa}B{\alpha}$ ($I{\kappa}B{\alpha}$), and their upstream kinases, $I{\kappa}B$ kinase (IKK) ${\alpha}/{\beta}$, mitogen-activated protein kinase kinase (MKK) 3/6, and MKK4. Furthermore, the expression of IL-1 receptor-associated kinase 1 (IRAK1) that regulates $NF-{\kappa}B$, p38, and the JNK signaling pathways, was also increased by MPQP. These results indicate that MPQP regulates the IRAK1-mediated inflammatory signaling pathways by targeting IRAK1 or its upstream factors.

• Molecules and Cells
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• v.25 no.2
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• pp.253-257
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• 2008

Acrolein is a highly electrophilic ${\alpha},{\beta}$-unsaturated aldehyde present in a number of environmental sources, especially cigarette smoke. It reacts strongly with the thiol groups of cysteine residues by Michael addition and has been reported to inhibit nuclear $factor-{\kappa}B$ ($NF-{\kappa}B$) activation by lipopolysaccharide (LPS). The mechanism by which it inhibits $NF-{\kappa}B$ is not clear. Toll-like receptors (TLRs) play a key role in sensing microbial components and inducing innate immune responses, and LPS-induced dimerization of TLR4 is required for activation of downstream signaling pathways. Thus, dimerization of TLR4 may be one of the first events involved in activating TLR4-mediated signaling pathways. Stimulation of TLR4 by LPS activates both myeloid differential factor 88 (MyD88)- and TIR domain-containing adapter inducing $IFN{\beta}$ (TRIF)-dependent signaling pathways leading to activation of $NF-{\kappa}B$ and IFN-regulatory factor 3 (IRF3). Acrolein inhibited $NF-{\kappa}B$ and IRF3 activation by LPS, but it did not inhibit $NF-{\kappa}B$ or IRF3 activation by MyD88, inhibitor ${\kappa}B$ kinase $(IKK){\beta}$, TRIF, or TNF-receptor-associated factor family member-associated $NF-{\kappa}B$ activator (TANK)-binding kinase 1 (TBK1). Acrolein inhibited LPS-induced dimerization of TLR4, which resulted in the down-regulation of $NF-{\kappa}B$ and IRF3 activation. These results suggest that activation of TLRs and subsequent immune/inflammatory responses induced by endogenous molecules or chronic infection can be modulated by certain chemicals with a structural motif that enables Michael addition.

• Biomolecules & Therapeutics
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• v.21 no.6
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• pp.435-441
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• 2013

Emodin, a naturally occurring anthraquinone derivative isolated from Polygoni cuspidati radix, has several beneficial pharmacologic effects, which include anti-cancer, anti-diabetic, and anti-inflammatory activities. In this study, the authors examined the effect of emodin on the production of proinflammatory cytokines, such as, tumor necrosis factor (TNF)-${\alpha}$ and interleukin (IL)-6, in mouse bone marrow-derived mast cells (BMMCs) stimulated with phorbol 12-myristate 13-acetate (PMA) plus the calcium ionophore A23187. To investigate the mechanism responsible for the regulation of pro-inflammatory cytokine production by emodin, the authors assessed its effects on the activations of transcriptional factor nuclear factor-${\kappa}B$ (NF-${\kappa}B$) and mitogen-activated protein kinases (MAPKs). Emodin attenuated the nuclear translocation of (NF)-${\kappa}B$ p65 and its DNA-binding activity by reducing the phosphorylation and degradation of $I{\kappa}B{\alpha}$ and the phosphorylation of $I{\kappa}B$ kinase B (IKK). Furthermore, emodin dose-dependently attenuated the phosphorylations of MAPKs, such as, extracellular signal-regulated kinase 1/2 (ERK1/2), p38 MAP kinase, and the stress-activated protein kinases (SAPK)/c-Jun-N-terminal kinase (JNK). Taken together, the findings of this study suggest that the anti-inflammatory effects of emodin on PMA plus A23187-stimulated BMMCs are mediated via the inhibition of NF-${\kappa}B$ activation and of the MAPK pathway.

• Journal of Acupuncture Research
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• v.26 no.3
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• pp.39-48
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• 2009

목적 : 이 연구는 봉약침의 주요성분인 멜리틴이 NF-${\kappa}$B의 활성억제를 통하여 세포자멸사를 유도하고, 전립선 암세포주인 DU-145 세포의 성장을 억제하는지를 확인하고 멜리틴의 NF-${\kappa}$B 활성억제기전을 살펴보고자 하였다. 방법 : 멜리틴을 처리한 후 DU-145의 성장억제를 관찰하기 위해 WST-1 assay를 시행하였고, 세포자멸 사의 관찰에는 DAPI stairung assay를 통한 세포형태관찰을 시행하였으며, 염증관련유전자 발현 관찰에는 western blot analysis를 시행하였고, 세포자멸사와 연관된 NF-${\kappa}$B의 활성 변화를 관찰하기 위해 EMSA와 luciferase assay를 시행하였으며, DU-145에서 멜리틴과 NF-${\kappa}$B의 상호작용을 관찰하기 위해 transient transfection assay를 시행 시 세포생존율과 NF-${\kappa}$B의 활성 변동을 측정하였다. 결과 : DU-145 세포에 멜리틴을 처리한 후, 전립선암세포의 성장, 세포자멸사의 유발, 염중관련유전자 발현 및 NF-${\kappa}$B의 활성, NF-${\kappa}$B의 p50 치환 후 NF-${\kappa}$B의 활성과 DU-145 세포 증식에 미치는 영향을 관찰하여 다음과 같은 결과를 얻었다. 1. DU-145 세포에서 멜리틴을 처리한 후 세포자멸사가 유도되어 세포성장이 억제되었다. 2. DU-145 세포에서 멜리틴을 처리한 후 염증관련유전자 발현 및 NF-${\kappa}$B의 활성에 유의한 감소를 나타내었다. 3. DU-145 세포에서 NF-${\kappa}$B의 p50와 IKK들을 치환하여 작용기를 없애고 멜리틴을 처리하였을 경우에도 세포활성 및 NF-${\kappa}$B의 활성의 유의한 감소를 나타내었다.

• Journal of Microbiology and Biotechnology
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• v.18 no.12
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• pp.1984-1989
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• 2008

Surfactin is a natural biosurfactant derived from Bacillus subtilis and has various biological activities such as anticancer, antiplatelet, and anti-inflammatory effects. In this study, the inhibitory mechanism of surfactin in NO production from macrophages was examined. Surfactin down regulated LPS-induced NO production in RAW264.7 cells and primary macrophages with $IC_{50}$ values of 31.6 and $22.4{\mu}M$, respectively. Immunoblotting analysis showed that surfactin strongly blocked the phosphorylation of IKK and $l{\kappa}B{\alpha}$ and the nuclear translocation of $NF-{\kappa}B$ (p65). Therefore, these data suggest that surfactin may act as a bacterium-derived anti-inflammatory agent with anti-$NF-{\kappa}B$ activity.

• Journal of Acupuncture Research
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• v.23 no.2
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• pp.33-46
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• 2006

Alzheimer's disease (AD) is the most prevalent form of neurodegenerative disease associated with aging in the human population. This disease is characterized by the extracellular deposition of beta-amyloid peptide $(A{\beta})$ in cerebral plaques. $A{\beta}$ is derived from the ${\beta}-amyloid$ precursor protein (APP) by the enzymes, ${\beta}-$ and ${\eta}o-secretase$. Compounds that ${\beta}-$ or ${\eta}o-secretase$ inhibit activity, can reduce the production of $A{\beta}$ peptides, and thus have therapeutic potential in the treatment of AD. Increasing body of evidence has been demonstrated that Bee Venom(BV) Acupuncture could compete with complex protein involving in multiple step of $NF-{\kappa}B$ activation and exert the anti-inflammatory potential of combined inhibition of the prostanoid and nitric oxide synthesis systems by inhibition of IKK and $NF-{\kappa}B$. In this study, I investigated possible effects of BV on memory dysfunction caused by lipopolysaccharide (LPS) and $A{\beta}$ through inhibition of secretases activities and $A{\beta}$ aggregation. I examined the improving effect of BV on the LPS (2.5 mg/Kg, i.p.)-induced memory dysfunction using passive avoidance response and water maze tests in the mice. BV (0.84, $1.67\;{\mu}g/ml$) reversed the LPS-induced memorial dysfunction in dose dependent manner. BV also dose-dependently attenuated LPS-induced ${\beta}$ and ${\eta}o-secretase$ activities in cerebral cortex and hippocampus of the mice brain. This study therefore suggests that BV acupuncture method may be useful for prevention of development or progression of AD.

• YAKHAK HOEJI
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• v.4 no.1
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• pp.50-52
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• 1959

In order to know contents of vitamin B$_{12}$ in the fermented foods in Korea, the contents of this vitamin are studied on the following foods; kimchies (pickled vegetables) .................. 39 chukkals (fermented and salted sea foods) ...... 8 fermented soy-bean products .................... 5 the kimchies and fermented soybean products studied in this paper, are from individual homes and chukkals are from markets. The content of vitamin B$_{12}$ is estimated by the microbiological assay method using lactobacillus leichmannii ATCC 7830. Details for assay are indicated in the original part of this paper. The pseudo-vitamin B$_{12}$ substances as thymidine which is active to the growth of lactobacillus leichmannii, are eliminated by the alkali treatment method of sample solution. According to the results as indicated in the table, the following conclusions are summerized; 1. Vitamin B$_{12}$ contents of kimchies for winter season are 1.03 to 1.52 mcg% in average. The hobakk-kimchi which contain the highest content of vitamin B$_{12}$ is not popular one among Korean. 2. Chukkals contain much higher content of vitamin B$_{12}$ varying from 0.91 to 11.10mcg%. 3. The soybean fermented foods, as kanjang, denjang, kochojang, contain lower content of vitamine B$_{12}$ varying from 0.08 to 0.52 mcg% containing higher content of pseudo-vitamin. 4. Based on daily consumption of kimchi in winter season by Chai, the consumption of this vitamin through kimchi is about 3 mcgs daily per capita. This will be a quite source of this vitamin for Korean as vitamin C. as vitamin C.

• YAKHAK HOEJI
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• v.4 no.1
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• pp.53-55
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• 1959

In order to confirm on production of vitamin $B_{12}$ during the kimchi fermentation period, the variation of its content is studied in this paper As a sample of kimchi for this fermentation study due to the seasonal condition, nabakkimchi which is aseasonal one in early spring, is prepared by author. The content of vitamin $B_{12}$ is estimated by the microbiological assay method using lactobacillus leichmannii A Tee 7830. Details for assay are indicated in the original part. And the pseudo-vitamin $B_{12}$ substances as thymidine which is active to the growth of lactobacillus leichmannii, are eliminated by the alkali treatment method of sample solution, According to the results shown in table 2 and 3 and figures 1 to 4, the following conclusions are summerized; 1. Vitamin $B_{12}$ produced during the fermentation period of kimchi. And the content of this vitamin during its optimum fermentation period, is much higher content compared with the theoretically calculated amount from its materials, This has been confirmed at the repeated experiment. The trend of variation during its period is indicated at the figures. 2. The sterilized kimchi inhibited the fermentation by sterilization at the preparation, did not increased its content showing only its theoretically calculated amount.

• Archives of Pharmacal Research
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• v.27 no.7
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• pp.683-692
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• 2004

Curcumin (diferuloylmethane) is a major naturally-occurring polyphenol of Curcuma species, which is commonly used as a yellow coloring and flavoring agent in foods. Curcumin has shown anti-carcinogenic activity in animal models. Curcumin possesses anti-inflammatory activity and is a potent inhibitor of reactive oxygen-generating enzymes such as lipoxygenase/cyclooxygenase, xanthine dehydrogenase/oxidase and inducible nitric oxide synthase; and an effective inducer of heme oxygenase-1. Curcumin is also a potent inhibitor of protein kinase C(PKC), EGF(Epidermal growth factor)-receptor tyrosine kinase and LĸB kinase. Subsequently, curcumin inhibits the activation of NF(nucleor factor)KB and the expressions of oncogenes including c-jun, c-fos, c-myc, NIK, MAPKs, ERK, ELK, PI3K, Akt, CDKs and iNOS. It is proposed that curcumin may suppress tumor promotion through blocking signal transduction path-ways in the target cells. The oxidant tumor promoter TPA activates PKC by reacting with zinc thiolates present within the regulatory domain, while the oxidized form of cancer chemopreventive agent such as curcumin can inactivate PKC by oxidizing the vicinal thiols present within the catalytic domain. Recent studies indicated that proteasome-mediated degradation of cell proteins playa pivotal role in the regulation of several basic cellular processes including differentiation, proliferation, cell cycling, and apoptosis. It has been demonstrated that curcumin-induced apoptosis is mediated through the impairment of ubiquitin-proteasome pathway. Curcumin was first biotransformed to dihydrocurcumin and tetrahydrocurcumin and that these compounds subsequently were converted to monoglucuronide conjugates. These results suggest that curcumin-glucuronide, dihydrocurcumin-glucuronide, tetrahydrocurcumin-glucuronide and tetrahydrocurcumin are the major metabolites of curcumin in mice, rats and humans.