• Asian Pacific Journal of Cancer Prevention
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• 제15권6호
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• pp.2911-2916
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• 2014

Oxaliplatin is a first-line therapy for colorectal cancer, but cancer cell resistance to the drug compromises its efficacy. To explore mechanisms of drug resistance, we treated colorectal cancer cells (HCT116 and SW620) long-term with oxaliplatin and established stable oxaliplatin-resistant lines (HCT116-OX and SW620-OX). Compared with parental cell lines, $IC_{50}$s for various chemotherapeutic agents (oxaliplatin, cisplatin and doxorubicin) were increased in oxaliplatin-resistant cell lines and this was accompanied by activation of nuclear factor erythroid-2 p45-related factor 2 (Nrf2) and NADPH quinone oxidoreductase 1 (NQO1). Furthermore, luteolin inhibited the Nrf2 pathway in oxaliplatin-resistant cell lines in a dose-dependent manner. Luteolin also inhibited Nrf2 target gene [NQO1, heme oxygenase-1 (HO-1) and $GST{\alpha}1/2$] expression and decreased reduced glutathione in wild type mouse small intestinal cells. There was no apparent effect in Nrf2-/- mice. Luteolin combined with other chemotherapeutics had greater anti-cancer activity in resistant cell lines (combined index values below 1), indicating a synergistic effect. Therefore, adaptive activation of Nrf2 may contribute to the development of acquired drug-resistance and luteolin could restore sensitivity of oxaliplatin-resistant cell lines to chemotherapeutic drugs. Inhibition of the Nrf2 pathway may be the mechanism for this restored therapeutic response.

• Asian Pacific Journal of Cancer Prevention
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• 제14권12호
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• pp.7111-7116
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• 2013

Introduction: Trastuzumab, an HER2-targeting agents, has shown efficacy in metastatic HER2-positive breast cancer patients. Single-agent clinical trials have evaluated therapeutic regimens using trastuzumab for metastatic breast cancer patients. The aim of our study is to evaluate the efficacy and safety of trastuzumab in combination with chemotherapy or hormone therapy in HER2-positive metastatic breast cancer patients. Methods: A literature research was conducted in PubMed and to identify appropriate studies from relevant reviews. Randomized controlled trials comparing chemotherapy or hormone therapy regimens in combination with trastuzumab were eligible. Dadta on clinical outcomes, including safety, efficacy, and patient characteristics were collected. Results: Seven articles describing five trials were included in our systematic review and meta-analysis. Partners of trastuzumab included in trials were anthracycline, paclitaxel, docetaxel, anastrozole and letrozole. The addition of trastuzumab to chemotherapy improved the overall survival (HR=0.79, 95%CI 0.65-0.96), while to hormone therapy did not (HR=0.85 95%CI 0.56-1.30). All trastuzumab-containing regimens increased cardiac toxicity (RR=3.37, 95%CI 1.26-9.02) and grade III-IV adverse events. Conclusions: Our study supports the addition of trastuzumab to chemotherapy which is effective and tolerated for metastatic breast cancer with HER2+ patients. Of note, more adverse events will occur followed the use of trastuzumab, especially cardiac toxicity, with two treatment regimens.

• Journal of Microbiology and Biotechnology
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• 제16권5호
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• pp.651-660
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• 2006

Natural products are a rich source of biologically active small molecules and a fertile area for lead discovery of new drugs [10, 52]. For instance, 5% of the 1,031 new chemical entities approved as drugs by the US Food and Drug Administration (FDA) were natural products between 1981 and 2002, and another 23% were natural product-derived molecules [53]. These molecules have evolved through millions of years of natural selection to interact with biomolecules in the cells or organisms and offer unrivaled chemical and structural diversity [14, 37]. Nonetheless, a large percentage of nature remains unexplored, in particular, in the marine and microbial environments. Therefore, natural products are still major valuable sources of innovative therapeutic agents for human diseases. However, even when a natural product is found to exhibit biological activity, the cellular target and mode of action of the compound are mostly mysterious. This is also true of many natural products that are currently under clinical trials or have already been approved as clinical drugs [11]. The lack of information on a definitive cellular target for a biologically active natural product prevents the rational design and development of more potent therapeutics. Therefore, there is a great need for new techniques to expedite the rapid identification and validation of cellular targets for biologically active natural products. Chemical genomics is a new integrated research engine toward functional studies of genome and drug discovery [40, 69]. The identification and validation of cellular receptors of biologically active small molecules is one of the key goals of the discipline. This eventually facilitates subsequent rational drug design, and provides valuable information on the receptors in cellular processes. Indeed, several biologically crucial proteins have already been identified as targets for natural products using chemical genomics approach (Table 1). Herein, the representative case studies of chemical genomics using natural products derived from microbes, marine sources, and plants will be introduced.

• Journal of Microbiology and Biotechnology
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• 제25권7호
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• pp.1036-1046
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• 2015

Extracts from Asian medicinal herbs are known to be successful therapeutic agents against cancer. In this study, the effects of three types of herbal extracts on anti-tumor growth were examined. Among the three types of herbal extracts, H9 showed stronger anti-tumor growth effects than H5 and H11 in vivo. To find the molecular mechanism by which H9 inhibited the proliferation of breast cancer cell lines, the levels of apoptotic markers were examined. Proapoptotic markers, including cleaved PARP and cleaved caspases 3 and 9, were increased, whereas the anti-apoptotic marker Bcl-2 was decreased by H9 treatment. Next, the combined effect of H9 with the chemotherapeutic drugs doxorubicin/cyclophosphamide (AC) on tumor growth was examined using 4T1-tumor-bearing mice. The combined treatment of H9 with AC did not show additive or synergetic anti-tumor growth effects. However, when tumor-bearing mice were co-treated with H9 and the targeted anti-tumor drug trastuzumab, a delay in tumor growth was observed. The combined treatment of H9 and trastuzumab caused an increase of natural killer (NK) cells and a decrease of myeloid-derived suppressor cells (MDSC). Taken together, H9 induces the apoptotic death of tumor cells while increasing anti-tumor immune activity through the enhancement of NK activity and diminishment of MDSC.

• 한국미생물·생명공학회지
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• 제40권4호
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• pp.409-413
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• 2012

인돌리시딘(indolicidin)은 소의 호중구(bovine neutrophils)로 부터 분리된 13개의 아미노산 잔기로 이루어 지고, 트립토판(tryptophan)을 많이 함유한 항균 펩타이드(antimicrobial peptide)이다. 인돌리시딘은 강력한 항균활성과 더불어 mammalian cells에 대해 독성을 나타낸다. 본 연구에서는 인돌리시딘 보다 서열이 짧으며, 보다 증가된 원핵세포 선택성(박테리아세포에 대해 독성을 나타내지만 mammalian cells에 대해서는 독성을 나타내지 않음을 의미함)을 지닌 새로운 짧은 항균 펩타아드를 개발하기 위해, 몇 종의 인돌리시딘 유사체 펩타이드를 설계하고 합성하였다. 결과적으로, 인돌리시딘 보다 서열이 짧으며(10개의 아미노산 잔기로 이루어짐), 증가된 원핵세포선택성을 지닌 4종의 새로운 펩타이드(SI, SI-PA, SI-WF 및 SI-WL)를 개발하였다. 본 연구를 통하여 가장 높은 원핵세포선택성을 나타내는 인돌리시딘 유사체 펩타이드 SI의 항균활성에는 중앙부위에 위치하는 소수성 및 방향족 아미노산이 중요하며, 2군데의 프로린(proline) 잔기는 중요하지 않다는 것을 알았다. 인돌리시딘과 유사체 펩타이드에 대한 원핵세포 선택성은 SI>SI-PA>SI-WF>SI-WL>ID>SI-WA의 순서 이였다. 따라서, 본 연구에서 설계되고 합성한 4종의 인돌리시딘 유사체 펩타이드(SI, SI-PA, SI-WF 및 SI-WL)는 박테리아 감염의 치료제로서 개발될 수 있을 것이다.

• Journal of Microbiology and Biotechnology
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• 제30권7호
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• pp.1051-1059
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• 2020

Overproduction and accumulation of melanin in the skin will darken the skin and cause skin disorders. So far, components that can inhibit tyrosinase, a melanin synthase of melanocytes, have been developed and used as ingredients of cosmetics or pharmaceutical products. However, most of existing substances can only inhibit the biosynthesis of melanin while melanin that is already synthesized and deposited is not directly decomposed. Thus, their effects in decreasing melanin concentration in the skin are weak. To overcome the limitation of existing therapeutic agents, we started to develop a substance that could directly biodegrade melanin. We screened traditional fermented food microorganisms for their abilities to direct biodegrade melanin. As a result, we found that a kimchi-derived Pediococcus acidilactici PMC48 had a direct melanin-degrading effect. This PMC48 strain is a new strain, different from P. acidilactici strains reported so far. It not only directly degrades melanin, but also has tyrosinase-inhibiting effect. It has a direct melanin-decomposition effect. It exceeds existing melanin synthesis-inhibiting technology. It is expected to be of high value as a raw material for melanin degradation drugs and cosmetics.

• The Korean Journal of Physiology and Pharmacology
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• 제16권2호
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• pp.79-89
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• 2012

We examine whether Phellodendron amurense (PA) and its major alkaloid compound, berberine (BER), improved memory defects caused by administering scopolamine in rats. Effects of PA and BER on the acetylcholinergic system and pro-inflammatory cytokines in the hippocampus were also investigated. Male rats were administered daily doses for 14 days of PA (100 and 200 mg/kg, i.p.) and BER (20 mg/kg, i.p.) 30 min before scopolamine injection (2 mg/kg, i.p.). Daily administration of PA and BER improved memory impairment as measured by the passive avoidance test and reduced the escape latency for finding the platform in the Morris water maze test. Administration of PA and BER significantly alleviated memory-associated decreases in cholinergic immunoreactivity and restored brain-derived neurotrophic factor and cAMP-response element-binding protein mRNA expression in the hippocampus. PA and BER also decreased significantly the expression of proinflammatory cytokines such as interleukin-$1{\beta}$, tumor necrosis factor-${\alpha}$ and cyclooxygenase-2 mRNA in the hippocampus. These results demonstrated that PA and BER had significant neuroprotective effects against neuronal impairment and memory dysfunction caused by scopolamine in rats. These results suggest that PA and BER may be useful as therapeutic agents for improving cognitive functioning by stimulating cholinergic enzyme activity and alleviating inflammatory responses.

• The Korean Journal of Physiology and Pharmacology
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• 제22권2호
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• pp.135-143
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• 2018

Tumor necrosis $factor-{\alpha}$ ($TNF{\alpha}$) and the angiotensin system are involved in inflammatory diseases and may contribute to acute kidney injury. We investigated the mechanisms by which $TNF{\alpha}$-converting enzyme (TACE) contributes to lipopolysaccharide (LPS)-induced renal inflammation and the effect of TACE inhibitor treatment on LPS-induced cellular injury in human renal proximal tubule epithelial (HK-2) cells. Mice were treated with LPS (10 mg/kg, i.p.) and HK-2 cells were cultured with or without LPS ($10{\mu}g/ml$) in the presence or absence of a type 1 TACE inhibitor ($1{\mu}M$) or type 2 TACE inhibitor ($10{\mu}M$). LPS treatment induced increased serum creatinine, $TNF{\alpha}$, and urinary neutrophil gelatinase-associated lipocalin. Angiotensin II type 1 receptor, mitogen activated protein kinase (MAPK), and TACE increased, while angiotensin-converting enzyme-2 (ACE2) expression decreased in LPS-induced acute kidney injury and LPS-treated HK-2 cells. LPS induced reactive oxygen species and the down-regulation of ACE2, and these responses were prevented by TACE inhibitors in HK-2 cells. TACE inhibitors increased cell viability in LPS-treated HK-2 cells and attenuated oxidative stress and inflammatory cytokines. Our findings indicate that LPS activates renin angiotensin system components via the activation of TACE. Furthermore, inhibitors of TACE are potential therapeutic agents for kidney injury.

• Journal of Korean Neurosurgical Society
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• 제40권3호
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• pp.180-185
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• 2006

Objective : Middle cerebral artery occlusion[MCAO] has widely been used to produce ischemic brain lesions. The lesions induced by MCAO tend to be variable in size because of the variance in the collateral blood supply found in the mouse brain. To establish a less invasive and reproducible focal ischemia model in mice, we modified the technique used for rat photo thrombosis model. Methods : Male C57BL/6 mice were subjected to focal cerebral ischemia by photothrombosis of cortical microvessels. Cerebral infarction was produced by intraperitoneal injection of Rose Bengal, a photosensitive dye and by focal illumination through the skull. Motor impairment was assessed by the accelerating rotarod and staircase tests. The brain was perfusion-fixed for histological determination of infarct volume four weeks after stroke. Results : The lesion was located in the frontal and parietal cortex and the underlying white matter was partly affected. A relatively constant infarct volume was achieved one month after photothrombosis. The presence of the photothrombotic lesion was associated with severe impairment of the motor performance measured by the rotarod and staircase tests. Conclusion : Photothrombotic infarction in mice is highly reproducible in size and location. This procedure can provide a simple method to produce cerebral infarction in a unilateral motor cortex lesion. In addition, it can provide a suitable model for study of potential neuroprotective and therapeutic agents in human stroke.

• Journal of Microbiology and Biotechnology
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• 제29권11호
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• pp.1707-1716
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• 2019

The development of new antimicrobial agents is essential for the effective treatment of diseases such as sepsis. We previously developed a new short peptide, Pap12-6, using the 12 N-terminal residues of papiliocin, which showed potent and effective antimicrobial activity against multidrug-resistant Gram-negative bacteria. Here, we investigated the antimicrobial mechanism of Pap12-6 and a newly designed peptide, Pap12-7, in which the 12^th Trp residue of Pap12-6 was replaced with Val to develop a potent peptide with high bacterial selectivity and a different antibacterial mechanism. Both peptides showed high antimicrobial activity against Gram-negative bacteria, including multidrug-resistant Gram-negative bacteria. In addition, the two peptides showed similar anti-inflammatory activity against lipopolysaccharide-stimulated RAW 264.7 cells, but Pap12-7 showed very low toxicities against sheep red blood cells and mammalian cells compared to that showed by Pap12-6. A calcein dye leakage assay, membrane depolarization, and confocal microscopy observations revealed that the two peptides with one single amino acid change have different mechanisms of antibacterial action: Pap12-6 directly targets the bacterial cell membrane, whereas Pap12-7 appears to penetrate the bacterial cell membrane and exert its activities in the cell. The therapeutic efficacy of Pap12-7 was further examined in a mouse model of sepsis, which increased the survival rate of septic mice. For the first time, we showed that both peptides showed anti-septic activity by reducing the infiltration of neutrophils and the production of inflammatory factors. Overall, these results indicate Pap12-7 as a novel non-toxic peptide with potent antibacterial and anti-septic activities via penetrating the cell membrane.