• 약학회지
• /
• 제45권3호
• /
• pp.287-292
• /
• 2001

To investigate whether phospholipase $A_2$pathway is involved in histamine release of rat peritoneal mast cells, we measured histamine release in the presence of various enzyme inhibitors involved in eicosanoid pathway, such as phospholipase $A_2$, cyclooxygenase and lipoxygenase. Phospholipase $A_2$inhibitors, manoalide and OPC, significantly inhibited histamine release induced by 100 $\mu$M ATP and 1$\mu$g/ml compound 48/80. Cyclooxygenase inhibitors, ibuprofen and indomethacin, significantly inhibited ATP-induced histamine release and lipoxygenase inhibitors, baicalein and caffeic acid, also significantly inhibited. To investigate the involvement of protein kinase in ATP- and compound 48/80-induced histamine release, we observed effects of protein kinase inhibitors on histamine release. Bisindolmaleimide (protein kinase C antagonist) dose-dependently inhibited both ATP and compound 48/80-induced histamine release. Tyrosine kinase inhibitors (methyl 2,5-dihydroxy cinnamate and genistein) dose-dependently inhibited ATP and compound 48/80-induced histamine release. Protein kinase C and tyrosine kinase seem to be involved in histamine release induced by ATP and compound 48/80. These results suggest that phospholipase $A_2$pathway as well as protein kinase C and tyrosine kinase are involved in histamine release of rat peritoneal mast cells by ATP and compound 48/80.

• Biomolecules & Therapeutics
• /
• 제27권5호
• /
• pp.423-434
• /
• 2019

HSP90 is a molecular chaperone that increases the stability of client proteins. Cancer cells show higher HSP90 expression than normal cells because many client proteins play an important role in the growth and survival of cancer cells. HSP90 inhibitors mainly bind to the ATP binding site of HSP90 and inhibit HSP90 activity, and these inhibitors can be distinguished as ansamycin and non-ansamycin depending on the structure. In addition, the histone deacetylase inhibitors inhibit the activity of HSP90 through acetylation of HSP90. These HSP90 inhibitors have undergone or are undergoing clinical trials for the treatment of cancer. On the other hand, recent studies have reported that various reagents induce cleavage of HSP90, resulting in reduced HSP90 client proteins and growth suppression in cancer cells. Cleavage of HSP90 can be divided into enzymatic cleavage and non-enzymatic cleavage. Therefore, reagents inducing cleavage of HSP90 can be classified as another class of HSP90 inhibitors. We discuss that the cleavage of HSP90 can be another mechanism in the cancer treatment by HSP90 inhibition.

• Biomolecules & Therapeutics
• /
• 제31권1호
• /
• pp.1-15
• /
• 2023

Autophagy is a process of eliminating damaged or unnecessary proteins and organelles, thereby maintaining intracellular homeostasis. Deregulation of autophagy is associated with several diseases including cancer. Contradictory dual roles of autophagy have been well established in cancer. Cytoprotective mechanism of autophagy has been extensively investigated for overcoming resistance to cancer therapies including radiotherapy, targeted therapy, immunotherapy, and chemotherapy. Selective autophagy inhibitors that directly target autophagic process have been developed for cancer treatment. Efficacies of autophagy inhibitors have been tested in various pre-clinical cancer animal models. Combination therapies of autophagy inhibitors with chemotherapeutics are being evaluated in clinal trials. In this review, we will focus on genetical and pharmacological perturbations of autophagy-related proteins in different steps of autophagic process and their therapeutic benefits. We will also summarize combination therapies of autophagy inhibitors with chemotherapies and their outcomes in pre-clinical and clinical studies. Understanding of current knowledge of development, progress, and application of cytoprotective autophagy inhibitors in combination therapies will open new possibilities for overcoming drug resistance and improving clinical outcomes.

• Asian Pacific Journal of Cancer Prevention
• /
• 제14권6호
• /
• pp.3975-3978
• /
• 2013

Background: Proteases play a regulatory role in a variety of pathologies including cancer, pancreatitis, thromboembolic disorders, viral infections and many others. One of the possible strategies to combat these pathologies seems to be the use of protease inhibitors. LC-pi I, II, III and IV (Lavatera cashmerian-protease inhibitors) have been found in vitro to strongly inhibit trypsin, chymotrypsin and elastase, proteases contributing to tumour invasion and metastasis, indicated possible anticancer effects. The purpose of this study was to check in vitro anticancer activity of these four inhibitors on human lung cancer cell lines. Material and Methods: In order to assess whether these inhibitors induced in vitro cytoxicity, SRB assay was conducted with THP-1 (leukemia), NCIH322 (lung) and Colo205, HCT-116 (colon) lines. Results: LC-pi I significantly inhibited the cell proliferation of all cells tested and also LC-pi II was active in all except HCT-116. Inhibition of cell growth by LC-pi III and IV was negligible. $IC_{50}$ values of LC-pi I and II for NCIH322, were less compared to other cell lines suggesting that lung cancer cells are more inhibited. Conclusion: These investigations might point to future preventive as well as curative solutions using plant protease inhibitors for various cancers, especially in the lung, hence warranting their further investigation.

• 한국식품과학회지
• /
• 제18권5호
• /
• pp.339-344
• /
• 1986

Trypsin inhibitor가 trypsin과 안정한 복합체를 형성하고 동시에 일반 단백질은 trypsin에 의하여 가수분해 되는 원리를 이용하여 trypsin inhibitor를 용이하게 검정 할 수 있는 방법을 고안하였다. trypsin으로 가수분해 시킨 대두추출액을 Sephadex G-50을 이용하여 trypsin-trypsin inhibitor 복합체를 분리시킨 후에 SDS 전기 영동으로 trypsin inhibitor를 복합체를 분리시킨 후에 SDS 전기 영동으로 trypsin inhibitor를 검정할 수 있었다. 이들 trypsin inhibitor는 trypsin에 의한 2차 가수분해에서도 가수분해 되지 않았으며, 또한 2차원 전기영동과 DEAE-Sephades A-25크로마토 그래피를 이용하여 trypsin inhibitor가 trypsin과 복합체를 형성하는 능력을 검정함으로써 본 방법의 유효성을 확인하였다. 본 실험 방법으로 대두(Hill 품종)의 trypsin inhibitor를 검정한 결과 7개의 trypsin inhibitor를 찾아 낼 수 있었다.

• Journal of Microbiology and Biotechnology
• /
• 제8권4호
• /
• pp.325-332
• /
• 1998

In vitro phosphorylation experiments with a cell extract of Streptomyces coelicolor A3(2) M130 in the presence of ${\gamma}-[^32P]$]ATP revealed the presence of multiple phosphorylated proteins, including the AfsR/AfsK kinases which control the biosynthesis of A-factor, actinorhodin, and undecylprodigiosin. Phosphorylation of AfsR by a cell extract as an AfsK source was significantly inhibited by Ser/Thr protein kinase inhibitors, staurosporine and K-252a, at concentrations giving 50% inhibition ($IC_50$) of $1{\mu}M\;and\;0.1{\mu}M$, respectively. Further in vitro experiments with the cell extracts showed that phosphorylation of multiple proteins was inhibited by various protein kinase inhibitors with different inhibitory profiles. Manganese and calcium ions in the reaction mixture also modulate phosphorylation of multiple proteins. Manganese at 10 mM greatly enhanced the phosphorylation and partially circumvented the inhibition caused by staurosporine and K-252a. A calcium-activated protein kinase(s) was little affected by these inhibitors. Herbimycin and radicicol, which are known as tyrosine kinase inhibitors, did not show any significant inhibition of AfsR phosphorylation. Consistent with the in vitro effect of the kinase inhibitors, they inhibited aerial mycelium formation and pigmented antibiotic production on solid media. On the contrary, when assayed in liquid culture, the amount of actinorhodin produced was increased by staurosporine and K-252a and greatly decreased by manganese. All of these data clearly show that the genus Streptomyces possesses several protein kinases of eukaryotic types which are involved in the regulatory network for morphogenesis and secondary metabolism.

• 통합자연과학논문집
• /
• 제12권4호
• /
• pp.133-141
• /
• 2019

Mesenchymal stem cells (MSCs) are known to differentiate into multiple lineages, making neurogenic differentiation an important target in the clinical field. In the present study, we induced the neurogenic differentiation of cells using histone deacetylase (HDAC) inhibitors and studied their mechanisms for further differentiation in vitro. We treated cells with the HDAC inhibitors, MS-275 and NaB; and found that the cells had neuron-like features such as distinct bipolar or multipolar morphologies with branched processes. The mRNA expressions encoding for NEFL, MAP2, TUJ1, OLIG2, and SYT was significantly increased following HDAC inhibitors treatment compared to without HDAC inhibitors; high protein levels of MAP2 and Tuj1 were detected by immunofluorescence staining. We examined the mechanisms of differentiation and found that the Wnt signaling pathway and downstream mitogen-activate protein kinase were involved in neurogenic differentiation of MSCs. Importantly, Wnt4, Wnt5a/b, and Wnt11 protein levels were highly increased after treatment with NaB; signals were activated through the regulation of Dvl2 and Dvl3. Interestingly, NaB treatment increased the levels of JNK and upregulated JNK phosphorylation. After MS-275 treatment, Wnt protein levels were decreased and GSK-3β was phosphorylated. In this cell, HDAC inhibitors controlled the non-canonical Wnt expression by activating JNK phosphorylation and the canonical Wnt signaling by targeting GSK-3β.

• Bulletin of the Korean Chemical Society
• /
• 제35권8호
• /
• pp.2494-2504
• /
• 2014

P38 mitogen activated protein (MAP) kinase is an important anti-inflammatory drug target, which can be activated by responding to various stimuli such as stress and immune response. Based on the conformation of the conserved DFG loop (in or out), binding inhibitors are termed as type-I and II. Type-I inhibitors are ATP competitive, whereas type-II inhibitors bind in DFG-out conformation of allosteric pocket. It remains unclear that how these allosteric inhibitors stabilize the DFG-out conformation and interact. Organosilicon compounds provide unusual opportunity to enhance potency and diversity of drug molecules due to their low toxicity. However, very few examples have been reported to utilize this property. In this regard, we performed docking of an inhibitor (BIRB) and its silicon analog (Si-BIRB) in an allosteric binding pocket of p38. Further, molecular dynamics (MD) simulations were performed to study the dynamic behavior of the simulated complexes. The difference in the biological activity and mechanism of action of the simulated inhibitors could be explained based on the molecular mechanics/generalized Born surface area (MM/GBSA) binding free energy per residue decomposition. MM/GBSA showed that biological activities were related with calculated binding free energy of inhibitors. Analyses of the per-residue decomposed energy indicated that van der Waals and non-polar interactions were predominant in the ligand-protein interactions. Further, crucial residues identified for hydrogen bond, salt bridge and hydrophobic interactions were Tyr35, Lys53, Glu71, Leu74, Leu75, Ile84, Met109, Leu167, Asp168 and Phe169. Our results indicate that stronger hydrophobic interaction of Si-BIRB with the binding site residues could be responsible for its greater binding affinity compared with BIRB.

• 정보학연구
• /
• 제5권3호
• /
• pp.65-80
• /
• 2002

최근 기업들의 주요 관심사는 세계적 통합활동과 지역활동과의 올바른 균형을 이루기 위한 적합한 사업 활동장소를 발견하고자 하는 것이다. 본 논문은 정보기술을 통하여 글로벌화가 가능할 것이라는 연구검토 안을 제시한다. 자료 수집 과정에서 글로벌화가 되기 위해 노력하는 지역에 초점을 맞추고 있고 경험적인 증거를 바탕으로 글로벌화에 대한 자료수집을 수행하는 것은 그리 바람직하지 않는다는 것을 보여주고 있다. 결과적으로 글로벌화에 역행하는 제한요인들이 존재할 수 있으며 이들을 부문별로 분류할 수 있다. 즉 지리적 제한 요인, 관계적 제한 요인 그리고 환경적 제한 요인들이다. 여기서는 이러한 요인들을 감소시키기 위한 정보 기술의 역할을 분석하며 그리고 이와 관련된 사례 연구에 대하여 제안하고자 한다. 정보 기술은 지리적 및 관계적 제한 요인들을 줄이기 위해 사용될 수 있다. 그러나 환경 적 제한요인에는 영향을 미치지 않는다. 그러나 후자의 제한요인의 범위가 향후 미래에는 보다 더 두드러지게 나타날 것으로 예측된다. 그러므로 정보기술은 세계적 통합으로 발전하는 글로벌화 쪽으로 균형을 맞추어 나갈 것이며 이러한 과정에서 새로운 문제점이 발생할 것으로 예상된다.

• Journal of Animal Science and Technology
• /
• 제64권4호
• /
• pp.603-620
• /
• 2022

Human activities have caused an increase in greenhouse gas emissions, resulting in climate change that affects many factors of human life including its effect on water and food quality in certain areas with implications for human health. CH₄ and N₂O are known as potent non-CO₂ GHGs. The livestock industry contributes to direct emissions of CH₄ (38.24%) and N₂O (6.70%) through enteric fermentation and manure treatment, as well as indirect N₂O emissions via NH₃ volatilization. NH₃ is also a secondary precursor of particulate matter. Several approaches have been proposed to address this issue, including dietary management, manure treatment, and the possibility of inhibitor usage. Inhibitors, including urease and nitrification inhibitors, are widely used in agricultural fields. The use of urease and nitrification inhibitors is known to be effective in reducing nitrogen loss from agricultural soil in the form of NH₃ and N₂O and can further reduce CH₄ as a side effect. However, the effectiveness of inhibitors in livestock manure systems has not yet been explored. This review discusses the potential of inhibitor usage, specifically of N-(n-butyl) thiophosphoric triamide, dicyandiamide, and 3,4-dimethylpyrazole phosphate, to reduce emissions from livestock manure. This review focuses on the application of inhibitors to manure, as well as the association of these inhibitors with health, toxicity, and economic benefits.