• Journal of Applied Biological Chemistry
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• 제50권2호
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• pp.52-57
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• 2007

Quantitative structure-activity relationships (QSARs) on the inhibition activities by oleanolic acid analogues (1-19) as a potent inhibitor against protein tyrosine phosphatase-1B were studied quantitatively using 2D-QSAR and HQSAR methodologies. The inhibition activity was dependent on the variations of $R_{4-}$substituent, and as shown in 2D-QSAR model ($r^2=0.928$), it has a tendency to increase as the negative Randic Indice (RI) goes up. The size of the molecular fragments used in HQSAR varied from five to eight. The fragment distinctions had the best statistic value, whose predictability is $q^2=0.785$ and correlation coefficient is $r^2=0.970$, on condition of connections. From the atomic contribution maps, the factor that contributes to the inhibition activities is the $C_{15}{\sim}C_{17}$ bond in the D ring. From the analysis result of these two the models, the structural distinctions and descriptors that contribute to the inhibition activities were obtained.

• 생명과학회지
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• 제24권9호
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• pp.1006-1011
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• 2014

인삼은 건강에 효과적인 약초라고 알려져 왔다. 인삼의 열매인 진생베리는 인삼의 주성분과 비슷한 ginsenoside, saponin, polyphenol, polyacetylene, alkaloid 등의 성분을 포함한다. 본 연구의 목적은 인삼과 같이 진생베리 열수 추출물(Ginseng berry water extract, GBE)이 당뇨와 연관된 세포 외 효소와 인슐린 신호전달 경로에 있는 분자의 발현에 어떤 효과를 가지고 있는지를 조사하였다. ${\alpha}$-Amylase와 ${\alpha}$-glucosidase는 섭취한 다당분자를 분해하여 포도당을 생성함으로 항당뇨 약물개발의 표적 효소이다. GBE에 의한 두 효소의 활성 억제능을 in vitro에서 측정하였으나 최고 $1,000{\mu}g/ml$ 농도에서도 효소활성 억제능이 나타나지 않았다. 인슐린 신호전달 경로의 영향을 확인하기 위해서 HepG2 세포에서 GBE에 의한 인슐린 신호전달 경로의 주요 단백질인 protein-tyrosine phosphatase 1B (PTP1B)와 Akt1의 발현수준 변화를 Western blot 방법으로 조사하였다. 이때 인슐린에 의한 이들 분자의 변화에 GBE가 영향을 주는 것으로 나타났다. PTP1B는 인슐린에 의해 증가된 발현량이 저농도의 GBE이 의해 더욱 증가하였으나, $200{\mu}g/ml$ 농도의 GBE에 의해서는 다소 감소하는 것으로 나타났다. 또한, Akt1도 인슐린에 의해 증가된 발현량이 GBE 농도에 따라 감소하는 것으로 나타났다.

• Bulletin of the Korean Chemical Society
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• 제34권4호
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• pp.1023-1024
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• 2013

• 대한약리학회:학술대회논문집
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• 대한약리학회 2006년도 The 6th Congress of the Federation of Asian and Oceanian Physiological Societies
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• pp.92.2-92.2
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• 2006

• BMB Reports
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• 제47권10호
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• pp.552-557
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• 2014

The main purpose of this study was to investigate whether type 3 muscarinic acetylcholine receptor (M3R) dysfunction induced vascular hyperpermeability. Transwell system analysis showed that M3R inhibition by selective antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) and small interfering RNA both increased endothelial permeability. Using coimmunoprecipitation and Western blot assay, we found that M3R inhibition increased VE-cadherin and ${\beta}$-catenin tyrosine phosphorylation without affecting their expression. Using PTP1B siRNA, we found that PTP1B was required for maintaining VE-cadherin and ${\beta}$-catenin protein dephosphorylation. In addition, 4-DAMP suppressed PTP1B activity by reducing cyclic adenosine monophosphate (cAMP), but not protein kinase $C{\alpha}$ ($PKC{\alpha}$). These data indicate that M3R preserves the endothelial barrier function through a mechanism potentially maintaining PTP1B activity, keeping the adherens junction proteins (AJPs) dephosphorylation.

• BMB Reports
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• 제34권6호
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• pp.517-525
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• 2001

Six renaturable protein kinases that utilize the myelin basic protein (MBP) as a substrate were activated during prolonged exposure of cardiac myocytes to okadaic acid (OA). We characterized the substrate preference and activation of these kinases, with particular emphasis on 3 novel kinases-MBPK-55, MBPK-62 and MBPK-87. The transcription factors c-Jun, Elk, ATF2, and c-Fos that are used to assess mitogen-activated protein kinase activation were all poor substrates for these three kinases. MAPKAPK2 was also not phosphorylated. In contrast, Histone IIIS was phosphorylated by MBPK-55 and MBPK-62. These protein kinases were activated in cultured cardiac fibroblasts, H9c2 cardiac myoblasts, and Cos cells. High concentrations (0.5 to $1\;{\mu}M$) of OA were essential for the activation of the protein kinases in all of the cell types examined, whereas calyculin A [an inhibitor of protein phosphatase 1 (PP1) and PP2A], cyclosporin A (a PP2B inhibitor), and an inactive OA analog all failed to activate these kinases. The high dose of okadaic acid that is required for kinase activation was also required for phosphatase inhibition, as assessed by immunoblotting whole cell lysates with anti-phosphothreonine antibodies. A variety of chemical inhibitors, including PD98059 (MEK-specific), genistein (tyrosine kinase-specific) and Bisindolylmaleimide I (protein kinase C-specific), failed to inhibit the OA activation of these kinases. Thus, MBPK-55 and MBPK-62 are also Histone IIIS kinases that are widely expressed and specifically activated upon exposure to high OA concentrations.

• 식품보건융합연구
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• 제5권3호
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• pp.21-33
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• 2019

The incidence of both obesity and Type 2 Diabetes Mellitus( DM) is increasing proportionately so that causes of deaths from these has overtaken from that of malnourishment. Hence it has been recommended to treat the 2 in parallel considering the role of diabesity on health. Important causes of T2DM are insulin resistance (IR) and /or inadequate insulin secretion. Protein tyrosine phosphatase 1B(PTPIB) has a negative impact in insulin signaling pathways and hence plays crucial role inT2DM,since its overexpression might induce IR. Thus PTPIB is considered a therapeutic target for both obesity and T2DM, there has been a search for novel ,promising natural inhibitors. We conducted a pubmed search for articles related to PTPIB inhibitors from natural causes be it marine sources or other natural sources. Out of 988 articles we selected 100 articles for review. Thus various bioactive molecules isolated from marine organisms that can acts as PTPIB Inhibitors and thus possess antidiabetic activity both in vitro/ in vivo studies ,besides products from fruits like Chinese raspberry or curcumin used as routine spices are described with their chemical classes, structure-activity relationships and potency as assessed by IC 50 values are discussed. More work is required to make this a reality.

• Molecules and Cells
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• 제40권4호
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• pp.280-290
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• 2017

Several lines of evidence suggest that endoplasmic reticulum (ER) stress plays a critical role in the pathogenesis of many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Protein tyrosine phosphatase 1B (PTP1B) is known to regulate the ER stress signaling pathway, but its role in neuronal systems in terms of ER stress remains largely unknown. Here, we showed that rotenone-induced toxicity in human neuroblastoma cell lines and mouse primary cortical neurons was ameliorated by PTP1B inhibition. Moreover, the increase in the level of ER stress markers ($eIF2{\alpha}$ phosphorylation and PERK phosphorylation) induced by rotenone treatment was obviously suppressed by concomitant PTP1B inhibition. However, the rotenone-induced production of reactive oxygen species (ROS) was not affected by PTP1B inhibition, suggesting that the neuroprotective effect of the PTP1B inhibitor is not associated with ROS production. Moreover, we found that MG132-induced toxicity involving proteasome inhibition was also ameliorated by PTP1B inhibition in a human neuroblastoma cell line and mouse primary cortical neurons. Consistently, downregulation of the PTP1B homologue gene in Drosophila mitigated rotenone- and MG132-induced toxicity. Taken together, these findings indicate that PTP1B inhibition may represent a novel therapeutic approach for ER stress-mediated neurodegenerative diseases.

• 대한약학회:학술대회논문집
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• 대한약학회 2002년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2
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• pp.243.2-244
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• 2002

Protein-tyrosine phosphatases (PTPs) constitute a family of receptor-like and cytoplasmic enzymes. which catalyze the dephosphorylation of phosphotyrosine residues in a variety of receptors and signaling molecules. Thirty subtypes of PTPs have been identified in human genomes. Among PTPs, PTP1 B has been suggested as a negative regulator of insulin signaling. Overexpression of this enzyme has been known as a cause of obesity and type II diabetes, so it is a target for drug discovery. (omitted)

• 생약학회지
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• 제47권1호
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• pp.29-37
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• 2016

Anti-diabetic potential of the leaves of A. elata through the inhibitory activity on PTP1B and ${\alpha}$-glucosidase has not been reported. In this study, the EtOAc fraction of methanolic extract from the leaves of A. elata showed potent inhibitory activity against the PTP1B and ${\alpha}$-glucosidase with $IC_{50}$ value of $96.29{\pm}0.3$ and $264.71{\pm}14.87{\mu}g/mL$, respectively. Three known triterpenoids, oleanolic acid, oleanolic acid-28-O-${\beta}$-D-glucopyranoside and oleanolic acid-3-O-${\beta}$-D-glucopyranoside were isolated from the most active EtOAc fraction. We determined the chemical structure of these triterpenoids through comparisons of published nuclear magnetic resonance (NMR) spectroscopic data. Furthermore, we screened these triterpenoids for their ability to inhibit PTP1B and ${\alpha}$-glucosidase over a range of concentrations ($12.5-50{\mu}M$). All three terpenoids significantly inhibited PTP1B in a concentration dependent manner and oleanolic acid effectively inhibited ${\alpha}$-glucosidase. In addition, these compounds revealed potent inhibitory activity with negative binding energies toward PTP1B, showing high affinity and tight binding capacity in the molecular docking studies. Therefore, the results of the present study clearly demonstrate that A. elata leaves and its triterpenoid constituents might be beneficial in the prevention or treatment of diabetic disease.