1154 ROLE OF PROTEIN TYROSINE-PHOSPHATASE 1B (PTP1B) ACTIVITY IN HCV-INDUCED HEPATOCELLULAR CARCINOMA: AN IN VITRO ANALYSIS

AbstractTen 3,5-dimethylcoumarins (1–6 and 8‒11) involving six new ones (1–6), together with a known 3-methylcoumarin (7), were isolated from the aerial parts of three Chelonopsis plants, C. praecox, C. odontochila, and C. pseudobracteata. The structures of the new compounds were determined by extensive HRESIMS, 1D and 2D NMR spectroscopic analyses. According to the substitution at C-5, these coumarins were classified into 5-methyl, 5-hydroxymethyl, 5-formyl, and 5-nor types. All the isolates were assayed for their inhibition on α-glucosidase, protein tyrosine phosphatase 1B, and T-cell protein tyrosine phosphatase in vitro. Graphic Abstract

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Simulasi Docking Senyawa Aglikon Kurkuligosida A dan Turunannya pada Protein Tyrosine Phosphatase 1B (PTP1B)

PHARMACY Jurnal Farmasi Indonesia (Pharmaceutical Journal of Indonesia) ◽

10.30595/pharmacy.v16i2.5734 ◽

2019 ◽

Vol 16 (2) ◽

pp. 216

Author(s):

Nursamsiar Nursamsiar ◽

Akbar Awaluddin ◽

Megawati Megawati ◽

Yulita M. Soko ◽

Muhammad Aswad

Keyword(s):

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Protein Tyrosine Phosphatase 1B ◽

Protein Tyrosine ◽

Autodock 4.2 ◽

Diabetes Melitus

Senyawa aglikon kurkuligosida A memiliki struktur yang mirip dengan senyawa licoagrochalcone yang terbukti memiliki aktivitas penghambatan yang kuat secara in vitro pada Protein Tyrosine Phosphatase 1B (PTP1B), yang dianggap sebagai target terapeutik untuk pengobatan diabetes melitus tipe 2. Penelitian ini bertujuan untuk mengetahui interaksi antara senyawa aglikon kurkuligosida A dan turunannya dengan PTP1B menggunakan metode simulasi docking. Simulasi docking dilakukan dengan menggunakan perangkat lunak AutoDock 4.2. Hasil docking menunjukan semua senyawa yang diuji dapat berinteraksi dengan sisi aktif PTP1B. Interaksi terbaik ditunjukkan oleh senyawa 31 (3,5-dihidroksibensil-3,5-dinitrobenzoate), senyawa 39 (3,5-dihidroksibensil-4-nitrobenzoate) dan senyawa 52 (4-hidroksibensil-4-nitro bensoat) dengan nilai energi bebas ikatan berturut-turut –9,40 kkal/mol ; –9,19 kkal/mol dan –9,03 kkal/mol. Ketiga senyawa tersebut memiliki interaksi dengan sisi aktif PTP1B dengan residu asam amino Ser216 dan Arg221. Semua senyawa turunan aglikon kurkuligosida A yang diuji juga memiliki pola pengikatan yang sama dengan ligan alami pada PTP1B.

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In Vitro Enzymatic Assays of Protein Tyrosine Phosphatase 1B

Current Protocols in Pharmacology ◽

10.1002/0471141755.ph0308s13 ◽

2001 ◽

Vol 13 (1) ◽

Cited By ~ 2

Author(s):

Thomas Lubben ◽

Jill Clampit ◽

Michael Stashko ◽

James Trevillyan ◽

Michael R. Jirousek

Keyword(s):

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Protein Tyrosine Phosphatase 1B ◽

Enzymatic Assays ◽

Protein Tyrosine

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IL-6 promotes PD-L1 expression in monocytes and macrophages by decreasing protein tyrosine phosphatase receptor type O expression in human hepatocellular carcinoma

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2019-000285 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000285 ◽

Cited By ~ 3

Author(s):

Wenjie Zhang ◽

Yang Liu ◽

Zhongyi Yan ◽

Hui Yang ◽

Wei Sun ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

T Cells ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Human Hepatocellular Carcinoma ◽

Receptor Type ◽

Protein Tyrosine ◽

Post Surgery ◽

Monocytes And Macrophages

BackgroundWe have previously discovered a relationship between the low expression of protein tyrosine phosphatase, receptor type O (PTPRO) in tumor-infiltrating T cells and immunosuppression. The aim of the present study was to investigate the relationship between decreased PTPRO and increased programmed death ligand 1 (PD-L1) in both the peripheral monocytes and tumor-infiltrating macrophages of human hepatocellular carcinoma (HCC).MethodsThe expression and correlation of all the indices were explored in monocytes and tumor-infiltrating macrophages within both human and mice HCC. The mechanic regulations were studied by using both in vitro and in vivo studies.ResultsWe found a significant decrease in PTPRO in HCC peripheral monocytes that was associated with increased PD-L1 expression in peripheral monocytes and tumor-associated macrophages (TAMs) in HCC. Monocyte PD-L1 and PTPRO therefore could serve as valuable prognostic indicators for post-surgery patients with HCC and were associated with increased T-cell exhaustion (Tim3+T cells). A depletion of PTPRO promoted PD-L1 secretion in both monocytes and macrophages through the JAK2/STAT1 and JAK2/STAT3/c-MYC pathways. Increased IL-6 expression was associated with activation of JAK2/STAT3/c-MYC and with decreased PTPRO expression through the STAT3/c-MYC/miR-25–3 p axis. Monocytes and TAMs showed significantly increased miR-25–3 p expression, which could target the 3′ untranslated region of PTPRO. The miR-25–3 p expression positively correlated with serum IL-6 levels, but inversely correlated with PTPRO in HCC monocytes. IL-6/STAT3/c-MYC activation enhanced in vitro miR-25–3 p transcription and decreased PTPRO, while further promoting PD-L1 secretion. Adoptive cell transfer of c-MYC/miR-25–3 p–modified monocytes promoted tumor growth by downregulating PTPRO and causing a PD-L1–induced immunosuppression in an orthotopic tumor transplantation model.ConclusionsIncreased serum IL-6 downregulated PTPRO expression in HCC monocytes and macrophages by activating STAT3/c-MYC/miR-25–3 p and by further enhancing PD-L1 expression through JAK2/STAT1 and JAK2/STAT3/c-MYC signaling.

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Correlation Between Nasal Epithelial Injury and In Vitro Cytotoxicity Using a Series of Small Molecule Protein Tyrosine Phosphatase 1B Inhibitors Investigated for Reversal of Leptin Resistance in Obesity

International Journal of Toxicology ◽

10.1177/1091581817711877 ◽

2017 ◽

Vol 36 (4) ◽

pp. 303-313

Author(s):

Alan P. Brown ◽

Chandrassegar Saravanan ◽

Patrick Devine ◽

Maria Magnifico ◽

Jiaping Gao ◽

...

Keyword(s):

Food Consumption ◽

Small Molecule ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Sodium Dodecylbenzene Sulfonate ◽

Protein Tyrosine Phosphatase 1B ◽

Protein Tyrosine ◽

Nasal Injury ◽

Ptp1b Inhibitors

This research provides a cautionary example when evaluating changes in behavioral end points with respect to postulated pharmacologic activity. Various small molecule substrate mimetic protein tyrosine phosphatase 1B (PTP1B) inhibitors were investigated as pharmacologic agents for decreasing food consumption using intranasal (IN) dosing as a means for direct nose-to-brain delivery along the olfactory/trigeminal nerve pathways. Although food consumption was decreased in diet-induced obese (DIO) mice, nasal discharge was observed. Studies were conducted to investigate local effects on the nasal airway and to develop structure–activity relationships. Intranasal administration of PTP1B inhibitors at ≥0.03 mg/d to DIO mice produced dose-dependent injury to various cell types of the nasal epithelia. Protein tyrosine phosphatase 1B inhibitors with calculated log octanol >3.0 were the most toxic. Whereas a pharmacologically inactive analog of a PTP1B inhibitor produced nasal injury, along with decreased food consumption, the marketed IN drug ketorolac produced no lesions at the same dose of 0.3 mg/d and only minor changes at 3 mg/d. Rat skin fibroblast cells were exposed in vitro to PTP1B inhibitors, ketorolac, paraquat, and the detergent sodium dodecylbenzene sulfonate (NDS) followed by measures of cytotoxicity. The most potent PTP1B inhibitors were similar to NDS, whereas ketorolac was the least toxic compound. Cytotoxic potency in vitro was similar to in vivo. In conclusion, PTP1B inhibitors injured nasal epithelium through a mechanism independent of PTP1B inhibition and likely due to nonspecific cytotoxicity such as disruption of the cell membrane. Decreased food consumption in DIO mice was due to toxicity rather than a pharmacologic mode of action.

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