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Src homology phosphotyrosyl phosphatase 2 (SHP2) is a protein tyrosine phosphatase encoded by PTPN11, which catalyzes the dephosphorylation of protein tyrosine. As a convergence node, SHP2 mediates multiple signaling pathways such as rat sarcoma (RAS)-rapidly accelerated fibrosarcoma (RAF)-mitogen-activated extracellular signal-regulated kinase (MEK)-extracellular regulated protein kinases (ERK), phosphatidylinositol 3-kinase (PI3K)-serine/threonine kinase (AKT), janus kinase (JAK)-signal transducer and activator of transcription (STAT) and programmed death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1). It can not only regulate the growth and proliferation of tumor cells, but also mediate the immune escape of tumor cells by influencing the tumor microenvironment. Given its dual biological functions in tumor immune regulation, SHP2 is a promising target for cancer immunotherapy. To date, several SHP2 allosteric inhibitors have been advanced into clinical trials for tumor immunotherapy with single or combination therapeutic strategies. Additionally, SHP2 activators also showed therapeutic potential in the field of tumor immune modulation. In this paper, we reviewed the dual function of SHP2 in both tumor and immune cells. Besides, the challenges and prospects of SHP2 modulators in cancer immunotherapy were also briefly discussed, aiming to explore new horizon of SHP2 modulators for tumor immunotherapy.
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OBJECTIVE To analyze the patents of new target oral drugs for type 2 diabetes mellitus （T2DM）， and to provide references for the research and development direction and patent layout of new domestic diabetes drugs. METHODS Based on global patent data in the HimmPat database， from multiple perspectives such as the number of patent applications and authorization， development trend， regional distribution and main applicants， statistics and analysis were performed for the patents related to 3 types of new target oral drugs for T2DM， such as glucokinase activator （GKA）， protein tyrosine phosphatase 1B inhibitor （PTP-1B-IN）， and 11β-hydroxysteroid dehydrogenase 1 inhibitor （11β-HSD1-IN）. RESULTS & CONCLUSIONS A total of 1 649 patents of GKA， 709 patents of PTP-1B-IN， 592 patents of 11β-HSD1-IN were obtained， the main applicants were well-known pharmaceutical companies， which possessed the core patents of pharmaceutical compounds. The research on GKA drugs was more mature， with a larger number of patent applications and a more comprehensive enterprise layout. Domestic enterprises， universities and research institutions had advantages in the field of PTP-1B-IN. Domestic enterprises and research institutions can leverage the advantages of traditional Chinese medicine and resources to enhance their research capabilities and improve technological competitiveness through core technology exploration， the exploration of process route， patent layout， industry- university-research cooperation and the establishment of patent pool.
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OBJECTIVES@#To observe the effect of type 2 diabetes mellitus (T2DM) on mandibular bone regeneration and the expression of factors related to T helper cell 17 (Th17 cell) and regulatory T cell (Treg cell) in mice.@*METHODS@#Thirty-six 6-week-old C57BL/6J male mice were randomly divided into normal control (NC) and T2DM groups. Fasting blood glucose levels were detected 0 d, 7 d, 14 d, and 28 d after surgery for mandibular defects. Hematoxylin-eosin (HE) staining was used in observing the bone after 7 d, 14 d, and 28 d of the healing process. Immunohistochemical staining was used in observing the expression of alkaline phosphatase (ALP), Runt-related transcription factor 2 (RUNX2), forkhead box protein P3 (Foxp3), retinoic acid related orphan receptor gamma T (RORγt), and protein tyrosine phosphatase non-receptor type 2 (PTPN2) after 7 d, 14 d, and 28 d of healing.@*RESULTS@#HE staining showed that the area with new bones in the T2DM group was significantly smaller than that in the NC group. Immunohistochemical staining showed that the expression of osteogenesis related proteins ALP and RUNX2 were significantly reduced in the T2DM group. In addition, the number of RORγt positive cells increased, whereas the number of Foxp3 positive cells and the expression PTPN2 decreased significantly in the mandibular bone defect in mice with T2DM.@*CONCLUSIONS@#T2DM significantly inhibit mandibular bone regeneration in mice. Decline in PTPN2 expression and the transition of Treg and Th17 may be the underlying molecular mechanisms.
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Animals , Male , Mice , Bone Regeneration , Diabetes Mellitus, Type 2 , Forkhead Transcription Factors , Mice, Inbred C57BL , TCF Transcription Factors , Th17 CellsABSTRACT
Objective:To investigate the expression of long non-coding RNA (lncRNA) BDNF-AS in kidney cancer tissues, and its effect on the proliferation and migration ability of kidney cancer cells and the molecular mechanism.Methods:Real-time reverse quantitative polymerase chain reaction (rRT-PCR) was used to detect the expression levels of BDNF-AS gene in renal cancer tissues, tumor-adjacent tissues of 67 renal cancer patients and normal renal tubular epithelial cells HK-2 and renal cancer cell lines A498, ACHN, OS-RC-2, Caki-1, 786-O in Huangshi Central Hospital of Edong Medical Group from May 2017 to July 2018. The kidney cancer cell line with the lowest expression of BDNF-AS was taken as the research object. Transient transfection with BDNF-AS overexpression plasmid was treated as the experiment group or a plasmid carrying meaningless sequences was treated as the control group. rRT-PCR was used to detect transfection efficiency. After the transfection with Caki-1 for 24 h, methythiazolyl tetrazolium (MTT) method was used to detect the proliferation of cells in both groups, Transwell migration assay was applied to detect the cell migration ability, rRT-PCR was used to detect the expression level of protein tyrosine phosphatase receptor type G (PTPRG) mRNA and Western blot was used to detect the expression level of PI3K-AKT pathway related-proteins.Results:The relative expression level of BDNF-AS in kidney cancer tissues was lower than that in tumor-adjacent tissues (0.96±0.24 vs. 4.62±0.84, t = 41.76, P < 0.01). The relative expression of BDNF-AS in kidney cancer cell lines was lower than that in normal renal tubular epithelial cells HK-2 (all P < 0.05), and the relative expression in Caki-1 cells was the lowest (0.10±0.01). The relative expression of BDNF-AS in the experimental group was higher than that in the control group ( P < 0.01). From the second day of transfection, the proliferation ability of Caki-1 cells in the experimental group was lower than that in the control group (all P < 0.05). The number of Caki-1 migrated cells in the experimental group was lower than that in the control group after migration for 15 h of Caki-1 cells transfected for 24 h [(51±8) vs. (192±25), t = 5.31, P < 0.01]. After 48 h transfection, the relative expression of PTPRG mRNA in Caki-1 cells ( P < 0.01) and protein expression of the experimental group were higher than those of the control group, the expression levels of PI3K-AKT signaling pathway related-proteins p-PI3K, p-AKT, p-Tpl2 in Caki-1 cells of the experimental group were lower than those of the control group. Conclusions:The expression of BDNF-AS is down-regulated in kidney cancer tissues and cell lines. Overexpression of BDNF-AS can inhibit the proliferation and migration ability of kidney cancer Caki-1 cells. The molecular mechanism may be related to the transduction that BDNF-AS promotes PTPRG gene expression and interferes with PI3K-AKT signaling pathway.
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OBJECTIVE@#Duranta repens is reported to contain a wide array of secondary metabolites, including α-amylase and α-glucosidase inhibitors, and - has potent antioxidant activity. The present study evaluated the network pharmacology of D. repens (whole plant) with targets related to diabetes mellitus and assessed its outcome by evaluating the effects of the hydroalcoholic extract of D. repens in streptozotocin-nicotinamide-induced diabetes mellitus in rats.@*METHODS@#Phytoconstituents of D. repens were retrieved from an open-source database and published literature, and their targets were predicted for diabetes mellitus using BindingDB and the therapeutic target database. Protein-protein interaction was predicted using STRING, and pathways involved in diabetes mellitus were identified using the Kyoto Encyclopedia of Genes and Genomes pathway browser. Druglikeness, ADMET profile (absorption, distribution, metabolism, excretion and toxicity) and cytotoxicity of compounds modulating proteins involved in diabetes were predicted using MolSoft, admetSAR2.0 and CLC-Pred, respectively. The interaction network among phytoconstituents, proteins and pathways was constructed using Cytoscape, and the docking study was performed using AutoDock4.0. The hydroalcoholic extract of D. repens was evaluated using streptozotocin-nicotinamide-induced diabetes mellitus animal model for 28 d, followed by an oral glucose tolerance test. At the end of the study, biochemical parameters like glycogen content, hepatic enzymes, antioxidant biomarkers and lipid profiles were quantified. Further, the liver and pancreas were collected for a histopathology study.@*RESULTS@#Thirty-six different secondary metabolites from D. repens were identified to regulate thirty-one targets involved in diabetes mellitus, in which protein-tyrosine phosphatase 1B (PTP1B) was primarily targeted. Enrichment analysis of modulated proteins identified 12 different pathways in diabetic pathogenesis in which the phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) signaling pathway was chiefly regulated. The docking study found that durantanin I possessed the highest binding affinity (-8.9 kcal/mol) with PTP1B. Similarly, ADMET profiling showed that the majority of bioactive constituents from D. repens had higher human intestinal absorptivity and minimal cytotoxicity to normal cell lines, than tumor cell lines. Further, an in vivo animal study reflected the efficacy of the hydroalcoholic extract of D. repens to lower the elevated blood glucose level by stimulating insulin secretion, maintaining pancreatic β cell mass, regulating glycolysis/gluconeogenesis and enhancing the glucose uptake in skeletal muscles.@*CONCLUSION@#The present study reflected the probable network interaction of bioactive constituents from D. repens, their targets and modulated pathways, which identified the prime regulation of the PI3K-Akt signaling pathway and PTP1B protein. Modulation of PTP1B protein and PI3K-Akt signaling pathway could contribute to enhancing glucose uptake, insulin production and glycolysis and decreasing gluconeogenesis in diabetes, which was evaluated via the experimental study.
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Protein tyrosine phosphatase H-type receptor (PTPRH) gene encodes a gastric cancer associated protein, which exerts its biological function through tyrosine phosphorylation in the post-translational COOH- terminal region. PTPRH is abnormally expressed in a variety of tumors, and its biological function is closely related to the occurrence, development and prognosis of tumors.
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Humans , Phosphorylation , Protein Tyrosine Phosphatases , Proteins , Stomach Neoplasms , TyrosineABSTRACT
To identify novel genes in castration-resistant prostate cancer (CRPC), we downloaded three microarray datasets containing CRPC and primary prostate cancer in Gene Expression Omnibus (GEO). R packages affy and limma were performed to identify differentially expressed genes (DEGs) between primary prostate cancer and CRPC. After that, we performed functional enrichment analysis including gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway. In addition, protein-protein interaction (PPI) analysis was used to search for hub genes. Finally, to validate the significance of these genes, we performed survival analysis. As a result, we identified 53 upregulated genes and 58 downregulated genes that changed in at least two datasets. Functional enrichment analysis showed significant changes in the positive regulation of osteoblast differentiation pathway and aldosterone-regulated sodium reabsorption pathway. PPI network identified hub genes like cortactin-binding protein 2 (CTTNBP2), Rho family guanosine triphosphatase (GTPase) 3 (RND3), protein tyrosine phosphatase receptor-type R (PTPRR), Jagged1 (JAG1), and lumican (LUM). Based on PPI network analysis and functional enrichment analysis, we identified two genes (PTPRR and JAG1) as key genes. Further survival analysis indicated a relationship between high expression of the two genes and poor prognosis of prostate cancer. In conclusion, PTPRR and JAG1 are key genes in the CRPC, which may serve as promising biomarkers of diagnosis and prognosis of CRPC.
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Five pairs of optically pure meroterpenoid enantiomers (1a/1b-5a/5b) and two known compounds (6 and 7) were isolated from Rhododendron fastigiatum. Compounds 1a/1b-5a/5b were resolved from naturally scalemic mixtures by chiral HPLC. Their structures were elucidated by spectroscopic methods, X-ray crystallographic experiments, and ECD analyses. Compounds 1a/1b, 2a/2b, 3b, 4a/4b, and 5a/5b were new meroterpenoids with different polycyclic systems. Two enantiomeric pairs (2a/2b and 3a/3b), 6, and 7 exhibited inhibitory effects on protein tyrosine phosphatase 1B (PTP1B) in vitro.
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Protein tyrosine phosphatase 1B (PTP1B) has led to an intense interest in developing its inhibitors as anti-diabetes, anti-obesity and anti-cancer agents. The fruits of Rubus chingii (Chinese raspberry) were used as a kind of dietary traditional Chinese medicine. The methanolic extract of R. chingii fruits exhibited significant PTP1B inhibitory activity. Further bioactivity-guided fractionation resulted in the isolation of three PTP1B inhibitory ursane-type triterpenes: ursolic acid (1), 2-oxopomolic acid (2), and 2α, 19α-dihydroxy-3-oxo-urs-12-en-28-oic acid (3). Kinetics analyses revealed that 1 was a non-competitive PTP1B inhibitor, and 2 and 3 were mixed type PTP1B inhibitors. Compounds 1-3 and structurally related triterpenes (4-8) were further analyzed the structure-activity relationship, and were evaluated the inhibitory selectivity against four homologous protein tyrosine phosphatases (TCPTP, VHR, SHP-1 and SHP-2). Molecular docking simulations were also carried out, and the result indicated that 1, 3-acetoxy-urs-12-ene-28-oic acid (5), and pomolic acid-3β-acetate (6) bound at the allosteric site including α3, α6, and α7 helix of PTP1B.
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Humans , Enzyme Inhibitors , Chemistry , Metabolism , Fruit , Chemistry , Kinetics , Methanol , Chemistry , Molecular Docking Simulation , Molecular Structure , Plant Extracts , Chemistry , Protein Binding , Protein Tyrosine Phosphatase, Non-Receptor Type 1 , Metabolism , Protein Tyrosine Phosphatases , Rubus , Chemistry , Structure-Activity Relationship , Triterpenes , Chemistry , MetabolismABSTRACT
Eleven flavonoids were isolated from the twigs of Broussonetia papyrifera by column chromatography over silica gel,ODS,MCI gel,and Sephadex LH-20,as well as RP-HPLC.Their structures were identified by spectroscopic methods including NMR,MS,UV,and IR as broupapyrin A(1),5,7,3',4'-tetrahydroxy-3-methoxy-8-geranylflavone(2),8-prenylquercetin-3-methyl ether(3),broussonol D(4),broussoflavonol B(5),uralenol(6),broussonol E(7),8-(1,1-dimethylallyl)-5'-(3-methylbut-2-enyl)-3',4',5,7-tetrahydroxyflanvonol(8),broussoflavonol E(9),4,2',4'-trihydroxychalcone(10),and butein(11).Compound 1 is a new isoprenylated flavonol.Compounds 3,6,10,and 11 were obtained from the genus Broussonetia for the first time,and 4 and 7 were firstly discovered in B.papyrifera.Compounds 1-5 and 7-9 showed significant inhibitory effects on PTP1 B with IC50 values ranging from(0.83±0.30) to(4.66±0.83) μmol·L-1.
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Broussonetia , Chemistry , Chromatography, High Pressure Liquid , Flavonoids , Pharmacology , Magnetic Resonance Spectroscopy , Phytochemicals , Pharmacology , Protein Tyrosine Phosphatase, Non-Receptor Type 1ABSTRACT
@#Objective: To detect the expression of non-receptor protein tyrosine phosphatase 6 (PTPN6) in different esophageal squamous cell carcinoma (ESCC) cell lines, and to investigate its effect on proliferation, migration and invasion ability of Eca109 and Yes-2 cell lines. Methods: qPCR was applied to detect the mRNA expression of PTPN6 in different ESCC cell lines (TE1, Eca109, Kyse150, Kyse170 and Yes-2). pcDNA3.1-PTPN6 plasmid was transiently transfected into Eca109 and Yes-2 cells respectively. The expression of PTPN6 was detected by real-time PCR and Wb. The effects of PTPN6 over-expression on the biological behaviors of ESCC cells were detected by MTS, colony formation assay, wound healing assay and Transwell assay, respectively. Results: The mRNA expression of PTPN6 was remarkably reduced in ESCC cell lines (TE1, Eca109, Kyse150, Kyse170 and Yes-2) compared to normal esophageal epithelial cells (HEEpiC) (P<0.05). Compared to the mock cells, significant up-regulation of PTPN6 was detected in pcDNA3.1-PTPN6 transfected Eca109 and Yes-2 cells (all P<0.05 or P<0.01); PTPN6 over-expression led to a significant inhibition in migration and invasion ability of Eca109 and Yes-2 cells (all P<0.05). Conclusions: Over-expression of PTPN6 may inhibit the proliferation, migration and invasion of ESCC cells, which might be an important factor influencing the biological characteristics of ESCC cells.
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Objective: To purify the recombinant protein by using the constructed pET28a-APTP-oc recombinant expression plasmid, and to prepare the rabbit polyclonal antibody against osteoclastic protein tyrosine phosphatase (PTP-oc) and to identify its properties. Methods: The constructed pET28a-APTP-oc recombinant plasmid vyas transformed into E.CO BL21 (DE3), and the isopropyl-ß-D-thiogalactoside (IPTG) vyas used to induce the expression of recombinant protein. The recombinant protein vyas purified by the method of Q fast flovy agarose and Ni-NTA agarose, and the purified recombinant protein vyas used as an antigen to immunize the rabbit to obtain PTP-oc polyclonal antibody. The titer and specificity of the antibody vyere identified by indirect ELISA and Western blotting methods. Results: The recombinant PTP-oc protein vyas successfully purified. The indirect ELISA results shovyed that after immunizing the rabbit vyith the recombinant PTP-oc protein, the polyclonal antibody vyith the titer of 1 : 3 2000 vyas gotten. The Western blotting results shovyed that the polyclonal antibody had high specificity. Conclusion: The PTP-oc recombinant protein is successfully purified, and the polyclonal antibody of PTP-oc is prepared successfully.
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Objective To analyze the relationship between the JAK2V617F mutation and the expressions of phosphorylated Janus kinase 2 (p-JAK2), suppressor of cytokine signaling 1 (SOCS1), and SH2-containing protein tyrosine phosphatase 1 (SHP1) in JAK2V617F mutation positive myeloproliferative neoplasm (MPN) tissues, and to investigate the effects of JAK2 inhibitor ruxolitinib on regulating the proliferation of JAK2V617F mutation positive human erythroleukemia cell lines HEL and the expressions of SOCS1 and SHP1 in HEL cells. Methods A total of 48 patients with JAK2V617F mutation positive MPN (MPN group) and 24 patients with anemia (control group) in Hebei General Hospital and The First People’s Hospital of Baoding from Jul. 2012 to Aug. 2016 were enrolled in this study. The protein expressions of p-JAK2, SOCS1 and SHP1 in bone marrow biopsies (BMBs) were detected by immunohistochemistry. The correlations between JAK2V617F mutation level and the protein expressions of SOCS1 and SHP1 were analyzed by Spearman rank correlation analysis. HEL cells were treated with ruxolitinib at different concentrations (50, 100, 250, 500 and 1 000 nmol/L), and the viability of cells was determined by CCK-8 assay. The JAK2V617F mutation levels in MPN tissues and HEL cells and the mRNA expressions of JAK2, SOCS1 and SHP1 in HEL cells were detected by qPCR. The protein expressions of JAK2, SOCS1 and SHP1 in HEL cells were detected by Western blotting analysis. Results The ratio of JAK2V617F/JAK2 was (57.33±20.82)% in the MPN group and was zero in the control group. The protein expressions of p-JAK2, SOCS1 and SHP1 in BMBs of MPN patients were significantly different from those in the control group (all P0.01). The protein expressions of SOCS1 and SHP1 were negatively correlated with the mutation level of JAK2V617F (r＝－0.648, －0.692; P0.05). The expressions of SOCS1 and SHP1 in MPN patients with JAK2V617F/JAK250% were significantly higher than those in MPN patients with JAK2V617F/JAK2≥50% (P0.01), while the expression of p-JAK2 was significantly lower than that in MPN patients with JAK2V617F/JAK2≥50% (P0.01). After treatment with 250 nmol/L ruxolitinib for 24 h, 48 h, and 72 h, the viabilities of HEL cells were (60.06±3.87)%, (52.05±2.88)%, and (36.43±2.01)%, respectively. With the increase of ruxolitinib concentrations, the mRNA and protein expressions of JAK2 and the protein expression of p-JAK2 were gradually decreased (P0.01, P0.05), while the mRNA and protein expressions of SOCS1 and SHP1 were gradually increased (all P0.01). Conclusion Ruxolitinib can inhibit the expressions of JAK and the phosphorylation of JAK in HEL cells, enhance the expressions of SOCS1 and SHP1, and reduce the viability of HEL cells.
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Protein tyrosine phosphatase 1B(PTP1B),a member of protein tyrosine phosphatases(PTPs),plays a key role in the negative regulation of insulin and leptin signalings.Recent studies showed that PTP1B had an important connection with endoplasmic reticulum(ER)stress, pancreatic beta cells proliferation and insulin secretion,and is closely related to the pathological process of type 2 diabetes mellitus(T2DM)and obesity. Therefore,PIP1B targeted inhibitors have become a research hotspot in the treatment of these metabolic disea-ses.Based on the structural features of PTP1B and its relationship with T2DM and obesity,PTP1B inhibitors were classified according to the sites of binding.Their latest research advances were reviewed in this paper,providing a reference for the development of anti-T2DM and anti-obesity drugs targeting PTP1B.
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Objective:To explore the correlation of tyrosine phosphatase-1/2 (SHP-1,SHP-2) with indoleamine 2,3-dioxygenase(IDO) in maternal fetal interface.Methods: The expression of SHP-1,SHP-2 and IDO were detected by Western blot method and the relationship of the proteins was analysed,in human chorionic villi and decidua tissues of 30 cases of artificial abortion patients.Results:The expression of SHP-1,SHP-2 were positively correlated withthe expression of IDO in human chorionic villi and de-cidua;the expression of SHP-1,SHP-2 and IDO in decidual tissues were higher than those in the villi.Conclusion: Normal physiological state of pregnancy,SHP-1 and SHP-2 may be involved in the regulation of immune tolerance by positive regulation of IDO expression at maternal fetal interface.
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Objective To investigate the effect of high expression of protein tyrosine phosphatase SHP-1 on the tumor cell invasiveness and chemosensitivity of esophageal squamous cell carcinoma.Methods EC9706 ceils of esophageal squamous cell carcinoma were divided into three groups:the blank group was not given any treatment;the experimental group used SHP-1 mimic instantaneous vector to transfect cells for 24 h,and used 10 μmol/L cisplatin to treat EC9706 cells for 12 h;the control group selected 10 μmol/L cisplatin to treat EC9706 cells for 12 h.Cell proliferation was detected by using methyl thiazolyl tetrazolium (MTT) assay,and cell invasion was detected by using Transwell chamber.The expression of SHP-1 mRNA was detected by using fluorescence quantitative polymerase chain reaction.The expression level of SHP-1 protein was detected by using Western blot.Results The expression of SHP-1 mRNA in the experimental group (3.42t0.14) was higher than that in the control group and the blank group (1.09±0.13,0.42±0.24,F =9.143,P ＜ 0.05).Compared with the control group and the blank group,the cell growth inhibition rate and the apoptosis index in the experimental group were increased (both P ＜ 0.05),and the differences between any two groups were also statistically significant (all P ＜ 0.05).The cell invasion rate in the experimental group,the control group and the blank group was (6.5±1.3) ％,(18.5±2.5) ％ and (45.2±7.2) ％,respectively,and the difference was statistically significant (F =11.853,P ＜ 0.05).Conclusion High expression of SHP-1 can inhibit the invasion of esophageal squamous cell carcinoma,improve chemosensitivity,promote apoptosis and inhibit cell proliferation,which could lay a theoretical foundation for improving the efficacy of chemotherapy for esophageal squamous cell carcinoma.
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Protein tyrosine phosphatases have long been considered key regulators of biological processes and are therefore implicated in the origins of various human diseases. Heterozygosity, mutations, deletions, and the complete loss of some of these enzymes have been reported to cause neurodegenerative diseases, autoimmune syndromes, genetic disorders, metabolic diseases, cancers, and many other physiological imbalances. Vaccinia H1-related phosphatase, also known as dual-specificity phosphatase 3, is a protein tyrosine phosphatase enzyme that regulates the phosphorylation of the mitogen-activated protein kinase signaling pathway, a central mediator of a diversity of biological responses. It has been suggested that vaccinia H1-related phosphatase can act as a tumor suppressor or tumor-promoting phosphatase in different cancers. Furthermore, emerging evidence suggests that this enzyme has many other biological functions, such as roles in immune responses, thrombosis, hemostasis, angiogenesis, and genomic stability, and this broad spectrum of vaccinia H1-related phosphatase activity is likely the result of its diversity of substrates. Hence, fully identifying and characterizing these substrate-phosphatase interactions will facilitate the identification of pharmacological inhibitors of vaccinia H1-related phosphatase that can be evaluated in clinical trials. In this review, we describe the biological processes mediated by vaccinia H1-related phosphatase, especially those related to genomic stability. We also focus on validated substrates and signaling circuitry with clinical relevance in human diseases, particularly oncogenesis.
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Humans , Dual Specificity Phosphatase 3/physiology , Neoplasms/enzymology , Signal Transduction , Survival Analysis , Mitogen-Activated Protein Kinases/metabolism , Neoplasms/mortalityABSTRACT
In order to find highly active antidiabetic agents, the 3-amino group of skeletal structure of thiazolidine-2,4-diones (TZDs) was modified to generate the new molecules TM1 and TM2 in the present research. The new molecules TM3-TM6 containing rhodanine structural units were designed based upon the bioisostere and combination principles. The target molecules TM7, which is similar to the traditional TZDs structurally, were designed by connecting the phenolic hydroxyl of the above target molecules to carbazole through a linker. All of these target compounds were synthesized successfully by selecting suitable synthetic routes with optimized procedures. The assay results of peroxisome proliferator activated receptor response element (PPRE) agonist activity revealed that the PPAR agonist activity was decreased due to the change of TZD ring. The assay of α-glucosidase inhibitory activity and protein tyrosine phosphatase-1B (PTP-1B) inhibitory activity showed that most of the seven serials target molecules have weak activities in vitro. However, 3 of the compounds exhibited strong PTP-1B inhibitory activities. TM2-6 exhibited the highest inhibitory activities, which reached 96.71% with IC50 1.48 mg·L-1. In addition, the toxicity prediction disclosed that the highly active compounds were almost non-toxic. These results provide a hint for the development of new antidiabetic
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Objective: To investigate the chemical constituents from the stem and leaves of Rubus caesius and the inhibitory activities on PTP 1B. Methods: Compounds were separated and purified by silica gel column chromatography, Sephadex LH-20 column chromatography, and preparative liquid chromatography. Their structures were identified by spectral methods. The PTP1B inhibitory activities were screened by microplate reader. Results: Five compounds were obtained from the stems of R. caesius respectively, elucidated as naringin (1), apigenin-7-O-β-D-glucopyranoside (2), isoquercitrin (3), hyperoside (4), and (-)-epicatechin 3-O-gallate (ECG) (5), and two compounds were obtained from the leaves respectively, elucidated as acteoside (6) and ellagic acid (7) respectively. Conclusion: Compounds 1-7 are isolated from this plant for the first time. Different fractions and compounds showed different PTP1B inhibitory activities and acteoside showed high PTP1B inhibitory activity with the IC50 value of (27.41 ± 0.61) μg/mL. This compound may be the main active composition of leaves ethyl acetate fraction.
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Tyrosine phosphorylation, a key post-translational mechanism, is necessary for metabolic homeostasis. Protein tyrsine phosphatase 1B(PTP1B), the main negative regulator in insulin signaling pathway, is becoming a potential target for the treatment of type 2 diabetes mellitus and related metabolic diseases. In thin paper, the structural properties of PTP1B and its regulation on the mass, insulin secretion, endoplasmic reticulum ER stress and inflammation in pancreatic ß cells are reviewed. It is indicated that PTP1B inhibition is important for the protection of ß cells and the treatment of type 2 diabetes mellitus.