High T3 Induces β-Cell Insulin Resistance via Endoplasmic Reticulum Stress

Hyperthyroidism can cause glucose metabolism disorders and insulin resistance. Insulin resistance in muscle and adipose tissues has been extensively studied, whereas investigations on β-cell insulin resistance are limited. This study preliminarily explored the effects of high T3 levels on β-cell line (MIN6) insulin resistance, as well as the roles of endoplasmic reticulum stress (ERS). In this study, we treated β-cell line with T3, with or without an inhibitor of phosphotyrosine phosphatases (PTPs, sodium vanadate) or ERS inhibitor (4-PBA). The results indicated that high levels of T3 significantly inhibited insulin secretion in β-cell line. In addition, we observed an upregulation of p-IRS-1ser307 and downregulation of Akt. These results can be corrected by sodium vanadate. Moreover, high T3 levels upregulate the ERS-related proteins PERK, IRE1, ATF6, and GRP78, as well as ERS-related apoptosis CHOP and caspase-12. Similarly, this change can be corrected by 4-PBA. These results suggest that high T3 levels can induce insulin resistance in β-cell line by activating ERS and the apoptotic pathway.

Prognostic Value of Phosphotyrosine Phosphatases in Hepatocellular Carcinoma

Background/Aims: During the occurrence and progression of hepatocellular carcinoma (HCC), phosphotyrosine phosphatases (PTPs) are usually described as tumor suppressors or proto-oncogenes, and to some degree are correlated with the prognosis of HCC. Methods: A total of 321 patients from the Cancer Genome Atlas (TCGA) database and 180 patients from our validated cohort with hepatocellular carcinoma were recruited in this study. Kaplan-Meier, univariate and multivariate Cox proportional hazards model were used to evaluate the risk factors for survival. Quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) were applied to detect the expression levels of PTP genes. Results: After screening the data of TCGA, we identified five PTPs as HCC overall survival related PTP genes, among which only three (PTPN12, PTPRN, PTPN18) exhibited differential expression levels in our 180 paired HCC and adjacent tissues (P< 0.001). Further analysis revealed that expression of PTPN18 was positively, but PTPRN was negatively associated with prognosis of HCC both in TCGA cohort and our own cohort. As to PTPN12, results turned out to be opposite according to HBV status. In detail, higher expression of PTPN12 was associated with better outcome in HBV group but worse prognosis in Non-HBV group. Conclusion: Our results suggested that PTPN12, PTPRN and PTPN18 were independent prognostic factors in HCC.

Gene Expression Profiles of Human Phosphotyrosine Phosphatases Consequent to Th1 Polarisation and Effector Function

Phosphotyrosine phosphatases (PTPs) constitute a complex family of enzymes that control the balance of intracellular phosphorylation levels to allow cell responses while avoiding the development of diseases. Despite the relevance of CD4 T cell polarisation and effector function in human autoimmune diseases, the expression profile of PTPs during T helper polarisation and restimulation at inflammatory sites has not been assessed. Here, a systematic analysis of the expression profile of PTPs has been carried out during Th1-polarising conditions and upon PKC activation and intracellular raise of Ca2+in effector cells. Changes in gene expression levels suggest a previously nonnoted regulatory role of several PTPs in Th1 polarisation and effector function. A substantial change in the spatial compartmentalisation of ERK during T cell responses is proposed based on changes in the dose of cytoplasmic and nuclear MAPK phosphatases. Our study also suggests a regulatory role of autoimmune-related PTPs in controlling T helper polarisation in humans. We expect that those PTPs that regulate T helper polarisation will constitute potential targets for intervening CD4 T cell immune responses in order to generate new therapies for the treatment of autoimmune diseases.

The Streptococcus thermophilus protein Wzh functions as a phosphotyrosine phosphatase

Amino acid residues that are important for metal binding and catalysis in Gram-positive phosphotyrosine phosphatases were identified in the Wzh protein of Streptococcus thermophilus MR-1C by using sequence comparisons. A His-tagged fusion Wzh protein was purified from Escherichia coli cultures and tested for phosphatase activity against synthetic phosphotyrosine and phosphoserine–threonine peptides. Purified Wzh released 2316.5 ± 138.7 pmol PO4·min−1·μg−1 from phosphotyrosine peptide-1 and 2345.7 ± 135.2 pmol PO4·min−1·μg−1 from phosphotyrosine peptide-2. The presence of the phosphotyrosine phosphatase inhibitor sodium vanadate decreased purified Wzh activity by 45%–50% at 1 mmol·L–1, 74%–84% at 5 mmol·L–1, and by at least 88% at 10 mmol·L–1. Purified Wzh had no detectable activity against the phosphoserine–threonine peptide. These results clearly establish that S. thermophilus MR-1C Wzh functions as a phosphotyrosine phosphatase that could function to remove phosphate groups from proteins involved in exopolysaccharide biosynthesis, including the protein tyrosine kinase Wze and priming glycosyltransferase.

Antitumour Effects of Somatostatin Analogues in the Treatment of Neuroendocrine Tumours

Neuroendocrine tumours (NETs) are rare and heterogeneous neoplasms that can present with functional syndromes due to the hypersecretion of peptides. Somatostatin analogues (SSAs) have been used since the 1980s for the treatment of neuroendocrine tumours, with the aim of controlling the symptoms of functioning tumours and improving patients’ quality of life. Data from preclinical studies offer evidence of both direct and indirect mechanisms by which SSAs can exert antitumour effects. The activation of somatostatin receptors by SSAs leads to the activation of phosphotyrosine phosphatases, which control downstream apoptotic and antiproliferation signalling pathways. Also, the suppression of secretion of several growth factors and inhibition of antiangiogenic activity by SSAs indirectly inhibits tumour cell proliferationin vitro. Previous uncontrolled studies had shown tumour shrinkage and disappearance in response to the SSA octreotide. Recent results from the randomised and placebo-controlled PROMID trial have demonstrated that octreotide has antitumour activity in patients with metastatic mid-gut NETs. This article examines recent data providing evidence of the antitumour activity of somatostatin analogues.

Antitumour Effects of Somatostatin Analogues in the Treatment of Neuroendocrine Tumours

Neuroendocrine tumours (NETs) are rare and heterogeneous neoplasms that can present with functional syndromes due to the hypersecretion of peptides. Somatostatin analogues (SSAs) have been used since the 1980s for the treatment of neuroendocrine tumours, with the aim of controlling the symptoms of functioning tumours and improving patients’ quality of life. Data from preclinical studies offer evidence of both direct and indirect mechanisms by which SSAs can exert antitumour effects. The activation of somatostatin receptors by SSAs leads to the activation of phosphotyrosine phosphatases, which control downstream apoptotic and antiproliferation signalling pathways. Also, the suppression of secretion of several growth factors and inhibition of antiangiogenic activity by SSAs indirectly inhibits tumour cell proliferationin vitro. Previous uncontrolled studies had shown tumour shrinkage and disappearance in response to the SSA octreotide. Recent results from the randomised and placebo-controlled PROMID trial have demonstrated that octreotide has antitumour activity in patients with metastatic mid-gut NETs. This article examines recent data providing evidence of the antitumour activity of somatostatin analogues.