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Three different subsets of circulating human monocytes, CD14

SIRT1, a class III histone/protein deacetylase (HDAC), has been associated with autoimmune diseases. There is a paucity of data about the role of SIRT1 in Graves’ disease. The aim of this study was to investigate the role of SIRT1 in the pathogenesis of GD. Here, we showed that SIRT1 expression and activity were significantly decreased in GD patients compared with healthy controls. The NF-κB pathway was activated in the peripheral blood of GD patients. The reduced SIRT1 levels correlated strongly with clinical parameters. In euthyroid patients, SIRT1 expression was markedly upregulated and NF-κB downstream target gene expression was significantly reduced. SIRT1 inhibited the NF-κB pathway activity by deacetylating P65. These results demonstrate that reduced SIRT1 expression and activity contribute to the activation of the NF-κB pathway and may be involved in the pathogenesis of GD.

Emerging evidence has indicated that transforming growth factor-beta 1 (TGF-β1) induces the epithelial–mesenchymal transition (EMT) in cancer cells, thus promoting their motility and invasiveness. Quercetin, a member of the polyphenolic flavonoid family, has been reported to display anticancer activity against a broad range of cancer cell types. Indeed, numerous studies have shown the cancer preventive effects and molecular mechanisms of quercetin in vitro using diverse cell model systems. However, the potential effect of quercetin on EMT remains unclear. In this study, we identified a unique function of quercetin in inhibiting the EMT process induced by TGF-β1. In particular, quercetin rescued the morphological changes and EMT-like phenotypes in TGF-β1-activated SW480 cells, and this inhibition of TGF-β1-induced EMT was mediated via the suppression of Twist1 expression. In addition, quercetin strongly suppressed TGF-β1-induced invasion of SW480 cells. Thus, quercetin may be considered a novel therapeutic agent for the treatment of patients with refractory cancer and for the prevention of the metastatic cascade initiated by EMT.

Oxalate and calcium are the major risk factors for calcium oxalate (CaOx) stone formation. However, the exact mechanism remains unclear. This study was designed to confirm the potential function of miR-155-5p in the formation of CaOx induced by oxalate and calcium oxalate monohydrate (COM). The HK-2 cells were treated by the different concentrations of oxalate and COM for 48 h. We found that oxalate and COM treatment significantly increased ROS generation, LDH release, cellular MDA levels, and H2O2 concentration in HK-2 cells. The results of qRT-PCR and western blot showed that expression of NOX2 was upregulated, while that of SOD-2 was downregulated following the treatment with oxalate and COM in HK-2 cells. Moreover, the results of miRNA microarray analysis showed that miR-155-5p was significantly upregulated after oxalate and COM treated in HK-2 cells, but miR-155-5p inhibitor treatment significantly decreased ROS generation, LDH release, cellular MDA levels, and H2O2 concentration in HK-2 cells incubated with oxalate and COM. miR-155-5p negatively regulated the expression level of MGP via directly targeting its 3′-UTR, verified by the Dual-Luciferase Reporter System. In vivo, polarized light optical microphotography showed that CaOx crystal significantly increased in the high-dose oxalate and Ca2+ groups compared to the control group. Furthermore, IHC analyses showed strong positive staining intensity for the NOX-2 protein in the high-dose oxalate and Ca2+-treated mouse kidneys, and miR-155-5p overexpression can further enhance its expression. However, the expression of SOD-2 protein was weakly stained. In conclusion, our study indicates that miR-155-5p promotes oxalate- and COM-induced kidney oxidative stress injury by suppressing MGP expression.

Prostate cancer (PCa) is the most common malignant tumor for men. But the mechanism is unclear.

According to the X-ray crystal structures of CYP17A1 (including its complexes with inhibitors), it is shown that a hydrogen bond exists between CYP17A1 and its inhibitors (such as abiraterone and TOK-001). Previous short MD simulations (50 ns) suggested that the binding of abiraterone to CYP17A1 is stronger than that of TOK-001. In this work, by carrying out long atomistic MD simulations (200 ns) of CYP17A1 and its complexes with abiraterone and TOK-001, we observed a binding mode between CYP17A1 and abiraterone, which is different from the binding mode between CYP17A1 and TOK-001. In the case of abiraterone binding, the unfilled volume in the active site cavity increases the freedom of movement of abiraterone within CYP17A1, leading to the collective motions of the helices G and B′ as well as the breaking of hydrogen bond existing between the 3β-OH group of abiraterone and N202 of CYP17A1. However, the unfilled volume in the active site cavity can be occupied by the benzimidazole ring of TOK-001, restraining the motion of TOK-001. By pulling the two inhibitors (abiraterone and TOK-001) out of the binding pocket in CYP17A1, we discovered that abiraterone and TOK-001 were moved from their binding sites to the surface of protein similarly through the channels formed by the helices G and B′. In addition, based on the free energy calculations, one can see that it is energetically favorable for the two inhibitors (abiraterone and TOK-001) to enter into the binding pocket in CYP17A1.

Cholesterol increases the risk of aggressive prostate cancer and has emerged as a potential therapeutic target for prostate cancer. The functional roles of cholesterol in prostate cancer metastasis are not fully understood. Here, we found that cholesterol induces the epithelial-to-mesenchymal transition (EMT) through extracellular-regulated protein kinases 1/2 pathway activation, which is mediated by EGFR and adipocyte plasma membrane-associated protein (APMAP) accumulation in cholesterol-induced lipid rafts. Mechanistically, APMAP increases the interaction with EGFR substrate 15-related protein (EPS15R) to inhibit the endocytosis of EGFR by cholesterol, thus promoting cholesterol-induced EMT. Both the mRNA and protein levels of APMAP are upregulated in clinical prostate cancer samples. Together, these findings shed light onto an APMAP/EPS15R/EGFR axis that mediates cholesterol-induced EMT of prostate cancer cells. Significance: This study delineates the molecular mechanisms by which cholesterol increases prostate cancer progression and demonstrates that the binding of cholesterol-induced APMAP with EPS15R inhibits EGFR internalization and activates ERK1/2 to promote EMT.

WHAT IS KNOWN AND OBJECTIVE Drug-drug interactions (DDI) are frequent causes of adverse clinical drug reactions. Efforts have been directed at the early stage to achieve accurate identification of DDI for drug safety assessments, including the development of in silico predictive methods. In particular, similarity-based in silico methods have been developed to assess DDI with good accuracies, and machine learning methods have been employed to further extend the predictive range of similarity-based approaches. However, the performance of a developed machine learning method is lower than expectations partly because of the use of less diverse DDI training data sets and a less optimal set of similarity measures. METHOD In this work, we developed a machine learning model using support vector machines (SVMs) based on the literature-reported established set of similarity measures and comprehensive training data sets. The established similarity measures include the 2D molecular structure similarity, 3D pharmacophoric similarity, interaction profile fingerprint (IPF) similarity, target similarity and adverse drug effect (ADE) similarity, which were extracted from well-known databases, such as DrugBank and Side Effect Resource (SIDER). A pairwise kernel was constructed for the known and possible drug pairs based on the five established similarity measures and then used as the input vector of the SVM. RESULT The 10-fold cross-validation studies showed a predictive performance of AUROC >0.97, which is significantly improved compared with the AUROC of 0.67 of an analogously developed machine learning model. Our study suggested that a similarity-based SVM prediction is highly useful for identifying DDI. CONCLUSION in silico methods based on multifarious drug similarities have been suggested to be feasible for DDI prediction in various studies. In this way, our pairwise kernel SVM model had better accuracies than some previous works, which can be used as a pharmacovigilance tool to detect potential DDI.

Background MicroRNAs are often abnormally expressed in human non‐small cell lung cancer (NSCLC) and are thought to play a critical role in the emergence or maintenance of NSCLC by binding to its target messenger RNA. We assessed the effects of miR‐155 on cell proliferation and invasion to elucidate the role played by miR‐155/PDCD 4 in NSCLC. Methods Quantitative reverse transcription‐PCR, Western blotting, and cell counting kit‐8, luciferase, and transwell invasion assays were conducted on a normal human bronchial epithelial cell line (BEAS‐2B) and three NSCLC cell lines (SPC‐A‐1, A549, and H2170). Results We confirmed that miR‐155 was upregulated, while PDCD 4 messenger RNA and protein levels were downregulated in NSCLC cell lines. miR‐155 negatively regulated PDCD 4 at both transcriptional and post‐transcriptional levels. Moreover, PDCD 4 was forecast as an assumed target of miR‐155 using bioinformatic methods and we demonstrated that PDCD 4 was a direct target of miR‐155 using luciferase reporter assays. Furthermore, PDCD 4 overexpression could restrain NSCLC proliferation and invasion induced by miR‐155. Conclusion Our results collectively demonstrate that miR‐155 exerts an oncogenic role in NSCLC by directly targeting PDCD 4.

BACKGROUND The aim of this study was to explore the association between glycated hemoglobin (HbA1c) level and albuminuria in young nondiabetic people with obesity. MATERIAL AND METHODS A total of 537 young nondiabetic people with obesity were enrolled in this cross-sectional study, which was approved by the Rui-jin Hospital Ethics Committee. Albuminuria was defined as a urinary albumin-to-creatinine ratio (ACR) ≥30 mg/g. Multivariate logistic regression was used to analyze the association between HbA1c level and albuminuria. RESULTS Urinary ACR progressively increased across the tertiles of HbA1c level (P for trend

Objective Thymic neuroendocrine tumor is the second-most prevalent cause of ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS), which is a rare disease characterized by ectopic ACTH oversecretion from nonpituitary tumors. However, the genetic abnormalities of thymic neuroendocrine tumors with EAS remain largely unknown. We aim to elucidate the genetic abnormalities and identify the somatic mutations of potential tumor-related genes of thymic neuroendocrine tumors with EAS by whole exome sequencing. Design and methods Nine patients with thymic neuroendocrine tumors with EAS who were diagnosed at Shanghai Clinical Center for Endocrine and Metabolic Diseases in Ruijin Hospital between 2002 and 2014 were enrolled. We performed whole exome sequencing on the DNA obtained from thymic neuroendocrine tumors and matched peripheral blood using the Hiseq2000 platform. Results We identified a total of 137 somatic mutations (median of 15.2 per tumor; range, 1–24) with 129 single-nucleotide mutations (SNVs). The predominant substitution in these mutations was C:G > T:A transition. Approximately 80% of detected mutations resulted in amino acid changes. However, we failed to discover any recurrent mutations in these nine patients. By functional predictions, HRAS, PAK1 and MEN1, previously reported in neuroendocrine tumors, were identified as candidate tumor-related genes associated with thymic neuroendocrine tumors. Conclusions Using whole exome sequencing, we identified genetic abnormalities in thymic neuroendocrine tumors with EAS. Thereby, this study acts as a further supplement of the genetic features of neuroendocrine tumors. Somatic mutations of three potential tumor-related genes (HRAS, PAK1 and MEN1) might contribute to the tumorigenesis of thymic neuroendocrine tumors with EAS.

VSIG4 has been recently described as a B7 family-related protein. The immunotherapeutic potential of dendritic cells (DCs) transfected with VSIG4 recombinant adenovirus has not been characterized. In the present study, DCs were transfected with human VSIG4 (hVSIG4) recombinant adenovirus, a novel costimulatory molecule known to be a potent inhibitor of T cell activation. Transfected DCs were cocultured with allogeneic T cells and proliferation, cytokine production and T cell activation marker expression were assessed. The results showed that T cell proliferation potential, cytokine production and activation marker expression were suppressed after coculture with hVSIG4 recombinant adenovirus-transfected DCs. These findings suggest that DCs transfected with hVSIG4 recombinant adenovirus are capable of inducing allogeneic T cell suppression, which represents an ideal strategy for manipulating the immune response to transplanation or autoimmune diseases.