SIRT2-dependent DKK1 deacetylation aggravates polycystic ovary syndrome by targeting the TGF-ß1/Smad3 signaling pathway.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is a prevalent metabolic and endocrine condition in females of reproductive age. This work was to discover the underlying role of Dickkopf 1 (DKK1) and its putative regulating mechanism in P COS. METHODS: Mice recieved dehydroepiandrosterone (DHEA) injection to establish the in vivo P COS model.Hematoxylin and eosin (H&E) staining was performed for histological analysis. RT-qP CR and Western blotting were used to detect gene and protein expression. CCK-8 and flow cytometry assays were applied to detect cell viability and apoptosis. Co-immunoprecipitation (Co-IP) and immunoprecipitation (IP) were applied to assess association between DKK1 and SIRT2. RESULTS: In this work, DKK1 is downregulated in P COS rats. It was revealed that DKK1 knockdown induced apoptosis and suppressed proliferation in KGN cells, whereas DKK1 overexpression had exactly the opposite effects. In addition, DKK1 deactivates the T GF-ß1/SMad3 signaling pathway, thereby controlling KGN cell proliferation and apoptosis. Besides, SIRT2 inhibition reversed the impact of DKK1 overexpression on KGN cell proliferation and apoptosis. Furthermore, SIRT2 downregulated DKK1 expression by deacetylating DKK1 in KGN cells. DISCUSSION: Altogether, we concluded that SIRT2-induced deacetylation of DKK1 triggers T GF-ß1/Smad3 hyperactivation, thereby inhibiting proliferation and promoting apoptosis of KGN cells. The above results indicated that DKK1 might function as a latent target for P COS treatment.

Downregulation of HHLA2 inhibits ovarian cancer progression via the NF-κB signaling pathway and suppresses the expression of CA9.

HHLA2 has been recently demonstrated to play multifaceted roles in several types of cancers. However, its underlying mechanism in the progression of human ovarian cancer (OC) remains largely unexplored. In the present study, we aimed to determine whether downregulation of HHLA2 inhibited malignant phenotypes of human OC cells and explore its specific mechanism. Our results revealed that downregulation of HHLA2 by transfection with a lentiviral vector significantly suppressed the viability, invasion, and migration of OC cells. Interaction study showed that downregulation of HHLA2 in OC cells reduced the expression of CA9 and increased the expressions of p-IKKß and p-RelA. Conversely, the viability, invasion, and migration of HHLA2-depleted OC cells were increased when CA9 was upregulated. In vivo, we found that downregulation of HHLA2 significantly inhibited tumor growth, which was reversed by CA9 overexpression. In addition, downregulation of HHLA2 inhibited the OC progression via activating the NF-κB signaling pathway and decreasing the expression of CA9. Collectively, our data suggested a link between HHLA2 and NF-κB axis in the pathogenesis of OC, and these findings might provide valuable insights into the development of novel potential therapeutic targets for OC.

[circ_0092315 Promotes Proliferation and Invasion of Papillary Thyroid Carcinoma Cells via Regulating microRNA-1256/High Mobility Group A2 axis].

Objective To investigate the role and mechanism of circ_0092315 in the proliferation and invasion of papillary thyroid carcinoma cells. Methods The expression of circ_0092315 in papillary thyroid carcinoma cells was examined by real-time fluorescence quantitative PCR.The proliferation and invasion of TPC-1 cells was assessed by CCK-8 and Transwell assays.The protein level of high mobility group A2 (HMGA2) was determined by Western blotting.The regulatory relationship of circ_0092315,microRNA-1256 (miR-1256),and HMGA2 was explored by bioinformatics tools,dual-luciferase reporter assay,real-time fluorescence quantitative PCR,and Western blotting. ++++Results circ_0092315 was overexpressed in papillary thyroid carcinoma cells (all P<0.001).circ_0092315 promoted the proliferation and invasion of TPC-1 cells (all P<0.001).The transfection of si-circ_0092315 up-regulated the expression of miR-1256 (P<0.001),and miR-1256 inhibitor up-regulated the protein level of HMGA2 (P<0.001). ++++Conclusion circ_0092315 is overexpressed in TPC-1 cells and it promotes the proliferation and invasion of TPC-1 cells by regulating the miR-1256/HMGA2 axis.

LINC00173 regulates polycystic ovarian syndrome progression by promoting apoptosis and repressing proliferation in ovarian granulosa cells via the microRNA-124-3p (miR-124-3p)/jagged canonical Notch ligand 1 (JAG1) pathway.

As an endocrine and metabolic disorder, polycystic ovarian syndrome (PCOS) is common in females at childbearing age. Our work was intended to uncover the underlying role of LINC00173 and its potential regulatory mechanism in PCOS based on two cell lines (PCOS granulosa cells and KGN cells) and an in vivo model established from Sprague Dawley rats. It was revealed that LINC00173 and JAG1 expressions were upregulated, while miR-124-3p was poorly expressed in PCOS patients and PCOS rats. Functional assays showed that LINC00173 overexpression repressed proliferation and stimulated apoptosis in granulosa cells and KGN cells, while LINC00173 downregulation exhibited the opposite effects. Besides, it was verified that LINC00173 upregulated JAG1 expression in KGN cells via competitively binding to miR-124-3p. Similarly, miR-124-3p abundance was inversely related to LINC00173 and JAG1 level in PCOS. Subsequently, rescue assays elucidated that miR-124-3p upregulation or downregulation eliminated the effects on KGN cell proliferation and apoptosis mediated by LINC00173 overexpression or knockdown. In addition, it was found that the JAG1 level in KGN cells was adversely modulated by miR-124-3p and positively modulated by LINC00173. Moreover, it was further demonstrated that the reduced cell vitality and increased apoptosis of KGN cells induced by overexpressing LINC00173 could be relieved by JAG1 deletion. These findings suggested that LINC00173 could be a latent regulating factor for PCOS progression via modulating the miR-124-3p/JAG1 cascade.

Biomarkers for Early Diagnostic of Mild Cognitive Impairment in Type-2 Diabetes Patients: A Multicentre, Retrospective, Nested Case-Control Study.

BACKGROUND: Both type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are common age-associated disorders and T2DM patients show an increased risk to suffer from AD, however, there is currently no marker to identify who in T2DM populations will develop AD. Since glycogen synthase kinase-3ß (GSK-3ß) activity, ApoE genotypes and olfactory function are involved in both T2DM and AD pathogenesis, we investigate whether alterations of these factors can identify cognitive impairment in T2DM patients. METHODS: The cognitive ability was evaluated using Minimum Mental State Examination (MMSE) and Clinical Dementia Rating (CDR), and the mild cognitive impairment (MCI) was diagnosed by Petersen's criteria. GSK-3ß activity in platelet, ApoE genotypes in leucocytes and the olfactory function were detected by Western/dot blotting, the amplification refractory mutation system (ARMS) PCR and the Connecticut Chemosensory Clinical Research Center (CCCRC) test, respectively. The odds ratio (OR) and 95% confidence intervals (95% CI) of the biomarkers for MCI diagnosis were calculated by logistic regression. The diagnostic capability of the biomarkers was evaluated by receiver operating characteristics (ROC) analyses. FINDINGS: We recruited 694 T2DM patients from Jan. 2012 to May. 2015 in 5 hospitals (Wuhan), and 646 of them met the inclusion criteria and were included in this study. 345 patients in 2 hospitals were assigned to the training set, and 301 patients in another 3 hospitals assigned to the validation set. Patients in each set were randomly divided into two groups: T2DM without MCI (termed T2DM-nMCI) or with MCI (termed T2DM-MCI). There were no significant differences for sex, T2DM years, hypertension, hyperlipidemia, coronary disease, complications, insulin treatment, HbA1c, ApoE ε2, ApoE ε3, tGSK3ß and pS9GSK3ß between the two groups. Compared with the T2DM-nMCI group, T2DM-MCI group showed lower MMSE score with older age, ApoE ε4 allele, higher olfactory score and higher rGSK-3ß (ratio of total GSK-3ß to Ser9-phosphorylated GSK-3ß) in the training set and the validation set. The OR values of age, ApoE ε4 gene, olfactory score and rGSK-3ß were 1.09, 2.09, 1.51, 10.08 in the training set, and 1.06, 2.67, 1.47, 7.19 in the validation set, respectively. The diagnostic accuracy of age, ApoE ε4 gene, olfactory score and rGSK-3ß were 0.76, 0.72, 0.66, 0.79 in the training set, and 0.70, 0.68, 0.73, 0.79 in the validation set, respectively. These four combined biomarkers had the area under the curve (AUC) of 82% and 86%, diagnostic accuracy of 83% and 81% in the training set and the validation set, respectively. INTERPRETATION: Aging, activation of peripheral circulating GSK-3ß, expression of ApoE ε4 and increase of olfactory score are diagnostic for the mild cognitive impairment in T2DM patients, and combination of these biomarkers can improve the diagnostic accuracy.

Effect of single nucleotide polymorphism in thrombin-activatable fibrinolysis inhibitor on the risk of diabetic macrovascular disease.

Hypofibrinolysis is commonly found in patients with diabetes mellitus and is associated with the increased risk for many diabetic complications. An important inhibitor of fibrinolysis, thrombin-activatable fibrinolysis inhibitor (TAFI), participates in hypofibrinolysis in diabetes mellitus and may be involved in diabetic macrovascular disease. The present study was designed to determine whether TAFI polymorphisms (505G/A and 1040C/T) and TAFI levels are correlated with the development of type 2 diabetes mellitus (T2DM) and macrovascular diseases (MVDs). A total of 249 clinical samples were collected, including 102 healthy individuals (H group), 44 T2DM patients without MVD (T group) and 103 T2DM patients with MVD (M group). The 505G/A polymorphism was equally represented in the three groups. In contrast, analysis of the 1040C/T polymorphism revealed a statistically lower percentage of the T allele in the M group than in the H group (P = 0.014). This difference was due to decreased T/T homozygotes in the M groups compared with the H group (P = 0.029). The antigen TAFI level was 31.72 ±â€Š13.64% in the H group, 62.56 ±â€Š18.77% in the T group (P < 0.05, compared with the H group) and 63.70 ±â€Š15.76% in the M group (P < 0.05, compared with the H group). As high plasma TAFI level is associated with the increasing risk of T2DM, it may thus serve as a potential marker for the diagnosis of T2DM.

Percutaneous transluminal embolization with coils-treatment of pulmonary arteriovenous malformations.

The clinical values of coils embolization in the treatment of pulmonary arteriovenous malformations (PAVM) and related complications were investigated. Eleven patients with PAVMs verified by pulmonary arterial angiography were treated by transcatheter coils embolization. Chest X-ray (11 cases), computer tomography (7 cases) and/or magnetic resonance imaging (2 cases) were performed before embolization. Blood-gas analysis was done in 5 cases before and after embolization. The follow-up materials of 8 patients were collected to evaluate the effect of embolization with coils. The clinical manifestations included cerebral embolus, hemoptysis and decreased oxygenation in 9 patients and the remaining 2 had no symptoms. 9/11 cases were found by chest X-ray and 8 were diagnosed definitely. 7/7, 2/2 cases were diagnosed by CT or MR and diagnosis was made in all cases. Embolization was performed in 29 vessels. Partial pressure of oxygen in arterial blood of 5 cases changed significantly before and after embolization. Slight complications occurred in 6 patients, such as low fever, chest pain, pleurisy. The follow-up results showed that 7 cases were cured effectively. No primary and secondary device migration, and no medical paradoxical embolization occurred. It was concluded that coils embolization is a well-established method for treating PAVMs. It is a minimally invasive lung preserving treatment with high efficiency and less complication.