Serum Fractalkine Levels Were Positively Associated with Disease Severity of Liver Cirrhosis.

OBJECTIVE: The chemokine receptor CX3CR1 and its specific ligand fractalkine (CX3CL1, FKN) has been implicated in modulating inflammatory and fibroproliferative diseases. The current study was performed to investigate the correlation of serum fractalkine levels with disease severity of liver fibrosis/cirrhosis (LC). METHODS: 162 LC patients and 140 healthy controls well enrolled in our study. Serum fractalkine levels were detected using commercial ELISA kit. Liver biopsy specimens were obtained using 16 G disposable needle in LC patients. The Child-Pugh grade was recorded to assess liver function. ROC curve analysis was performed to assess the potential diagnostic power of serum fractalkine with regard to the disease severity of Child-Pugh grade system. Pathological assessment of cirrhotic severity was performed by Laennec staging system. The L3 skeletal muscle index (L3SMI) was applicated to assess the nutrition status. RESULTS: Serum fractalkine levels were significantly higher in LC patients compared with healthy controls. The case group included 50 Child-Pugh A patients, 59 Child-Pugh B patients, and 53 Child-Pugh C patients. Cirrhosis patients with Child-Pugh C had drastically higher serum fractalkine levels compared with those with Child-Pugh B and A. Child-Pugh B patients showed significantly higher serum PACAP concentrations compared with those with Child-Pugh A. ROC curve analysis demonstrated that serum fractalkine may act as a potential indicator for disease progression of LC determined by Child-Pugh classification. Besides, serum fractalkine levels were positively related to ALT and AST concentrations and negatively related to L3SMI. CONCLUSION: Serum fractalkine levels were positively associated with disease severity of LC.

CircCCT3 Acts as a Sponge of miR-613 to Promote Tumor Growth of Pancreatic Cancer Through Regulating VEGFA/VEGFR2 Signaling.

BACKGROUND: Circular RNAs (CircRNAs) have been recently implicated in the progression of pancreatic cancer (PC). AIMS: To investigate the involvement of CircCCT3 in PC and studying its interactions and functioning during the progression of PC in vitro and in vivo, using methods of molecular biology and bioinformatics. STUDY DESIGN: Experimental study. METHODS: The expressions of CircCCT3 and miR-613 in pancreatic carcinoma tissues and cell lines were evaluated by quantitative real-time polymerase chain reaction (PCR). The relationship between clinical pathologic features as well as the survival rate and CircCCT3 expression was analyzed with chi-square test and the Kaplan-Meier method. CCK-8, wound healing, transwell assays, and the fluorescein isothiocyanate- AnnexinV/propidium iodide (FITC-AnnexinV/PI) assay were used to assess cell proliferation, migration, invasion, and apoptosis after CircCCT3 overexpression or downregulation. The Dual- Luciferase reporter assay, RNA immunoprecipitation (RIP), RNA pull-down and fluorescence in situ hybridization (FISH) assays were performed to validate the potential interaction of CircCCT3, miR-613, and vascular endothelial growth factor (VEGFA). The nude mouse xenograft tumor assay was used to detect CircCCT3 effects on pancreatic tumorigenesis in vivo. Western blotting analysis was performed to examine the VEGFA and the vascular endothelial growth factor receptor 2 (VEGFR2) protein expressions following. RESULTS: CircCCT3 expression was significantly increased in PC tissues (3.41 ± 0.57 vs. 1.00 ± 0.10, P < .01) and cell lines (Patu8988 2.57 ± 0.20; SW1990 2.88 ± 0.10; BxPC-3 2.45 ± 0.20; Panc02 2.99 ± 0.10 vs. H6c7 1.00 ± 0.10; all P < .001). CircCCT3 expression was negatively correlated with miR-613 expression. PC patients with high CircCCT3 expression exhibited significantly poorer overall survival rate than those patients with low CircCCT3 expression (P = .013). Moreover, it was found that CircCCT3 promoted cell proliferation, migration, and invasion, and inhibited cell apoptosis in PC cells. The CircCCT3 acted as a sponge for the miR-613 to facilitate VEGFA and VEGFR2 expression. si-CirCCT3 also inhibited tumor growth of PC in nude mice. si-CircCCT3 reduced VEGFA and VEGFR2 expression, whereas overexpression of CircCCT3 increased VEGFA and VEGFR2 expression. CONCLUSION: Increased CircCCT3 suggests a poor prognosis for PC patients and promotes the migration and invasion through targeting VEGFA/VEGFR2 signaling. CircCCT3 may serve as a potential and promising therapeutic target for PC treatment.

Noninvasive model for predicting future ischemic strokes in patients with silent lacunar infarction using radiomics.

BACKGROUND: This study aimed to investigate integrating radiomics with clinical factors in cranial computed tomography (CT) to predict ischemic strokes in patients with silent lacunar infarction (SLI). METHODS: Radiomic features were extracted from baseline cranial CT images of patients with SLI. A least absolute shrinkage and selection operator (LASSO)-Cox regression analysis was used to select significant prognostic factors based on ModelC with clinical factors, ModelR with radiomic features, and ModelCR with both factors. The Kaplan-Meier method was used to compare stroke-free survival probabilities. A nomogram and a calibration curve were used for further evaluation. RESULTS: Radiomic signature (p < 0.01), age (p = 0.09), dyslipidemia (p = 0.03), and multiple infarctions (p = 0.02) were independently associated with future ischemic strokes. ModelCR had the best accuracy with 6-, 12-, and 18-month areas under the curve of 0.84, 0.81, and 0.79 for the training cohort and 0.79, 0.88, and 0.75 for the validation cohort, respectively. Patients with a ModelCR score < 0.17 had higher probabilities of stroke-free survival. The prognostic nomogram and calibration curves of the training and validation cohorts showed acceptable discrimination and calibration capabilities (concordance index [95% confidence interval]: 0.7864 [0.70-0.86]; 0.7140 [0.59-0.83], respectively). CONCLUSIONS: Radiomic analysis based on baseline CT images may provide a novel approach for predicting future ischemic strokes in patients with SLI. Older patients and those with dyslipidemia or multiple infarctions are at higher risk for ischemic stroke and require close monitoring and intensive intervention.

Diagnostic value of STAF score in combination with D-dimer in cardioembolism.

The aim of this study was to evaluate the diagnostic value of the Score for the Targeting of Atrial Fibrillation (STAF) in combination with the serum D-dimer (DD) levels in cardioembolism(CE).This study was a retrospective case-onlystudy, consecutively including patients with acute ischemic stroke. All patients were evaluated following the STAF scoring criteria and were classified according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) etiology classification criteria. A total of 317 patients were enrolled, including 37 CE cases (11.67%). STAF ≥5 showed a sensitivity of 89% and a specificity of 91% for the diagnosis of CE, whereas DD >791.30 ng/mL had a sensitivity of 58% and a specificity of 78%. When the STAF was used in combination with the DD level, the sensitivity was 95%, and the specificity was 100%.STAF score is an excellent tool for the diagnosis of CE when combined with DD, and can facilitate the etiological classification of acute ischemic stroke.

Prevalence, risk factors, and prognosis of orthostatic hypotension in diabetic patients: A systematic review and meta-analysis.

BACKGROUND: Orthostatic hypotension (OH) is a major clinical sign of cardiovascular autonomic dysfunction in diabetic patients. Our aim was to quantitatively evaluate the prevalence and risk factors of OH in patients with diabetes mellitus (DM) and assess its prognosis. METHODS: A comprehensive search of the PubMed, Embase, China National Knowledge Infrastructure, VIP Chinese Journal, Wanfang, and SINOMED databases was conducted for related published work up to September 25, 2016, and manually searched eligible studies from the references in accordance with the inclusion criteria. RESULTS: We included 21 studies in the analysis, with a total sample size of 13,772. The pooled prevalence of OH in DM was 24% (95% confidence interval [CI]: 19-28%). Potential risk factors, that is, glycosylated hemoglobin A (HbA1c) (odds ratio [OR], 1.13, 95% CI, 1.07-1.20), hypertension (OR, 1.02, 95% CI, 1.01-1.02), and diabetic nephropathy (OR, 2.37, 95% CI, 1.76-3.19), were significantly associated with OH in DM. In addition, the prognosis of OH in DM was associated with higher risk of total mortality and cardiovascular events. CONCLUSION: The pooled prevalence of OH in DM appears high. HbA1c, hypertension, and diabetic nephropathy are risk factors for OH in DM. OH indicates poor prognosis in diabetic patients. Attention should be focused on diabetic patients with the stated risk factors to prevent OH.

The PTEN inhibitor bpV(pic) promotes neuroprotection against amyloid ß-peptide (25-35)-induced oxidative stress and neurotoxicity.

OBJECTIVES: The aim of this study was to elucidate the mechanism underlying the neuroprotective effects of the phosphatase and tensin homolog (PTEN) inhibitor, bisperoxovanadium-pic [bpV(pic)]. METHODS: We determined the effects of bpV(pic) on amyloid-ß-peptide-(25-35)-induced neurotoxicity, particularly intracellular reactive oxygen species (ROS) production and mitochondria-mediated apoptotic signaling, in a human neuroblastoma (SH-SY5Y) cell model. RESULTS: We found that exposure of SH-SY5Y cells to amyloid ß peptides (Aß25-35) resulted in a significant reduction in cell viability accompanied by increased lactate dehydrogenase (LDH) release, elevated levels of intracellular ROS, and decreased superoxide dismutase (SOD) activities, all of which were reversed by co-treatment with bpV(pic). Moreover, bpV(pic) induced significant protection against Aß25-35-induced apoptosis, and effectively suppressed mitochondria-dependent apoptotic signaling triggered by Aß25-35. DISCUSSION: Aß peptides are thought to cause neurodegeneration in Alzheimer's disease (AD), via the induction of free radical oxidative stress. Our results indicate that bpV(pic) provides protection against Aß25-35-induced oxidative stress and neurotoxicity, suggesting that bpV(pic) could be a potential therapeutic candidate in the treatment of neurodegenerative diseases such as AD.

[The protective effect of exenatide on the renal injury in diabetic rats].

OBJECTIVE: To investigate the protective effect of exenatide (Ex) on the renal injury in streptozotocin-induced diabetic rats. METHODS: Sprague-Dawley rats were randomly divided into 2 groups:normal control group (NC group, n=8) and model group. Model group was injected with low dose of streptozotocin (30 mg·kg-1) after the rats were fed with high fat and high glucose diet for 4 weeks. Seventy-two hours later, rats of blood glucose level ≥ 16.7 mmol·L-1 were divided into diabetes mellitus group (DM, n=10) and two exenatide-treated groups (Ex groups,3 or 6µg·kg-1, n=8). Ex groups subcutaneously injected with exenatide for 12 weeks, but NC group and DM group were injected with the same volume of solvent. Changes in glycolipid metabolism and renal function such as serum creatinine (Scr), urine creatinine (Ucr), blood urea nitrogen (BUN), 24 hour urine micro-albumin (24 h UMA)in the 4 groups of rats were determined and creatinine clearance rate (Ccr) were calculated. Renal oxidative stress parameters such as superoxide dismutase (SOD), malondialdehyde(MDA), glutathione per-oxidase (GSH-Px) were measured. Hematoxylin-eosin (HE) staining was used to examine pathological morphology in the renal tissues and ELISA was performed to determine the level of advanced glycation end products(AGEs), the glycosylation end product in renal tissues. RESULTS: Compared to the DM group,glycolipid metabolic abnormalities in the exenatide-treated groups were significantly ameliorated with lower levels of blood glucose,HbAlc, cholesterol and triglyceride (P < 0.05). The renal function index was markedly improved (P < 0.05) with Ccr reduced, indicating a high glomerular filtration status. Meanwhile, exenatide treatment improved the diabetes-induced pathological changes in renal morphology, substantially increased the activities of SOD and GSH-Px, and reduced the levels of MDA and AGEs. CONCLUSIONS: Exe-natide has the renal protective effect probably by the mechanisms of inhibition of AGEs production and reduction of oxidative stress in the renal tissues of diabetic rats.

Exendin-4 protects Aß(1-42) oligomer-induced PC12 cell apoptosis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) increases the risk of developing Alzheimer's disease. Most recently, GLP-1 analogs have been shown to have a significant neuroprotective role in several neurodegenerative diseases. However, few are known on its potential mechanism. OBJECTIVE: In this study, we report the effect of exendin-4 (Ex-4), a GLP-1 receptor agonist, on amyloid-ß(1-42) peptide oligomer-induced apoptosis in a PC12 neuronal cell model. METHODS: MTT, DAPI and Annexin-V/PI assays revealed that the viability of PC12 cells decreased in a dose- and time-dependent manner after exposure to amyloid-ß(1-42) oligomers. This apoptotic effect could be attenuated by Ex-4 (100-300 nM) pre-treatment, compared with the PC12 cells treated with amyloid-ß(1-42) oligomers alone. Moreover, treatment with amyloid-ß(1-42) oligomers (10 µM) resulted in a decrease in active- and pro-caspase-3 expression, as well as in Bcl-2 protein expression; suggesting that amyloid-ß(1-42) oligomers impaired neuronal cells via the apoptosis signaling pathway. A further study of this mechanism revealed that amyloid-ß oligomers (AßOs) decreased the phosphorylation of Akt and CREB. As expected, pre-treatment with Ex-4 (300 nM) increased the expression of anti-apoptotic protein Bcl-2 and reduced active caspase-3 expression levels. In addition, Ex-4 upregulated the phosphorylation levels of Akt and CREB. CONCLUSIONS: These findings indicate that GLP-1 analogue Ex-4 has a neuroprotective effect against AßO-induced PC12 cell apoptosis through reversing the impairment of the neuronal survival signaling pathway. This strongly suggests that Ex-4 is a potential therapeutic option for ameliorating AßO-induced neurotoxicity in the clinical application of Ex-4 for AD treatment, particularly when associated with diabetes.

Liraglutide prevents beta-amyloid-induced neurotoxicity in SH-SY5Y cells via a PI3K-dependent signaling pathway.

OBJECTIVES: The aim of the study was to investigate the effects of the GLP-1 analog liraglutide on beta-amyloid (Aß)-induced neurotoxicity in the human neuroblastoma cell line SH-SY5Y and study the underlying mechanisms. METHODS: Cultured SH-SY5Y cells in vitro were randomly divided into normal control group, beta-amyloid (Aß) group (20, 40, and 80 uM), and liraglutide pre-treatment group (10, 100, and 200 nM). Cell viability was determined by CCK-8 and lactate dehydrogenase (LDH). Based on its higher protection potentials, the effect of the liraglutide (100 nM) and wortmannin (200 nM) on beta-amyloid (Aß) group (40 uM) damage in human SH-SY5Ycells was examined by DAPI fluorescence staining and flow cytometry. Caspase-3, Bcl-2, Bax, Cyt-C, Akt, and P-Akt expression were detected by western blotting. RESULTS: We found that exposure of SH-SY5Y to Aß (25-35)-induced cytotoxicity, increased lactate dehydrogenase (LDH) leakage, and cellular apoptosis. Interestingly, pre-treatment with liraglutide reversed these reactions. Liraglutide afforded protection against Aß (25-35)-induced toxicity by inhibiting apoptosis, which was also confirmed by the activated caspase-3 assay. P-Akt and Bcl-2/Bax expression increased after pre-treatment with liraglutide in SH-SY5Y cells exposed to Aß (25-35), whereas cytochrome-c release decreased. This effect could be reversed by wortmannin, an inhibitor of PI3K (phosphoinositide 3-kinase). DISCUSSION: These findings suggest that liraglutide prevented Aß (25-35)-induced neurotoxicity by inhibiting neuronal apoptosis and liraglutide may have a neuroprotective effect through activation of the PI3K/Akt signaling pathway. Thus, liraglutide may be a preventive or therapeutic agent for Alzheimer's disease.

Accuracy and precision assessment of a new blood glucose monitoring system.

BACKGROUND: Blood glucose self-monitoring by individuals with diabetes is essential in controlling blood glucose levels. The International Organization for Standardization (ISO) introduced new standards for blood glucose monitoring systems (BGMS) in 2013 (ISO 15197: 2013). The CONTOUR PLUS® (CONTOUR PLUS) BGMS has been demonstrated to meet the 2013 ISO standards; however, no Chinese data on CONTOUR PLUS accuracy and precision have been published. METHODS: This study evaluated the accuracy and precision of CONTOUR PLUS BGMS in quantitative glucose testing of capillary and venous whole blood samples obtained from 363 patients at three different hospitals. RESULTS: Results of fingertip and venous blood glucose measurements by the CONTOUR PLUS system were compared with laboratory reference values to determine accuracy. Accuracy was 98.1% (96.06%-99.22%) for fingertip blood tests and 98.1% (96.02%-99.21%) for venous blood tests. Precision was evaluated across a wide range of blood glucose values (5.1-17.2 mmol/L), testing three blood samples repeatedly 15 times with the CONTOUR PLUS blood glucose meter using test strips from three lots. All within-lot results met ISO criteria (i.e., SD<0.42 mmol/L for blood glucose concentration <5.55 mmol/L; CV<7.5% for blood glucose concentration ≥5.55 mmol/L). Between-lot variations were 1.5% for low blood glucose concentration, 2.4% for normal and 3.4% for high. CONCLUSIONS: Accuracy of both fingertip and venous blood glucose measurements by the CONTOUR PLUS system was >95%, confirming that the system meets ISO 15197: 2013 requirements.

[The Effect of recombinant adiponectin on apoptosis induced by t-BHP in human umbilical vein endothelial cells].

OBJECTIVE: To investigate the protective effect and possible mechanism of recombinant adiponectin on apoptosis in Human Umbilical Vein Endothelial Cells (HUVECs) induced by tert-butyl hydroperoxide (t-BHP). METHODS: HUVECs were cultured in vitro and apoptosis was induced by t-BHP. On this basis, HUVECs were transfected with adenovirus carrying adiponectin prior to exposure to t-BHP, to further explore the protective effect of adiponectin on apoptosis induced by t-BHP. The percentage of cell viability was determined by MTT assay. The apoptotic rate was evaluated by fluorescence microsopic analysis with Hochest/PI staining. The protein levels of p-JNK, JNK and Caspase 3 were detected by Western blot. RESULTS: Following t-BHP 100 µmol/L administration for 8 h, the ratio of apoptotic cells was increased. Western blot revealed that the protein levels of p-JNK and active caspase 3 were increased(P<0.01) compared to the control group. When cells were pretreated by adenovirus with adiponectin, the apoptosis rate and protein levels of p-JNK and active caspase 3 were decreased significantly(P<0.01). CONCLUSIONS: Continuous exposure to t-BHP induced apoptosis in HUVECs. Recombinant adiponectin protected HUVECs from apoptosis induced by t-BHP, which was correlated with the downregulation of p-JNK and active Caspase 3.

[Effects of exendin-4 on methylglyoxal-induced oxidative stress in PC12 cells].

OBJECTIVE: To study whether Exendin-4(Ex-4) could influence oxidative stress in PC12 cells induced by methylglyoxal and its underlying mechanism. METHODS: PC12 cells were cultured with methylglyoxal (0,0.25,0.50,0.75,1.0,2.0 mmol/L) for 12~48 h, or PC12 cells were pretreated with Ex-4 (25, 50, 100, 200 nmol/L) for 24 h then incubatedwith methylglyoxal (0.75 mmol/L) for 24 h. MTT assay was used to measure cell viability. Fluorescent probe method was used to detect reactive oxygen species (ROS) expression. Xanthine oxidase method was used to detect superoxide dismutase (SOD)activity. With pretreatment of Exendin-4 (100 nmol/L) for 24 h,the expressions ofP-IκBα, Inhibitor of NF-κB-α IκBα were detected by Western blot after PC12 cells were exposed to methylglyoxal (0.75 mmol/L) for 1 h. RESULTS: Following methylglyoxal administration, cell viability was gradually decreased in a dose-and time-dependent manner. Pretreatment with Ex-4 for 24 hours, cellviability were gradually increased compared with methylglyoxal-alone group. Pretreatment with Ex-4 (100 nmol/L) for 24 hours, ROS expression was reduced by65.30% (P<0.01) compared with methylglyoxal-alone group, ROS expression in NAC-pretreatment group was reduced by 107.40% (P<0.01); SOD activity in the Ex-4 pretreatment group was increased by 5.30 U/mg prot (P<0.01), SOD activity in the NAC pretreatment group was increased by 8.53 U/mg prot (P<0.01);the ratio of P-IκB-α/IκB-α in the Ex-4 pretreatment group was reduced by 25.50% (P<0.01), the ratio of P-IκB-α/IκB-α in the NAC pretreatment group was reduced by 35.14% (P<0.01). CONCLUSIONS: This study demonstrates that Ex-4 can increase the viabilities of PC12 cells and protect PC12 cells from oxidative stress induced by methylglyoxal, the mechanism may involve in suppressing the activation of protein IκB-α.

Symptomatic intracerebral hemorrhage after intravenous thrombolysis in Chinese patients: comparison of prediction models.

BACKGROUND: To assess the performance of risk scores in predicting symptomatic intracranial hemorrhage (SICH) after intravenous thrombolysis (IVT). METHODS: A multicenter prospective study was performed in 811 patients who underwent IVT with standard-dose recombinant tissue plasminogen activator within 4.5 hours of acute ischemic stroke (AIS) onset in 67 stroke centers involved in the Thrombolysis Implementation and Monitor of acute ischemic Stroke in China program from May 2007 to April 2012. SEDAN (blood sugar, early infarct signs, [hyper]dense cerebral artery sign, age) score, Safe Implementation of Thrombolysis in Stroke (SITS)-SICH score, Glucose Race Age Sex Pressure Stroke Severity (GRASPS) score, Multicenter Stroke Survey (MSS) score, and Stroke Prognostication using Age and National Institutes of Health Stroke Scale (SPAN)-100 index were calculated in selected patients, and their predictive performance for SICH was compared according to the National Institute of Neurological Disorders and Stroke (NINDS), Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST), and European Cooperative Acute Stroke Study (ECASS)-II criteria. RESULTS: For predicting the risk of SICH (NINDS definition) after IVT, the area under the receiver operating characteristic (ROC) curve of MSS score was the highest (.71, P < .0001). For predicting the risk of SICH (SITS-MOST definition) after IVT, the area under the ROC curve of GRASPS score was the highest (.73, P = .005). For predicting SICH (ECASS-II definition) after IVT, the area under the ROC curve of MSS score was the highest (.73, P < .0001). CONCLUSIONS: SITS-SICH, GRASPS, and MSS scores predicted the risk of SICH after IVT in patients with AIS, but only the latter 2 were better in the Chinese population. MSS score had the best predictive performance for SICH using NINDS and ECASS-II definitions, whereas GRASPS score was the best for SICH using the SITS-MOST definition.

The role of hs-CRP, D-dimer and fibrinogen in differentiating etiological subtypes of ischemic stroke.

The aim of this study was to evaluate the diagnostic value of the serum biochemical markers high-sensitivity C-reactive protein (hs-CRP), D-dimer (DD) and fibrinogen (Fg) in differentiating etiological subtypes of ischemic stroke. This study was a retrospective case-only study, consecutively including patients with acute ischemic stroke. All patients were classified into subtypes using the TOAST classification system. A total of 317 patients were evaluated. Hs-CRP and DD levels were significantly different among the subtypes and were the highest in CE, followed by LAA and SAA; no significant difference between the subtypes was found for Fg. Hs-CRP > 6.96 mg/L was classified as the CE subtype, with a sensitivity of 41% and a specificity of 74%; DD > 791.30 ng/mL was classified as CE, with a sensitivity of 58% and a specificity of 78%. The combination of hs-CRP and DD classification as CE yielded a sensitivity of 65% and a specificity of 91%. DD > 791.30 ng/mL was considered an independent predictive factor of CE. Hs-CRP and DD could be useful for identifying the etiological subtypes of acute ischemic stroke, especially for predicting CE. The diagnostic value of DD was higher than that of hs-CRP.

Goiter and hearing impairment: A case of a male patient with Pendred syndrome.

Pendred syndrome is a rare genetic disease that causes a disturbance in thyroid hormone synthesis, which results in thyroid dysfunction and the development of goiter and sensorineural deafness. The present report describes the case of a young euthyroid male, who developed a large goiter and hearing impairment, despite no family history of these conditions. A left lobectomy and a subtotal right lobectomy were performed, and the patient was administered permanent hormone replacement therapy with thyroxine. Patients with Pendred syndrome exhibit distinct clinical features and the mechanisms associated with the molecular genetics of this disease have been clarified. Thus, gene detection is considered to be a reliable diagnostic method. Certain patients require surgical intervention in order to relieve the symptoms. Misdiagnosis can be significantly reduced by increasing the understanding of Pendred syndrome.

Robust evidence for five new Graves' disease risk loci from a staged genome-wide association analysis.

Graves' disease (GD), characterized by autoantibodies targeting antigens specifically expressed in thyroid tissues causing hyperthyroidism, is triggered by a combination of genetic and environmental factors. However, only a few loci for GD risk were confirmed in the various ethnic groups, and additional genetic determinants have to be detected. In this study, we carried out a three-stage study in 9529 patients with GD and 9984 controls to identify new risk loci for GD and found genome-wide significant associations in the overall populations for five novel susceptibility loci: the GPR174-ITM2A at Xq21.1, C1QTNF6-RAC2 at 22q12.3-13.1, SLAMF6 at 1q23.2, ABO at 9q34.2 and an intergenic region harboring two non-coding RNAs at 14q32.2 and one previous indefinite locus, TG at 8q24.22 (Pcombined < 5 × 10(-8)). The genotypes of corresponding variants at 14q32.2 and 8q24.22 were correlated with the expression levels of C14orf64 and a TG transcript skipping exon 46, respectively. This study increased the number of GD loci with compelling evidence and indicated that non-coding RNAs might be potentially involved in the pathogenesis of GD.

Exendin-4 Protects MIN6 Cells from t-BHP-Induced Apoptosis via IRE1-JNK-Caspase-3 Signaling.

Objectives. This study aimed to explore the effect of exendin-4 on t-BHP-induced apoptosis in pancreatic ß cells and the mechanism of action. Methods. Murine MIN6 pancreatic ß cells were treated with exendin-4 in the presence or absence of tert-butyl hydroperoxide (t-BHP). Cell survival was assessed by MTT staining. The percentage of apoptotic cells was determined by fluorescence microscopy analysis after Hoechst/PI staining and flow cytometric assay after Annexin V-FITC/PI staining. The activity of caspase-3 was determined using a caspase-3 activity kit. Expression of P-IRE1α, IRE1α, C-Jun N-terminal kinase (JNK), P-JNK, C-JUN, and P-C-JUN was detected by western blotting. Results. Exendin-4 was found to inhibit t-BHP-induced apoptosis in pancreatic ß-cells by downregulating caspase-3 activity. Exendin-4 also inhibited the endoplasmic reticulum transmembrane protein IRE1, the apoptosis-related signaling molecule JNK, and c-Jun activation. Conclusions. Our findings suggest that exendin-4 ultimately reduces t-BHP-induced ß-cell apoptosis. IRE1-JNK-c-Jun signaling is involved in the exendin-4-mediated modulation of ß-cell apoptosis.

Oridonin induces apoptosis and senescence by increasing hydrogen peroxide and glutathione depletion in colorectal cancer cells.

We recently demonstrated that oridonin could induce apoptosis and senescence of colon cancer cells in vitro and in vivo. However, the underlying mechanism remains unknown. In this study, the involvement of reactive oxygen species in oridonin-induced cell death and senescence was investigated in colon adenocarcinoma-derived SW1116 cells. Oridonin increased intracellular hydrogen peroxide levels and reduced the glutathione content in a dose-dependent manner. N-acetylcysteine, a reactive oxygen species scavenger, not only blocked the oridonin-induced increase in hydrogen peroxide and glutathione depletion, but also blocked apoptosis and senescence induced by oridonin, as evidenced by the decrease in Annexin V and senescence-associated ß-galactosidase- positive cells and the inhibition of oridonin-induced upregulation of p53 and p16 and downregulation of c-Myc. Moreover, exogenous catalase could inhibit the increase in hydrogen peroxide and apoptosis induced by oridonin, but not the glutathione depletion and senescence. Furthermore, thioredoxin reductase (TrxR) activity was reduced by oridonin in vitro and in cells, which may cause the increase in hydrogen peroxide. In conclusion, the increase in hydrogen peroxide and glutathione depletion account for oridonin-induced apoptosis and senescence in colorectal cancer cells, and TrxR inhibition is involved in this process. Given the importance of TrxR as a novel cancer target in colon cancer, oridonin would be a promising clinical candidate. The mechanism of oridonin-induced inhibition of TrxR warrants further investigation.

A genome-wide association study identifies two new risk loci for Graves' disease.

Graves' disease is a common autoimmune disorder characterized by thyroid stimulating hormone receptor autoantibodies (TRAb) and hyperthyroidism. To investigate the genetic architecture of Graves' disease, we conducted a genome-wide association study in 1,536 individuals with Graves' disease (cases) and 1,516 controls. We further evaluated a group of associated SNPs in a second set of 3,994 cases and 3,510 controls. We confirmed four previously reported loci (in the major histocompatibility complex, TSHR, CTLA4 and FCRL3) and identified two new susceptibility loci (the RNASET2-FGFR1OP-CCR6 region at 6q27 (P(combined) = 6.85 × 10(-10) for rs9355610) and an intergenic region at 4p14 (P(combined) = 1.08 × 10(-13) for rs6832151)). These newly associated SNPs were correlated with the expression levels of RNASET2 at 6q27, of CHRNA9 and of a previously uncharacterized gene at 4p14, respectively. Moreover, we identified strong associations of TSHR and major histocompatibility complex class II variants with persistently TRAb-positive Graves' disease.