High remnant-cholesterol levels increase the risk for end-stage renal disease: a nationwide, population-based, cohort study.

BACKGROUND: The effect of remnant-cholesterol (remnant-C) on incident end-stage renal disease (ESRD) has not been studied longitudinally. This retrospective cohort study evaluated the association between remnant-C and the development of ESRD in a nationwide Korean cohort. METHODS: Participants in a National Health Insurance Service health examination (n = 3,856,985) were followed up until the onset of ESRD. The median duration of follow-up was 10.3 years. The Martin-Hopkins equation was used to determine low-density lipoprotein cholesterol (LDL-C) levels from directly measured triglyceride, high-density lipoprotein cholesterol (HDL-C), and total cholesterol levels. Remnant-C levels were determined by subtracting HDL-C and LDL-C from total cholesterol. The risk for incident ESRD was calculated for each quartile of remnant-C, adjusting for conventional risk factors such as baseline renal function, comorbidities, and total cholesterol levels. RESULTS: ESRD developed in 11,073 (0.29%) participants. The risk for ESRD exhibited a gradual increase according to higher levels of remnant-C, with a 61% increased risk in the highest quartile than in the lowest (hazard ratio [HR] 1.61 [95% confidence interval (CI) 1.50-1.72]). The elevated risk for ESRD in the highest quartile versus the lowest quartile was more prominent in younger than in older subjects (20-29 years, HR 4.07 [95% CI 2.85-5.83]; 30-39 years, HR 2.39 [95% CI 1.83-3.13]; ≥ 70 years, HR 1.32 [95% CI 1.16-1.51]). In addition, the increased risk for ESRD related to higher remnant-C levels was greater in females than in males. CONCLUSIONS: Independent of conventional risk factors, remnant-C levels were positively associated with incident ESRD, particularly in younger populations and adult females. Reducing remnant-C levels may be a novel preventive strategy against ESRD.

Cholecystectomy increases the risk of metabolic syndrome in the Korean population: a longitudinal cohort study.

Background: Cholecystectomy is a common surgical procedure to treat symptomatic gallstones; however, the long-term outcomes after cholecystectomy are unknown. Therefore, we aimed to investigate whether incident metabolic syndrome (MetS) is associated with cholecystectomy through a large, population-based, longitudinal study. Methods: Subjects aged ≥20 years who underwent cholecystectomy from 2010 to 2014 (n=76,485) and controls (n=76,485), matched for age and sex, were identified from the Korean National Health Insurance Corporation. Cox proportional hazards analyses were performed to evaluate the association between cases and incident MetS, and hazard ratios and 95% confidence intervals (CIs) were calculated. Results: A total of 152,970 patients were included. Mean age was 52.47±12.76 years, and 50.65% of participants were male. During the follow-up period, there were 38,979 (25.48%) newly diagnosed MetS cases in the study participants. The risk of MetS in the cholecystectomy group was approximately 20% higher than that in the control group [adjusted odds ratio (OR), 1.20; 95% CI: 1.17-1.23]. In the fully adjusted models, the corresponding ORs for new-onset high waist circumference (WC), low high-density lipoprotein cholesterol (HDL-C) levels, high triglycerides (TG) levels, high blood pressure (BP), and high blood glucose levels were 1.16 (1.13-1.19), 1.19 (1.16-1.22), 1.25 (1.22-1.28), 1.27 (1.23-1.31), and 1.21 (1.18-1.24), respectively. Cholecystectomy was an independent risk factor of incident MetS, after adjusting for potential confounding factors. In the subgroup analyses, the cholecystectomy group had a higher risk of MetS than the control group in subjects without hypertension or dyslipidemia, respectively. Conclusions: In this large, population-based study, cholecystectomy was associated with an increased risk of developing MetS, independent of other confounding factors. Therefore, careful monitoring of metabolic variables and long-term follow-up are required to evaluate MetS risk after cholecystectomy.

Association between Sleep Duration and Incident Diabetes Mellitus in Healthy Subjects: A 14-Year Longitudinal Cohort Study.

BACKGROUND: This study aimed to investigate whether sleep duration and/or quality are associated with incident diabetes mellitus (DM). METHODS: A total of 8816 of 10,030 healthy participants were enrolled in a prospective cohort study. Sleep duration and quality questionnaires were completed. Sleep quality was assessed using the Epworth Sleepiness Scale (ESS), which measures excessive daytime sleepiness in individuals. RESULTS: During the 14-year follow-up period, 18% (1630/8816) were diagnosed with DM. A U-shaped relationship was observed between sleep duration and incident DM, with the highest risk observed when sleep duration was ≥10 h/day (hazard ratios (HR) 1.65 [1.25-2.17]). This group exhibited decreased insulin glycogenic index, a marker of insulin secretory function, during the study period. Among study participants who slept less than 10 h/day, the risk of incident DM increased when the ESS score was >10. CONCLUSIONS: We found that the association between sleep duration and incident DM was U-shaped; both short (≤5 h) and long (≥10 h) sleep durations were associated with an increased risk for the occurrence of incident DM. When sleep duration was 10 h or longer per day, there was a tendency to develop DM due to decreased insulin secretory function.

Remnant Cholesterol Is an Independent Predictor of Type 2 Diabetes: A Nationwide Population-Based Cohort Study.

OBJECTIVE: Although the atherogenic effect of remnant cholesterol (remnant-C) has been widely recognized, the relationship between remnant-C and glucose metabolism remains unclear. This retrospective, longitudinal study investigated the relationship between remnant-C and incident type 2 diabetes (T2D) in a nationwide cohort of Korean adults. RESEARCH DESIGN AND METHODS: A total of 8,485,539 Korean adults without diabetes participated in the national health screening in 2009 and were followed up until 2019. The relationship between remnant-C quartiles and incident T2D was examined by Cox regression models. The risk of incident T2D over the continuum of remnant-C was examined with cubic spline analysis. RESULTS: During the median follow-up period of 9.28 years, 584,649 individuals (6.8%) developed T2D. In multivariable-adjusted analyses, participants in the upper quartile of remnant-C had a higher risk of T2D, with hazard ratios of 1.25 (95% CI 1.24-1.27) in the second quartile, 1.51 (95% CI 1.50-1.53) in the third quartile, and 1.95 (95% CI 1.93-1.97) in the fourth quartile, compared with the lowest quartile. The increase in the risk of T2D owing to high remnant-C concentration was more profound in individuals with fewer traditional T2D risks, such as women, and absence of metabolic abnormalities, including impaired fasting glucose, hypertension, and atherogenic dyslipidemia. Moreover, the magnitude of the increased risk for incident T2D in individuals with higher remnant-C quartiles was higher in younger participants than older participants. CONCLUSIONS: These findings indicate that remnant-C profiles provide additional information in predicting future progression of T2D, independent of the conventional lipid parameters.

Waist circumference and end-stage renal disease based on glycaemic status: National Health Insurance Service data 2009-2018.

BACKGROUND: Obesity is associated with an increased risk of developing type 2 diabetes mellitus (T2DM) and end-stage renal disease (ESRD). This study aimed to examine the effect of waist circumference (WC) on the risk for ESRD based on glycaemic status in a Korean population-based sample. METHODS: This cohort study with a 9.2-year follow-up period used a population-based National Health Insurance Service health checkup database with approximately 10 585 852 participants who were followed up from 2009 to the time of ESRD diagnosis. WC was categorized into seven levels in 5-cm increments, with Level 4 as the reference group. Glycaemic status was categorized into the following groups: normal fasting glucose (NFG), impaired fasting glucose (IFG), newly diagnosed T2DM, T2DM treated with ≤2 oral hypoglycaemic agents (OHAs) and diabetes treated with ≥3 OHAs or insulin. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for ESRD according to WC values and glycaemic status of the participants. RESULTS: The study finally included 10 177 245 patients with a mean age of 47.1 (13.8) years. The study population included 5 604 446 men (55.1%) and 4 572 799 women (45.9%). In total, 8.3% (n = 877 143) of the study population had diabetes. During the mean follow-up of 9.2 (1.0) years (93 554 951 person-years of follow-up), 23 031 individuals were newly diagnosed with ESRD. The ESRD risk increased in parallel with an increase in WC in participants without T2DM, that is, the NFG and IFG groups (adjusted HRs [95% CIs] of WC Levels 4, 5 and 6: 1.17 [1.09-1.26], 1.37 [1.25-1.51] and 1.84 [1.63-2.07] in the NFG group and 1.06 [0.97-1.16], 1.23 [1.10-1.38] and 1.80 [1.57-2.06] in the IFG group, respectively). In patients with T2DM, the risk for ESRD was significantly increased in those with a low WC (adjusted HRs [95% CIs] of WC Level 1: 2.23 [1.77-2.80], 3.18 [2.70-3.74] and 10.31 [9.18-11.59] in patients with newly diagnosed diabetes, patients on ≤2 OHAs and those on ≥3 OHAs or insulin, respectively). The association between WC and ESRD thus showed a J-shaped pattern in patients with newly diagnosed T2DM and a U-shaped pattern in those on ≤2 OHAs and on ≥3 OHAs or insulin. CONCLUSIONS: Central obesity substantially increases the risk of developing ESRD regardless of glycaemic status. The harmful effects of low WC only become significant with the progression of T2DM.

Cholecystectomy Increases the Risk of Type 2 Diabetes in the Korean Population: Data From the National Health Insurance Cooperation Health Checkup 2010-2017.

OBJECTIVE: This study assessed whether cholecystectomy is a risk factor for newly developed type 2 diabetes mellitus (T2DM) in the Korean population. BACKGROUND: There is a lack of evidence that cholecystectomy is independently associated with insulin resistance and T2DM. METHODS: This study included all patients aged more than 20 years who had undergone cholecystectomy from 2010 to 2015 (n=55,166) and age-matched and sex-matched control subjects without cholecystectomy (n=110,332) using the National Health Insurance Service database. They were followed up until the date of newly developed T2DM or study end and the incidence of T2DM was traced over a maximum observation period of 7 years. RESULTS: Overall, 55,166 patients who underwent cholecystectomy and 110,332 age-matched and sex-matched controls were followed up for ∼4.7 years, during which, incident T2DM occurred in 5982 (3.61%) patients. Cholecystectomy was associated with 20% higher risk of T2DM after adjustment for all covariates. The cumulative incidence of T2DM also significantly increased in the cholecystectomy group for ∼7 years ( P <0.001). The adjusted hazard ratio (HR) for T2DM was the highest in the group with both cholecystectomy and obesity using the control without both cholecystectomy and obesity as a reference [HR=1.41, 95% confidence interval (CI): 1.29-1.56]. The group with cholecystectomy without obesity showed the comparable risk of incident T2DM compared with the group without cholecystectomy with obesity (HR=1.29, 95% CI: 1.20-1.40 for cholecystectomy without obesity and HR=1.24, 95% CI: 1.14-1.36 for control with obesity). CONCLUSIONS: These results provide evidence that cholecystectomy is associated with an increased risk of newly developed T2DM in the Korean population. Further research is required to elucidate the mechanism of the association between cholecystectomy and incident diabetes.

Remnant cholesterol and the risk of cardiovascular disease in type 2 diabetes: a nationwide longitudinal cohort study.

BACKGROUND: Elevated remnant cholesterol (remnant-C) is considered a risk factor for cardiovascular disease (CVD); however, whether this notion applies to the East Asian population with type 2 diabetes (T2D) has not been established. This study investigated the association between remnant-C concentrations and the risk of CVD in Korean patients with T2D. METHODS: By using the Korean National Health Insurance Service database, 1,956,452 patients with T2D and without atherosclerotic CVD who underwent regular health checks between 2009 and 2012 were included. Cox regression analyses were conducted to assess the association between remnant-C concentrations and incident CVD comprising myocardial infarction (MI) and ischemic stroke. RESULTS: In total, 50,120 (2.56%) cases of MI and 73,231 (3.74%) cases of ischemic strokes occurred during a median follow-up of 8.1 years. The adjusted hazard ratios for MI and stroke in the highest remnant-C quartile were 1.281 (95% confidence interval [CIs], 1.249-1.314) for MI and 1.22 (1.195-1.247) for ischemic stroke, compared to those in the lowest quartiles. The results were similar, based on stratified analysis by age, sex, use of statin or fibrate, and levels of other cholesterol. The increased risk of CVD in the highest remnant-C quartile was profound in patients who had a longer T2D duration. A remnant-C concentration ≥ 30 mg/dL differentiated patients who were at a higher risk of CVD, compared to patients with a lower concentrations, regardless of whether LDL-C levels were or were not on target at ≤ 100 mg/dL. CONCLUSION: In Korean patients with T2D, remnant-C was associated with CVD, independent of the LDL-C level or other conventional CVD risk factors. Our finding confirmed evidence of the causal role of remnant-C on CVD, as a residual risk of CVD, in East Asian patients with T2D.

Association of the atherogenic index of plasma with cardiovascular risk beyond the traditional risk factors: a nationwide population-based cohort study.

BACKGROUND: The atherogenic index of plasma (AIP) is composed of triglycerides and high-density lipoprotein cholesterol and is a novel marker for assessing the risk of atherogenicity and cardiometabolic health. An association between AIP and greater frequency of major adverse cardiovascular events (MACEs) in patients with type 2 diabetes mellitus and high cardiovascular (CV) disease risk has been reported. However, only few studies have examined the correlation between AIP and CV risk in general populations. We thus aimed to evaluate the relationship between AIP and CV diseases using a large-scale population dataset from the Korean National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS). METHODS: A total of 514,866 participants were enrolled from the NHIS-HEALS and classified according to the AIP quartiles. We performed univariate and multivariate Cox proportional hazards regression analyses to determine the association between AIP and MACEs, CV events, and CV mortality. RESULTS: During follow-up, we documented 12,133, 11,055, and 1942 cases of MACEs, CV events, and CV mortality, respectively. The multivariate-adjusted hazard ratios [HRs; 95% confidence interval (CI)] for MACEs gradually and significantly increased with the AIP quartiles [1.113 (1.054-1.175) in Q2, 1.175 (1.113-1.240) in Q3, and 1.278 (1.209-1.350) in Q4], following an adjustment for the conventional CV risk factors, including age, sex, body mass index, smoking, alcohol drinking, physical activities, household income, fasting glucose, systolic blood pressure, low-density lipoprotein cholesterol, and estimated glomerular filtration rate. In subgroup analyses, the association of AIP with MACEs and CV events was particularly outstanding in patients with diabetes. CONCLUSIONS: AIP was significantly associated with CV risks after adjusting for the traditional risk factors. Therefore, it may be used as an effective mass screening method to identify patients at a high risk of CV events.

Heat Shock Protein 90 Inhibitors AUY922, BIIB021 and SNX5422 Induce Bim-mediated Death of Thyroid Carcinoma Cells.

BACKGROUND/AIM: Heat shock protein 90 (HSP90) controls maturation of oncogenic client proteins of cancer cells, and thus we studied the effect of HSP 90 inhibitors on cell survival and survival-related mediators in thyroid carcinoma cells. MATERIALS AND METHODS: Human TPC-1 and SW1736 thyroid carcinoma cells were utilized. Cell viability, cytotoxic activity and apoptosis were estimated using CCK-8 assay, cytotoxicity assay and FACS analysis, respectively. RESULTS: AUY922, BIIB021 and SNX5422 decreased cell viability, and increased cytotoxic activity and the proportion of apoptotic cells. The protein levels of cleaved PARP, cleaved caspase-3, Bax and Bim were elevated, and Bcl2 protein levels were reduced. Knockdown of Bax did not change cell viability, cytotoxic activity, the proportion of apoptotic cells and cleaved caspase-3 protein levels. Meanwhile, knockdown of Bim enhanced cell viability, and diminished cytotoxic activity, the proportion of apoptotic cells and cleaved caspase-3 protein levels. AUY922, BIIB021 and SNX5422 increased the protein levels of phospho-AMPK, and decreased those of phospho-ERK1/2, and total and phospho-AKT. CONCLUSION: AUY922, BIIB021 and SNX5422 induce cytotoxicity by modulating Bim and ERK1/2, AKT and AMPK signaling in thyroid carcinoma cells.

Relationships between Thigh and Waist Circumference, Hemoglobin Glycation Index, and Carotid Plaque in Patients with Type 2 Diabetes.

BACKGROUND: This study investigated the relationships of thigh and waist circumference with the hemoglobin glycation index (HGI) and carotid atherosclerosis in patients with type 2 diabetes. METHODS: This observational study included 3,075 Korean patients with type 2 diabetes, in whom anthropometric measurements and carotid ultrasonography were conducted. HGI was defined as the measured hemoglobin A1c (HbA1c) level minus the predicted HbA1c level, which was calculated using the linear relationship between HbA1c and fasting plasma glucose levels. Carotid atherosclerosis was defined as a clearly isolated focal plaque or focal wall thickening >50% of the surrounding intima-media thickness. RESULTS: The frequency of a positive HGI decreased with increasing thigh circumference in men and increased with increasing waist circumference in women after adjusting for potential confounding variables. Thigh and waist circumference had a combined augmentative effect on the likelihood of positive HGI, which was dramatically higher in patients in higher waist-to-thigh ratio quartiles (adjusted odds ratios for the highest compared to the lowest quartile: 1.595 in men and 1.570 in women). Additionally, the larger the thigh circumference, the lower the risk of carotid atherosclerosis, although in women, this relationship lacked significance after adjustment for potential confounders. CONCLUSION: HGI was associated with thigh circumference in men and waist circumference in women. In addition, the combination of low thigh circumference and high waist circumference was strongly associated with a higher HGI in Korean patients with type 2 diabetes. In particular, thigh circumference was associated with carotid atherosclerosis in men. However, further longitudinal studies are warranted.

Underweight Increases the Risk of End-Stage Renal Diseases for Type 2 Diabetes in Korean Population: Data From the National Health Insurance Service Health Checkups 2009-2017.

OBJECTIVE: There is a controversy over the association between obesity and end-stage renal disease (ESRD) in people with or without type 2 diabetes; therefore, we examined the effect of BMI on the risk of ESRD according to glycemic status in the Korean population. RESEARCH DESIGN AND METHODS: The study monitored 9,969,848 participants who underwent a National Health Insurance Service health checkup in 2009 from baseline to the date of diagnosis of ESRD during a follow-up period of ∼8.2 years. Obesity was categorized by World Health Organization recommendations for Asian populations, and glycemic status was categorized into the following five groups: normal, impaired fasting glucose (IFG), newly diagnosed diabetes, diabetes <5 years, and diabetes ≥5 years. RESULTS: Underweight was associated with a higher risk of ESRD in all participants after adjustment for all covariates. In the groups with IFG, newly diagnosed type 2 diabetes, diabetes duration <5 years, and diabetes ≥5 years, the hazard ratio (HR) of the underweight group increased with worsening glycemic status (HR 1.431 for IFG, 2.114 for newly diagnosed diabetes, 4.351 for diabetes <5 years, and 6.397 for diabetes ≥5 years), using normal weight with normal fasting glucose as a reference. The adjusted HRs for ESRD were also the highest in the sustained underweight group regardless of the presence of type 2 diabetes (HR 1.606 for nondiabetes and 2.14 for diabetes). CONCLUSIONS: Underweight showed more increased HR of ESRD according to glycemic status and diabetes duration in the Korean population. These associations also persisted in the group with sustained BMI during the study period.

Evodiamine in combination with histone deacetylase inhibitors has synergistic cytotoxicity in thyroid carcinoma cells.

PURPOSE: The impact of evodiamine in combination with histone deacetylase (HDAC) inhibitors on survival of thyroid carcinoma cells was identified. METHODS: TPC-1 and SW1736 human thyroid carcinoma cells were used. RESULTS: After treatment with evodiamine and PXD101, cell viability, the percentage of viable cells and Bcl2 protein levels decreased, whereas cytotoxic activity, the percentage of apoptotic cells, the protein levels of γH2AX, acetyl. histone H3 and cleaved PARP, and reactive oxygen species (ROS) production increased. In cells treated with both evodiamine and PXD101, compared with PXD101 alone, decrement of cell viability, the percentage of viable cells, and Bcl2 protein levels as well as increment of cytotoxic activity, the percentage of apoptotic cells, the protein levels of γH2AX and cleaved PARP, and ROS production were significant, causing decrement of Bcl2/Bax ratio. Furthermore, all of the combination index values were <1.0, suggesting synergistic cytotoxicity of two agents. Wortmannin decreased cell viability and the percentage of viable cells, whereas it increased cytotoxic activity and the percentage of apoptotic cells without alteration in ROS production. The changes in cells treated with both evodiamine and suberoylanilide hydroxamic acid or trichostatin A were similar to those in cells treated with both evodiamine and PXD101. CONCLUSIONS: Our results demonstrate that evodiamine synergizes with HDAC inhibitors in inducing cytotoxic activities by involving survival-related proteins and ROS in thyroid carcinoma cells. Moreover, repression of PI3K/Akt signaling synergistically reinforces cytotoxicity of evodiamine combined with HDAC inhibitors in thyroid carcinoma cells.

Association between metabolic parameters and glomerular hyperfiltration in a representative Korean population without chronic kidney disease.

AIMS: To investigate associations of glomerular hyperfiltration with other metabolic factors in a nationally representative dataset. METHODS: We analyzed cross-sectional data from 15,918 subjects with estimated glomerular filtration rate (eGFR) >60 ml/min/1.73 m2 and urine albumin creation ratio (ACR) <30 mg/g, who participated in the 5th and 6th Korea National Health and Nutrition Examination Surveys. Hyperfiltration was defined as eGFR (CKD-EPI equation) exceeding the age- and sex-specific 95th percentile for healthy control subjects. RESULTS: Prevalence of hyperfiltration was 5.2% and that among normal, prediabetic, and diabetic subjects was 4.9%, 5.6%, and 7.3%, respectively, after adjusting for age, sex, and body weight (p for trend = 0.008). In a multiple logistic regression analysis, hyperfiltration was associated with a body mass index ≥30 kg/m2 [odds ratio (OR) = 3.461, p<0.001], waist circumference 85 cm (men) or 80 cm (women) (OR = 1.425, p = 0.015), systolic blood pressure 120-129 mmHg (OR = 1.644, p = 0.022), fasting plasma glucose 140 mg/dL (OR = 1.695, p = 0.033) and t serum triglyceride level 500 mg/dL (OR = 2.988, p = 0.001), and was independently associated with the ACR (B = 0.053, p<0.001). CONCLUSIONS: In a general Korean population, both hyperfiltration and ACR were associated with similar metabolic parameters, and hyperfiltration correlated independently with a high ACR. Longitudinal studies are needed to further explore risks of hyperfiltration and microalbuminuria.

Evodiamine Suppresses Survival, Proliferation, Migration and Epithelial-Mesenchymal Transition of Thyroid Carcinoma Cells.

BACKGROUND/AIM: The aim of this study was to evaluate the effect of evodiamine alone or in combination with chemotherapeutic agents on thyroid carcinoma cells. MATERIALS AND METHODS: TPC-1 and SW1736 thyroid carcinoma cells were used. Cell viability, cytotoxic activity, apoptosis and migration were examined by applying appropriate methods. Drug combination analysis was performed. RESULTS: Evodiamine treatment of cells decreased cell viability, and Bcl2 and phospho-AKT protein levels. Cytotoxic activity and the percentage of apoptotic cells increased. After co-treatment of wortmannin, cell viability, and phospho-AKT and Bcl2 protein levels decreased, and cytotoxic activity increased. In transforming growth factor-ß-treated cells, evodiamine attenuated variations in morphology, growth and migration, and increased p21 and p53 protein levels, and decreased ß-catenin, N-cadherin, vimentin, phospho-AKT, matrix metalloproteinase-2 and matrix metalloproteinase-9 protein levels. When cells were treated with both evodiamine and chemotherapeutic agents, all combination index values were lower than 1.0. CONCLUSION: Evodiamine was cytotoxic towards thyroid carcinoma cells, and repression of AKT reinforced evodiamine-induced cytotoxicity. Furthermore, evodiamine ameliorated proliferation, migration and epithelial-mesenchymal transition, and synergized with chemotherapeutic agents.

Enigma Plays Roles in Survival of Thyroid Carcinoma Cells through PI3K/AKT Signaling and Survivin.

BACKGROUND/AIM: The aim of the present study was to assess the role of enigma protein in survival of thyroid carcinoma cells. MATERIALS AND METHODS: BCPAP and 8505C human thyroid carcinoma cells were used. Cell viability using CCK-8 assay, the percentage of dead cells using trypan blue assay, cytotoxic activity using cytotoxicity assay, cell growth rate and cell migration using wound-healing assay were performed. RESULTS: In enigma siRNA-transfected cells, cell viability, and the protein levels of AKT and survivin decreased. The percentage of dead cells, cytotoxic activity and cleaved poly (ADP-ribose) polymerase (PARP) protein levels increased. After transfection of p110α plasmid, the alterations in cell viability, the percentage of dead cells, cytotoxic activity, and protein levels of AKT, survivin and cleaved PARP were abrogated. Cell growth rate and cell migration were reduced with reduction of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) protein levels, as well as increased p53 and p21 protein levels. CONCLUSION: Enigma affects cell survival through modulation of phosphatidylinositol-3 kinase/AKT signaling and survivin, and regulates cell proliferation and migration via involvement of MMP-2, MMP-9, p53 and p21 in thyroid carcinoma cells.

Synergistic cytotoxicity of the dipeptidyl peptidase-IV inhibitor gemigliptin with metformin in thyroid carcinoma cells.

PURPOSE: The influence of the dipeptidyl peptidase-IV inhibitor, gemigliptin alone or in combination with metformin on survival, proliferation, and migration of thyroid carcinoma cells was investigated. METHODS: SW1736 and TPC-1 human thyroid carcinoma cells were used. RESULTS: Gemigliptin and metformin caused cell death in a dose-dependent manner. In cells treated with both gemigliptin and metformin, compared with metformin alone, all of the combination index values were lower than 1.0, suggesting synergistic cytotoxicity of two agents. Cell viability, the percentage of viable cells, ATP levels, and mitochondrial membrane potential decreased; however, cytotoxic activity, and the protein levels of cleaved PARP, phospho-Akt and phospho-AMP-activated protein kinase (AMPK) increased. Administration of wortmannin, but not compound C, further decreased cell viability, and further increased cytotoxic activity. Moreover, compared with control, cell proliferation and migration as well as the protein levels of p53, p21, vascular cell adhesion molecule-1 (VCAM-1), and phospho-extracellular signal-regulated kinase (ERK) 1/2 decreased. The decrement of matrix metalloproteinase-2 and matrix metalloproteinase-9 protein levels was cell specific. CONCLUSIONS: Our results demonstrate that gemigliptin induces cytotoxic activity, and has a synergistic activity with metformin in inducing cytotoxicity via regulation of Akt and AMPK in thyroid carcinoma cells. Furthermore, gemigliptin augments the inhibitory effect of metformin on proliferation and migration through involvement of matrix metalloproteinase-2, matrix metalloproteinase-9, p53, p21, VCAM-1, and ERK in thyroid carcinoma cells.

Baseline Renal Function Predicts Hyponatremia in Liver Cirrhosis Patients Treated with Terlipressin for Variceal Bleeding.

OBJECTIVES: Terlipressin is safely used for acute variceal bleeding. However, side effects, such as hyponatremia, although very rare, can occur. We investigated the development of hyponatremia in cirrhotic patients who had acute variceal bleeding treated with terlipressin and the identification of the risk factors associated with the development of hyponatremia. DESIGN AND METHODS: This retrospective, case-control study investigated 88 cirrhotic patients who developed hyponatremia and 176 controls that did not develop hyponatremia and were matched in terms of age and gender during the same period following terlipressin administration. RESULTS: The overall change in serum sodium concentration and the mean lowest serum sodium concentration were 3.44 ± 9.55 and 132.44 ± 8.78 mEq/L during treatment, respectively. Multivariate analysis revealed that baseline serum sodium was an independent positive predictor, and the presence of baseline serum creatinine, HBV, DM, creatinine, and shock on admission was independent negative predictors of hyponatremia (P < 0.05). CONCLUSION: The presence of HBV, DM, the baseline serum sodium, shock on admission, and especially baseline creatinine may be predictive of the development of hyponatremia after terlipressin treatment. Therefore, physicians conduct vigilant monitoring associated with severe hyponatremia when cirrhotic patients with preserved renal function are treated with terlipressin for variceal bleeding.

The dipeptidyl peptidase-IV inhibitor gemigliptin alone or in combination with NVP-AUY922 has a cytotoxic activity in thyroid carcinoma cells.

The effect of the dipeptidyl peptidase-IV inhibitor gemigliptin alone or in combination with the heat shock protein 90 inhibitor NVP-AUY922 (AUY922) on survival of thyroid carcinoma cells was elucidated. The SW1736 and TPC-1 human thyroid carcinoma cells were used. Cell viability, the percentage of viable cells, cytotoxic activity, the percentage of apoptotic cells, and mitochondrial membrane potential were measured. To evaluate the combined effect of gemigliptin with AUY922, the interactions were estimated by calculating combination index. Gemigliptin led to cell death in conjunction with overexpression of the phosphorylated protein levels of Akt, extracellular signal-regulated kinase 1/2, and adenosine monophosphate-activated protein kinase. In gemigliptin-treated cells, wortmannin augmented cell death, whereas AZD6244 and compound C did not affect cell survival. Wortmannin decreased phosphorylated adenosine monophosphate-activated protein kinase protein levels, and AZD6244 increased phosphorylated Akt protein levels. Meanwhile, cotreatment of both gemigliptin and AUY922, compared with treatment of AUY922 alone, potentiated cell death. All the combination index values were lower than 1.0, suggesting synergistic cytotoxicity of gemigliptin with AUY922. In treatment of both gemigliptin and AUY922, compared with AUY922 alone, the protein levels of total and phosphorylated Akt, phosphorylated extracellular signal-regulated kinase 1/2, and phosphorylated adenosine monophosphate-activated protein kinase increased without alteration in those of total extracellular signal-regulated kinase 1/2 and total adenosine monophosphate-activated protein kinase. The percentage of apoptotic cells increased. The protein levels of Bax and cleaved poly (ADP-ribose) polymerase increased, whereas Bcl2 protein levels were unchanged, resulting in increment of Bax/Bcl2 ratio. Transfection of Bax small interfering RNA did not cause any variation in cell viability, the percentage of viable cells and cytotoxic activity. Our results demonstrate that gemigliptin exerts a cytotoxic activity with concomitant alterations in expression of Akt, extracellular signal-regulated kinase 1/2, and adenosine monophosphate-activated protein kinase in thyroid carcinoma cells. Furthermore, gemigliptin synergizes with AUY922 in induction of cytotoxicity via regulation of Akt, extracellular signal-regulated kinase 1/2, and adenosine monophosphate-activated protein kinase as well as involvement of Bcl2 family proteins in thyroid carcinoma cells.