[Efficacy and safety of various doses of hybutimibe monotherapy or in combination with atorvastatin for primary hypercholesterolemia: a multicenter, randomized, double-blind, double-dummy, parallel-controlled phase â ¢ clinical trial].

Objective: To evaluate the efficacy and safety of hybutimibe monotherapy or in combination with atorvastatin in the treatment of primary hypercholesterolemia. Methods: This was a multicenter, randomized, double-blind, double-dummy, parallel-controlled phase Ⅲ clinical trial of patients with untreated primary hypercholesterolemia from 41 centers in China between August 2015 and April 2019. Patients were randomly assigned, at a ratio of 1∶1∶1∶1∶1∶1, to the atorvastatin 10 mg group (group A), hybutimibe 20 mg group (group B), hybutimibe 20 mg plus atorvastatin 10 mg group (group C), hybutimibe 10 mg group (group D), hybutimibe 10 mg plus atorvastatin 10 mg group (group E), and placebo group (group F). After a dietary run-in period for at least 4 weeks, all patients were administered orally once a day according to their groups. The treatment period was 12 weeks after the first dose of the study drug, and efficacy and safety were evaluated at weeks 2, 4, 8, and 12. After the treatment period, patients voluntarily entered the long-term safety evaluation period and continued the assigned treatment (those in group F were randomly assigned to group B or D), with 40 weeks' observation. The primary endpoint was the percent change in low density lipoprotein cholesterol (LDL-C) from baseline at week 12. Secondary endpoints included the percent changes in high density lipoprotein cholesterol (HDL-C), triglyceride (TG), apolipoprotein B (Apo B) at week 12 and changes of the four above-mentioned lipid indicators at weeks 18, 24, 38, and 52. Safety was evaluated during the whole treatment period. Results: Totally, 727 patients were included in the treatment period with a mean age of (55.0±9.3) years old, including 253 males. No statistical differences were observed among the groups in demographics, comorbidities, and baseline blood lipid levels. At week 12, the percent changes in LDL-C were significantly different among groups A to F (all P<0.01). Compared to atorvastatin alone, hybutimibe combined with atorvastatin could further improve LDL-C, TG, and Apo B (all P<0.05). Furthermore, there was no significant difference in percent changes in LDL-C at week 12 between group C and group E (P=0.991 7). During the long-term evaluation period, there were intergroup statistical differences in changes of LDL-C, TG and Apo B at 18, 24, 38, and 52 weeks from baseline among the statins group (group A), hybutimibe group (groups B, D, and F), and combination group (groups C and E) (all P<0.01), with the best effect observed in the combination group. The incidence of adverse events was 64.2% in the statins group, 61.7% in the hybutimibe group, and 71.0% in the combination group during the long-term evaluation period. No treatment-related serious adverse events or adverse events leading to death occurred during the 52-week study period. Conclusions: Hybutimibe combined with atorvastatin showed confirmatory efficacy in patients with untreated primary hypercholesterolemia, which could further enhance the efficacy on the basis of atorvastatin monotherapy, with a good overall safety profile.

[Platelet derived growth factor-BB regulates phenotype transformation of pulmonary artery smooth muscle cells via SIRT3 affecting glycolytic pathway].

Objective: To investigate whether platelet-derived growth factor-BB (PDGF-BB) can regulate phenotypic transformation of pulmonary artery smooth muscle cells (PASMCs) via SIRT3 affecting glycolytic pathway. Methods: The PASMCs were isolated from Sprague Dawley rats. PASMCs were divided into 3 groups by using 2-deoxyglucose (2-DG), an inhibitor of the glycolytic pathway: normal control group, PDGF-BB group(30 ng/ml) and PDGF-BB (30 ng/ml)+2-DG (10 mmol/L) group. In lentivirus-mediated overexpression assay, cells were divided into control group, PDGF-BB group(30 ng/ml), PDGF-BB+deacetylase sirtuin-3 (SIRT3) overexpression group and PDGF-BB+empty vector group. The expression levels of phenotype related index such as α-smooth muscle actin (α-SMA), smooth muscle myosin heavy chain (SM-MHC), calponin, vimentin were detected by qRT-PCR and Western blot. Meanwhile, the expression of α-SMA was detected by cellular immunofluorescence staining. EDU staining was used to detect the proliferation of PASMCs. The expression of SIRT3 was detected by Western blot. The expressions of glucose transporter 1 and aerobic glycolytic enzymes were detected by qRT-PCR and Western blot in lentivirus-mediated overexpression assay. Results: (1) PDGF-BB affects PASMCs phenotypic transformation through glycolytic pathway: compared with normal control group, PDGF-BB significantly decreased the expressions of contractile phenotype markers such as α-SMA, SM-MHC, calponin mRNA and protein (all P<0.05), but it increased the expressions of the synthetic phenotype marker vimentin mRNA and protein (both P<0.05). Cellular immunofluorescence assay showed that PDGF-BB significantly decreased the number of α-SMA positive cells, while 2-DG reversed the process. (2) PDGF-BB promoted cell proliferation through glycolytic pathway: the proliferation of PASMCs was significantly higher in PDGF-BB group than in control group (P<0.05), and which could be significantly reduced by 2-DG (P<0.05). (3) PDGF-BB inhibited the expression of SIRT3 protein in PASMCs: the expression of SIRT3 protein in PDGF-BB group was lower than that in control group (P<0.05). (4) PDGF-BB affected glycolytic pathway through SIRT3:compared with the control group, PDGF-BB significantly increased the expression levels of glucose transporter 1 (Glut1), hexokinase 2 (HK2) and 6-phosphfructo-2-kinase 3 (PFKFB3) mRNA (all P<0.05), which was reserved by over-expression of SIRT3. There were no significant difference in mRNA expression levels between PDGF-BB group and PDGF-BB+empty vector group (P>0.05).Compared with the control group, PDGF-BB significantly increased the expression levels of Glut1, HK2 and PFKFB3 protein(all P<0.05), which was reserved by over-expression of SIRT3. There were no significant differences in protein expression levels between PDGF-BB group and PDGF-BB+empty vector group (all P>0.05). Conclusion: PDGF-BB regulates phenotypic transformation of PASMCs via SIRT3 affecting glycolytic pathway.

Risks of undernutrition and malnutrition in hospitalized pediatric patients with spinal cord injury.

STUDY DESIGN: Prospective study. OBJECTIVES: To describe the nutritional risk/status of Chinese children with spinal cord injury (SCI) at admission and determine the relationship between nutritional risk/status and demography/SCI characteristics. SETTING: China Rehabilitation Research Center, Beijing, China. METHODS: Baseline clinical data, appetite level, anthropometric measurements and Screening Tool for the Assessment of Malnutrition in Pediatrics (STAMP) scores were obtained for pediatric SCI patients. The relationships among the demographic/SCI characteristics and STAMP score and z-scores of weight-for-age (WAZ), height-for-age (HAZ) and body mass index-for-age (BAZ) were assessed. The risk of undernutrition was compared with actual nutritional status. RESULTS: Forty-five children including 12 boys and 33 girls were included. The risks of undernutrition using the STAMP tool and malnutrition were 51.1% and 55.6%, respectively. Children with different demographic characteristics had similar nutritional status and risk of malnutrition. The risk of undernutrition was associated with nutritional status, including WAZ (P<0.001), HAZ (P=0.001), BAZ (P<0.001) and appetite level (P<0.001). Compared with nutritional status, STAMP had a sensitivity of 100%, a specificity of 73.3% and an overall agreement of 82.2%. As the duration of SCI increased, the risks of overweight and stunting increased. CONCLUSIONS: Nutritional screening in all pediatric SCI patients should be performed periodically. The decreasing trends in nutritional status and appetite level after SCI require special attention. The STAMP may be an alternative method for assessing nutritional status in Chinese children with SCI.

[Feasibility and efficacy of the regional cooperative ST-segment elevation myocardial infarction rescue network among the prefectural-level city hospitals].

Objective: To investigate the feasibility and efficacy of the establishment of regional cooperative acute ST-segment elevation myocardial infarction (STEMI) rescue network among the prefectural-level city hospitals in China. Methods: Based on real-time remote electrocardiogram transmission and "120" emergency systems, we established a regional collaborative STEMI treatment network with our hospital as the network unclears including 8 second-class affiliated hospitals of Jiangsu University in 2013. STEMI treatment time, therapeutic effects and economic indexes were compared before (from January 2010 to December 2012, 180 cases, pre-network) and after (From January 2013 to December 2015, 374 cases, post-network) the establishment of the regional collaborative STEMI treatment network. Results: Post establishment of the rescue network, mean first medical contact (FMC) to balloon (FMC-to-B) time, referral time and obtaining informed consent time were all significantly decreased from (191±41), (94±18), (25±9) minutes to (93±19), (53±18), (7±5) minutes, respectively, in comparison with the pre-network era(all P<0.05). There was a trend of prolonged FMC-to-B time in proportion to aging of STEMI patients(trend P<0.05). Three months post discharge, LVEF was higher (55.3%±10.7% vs. 48.8%±12.1%, P<0.05) and LVEDd was lower ((49.1±10.8)mm vs.(51.8±9.2)mm, P<0.05) in the post-network group compared to pre-network group.In-hospital mortality was also significantly reduced post the establishment of the rescue network (2.14%(8/374) vs. 3.89%(7/180), P<0.05). The results also showed that the total costs (42 017(25 069, 75 148)yuan vs.51 030(28 137, 105 861)yuan), days of hospitalization ((9.1±4.5) days vs. (15.3±4.8)days) and percentage of medicine and consumables were all significantly decreased in the post-network group compared to pre-network group(all P<0.05). Conclusion: Establishment of the regional cooperative rescue network is feasible among the prefectural-level city hospitals in China. Establishment of such network can improve the prognosis and decrease the FMC-to-B time, the rate of in-hospital mortality and financial burden of patients with STEMI, and serves as an effective strategy to improve the rescue ability for STEMI patients.

[Docosahexaenoic acid inhibits hypoxia-induced pulmonary arterial smooth muscle cells phenotype switching by inhibiting NFATc1 signaling].

Objective: To explore the molecular mechanism of docosahexaenoic acid (DHA) on regulating the phenotype switching of hypoxia-induced pulmonary arterial smooth muscle cells (PASMCs). Methods: The PASMCs were isolated from Sprague Dawley rats. PASMCs were divided into five groups: normal control group, hypoxia group (1%O(2, )94%N(2, )5% CO(2) stimulation for 12 hours), hypoxia+ DHA group (10 µmol/L DHA pretreatment followed by 12 hours hypoxia), hypoxia+ DHA+ NFATc1 overexpression group (transfection of the NFATc1 lentivirus for 24 hours, followed by hypoxia stimulation for 12 hours after 10 µmol/L DHA treatment), and hypoxia+ DHA+ siNFATc1 group (transfection the siNFATc1 for 24 hours, followed by hypoxia stimulation for 12 hours after 10 µmol/L DHA treatment). The hypoxia stimulation was achieved by use of a special hypoxia incubator (1%O(2, )94%N(2, )5%CO(2)). The expressions of NFATc1 of various groups were determined by qRT-PCR and Western blot. The expression of α-SMA was determined by immunofluorescence staining, qRT-PCR and Western blot. The expression of SM22 was determined by qRT-PCR. The proliferation of PASMC was determined by EDU staining. Results: The mRNA and protein expression levels of NFATc1 were significantly upregulated in hypoxia group compared with the normal control group (P<0.05), while hypoxia-induced upregulation of NFTAc1 could be significantly downregulated by DHA treatment (P<0.05). The α-SMA positive cell number, protein and mRNA levels of α-SMA and the mRNA level of SM22 were significantly lower in the hypoxia group than in normal control group, which could be significantly reversed by DHA, the protective effects could then be abolished by NFATc1 overexpression. Above indices were significantly lower in the hypoxia+ DHA+ siNFATc1 group than in hypoxia+ DHA+ NFATc1 overexpression group (P<0.05). The proliferation of PASMCs was significantly higher in the hypoxia group than in the control group (P<0.05), and which could be significantly reduced by DHA (P<0.05), and the protective effect of DHA could be significantly abolished by overexpression of NFATc1 (P<0.05). The proliferation of PASMCs was significantly lower in the hypoxia+ DHA+ siNFATc1 group than in the hypoxia+ DHA+ overexpression NFATc1 group (P<0.05). Conclusion: DHA could prevent hypoxia-induced PASMCs phenotype switching and proliferation by inhibiting NFATc1 signaling.

Body roundness index and body adiposity index: two new anthropometric indices to identify metabolic syndrome among Chinese postmenopausal women.

OBJECTIVES: Body roundness index (BRI) and body adiposity index (BAI) have been recently proposed to assess obesity. The objectives of this cross-sectional study were to compare their potential for identifying metabolic syndrome (MetS) with traditional obesity indices in Chinese postmenopausal women. METHODS: A total of 817 participants were involved in this study. Odds ratio and corresponding 95% confidence intervals (CI) between MetS and all indices were evaluated by binary logistic regression analysis. Receiver operating characteristic curve and area under curve (AUC) were employed to evaluate the abilities to identify MetS among all the indices. The differences in the AUC values between traditional indices and BAI as well as BRI were also evaluated. RESULTS: The upper values of all indices were significantly associated with the presence of MetS after adjusting for potential confounders, except for BAI. There were no significant differences in the AUC values between BRI and the traditional indices; however, the AUC values of all the traditional indices were significantly larger than that of BAI. CONCLUSIONS: Neither BAI nor BRI was superior to traditional obesity indices for predicting MetS. BAI showed the weakest predictive ability, while BRI showed potential for use as an alternative obesity measure in assessment of MetS.

Relationship between serum uric acid levels and metabolic syndrome in Chinese postmenopausal women.

OBJECTIVE: Serum uric acid levels have been reported to be associated with metabolic syndrome (MetS). However, few studies specifically examining the relationship between serum uric acid (SUA) levels and MetS in postmenopausal women have been reported in China. Thus, we conducted this study in order to assess the relationship between SUA levels and MetS in Chinese postmenopausal women. METHODS: A cross-sectional study of 1022 Chinese postmenopausal women (aged 42-80 years) who participated in annual health check-ups was employed. MetS was defined by National Cholesterol Education Program/Adult Treatment Panel III criteria (NCEP-ATP III). Of all the participants, 385 women were diagnosed with MetS (MetS group) and the others were without MetS (non-MetS group). SUA quartiles were defined as follows: Q1, < 3.9 mg/dl; Q2, 3.9-4.5 mg/dl; Q3, 4.6-5.1 mg/dl; Q4, 5.2-6.0 mg/dl. The association between SUA quartiles and MetS was assessed using binary logistic regression. RESULTS: The adjusted odds ratio (95% confidence interval) for the presence of metabolic syndrome in the highest SUA quartile vs. the lowest quartile was 3.768 (2.386-5.950) for all women (p < 0.01) after adjusting for age, body mass index, blood urea nitrogen, serum creatinine, total cholesterol, low density lipoprotein cholesterol and C-reactive protein. The presence of MetS significantly increased in the second, third and fourth quartiles of SUA. The prevalence of MetS increased gradually with an increasing serum uric acid quartile (p for trend < 0.001). CONCLUSION: Higher SUA levels are positively and independently associated with the presence of MetS in Chinese postmenopausal women.

Relationship between serum uric acid levels and hepatic steatosis in non-obese postmenopausal women.

OBJECTIVE: Serum uric acid levels have been reported to be associated with non-alcoholic fatty liver disease (NAFLD). However, very few studies specifically examining the relationship between serum uric acid (SUA) levels and NAFLD in postmenopausal women have been reported in China, especially in postmenopausal women with normal body mass index (BMI) in whom NAFLD is not uncommon. METHODS: A cross-sectional study was employed of 528 Chinese normal-BMI postmenopausal women (aged 41-79 years) who participated in annual health check-ups. NAFLD is defined as a hepatic steatosis observed on liver ultrasonography in the absence of a second cause. Of all the participants, 121 women were diagnosed with hepatic steatosis (NAFLD group) and the others were without (non-NAFLD group). SUA quartiles were defined as follows: Q1, < 3.8 mg/dl; Q2, 3.8-4.4 mg/dl; Q3, 4.5-5.0 mg/dl; Q4, 5.1-6.0 mg/dl. Stepwise multivariable regression analysis was used to assess the relationships between SUA level and other variables. The association between SUA quartiles and hepatic steatosis was assessed using binary logistic regression. RESULTS: Compared to the non-NAFLD group, the mean level of SUA was significantly higher in the NAFLD group (p < 0.01). The adjusted odds ratio (95% confidence interval) for the presence of hepatic steatosis in the highest SUA quartile vs. the lowest quartile was 2.774 (1.396-5.513) for all women (p < 0.01) after adjusting for the factors which were independently associated with uric acid level including waist circumference, high blood pressure, blood urea nitrogen, creatinine, γ-glutamyltransferase, and triglycerides. Most estimates changed little after further adjustment for age, metabolic syndrome, drinking status, and smoking status. The presence of hepatic steatosis significantly increased in the third and fourth quartiles of SUA. The prevalence of hepatic steatosis increased gradually with an increasing SUA quartile (p for trend < 0.01). CONCLUSION: Higher SUA levels even within the normal range are positively and independently associated with the presence of hepatic steatosis in Chinese postmenopausal women with normal BMI.

Long non­coding RNA XIST promotes cell proliferation of pancreatic cancer through miR­137 and Notch1 pathway.

OBJECTIVE: Long non-coding ribonucleic acids X-inactive specific transcript (lncRNA XIST) is one lncRNAs which involved in multiple human cancers. However, the functions and potential molecular regulatory mechanisms of XIST/microRNA-137 (miR­137) in pancreatic cancer (PC) still need to explore. PATIENTS AND METHODS: PC tissues and cell lines were analyzed for XIST, miR-137 and Notch1 expressions through quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Nude mouse xenograft tumor assay was used to detect XIST effects on pancreatic tumorigenesis in vivo. Cell Counting Kit (CCK-8) assay was performed to detect PC cell proliferation. Dual-Luciferase reporter assay, qRT-PCR, RNA immunoprecipitation (RIP) and Western blot assays were applied to validate the target relationship of XIST, miR­137 and Notch1. RESULTS: Results demonstrated that XIST expression was increased in PC tissues and cells. XIST knockdown inhibited PC cell proliferation in vitro and also repressed the tumor growth in vivo. XIST directly interacted with miR-137 and negatively regulated its expression. Notch1 was identified as a target gene of miR-137 and XIST acted as a competitive endogenous RNA (ceRNA) to positively regulate Notch1 expression by suppressing miR-137. In addition, we detected miR-137 was negatively correlated with XIST and Notch1 respectively, and a positive correlation between Notch1 and XIST expression in PC tissues. Furthermore, Notch1 overexpression could offset the suppressing effect of XIST knockdown or miR-137 overexpression on cell proliferation. Therefore, XIST may play an important role in promoting cell proliferation through miR­137 and Notch1 pathway in PC. CONCLUSIONS: To sum up, these results proposed that XIST functioned as an endogenous sponge in promoting PC cell proliferation through competing for miR-137 to regulate Notch1 expression, and may provide more therapeutic targets for the patients with PC.

Long non-coding TUG1 accelerates prostate cancer progression through regulating miR-128-3p/YES1 axis.

OBJECTIVE: Dysregulation of long non-coding RNAs (lncRNAs) is being found to have relevance to human cancers, including prostate cancer (PCa). Taurine-upregulated gene 1 (TUG1) has been demonstrated to have a potential oncogenic role in PCa. Then the aim of this study was to investigate the molecular mechanisms of TUG1 on PCa progression. PATIENTS AND METHODS: The expression levels of TUG1, YES proto-oncogene 1 (YES1) mRNA and miR-128-3p were assessed using quantitative real-time polymerase chain reaction. Cell proliferation ability, apoptosis, and migration and invasion capacities were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, flow cytometry and transwell assay, respectively. Western blot analysis was employed to evaluate the indicated proteins levels. The interaction between miR-128-3p and TUG1 or YES1 was determined using the Dual-Luciferase reporter assay. In vivo assay was used to observe the effect of TUG1 on tumor growth in vivo. RESULTS: Our data indicated that TUG1 was upregulated in PCa tissues and cells and predicted poor prognosis. TUG1 knockdown weakened PCa cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and accelerated cell apoptosis in vitro. Mechanistically, TUG1 directly interacted with miR-128-3p and miR-128-3p mediated the regulatory effects of TUG1 depletion on PCa cell progression. YES1 was a direct target of miR-128-3p and TUG1 modulated YES1 expression by sponging miR-128-3p. Moreover, TUG1 silencing repressed PCa cell progression in vitro through YES1. Additionally, TUG1 silencing mitigated tumor growth in vivo. CONCLUSIONS: Our study suggested that TUG1 silencing retarded PCa cell progression in vitro and tumor growth in vivo through miR-128-3p/YES1 axis, showing that targeting TUG1 might be a novel therapeutic strategy for PCa management.

MiRNA-92a promotes cell proliferation and invasion through binding to KLF4 in glioma.

OBJECTIVE: Glioma is one of the most frequent brain tumors in adults, and it has a low 5-year survival rate. MicroRNA-92a (miR-92a) has been reported to be upregulated and acted as an oncogene in many cancers. The purpose of this study was to explore the molecular mechanisms of miR-92a and kruppel-like factor 4 (KLF4) in glioma. PATIENTS AND METHODS: Western blotting assay and quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) were applied to calculate the relative expression of interest proteins and mRNAs. Luciferase ability assay was conducted to evaluate whether miR-92a was targeting to KLF4. RESULTS: A higher expression of miR-92a was observed in glioma tissues compared with the corresponding adjacent non-tumor tissues. The upregulation of miR-92a predicted poor prognostic characteristics of glioma. The overexpression miR-92a significantly promoted cell proliferation an invasion, while the knockdown of miR-92a presented the opposite results. MiR-92a bound to KLF4 and mediated the expression of KLF4 in glioma cells. The knockdown of miR-92a inhibited cell invasion-mediated EMT. Furthermore, the knockdown of miR-92a suppressed cell proliferation through the KLF4/AKT/mTOR signal pathway. CONCLUSIONS: MiR-92a promoted the proliferation through the KLF4/AKT/mTOR signal pathway in glioma. The newly identified miR-92a/KLF4/AKT/mTOR axis provides novel insight into the pathogenesis of glioma.

Taiwanese marine microbenthic algal communities remain similar yet chlorophyll a concentrations rise in mesocosms with elevated CO2 and temperature.

The effects of increasing CO2 concentrations and temperature on microalgal assemblages were examined in Taiwan using mesocosms that simulate coral reef ecosystem. We assessed changes in abundance and diversity of benthic algae grown at 25°C and 28°C, under ambient (~400µatm) and at high CO2 conditions (800-1000µatm). Total alkalinity, pCO2, and the aragonite saturation state, were all significantly different between control and high CO2 treatments in both temperature treatments. Chl a concentration increased significantly in CO2-treated groups at 25°C, but benthic microalgal abundance was not significantly different. The number of microalgal species and the microalgal community structure did not differ between control and CO2-treated groups at both temperatures. Our results suggest that increasing CO2 may boost benthic microalgal primary productivity if sufficient nutrients are available, although site-specific responses are difficult to predict.

Comparison of the pharmacologic action of two isoquinoline alkaloids on rat cardiac tissue.

We investigated the action of two synthetic isoquinoline alkaloids, 3,4-dihydroxybenzyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CSH109) and 2-bromo-3,4-dimethoxybenzyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (CSH118) on rat cardiac tissue. In the right atria, CSH109 increased the amplitude of contractions and spontaneous beats dose-dependently. In the driven left atria and right ventricular strips, CSH109 caused a similar increase in contractions. The positive inotropic and chronotropic actions of CSH109 were antagonized by propranolol. CSH118 caused the spontaneous beats in the right atria to slow down. CSH118, however, failed to antagonize the positive inotropic effect and positive chronotropic effect of isoprenaline. Electrophysiologic study revealed that 3 microM CSH118 markedly reduced fast action potential upstroke and prolonged the action potential duration (APD50) of rat ventricular cells from 34 +/- 8 msec to 122 +/- 29 msec (n = 6). CSH109 prolonged APD50 slightly from 24 +/- 4 msec to 38 +/- 7 msec (n = 4). Under voltage clamp conditions, CSH109 significantly increased the L-type calcium inward current (ICa). The TTX-sensitive sodium inward current (INa), transient outward (Ito) and late outward current (I800), however, were unaffected. The increase in ICa by CSH109 was effectively antagonized by propranolol. Contrary to the action of CSH109, CSH118 strongly suppressed INa, ICa, Ito and I400. The inhibition of INa by 1.5 to 9 microM CSH118 was associated with negative shifting of its steady state inactivation curve. It is concluded that CSH109 exerts a cardiac effect by activating the B-adrenoceptor. CSH118, however, is a broad spectrum ionic channel blocker.

MAPK signaling mediates sinomenine hydrochloride-induced human breast cancer cell death via both reactive oxygen species-dependent and -independent pathways: an in vitro and in vivo study.

Sinomenine, the main alkaloid extracted from the medicinal plant Sinomenium acutum, is known for its anti-inflammatory effects. Recent studies have suggested its anti-cancer effect in synovial sarcoma, lung cancer and hepatic cancer. However, the underlying molecular mechanism for its anti-cancer effect still remains unclear. This study investigated the anti-tumor activity of sinomenine hydrochloride (SH), a hydrochloride form of sinomenine, in human breast cancer cells in vitro and in vivo. We found that SH potently inhibited cell viability of a broad panel of breast cancer cell lines. Two representative breast cancer cell lines, namely ER(-)/PR(-) MDA-MB-231 and ER(+)/PR(+) MCF-7, were used for further investigation. The results showed that SH induced G1/S cell cycle arrest, caused apoptosis and induced ATM/Chk2- and ATR/Chk1-mediated DNA-damage response in MDA-MB-231 and MCF-7. The anti-cancer effect of SH was regulated by increased expression levels of p-ERK, p-JNK and p-38 MAPK. Further studies showed that SH resulted in an increase in reactive oxygen species (ROS) and inhibition of ROS by N-acetyl-L-cysteine (NAC) almost blocked SH-induced DNA damage but only mitigated SH-induced MAPK expression changes, suggesting that both ROS-dependent and -independent pathways were involved in MAPK-mediated SH-induced breast cancer cell death. The in vivo study demonstrated that SH effectively inhibited tumor growth without showing significant toxicity. In conclusion, SH induced breast cancer cell death through ROS-dependent and -independent pathways with an upregulation of MAPKs, indicating that SH may be a potential anti-tumor drug for breast cancer treatment.

Blood trace minerals concentrations and oxidative stress in patients with obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with increased oxidative stress. Certain essential trace minerals have shown to play an important role in the maintenance of redox homeostasis. We determined the concentrations of trace minerals in OSA patients and assessed their relationships to OSA severity as indicated by the apnea/ hypopnea index (AHI). METHODS: We enrolled 44 patients with newly diagnosed mild to moderate OSA and 20 without OSA. The following parameters were measured: polysomnographic values of nocturnal sleep; plasma trace minerals zinc (Zn), copper (Cu), iron (Fe), and erythrocyte selenium (Se); oxidative stress status; and plasma high-sensitivity C-reactive protein (hs-CRP) and tumor necrosis factor-α (TNF-α). RESULTS: Compared to controls matched for age, gender, and body mass index, OSA patients had lower concentrations of plasma Zn and erythrocyte Se and higher plasma concentrations of Cu and Fe. OSA patients had significantly higher plasma concentrations of hs-CRP, TNF-α, and malondialdehyde (MDA), and lower erythrocyte antioxidant enzyme glutathione peroxidase (GPx) and superoxide dismutase activities. Significant differences in all the above parameters were also found in patients with moderate OSA compared to those with mild OSA. Furthermore, AHI values correlated significantly with neck circumference, GPx activity, and MDA, hs-CRP, and TNF-α concentrations in OSA patients. AHI values were also negatively associated with concentrations of plasma Zn and erythrocyte Se, but were positively linked to plasma concentrations of Fe and Cu. CONCLUSIONS: Abnormal concentrations of these trace minerals may reflect oxidative damage and inflammatory response, thus increasing the severity of OSA.

Hodgkin and non-Hodgkin lymphoma: local-regional radiation therapy after bone marrow transplantation.

PURPOSE: To assess the acute toxicity and therapeutic effect of local-regional radiation therapy after bone marrow transplantation performed for lymphoma in resistant relapse. MATERIALS AND METHODS: Twenty-one patients with Hodgkin (n = 12) or non-Hodgkin lymphoma (n = 9) underwent local-regional radiation therapy after bone marrow transplantation. Posttransplantation radiation was delivered to the dominant site of pretransplantation disease. Three patients with Hodgkin lymphoma and four with non-Hodgkin lymphoma underwent radiation therapy for posttransplantation recurrence. Total body irradiation was used in 10 patients. Mean radiation dose was lower in patients who underwent total body irradiation than in those who did not (P = .05). RESULTS: Nineteen of 21 patients completed local-regional therapy. Nonhematologic toxicity was mild in 20 patients. Hematologic toxicity was severe in five patients, four of whom began radiation therapy with low platelet counts. In-field disease progression occurred in six of 15 patients with relapse, including four with disease progression at the start of radiation therapy. Median progression-free survival was 12 months in patients with Hodgkin lymphoma and 1 month in patients with non-Hodgkin lymphoma. CONCLUSION: Posttransplantation local-regional radiation therapy can be safely administered in patients with lymphoma. Severe hematologic toxicity is a concern, however, in patients with low platelet counts.