Pharmacokinetics and pharmacodynamics of cinacalcet in patients with renal failure receiving hemodialysis and hemodiafiltration therapy
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OBJECTIVE: Few studies have focused on the effects of dialysis on cinacalcet. In addition, there is no data available on hemodiafiltration (HDF) all over the world. Therefore, we studied the pharmacokinetics (PK) and pharmacodynamics (PD) of cinacalcet in patients undergoing hemodialysis (HD) or HDF to provide more guiding information on its use in these patients, especially in China. MATERIALS AND METHODS: In this open-label, single-dose, single-center study of 7 patients with renal failure who underwent dialysis, patients were randomly allocated to two groups consisting of 4 and 3 patients who received low-flux HD and HDF treatments, respectively. All participants underwent dialysis for 4 hours immediately after receiving single oral doses of a 25 mg cinacalcet tablet. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and electrochemical luminescence (EI) were used to determine the cinacalcet plasma concentrations and intact parathyroid hormone (iPTH) serum levels, respectively. RESULTS: Peak concentration (Cmax) and area under the curve (AUC) from time 0 to 24 hours (AUC0-24h) of the low-flux HD therapy group were 21.8 ± 18.6 ng/mL and 145.3 ± 91.8 ng×h/mL, respectively, which were similar to those of the HDF group (30.9 ± 7.9 ng/mL and 161.6 ± 26.5 ng×h/mL, respectively). iPTH concentrations of the HD therapy group decreased after cinacalcet administration and increased following its clearance. However, iPTH levels of subjects receiving HDF therapy did not change. CONCLUSION: Compared with healthy Chinese subjects, patients with renal failure had a higher Cmax and AUC0-24h, slightly prolonged time to Cmax (tmax) after administration of the same dose of cinacalcet. On HD treatment day, variation trends of iPTH in Chinese patients and healthy subjects were similar and significantly different from that on the HDF treatment day. Considering the high protein binding rate of cinacalcet, this may lead to the great free-drug clearance during HDF treatment.

Stat3-Atg5 signal axis inducing autophagy to alleviate hepatic ischemia-reperfusion injury.

In performing our experiment, impaired autophagy increased hepatocellular damage during the reperfusion period. It was demonstrated by the effect of blocking autophagy using bafilomycin A1 or knocking Atg5 gene out reduces the anti-apoptotic effect of Stat3. Here we focus on the role of signal transducer and activator of transcription 3 (Stat3) in regulating autophagy to alleviate hepatic IRI. We found that Stat3 was up-regulated during hepatic IRI and was associated with an activation of the autophagic signaling pathway. This increased Stat3 expression, which was allied with high autophagic activity, alleviated liver damage to IR, an effect which was abrogated by Stat3 epletion as demonstrated in both in vivo and in vitro methods. The levels of Atg5 protein were decreased when Stat3 was inhibited by HO 3867 or siStat3. We conclude that Stat3 appeared to exert a pivotal role in hepatic IRI, by activating autophagy to alleviate hepatic IRI, and Atg5 was required for this process. The identification of this novel pathway, that links expression levels of Stat3 with Atg5-mediated autophagy, may provide new insights for the generation of novel protective therapies directed against hepatic IRI.

[Surgical management of infective endocarditis with cerebrovascular complications].

OBJECTIVE: To investigate the result of surgical treatment of active infective endocarditis in patients with recent cerebrovascular events, and to evaluate the optimal indication and timing of surgical intervention. METHODS: The clinical data of 26 patients with cerebrovascular complications before surgery Between December 2007 and December 2013 were analyzed retrospectively. There were 17 male and 9 female patients, aged (42±14) years. Types of disease included single aortic valvular disease (n=8), single mitral valvular disease (n=12), multiple valvular disease (n=5), and aortic valvular disease with ventricular septal defect (n=1). Type of cerebrovascular complication included cerebral infarction (n=25) and cerebral hemorrhage (n=1). Thirty-one valves were involved in 26 patients, mechanical prosthetic valve replacement (n=25), bioprosthetic valve replacement (n=4), and mitral valve repair (n=2). RESULTS: The interval between onset of cerebrovascular event and surgical intervention was less than 14 days (n=3), 14 to 21 days (n=13), over 21 days (n=10), and the mean was (20±4) days. There were 33 vegetations found intraoperatively. The mean size of vegetations was (10±4) mm and 19 were found in mitral valve. Two patients died in hospital. One case relapsed after 1 year and underwent reoperation for prosthetic valve endocarditis. The remaining patients recovered with cardiac function of New York Heart Association class I to II after the period of 3 months to 5 years follow-up. CONCLUSIONS: Appropriate surgery may effectively improve the outcome of IE patients with cerebrovascular complications. The surgical indications and risks of further neurologic deterioration after cardiac surgery should be assessed comprehensively before surgical intervention.

Expression patterns of microRNA-218 and its potential functions by targeting CIP2A and BMI1 genes in melanoma.

Melanoma is the most aggressive skin cancer, and it is typically resistant or rapidly develops resistance to a variety of chemotherapeutic agents. microRNAs (miRNAs) play a part in the occurrence and development of malignant melanoma. In this study, we analyzed the miR-218 expression level in melanoma patients and cell lines and observed alterations in proliferation, cell cycle, migration, and invasion by increasing miR-218 expression in melanoma cell lines. We also performed bioinformatic analyses using TargetScan and miRanda and cloned both the wild-type and mutant versions of the human cancerous inhibitor of protein phosphatase 2A (CIP2A) and B lymphoma Mo-MLV insertion region 1 (BMI1) 3'-UTR fragments into the pmirGLO reporter vector. We then used the Dual-Luciferase assay system, quantitative real-time RT-PCR (qRT-PCR), and Western blot analysis to determine that miR-218 targeted the 3'-UTR of the oncogenes CIP2A and BMI1 and thus regulated the biological process of melanoma. We further demonstrated that CIP2A and BMI1 knockdown phenocopies miR-218 overexpression. In conclusion, our findings have shown that miR-218 is downregulated in melanoma. By targeting CIP2A and BMI1, miR-218 regulates the proliferation, migration, and invasion of the melanoma cell lines A375 and SK-MEL-2, indicating that miR-218 plays a pivotal role in melanoma development.

Novel method for determination of colistin sulfate in human plasma by high-performance liquid chromatography-tandem mass spectrometry and its clinical applications in critically ill patients.

Colistin is a last-resort antibiotic used for treating infections caused by carbapenem-resistant Gram-negative bacteria, particularly in critically patients, nevertheless its therapeutic window is narrow, and requires monitoring. A determination method suitable for clinical detection is conducive to ensure its efficacy and safety of patients with severe infection. We developed and validated a concise and accurate high-performance liquid chromatography-tandem mass spectrometry method for the determination of colistin A and B in human plasma. We used a Kinetex C18 column (50 mm × 2.1 mm, 2.6 µm) with acetonitrile (containing 0.1% formic acid) as the protein precipitant and water (containing 0.2% formic acid and 5 mmol/L ammonium formate) - acetonitrile (containing 0.2% formic acid) as the gradient elution. The calibration curves were linear over concentration ranges of 0.06-4.00 µg/mL (colistin A) and 0.1-7.0 µg/mL (colistin B). The precision, accuracy, matrix effect, extraction recovery, and stability were all validated. This method was applied to the therapeutic drug monitoring for 50 critically ill patients. The trough, peak, and average steady-state concentrations of these patients were 0.8 ± 0.4, 1.4 ± 0.5, and 1.0 ± 0.4 µg/mL, respectively. And the concentrations of colistin in human plasma were closely related to the patient's renal function.

A Cross-sectional Comparative Analysis of Eleven Population Pharmacokinetic Models for Docetaxel in Chinese Breast Cancer Patients.

OBJECTIVE: Various population pharmacokinetic (PPK) models have been established to help determine the appropriate dosage of docetaxel, however, no clear consensus on optimal dosing has been achieved. The purpose of this study is to perform an external evaluation of published models in order to test their predictive performance, and to find an appropriate PPK model for Chinese breast cancer patients. METHODS: A systematic literature search of docetaxel PPK models was performed using PubMed, Web of Science, China National Knowledge Infrastructure, and WanFang databases. The predictive performance of eleven identified models was evaluated using prediction-based and simulation-based diagnostics on an independent dataset (112 docetaxel concentrations from 56 breast cancer patients). The -2×log (likelihood) and Akaike information criterion were also calculated to evaluate model fit. RESULTS: The median prediction error of eight of the eleven models was less than 10%. The model fitting results showed that the three-compartment model of Bruno et al. had the best prediction performance and that the three compartment model of Wang et al. had the best simulation effect. Furthermore, although the covariates that significantly affect PK parameters were different between them, seven models demonstrated that docetaxel PK parameters were influenced by liver function. CONCLUSIONS: Three compartment PPK models may be predictive of optimal docetaxel dosage for Chinese breast cancer patients. However, for patients with impaired liver function, the choice of which model to use to predict the blood concentration of docetaxel still requires great care.

Population pharmacokinetics of cyclosporine A based on NONMEM in Chinese allogeneic hematopoietic stem cell transplantation recipients.

To set up a population pharmacokinetic (PPK) model of cyclosporine A (CsA) in Chinese allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients to provide reference for individualized medication in clinical practice. 281 trough plasma concentrations of CsA and covariates such as demographics, clinical laboratory values and coadministration were retrospectively collected from 73 allo-HSCT patients. Population modeling was performed using general model of NONMEM expressed by differential equation. Hematocrit (HCT), plasma albumin (ALB) level, and coadministration of itraconazole (ITR) were found to significantly affect the clearance of CsA (CL, L/h). The final model formula was: CL = 28.2 × [1 - 0.0263 × (HCT - 26.62)] × [1 - 0.0289 × (ALB - 37.63)] × [1 - 0.146 × ITR] (L/h); V = 1,080 (L); K (a) = 1.28 (h⁻¹); F = 0.711. The interindividual variabilities for CL, V and F were 21.4, 41.5 and 6.07 %, respectively. The residual error was 0.00422 mg/L. The PPK model was validated to be effective and stable by bootstrap method. Clinical applications showed there was a good linear correlation between the predicted concentrations and the observed (y = 1.0095x + 0.0082, r = 0.9309, p < 0.0001). The PPK final model of CsA in Chinese allo-HSCT patients can be established using the NONMEM program which can be applied in clinical allo-HSCT practice when characteristics of patients fit in with those of subpopulation in the study.

Long-acting versus short-acting granulocyte colony-stimulating factors among cancer patients after chemotherapy in China: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Granulocyte colony-stimulating factors (G-CSFs) include long-acting ones and short-acting ones. They have been mainly applied in Chinese clinical practice for years to prevent neutropenia. However, which type of G-CSF is more superior has not been conclusively determined. METHODS: A systematic literature search was conducted using the PubMed, Embase, Cochrane Library, clinical trials.gov, China National Knowledge Infrastructure, and WAN FANG databases for related studies published till August 2021. Revman 5.3 software was used to assess the effectiveness and safety of these 2 types of G-CSFs in patients undergoing chemotherapy. RESULTS: Ten studies involving 1916 patients were included in our meta-analysis to compare the effectiveness and safety of long-acting G-CSFs and short-acting G-CSFs. We found that the incidence of febrile neutropenia (relative risk [RR] 0.82; 95% confidence interval [CI] 0.57-1.17), the recovery time of the absolute neutrophil count (mean difference -0.23; 95% CI -0.49 to 0.03), and the fatigue rate (RR 0.82; 95% CI 0.62-1.07) were similar between the long- and the short-acting G-CSFs. However, the long-acting G-CSFs significantly decreased the incidence (RR 0.86; 95% CI 0.76-0.96) and shortened the duration (mean difference -0.19; 95% CI -0.38 to 0.00) of severe (grade ≥3) neutropenia, and decreased the rate of bone and/or muscle pain (RR 0.75; 95% CI 0.58-0.98). CONCLUSION: Primary prophylaxis with long-acting G-CSFs was more effective and safer than primary prophylaxis with short-acting G-CSFs in Chinese adults undergoing chemotherapy.

The association between 5, 10 - methylenetetrahydrofolate reductase and the risk of unexplained recurrent pregnancy loss in China: A Meta-analysis.

BACKGROUD: To analyze the correlation between gene polymorphisms of 5,10- methylenetetrahydrofolate reductase (MTHFR) and risk of unexplained recurrent pregnancy loss (URPL) in Chinese women. METHODS: Eligible studies were searched in Pubmed, Embase, Web of Science, Wanfang, and China National Knowledge Infrastructure (CNKI) databases. Established inclusion criteria were used to screening articles, subsequently evaluate the quality of the included studies, Stata 16.0 PM and RevMan 5.3 software were conducted for meta-analysis. The pooled odds ratio (OR) with 95% confidence interval (CI) was determined to assess the relationship between MTHFR and risk of URPL in Chinese women. RESULTS: For MTHFR C677T, fifty studies were included, involving 6677 URPL cases and 8111 controls. The overall results showed that MTHFR C677T was significantly correlated with URPL risk, especially in the homozygous model (TT vs CC; OR 3.06; 95% CI 2.56-3.66). For MTHFR A1298C, twenty-first studies were included, involving 3439 URPL cases and 3155 controls. The results showed that MTHFR A1298C was also significantly correlated with URPL risk in recessive (CC vs AC + AA; OR 1.55; 95% CI 1.25-1.93) and homozygous (CC vs AA; OR 1.53; 95% CI 1.22-1.91) models. In addition, sub-group results showed that no significant difference between north and south China populations in the MTHFR gene polymorphisms and URPL risk. Of note, the patients carrying MTHFR C677T and MTHFR A1298C joint mutants had no synergistic effect (OR 2.71; 95% CI 0.84-8.70) on the occurrence of URPL compared with the wild-type homozygous genotype (MTHFR 677CC/ MTHFR 1298AA). CONCLUSION: Studies included in this meta-analysis suggested that MTHFR 677T allele and 677TT genotype and MTHFR 1298CC genotype were both associated with URPL; testing MTHFR C677T gene polymorphism was a more appropriate target compared with other mutations in the prediction of URPL.

Gene polymorphism-related differences in the outcomes of abiraterone for prostate cancer: a systematic overview.

Numerous prostate cancer (PC) associated genes have been reported in previous genome-wide association studies. Elucidation of prostate cancer pharmacogenomics have enhanced studies into the impact of germline genetic changes on treatment, in addition to evaluating related genomic alterations and biomarkers in prostate tumor tissues. Currently, Abiraterone (Abi) is used as one of the therapeutic options for PC. In this article, germline variants that have been associated with responses to Abi in patients with advanced PC are summarized. These include biomarker genes such as CYP17A1, AR-V7, HSD3B1, SLCO2B1, SULT1E1, and SRD5A2 that are involved in homologous recombination, as well as in gene expression mutations in important signaling pathways, such as WNT and Abi metabolic pathways.

Population pharmacokinetic model of digoxin in older Chinese patients and its application in clinical practice.

AIM: To establish a population pharmacokinetic (PPK) model of digoxin in older Chinese patients to provide a reference for individual medication in clinical practice. METHODS: Serum concentrations of digoxin and clinically related data including gender, age, weight (WT), serum creatinine (Cr), alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), albumin (ALB), and co-administration were retrospectively collected from 119 older patients taking digoxin orally for more than 7 d. NONMEM software was used to get PPK parameter values, to set up a final model, and to assess the models in clinical practice. RESULTS: Spironolactone (SPI), WT, and Cr markedly affected the clearance rate of digoxin. The final model formula is Cl/F=5.9x[1-0.412 x SPI] x [1-0.0101x(WT-62.9)] x [1-0.0012x(Cr-126.8)] (L/h); Ka=1.63 (h(-1)); V(d)/F=550 (L). The population estimates for Cl/F and V(d)/F were 5.9 L/h and 550 L, respectively. The interindividual variabilities (CV) were 49.0% for Cl/F and 94.3% for V(d)/F. The residual variability (SD) between observed and predicted concentrations was 0.365 microg/L. The difference between the objective function value and the primitive function value was less than 3.84 (P>0.05) by intra-validation. Clinical applications indicated that the percent of difference between the predicted concentrations estimated by the PPK final model and the observed concentrations were -4.3%-+25%. Correlation analysis displayed that there was a linear correlation between observed and predicted values (y=1.35x+0.39, r=0.9639, P<0.0001). CONCLUSION: The PPK final model of digoxin in older Chinese patients can be established using the NONMEM software, which can be applied in clinical practice.

[Resveratrol reduces apoptosis of mouse RAW264.7 macrophage via down-regulating HIF-1α].

Objective To investigate the protective effect of resveratrol (Res) against mouse RAW264.7 macrophage injury induced by cobalt chloride (CoCl2) and its mechanism. Methods Macrophages were divided into control group, CoCl2 group and Res pretreatment group. CoCl2 group was treated with 500 µmol/L CoCl2 for 8 hours, and Res pretreatment group was pretreated with 40 µmol/L Res for 2 hours followed by 500 µmol/L CoCl2 treatment for 8 hours. The cell vitality and apoptotic rate in every group were detected by CCK-8 assay and flow cytometry. The distributions of caspase-3 and hypoxia-inducible factor 1 alpha (HIF-1α), as well as the influences of CoCl2 and Res on their expression were detected by immunofluorescence cytochemistry. The levels of superoxide dismutase (SOD) and malondialdehyde (MDA) in every group were measured by the corresponding kits. The expression levels of Bcl2, BAX, c-caspase-3 and HIF-1α in every group were observed by Western blot analysis. Results Compared with the CoCl2 group, pretreatment with Res increased cell vitality, decreased apoptosis, enhanced the activity of SOD, and reduced the level of MDA. The caspase-3 was mainly distributed in the cytoplasm, and HIF-1α was mainly distributed on the nucleus. Compared with the CoCl2 group, Res up-regulated the expression of Bcl2 and down-regulated the expression of BAX, cleaved caspase-3 and HIF-1α. Conclusion Res can decrease apoptosis in macrophages, which may occur via reducing the accumulation of intracellular reactive oxygen species, enhancing cell antioxidant capacity, and down-regulating the expression of HIF-1α on cells.

MEX3A is upregulated in esophageal squamous cell carcinoma (ESCC) and promotes development and progression of ESCC through targeting CDK6.

Esophageal squamous cell carcinoma (ESCC) is one of the most commonly diagnosed malignant tumors worldwide and identified as a serious threat to human health. The role of MEX3A in ESCC remains unclear. In this study, we found that MEX3A was upregulated in tumor tissues of ESCC and positively associated with more advanced tumor stage, higher risk of lymphatic metastasis and poor prognosis. The downregulation of MEX3A in ESCC cell lines could induce inhibition of cell proliferation, colony formation, cell migration, and the promotion of cell apoptosis, while MEX3A overexpression exhibited opposite effects. In vivo experiments also verified the inhibition of ESCC induced by MEX3A knockdown. Moreover, we identified CDK6 as a potential target of MEX3A, which was also upregulated in ESCC. Further studies demonstrated that knockdown of CDK6 showed similar effects on the development of ESCC with MEX3A. More importantly, it was illustrated that CDK6 knockdown could alleviate the promotion effects of MEX3A overexpression on ESCC. In conclusion, MEX3A was identified as a tumor promotor in the development and progression of ESCC by targeting CDK6, which may be considered as a novel prognostic indicator and therapeutic target in treatment of ESCC.

Population pharmacokinetics of sirolimus in de novo Chinese adult renal transplant patients.

AIMS: This study was aimed at determining the population pharmacokinetics of sirolimus and identifying factors that explain pharmacokinetic variability in de novo Chinese adult renal transplant patients. METHODS: Data were retrospectively extracted from a formal multicentre clinical trial, which was originally designed to evaluate the safety and efficacy of cyclosporin dose reduction and cyclosporin elimination in patients receiving sirolimus. All patients received 12-month treatment, i.e. induction therapy with cyclosporin, sirolimus and corticosteroids during the first 3 months followed by either cyclosporin dose reduction or cyclosporin discontinuation thereafter. Eight-hundred and four sirolimus trough blood concentrations (C(0)) from 112 patients were used to develop a population pharmacokinetic model using the NONMEM program. A one-compartment model with first-order absorption and elimination was selected as the base model. The influence of demographic characteristics, biochemical and haematological indices, cyclosporin daily dose, cyclosporin C(0) as well as other commonly used co-medications were explored. RESULTS: The typical values with interindividual variability for apparent clearance (CL/F) and apparent volume of distribution (V/F) were 10.1 l h(-1) (23.8%) and 3670 l (56.7%), respectively. The residual variability was 29.9%. CL/F decreased significantly with silymarin or glycyrrhizin co-therapy in hepatically impaired patients, and with increasing total cholesterol levels or cyclosporin C(0). Moreover, CL/F increased nonlinearly with increasing sirolimus daily dose. The median parameter estimates from a nonparametric bootstrap procedure were comparable and within 5% of the estimates from NONMEM. CONCLUSIONS: These results provide important information for clinicians to optimize sirolimus regimens in Chinese renal transplant patients.

A pH-Induced Reversible Assembly System with Resveratrol-Controllable Loading and Release for Enhanced Tumor-Targeting Chemotherapy.

In this report, we present a pH-induced reversible assembly system (PIRAS) based on ferritin (Ft) for targeted tumor therapy. It has been developed to easily load and release of the anticancer drug resveratrol (RV), based on its natural pH-sensitivity and unique hollow cavity of Ft. A tumor-specific target peptide Arg-Gly-Asp (RGD) was conjugated onto the surface of RV-loaded Ft (RV@Ft), to form biocompatible nanoparticles (RV@Ft-RGD). The pH-sensitivity of Ft allows it to be denatured into a hollow porous nanosphere under acidic condition and renatured into a sealed hollow nanosphere under neutral condition. Using pH manipulation, RV@Ft-RGD, with a ~ 21 nm diameter, showed a high RV loading ratio of 79.6%. pH-triggered RV release was then measured at a ratio of 50.3% at pH5.0 over 24 h. Under neutral condition, the RV@Ft-RGD showed excellent stability over 20 days. Confocal fluorescence imaging showed that RV@Ft-RGD had a high cell uptake ratio and co-localization with the lysosome, mainly due to the RGD-mediated target effect. Based on the high drug loading, pH-triggered release, and tumor cell targeting effect, RV@Ft-RGD showed great cell-killing ability in vitro and in vivo. The biocompatibility in vitro and in vivo was also demonstrated to be excellent, without systematic toxicity. The design concept of PIRAS based on Ft significantly inhibits tumor growth and simultaneously further broadens the application of Ft in nanomedicine.

The Evolution of Population Pharmacokinetic Model of Oral Phenytoin for Early Seizure Prophylaxis Post-Craniotomy.

BACKGROUND: This study aimed to re-establish a Population Pharmacokinetic (PPK) model of oral phenytoin to further optimize the individualized medication regimen based on our previous research. METHODS: Patients with intracranial malignant tumor requiring craniotomy were prospectively enrolled according to the inclusion criteria. Genotypes of CYP2C9*1 or *3 and CYP2C19*1, *2 or *3 were determined by real time PCR (TaqMan probe) method. Serum concentrations of phenytoin on the 4th and 7th day after oral administration were determined using fluorescence polarization immunoassay. The PPK parameters were estimated using Nonlinear Mixed Effects Models (NONMEM) and internal validation was performed using bootstraps. The predictive performance of the final model was evaluated by Normalized Predictive Distribution Errors (NPDEs) and diagnostic goodness- of-fit plots. RESULTS: A total of 390 serum samples were collected from 170 patients in PPK model building group. The population typical values for Vm, Km and the apparent volume of distribution (V) in the final model were 17.5 mg/h, 6.41 mg/L and 54.8 L, respectively. Internal validation by bootstraps showed that the final model was stable and reliable. NPDEs with a normal distribution and a scatterplot with symmetrical distribution showed that the final model had good predictive capability. Individualized dose regimens of additional 40 patients in the external validation group were designed by the present final PPK model. The percentages of patients with serum concentrations within the therapeutic range were 61.53% (24/39) on the 4th day and 94.87% (37/39) on the 7th day, which were higher than the 39.33% (59/150) and 52.10% (87/167) of above 170 patients (P < 0.0001). CONCLUSION: The present PPK final model for oral phenytoin may be used to further optimize phenytoin individualized dose regimen to prevent early seizure in patients after brain injury if patient characteristics meet those of the population studied.

Circular RNA ciRS-7 triggers the migration and invasion of esophageal squamous cell carcinoma via miR-7/KLF4 and NF-κB signals.

Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent and deadly cancers worldwide, especially in Eastern Asia. It has been indicated that circular RNAs (circRNA) are the key regulators in the development and progression of human cancers. We therefore evaluated the expression and regulation effects of ciRS-7 on the progression of ESCC, which is a recently identified circRNA and acts as a natural competing endogenous RNA. The expression of ciRS-7 was significantly increased in the ESCC tissues and cells as compared with their corresponding controls. In vitro study showed that ciRS-7 can promote the migration and invasion of ESCC cells. Over expression of miR-7, one of well-known targets of ciRS-7, can attenuate ciRS-7 induced invasion of ESCC cells and over expression of matrix metalloproteinase 2 (MMP2). The expression of stem cell marker Kruppel-like factor-4 (KLF-4), which has been reported as the target of miR7, increased significantly in ciRS-7 transfected ESCC cells. Knockdown of KLF-4 also attenuated over expression of ciRS-7 induced cell invasion. In addition, BAY 11-7082, the inhibitor of NF-κB, partially reversed ciRS-7 induced cell invasion. Mechanically studies indicated that ciRS-7 increased the expression of p65 via increasing the phosphorylation of IKK-α. Collectively, our present study revealed that ciRS-7 can trigger the migration and invasion of ESCC cells via miR-7/KLF4 and NF-κB signals. Targeted inhibition of ciRS-7 might be a potential approach for ESCC treatment.

LncRNA SNHG1 upregulates ROCK2 to reduce cisplatin sensitivity of NSCLC cells by targeting miR-101-3p.

BACKGROUND: Cisplatin is the most commonly used chemotherapy drug in clinical settings, and decreased sensitivity or resistance to cisplatin is the main cause of chemotherapy failure or death among cancer patients. Long non-coding RNA (lncRNA) SNHG1 is highly expressed in non-small cell lung cancer (NSCLC) tissues and promotes the proliferation of NSCLC cells, but the effect of SNHG1 on cisplatin sensitivity of NSCLC cells is unclear. METHODS: We compared the expression of SNHG1 in cisplatin-sensitive and insensitive NSCLC tissues and explored the molecular mechanism of SNHG1 regulation of the sensitivity of NSCLC cells to cisplatin in vitro. RESULTS: We found that SNHG1 is upregulated in cisplatin insensitive NSCLC tissues and cells, and that it can regulate cisplatin sensitivity of NSCLC cells in vitro. Furthermore, we also found that the expression of miR-101-3p in NSCLC tissues is negatively correlated with SNHG1 or ROCK2. Additionally, in NSCLC cells, SNHG1 and miR-101-3p are mutually suppressed, but miR-101-3p targets the inhibition of ROCK2. More importantly, the regulation of ROCK2 expression in vitro can also change the sensitivity of NSCLC cells to cisplatin. CONCLUSIONS: In summary, our results provide novel mechanistic insights into the role of SNHG1/miR-101-3p/ROCK2 signaling in cisplatin resistance of NSCLC cells.

Dietary n-3 fatty acids attenuate cardiac allograft vasculopathy via activating peroxisome proliferator-activated receptor-gamma.

Recent in vitro data suggested that n-3 fatty acids could inhibit the activation of PPAR gamma. This study was designed to test the hypothesis that fish oil ameliorates CAV development via activating PPAR gamma in an inbred rat model of heart transplantation. Animals were divided into four groups: isograft, control (CsA + vehicle), LFO-treated group (CsA + 0.3% v/w fish oil), and HFO-treated group (CsA + 0.6% v/w fish oil). CsA was administered at 1.5 mg/kg/day for two wk postoperatively. Recipients were treated with fish oil or vehicle daily for eight wk. The histopathological and immunohistochemical examination, activity of NF-kappaB and PPAR gamma, intragraft chemokine levels, and chemokine receptor expression were analyzed. Both LFO and HFO significantly decreased the CAV score, inhibited recruitment of T lymphocytes and macrophages, elevated the activity of PPAR gamma, inhibited the activity of NF-kappaB, reduced levels of intragraft MCP-1 and IP-10 as well as downregulated expression of chemokine receptors CCR2. CXCR3 expression was not affected. Our results demonstrated that fish oil might attenuate CAV development, possibly through activating PPAR gamma and subsequently inhibiting the NF-kappaB activation, the chemokines secretion, as well as the CCR2 expression.

Repeated positive acceleration exposure exacerbates endothelial dysfunction in high-fat-diet-induced hyperlipidemic rats.

INTRODUCTION: It remains unclear whether exposure to repeated positive acceleration (+Gz) can exacerbate endothelial dysfunction on the basis of hyperlipidemia. The aim of this study was to investigate the effect of repeated +Gz exposure on endothelial function in high-fat-diet-induced hyperlipidemic rats. MATERIAL AND METHODS: Male Sprague-Dawley rats were randomly divided into control, repeat +Gz exposure, high-fat diet (HFD), and +Gz + HFD groups. The rats in the +Gz group were exposed to +Gz and the rats in the HFD group were fed a diet with 2% cholesterol. The rats in the +Gz + HFD group received both the +Gz exposure and HFD. Eight weeks later, the endothelium-dependent relaxation of the aorta was tested and the ultrastructure of the endothelial cells was observed using transmission electron microscopy. Quantitative real-time polymerase chain reaction and Western blot were used to detect the mRNA and protein expression of endothelial function-associated proteins. RESULTS: Repeated +Gz exposure elevated the serum level of LDL-C in HFD rats. In the +Gz + HFD rats, the ACh-induced relaxation in the aorta rings was significantly attenuated and the endothelial cells of the aorta were dramatically damaged compared with HFD rats. Nitric oxide content and eNOS expression in the aortic tissue were markedly decreased and the oxidative stress was more serious in the +Gz + HFD rats compared with HFD rats. In addition, repeated +Gz exposure significantly increased serum ox-LDL level and LOX-1 expression in the aorta of HFD rats, thereby activating NF-κB p65 and upregulating the expression of interleukin 6, ICAM-1 and VAP-1. CONCLUSIONS: Repeated +Gz exposure promotes endothelial dysfunction in HFD-induced hyperlipidemic rats.