Since the utilization of anthracyclines in cancer therapy, severe cardiotoxicity has become a major obstacle. The major challenge in treating cancer patients with anthracyclines is minimizing cardiotoxicity without compromising antitumor efficacy. Herein, histone deacetylase SIRT6 expression was reduced in plasma of patients treated with anthracyclines-based chemotherapy regimens. Furthermore, overexpression of SIRT6 alleviated doxorubicin-induced cytotoxicity in cardiomyocytes, and potentiated cytotoxicity of doxorubicin in multiple cancer cell lines. Moreover, SIRT6 overexpression ameliorated doxorubicin-induced cardiotoxicity and potentiated antitumor efficacy of doxorubicin in mice, suggesting that SIRT6 overexpression could be an adjunctive therapeutic strategy during doxorubicin treatment. Mechanistically, doxorubicin-impaired mitochondria led to decreased mitochondrial respiration and ATP production. And SIRT6 enhanced mitochondrial biogenesis and mitophagy by deacetylating and inhibiting Sgk1. Thus, SIRT6 overexpression coordinated metabolic remodeling from glycolysis to mitochondrial respiration during doxorubicin treatment, which was more conducive to cardiomyocyte metabolism, thus protecting cardiomyocytes but not cancer cells against doxorubicin-induced energy deficiency. In addition, ellagic acid, a natural compound that activates SIRT6, alleviated doxorubicin-induced cardiotoxicity and enhanced doxorubicin-mediated tumor regression in tumor-bearing mice. These findings provide a preclinical rationale for preventing cardiotoxicity by activating SIRT6 in cancer patients undergoing chemotherapy, but also advancing the understanding of the crucial role of SIRT6 in mitochondrial homeostasis.

Although primary vesical calculi is an ancient disease, the mechanism of calculi formation remains unclear. In this study, we established a novel primary vesical calculi model with d,l-choline tartrate in mice. Compared with commonly used melamine and ethylene glycol models, our model was the only approach that induced vesical calculi without causing kidney injury. Previous studies suggest that proteins in the daily diet are the main contributors to the prevention of vesical calculi, yet the effect of fat is overlooked. To assay the relationship of dietary fat with the formation of primary vesical calculi, d,l-choline tartrate-treated mice were fed a high-fat, low-fat, or normal-fat diet. Genetic changes in the mouse bladder were detected with transcriptome analysis. A high-fat diet remarkably reduced the morbidity of primary vesical calculi. Higher fatty acid levels in serum and urine were observed in the high-fat diet group, and more intact epithelia in bladder were observed in the same group compared with the normal- and low-fat diet groups, suggesting the protective effect of fatty acids on bladder epithelia to maintain its normal histological structure. Transcriptome analysis revealed that the macrophage differentiation-related gene C-X-C motif chemokine ligand 14 (Cxcl14) was upregulated in the bladders of high-fat diet-fed mice compared with those of normal- or low-fat diet-fed mice, which was consistent with histological observations. The expression of CXCL14 significantly increased in the bladder in the high-fat diet group. CXCL14 enhanced the recruitment of macrophages to the crystal nucleus and induced the transformation of M2 macrophages, which led to phagocytosis of budding crystals and prevented accumulation of calculi. In human bladder epithelia (HCV-29) cells, high fatty acid supplementation significantly increased the expression of CXCL14. Dietary fat is essential for the maintenance of physiological functions of the bladder and for the prevention of primary vesical calculi, which provides new ideas for the reduction of morbidity of primary vesical calculi.

Objective:To investigate the prognosis of severe hyperbilirubinemia in full-term infants who met the exchange transfusion criteria and were treated by blood exchange transfusion and phototherapy.Methods:A total of 168 full-term infants with severe hyperbilirubinemia who met the criteria for exchange transfusion and were hospitalized in the Neonatology Department of seven tertiary hospitals in Hebei Province from June 2017 to December 2018 were retrospectively included. According to the treatment protocol, they were divided into two groups: exchange transfusion group (38 cases) and phototherapy group (130 cases). Two independent sample t-test and Chi-square test were used to compare the clinical manifestations and follow-up results between the two groups. Multivariate logistic regression was used to analyze the risk factors for poor prognosis. Results:Neonatal severe hyperbilirubinemia in the exchange transfusion and phototherapy group were both mainly caused by hemolytic disease [42.1%(16/38) and 29.2%(38/130)], sepsis [28.9%(11/38) and 11.5%(15/130)] and early-onset breastfeeding jaundice [15.8%(6/38) and 11.5%(15/130)]. Total serum bilirubin level on admission in the exchange transfusion group was significantly higher than that in the phototherapy group [(531.7±141.3) vs (440.0±67.4) μmol/L, t=3.870, P<0.001]. Moreover, the percentage of patients with mild, moderate and severe acute bilirubin encephalopathy in the exchange transfusion group were higher than those in the phototherapy group [15.8%(6/38) vs 3.8%(5/130), 7.9%(3/38) vs 0.8%(1/130), 13.2%(5/38) vs 0.0%(0/130); χ2=29.119, P<0.001]. Among the 168 patients, 135 were followed up to 18-36 months of age and 12 showed poor prognosis (developmental retardation or hearing impairment) with four in the exchange transfusion group (12.9%, 4/31) and eight in the phototherapy group (7.7%, 8/104). Multivariate logistic regression analysis showed that for full-term infants with severe hyperbilirubinemia who met the exchange transfusion criteria, phototherapy alone without blood exchange transfusion as well as severe ABE were risk factors for poor prognosis ( OR=14.407, 95% CI: 1.101-88.528, P=0.042; OR=16.561, 95% CI: 4.042-67.850, P<0.001). Conclusions:Full-term infants who have severe hyperbilirubinemia and meet the exchange transfusion criteria should be actively treated with blood exchange transfusion, especially for those with severe ABE, so as to improve the prognosis.

Objective:To investigate the assisted pregnancy clinical effect of autologous peripheral blood mononuclear cells (PBMCs) combined with low molecular weight heparin (LMWH) on patients with intrauterine adhesion separation.Methods:Nine patients with intrauterine adhesion separation were treated with intrauterine perfusion of PBMCs 48 hours before transplantation. The low molecular weight heparin 3 200 IU injected daily subcutaneously were carried out on the day of transplantation. Measurement of endometrial thickness and observation of pregnant outcome were perfomed.Results:After 9 patients were injected into the uterine cavity with autologous PBMCs. It was found that, compared to the previous, the thickness of the endometrium was increased, and the morphology of the endometrium was improved in 6 cases. After transplantation, 7 cases of the patients were clinically pregnant, 1 of the patients was biochemically pregnant, and 1 of the patients was not pregnant; among the 7 clinical pregnancy cases, 1 case was intrauterine compound pregnancy (operation on the affected side of fallopian tube pregnancy had been performed), another 2 cases had embryo termination at the 7-8th week of gestation by B-scan ultrasonography analysis. However, 3 cases of clinical pregnancy in 4 patients with repeated implantation failure. At present, 2 cases were in live labor, and the other three cases were in normal continuous pregnancy.Conclusions:Intrauterine perfusion of human PBMCs combined with low molecular weight heparin is beneficial to the improvement of endometrial receptivity and the pregnancy outcome of some patients after the separation of intrauterine adhesions.

BACKGROUNDNumerous studies have investigated the association between adiponectin concentrations and diabetic retinopathy (DR) caused by type 2 diabetic mellitus. However, the results remain conflicting. We performed a meta-analysis to explore the relationship between adiponectin concentrations and risk of DR caused by type 2 diabetic mellitus from published articles.

METHODSA published literature search was performed through the PubMed, Cochrane Library, EMBASE, Science Citation Index Expanded database, Chinese CNKI, and Chinese Wan Fang databases for articles published in English and Chinese. Pooled standardized mean differences (SMDs) and 95% confidence intervals (95% CIs) were calculated using random or fixed effects model. Heterogeneity between studies was assessed using the Cochrane Q test and I(2) statistics.

RESULTSNineteen studies with a total of 1 545 cases and 1 502 controls were retrieved. The original meta-analysis found a significant difference in the adiponectin concentrations between the DR and non-DR (NDR) groups. After excluding the high heterogeneity studies, the second meta-analysis also demonstrated the significant association (SMD (95% CI) = -0.62 (-0.80 to -0.44), P = 0.0001). According to the available data, there was statistical significance in the adiponectin concentrations considering non-proliferative DR (NPDR) versus NDR, PDR versus NPDR in Chinese populations with high heterogeneity.

CONCLUSIONAdiponectin concentrations are correlated with DR; however, the relationship between adiponectin concentrations and DR needs more in-depth investigations with larger sample sizes.

Adiponectin ; blood ; Diabetes Mellitus, Type 2 ; complications ; Diabetic Retinopathy ; blood ; etiology

BACKGROUNDVascular endothelial growth factor (VEGF) is a major mediator of angiogenesis, and plays a key role in the pathogenesis of diabetic retinopathy (DR). This study was designed to identify the possible role of VEGF gene polymorphisms in the development of DR in type 2 diabetic patients in Chinese and clarify the relationship between VEGF serum levels and the risk of DR.

METHODSThis cross-sectional study included 1 040 Chinese subjects with type 2 diabetes mellitus. There were 372 patients diagnosed with DR in the case group and 668 patients without DR in the control group. DNA from each patient was analyzed for VEGF polymorphisms of -2578A/C (rs699947), -1154G/A (rs1570360), -460C/T (rs833061), +405C/G (rs2010963), and +936C/T (rs3025039) using MassARRAY compact analyzer. The VEGF serum levels were quantified by enzyme-linked immunosorbent assay (ELISA).

RESULTSNo evidence of association was observed between -2578 A/C (rs699947), +405C/G (rs2010963), +936C/T (rs3025039), and DR risk under stringent Bonferroni's correction. However, VEGF serum levels were significantly higher in DR patients than those of control group. The genetic variation of VEGF polymorphisms influenced VEGF serum levels; subjects carrying the VEGF -2578 C/C (rs699947) genotype had greater VEGF serum levels than those carrying the C/A genotype and VEGF serum levels were significantly higher in CC genotype of the +405C/G (rs2010963) compared with those of the other genotypes.

CONCLUSIONSThe data did not suggest significant association between the VEGF polymorphisms and DR risk under stringent Bonferroni's correction. However, our study indicated that DR patients have higher VEGF levels than diabetic patients without retinopathy, and -2578A/C (rs699947) and +405C/G (rs2010963) may be important factors in determining serum VEGF levels.

Aged ; Asian Continental Ancestry Group ; genetics ; Cross-Sectional Studies ; Diabetes Mellitus, Type 2 ; complications ; Diabetic Retinopathy ; blood ; genetics ; Female ; Humans ; Male ; Polymorphism, Genetic ; Vascular Endothelial Growth Factor A ; blood ; genetics

Objective To explore the potential mechanism of abnormal behavior resulted from maternal separation in neo-natal period in rat. Methods Neonatal rats were equally and randomly divided into maternal separation group and control group. The rats in maternal separation group were separated from the dam for 3h per day on postnatal days (PND) 2 to 21, nothing was done to the rats in the control group. The brain tissues were taken out after being killed on PND 7, 14, and 21. The expressions of Caveolin-l, BDNF and GFAP in hippocampal formation were detected by immunohistochemistry. Semiquantitative assessment of immunohistochemical images was performed by Image-Pro Plus software. Results Compared with control groups, the expres-sion of Caveolin-l on PND 7 had no signiifcant change, while BDNF and GFAP were signiifcantly increased in maternal separa-tion group (P<0.05). On PND 14 and 21, the expressions of Caveolin-l, BDNF and GFAP were signiifcantly decreased in maternal separation group (P<0.05). Conclusions Decreased expressions of Caveolin-l, BDNF and GFAP caused by maternal separation in neonatal period may be associated with abnormal behaviors in adulthood in rat.

ObjectiveTo compare the effects on left ventricular remodeling of bone marrow mononuclear cells transplantation one week and three months after acute myocardial infarction.MethodsAcute myocardial infarction models were successfully established in 15 swine,which were randomly divided into three groups:placebo group,early transplantation group and late trasplantation group.One week after model had been established,early transplantation group underwent bone marrow mononuclear cells transplantation,and then so did the late trasplantation group three months after acute myocardial infarction.B-ultrasound and single photon emission computed tomography (SPECT) examinations were performed to assess the left ventricular end diastolic dimension( LVd),left ventricular end diastolic volume(EDV) and left ventricular ejection fraction(EF) before and one week,three months,six months after acute myocardial infarction.ResultsThe LVd of late transplantation group [ (54.20:t:3.70) mm] was lower than placebo group [ (63.20 ±5.63)mm],but higher than early transplantation group [ (47.40 ± 1.14)mm].The EDV of late transplantation group [ ( 163.00 ±6.96)ml] was lower than placebo group [ (209.40 ± 18.69)ml],but higher than early transplantation group [ ( 135.40 ± 4.93 ) ml ].The EF of late transplantation group (0.25 ±0.02) was higher than placebo group (0.19 ±0.02),but lower than early transplantation group (0.37 ±0.02).ConclusionsBone marrow mononuclear cells transplantation can alleviate progressing ventricular remodeling,even it is performed three month after acute myocardial infarction,but its therapeutic effects are inferior to early transplantation's.

Objective To evaluate the quality of Psoralea corylifolia collected from 12 provinces of China.Methods An HPLCDAD-MS/MS method was used to identify,determine,and estimate 14 representative bioactive compounds in P.corylifolia.Then on the basis of the content data,the chemometrics method was used to differentiate 20 samples from different regions.Results The quality of P.corylifolia from 12 different provinces of China was evaluated by this method.Though the samples showed similar profiles,content of the detected markers varied significantly in different regions and batches.According to the results of the hierarchical cluster analysis and principle component analysis,it can be concluded that the samples from different origins could be clustered reasonably into two groups,as well as successfully distinguished.Conclusion A simple and reliable new method which used HPLC-DAD-MS/MS and chemometrics has been developed to characterize,classify,and control the quality of P.corylifolia.