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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.
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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.
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BACKGROUND AND PURPOSE: There is conflicting evidence in the literature on the association between benzodiazepines (BDZs) and the risk of dementia. This meta-analysis aimed to determine the relationship between the long-term usage of BDZs and the risk of dementia. METHODS: The PubMed and Embase databases were systematically searched for relevant publications up to September 2017. The literature search focused on observational studies that analyzed the relationship between the long-term use of BDZs and the risk of dementia. Pooled rate ratios (RRs) with 95% confidence interval (CI) were assessed using a random-effects model. The robustness of the results was checked by performing subgroup and sensitivity analyses. RESULTS: Ten studies were included: six case–control and four cohort studies. The pooled RR for developing dementia was 1.51 (95% CI=1.17–1.95, p=0.002) in patients taking BDZ. The risk of dementia was higher in patients taking BDZs with a longer half-life (RR=1.16, 95% CI=0.95–1.41, p=0.150) and for a longer time (RR=1.21, 95% CI=1.04–1.40, p=0.016). CONCLUSIONS: This meta-analysis that pooled ten studies has shown that BDZ significantly increases the risk of dementia in the elderly population. The risk is higher in patients taking BDZ with a longer half-life (>20 hours) and for a longer duration (>3 years).
Assuntos
Idoso , Humanos , Benzodiazepinas , Estudos de Coortes , Demência , Meia-VidaRESUMO
Objective To investigate the predictive value of neutrophil and lymphocyte ratios (NLR)for the prognosis in patients with acute cerebral infarction. Methods From January 2014 to December 2015,307 consecutive patients with acute cerebral infarction admitted to the Department of Neurology,the Fifth Affiliated Hospital of Zhengzhou University were enrolled retrospectively,including 80 females and 227 males. They were divided into ether a good prognosis group (n = 195)or a poor prognosis group (n = 112)according to the scoring criteria of the modified Rankin scale (mRS). The age,gender, past medical history,National Institutes of Health stroke scale (NIHSS)score were documented on admission. The NLR values were calculated according to the neutrophil and lymphocyte counts on admission. Logistic regression analysis was used to analyze the influencing factors of poor prognosis of acute cerebral infarction. The receiver operating characteristic curve (ROC)was used to evaluate the predictive effect of the NLR level on patients with acute cerebral infarction on admission. Results (1)Compared with the good prognosis group,the age,incidence of recurrent cerebral infarction,NIHSS score on admission, NLR levels on admission in the poor prognosis group were higher. There were significant differences between groups (69 ± 12 years vs. 62 ± 14 years,25. 0% [28 / 112]vs. 14. 4% [28 / 195],5. 00 [3. 00, 9. 00]vs. 3. 00 [1. 75,5. 00],and 3. 66 [2. 62,7. 91]vs. 2. 47 [1. 94,3. 40];all P 0. 05). (2)Multivariate logistic regression analysis showed that the increase of the age,NLR level on admission,and increased NIHSS score on admission,were independent risk factor for poor prognosis (OR 1. 030,1. 148,and 1. 427,respectively,95% CI were 1. 007 -1. 053,1. 059 -1. 246,and 1. 247 -1. 634, respectively;all P < 0. 05). (3)The diagnostic cut-off value of the NLR level on admission for the poor prognosis in patients with acute cerebral infarction was 2. 84. Its sensitivity was 69. 6% and specificity was 64. 6% . Conclusion The increase of the NLR level on admission had certain reference function on the poor prognosis in patients with acute ischemic stroke.
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Objective To investigate the effects of Blastocyst MHC gene transfection to coronary on the survival time of mouse heart grafts and the mechanism. Methods Inbred male Balb/c mice and C57BL/6 mice were selected as donors and recipients respectively, to construct mouse cervical heart transplantation models. In the control group, the donor hearts were perfused using the 0～4 ℃ St. ThomasⅡ solution; in the cyclosporine A (CsA) group, the donor hearts were perfused as same as the control's and received intraperitoneal injection of CsA (5 rng·g-1·d-1) after surgery; in the transfection group, the donor hearts were perfused using St. Thomas Ⅱ solution with Blastocyst MHC gene plasmid; in the combined treatment group, the donor hearts were perfused using St. Thomas Ⅱ solution with Blastocyst MHC gene plasmid and received intraperitoneal injection of CsA (5 mg·g-1·d-1) after surgery. The survival time of transplanted heart allografts were observed, and their histopathological changes and the degrees of coronary intimal hyperplasia were estimated.Blastocyst MHC gene mRNA expression levels were detected by real-time fluorescence quantitative RT-PCR. Flow cytometry was applied in assessment of the levels of CD4+ CD25+ regulatory T cells (Treg) and CD3+ CD8+ T cells. Results The survival time in the CsA group, transfection group and combined treatment group was significantly longer than in the control group (P＜0.05) and that in the combined treatment group was the longest, up to (20. 50 ± 5. 61) days. On the postoperative day 1 and 3, Blastocyst MHC gene mRNA expression level in the transfection group was significantly higher than that in the control group (P＜0.05). On the postoperative day 7, the degrees of rejection and coronary intimal hyperplasia in the combined treatment group were the lightest. On the postoperative day 7 the number of Tregs in the CsA group and the combined treatment group was significantly increased as compared with that in the control group (P＜0.05), but that of CD3 + CD8+ T cells in the CsA group and the combined treatment group was less than that in the control group (P＜0.05). Conclusion Blastocyst MHC gene transfection in mouse transplanted cardiac allograft can extend its survival time through upregulation of Treg and downregulation of CD3 + CD8 + T cells in the mice. The combination of Blastocyst MHC gene and CsA may exert the synergic effects.
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Objective Cervical heterotopic heart transplantation model was established in different inbred strains of mice with modified cuff technique. Inbred male Balb/c mice and C57BL/6 mice were selected as donors and recipients, respectively. Mice were randomly assigned into four groups: control group (the donor hearts were perfused through coronary artery with 200 μl, 0℃～4℃ St. Thomas Ⅱ solution during 2 to 3 min, then they were immersed in it for 15 min), CsA group ( the donor hearts were perfused with the same method as for the control's and intraperitoneal injection of CsA 5 mg· g-1 · d -1 was given after surgery ), H2-B1 transfection group (the donor hearts were perfused through coronary artery with 200 μl, 0℃ -4℃ St. Thomas Ⅱ solution contained with 30 μg H2-Bl plasmid vectors during 2 to 3 min, then they were immersed in it for 15 min ), and H2-B1 + CsA group ( the donor hearts were perfused with St. Thomas Ⅱ solution contained H2-Bl gene plasmid and intraperitoneal injection of CsA was given after surgery as mentioned above. ). At 1,3 and 7 days after transplantation, three allografts were harvested at each time points in all of the groups, respectively, for pathological examination and analysis of CD40 expression with immunohistochemistry assays. The expression of Th1/Th2 cytokines were also determined with flow cytometry. The survival time of rest allografts were observed. Results Histological features for rejection were observed more apparent in the grafts of control group than those in other groups, especially those in H2-Bl + CsA group. The expression of CD40 in H2-Bl + CsA group and CsA group was lower significantly than that of the control group ( P ＜0.01 ), so was the expression of CD40 in the H2-Bl group as compare with that of the control group (P ＜0.05). No significant difference between H2-Bl group and CsA group (P ＞0.05 ) at 7 days was observed. The expression of IL-2, TNF-α (Th1 cytokines) in control group was much higher than that in other groups, and the expression of IL-4 ( Th2 cytokine) in control group was much lower ( P ＜0.05 ). The level of IL-4 in CsA group increased significantly at 3 days ( P ＜ 0.05 ), with a peak level at 7 days after transplantation (P＜0.01). The survival time of grafts was significantly prolonged in CsA group (P＜0.01), H2-Bl group (P＜0.05) and H2-Bl+CsA group(P＜0.01). Conclusion Treating the donor hearts with H2-Bl plasmid vectors at the time of transplantation may suppress rejection in the heart allografts and prolong the survival time through some presumed mechanisms such as preventing upregulation of CD40 expression, relucing the production of IL-2 and TNF-α, increasing the production of IL-4, and as a result, inducing immune tolerance, as well as improving the function of transplanted heart grafts.