Effects of Benzo(a)pyrene on the Contractile Function of the Thoracic Aorta of Sprague-dawley Rats

Abstract Objective To evaluate the possible vascular effects of an environment carcinogen benzo（a）pyrene （BaP）. Methods The cytotoxicit of BaP and rat liver S9 （0.25 mg/mL）-activated BaP were examined by MTT assay. Thoracic aortic rings were dissected from Sprague-Dawley rats. Contraction of aortic rings was induced by 60 mmol/L KCl or 10-6 mol/L phenylephrine （PE） in an ex-vivo perfusion system after BaP （100 tlmol/L） incubation for 6 h. [Ca^2＋]i was measured using Fluo-4/AM. For in-vivo treatment, rats were injected with BaP for 4 weeks （10 mg/kg, weekly, i.p.）. Results BaP （1-500 μm） did not significantly affect cell viability; S9-activated BaP stimulated cell proliferation. BaP did not affect the contractile function of endothelium-intact or -denuded aortic rings. BaP did not affect ATP-induced （[Ca2＋]i） increases in human umbilical vein endothelial cells. In BaP-treated rats, heart rate and the number of circulating inflammatory cells were not affected. Body weight decreased while blood pressure increased significantly. The maximum aortic contractile responses to PE and KCI and the maximum aortic relaxation response to acetylcholine were significantly decreased by 25.0%, 34.2%, and 10.4%, respectively. Conclusion These results suggest, in accordance with its DNA-damaging properties, that metabolic activation is a prerequisite for BaP-induced cardiovascular toxicity.

Direct evidence of VEGF-mediated neuroregulation and afferent explanation of blood pressure dysregulation during angiogenic therapy

Objective:Oncocardiology is increasingly hot research field/topic in the clinical management of cancer with anti-angiogenic therapy of vascular endothelial growth factor(VEGF)that may cause cardiovascular toxicity,such as hypertension via vascular dysfunction and attenuation of eNOS/NO signaling in the baroreflex afferent pathway.The aim of the current study was to evaluate the potential roles of VEGF/VEGF receptors(VEGFRs)expressed in the baroreflex afferent pathway in autonomic control of blood pressure(BP)regulation.Methods:The distribution and expression of VEGF/VEGFRs were detected in the nodose ganglia(NG)and nucleus of tractus solitary(NTS)using immunostaining and molecular approaches.The direct role of VEGF was tested by NG microinjection under physiological and hypertensive conditions.Results:Immunostaining data showed that either VEGF or VEGFR2/VEGFR3 was clearly detected in the NG and NTS of adult male rats.Microinjection of VEGF directly into the NG reduced the mean blood pressure(MBP)dose-dependently,which was less dramatic in renovascular hypertension(RVH)rats,suggesting the VEGF-mediated depressor response by direct activation of the 1st-order baroreceptor neurons in the NG under both normal and disease conditions.Notably,this reduced depressor response in RVH rats was directly caused by the downregulation of VEGFR2,which compensated the up regulation of VEGF/VEGFR3 in the NG during the development of hypertension.Conclusion:It demonstrated for the first time that the BP-lowering property of VEGF/VEGFRs signaling via the activation of baroreflex afferent function may be a common target/pathway leading to BP dysregulation in anti-angiogenic therapy.

Cardiovascular disease burden in patients with urological cancers:The new discipline of uro-cardio-oncology

Cancer remains a major cause of mortality worldwide,and urological cancers are the most common cancers among men.Several therapeutic agents have been used to treat urological cancer,leading to improved survival for patients.However,this has been accompanied by an increase in the frequency of survivors with cardiovascular complications caused by anticancer medications.Here,we propose the novel discipline of uro-cardio-oncology,an evolving subspecialty focused on the complex interactions between cardiovascular disease and urological cancer.In this comprehensive review,we discuss the various cardiovascular toxicities induced by different classes of antineoplastic agents used to treat urological cancers,including androgen deprivation therapy,vascular endothelial growth factor receptor tyrosine kinase inhibitors,immune checkpoint inhibitors,and chemotherapeutics.In addition,we discuss possible mechanisms underlying the cardiovascular toxicity associated with anticancer therapy and outline strategies for the surveillance,diagnosis,and effective management of cardiovascular complications.Finally,we provide an analysis of future perspectives in this emerging specialty,identifying areas in need of further research.

Toxicity comparison of different active fractions extracted from radix Sophorae tonkinensis in zebrafish

Radix Sophorae tonkinensis(RST) is a widely used herb in Traditional Chinese Medicine(TCM) for treating infectious and inflammatory diseases. However, the toxicity data for RST are limited. The aim of this work is to assess and compare the toxicity of the whole RST extract and its five active fractions using the zebrafish model. Five active fractions of RST were prepared using five different types of solvents, which included dealkalized water, ethanol, n-butyl ethanol, dichloromethane, and diethyl ether. The chemical profiles of the active fractions were determined by high-performance liquid chromatography(HPLC), and the toxicity observed in the zebrafish model was confirmed using mouse models. In the zebrafish model, cardiovascular toxicity was observed for the fraction extracted using diethyl ether, and hepatotoxicity was observed for the whole RST extract and the fractions extracted using water and ethanol, whereas both cardiovascular and hepatic toxicities were observed for the fractions extracted using n-butyl ethanol and dichloromethane. The hepatotoxicity of the fractions extracted using n-butyl ethanol and dichloromethane was also observed in mice. Our findings provide the toxicity data for RST and its five active fractions through modeling in a zebrafish, and indicate that the different fractions may each have a different toxicity, which is helpful for the optimal use of RST in clinical practice.

Value of Myocardial Strain in Monitoring Fluorouracil-Based Chemotherapy-Related Cardiac Dysfunction in Gastrointestinal Cancer Patients

Objective To investigate the predictive value of myocardial strain for cardiotoxicity associated with fluorouracil-based chemotherapies in gastrointestinal cancer patients.Methods Patients with diagnosis of gastrointestinal cancers,who were hospitalized for chemotherapy involving antimetabolic drugs,were eligible in this prospective study.Echocardiography was performed before and after each chemotherapy cycle during hospitalization until the completion of chemotherapy.Cancer therapy-related cardiac dysfunction(CTRCD)was identified if there was a decrease in left ventricular ejection fraction(LVEF)by at least 5%to an absolute value of<53%from the baseline,accompanied by symptoms or signs of heart failure;or a decrease in LVEF of at least 10%to an absolute value of<53%from the baseline,without symptoms or signs of heart failure.Subclinical cardiac impairment is defined as a decrease in the left ventricular global longitudinal strain(GLS)of at least 15%from baseline.Clinical data and myocardial strain variables were collected.Changes of echocardiographic indexes after chemotherapy at each cycle were observed and compared to those of pre-chemotherapy.Cox regression analysis was used to determine the associated indexes to CTRCD,and receiver operating characteristic(ROC)curves were plotted for evaluation of their predicting efficacy.Results Fifty-one patients completed 4 cycles of chemotherapy and were enrolled in the study analysis.LVEF,GLS,GLS epicardium(GLS-epi),and GLS endocardium(GLS-endo)were decreased after the 4 cycles of chemotherapy.Throughout the chemotherapy period,6 patients(11.8%)progressed to CTRCD.The Cox regression analysis revealed that the change in left atrial ejection fraction(LAEF)and LAS during the reservoir(LASr)phase after the first cycle of chemotherapy(C1v-LAEF and C1v-LASr,respectively)were significantly associated with the development of CTRCD[C1v-LAEF(HR=1.040;95%CI:1.000-1.082;P=0.047);C1v-LASr(HR=1.024;95%CI:1.000-1.048;P=0.048)].The sensitivity and specificity were 50.0%and 93.3%,respectively,for C1v-LAEF predicting CTRCD when C1v-LAEF>19.68%was used as the cut-off value,and were 66.7%and 75.6%,respectively,for C1v-LASr predicting CTRCD when C1v-LASr>14.73%was used as the cut-off value.The areas under the ROC curve(AUC)for C1v-LAEF and C1v-LASr predicting CTRCD were 0.694 and 0.707,respectively.Conclusion GLS changes among patients with subclinical impairment of cardiac function who were treated with fluorouracil-based chemotherapies,and C1v-LAEF and C1v-LASr of the left atrium are early predictors of cardiac function deterioration.