Browsing by Author "Zhou, Yun"

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    Precision cardio-oncology: understanding the cardiotoxicity of cancer therapy
    (Nature Research, 2017-09-12) Han, Xinqiang; Zhou, Yun; Liu, Wendi; Medicine, School of Medicine
    Current oncologic treatments have brought a strong reduction in mortality in cancer patients. However, the cancer therapy-related cardiovascular complications, in particular chemo-therapy and radiation therapy-induced cardiotoxicities are a major cause of morbidity and mortality in people living with or surviving cancer. The simple fact is that all antineoplastic agents and radiation therapy target tumor cells but also result in collateral damage to other tissues including the cardiovascular system. The commonly used anthracycline chemotherapy agents can induce cardiomyopathy and congestive heart failure. Targeted therapies with human epidermal growth factor antibodies, tyrosine kinase inhibitors or vascular endothelial growth factor antibodies, and the antimetabolites also have shown to induce cardiomyopathy and myocardial ischemia. Cardiac arrhythmias and hypertension have been well described with the use of tyrosine kinase inhibitors and antimicrotubule agents. Pericarditis can happen with the use of cyclophosphamide or cytarabine. Mediastinal radiation can cause constrictive pericarditis, myocardial fibrosis, valvular lesions, and coronary artery disease. Despite significant progresses in the understanding of the molecular and pathophysiologic mechanisms behind the cardiovascular toxicity of cancer therapy, there is still lack of evidence-based approach for the monitoring and management of patients. This review will focus mainly on the recent advances in the molecular mechanisms of cardiotoxicity related to common cancer therapies while introducing the concept of cardio-oncology service. Applying the general principles of multi-disciplinary approaches toward the diagnosis, prevention, monitoring, and treatment of cancer therapy-induced cardiomyopathy and heart failure will also be discussed.
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    The betaine/GABA transporter and betaine: roles in brain, kidney, and liver
    (Frontiers Media, 2014-04-24) Kempson, Stephen A.; Zhou, Yun; Danbolt, Niels C.; Medicine, School of Medicine
    The physiological roles of the betaine/GABA transporter (BGT1; slc6a12) are still being debated. BGT1 is a member of the solute carrier family 6 (the neurotransmitter, sodium symporter transporter family) and mediates cellular uptake of betaine and GABA in a sodium- and chloride-dependent process. Most of the studies of BGT1 concern its function and regulation in the kidney medulla where its role is best understood. The conditions here are hostile due to hyperosmolarity and significant concentrations of NH4Cl and urea. To withstand the hyperosmolarity, cells trigger osmotic adaptation, involving concentration of a transcriptional factor TonEBP/NFAT5 in the nucleus, and accumulate betaine and other osmolytes. Data from renal cells in culture, primarily MDCK, revealed that transcriptional regulation of BGT1 by TonEBP/NFAT5 is relatively slow. To allow more acute control of the abundance of BGT1 protein in the plasma membrane, there is also post-translation regulation of BGT1 protein trafficking which is dependent on intracellular calcium and ATP. Further, betaine may be important in liver metabolism as a methyl donor. In fact, in the mouse the liver is the organ with the highest content of BGT1. Hepatocytes express high levels of both BGT1 and the only enzyme that can metabolize betaine, namely betaine:homocysteine -S-methyltransferase (BHMT1). The BHMT1 enzyme removes a methyl group from betaine and transfers it to homocysteine, a potential risk factor for cardiovascular disease. Finally, BGT1 has been proposed to play a role in controlling brain excitability and thereby represents a target for anticonvulsive drug development. The latter hypothesis is controversial due to very low expression levels of BGT1 relative to other GABA transporters in brain, and also the primary location of BGT1 at the surface of the brain in the leptomeninges. These issues are discussed in detail.