Current medicinal chemistry
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Renin-angiotensin II-aldosterone axis has long been known as a regulator of blood pressure and fluid homeostasis. Yet, local renin-angiotensin II systems have been discovered and novel actions of angiotensin II (AngII) have emerged among which its ability to act as a immunomodulator and profibrotic molecule. The enzyme responsible for its synthesis, Angiotensin-converting-enzyme (ACE), is present in high concentrations in lung tissue. ⋯ The balance between ACE and ACE2 is crucial for controlling AngII levels. ACE and ACE2 also appear to modify the severity of Acute Respiratory Distress Syndrome (ARDS), with ACE2 playing a protective role. Finally, mention is made to the recent discovery of ACE2 as a receptor for the SARS Corona Virus.
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Dyslipidemia is one of the main risk factors leading to atherosclerotic cardiovascular disease (CVD). According to recent treatment guidelines, subjects at substantial risk of CVD should meet more aggressive targets for low-density lipoprotein(LDL)-cholesterol levels. Treatment with statins fails to protect a significant percentage of patients from cardiovascular events despite efficient cholesterol-lowering. ⋯ Squalene synthase inhibitors, antisense oligonucleotides targeting the production of apolipoprotein(apo)B-100, inhibitors of proprotein convertase subtilisin/kexin type 9, microsomal triglyceride transfer protein inhibitors, peroxisome proliferator-activated receptor agonists, and thyroid hormone receptor agonists are some of the alternative approaches for lipid-lowering. Moreover, HDL-targeted therapies such as the cholesteryl ester transfer protein inhibitors, HDLderived proteins, and mimetic peptides/lipids can increase HDL-cholesterol levels or improve the antiatherosclerotic properties of HDL. In conclusion, the emergence of agents that act in monotherapy or in combination with available lipid-modifying drugs may allow more effective management of dyslipidemia and, consequently, reduce the burden of CVD.
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Angiogenesis is known to be essential for the development and progression of cancer. Vascular endothelial growth factor (VEGF) is a critical mediator in tumor angiogenesis for many solid malignancies, including breast cancer. Increased levels of VEGF have been associated with poor clinical outcomes, including reduced survival. ⋯ Several trials to define the role of bevacizumab in different setting of disease and in combination with different chemotherapy regimens and targeted therapy in breast cancer patients are ongoing. Other small molecule inhibitors of VEGF tyrosine kinase activity (TKIs) such as sunitinib, vandetanib and sorafenib are being tested in MBC. This review will focus on bevacizumab and on the developements of the main antiangiogenic agents in the treatment of breast cancer.
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Methylxanthines, such as theophylline, have been used to treat cardiorespiratory disorders, whereas caffeine is the most widely consumed psychoactive agent in various soft drinks. Because of the worldwide use of these drugs and the recently synthesized xanthine derivatives, an intensive research on the cardiac actions of these substances is under progress. This review focuses on the molecular mechanisms involved in the actions of xanthine derivatives with special reference to their adenosine receptor antagonistic properties. ⋯ Upregulation of adenosine receptors and increased effectiveness of adenosine receptor-related cardiovascular functions have been observed after long-lasting treatment with methylxanthines. In addition, there are data indicating that blood adenosine level increases after long-term caffeine administration. Since the salutary actions (and also the adverse reactions) of a number of xanthine derivatives are repeatedly shown, the main goal is the development of novel structures that mimic the actions of the conventional methylxanthines as lead compounds, but their adenosine receptor subtype-specificity is higher, their water solubility is optimal, and the unwanted reactions are minimized.