Cardiac arrhythmias can cause sudden cardiac death (SCD) and add to the current heart failure (HF) health crisis. Nevertheless, the pathological processes underlying arrhythmias are unclear. Arrhythmic conditions are associated with systemic and cardiac oxidative stress caused by reactive oxygen species (ROS). In excitable cardiac cells, ROS regulate both cellular metabolism and ion homeostasis. Increasing evidence suggests that elevated cellular ROS can cause alterations of the cardiac sodium channel (Nav1.5), abnormal Ca2+ handling, changes of mitochondrial function, and gap junction remodeling, leading to arrhythmogenesis. This review summarizes our knowledge of the mechanisms by which ROS may cause arrhythmias and discusses potential therapeutic strategies to prevent arrhythmias by targeting ROS and its consequences.

heart failure is a major cause of mortality in the elderly population. It is often preceded by diastolic dysfunction, which is characterized by impaired active relaxation and increased stiffness. We tested the hypothesis that senescence-prone (SAMP8) mice would develop diastolic dysfunction compared with senescence-resistant controls (SAMR1). Pulsed-wave Doppler imaging of the ratio of blood flow velocity through the mitral valve during early (E) vs. late (A) diastole was reduced from 1.3 Ϯ 0.03 in SAMR1 mice to 1.2 Ϯ 0.03 in SAMP8 mice (P Ͻ 0.05). Tissue Doppler imaging of the early (E') and late (A') diastolic mitral annulus velocities found E' reduced from 25.7 Ϯ 0.9 mm/s in SAMR1 to 21.1 Ϯ 0.8 mm/s in SAMP8 mice and E'/A' similarly reduced from 1.1 Ϯ 0.02 to 0.8 Ϯ 0.03 in SAMR1 vs. SAMP8 mice, respectively (P Ͻ 0.05). Invasive hemodynamics revealed an increased slope of the end-diastolic pressure-volume relationship (0.5 Ϯ 0.05 vs. 0.8 Ϯ 0.14; P Ͻ 0.05), indicating increased left ventricular chamber stiffness. There were no differences in systolic function or mean arterial pressure; however, diastolic dysfunction was accompanied by increased fibrosis in the hearts of SAMP8 mice. In SAMR1 vs. SAMP8 mice, interstitial collagen area increased from 0.3 Ϯ 0.04 to 0.8 Ϯ 0.09% and perivascular collagen area increased from 1.0 Ϯ 0.11 to 1.6 Ϯ 0.14%. Transforming growth factor-␤ and connective tissue growth factor gene expression were increased in the hearts of SAMP8 mice (P Ͻ 0.05 for all data). In summary, SAMP8 mice show increased fibrosis and diastolic dysfunction similar to those seen in humans with aging and may represent a suitable model for future mechanistic studies. heart failure; transforming growth factor; aging HEART FAILURE IS A MAJOR AND growing public health concern in the United States; there are an estimated 5 million people living with this disease, and another 550,000 patients will be diagnosed yearly (6). Approximately one-half of all heart failure patients in the United States suffer from diastolic heart failure, and it is a major cause of mortality in the elderly population (35). Diastolic heart failure describes a group of patients whose clinical manifestation of congestive heart failure is characterized by normal left ventricular diastolic volume, a normal ejection fraction, delayed active relaxation, and increased passive stiffness of the left ventricle (34). Diastolic dysfunction precedes diastolic heart failure and is often clinically silent; it is characterized by abnormal ventricular distensibility, relaxation, and filling (1). Both diastolic dysfunction and diastolic heart failure are most common in the elderly population. In a study that examined the prevalence of this form of heart failure, 50% of patients over the age of 70 showed evidence of diastolic heart failure. Studies (35) indicate that the most important determinants for development of diastolic dysfunction and diastolic heart failure are age and hypertension. Although the exact molecular mechanisms behind diastolic dysfuncti...

Material collected from a parkway in the city of Chicago afforded the isolation of a Nostoc species (UIC 10022A). The extract of this strain displayed significant inhibition of the 20S proteasome as well as antiproliferative activity against HT29, MCF7, NCI-H460, and SF268 cancer cell lines. A standardized dereplication protocol allowed for the rapid identification of three known (11-13) and nine new (1-9) chlorinated cylindrocyclophanes from less than 100 mg of organic extract. Scaleup isolation of 1-9 and 11-13 from a larger extract was guided by LC-UV-MS data. In addition, KBr enrichment of the culture media afforded the isolation of a brominated cylindrocyclophane (10). Biological evaluation of 1-5, 9, and 10-13 revealed a large range of activity against the 20S proteasome and allowed the determination of preliminary structure-activity relationships (SAR) of the cylindrocyclophane pharmacophore.Cyanobacteria are considered a promising source for new pharmaceutical lead compounds and a large number of chemically diverse metabolites have been obtained from cyanobacteria. [1][2][3][4][5] In particular, members of the genus Nostoc have been a valuable source of biologically active compounds. The most prominent example is the cryptophycins, which were first isolated from a lichen cyanobiont. 6 These potent tubulin inhibitors eventually led to the development of a semi-synthetic clinical candidate. [7][8][9] Other examples of compounds isolated from cyanobacteria of the genus Nostoc are the cytotoxic nostocyclopeptides, 10 the antimicrobial nostocyclyne A, 11 as well as protease inhibitors such as the insulapeptolides, 12 nostopeptins, 13, 14 and microviridins G and H. 15 In all of these cases, the source organism was of freshwater or terrestrial origin.As part of our ongoing effort to find novel bioactive natural products from cultured freshwater and terrestrial cyanobacteria from the U.S. Great Lakes region, 16 we have evaluated cyanobacterial extracts for inhibition of the 20S proteasome. The 20S proteasome is the catalytic core of the proteasome complex and plays a pivotal role in the control of cell proliferation, apoptosis, and differentiation in a variety of normal and tumor cells. [17][18][19] Currently, there is one proteasome inhibitor, bortezomib (Velcade) approved by the U.S. Food and Drug Administration. 20 Bortezomib was first approved in May 2003 for the treatment of multiple myeloma, however it has been shown to be effective against other * To whom correspondence should be addressed. . orjala@uic.edu. † Department of Medicinal Chemistry and Pharmacognosy ‡ Center for Biostatistics Supporting Information Available: The 1 H, gCOSY, gHSQC and gHMBC spectra of 1 -10; The DEPTQ spectra of 1, 7 and 10; The gTOCSY spectrum of 7; Photomicrograph and morphological description of Nostoc sp. UIC 10022A. This material is available free of charge via the Internet at http://pubs.acs.org. (HT-29, NCI-H460, SF268, and MCF7). HPLC MS/NMR dereplication allowed for identification of a series of cylindrocycl...

An efficient method has been developed to synthesize casimiroin (1), a component of the edible fruit of Casimiroa edulis, on a multigram scale in good overall yield. The route was versatile enough to provide an array of compound 1 analogues that were evaluated as QR2 and aromatase inhibitors. In addition, X-ray crystallography studies of QR2 in complex with compound 1 and one of its more potent analogs has provided insight into the mechanism of action of this new series of QR2 inhibitors. The initial biological investigations suggest that compound 1 and its analogues merit further investigation as potential chemopreventive or chemotherapeutic agents.