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Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.
Systematic, faunistic and ecological aspects of the six families and 34 species and subspecies in the order Ephemeroptera currently recorded from Cuba are reviewed based primarily on a reference collection located at the Universidad de Oriente (Santiago de Cuba), collections at the Institute of Ecology and Systematics (Havana) and historic literature. A key to nymphs is included with photographs of significant features of many species. An annotated list of species is presented with comments on type localities, species ecology and distribution. The morpho- ecological types of the nymphs are updated according to current taxonomic changes, and indicator species of organic contamination are analyzed according to the BMWP-Cub index. Based on present data, mayflies are best collected between January and June although many species are present throughout the year, and almost half of the species are widely distributed. Possible routes of penetration from the continents toward Cuba are from South America through the arc of islands formed by the Lesser Antilles, from Central and South America through the peninsula of Yucatan, and via an ancient landspan or island chain from northern South America (GAARlandia). With one exception, there is no evidence for dispersal of species from North America (through Florida) to Cuba (and then to the Antilles) or vice versa. The pattern of geographical distribution of Ephemeroptera inside Cuba is very similar to that of the orders Trichoptera and Odonata. The greatest number of species is found in the Eastern region and the fewest in the Central and Central-East regions. The high endemism (76.5%) is probably due to geographical isolation and processes that bring about this phenomenon together with the low vagility that characterizes the order.
Vascular biotransformation of organic nitrates is independent of cytochrome P450 monooxygenases
(2021)
Background and Purpose: Organic nitrates such as nitroglycerin (NTG) or pentaerythritol tetranitrate (PETN) have been used for over a century in the treatment of angina or ischaemic heart disease. These compounds are prodrugs which release their nitrovasodilators upon enzymic bioactivation by aldehyde dehydrogenase (ALDH2) or cytochromes P450 (CYP). Whereas ALDH2 is known to directly activate organic nitrates in vessels, the contribution of vascular CYPs is unknown and was studied here.
Experimental Approach: As all CYPs depend on cytochrome P450 reductase (POR) as electron donor, we generated a smooth muscle cell-specific, inducible knockout mouse of POR (smcPOR−/−) to investigate the contribution of POR/CYP to vascular biotransformation of organic nitrates.
Key Results: Microsomes containing recombinant CYPs expressed in human vascular tissues released nitrite from NTG and PETN with CYP2C9 and CYP2C8 being most efficient. SFK525, a CYP suicide inhibitor, blocked this effect. smcPOR−/− mice exhibited no obvious cardiovascular phenotype (normal cardiac weight and endothelium-dependent relaxation) and plasma and vascular nitrite production was similar to control (CTL) animals. NTG- and PETN-induced relaxation of isolated endothelium-intact or endothelium-denuded vessels were identical between CTL and smcPOR−/−. Likewise, nitrite release from organic nitrates in aortic rings was not affected by deletion of POR in smooth muscle cells (SMCs). In contrast, inhibition of ALDH2 by benomyl (10 μM) inhibited NTG-induced nitrite production and relaxation. Deletion of POR did not modulate this response.
Conclusions and Implications: Our data suggest that metabolism by vascular CYPs does not contribute to the pharmacological function of organic nitrates.
Epoxyeicosatrienoic acids (EETs) are signaling lipids produced by the cytochrome P450-(CYP450)-mediated epoxygenation of arachidonic acid. EETs have numerous biological effects on the vascular system, but aspects including their species specificity make their effects on vascular tone controversial. CYP450 enzymes require the 450-reductase (POR) for their activity. We set out to determine the contribution of endothelial CYP450 to murine vascular function using isolated aortic ring preparations from tamoxifen-inducible endothelial cell-specific POR knockout mice (ecPOR−/−). Constrictor responses to phenylephrine were similar between control (CTR) and ecPOR−/− mice. Contrastingly, sensitivity to the thromboxane receptor agonist U46619 and prostaglandin E2 (PGE2) was increased following the deletion of POR. Ex vivo incubation with a non-hydrolyzable EET (14,15-EE-8(Z)-E, EEZE) reversed the increased sensitivity to U46619 to the levels of CTR. EETs had no effect on vascular tone in phenylephrine-preconstricted vessels, but dilated vessels contracted with U46619 or PGE2. As U46619 acts through RhoA-dependent kinase, this system was analyzed. The deletion of POR affected the expression of genes in this pathway and the inhibition of Rho-GTPase with SAR407899 decreased sensitivity to U46619. These data suggest that EET and prostanoid crosstalk at the receptor level and that lack of EET production sensitizes vessels to vasoconstriction via the induction of the Rho kinase system.