Genetic deficiency or pharmacological inhibition of miR-33 protects from kidney fibrosis

Previous work has reported the important links between cellular bioenergetics and the development of chronic kidney disease, highlighting the potential for targeting metabolic functions to regulate disease progression. More recently, it has been shown that alterations in fatty acid oxidation (FAO) can have an important impact on the progression of kidney disease. In this work, we demonstrate that loss of miR-33, an important regulator of lipid metabolism, can partially prevent the repression of FAO in fibrotic kidneys and reduce lipid accumulation. These changes were associated with a dramatic reduction in the extent of fibrosis induced in 2 mouse models of kidney disease. These effects were not related to changes in circulating leukocytes because bone marrow transplants from miR-33–deficient animals did not have a similar impact on disease progression. Most important, targeted delivery of miR-33 peptide nucleic acid inhibitors to the kidney and other acidic microenvironments was accomplished using pH low insertion peptides as a carrier. This was effective at both increasing the expression of factors involved in FAO and reducing the development of fibrosis. Together, these findings suggest that miR-33 may be an attractive therapeutic target for the treatment of chronic kidney disease

Impaired Cholesterol Efflux in Senescent Macrophages Promotes Age-Related Macular Degeneration

Pathologic angiogenesis mediated by abnormally polarized macrophages plays a central role in common age-associated diseases such as atherosclerosis, cancer, and macular degeneration. Here we demonstrate that abnormal polarization in older macrophages is caused by programmatic changes that lead to reduced expression of ATP binding cassette transporter ABCA1. Downregulation of ABCA1 by microRNA-33 impairs the ability of macrophages to effectively efflux intracellular cholesterol, which in turn leads to higher levels of free cholesterol within senescent macrophages. Elevated intracellular lipid polarizes older macrophages to an abnormal, alternatively activated phenotype that promotes pathologic vascular proliferation. Mice deficient for Abca1, but not Abcg1, demonstrate an accelerated aging phenotype, whereas restoration of cholesterol efflux using LXR agonists or miR-33 inhibitors reverses it. Monocytes from older humans with age-related macular degeneration showed similar changes. These findings provide an avenue for therapeutic modulation of macrophage function in common age-related diseases. [Display omitted] ► Macrophage senescence impairs cholesterol efflux and promotes macular degeneration ► Senescent macrophages polarize to a proangiogenic, disease-promoting phenotype ► Macrophage cholesterol efflux is regulated by miR33 and its target ABCA1 ► Age-related decrease in macrophage cholesterol efflux is therapeutically reversibl

Chapter One - The mechanisms and cell signaling pathways of programmed cell death in the bacterial world

While programmed cell death was once thought to be exclusive to eukaryotic cells, there are now abundant examples of well regulated cell death mechanisms in bacteria. The mechanisms by which bacteria undergo programmed cell death are diverse, and range from the use of toxin-antitoxin systems, to prophage-driven cell lysis. Moreover, some bacteria have learned how to coopt programmed cell death systems in competing bacteria. Interestingly, many of the potential reasons as to why bacteria undergo programmed cell death may parallel those observed in eukaryotic cells, and may be altruistic in nature. These include protection against infection, recycling of nutrients, to ensure correct morphological development, and in response to stressors. In the following chapter, we discuss the molecular and signaling mechanisms by which bacteria undergo programmed cell death. We conclude by discussing the current open questions in this expanding field.https://nsuworks.nova.edu/cnso_bio_facbooks/1036/thumbnail.jp