Microglia States are Susceptible to Senescence and Cholesterol Dysregulation in Alzheimer's Disease.

Cellular senescence is a major contributor to aging-related degenerative diseases, including Alzheimer's disease (AD) but much less is known on the key cell types and pathways driving mechanisms of senescence in the brain. We hypothesized that dysregulated cholesterol metabolism is central to cellular senescence in AD. We analyzed whole transcriptomic data and utilized single-cell RNA seq integration techniques to unveil the convoluted cell-type-specific and sub-cell-type-state-specific senescence pathologies in AD using both ROSMAP and Sea-AD datasets.

Development of Calcium-Dependent Phospholipase A2 Inhibitors to Target Cellular Senescence and Oxidative Stress in Neurodegenerative Diseases.

Cellular senescence is a critical process underlying aging and is associated with age-related diseases such as Alzheimer's disease. Lipids are implicated in cellular senescence. Fatty acids, particularly eicosanoids, have been associated with various forms of senescence and inflammation, and the associated reactive oxygen species production has been proposed as a therapeutic target for mitigating senescence.

Cellular senescence induced by cholesterol accumulation is mediated by lysosomal ABCA1 in APOE4 and AD.

Background: Cellular senescence is a hallmark of aging and has been implicated in Alzheimer's disease (AD) pathogenesis. Cholesterol accumulation drives cellular senescence; however, the underlying mechanisms are unclear. ATP-binding cassette transporter A1 (ABCA1) plays an important role in cholesterol homeostasis.

Severe Acute Respiratory Syndrome Coronavirus 2 Infection Alters Mediators of Lung Tissue Remodeling In Vitro and In Vivo.

Background: Altered mediators of airway tissue remodeling such as matrix metalloproteinases (MMPs) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may contribute to morbidity in coronavirus disease 2019 (COVID-19); however, the differential impact of SARS-CoV-2 variants of concern (VOCs) on MMPs is unknown.

Methods: Using both in vitro human airway cell culture model and in vivo transgenic mouse model of SARS-CoV-2 infection, we studied the differential effect of SARS-CoV-2 VOCs on expression of key MMPs and inflammatory mediators in airway cells and tissues.

Results: The most consistent findings with all SARS-CoV-2 variants in infected compared to uninfected human bronchial epithelial cell air-liquid interface cultures were the SARS-CoV-2-induced increases in MMP-12 and tissue inhibitor of MMPs.

Mitoquinone Mesylate and Mitochondrial DNA in End Organs in Humanized Mouse Model of Chronic Treated Human Immunodeficiency Virus Infection.

No treatment exists for mitochondrial dysfunction, a contributor to end-organ disease in human immunodeficiency virus (HIV). The mitochondrial antioxidant mitoquinone mesylate (MitoQ) attenuates mitochondrial dysfunction in preclinical mouse models of various diseases but has not been used in HIV. We used a humanized murine model of chronic HIV infection and polymerase chain reaction to show that HIV-1-infected mice treated with antiretroviral therapy and MitoQ for 90 days had higher ratios of human and murine mitochondrial to nuclear DNA in end organs compared with HIV-1-infected mice on antiretroviral therapy.

Mitoquinone mesylate targets SARS-CoV-2 infection in preclinical models.

Unlabelled: To date, there is no effective oral antiviral against SARS-CoV-2 that is also anti-inflammatory. Herein, we show that the mitochondrial antioxidant mitoquinone/mitoquinol mesylate (Mito-MES), a dietary supplement, has potent antiviral activity against SARS-CoV-2 and its variants of concern and . Mito-MES had nanomolar antiviral potency against the Beta and Delta SARS-CoV-2 variants as well as the murine hepatitis virus (MHV-A59).

The ApoA-I mimetic peptide 4F attenuates in vitro replication of SARS-CoV-2, associated apoptosis, oxidative stress and inflammation in epithelial cells.

An oral antiviral against SARS-CoV-2 that also attenuates inflammatory instigators of severe COVID-19 is not available to date. Herein, we show that the apoA-I mimetic peptide 4 F inhibits Spike mediated viral entry and has antiviral activity against SARS-CoV-2 in human lung epithelial Calu3 and Vero-E6 cells. In SARS-CoV-2 infected Calu3 cells, 4 F upregulated inducers of the interferon pathway such as MX-1 and Heme oxygenase 1 (HO-1) and downregulated mitochondrial reactive oxygen species (mito-ROS) and CD147, a host protein that mediates viral entry.