Chronic Endurance Exercise Impairs Cardiac Structure and Function in Middle-Aged Mice with Impaired Nrf2 Signaling.

Nuclear factor erythroid 2 related factor 2 (Nrf2) signaling maintains the redox homeostasis and its activation is shown to suppress cardiac maladaptation. Earlier we reported that acute endurance exercise (2 days) evoked antioxidant cytoprotection in young WT animals but not in aged WT animals. However, the effect of repeated endurance exercise during biologic aging (WT) characterized by an inherent deterioration in Nrf2 signaling and pathological aging (pronounced oxidative susceptibility-Nrf2 absence) in the myocardium remains elusive.

Numtogenesis as a mechanism for development of cancer.

Transfer of genetic material from cytoplasmic organelles to the nucleus, an ongoing process, has implications in evolution, aging, and human pathologies such as cancer. The transferred mitochondrial DNA (mtDNA) fragments in the nuclear genome are called nuclear mtDNA or NUMTs. We have named the process numtogenesis, defining the term as the transfer of mtDNA into the nuclear genome, or, less specifically, the transfer of mitochondria or mitochondrial components into the nucleus.

Defining the momiome: Promiscuous information transfer by mobile mitochondria and the mitochondrial genome.

Mitochondria are complex intracellular organelles that have long been identified as the powerhouses of eukaryotic cells because of the central role they play in oxidative metabolism. A resurgence of interest in the study of mitochondria during the past decade has revealed that mitochondria also play key roles in cell signaling, proliferation, cell metabolism and cell death, and that genetic and/or metabolic alterations in mitochondria contribute to a number of diseases, including cancer. Mitochondria have been identified as signaling organelles, capable of mediating bidirectional intracellular information transfer: anterograde (from nucleus to mitochondria) and retrograde (from mitochondria to nucleus).

Mitochondrial determinants of cancer health disparities.

Mitochondria, which are multi-functional, have been implicated in cancer initiation, progression, and metastasis due to metabolic alterations in transformed cells. Mitochondria are involved in the generation of energy, cell growth and differentiation, cellular signaling, cell cycle control, and cell death. To date, the mitochondrial basis of cancer disparities is unknown.

Constitutive activation of Nrf2 induces a stable reductive state in the mouse myocardium.

Redox homeostasis regulates key cellular signaling pathways in both physiology and pathology. The cell's antioxidant response provides a defense against oxidative stress and establishes a redox tone permissive for cell signaling. The molecular regulation of the well-known Keap1/Nrf2 system acts as sensor responding to changes in redox homeostasis and is poorly studied in the heart.

Repositioning chlorpromazine for treating chemoresistant glioma through the inhibition of cytochrome c oxidase bearing the COX4-1 regulatory subunit.

Patients with glioblastoma have one of the lowest overall survival rates among patients with cancer. Standard of care for patients with glioblastoma includes temozolomide and radiation therapy, yet 30% of patients do not respond to these treatments and nearly all glioblastoma tumors become resistant. Chlorpromazine is a United States Food and Drug Administration-approved phenothiazine widely used as a psychotropic in clinical practice.

Measuring nitrate reductase activity from human and rodent tongues.

Reduction of salivary nitrate to nitrite by oral microbes expressing nitrate-reductase has emerged as a crucial pathway in systemic NO homeostasis in humans and other mammals. Selective depletion of oral microbes prevents dietary nitrate-dependent lowering of blood pressure, inhibition of platelet aggregation and ischemic injury. To date, most studies interrogate enterosalivary nitrate reduction by following changes in saliva or plasma nitrite and NO-signaling (functional) end points.

Migration of mitochondrial DNA in the nuclear genome of colorectal adenocarcinoma.

Background: Colorectal adenocarcinomas are characterized by abnormal mitochondrial DNA (mtDNA) copy number and genomic instability, but a molecular interaction between mitochondrial and nuclear genome remains unknown. Here we report the discovery of increased copies of nuclear mtDNA (NUMT) in colorectal adenocarcinomas, which supports link between mtDNA and genomic instability in the nucleus. We name this phenomenon of nuclear occurrence of mitochondrial component as numtogenesis.

Single molecule mtDNA fiber FISH for analyzing numtogenesis.

Somatic human cells contain thousands of copies of mitochondrial DNA (mtDNA). In eukaryotes, natural transfer of mtDNA into the nucleus generates nuclear mitochondrial DNA (NUMT) copies. We name this phenomenon as "numtogenesis".

Nitrite therapy prevents chlorine gas toxicity in rabbits.

Chlorine (Cl) gas exposure and toxicity remains a concern in military and industrial sectors. While post-Cl exposure damage to the lungs and other tissues has been documented and major underlying mechanisms elucidated, no targeted therapeutics that are effective when administered post-exposure, and which are amenable to mass-casualty scenarios have been developed. Our recent studies show nitrite administered by intramuscular (IM) injection post-Cl exposure is effective in preventing acute lung injury and improving survival in rodent models.

Validation of two point-of-care tests against standard lab measures of NO in saliva and in serum.

Nitric oxide (NO) is an endogenous signaling molecule, which plays important roles in cardiometabolic health. A significant source of NO is dietary nitrate (NO), which is initially metabolized by oral bacteria into nitrite (NO) and is subsequently converted into NO once digested in the acidic gastric environment. Inexpensive non-invasive tests for measuring nitrite from saliva have been developed as a means for individuals to monitor their NO bioavailability.

Trehalose does not improve neuronal survival on exposure to alpha-synuclein pre-formed fibrils.

Parkinson's disease is a debilitating neurodegenerative disorder that is pathologically characterized by intracellular inclusions comprised primarily of alpha-synuclein (αSyn) that can also be transmitted from neuron to neuron. Several lines of evidence suggest that these inclusions cause neurodegeneration. Thus exploring strategies to improve neuronal survival in neurons with αSyn aggregates is critical.

Inhibition of autophagy with bafilomycin and chloroquine decreases mitochondrial quality and bioenergetic function in primary neurons.

Autophagy is an important cell recycling program responsible for the clearance of damaged or long-lived proteins and organelles. Pharmacological modulators of this pathway have been extensively utilized in a wide range of basic research and pre-clinical studies. Bafilomycin A1 and chloroquine are commonly used compounds that inhibit autophagy by targeting the lysosomes but through distinct mechanisms.

Absorbance and redox based approaches for measuring free heme and free hemoglobin in biological matrices.

Cell-free heme (CFH) and hemoglobin (Hb) have emerged as distinct mediators of acute injury characterized by inflammation and microcirculatory dysfunction in hemolytic conditions and critical illness. Several reports have shown changes in Hb and CFH in specific pathophysiological settings. Using PBS, plasma from patients with sickle cell disease, acute respiratory distress syndrome (ARDS) patients and supernatants from red cells units, we found that commonly used assays and commercially available kits do not distinguish between CFH and Hb.

A biphasic effect of TNF-α in regulation of the Keap1/Nrf2 pathway in cardiomyocytes.

Antagonizing TNF-α signaling attenuates chronic inflammatory disease, but is associated with adverse effects on the cardiovascular system. Therefore the impact of TNF-α on basal control of redox signaling events needs to be understand in more depth. This is particularly important for the Keap1/Nrf2 pathway in the heart and in the present study we hypothesized that inhibition of a low level of TNF-α signaling attenuates the TNF-α dependent activation of this cytoprotective pathway.

Identification of Small Molecule Inhibitors of Human Cytochrome c Oxidase That Target Chemoresistant Glioma Cells.

The enzyme cytochrome c oxidase (CcO) or complex IV (EC 1.9.3.

Solubility and diffusion of oxygen in phospholipid membranes.

The transport of oxygen and other nonelectrolytes across lipid membranes is known to depend on both diffusion and solubility in the bilayer, and to be affected by changes in the physical state and by the lipid composition, especially the content of cholesterol and unsaturated fatty acids. However, it is not known how these factors affect diffusion and solubility separately. Herein we measured the partition coefficient of oxygen in liposome membranes of dilauroyl-, dimiristoyl- and dipalmitoylphosphatidylcholine in buffer at different temperatures using the equilibrium-shift method with electrochemical detection.

There is blood in the water: hemolysis, hemoglobin, and heme in acute lung injury.

The major role of red blood cells (RBCs) is to deliver oxygen and remove carbon dioxide within organisms through the unique properties of hemoglobin. Although beneficial within RBCs, when outside hemoglobin and its breakdown products (heme, iron) induce proinflammatory responses affecting various cellular responses. Although these effects are considered to be prominent in disorders with increased hemolysis, recent evidence suggests that this process may be active in nonhemolytic disorders such as acute lung injury/acute respiratory distress syndrome.

O-GlcNAcylation and neurodegeneration.

O-GlcNAcylation is a dynamic form of protein glycosylation which involves the addition of β-d-N-acetylglucosamine (GlcNAc) via an O-linkage to serine or threonine residues of nuclear, cytoplasmic, mitochondrial and transmembrane proteins. The two enzymes responsible for O-GlcNAc cycling are O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA); their expression and activities in brain are age dependent. More than 1000 O-GlcNAc protein targets have been identified which play critical roles in many cellular processes.

The emerging role of gasotransmitters in the pathogenesis of tuberculosis.

Mycobacterium tuberculosis (Mtb) is a facultative intracellular pathogen and the second largest contributor to global mortality caused by an infectious agent after HIV. In infected host cells, Mtb is faced with a harsh intracellular environment including hypoxia and the release of nitric oxide (NO) and carbon monoxide (CO) by immune cells. Hypoxia, NO and CO induce a state of in vitro dormancy where Mtb senses these gases via the DosS and DosT heme sensor kinase proteins, which in turn induce a set of ∼47 genes, known as the Mtb Dos dormancy regulon.

Exercise, Nrf2 and Antioxidant Signaling in Cardiac Aging.

Aging is represented by a progressive decline in cellular functions. The age-related deformities in cardiac behaviors are the loss of cardiac myocytes through apoptosis or programmed cell death. Oxidative stress (OS) and its deleterious consequence contribute to age-related mechanical remodeling, reduced regenerative capacity, and apoptosis in cardiac tissue.

Metabolic, autophagic, and mitophagic activities in cancer initiation and progression.

Cancer is a complex disease marked by uncontrolled cell growth and invasion. These processes are driven by the accumulation of genetic and epigenetic alterations that promote cancer initiation and progression. Contributing to genome changes are the regulation of oxidative stress and reactive species-induced damage to molecules and organelles.

Diagnosis and Treatment of Alcoholic Hepatitis: A Systematic Review.

Alcoholic hepatitis (AH) occurs in about one-third of individuals reporting long-term heavy alcohol use. It is associated with high short-term mortality, economic burden, and hospital resources utilization. We performed this systematic review to (i) describe clinical characteristics and genomics associated with the risk of AH; (ii) discuss role and limitations of liver biopsy and prognostic scoring systems; (iii) summarize evidence regarding the currently available therapies including liver transplantation; and (iv) outline emerging therapies with areas of unmet need.