Interactions of Cellular Energetic Gene Clusters in the Alzheimer's Mouse Brain.

Alzheimer's disease (AD) is the most common cause of dementia in the aging population. The pathological characteristics include extracellular senile plaques and intracellular neurofibrillary tangles. In addition, mitochondrial dysfunction, oxidative stress, and neuroinflammation contribute to AD pathogenesis. In this study, we sought to determine the crosstalk between different pathways in the brain of 5XFAD mice, a mouse model for amyloid pathology, by RNA-seq analysis. We observed significant changes in the expression of genes (1288 genes; adj p value < 0.05; log2-fold > 1 and < 1) related to pathways including oxidation-reduction, oxidative phosphorylation, innate immune response, ribosomal protein synthesis, and ubiquitin proteosome system. The most striking feature was the downregulation of genes related to oxidation-reduction process with changes in the expression of a large number of mitochondrial genes. We also observed an upregulation of several immune response genes. Gene interaction network of oxidation-reduction related genes further confirmed a tight cluster of mitochondrial genes. Furthermore, gene interaction analysis of all the 1288 genes showed at least three distinct interaction clusters, with the predominant one relating to cellular energetics. In summary, we identified 1288 genes distinctly different in the 5XFAD brain compared to the WT brain and found cellular energetics to be the most distinct gene cluster in the AD mouse brain.

Advances in Rodent Experimental Models of Sepsis.

In the development of therapeutic strategies for human diseases, preclinical experimental models have a key role. However, the preclinical immunomodulatory therapies developed using rodent sepsis were not successful in human clinical trials. Sepsis is characterized by a dysregulated inflammation and redox imbalance triggered by infection. Human sepsis is simulated in experimental models using methods that trigger inflammation or infection in the host animals, most often mice or rats. It remains unknown whether the characteristics of the host species, the methods used to induce sepsis, or the molecular processes focused upon need to be revisited in the development of treatment methods that will succeed in human clinical trials. Our goal in this review is to provide a survey of existing experimental models of sepsis, including the use of humanized mice and dirty mice, and to show how these models reflect the clinical course of sepsis. We will discuss the strengths and limitations of these models and present recent advances in this subject area. We maintain that rodent models continue to have an irreplaceable role in studies toward discovering treatment methods for human sepsis.

Regulating mitochondrial metabolism by targeting pyruvate dehydrogenase with dichloroacetate, a metabolic messenger.

Dichloroacetate (DCA) is a naturally occurring xenobiotic that has been used as an investigational drug for over 50 years. Originally found to lower blood glucose levels and alter fat metabolism in diabetic rats, this small molecule was found to serve primarily as a pyruvate dehydrogenase kinase inhibitor. Pyruvate dehydrogenase kinase inhibits pyruvate dehydrogenase complex, the catalyst for oxidative decarboxylation of pyruvate to produce acetyl coenzyme A. Several congenital and acquired disease states share a similar pathobiology with respect to glucose homeostasis under distress that leads to a preferential shift from the more efficient oxidative phosphorylation to glycolysis. By reversing this process, DCA can increase available energy and reduce lactic acidosis. The purpose of this review is to examine the literature surrounding this metabolic messenger as it presents exciting opportunities for future investigation and clinical application in therapy including cancer, metabolic disorders, cerebral ischemia, trauma, and sepsis.

BACH1-Hemoxygenase-1 axis regulates cellular energetics and survival following sepsis.

Sepsis is a complex disease due to dysregulated host response to infection. Oxidative stress and mitochondrial dysfunction leading to metabolic dysregulation are among the hallmarks of sepsis. The transcription factor NRF2 (Nuclear Factor E2-related factor2) is a master regulator of the oxidative stress response, and the NRF2 mediated antioxidant response is negatively regulated by BTB and CNC homology 1 (BACH1) protein. This study tested whether Bach1 deletion improves organ function and survival following polymicrobial sepsis induced by cecal ligation and puncture (CLP). We observed enhanced post-CLP survival in Bach1-/- mice with a concomitantly increased liver HO-1 expression, reduced liver injury and oxidative stress, and attenuated systemic and tissue inflammation. After sepsis induction, the liver mitochondrial function was better preserved in Bach1-/- mice. Furthermore, BACH1 deficiency improved liver and lung blood flow in septic mice, as measured by SPECT/CT. RNA-seq analysis identified 44 genes significantly altered in Bach1-/- mice after sepsis, including HMOX1 and several genes in lipid metabolism. Inhibiting HO-1 activity by Zinc Protoporphyrin-9 worsened organ function in Bach1-/- mice following sepsis. We demonstrate that mitochondrial bioenergetics, organ function, and survival following experimental sepsis were improved in Bach1-/- mice through the HO-1-dependent mechanism and conclude that BACH1 is a therapeutic target in sepsis.

Juvenile Plasma Factors Improve Organ Function and Survival following Injury by Promoting Antioxidant Response.

Studies have shown that factors in the blood of young organisms can rejuvenate the old ones. Studies using heterochronic parabiosis models further reinforced the hypothesis that juvenile factors can rejuvenate aged systems. We sought to determine the effect of juvenile plasma-derived factors on the outcome following hemorrhagic shock injury in aged mice. We discovered that pre-pubertal (young) mice subjected to hemorrhagic shock survived for a prolonged period, in the absence of fluid resuscitation, compared to mature or aged mice. To further understand the mechanism of maturational dependence of injury resolution, extracellular vesicles isolated from the plasma of young mice were administered to aged mice subjected to hemorrhagic shock. The extracellular vesicle treatment prolonged life in the aged mice. The treatment resulted in reduced oxidative stress in the liver and in the circulation, along with an enhanced expression of the nuclear factor erythroid factor 2-related factor 2 (Nrf2) and its target genes, and a reduction in the expression of the transcription factor BTB and CNC homology 1 (Bach1). We propose that plasma factors in the juvenile mice have a reparative effect in the aged mice in injury resolution by modulating the Nrf2/Bach1 axis in the antioxidant response pathway.

Regulation of NAD+ metabolism in aging and disease.

More than a century after discovering NAD+, information is still evolving on the role of this molecule in health and diseases. The biological functions of NAD+ and NAD+ precursors encompass pathways in cellular energetics, inflammation, metabolism, and cell survival. Several metabolic and neurological diseases exhibit reduced tissue NAD+ levels. Significantly reduced levels of NAD+ are also associated with aging, and enhancing NAD+ levels improved healthspan and lifespan in animal models. Recent studies suggest a causal link between senescence, age-associated reduction in tissue NAD+ and enzymatic degradation of NAD+. Furthermore, the discovery of transporters and receptors involved in NAD+ precursor (nicotinic acid, or niacin, nicotinamide, and nicotinamide riboside) metabolism allowed for a better understanding of their role in cellular homeostasis including signaling functions that are independent of their functions in redox reactions. We also review studies that demonstrate that the functional effect of niacin is partially due to the activation of its cell surface receptor, GPR109a. Based on the recent progress in understanding the mechanism and function of NAD+ and NAD+ precursors in cell metabolism, new strategies are evolving to exploit these molecules' pharmacological potential in the maintenance of metabolic balance.

Pulmonary function changes in older adults with and without metabolic syndrome.

The low-grade inflammation associated with metabolic syndrome (MS) triggers functional and structural alterations in several organs. Whereas lung function impairment is well reported for older adult population, the effect of MS on functional and immunological responses in the lungs remains unclear. In this cross-sectional study we determined whether MS alters pulmonary function, and immunological responses in older adults with MS. The study sample consisted of older adults with MS (68 ± 3 years old; n = 77) and without MS (67 ± 3 years old; n = 77). Impulse oscillometry was used to evaluate airway and tissue resistance, and reactance. Biomarkers of inflammation and fibrosis were assessed in the blood and in breath condensate. The total resistance of the respiratory system (R5Hz; p < 0.009), and the resistance of the proximal (R20Hz; p < 0.001) and distal (R5Hz-R20Hz; p < 0.004) airways were higher in MS individuals compared to those without MS. Pro-inflammatory (leptin, IL-1beta, IL-8, p < 0.001; TNF-alpha, p < 0.04) and anti-inflammatory cytokines (adiponectin, IL-1ra, IL-10, p < 0.001), anti-fibrotic (relaxin 1, relaxin 3, Klotho, p < 0.001) and pro-fibrotic (VEGF, p < 0.001) factors were increased in sera and in breath condensate individuals with MS. The results show that MS adversely affect lung mechanics, function, and immunological response in older adults. The data offer a metabolic basis for the inflammaging of the lungs and suggest the lungs as a potential therapeutic target for controlling the immune response and delaying the onset of impaired lung function in older adults with MS.

Dysregulation of cellular energetics in Gulf War Illness.

Gulf War Illness (GWI) is estimated to have affected about one third of the Veterans who participated in the first Persian Gulf War. The symptoms of GWI include chronic neurologic impairments, chronic fatigue syndrome, as well as fibromyalgia and immune system disorders, collectively referred to as chronic multi-symptom illness. Thirty years after the war, we still do not have an effective treatment for GWI. It is necessary to understand the molecular basis of the symptoms of GWI in order to develop appropriate therapeutic strategies. Cellular energetics are critical to the maintenance of cellular homeostasis, a process that is highly dependent on intact mitochondrial function and there is significant evidence from both human studies and animal models that mitochondrial impairments may lead to GWI symptoms. The available clinical and pre-clinical data suggest that agents that improve mitochondrial function have the potential to restore cellular energetics and treat GWI. To date, the experiments conducted in animal models of GWI have mainly focused on neurobehavioral aspects of the illness. Additional studies to address the fundamental biological processes that trigger the dysregulation of cellular energetics in GWI are warranted to better understand the underlying pathology and to develop new treatment methods. This review highlights studies related to mitochondrial dysfunction observed in both GW veterans and in animal models of GWI.

Rapid senescence-like response after acute injury.

Cellular senescence is a state of irreversible growth arrest. Short-term programmed senescence such as in embryonic development and slowly progressing senescence as in aging are both well described. However, acute senescence in living organisms is not well understood. We hypothesized that hemorrhagic shock injury (HI) caused by whole body hypoxia and nutrient deprivation, resulting in organ dysfunction due to severe blood loss, could lead to acute senescence in vivo. Our experiments, for the first time, demonstrate a rapidly emerged, senolytics-responsive, senescence-like response in the rat liver in less than five hr following hemorrhagic shock. We conclude that the senescence, or pseudosenescence, observed is necessary to maintain tissue homeostasis following the injury.

A Combination Treatment Strategy for Hemorrhagic Shock in a Rat Model Modulates Autophagy.

Hemorrhagic shock leads to whole body hypoxia and nutrient deprivation resulting in organ dysfunction and mortality. Previous studies demonstrated that resveratrol, dichloroacetate, and niacin improve organ function and survival in rats following hemorrhagic shock injury (HI). We hypothesized that a combinatorial formula that collectively promotes survival will decrease the dose of individual compounds toward effective therapy for HI. Sprague-Dawley rats were subjected to HI by withdrawing 60% blood volume. NiDaR (Niacin-Dichloroacetate-Resveratrol; 2 mg/kg dose of each) or vehicle was administered following the shock in the absence of fluid resuscitation, and survival monitored. In order to study alterations in molecular mediators, separate groups of rats were administered NiDaR or vehicle along with resuscitation fluid, following HI. We observed significant improvement (p < 0.05) in survival following HI in animals that received NiDaR, in the absence of fluid resuscitation. In NiDaR treated animals that received resuscitation fluid, MAP was significantly increased compared to Veh-treated rats. HI-induced increase in systemic IL-6 levels and tissue expression of IL-6, IL-10, IL-1ß, and IL-18 genes in the heart were attenuated with NiDaR treatment. NiDaR promoted autophagy following HI as demonstrated by reduced p-mTOR, increased p-ULK1 and p-Beclin. The combinatorial formula, NiDaR, reduced inflammation, promoted autophagy, and reduced doses of individual compounds used, and may be more effective in genetically heterogeneous population. In conclusion our experiments demonstrated that the combinatorial drug treatment has salutary effect in rats following HI.