The Complex Genetic and Epigenetic Regulation of the Nrf2 Pathways: A Review.

Nrf2 is a major transcription factor that significantly regulates-directly or indirectly-more than 2000 genes. While many of these genes are involved in maintaining redox balance, others are involved in maintaining balance among metabolic pathways that are seemingly unrelated to oxidative stress. In the past 25 years, the number of factors involved in the activation, nuclear translocation, and deactivation of Nrf2 has continued to expand.

Phytochemical compound PB125 attenuates skeletal muscle mitochondrial dysfunction and impaired proteostasis in a model of musculoskeletal decline.

Impaired mitochondrial function and disrupted proteostasis contribute to musculoskeletal dysfunction. However, few interventions simultaneously target these two drivers to prevent musculoskeletal decline. Nuclear factor erythroid 2-related factor 2 (Nrf2) activates a transcriptional programme promoting cytoprotection, metabolism, and proteostasis.

Effects of the Phytochemical Combination PB123 on Nrf2 Activation, Gene Expression, and the Cholesterol Pathway in HepG2 Cells.

There has been a long history of human usage of the biologically-active phytochemicals in , , and for health purposes, and we recently reported on a combination of those plant materials as the PB123 dietary supplement. In the present work we extended those studies to evaluate activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor and differential gene expression in cultured HepG2 (hepatocellular carcinoma) cells treated with PB123. We determined transcriptome changes using mRNA-seq methods, and analyzed the affected pathways using Ingenuity Pathway Analysis and BioJupies, indicating that primary effects included increasing the Nrf2 pathway and decreasing the cholesterol biosynthesis pathway.

Nrf2 activator PB125® as a carnosic acid-based therapeutic agent against respiratory viral diseases, including COVID-19.

PB125® is a phytochemical composition providing potent Nrf2 activation as well as a number of direct actions that do not involve Nrf2. Nrf2 is a transcription actor that helps maintain metabolic balance by providing redox-sensitive expression of numerous genes controlling normal day-to-day metabolic pathways. When ordinary metabolism is upset by extraordinary events such as injury, pathogenic infection, air or water pollution, ingestion of toxins, or simply by the slow but incessant changes brought about by aging and genetic variations, Nrf2 may also be called into action by the redox changes resulting from these events, whether acute or chronic.

Phytochemical and Biological Investigation of Helianthemum nummularium, a High-Altitude Growing Alpine Plant Overrepresented in Ungulates Diets.

is a European shrub growing at high altitude where it copes with a high level of stress. It was found to be overexpressed in ungulates diets compared to more abundant surrounding plants. These elements combined with the fact that from the Alps has never been investigated prompted us to study the phytochemical composition of its aerial parts.

Nrf2 Activator PB125 as a Potential Therapeutic Agent against COVID-19.

Nrf2 is a transcription factor that regulates cellular redox balance and the expression of a wide array of genes involved in immunity and inflammation, including antiviral actions. Nrf2 activity declines with age, making the elderly more susceptible to oxidative stress-mediated diseases, which include type 2 diabetes, chronic inflammation, and viral infections. Published evidence suggests that Nrf2 activity may regulate important mechanisms affecting viral susceptibility and replication.

Nrf2 Activator PB125® as a Potential Therapeutic Agent Against COVID-19.

Nrf2 is a transcription factor that regulates cellular redox balance and the expression of a wide array of genes involved in immunity and inflammation, including antiviral actions. Nrf2 activity declines with age, making the elderly more susceptible to oxidative stress-mediated diseases, which include type 2 diabetes, chronic inflammation, and viral infections. Published evidence suggests that Nrf2 activity may regulate important mechanisms affecting viral susceptibility and replication.

MiR-144 mediates Nrf2 inhibition and alveolar epithelial dysfunction in HIV-1 transgenic rats.

Chronic HIV infection causes redox stress and increases the risk of acute and chronic lung injury, even when individuals are adherent to antiretroviral therapy. HIV-1 transgene expression in rats inhibits nuclear factor (erythroid-derived 2)-like 2 (Nrf2), which regulates antioxidant defenses and alveolar epithelial cell (AEC) barrier function, but the mechanism is unknown. In this study, we present novel evidence that these pathological effects of HIV are mediated by microRNA-144 (miR-144).

Phytochemical Combination PB125 Activates the Nrf2 Pathway and Induces Cellular Protection against Oxidative Injury.

Bioactive phytochemicals in , , and have a long history of human use to promote health. In this study we examined the cellular effects of a combination of extracts from these plant sources based on specified levels of their carnosol/carnosic acid, withaferin A, and luteolin levels, respectively. Individually, these bioactive compounds have previously been shown to activate the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor, which binds to the antioxidant response element (ARE) and regulates the expression of a wide variety of cytoprotective genes.

Aqueous Plasma Pharmacy: Preparation Methods, Chemistry, and Therapeutic Applications.

Plasma pharmacy is a subset of the broader field of plasma medicine. Although not strictly defined, the term aqueous plasma pharmacy (APP) is used to refer to the generation and distribution of reactive plasma-generated species in an aqueous solution followed by subsequent administration for therapeutic benefits. APP attempts to harness the therapeutic effects of plasma-generated oxidant species within aqueous solution in various applications, such as disinfectant solutions, cell proliferation related to wound healing, and cancer treatment.

The clinical potential of influencing Nrf2 signaling in degenerative and immunological disorders.

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2; encoded in humans by the NFE2L2 gene) is a transcription factor that regulates the gene expression of a wide variety of cytoprotective phase II detoxification and antioxidant enzymes through a promoter sequence known as the antioxidant-responsive element (ARE). The ARE is a promoter element found in many cytoprotective genes; therefore, Nrf2 plays a pivotal role in the ARE-driven cellular defense system against environmental stresses. Agents that target the ARE/Nrf2 pathway have been tested in a wide variety of disorders, with at least one new Nrf2-activating drug now approved by the US Food and Drug Administration.

Oxidative stress in health and disease: the therapeutic potential of Nrf2 activation.

For the past 40 years or so, oxidative stress has been increasingly recognized as a contributing factor in aging and in various forms of pathophysiology generally associated with aging. Our view of oxidative stress has been largely "superoxide-centric", as we focused on the pathological sources of this oxygen-derived free radical and the types of molecular havoc it can wreak, as well as on the protection provided by the antioxidant enzymes, especially the superoxide dismutases, catalases, and glutathione peroxidases. In the last decade our view of oxidative stress has broadened considerably, and it is now often seen as an imbalance that has its origins in our genes, and the ways in which gene expression is regulated.

Solubility of α-Tocopheryl Succinate in Supercritical Carbon Dioxide Using Offline HPLC-MS/MS Analysis.

The solubility of the vitamin E-related compound α-tocopheryl succinate in supercritical carbon dioxide was measured at pressures ranging from (15.0 to 30.0) MPa and temperatures of (40 and 50) °C using a simple microsampling type apparatus with a 100.

Solubility of the sesquiterpene alcohol patchoulol in supercritical carbon dioxide.

The solubility of the sesquiterpene alcohol patchoulol in supercritical carbon dioxide was measured at P ranging from 10.0 MPa to 25.0 MPa and T of 40.

Feasibility of tissue plasminogen activator formulated for pulmonary delivery.

Purpose: This study was conducted to assess the feasibility of a pulmonary formulation of tissue plasminogen activator (tPA) for nebulization into the airway by measuring protein stability, biologic activity, particle size, and estimating human lung distribution.

Methods: Formulations were derived by varying the surfactant and protein concentrations. Protein stability and recovery of each nebulized tPA formulation were assessed by ultraviolet spectroscopy.

Microparticle-based lung delivery of INH decreases INH metabolism and targets alveolar macrophages.

Microparticles prepared by the precipitation with a compressed antisolvent (PCA) process were evaluated for their potential in targeting an ionizable prodrug of isoniazid (INH), isoniazid methanesulfonate (INHMS), for sustained delivery of INH to alveolar macrophages (AMs). The charged prodrug was ion-paired with two different hydrophobic cations (tetrapentylammonium (TPA)- and tetraheptylammonium (THA)-bromide), and loaded separately into the poly(l-lactide) (PLA) microparticles. The drug/polymer particles were spherical in shape and between 1 and 3 mum in diameter.

Aerosol-administered alpha-tocopherol attenuates lung inflammation in rats given lipopolysaccharide intratracheally.

Intrapulmonary administration of bacterial lipopolysaccharide (LPS) induces a well-characterized lung inflammatory response involving alveolar macrophage activation, proinflammatory cytokine elaboration, and neutrophil influx. Vitamin E, a lipophilic antioxidant consisting of a family that includes tocopherols and tocotrienols, has previously been shown to have a variety of anti-inflammatory effects, raising interest in its possible uses in disease prevention or therapy. Because aerosol delivery is a specific and rapid way to administer agents to the lungs, the authors undertook to determine whether inhaled vitamin E aerosols would have an anti-inflammatory effect in the lungs.

Serum ferritin increases in hemorrhaged rats that develop acute lung injury: effect of an iron-deficient diet.

For unknown reasons, serum ferritin levels increase in patients at risk for and with acute lung injury (ALI). To improve understanding of the relationship between serum ferritin alterations and the development of ALI, we investigated the effect of iron deficiency on the serum ferritin response of rats subjected to hemorrhage. We found that rats fed an iron-deficient diet for 6 weeks had decreased hemoglobin, hematocrit, liver total iron, liver total iron-binding capacity, and liver ferritin concentrations but the same serum ferritin concentrations as rats fed a control diet.

In vitro and in vivo evaluation of the effects of PLA microparticle crystallinity on cellular response.

Previous research suggests that crystallinity of poly(L-lactide) P(L)LA microparticles can influence surface free energy, which in turn might influence biocompatibility. This work studies the cellular response to P(L)LA microparticles of different crystallinity both in vitro and in vivo. Following incubation with P(L)LA microparticles, the in vitro production of reactive oxygen intermediates (ROI) was measured as a marker of cellular response.

Transforming growth factor beta contributes to lung leak in rats given interleukin-1 intratracheally.

Interleukin-1 (IL-1) is increased in lung lavages obtained from patients with acute lung injury (ALI) and administering recombinant human IL-1alpha (rhIL-1alpha) (50 ng) intratracheally causes an acute, neutrophil-dependent, oxidative lung leak in rats that closely resembles human ALI. In the present work, the authors tested the hypothesis that transforming growth factor beta (TGFbeta) contributes to the lung inflammation and injury that develops in rats given IL-1 intratracheally. They found that intravenous administration of a monoclonal antibody to TGFbeta (1.

Platelet-activating factor induces lung inflammation and leak in rats: hydrogen peroxide production along neutrophil-lung endothelial cell interfaces.

Interleukin-1 (IL-1) levels and neutrophils are increased in the lung-lavage fluid of patients with acute lung injury (ALI), and instilling IL-1 intratracheally into rats causes rapid lung-neutrophil influx and neutrophil-dependent lung leakage. IL-1 insufflation also increases platelet-activating factor (PAF) activity in rat lung, and PAF is increased in the lung-lavage fluid of ALI patients. To assess the direct effects of PAF on the lung, we administered PAF intratracheally in rats.

Ferritin and desferrioxamine attenuate xanthine oxidase-dependent leak in isolated perfused rat lungs.

Iron, through its participation in reactions that generate reactive oxygen species, may contribute to the oxidative lung injury observed in patients with acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). A number of investigators have shown that the endogenous iron storage protein ferritin increases in the blood of patients with and at-risk for ALI and ARDS, but the significance of these increases are not known. In the present investigation, we measured lung tissue levels of thiobarbituric acid reactive substances (TBARS) and lung leak in isolated rat lungs perfused with xanthine oxidase (XO) and purine, an enzymatic system which generates reactive oxygen species.