Compounds that modulate oxidative stress
View Patent ↗The present invention provides methods of identifying compounds that selectively induce an oxidative stress response in a biological sample. The present invention further provides methods of treating a subject having a disease associated with oxidative stress using compounds that selectively induce an oxidative stress response in the subject. The invention further provides methods of selectively inducing an oxidative stress response in a cell.
1. A method of selectively inducing an oxidative stress response in a cell, the method comprising:
contacting a cell with a selective inducer compound,
wherein the selective inducer compound
i) is a non-naturally-occurring organic compound,
ii) induces expression in the cell of at least the oxidative stress-responsive genes heme oxygenase 1 (HMOX1), NAD(P)H:quinine oxidoreductase (NQO1), and thioredoxin reductase 1 (TXNRD 1);
iii) does not significantly activate the cellular stress response in the cell, wherein activation of the cellular stress response comprises inducing expression of at least the cellular stress genes Growth arrest and DNA-damage-inducible, alpha (GADD45A) and Heatshock 70kDa protein 6 (HSPA6); and
iv) does not significantly activate nuclear factor-kappaB (NF-κB) in the cell, wherein activation of NF-κB is determined by measuring the induction of expression of intercellular adhesion molecule (ICAM-1);
wherein the cell is selected from the group consisting of a lymphocyte, a granulocyte, a monocyte, a macrophage, a mast cell, a thrombocyte, an erythrocyte, a megakaryocyte, a dendritic cell, a glial cell, a pneumocyte, a Clara cell, a goblet cell, a myocardiocyte, a pericyte, a hepatocyte, a Kupffer cell, a Paneth cell, an osteoblast, an osteocyte, a chondroblast, a chondrocyte, a keratinocyte, a melanocyte, a myocyte, an adipocyte, a fibroblast, a tendon cell, an epithelial cell, an endothelial cell, a smooth muscle cell, a skeletal muscle cell, an embryonic stem cell, a neural stem cell, a skin stem cell, a mesenchymal stem cell, a hematopoietic stem cell, a stromal stem cell, and an epithelial stem cell.
2. The method of claim 1 , wherein the cell is a mesenchymal stem cell, an osteocyte, or a chondrocyte.
3. The method of claim 1 , where the contacting occurs in vivo in a mammalian subject.
4. The method of claim 1 , where the contacting occurs ex vivo.
5. The method of claim 1 , wherein the selective inducer compound induces expression of at least one oxidative stress-responsive gene in the cell by at least about two-fold as compared to an untreated cell, wherein the oxidative stress-response gene is selected from the group consisting of heme oxygenase 1 (HMOX1), NAD(P)H:quinine oxidoreductase (NQO1), and thioredoxin reductase 1 (TXNRD1).
6. The method of claim 1 , wherein the selective inducer compound does not significantly increase reactive oxygen species (ROS) production in the cell.
7. The method of claim 1 , wherein the selective inducer compound does not significantly decrease the level of glutathione in the cell.