Vitagenes, cellular stress response, and acetylcarnitine: Relevance to hormesis

Abstract

Modulation of endogenous cellular defense mechanisms via the stress response signaling represents an innovative approach to therapeutic intervention in diseases causing chronic damage, such as neurodegeneration and cancer. Protein thiols play a key role in redox sensing, and regulation of cellular redox state is crucial mediator of multiple metabolic, signaling, and transcriptional processes. Maintenance of optimal long-term health conditions is accomplished by a complex network of longevity assurance processes that are controlled by vitagenes, a group of genes involved in preserving cellular homeostasis during stressful conditions. Vitagenes encode for heat shock proteins (Hsp) Hsp32, Hsp70, the thioredoxin, and the sirtuin protein systems. Dietary antioxidants, such as polyphenols and L-carnitine/acetyl-L-carnitine, have recently been demonstrated to be neuroprotective through the activation of hormetic pathways, including vitagenes. The hormetic dose-response, challenges long-standing beliefs about the nature of the dose-response in a low dose zone, having the potential to affect significantly the design of pre-clinical studies and clinical trials as well as strategies for optimal patient dosing in the treatment of numerous diseases. Given the broad cytoprotective properties of the heat shock response, there is now strong interest in discovering and developing pharmacological agents capable of inducing these responses. In this review we discuss the most current and up-to-date understanding of the possible signaling mechanisms by which acetylcarnitine by activating vitagenes can differentially modulate signal transduction cascades inducing apoptosis/cell death in abnormal cancer cells but at the same time enhancing defensive enzymes to protect against carcinogenesis and neurodegeneration in normal cells. (c) 2009 International Union of Biochemistry and Molecular Biology, Inc.

Redox regulation of cellular stress response in multiple sclerosis

“…HO is present in various tissues with the highest activity in the brain, liver, spleen, and testes. There are three isoforms of heme oxygenase, HO-1 or inducible isoform [13,16,22], HO-2 or constitutive isoform [49], and the recently discovered HO-3, cloned only in rat to date [50]. Elevation of HO-1 expression and activity in MS is probably due to elevated oxidative stress.…”

“…In addition, cytokines, immunoglobulins, and complement complexes may elicit a survival response in the oligodendrocytes, involving the induction of endogenous heat shock proteins and other protective molecules, which indicates that redox systems and therefore the oxidant/antioxidant balance in these cells are of great importance in MS [9][10][11][12]. The adaptation and survival of cells and organisms requires the ability to sense proteotoxic insults and to coordinate protective cellular stress response pathways and chaperone networks related to protein quality control [13]. Despite the abundance and apparent capacity of chaperones and other components of homeostasis to restore folding equilibrium, brain cells appears poorly adapted for chronic proteotoxic stress which increases in neurodegenerative diseases such as MS [14].…”

Cellular Stress Responses, The Hormesis Paradigm, and Vitagenes: Novel Targets for Therapeutic Intervention in Neurodegenerative Disorders

“…(97-100, 105-108, 281). These include members of the Hsp family, such as heme oxygenase-1 and Hsp72, sirtuins, and the thioredoxin=thioredoxin reductase system (103,106,107). Recent studies have shown that the HSR contributes to establishing a cytoprotective state in a wide variety of human diseases, including inflammation, cancer, aging, and neurodegenerative disorders.…”

“…Cellular stress response (Fig. 4) requires the activation of pro-survival pathways that, under control of protective genes called vitagenes (99,100,(106)(107)(108), result in the production of molecules (Hsps, glutathione, and bilirubin) endowed with antioxidant and antiapoptotic activities. Generally, molecular chaperones help hundreds of signaling molecules to keep their activation-competent state, and regulate various signaling processes ranging from signaling at the plasma membrane to transcription.…”

Redox-regulating sirtuins in aging, caloric restriction, and exercise

“…Moreover, in addition to phosphorylation, it appears that Snitrosylation of SIRT1 impairs the catalytic activity of enzymes via a nitrosylated glyceraldehyde-3-phosphate dehydrogenasemediated process [12]. Additionally, thioredoxin (Trx) regulates cellular redox balance through reversible oxidization of its redoxactive cysteine residues (-Cys-Gly-Pro-Cys-), which can mediate protein S-denitrosylation [13][14][15] and hence the activity of sirtuins. The deacetylase domain of sirtuins consists of approximately 250 amino acids, differentiated by divergent N-and Cterminal extensions [16].…”