Identification of differentially expressed genes induced in the rat brain by acetyl-l-carnitine as evidenced by suppression subtractive hybridisation

Traina, Giovanna; Valleggi, Simona; Bernardi, Rodolfo; Rizzo, Milena; Calvani, Menotti; Nicolai, Raffaella; Mosconi, Luigi; Durante, M.; Brunelli, Marcello

doi:10.1016/j.molbrainres.2004.09.006

Cited by 26 publications

(38 citation statements)

References 47 publications

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“…Of the different 14-3-3 family members, 14-3-3 ␥ alone is specifically induced in the nervous tissue when subjected to oxidative stress or metabolic stimuli (Traina et al, 2004;Chen et al, 2005). Furthermore, knockdown of 14-3-3 ␥ proteins by antisense RNA resulted in enhanced apoptosis in astrocytes subjected to ischemia (Chen et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Differential role of 14‐3‐3 family members in Xenopus development

Lau

Muslin

2006

Developmental Dynamics

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The 14-3-3 proteins are intracellular dimeric phosphoserine/threonine binding molecules that participate in signal transduction, checkpoint control, nutrient sensing, and cell survival pathways. Previous work established that 14-3-3 proteins are required in early Xenopus laevis development by modulating fibroblast growth factor signaling. Although this general requirement for 14-3-3 proteins in Xenopus early embryogenesis is established, there is no information about the specific role of individual 14-3-3 genes. Botanical studies previously demonstrated functional specificity among 14-3-3 genes during plant development. In this study, an antisense morpholino oligo microinjection approach was used to characterize the requirement for six specific 14-3-3 family members in Xenopus embryogenesis. Microinjection experiments followed by Western blot analysis showed that morpholinos reduced specific 14-3-3 protein levels. Embryos lacking specific 14-3-3 isoforms displayed unique phenotypic defects. In particular, reduction of 14-3-3 tau () protein, and to a lesser extent, 14-3-3 epsilon (⑀), resulted in embryos with prominent gastrulation and axial patterning defects and reduced mesodermal marker gene expression. In contrast, reduction of 14-3-3 zeta () protein caused no obvious phenotypic abnormalities. Reduction of 14-3-3 gamma (␥) protein resulted in eye defects without gastrulation abnormalities. Therefore, individual 14-3-3 genes have separable functions in vertebrate embryonic development.

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Section: Discussionmentioning

confidence: 99%

Differential role of 14‐3‐3 family members in Xenopus development

Lau

Muslin

2006

Developmental Dynamics

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“…Fifty-day-old male Wistar rats weighting approximately 200-250 g from the same litter bred, housed at a temperature of 22°C, were intraperitoneally injected daily for 21 days either with ALC (Sigma-Tau Laboratories, Pomezia, Italy, at doses of 40 and 100 mg/kg body weight (bw)) or LC (100 mg/kg bw; treated groups) or saline (control group), as previously described [7]. The animals were anesthetized with ether and then killed by decapitation.…”

Section: Dissection Of the Brainmentioning

confidence: 99%

“…Total RNA was isolated from rat brains of four control and four ALC-treated (100 mg/kg bw) animals following [7]. Briefly, 2 μg of poly (A) + RNAs was purified from the pools of total RNAs of brain (except cerebellum and spinal cord) of both control and treated rats using the PolyATtract mRNA Isolation System (Promega Corp., Madison, WI).…”

Section: Subtracted Cdna Library Constructionmentioning

confidence: 99%

“…We therefore worked out an extensive study in the brain of rats subjected to a chronic ALC treatment in order to evaluate the possibility that ALC might affect the gene expression. We performed a comprehensive analysis of all the genes that might be up-or downregulated after long-lasting ALC treatment by using the suppressive subtractive hybridization (SSH) methodology [7]. In this paper, we report that ALC downregulates all the isoforms of myelin basic protein (MBP) gene expression, suggesting a possible role in the control of myelin stability.…”

Section: Introductionmentioning

confidence: 99%

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Modulation of Myelin Basic Protein Gene Expression by Acetyl-l-Carnitine

et al. 2011

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Acetyl-L-carnitine (ALC), the acetyl ester of L-carnitine, is a naturally occurring molecule which plays an essential role in intermediary and mitochondrial metabolism. It has also neurotrophic and antioxidant actions, demonstrating efficacy and high tolerability in the treatment of neuropathies of various etiologies. ALC is a molecule of considerable interest for its clinical application in various neural disorders, although little is known regarding its effects on gene expression. Suppression subtractive hybridization methodology was used for the generation of subtracted complementary DNA libraries and the subsequent identification of differentially expressed transcripts in the rat brain after chronic ALC treatments. We provided evidence for a downregulation of the expression of all of the isoforms of myelin basic protein gene following prolonged ALC treatment, indicating a possible role in the modulation of myelin basic protein turnover, stabilizing and maintaining myelin integrity.

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“…Besides the afore mentioned role on mitochondrial bioenergetics, which allows brain cells to restore altered redox balance [3,45], ALC is neuroprotective through a variety of other effects such as the increase in PKC activity [41], and modulation of synaptic plasticity via NMDA receptor expression and increase in the production of neurotrophins [202]. Importantly, treatment with ALC induces up-regulation of the gene coding for Hsp72 explaining its protective effects in inflammation, neurodegenerative disorders, and aging [203][204][205]. Another gene identified that is positively modulated by acetylcarnitine in the brain is the mitochondrial voltage-dependent anion channel (VDAC) protein [206].…”

Section: The Carnitine System: Physiological Roles Insufficiency Andmentioning

confidence: 99%

Cellular Stress Responses, Mitostress and Carnitine Insufficiencies as Critical Determinants in Aging and Neurodegenerative Disorders: Role of Hormesis and Vitagenes

et al. 2010

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The widely accepted oxidative stress theory of aging postulates that aging results from accumulation of oxidative damage. A prediction of this theory is that, among species, differential rates of aging may be apparent on the basis of intrinsic differences in oxidative damage accrual. Although widely accepted, there is a growing number of exceptions to this theory, most contingently related to genetic model organism investigations. Proteins are one of the prime targets for oxidative damage and cysteine residues are particularly sensitive to reversible and irreversible oxidation. 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 and stability. The toxic effects that stem from the misassembly or aggregation of proteins or peptides, in any cell type, are collectively termed proteotoxicity. Despite the abundance and apparent capacity of chaperones and other components of homeostasis to restore folding equilibrium, the cell appears poorly adapted for chronic proteotoxic stress which increases in cancer, metabolic and neurodegenerative diseases. Pharmacological modulation of cellular stress response pathways has emerging implications for the treatment of human diseases, including neurodegenerative disorders, cardiovascular disease, and cancer. A critical key to successful medical intervention is getting the dose right. Achieving this goal can be extremely challenging due to human inter-individual variation as affected by age, gender, diet, exercise, genetic factors and health status. The nature of the dose response in and adjacent to the therapeutic zones, over the past decade has received considerable advances. The hormetic dose-response, challenging long-standing beliefs about the nature of the dose-response in a lowdose zone, has 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 stress responses, including carnitines. This paper describes in mechanistic detail how hormetic dose responses are mediated for endogenous cellular defense pathways, including the possible signaling mechanisms by which the carnitine system, by interplaying metabolism, mitochondrial energetics and activation of critical vitagenes, modulates signal transduction cascades that confer cytoprotection against chronic degenerative damage associated to aging and neurodegenerative disorders.

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Identification of differentially expressed genes induced in the rat brain by acetyl-l-carnitine as evidenced by suppression subtractive hybridisation

Cited by 26 publications

References 47 publications

Differential role of 14‐3‐3 family members in Xenopus development

Differential role of 14‐3‐3 family members in Xenopus development

Modulation of Myelin Basic Protein Gene Expression by Acetyl-l-Carnitine

Cellular Stress Responses, Mitostress and Carnitine Insufficiencies as Critical Determinants in Aging and Neurodegenerative Disorders: Role of Hormesis and Vitagenes

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