Online citations, reference lists, and bibliographies.

Hormesis, Cellular Stress Response, And Redox Homeostasis In Autism Spectrum Disorders.

Vittorio Calabrese, Joseph Giordano, M. Ruggieri, Deja Berritta, A. Trovato, M.L. Ontario, R. Bianchini, E.J. Calabrese
Published 2016 · Medicine, Biology
Cite This
Download PDF
Analyze on Scholarcy
Share
In the United States, 1.1-1.5% of children have been diagnosed with autism spectrum disorders (ASD), corresponding to a 30% increase in incidence and prevalence. Social and communication impairments are the main signs and symptoms of ASD, and currently available medications have been ineffective in reducing these core deficits. Observational studies have indicated that children with ASD tend to show improved cognition and behavior after febrile illness, which is associated with alteration of metabolic pathways, leading to cellular stress responses and increased expression of heat shock proteins (Hsps). Sulforaphane and hydroxytyrosol, phytochemicals derived from cruciferous vegetables and extra virgin olive oil, respectively, can induce metabolic effects in cellular stress responses that are similar to those produced by fever. Thus, modulation of endogenous cellular defense mechanisms may be an innovative approach for therapeutic intervention in ASD and other disorders associated with neuroinflammation and neurodegeneration. This Review introduces the hormetic dose-response concept and presents possible mechanisms and applications for neuroprotection. We address the emerging role of Hsps in the neuroprotective network of redox stress-responsive mechanisms and propose the potential therapeutic utility of the nutritional antioxidants sulforaphane and hydroxytyrosol against particular signs and symptoms of ASD. We argue that such research findings must be approached with pragmatism and prudence. It is vital to capitalize on recent and ongoing investments in brain science research and to refine neuroscientific knowledge and capability for more accurate diagnosis and safe, effective, and ethically sound treatment of ASD and other neuropsychiatric spectrum disorders. © 2016 Wiley Periodicals, Inc.
This paper references
10.1111/jnc.13042
Rotenone decreases intracellular aldehyde dehydrogenase activity: implications for the pathogenesis of Parkinson's disease.
David S. Goldstein (2015)
10.1002/mnfr.200700316
Curcumin and the cellular stress response in free radical-related diseases.
Vittorio Calabrese (2008)
10.1016/c2009-0-11128-5
Self-modifying systems in biology and cognitive science
George Kampis (1991)
10.1007/s11064-016-1959-0
3,4-Dihydroxyphenylethanol (Hydroxytyrosol) Mitigates the Increase in Spontaneous Oxidation of Dopamine During Monoamine Oxidase Inhibition in PC12 Cells
David S. Goldstein (2016)
Proteostasis control by the unfolded
C Hetz (2015)
10.1038/nrn2214
Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity
Vittorio Calabrese (2007)
10.2741/3250
Vitagenes, dietary antioxidants and neuroprotection in neurodegenerative diseases.
Vittorio Calabrese (2009)
10.1002/ptr.5339
Role of Hydroxytyrosol-dependent Regulation of HO-1 Expression in Promoting Wound Healing of Vascular Endothelial Cells via Nrf2 De Novo Synthesis and Stabilization.
Houda Zrelli (2015)
10.1007/s00401-009-0560-x
The ubiquitin proteasome system in neuropathology
Norman L Lehman (2009)
10.1080/10408440801981957
Neuroscience and Hormesis: Overview and General Findings
Edward J. Calabrese (2008)
10.1016/j.neures.2010.07.2216
Autism Spectrum Disorder is related to endoplasmic reticulum stress induced by mutations in the synaptic cell adhesion molecule, CADM1
Eriko Fujita (2010)
10.1080/10408440802014261
Modulation of the Epileptic Seizure Threshold: Implications of Biphasic Dose Responses
Edward J. Calabrese (2008)
10.1089/ars.2009.3074
Cellular stress responses, the hormesis paradigm, and vitagenes: novel targets for therapeutic intervention in neurodegenerative disorders.
Vittorio Calabrese (2010)
10.1016/j.freeradbiomed.2014.07.030
Bisphenol A induces oxidative stress and mitochondrial dysfunction in lymphoblasts from children with autism and unaffected siblings.
Kulbir Kaur (2014)
10.1007/s10522-015-9601-0
What is hormesis and its relevance to healthy aging and longevity?
Edward J. Calabrese (2015)
10.2174/138920312799277956
HSF transcription factor family, heat shock response, and protein intrinsic disorder.
Sandy D Westerheide (2012)
University of Dundee Loss of Nrf 2 abrogates the protective effect of Keap 1 down regulation in a preclinical model of cutaneous squamous cell carcinoma
Elena V. Knatko (2016)
Defining hormesis. Commentary. Authors reply
Edward J. Calabrese (2002)
Hydroxytyrosol mildly improve cognitive function
J. Liu (2016)
10.1007/s12079-014-0243-9
Heat shock proteins in neurodegenerative disorders and aging
Rehana K. Leak (2014)
10.3109/09553002.2013.752594
Reduction of arthritic symptoms by low dose radiation therapy (LD-RT) is associated with an anti-inflammatory phenotype
Edward J. Calabrese (2013)
10.1038/embor.2010.203
BAG3 mediates chaperone-based aggresome-targeting and selective autophagy of misfolded proteins.
Martin Gamerdinger (2011)
Electrophilic nitro-fatty acids inhibit vascular inflammation
Luis Márquez Villacorta (2013)
10.1016/j.phrs.2015.12.021
Preconditioning is hormesis part I: Documentation, dose-response features and mechanistic foundations.
Edward J. Calabrese (2016)
10.1089/ars.2016.6662
Loss of NAD-Dependent Protein Deacetylase Sirtuin-2 Alters Mitochondrial Protein Acetylation and Dysregulates Mitophagy.
Guoxiang Liu (2017)
10.1002/biof.22
Vitagenes, cellular stress response, and acetylcarnitine: relevance to hormesis.
Vittorio Calabrese (2009)
10.1016/j.phrs.2015.12.020
Preconditioning is hormesis part II: How the conditioning dose mediates protection: Dose optimization within temporal and mechanistic frameworks.
Edward J. Calabrese (2016)
The mechanistic paradox
J. Giordano (2010)
10.1080/10408440802026281
Pain and U-Shaped Dose Responses: Occurrence, Mechanisms, and Clinical Implications
Edward J. Calabrese (2008)
10.1016/j.jprot.2013.06.025
The role of heat stress on the age related protein carbonylation.
Perinur Bozaykut (2013)
10.1101/sqb.2012.76.010637
The heat shock response: systems biology of proteotoxic stress in aging and disease.
Richard I. Morimoto (2011)
10.1042/bj3330407
Protection from oxidative inactivation of the 20S proteasome by heat-shock protein 90.
Mariangela Conconi (1998)
10.1016/j.taap.2004.06.023
The occurrence of hormetic dose responses in the toxicological literature, the hormesis database: an overview.
Edward J. Calabrese (2005)
10.1007/s11064-006-9203-y
Redox Regulation of Cellular Stress Response in Aging and Neurodegenerative Disorders: Role of Vitagenes
Vittorio Calabrese (2006)
10.1038/srep25804
Loss of Nrf2 abrogates the protective effect of Keap1 downregulation in a preclinical model of cutaneous squamous cell carcinoma
Elena V. Knatko (2016)
10.1007/978-1-4419-7002-2_11
Protein homeostasis in models of aging and age-related conformational disease.
Elise A Kikis (2010)
10.1080/10408440802014238
An Assessment of Anxiolytic Drug Screening Tests: Hormetic Dose Responses Predominate
Edward J. Calabrese (2008)
10.1242/jeb.091249
Transcellular chaperone signaling: an organismal strategy for integrated cell stress responses
Patricija van Oosten-Hawle (2014)
10.12703/P6-7
Proteostasis and longevity: when does aging really begin?
John Labbadia (2014)
Study of the anti-inflammatory effect
C Weiss (2015)
Preconditioning is hormesis
Calabrese EJ. (2016)
Prevalence of autism spectrum disorder among children aged 8 years - autism and developmental disabilities monitoring network, 11 sites, United States, 2010.
Jon Baio (2014)
10.1016/j.exger.2012.02.004
Hormesis: Toxicological foundations and role in aging research
Edward J. Calabrese (2013)
The heme oxygenase/bili
C Mancuso (2013)
10.1007/s10522-016-9646-8
Pre- and post-conditioning hormesis in elderly mice, rats, and humans: its loss and restoration
Edward J. Calabrese (2016)
10.1007/s12017-009-8058-1
Nicotinamide Prevents NAD+ Depletion and Protects Neurons Against Excitotoxicity and Cerebral Ischemia: NAD+ Consumption by SIRT1 may Endanger Energetically Compromised Neurons
Dong Xiang Liu (2009)
10.2174/156652412803306675
HSF1, a versatile factor in tumorogenesis.
Stuart K. Calderwood (2012)
10.1080/10408440802004023
Astrocytes: Adaptive Responses to Low Doses of Neurotoxins
Edward J. Calabrese (2008)
10.1021/acs.jmedchem.5b00669
Hydroxytyrosol-Derived Compounds: A Basis for the Creation of New Pharmacological Agents for Cancer Prevention and Therapy.
Roberta Bernini (2015)
10.1201/b11861-2
Neurotechnology as Demiurgical Force: Avoiding Icarus’ Folly
James Giordano (2012)
10.1073/pnas.1422473112
Reply to Scahill: Behavioral outcome measures in autism
P. G. Talalay (2015)
10.1016/j.canlet.2015.04.010
Modulation of inflammation by low and high doses of ionizing radiation: Implications for benign and malign diseases.
Benjamin Frey (2015)
10.2174/1871527315666160413122525
Sulforaphane Treatment of Young Men with Autism Spectrum Disorder.
Kanwaljit Singh (2016)
10.1042/BST20150011
Dual regulation of transcription factor Nrf2 by Keap1 and by the combined actions of β-TrCP and GSK-3.
John D. Hayes (2015)
10.1080/10408440801981965
Dose-Response Features of Neuroprotective Agents: An Integrative Summary
Edward J. Calabrese (2008)
10.1016/j.jnutbio.2014.12.013
Role of the catechol group in the antioxidant and neuroprotective effects of virgin olive oil components in rat brain.
José Pedro De La Cruz (2015)
10.1191/0960327102ht217oa
Defining hormesis
Edward J. Calabrese (2002)
10.1007/s11064-010-0307-z
Cellular Stress Responses, Mitostress and Carnitine Insufficiencies as Critical Determinants in Aging and Neurodegenerative Disorders: Role of Hormesis and Vitagenes
Vittorio Calabrese (2010)
10.1080/10408440802004049
P-Glycoprotein Efflux Transporter Activity Often Displays Biphasic Dose-Response Relationships
Edward J. Calabrese (2008)
10.1016/j.yrtph.2011.06.003
The hormesis database: the occurrence of hormetic dose responses in the toxicological literature.
Edward J. Calabrese (2011)
10.1002/aur.1623
Dopaminergic variants in siblings at high risk for autism: Associations with initiating joint attention.
Devon N. Gangi (2016)
Proteostasis and longevity: when
J Labbadia (2014)
The heat shock response: systems biology
RI 29632–639.Morimoto (2011)
Protein homeostasis
EA Kikis (2010)
10.1042/BJ20150274
Autism-associated R451C mutation in neuroligin3 leads to activation of the unfolded protein response in a PC12 Tet-On inducible system
Lisa Ulbrich (2016)
10.1016/j.freeradbiomed.2012.04.012
Role of 4-hydroxynonenal in chemopreventive activities of sulforaphane.
Rajendra P Sharma (2012)
10.1016/j.freeradbiomed.2011.06.015
HSP70 mediates dissociation and reassociation of the 26S proteasome during adaptation to oxidative stress.
Tilman Grune (2011)
10.1074/jbc.M110.190710
Electrophilic Nitro-fatty Acids Activate NRF2 by a KEAP1 Cysteine 151-independent Mechanism*
Emilia Kansanen (2011)
10.1080/10408440802026315
Addiction and Dose Response: The Psychomotor Stimulant Theory of Addiction Reveals That Hormetic Dose Responses Are Dominant
Edward J. Calabrese (2008)
The heme oxygenase/biliverdin reductase system: a potential drug target in Alzheimer’s disease.
Cesare Mancuso (2013)
10.1002/aur.1565
Altered kynurenine pathway metabolism in autism: Implication for immune-induced glutamatergic activity.
Chai K Lim (2016)
10.1172/JCI70799
The future of molecular chaperones and beyond.
Rona G. Giffard (2013)
10.1007/s11064-010-0304-2
Oxidative Stress, Redox Homeostasis and Cellular Stress Response in Ménière’s Disease: Role of Vitagenes
Vittorio Calabrese (2010)
Electrophilic nitrofatty acids activate NRF 2 by a KEAP 1 cysteine 151independent mechanism
E Kansanen (2011)
10.3390/molecules20034655
Potential Role of Olive Oil Phenolic Compounds in the Prevention of Neurodegenerative Diseases
Jose Rodríguez-Morató (2015)
10.1038/nchembio.763
Small Molecule Proteostasis Regulators for Protein Conformational Diseases
Barbara Calamini (2011)
10.1016/j.tins.2006.09.001
Neurohormetic phytochemicals: low-dose toxins that induce adaptive neuronal stress responses
Mark P. Mattson (2006)
10.1016/j.comppsych.2016.03.011
Validation of the French Autism Spectrum Quotient scale and its relationships with schizotypy and Eysenckian personality traits.
Guillaume Sierro (2016)
10.1016/j.freeradbiomed.2015.06.021
Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease.
Lauren E Tebay (2015)
10.1080/10408440801981973
Pharmacological Enhancement of Neuronal Survival
Edward J. Calabrese (2008)
10.1074/jbc.M110.152686
Sulforaphane Activates Heat Shock Response and Enhances Proteasome Activity through Up-regulation of Hsp27*
Nanqin Gan (2010)
10.1080/10408440801981981
Enhancing and Regulating Neurite Outgrowth
Edward J. Calabrese (2008)
10.1016/j.freeradbiomed.2012.09.023
Histone deacetylase 6 (HDAC6) plays a crucial role in p38MAPK-dependent induction of heme oxygenase-1 (HO-1) in response to proteasome inhibition.
Marc Kästle (2012)
10.2174/1871527315666160413120414
Biomarker-Guided Strategy for Treatment of Autism Spectrum Disorder (ASD).
Hua Liu (2016)
10.1016/j.mito.2013.08.006
Metabolic features of the cell danger response.
Robert K. Naviaux (2014)
10.1038/nature07953
Autism genome-wide copy number variation reveals ubiquitin and neuronal genes
Joseph T. Glessner (2009)
10.1002/mnfr.201600332
Hydroxytyrosol mildly improve cognitive function independent of APP processing in APP/PS1 mice.
Yunhua Peng (2016)
Heat shock proteins in neurodegenerative disorders
RK Leak (2014)
10.1016/j.arr.2007.08.007
Hormesis defined
Mark P. Mattson (2008)
10.3109/10408444.2013.808172
Hormetic mechanisms
Edward J. Calabrese (2013)
10.1111/cei.12344
Low and moderate doses of ionizing radiation up to 2 Gy modulate transmigration and chemotaxis of activated macrophages, provoke an anti-inflammatory cytokine milieu, but do not impact upon viability and phagocytic function.
Roland Wunderlich (2015)
10.2745/dds.18.343
[Histone deacetylase].
Akihiro Ito (2012)
10.1073/pnas.1416940111
Sulforaphane treatment of autism spectrum disorder (ASD)
Kanwaljit Singh (2014)
10.3945/ajcn.2009.27718
Alcohol consumption is associated with high concentrations of urinary hydroxytyrosol.
Helmut Schröder (2009)
10.1007/s11064-008-9775-9
Cellular Stress Response: A Novel Target for Chemoprevention and Nutritional Neuroprotection in Aging, Neurodegenerative Disorders and Longevity
Vittorio Calabrese (2008)
10.1897/07-541.1
Hormesis: Why it is important to toxicology and toxicologists
Edward J. Calabrese (2007)
10.1007/s00066-015-0848-9
Study of the anti-inflammatory effects of low-dose radiation
Martin Large (2015)
Loss of Sirt 2 alters mitochondrial protein acetylation , morphology , and dysregulates mitophagy
G Liu (2016)
10.1089/ARS.2009.2721
Nitric oxide in cell survival: a janus molecule.
Vittorio Calabrese (2009)
10.1038/ncomms11173
Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration
Brandon L Pearson (2016)
10.1080/10408440802014287
Drug Therapies for Stroke and Traumatic Brain Injury Often Display U-Shaped Dose Responses: Occurrence, Mechanisms, and Clinical Implications
Edward J. Calabrese (2008)
10.1016/j.bbadis.2011.11.002
Cellular stress responses, hormetic phytochemicals and vitagenes in aging and longevity.
Vittorio Calabrese (2012)
Bisphenol A induces oxi
K Kaur (2014)
10.1007/978-1-60327-029-8_17
Redox homeostasis and cellular stress response in aging and neurodegeneration.
Vittorio Calabrese (2010)
10.1111/j.1471-4159.2011.07189.x
Brain region-specific deficit in mitochondrial electron transport chain complexes in children with autism.
Abha Chauhan (2011)
10.1242/dmm.014753
Creating a path from the heat shock response to therapeutics of protein-folding diseases: an interview with Rick Morimoto
Rick Morimoto (2014)
Autism genome-wide copy number
JT Glessner (2009)
10.1088/0034-4885/61/4/002
Neural networks as spatio-temporal pattern-forming systems
Bard Ermentrout (1998)
10.1016/j.chembiol.2011.09.008
HSF1-dependent upregulation of Hsp70 by sulfhydryl-reactive inducers of the KEAP1/NRF2/ARE pathway.
Ying Zhang (2011)
10.1007/s00394-006-0596-9
Is dopamine behind the health benefits of red wine?
Rafael de la Torre (2006)
10.1080/10408440802003991
Alzheimer's Disease Drugs: An Application of the Hormetic Dose-Response Model
Edward J. Calabrese (2008)
10.1007/978-94-007-2488-4_10
Integrative Convergence in Neuroscience: Trajectories, Problems, and the Need for a Progressive Neurobioethics
James Giordano (2012)
10.1038/ncb3184
Proteostasis control by the unfolded protein response
Claudio Hetz (2015)
10.1201/b11861-7
Neuroprotective Agents Commonly Display Hormesis: Implications for Nanoneuropharmacology
Edward J. Calabrese (2012)
10.1042/BST20150003
The spatiotemporal regulation of the Keap1–Nrf2 pathway and its importance in cellular bioenergetics
Albena T. Dinkova-Kostova (2015)
Nicotinamide prevents NAD1 depletion and protects neurons against excitotoxicity and cerebral ischemia: NAD1 consumption by SIRT1 may endanger
D Liu (2009)



This paper is referenced by
10.1002/jnr.23986
Inflammasomes, hormesis, and antioxidants in neuroinflammation: Role of NRLP3 in Alzheimer disease
Manuela Pennisi (2017)
10.3390/antiox8070235
Antioxidant Defence Systems and Oxidative Stress in Poultry Biology: An Update
Peter F Surai (2019)
10.1016/j.bbr.2017.07.019
Decrease in endogenous brain allopregnanolone induces autism spectrum disorder (ASD)-like behavior in mice: A novel animal model of ASD
Ken Ebihara (2017)
10.1002/9780470015902.A0025846
Autism Spectrum Disorders: Genes and Genomic Mechanisms
Daniel José Olazabal Guerra (2017)
10.3390/ijms21062138
Hericium Erinaceus Prevents DEHP-Induced Mitochondrial Dysfunction and Apoptosis in PC12 Cells
Ines Amara (2020)
10.1186/s12979-017-0108-1
Neuroinflammation and neurohormesis in the pathogenesis of Alzheimer’s disease and Alzheimer-linked pathologies: modulation by nutritional mushrooms
Angela Trovato Salinaro (2017)
10.1016/j.jprot.2019.103537
Brain protein changes in Mecp2 mouse mutant models: Effects on disease progression of Mecp2 brain specific gene reactivation.
Alessio Cortelazzo (2019)
Sulforaphane Protects against Brain Diseases: Roles of Cytoprotective Enzymes
Y Sun (2017)
10.1016/j.neubiorev.2019.05.010
Polyphenols as food bioactive compounds in the context of Autism Spectrum Disorders: A critical mini-review
Diana Serra (2019)
10.1007/s10522-015-9594-8
How the effects of aging and stresses of life are integrated in mortality rates: insights for genetic studies of human health and longevity
Anatoliy I. Yashin (2015)
10.1007/s12035-019-01742-2
Oxidative Stress in Autism Spectrum Disorder
Geir Bjorklund (2020)
10.1016/j.phrs.2019.104579
Pharmacological, non-pharmacological and stem cell therapies for the management of autism spectrum disorders: a focus on human studies.
Francesca Pistollato (2019)
10.1016/j.arr.2017.12.004
Poor cognitive ageing: Vulnerabilities, mechanisms and the impact of nutritional interventions
Sophie Miquel (2018)
10.1016/j.envres.2018.04.034
Environmental hormesis and its fundamental biological basis: Rewriting the history of toxicology.
Evgenios Agathokleous (2018)
10.1016/j.envres.2016.12.023
May traffic air pollution be involved in autism spectrum disorder?
Salvatore Chirumbolo (2017)
10.1016/j.envres.2018.05.020
Toxic metal(loid)‐based pollutants and their possible role in autism spectrum disorder
Geir Bjorklund (2018)
10.1124/jpet.118.254755
CXA-10, a Nitrated Fatty Acid, Is Renoprotective in Deoxycorticosterone Acetate-Salt Nephropathy
Cynthia M. Arbeeny (2019)
10.3389/fpls.2017.01762
Plant Hormesis Management with Biostimulants of Biotic Origin in Agriculture
Marcela Vargas-Hernandez (2017)
10.4103/bc.bc_10_19
Restoring cerebral circulation and function postmortem: A multidimensional analysis
Joseph DeFranco (2019)
10.1155/2019/2716870
Sulforaphane: Its “Coming of Age” as a Clinically Relevant Nutraceutical in the Prevention and Treatment of Chronic Disease
Christine A. Houghton (2019)
Semantic Scholar Logo Some data provided by SemanticScholar