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Siniscalco D.,The Second University of Naples | Siniscalco D.,Center for Autism La Forza del Silenzio | Bradstreet J.J.,Western University of Health Sciences | Cirillo A.,National Research Council Italy | Antonucci N.,Biomedical Center for Autism Research and Treatment
Journal of Neuroinflammation | Year: 2014

Background: Immune system dysregulation is well-recognized in autism and thought to be part of the etiology of this disorder. The endocannabinoid system is a key regulator of the immune system via the cannabinoid receptor type 2 (CB2R) which is highly expressed on macrophages and microglial cells. We have previously published significant differences in peripheral blood mononuclear cell CB2R gene expression in the autism population. The use of the Gc protein-derived Macrophage Activating Factor (GcMAF), an endogenous glycosylated vitamin D binding protein responsible for macrophage cell activation has demonstrated positive effects in the treatment of autistic children. In this current study, we investigated the in vitro effects of GcMAF treatment on the endocannabinoid system gene expression, as well as cellular activation in blood monocyte-derived macrophages (BMDMs) from autistic patients compared to age-matched healthy developing controls.Methods: To achieve these goals, we used biomolecular, biochemical and immunocytochemical methods.Results: GcMAF treatment was able to normalize the observed differences in dysregulated gene expression of the endocannabinoid system of the autism group. GcMAF also down-regulated the over-activation of BMDMs from autistic children.Conclusions: This study presents the first observations of GcMAF effects on the transcriptionomics of the endocannabinoid system and expression of CB2R protein. These data point to a potential nexus between endocannabinoids, vitamin D and its transporter proteins, and the immune dysregulations observed with autism. © 2014 Siniscalco et al.; licensee BioMed Central Ltd.


Siniscalco D.,The Second University of Naples | Siniscalco D.,Center for Autism La Forza del Silenzio | Mijatovic T.,Red Laboratories | Bosmans E.,Red Laboratories | And 6 more authors.
In Vivo | Year: 2016

Background/Aim: Autism spectrum disorders (ASD) are complex, and severe heterogeneous neurodevelopmental pathologies with accepted but complex immune system abnormalities. Additional knowledge regarding potential immune dysfunctions may provide a greater understanding of this malady. The aim of this study was to evaluate the CD57+CD3- mature lymphocyte subpopulation of natural killer cells as a marker of immune dysfunction in ASD. Materials and Methods: Three-color flow cytometry-based analysis of fresh peripheral blood samples from children with autism was utilized to measure CD57+CD3- lymphocytes. Results. A reduction of CD57+CD3- lymphocyte count was recorded in a significant number of patients with autism. Discussion and conclusion: We demonstrated that the number of peripheral CD57+CD3- cells in children with autism often falls below the clinically accepted normal range. This implies that a defect in the counter-regulatory functions necessary for balancing pro-inflammatory cytokines exists, thus opening the way to chronic inflammatory conditions associated with ASD. © Copyright 2016 by The International Institute of Anticancer Research.


Siniscalco D.,The Second University of Naples | Siniscalco D.,Center for Autism La Forza del Silenzio | Cirillo A.,National Research Council Italy | Bradstreet J.J.,International Child Development Resource Center | Antonucci N.,Biomedical Center for Autism Research and Treatment
International Journal of Environmental Research and Public Health | Year: 2013

Autism and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders characterized by dysfunctions in social interactions, communications, restricted interests, and repetitive stereotypic behaviors. Despite extensive genetic and biological research, significant controversy surrounds our understanding of the specific mechanisms of their pathogenesis. However, accumulating evidence points to the involvement of epigenetic modifications as foundational in creating ASD pathophysiology. Epigenetic modifications or the alteration of DNA transcription via variations in DNA methylation and histone modifications but without alterations in the DNA sequence, affect gene regulation. These alterations in gene expression, obtained through DNA methylation and/or histone modifications, result from transcriptional regulatory influences of environmental factors, such as nutritional deficiencies, various toxicants, immunological effects, and pharmaceuticals. As such these effects are epigenetic regulators which determine the final biochemistry and physiology of the individual. In contrast to psychopharmacological interventions, bettering our understanding of how these gene-environmental interactions create autistic symptoms should facilitate the development of therapeutic targeting of gene expression for ASD biomedical care. © 2013 by the authors; licensee MDPI, Basel, Switzerland.


Siniscalco D.,The Second University of Naples | Siniscalco D.,Center for Autism La Forza del Silenzio | Antonucci N.,Biomedical Center for Autism Research and Treatment
Current Protein and Peptide Science | Year: 2013

Autism and autism spectrum disorders (ASDs) are heterogeneous, severe neurodevelopmental pathologies. These enigmatic conditions have their origins in the interaction of multiple genes and environmental factors. Dysfunctions in social interactions and communication skills, restricted interests, repetitive and stereotypic verbal and non-verbal behaviours are the main core symptoms. Several biochemical processes are associated with ASDs: oxidative stress; endoplasmic reticulum stress; decreased methylation capacity; limited production of glutathione; mitochondrial dysfunction; intestinal impaired permeability and dysbiosis; increased toxic metal burden; immune dysregulation. Current available treatments for ASDs can be divided into behavioural, nutritional and medical approaches, although no defined standard approach exists. Dietary bioactive proteins and peptides show potential for application as health-promoting agents. Nowadays, increasing studies highlight a key role of bioactive proteins and peptides in ASDs. This review will focus on the state-of-the-art regarding the involvement of dietary bioactive proteins and peptides in ASDs. Identification of novel therapeutic targets for ASD management will be also discussed. © 2013 Bentham Science Publishers.


Siniscalco D.,The Second University of Naples | Siniscalco D.,Center for Autism La Forza del Silenzio | Bradstreet J.J.,International Child Development Resource Center | Antonucci N.,Biomedical Center for Autism Research and Treatment
Frontiers in Immunology | Year: 2013

Autism and autism spectrum disorders (ASDs) are heterogeneous, severe neuro-developmental disorders with core symptoms of dysfunctions in social interactions and communication skills, restricted interests, repetitive - stereotypic verbal and non-verbal behaviors. Biomolecular evidence points to complex gene-environmental interactions in ASDs. Several biochemical processes are associated with ASDs: oxidative stress (including endoplasmic reticulum stress), decreased methylation capacity, limited production of glutathione; mitochondrial dysfunction, intestinal dysbiosis, increased toxic metal burden, and various immune abnormalities. The known immunological disorders include: T-lymphocyte populations and function, gene expression changes in monocytes, several autoimmune-related findings, high levels of N-acetylgalactosaminidase (which precludes macrophage activation), and primary immune deficiencies. These immunological observations may result in minicolumn structural changes in the brain, as well as, abnormal immune mediation of synaptic functions. Equally, these immune dysregulations serve as the rationale for immune-directed interventions such as hematopoietic stem cells (HSCs), which are pivotal in controlling chronic inflammation and in the restoration of immunological balance. These properties make them intriguing potential agents for ASD treatments. This prospective review will focus on the current state-of-the-art knowledge and challenges intrinsic in the application of HSCs for ASD-related immunological disorders. © 2013 Siniscalco, Bradstreet and Antonucci.


PubMed | Red Laboratories, The Second University of Naples, Himmunitas vzw, University of Veterinary And Pharmaceutical Sciences Brno and 2 more.
Type: Journal Article | Journal: In vivo (Athens, Greece) | Year: 2016

Autism spectrum disorders (ASD) are complex, and severe heterogeneous neurodevelopmental pathologies with accepted but complex immune system abnormalities. Additional knowledge regarding potential immune dysfunctions may provide a greater understanding of this malady. The aim of this study was to evaluate the CD57(+)CD3(-) mature lymphocyte subpopulation of natural killer cells as a marker of immune dysfunction in ASD.Three-color flow cytometry-based analysis of fresh peripheral blood samples from children with autism was utilized to measure CD57(+)CD3(-) lymphocytes.A reduction of CD57(+)CD3(-) lymphocyte count was recorded in a significant number of patients with autism.We demonstrated that the number of peripheral CD57(+)CD3(-) cells in children with autism often falls below the clinically accepted normal range. This implies that a defect in the counter-regulatory functions necessary for balancing pro-inflammatory cytokines exists, thus opening the way to chronic inflammatory conditions associated with ASD.


Siniscalco D.,The Second University of Naples | Siniscalco D.,Center for Autism | Sapone A.,The Second University of Naples | Sapone A.,University of Maryland, Baltimore | And 4 more authors.
Journal of Biomedicine and Biotechnology | Year: 2012

Autism and autism spectrum disorders (ASDs) are heterogeneous neurodevelopmental disorders. They are enigmatic conditions that have their origins in the interaction of genes and environmental factors. ASDs are characterized by dysfunctions in social interaction and communication skills, in addition to repetitive and stereotypic verbal and nonverbal behaviours. Immune dysfunction has been confirmed with autistic children. There are no defined mechanisms of pathogenesis or curative therapy presently available. Indeed, ASDs are still untreatable. Available treatments for autism can be divided into behavioural, nutritional, and medical approaches, although no defined standard approach exists. Nowadays, stem cell therapy represents the great promise for the future of molecular medicine. Among the stem cell population, mesenchymal stem cells (MSCs) show probably best potential good results in medical research. Due to the particular immune and neural dysregulation observed in ASDs, mesenchymal stem cell transplantation could offer a unique tool to provide better resolution for this disease. Copyright 2012 Dario Siniscalco et al.


Siniscalco D.,The Second University of Naples | Siniscalco D.,Center for Autism | Bradstreet J.J.,International Child Development Resource Center | Sych N.,Cell Therapy Center ll | Antonucci N.,Biomedical Center for Autism Research and Treatment
Stem Cells International | Year: 2013

Autism and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders. ASDs are clinically defined by deficits in communication, social skills, and repetitive and/or restrictive interests and behaviours. With the prevalence rates for ASDs rapidly increasing, the need for effective therapies for autism is a priority for biomedical research. Currently available medications do not target the core symptoms, can have markedly adverse side-effects, and are mainly palliative for negative behaviours. The development of molecular and regenerative interventions is progressing rapidly, and medicine holds great expectations for stem cell therapies. Cells could be designed to target the observed molecular mechanisms of ASDs, that is, abnormal neurotransmitter regulation, activated microglia, mitochondrial dysfunction, blood-brain barrier disruptions, and chronic intestinal inflammation. Presently, the paracrine, secretome, and immunomodulatory effects of stem cells would appear to be the likely mechanisms of application for ASD therapeutics. This review will focus on the potential use of the various types of stem cells: embryonic, induced pluripotential, fetal, and adult stem cells as targets for ASD therapeutics. © 2013 Dario Siniscalco et al.


PubMed | National Research Council Italy, The Second University of Naples and Biomedical Center for Autism Research and Treatment
Type: | Journal: Case reports in psychiatry | Year: 2015

Introduction. Autism spectrum disorders are defined by behavioral and language atypias. Growing body of evidence indicates inflammatory mediators may contribute to the condition. Palmitoylethanolamide (PEA) is naturally occurring and has been available as a nonprescription medical food supplement in Europe since 2008. PEA has been tested in thousands of human subjects without any noted significant side effects. Here we report the first cases of the administration of PEA to two children with autism. Case Presentations. The first 13-year-old male child (Subject 1) presented with a total IgE of 572IU/mL (nl < 200) and with low mature CD57(+) natural killer cell counts (32cells/L; nl = 60-300cells/L) and with significant eczema and allergic stigmata. Expressive language, as measured by mean length of utterance, and overall autism severity as measured by the Childhood Autism Rating Scale, Second Edition, improved significantly. Atopic symptoms diminished. No side effects were reported. The second male child, age 15 (Subject 2), also displayed noticeable and rapid improvements in cognitive, behaviors, and sociability. Conclusion. Currently, there is no definitive treatment for autism condition. Palmitoylethanolamide could be an effective treatment for autism syndrome. We propose appropriate double-blind clinical trials to further explore palmitoylethanolamide efficacy and safety.


Siniscalco D.,The Second University of Naples | Siniscalco D.,Center for Autism | Antonucci N.,Biomedical Center for Autism Research and Treatment
Medical Hypotheses | Year: 2013

Autism and autism spectrum disorders (ASDs) are heterogeneous, severe neurodevelopmental pathologies. The main core symptoms are: dysfunctions in social interactions and communication skills, restricted interests, repetitive and stereotypic verbal and non-verbal behaviors. Several biochemical processes are associated with ASDs: oxidative stress; endoplasmic reticulum stress; decreased methylation capacity; limited production of glutathione; mitochondrial dysfunction; intestinal dysbiosis; increased toxic metal burden; immune dysregulation. Current available treatments for ASDs can be divided into behavioral, nutritional and medical approaches, although no defined standard approach exists. Current drugs fail to benefit the ASD core symptoms and can have marked adverse effects, are mainly palliative and only sometimes efficacy in attenuating specific autistic behaviors. Helminthic therapy shows potential for application as anti-inflammatory agent. Several human diseases can be treated by helminths (i.e. inflammatory bowel disease, asthma, multiple sclerosis and autoimmune diabetes). Trichuris suis ova (TSO) show strong immunomodulatory properties. Authors hypothesize that TSO could be useful in addressing ASD immune dysregulations. TSO could be a novel therapeutic option for ASD management. © 2013 Elsevier Ltd.

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