Expression of inflammatory cytokines, Bcl2 and cathepsin D are altered in lymphoblasts of autistic subjects

Malik, Mazhar N.; Sheikh, Ashfaq M.; Wen, Gen; Spivack, Warren D.; Brown, W. Ted; Li, Xiaohong

doi:10.1016/j.imbio.2010.03.001

Cited by 83 publications

(66 citation statements)

References 42 publications

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“…47,48 Previously, we found that the apoptosis-related proteins Bcl-2, p53, and cathepsin D are altered in both the brain and the lymphoblasts of autistic subjects. 4,32,49 The pathogenesis of autism may involve enhanced apoptosis in the brain and lymphoblasts. It is possible that the down-regulation of FAK-Src activities may contribute to an alteration of apoptosisrelated proteins in autism.…”

Section: Discussionmentioning

confidence: 99%

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Abnormal Cell Properties and Down-Regulated FAK-Src Complex Signaling in B Lymphoblasts of Autistic Subjects

Wei

Malik

Sheikh

et al. 2011

The American Journal of Pathology

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Recent studies suggest that one of the major pathways to the pathogenesis of autism is reduced cell migration. Focal adhesion kinase (FAK) has an important role in neural migration, dendritic morphological characteristics, axonal branching, and synapse formation. The FAK-Src complex, activated by upstream reelin and integrin ␤1, can initiate a cascade of phosphorylation events to trigger multiple intracellular pathways, including mitogen-activated protein kinaseextracellular signal-regulated kinase and phosphatidylinositol 3-kinase-Akt signaling. In this study, by using B lymphoblasts as a model, we tested whether integrin ␤1 and FAK-Src signaling are abnormally regulated in autism and whether abnormal FAK-Src signaling leads to defects in B-lymphoblast adhesion, migration, proliferation, and IgG production. To our knowledge, for the first time, we show that protein expression levels of both integrin ␤1 and FAK are significantly decreased in autistic lymphoblasts and that Src protein expression and the phosphorylation of an active site (Y416) are also significantly decreased. We also found that lymphoblasts from autistic subjects exhibit significantly decreased migration, increased adhesion properties, and an impaired capacity for IgG production. The overexpression of FAK in autistic lymphoblasts countered the adhesion and migration defects. In addition, we demonstrate that FAK mediates its effect through the activation of Src, phosphatidylinositol 3-kinase-Akt, and mitogen-activated protein kinase signaling cascades and that paxillin is also likely involved in the regulation of adhesion and migration in autistic lymphoblasts. Autism is a severe neurodevelopmental disorder characterized by problems in communication, social skills, and repetitive behavior. Susceptibility to autism is clearly attributable to the interplay of genetic and environmental factors, 1-10 but the etiology of this disorder is unknown and no biomarkers have yet been proved characteristic of autism. Recent research 11 is beginning to depict three major pathways as being potentially involved in the pathogenesis of autism (ie, reduced cell migration, excitatory-inhibitory imbalance, and abnormal synaptogenesis). The reelin protein encoded by the RELN gene plays a pivotal role in neuronal cell migration and the prenatal development of neural connections.12 Reelin has coexpressed with HAR1F, which is a novel RNA gene expressed specifically in Cajal-Retzius neurons in the developing human neocortex from gestational week 7 to 19 (a crucial period for cortical neuron specification and migration). 13 Linkage between RELN and autism is a replicated genetic finding in autism research, and reelin has been reduced in the serum and brain specimens of autistic subjects.14,15 Reelin can act through ␣3␤1 integrins and exert proteolytic activity on extracellular matrix (ECM) proteins, which are crucial for neuronal migration. 16 Most recently, emerging evidence 17 indicates that synaptic cell adhesion pathways are disrupted in some

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Section: Discussionmentioning

confidence: 99%

“…32 Antibodies to integrin, FAK, Src, phosphorylated Src, and paxillin were purchased from Cell Signaling and used at concentrations suggested by the supplier.…”

Section: Western Blot Analysismentioning

confidence: 99%

Abnormal Cell Properties and Down-Regulated FAK-Src Complex Signaling in B Lymphoblasts of Autistic Subjects

Wei

Malik

Sheikh

et al. 2011

The American Journal of Pathology

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“…Among the biomarkers of oxidative stress are small biomolecules such as glutathione GSH and SOD, which are depleted in the presence of organic radicals and peroxides [51]. Autism is a disorder characterised by enhanced oxidative stress [52], decreased levels of the antioxidant enzymes SOD and GSH-Px [53], brain Inflammation, apoptosis [54], increased the levels of the proinflammatory cytokines TNF-a and IL-6 [54] and impaired mitochondrial energy production [55]. Therefore, gold nanoparticles may at least partially improve some of the symptoms of autism (Table 1,2&3).…”

Section: Discussionmentioning

confidence: 99%

Pancreatic Response to Gold Nanoparticles Includes Decrease of Oxidative Stress and Inflammation In Autistic Diabetic Model

Selim¹,

Abd‐Elhakim

Al-Ayadhi

2015

Cell Physiol Biochem

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Background: Gold nanoparticles (AuNPs) have a wide range of applications in various fields. This study provides an understanding of the modulatory effects of AuNPs on an antioxidant system in male Wistar diabetic rats with autism spectrum disorder (ASD). Normal littermates fed by control mothers were injected with citrate buffer alone and served as normal, untreated controls controlin this study. Diabetes mellitus (DM) was induced by administering a single intraperitoneal injection of streptozotocin (STZ) (100 mg/kg) to the pups of (ND) diabetic group, which had been fasted overnight. Autistic pups from mothers that had received a single intraperitoneal injection of 600 mg/kg sodium valproate on day 12.5 after conception were randomly divided into 2 groups (n 2 7/group) as follow; administering single intraperitoneal injection of streptozotocin (STZ) ( (100 mg/kg) to the overnight fasted autistic pups of (AD) autistic diabetic group. The treatment was started on the 5th day after STZ injection with the same dose as in group II and it was considered as 1st day of treatment with gold nanoparticles for 7 days to each rat of (group IV) treated autistic diabetic group(TAD) at a dosage of 2.5 mg/kg. b. wt. Results: At this dose of administration AuNPs, the activities of hepatic superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase were greater in group TAD compared with the control group (P < 0.05). Oxidised glutathione levels were lower (P > 0.05) in the liver of autistic diabetic AuNPs -supplemented rats, whereas reduced glutathione was markedly higher than in control rats, especially after administration of AuNPs. Moreover, the kidney functions in addition to the fat profile scoring supported the protective potential of that dose of AuNPs. The beta cells revealed euchromatic nuclei with no evidence of separation of nuclear membrane. Conclusions: Our results showed that AuNPs improved many of the oxidative stress parameters (SOD, GPx and, CAT), plasma antioxidant capacity (ORAC) and lipid profile relative to the other parameters. In addition to the apparent reversibility of the pancreatic B cell in group IV which may reflect the regenerative capacity of AuNPs.

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“…The plasma of autistic patients presents increased levels of proinflammatory cytokines such as IL-1β, IL-6, and TNF-α (Ashwood et al 2011a;Malik et al 2011), and reduced levels of anti-inflammatory cytokines such as TGF-β1 (Ashwood et al 2008a). In addition, peripheral blood mononuclear cells (PBMC) from subjects with ASD show greater lipopolysaccharide-stimulated production of IL-1β (Enstrom et al 2010b), TNF-α, and IL-6 (Jyonouchi et al 2008) than those from controls.…”

Section: Cytokines As Mediators For Autism Developmentmentioning

confidence: 99%

Understanding on Neuroimmunology in Autism Spectrum Disorder

Depino

Robinson-Agramonte

2015

Translational Approaches to Autism Spectrum Disorder

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Autism spectrum disorders (ASD) are a group of severe pervasive neurodevelopmental disorders (PDD) affecting between 1 and 3 % of pediatric populations. It is characterized by a highly variable impairment in social interaction and verbal and nonverbal communication, as well as by a stereotyped repetitive behavior, learning problems, and aloofness. ASD behavioral symptoms are frequently accompanied by immunological derangements, including cellular immune dysregulation, chronic inflammatory states, and neuroimmune alterations. Currently, the involvement of the immune pathology in autism remains unclear, and we consider that a better understanding would be useful for earlier clinical and therapeutic interventions. The main aim of this chapter is to review the most current aspects regarding the etiology of autism, with particular reference to the contribution of inflammatory events occurring in the periphery and into the brain, and how they can influence the abnormal development of the offspring and modulate the typical behaviors frequently observed in autism.

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Expression of inflammatory cytokines, Bcl2 and cathepsin D are altered in lymphoblasts of autistic subjects

Cited by 83 publications

References 42 publications

Abnormal Cell Properties and Down-Regulated FAK-Src Complex Signaling in B Lymphoblasts of Autistic Subjects

Abnormal Cell Properties and Down-Regulated FAK-Src Complex Signaling in B Lymphoblasts of Autistic Subjects

Pancreatic Response to Gold Nanoparticles Includes Decrease of Oxidative Stress and Inflammation In Autistic Diabetic Model

Understanding on Neuroimmunology in Autism Spectrum Disorder

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