Relationship Between Sonic Hedgehog Protein, Brain-Derived Neurotrophic Factor and Oxidative Stress in Autism Spectrum Disorders

The etiology of autism spectrum disorders (ASD) is not well known but oxidative stress has been suggested to play a pathological role. We report here that the serum levels of Sonic hedgehog (SHH) protein and brain-derived neurotrophic factor (BDNF) might be linked to oxidative stress in ASD. By using the whole blood or polymorphonuclear leukocytes, we demonstrated that autistic children produced a significantly higher level of oxygen free radicals (OFR). In addition, we found significantly higher levels of serum SHH protein in children with mild as well as severe form of autism. We also found that the serum level of BDNF was significantly reduced in autistic children with mild form of the disorder but not with severe form of the disorder. Our findings are the first to report a correlation between SHH, BDNF and OFR in autistic children, suggesting a pathological role of oxidative stress and SHH in autism spectrum disorders

Novel metabolic biomarkers related to sulfur-dependent detoxification pathways in autistic patients of Saudi Arabia

<p>Abstract</p> <p>Background</p> <p>Xenobiotics are neurotoxins that dramatically alter the health of the child. In addition, an inefficient detoxification system leads to oxidative stress, gut dysbiosis, and immune dysfunction. The consensus among physicians who treat autism with a biomedical approach is that those on the spectrum are burdened with oxidative stress and immune problems. In a trial to understand the role of detoxification in the etiology of autism, selected parameters related to sulfur-dependent detoxification mechanisms in plasma of autistic children from Saudi Arabia will be investigated compared to control subjects.</p> <p>Methods</p> <p>20 males autistic children aged 3-15 years and 20 age and gender matching healthy children as control group were included in this study. Levels of reduced glutathione (GSH), total (GSH+GSSG), glutathione status (GSH/GSSG), glutathione reductase (GR), glutathione- s-transferase (GST), thioredoxin (Trx), thioredoxin reductase (TrxR) and peroxidoxins (Prxs I and III) were determined.</p> <p>Results</p> <p>Reduced glutathione, total glutathione, GSH/GSSG and activity levels of GST were significantly lower, GR shows non-significant differences, while, Trx, TrxR and both Prx I and III recorded a remarkably higher values in autistics compared to control subjects.</p> <p>Conclusion</p> <p>The impaired glutathione status together with the elevated Trx and TrxR and the remarkable over expression of both Prx I and Prx III, could be used as diagnostic biomarkers of autism.</p

Goat and buffalo milk fat globule membranes exhibit better effects at inducing apoptosis and reduction the viability of HT-29 cells

Bovine milk fat globule membrane (MFGM) has shown many health benefits, however, there has not been much study on non-cattle MFGMs. The purpose of this study was to compare the anti-proliferation effects and investigate the mechanisms of MFGMs from bovine, goat, buffalo, yak and camel milk in HT-29 cells. Results showed that protein content in MFGM of yak milk is the highest among five MFGM. All MFGMs inhibited cellular proliferation which was in agreement with cell morphology and apoptosis. However, the number of cells in S-phase from 24 h to 72 h was increased significantly by treatment with goat, buffalo and bovine MFGMs (100 μg/mL), but not yak and camel. All MFGMs treatment significantly reduced the mitochondrial membrane potential (with an order of goat>buffalo>bovine>camel>yak) and Bcl-2 expression, but increased the expression of both Bax and Caspase-3. Taken together, the results indicate that all MFGMs, especially goat and buffalo MFGMs, showed better effects at inducing apoptosis and inhibition of the proliferation of HT-29 cells. The mechanism might be arresting the cell cycle at S phase, depolarization of mitochondrial membrane potential, down-regulation of Bcl-2 expression and increase of Bax and Caspase-3 expression

Altered Activation of Innate Immunity Associates with White Matter Volume and Diffusion in First-Episode Psychosis

First-episode psychosis (FEP) is associated with inflammatory and brain structural changes, but few studies have investigated whether systemic inflammation associates with brain structural changes in FEP. Thirty-seven FEP patients (median 27 days on antipsychotic medication), and 19 matched controls were recruited. Serum levels of 38 chemokines and cytokines, and cardiovascular risk markers were measured at baseline and 2 months later. We collected T1-and diffusion-weighted MRIs with a 3 T scanner from the patients at baseline. We analyzed the association of psychosis-related inflammatory markers with gray and white matter (WM) volume using voxel-based morphometry and WM diffusion using tract-based spatial statistics with whole-brain and region-of-interest (ROI) analyses. FEP patients had higher CCL22 and lower TGFa, CXCL1, CCL7, IFN-alpha 2 and ApoA-I than controls. CCL22 decreased significantly between baseline and 2 months in patients but was still higher than in controls. The association between inflammatory markers and FEP remained significant after adjusting for age, sex, smoking and BMI. We did not observe a correlation of inflammatory markers with any symptoms or duration of antipsychotic treatment. Baseline CCL22 levels correlated negatively with WM volume and positively with mean diffusivity and radial diffusivity bilaterally in the frontal lobes in ROI analyses. Decreased serum lan association between circulating chemokine levels and WM in FEP patients. Interestingly, CCL22 has been previously implicated in autoimmune diseases associated with WM pathology. The results suggest that an altered activation of innate immunity may contribute to WM damage in psychotic disorders.evel of ApoA-I was associated with smaller volume of the medial temporal WM. In whole-brain analyses, CCL22 correlated positively with mean diffusivity and radial diffusivity, and CXCL1 associated negatively with fractional anisotropy and positively with mean diffusivity and radial diffusivity in several brain regions. This is the first report to demonstratePeer reviewe

Metabolic biomarkers related to oxidative stress and antioxidant status in Saudi autistic children.

OBJECTIVE: Measurement of oxidative stress and antioxidant-related parameters (enzymatic and non-enzymatic) in Saudi autistic children. DESIGN AND METHODS: 30 autistic children (22 males and 8 females) aged 3-15 years (25/30 of these were below 8 years old), and 30 healthy children as control group were included in this study. Levels of lipid peroxides, vitamin E, vitamin C, glutathione together with enzymatic activities of glutathione peroxidase (GSH-Px), and catalase were determined in plasma while superoxide dismutase (SOD was measured in red blood cells of both groups. RESULTS: Lipid peroxidation was found to be significantly higher in autistic compared to control Saudi children. On the other hand, vitamin E and glutathione were remarkably lower in autistic patients while vitamin C shows non-significant lower values. Regarding the enzymatic antioxidants, both glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were significantly higher in autistic compared to control while catalase recorded more or less similar activities in both groups. CONCLUSION: Saudi autistic children are under H(2)O(2) stress due to GSH depletion, over expression of SOD together with the unchanged catalase enzyme. This could be helpful in the early diagnosis of young autistic patients and suggesting the possibility of antioxidant supplementation for the early intervention with autistic children.Research Center and KACS

A Disintegrin and Metalloproteinase Protein 8 (ADAM 8) in Autism Spectrum Disorder: Links to Neuroinflammation

Laila Al-Ayadhi,1,2 Amani Abualnaja,3 Abdullah AlZarroug,3 Turki Alharbi,3 Abdulrahman M Alhowikan,1,2 Dost M Halepoto,1 Sarah Al-Mazidi4 1Autism Research and Treatment Centre, Faculty of Medicine, King Saud University, Riyadh, 11461, Saudi Arabia; 2Department of Physiology, Faculty of Medicine, King Saud University, Riyadh, 11461, Saudi Arabia; 3College of Medicine, Imam Mohammad Ibn Saud Islamic University, Riyadh, 11432, Saudi Arabia; 4College of Medicine, Department of Physiology, Imam Mohammad Ibn Saud Islamic University, Riyadh, 11432, Saudi ArabiaCorrespondence: Sarah Al-Mazidi, College of Medicine, Department of Physiology, Imam Mohammad Ibn Saud Islamic University, P.O Box: 5701, Riyadh, 11432, Saudi Arabia, Tel +966-553-007-441, Email [email protected]: Converging lines of evidence confirmed neuroinflammation’s role in autism spectrum disorder (ASD) etiological pathway. A disintegrin and metalloproteinase 8 (ADAM8) play major roles in inflammatory and allergic processes in various diseases.Aim: This study aimed to investigate ADAM8 plasma levels in autistic children compared to healthy controls. Also, to discover the association between ADAM8, disease severity, and neuroinflammation in ASD.Methodology: This case–control study included children with ASD (n=40) and aged-matched healthy controls (n=40). The plasma levels of the ADAM 8 were determined using enzyme-linked immunosorbent assay (ELISA). The assessment of ASD severity and social and sensory behaviors were categorized as mild, moderate and severe. Correlations among ADAM8 plasma levels and ASD severity scores [Childhood Autism Rating Scale (CARS), Social Responsiveness Scale (SRS) and Short Sensory Profile (SSP)] were obtained by Spearman correlation coefficient (r).Results: ASD children (n=40), including severe autism (n=21) and mild-to-moderate autism (n=19), showed significantly (p ≤ 0.05) lower plasma levels of ADAM8 [4683 (2885– 5229); 4663 (4060– 5000); 4632 (2885– 5229)], respectively, than those of healthy controls [5000 (4047– 5000)] [median (IQR) pg/mL]. However, there was no significant difference between the ADAM8 levels of children with severe and mild-to-moderate autism (p = 0.71). Moreover, ADAM8 plasma levels were not significantly correlated with the severity of ASD measured by behavioral scales [CARS (r= − 0.11, p=0.55), SRS (r=0.11, p= 0.95), SSP (r=− 0.23, p=0.23)].Conclusion: The low ADAM8 plasma levels in children with ASD possibly indicated that ADAM8 might be implicated in the pathogenesis of ASD but not in the severity of the disease. These results should be interpreted with caution until additional studies are carried out with larger populations to decide whether the reduction in plasma ADAM8 levels is a mere consequence of ASD or if it plays a pathogenic role in the disease.Keywords: autism spectrum disorder, neuroinflammation, a disintegrin and metalloprotease 8, neurodevelopmental disorde