Blood exosome sensing via neuronal insulin-like growth factor-1 regulates autism-related phenotypes.

The development and progression of autism spectrum disorder (ASD) is characterized by multiple complex molecular events, highlighting the importance of the prefrontal brain regions in this process. Exosomes are nanovesicles that play a critical role in intercellular communication. Peripheral systems influence brain function under both physiological and pathological conditions. We investigated whether this influence was mediated by the direct sensing of peripheral blood exosomes by brain cells. Administration of serum exosomes from rats with valproic acid-induced ASD resulted in ASD-related phenotypes in mice, whereas exosomes from normal rats did not exhibit such effects. RNA sequencing and bioinformatics analysis suggested that negative regulation of medial prefrontal cortex (mPFC) insulin-like growth factor 1 (IGF-1) by exosome-derived miR-29b-3p may contribute to these ASD-associated effects. Further evidence showed that miR-29b-3p-enriched exosomes crossed the blood-brain barrier to reach the mPFC, subsequently inducing the suppression of IGF-1 expression in neurons. Optogenetic activation of excitatory neurons in the mPFC improved behavioral abnormalities in exosome-treated mice. The addition of exogenous IGF-1 or inhibition of miR-29b-3p expression in the mPFC also rescued the ASD-related phenotypes in mice. Importantly, administration of miR-29b-3p-enriched serum exosomes from human donors with ASD into the mouse medial prefrontal cortex was sufficient to induce hallmark ASD behaviors. Together, our findings indicate that blood-brain cross-talk is crucial for ASD pathophysiology and that the brain may sense peripheral system changes through exosomes, which could serve as the basis for future neurological therapies.

Oxidative stress marker aberrations in children with autism spectrum disorder: a systematic review and meta-analysis of 87 studies (N = 9109).

There is increasing awareness that oxidative stress may be implicated in the pathophysiology of autism spectrum disorder (ASD). Here we aimed to investigate blood oxidative stress marker profile in ASD children by a meta-analysis. Two independent investigators systematically searched Web of Science, PubMed, and Cochrane Library and extracted data from 87 studies with 4928 ASD children and 4181 healthy control (HC) children. The meta-analysis showed that blood concentrations of oxidative glutathione (GSSG), malondialdehyde, homocysteine, S-adenosylhomocysteine, nitric oxide, and copper were higher in children with ASD than that of HC children. In contrast, blood reduced glutathione (GSH), total glutathione (tGSH), GSH/GSSG, tGSH/GSSG, methionine, cysteine, vitamin B9, vitamin D, vitamin B12, vitamin E, S-adenosylmethionine/S-adenosylhomocysteine, and calcium concentrations were significantly reduced in children with ASD relative to HC children. However, there were no significance differences between ASD children and HC children for the other 17 potential markers. Heterogeneities among studies were found for most markers, and meta-regressions indicated that age and publication year may influence the meta-analysis results. These results therefore clarified blood oxidative stress profile in children with ASD, strengthening clinical evidence of increased oxidative stress implicating in pathogenesis of ASD. Additionally, given the consistent and large effective size, glutathione metabolism biomarkers have the potential to inform early diagnosis of ASD.

Oxidative Stress Marker Aberrations in Multiple Sclerosis: A Meta-Analysis Study.

Oxidative stress has been suggested to play a key role in multiple sclerosis (MS), but clinical data on oxidative stress markers in MS patients were inconsistent. This study sought to quantitatively summarize the data of oxidative stress markers in the blood and cerebrospinal fluid (CSF) of patients with MS in the literature. We conducted a systematic search of PubMed and Web of Science and included studies if they provided data on the concentrations of oxidative stress markers in the peripheral blood and CSF of MS patients and healthy control (HC) subjects. The systematic search resulted in the inclusion of 31 studies with 2,001 MS patients and 2,212 HC subjects for meta-analysis. Random-effects meta-analysis demonstrated that patients with MS had significantly increased concentrations of blood oxidative stress markers compared with HC subjects for malondialdehyde (MDA; Hedges' g, 2.252; 95% CI, 1.080 to 3.424; p < 0.001) and lipid hydroperoxide by tert-butyl hydroperoxide-initiated chemiluminescence (CL-LOOH; Hedges' g, 0.383; 95% CI, 0.065 to 0.702; p = 0.018). In contrast, concentrations of albumin (Hedges' g, -1.036; CI, -1.679 to -0.394; p = 0.002) were significantly decreased in MS patients when compared with those in HC subjects. However, the other analyzed blood oxidative stress markers did not show significant differences between cases and controls. Furthermore, this meta-analysis showed significant association between CSF MDA and MS (Hedges' g, 3.275; 95% CI, 0.859 to 5.691; p = 0.008). Taken together, our results revealed increased blood and CSF MDA and decreased blood albumin levels in patients with MS, strengthening the clinical evidence of increased oxidative stress in MS.