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- W3191208519 abstract "Background: Methylmalonic acid (MMA) combined with homocysteine (HCY) limits the survival and function of neurons during the development of cobalamin C (cblC) deficiency, yet no effective medication currently exists to ameliorate the damage.Methods: We designed a novel second-tier assay utilizing ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Plasma exosomes were isolated by ultracentrifugation and identified by RT-qPCR assays combined with luciferase activity. Additionally, DNA sequencing followed by tandem mass spectrometry (MS/MS) was performed to characterize individuals with cblC deficiency.Findings: Two previously unreported variants (c.228_231del and c.626_627del) in the MMACHC gene were identified. Second-tier test were offered dramatic power in predicting cblC deficiency outcomes. By demonstrating a proof-of-concept for plasma exosomal therapy methodology, we found that plasma exosomes can penetrate the blood-brain barrier (BBB) with accumulation in the hippocampus, and healthy plasma exosomes substantially can reduce neuronal apoptosis and repaired neurological deficits in cells and mouse models. Mechanistically, plasma exosomal miR-382-5p bound to the 3’-untranslated region (UTR) with downregulating MMACHC target gene transcription.Interpretation: The second-tier approach reduced false positives by 92% in individuals with cblC deficiency. Challenges remain in newborn screeing, and plasma exosomes might be therapeutically exploited to improve neural recovery of cblC deficiency.Funding: This work was supported by grants from the National Natural Science Foundation of China (No. 81671164, 81171075); Postgraduate Research & Practice Innovation Program of Jiangsu Province (Grant number: KYCX19_2211); Jiangsu Province Maternal and Child Health Project (Grant number: F201912) and Xuzhou Science and Technology Program (Grant number: KC19028).Declaration of Interests: The authors declare no conflict of interest.Ethics Approval Statement: The protocol was reviewed and approved by the Ethics Committee of the Affiliated Xuzhou Maternity and Child Health Care Hospital of Xuzhou Medical University, the committee’s reference number: [2019] No.9.All animal experiments were conducted after the approval of the local animal care committees (License ID: SYXK(Su)2015- 0030) and in accordance with the guidelines of the animal facility of Xuzhou Medical University." @default.
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- W3191208519 date "2021-01-01" @default.
- W3191208519 modified "2023-09-27" @default.
- W3191208519 title "Plasma Exosomes From Healthy Individuals Could Protect Against Hippocampal Neuron Injury Induced by MMACHC Variants in Cobalamin (cblC) Deficiency" @default.
- W3191208519 doi "https://doi.org/10.2139/ssrn.3807236" @default.
- W3191208519 hasPublicationYear "2021" @default.
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