MOLECULAR PSYCHIATRY
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2025
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IF 10.1
Qin Qian,Li Mengyue,Fan Linlin,Zeng Xin,Zheng Danyang,Wang Han,Jiang Yutong,Ma Xinrui,Xing Lei,Wu Lijie,Liang Shuang
Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder. The microglia activation is a hallmark of ASD, which involves increased glycolysis. Elevated glycolysis regardless of oxygen availability, known as “Warburg effect”, is crucial to pathogenesis in neuropsychiatric disorders. Psychiatric risk gene MIR137 plays an important role in neurogenesis and neuronal maturation, but the impact on neuroinflammation and glucose metabolism remains obscure. Extracellular vesicles (EVs) can delivery miR-137 crossing the blood-brain barrier. Meanwhile, EVs can help miR-137 avoid being rapidly degraded by endogenous nucleases. Here, after first detecting miR-137 decreased both in the peripheral blood of individuals with ASD and the serum and cerebellum of BTBR mice, we demonstrated that microglia activation, the level of lactate and key enzymes (HK2, PKM2 and LDHA) involved in glycolysis were increased significantly in BTBR mice. Of particular note, EVs engineered by rabies virus glycoprotein (RVG) could promote the miR-137 (RVG-miR137-EVs) targeted to the brain accurately, and alleviated autism-like behaviors. Pro-inflammatory activation of BTBR mice was considerably inhibited by RVG-miR137-EVs via tail vein administration, accompanied by decreased lactate production. Mechanically, these effects were attributed to TLR4 , the key target gene, which was regulated by miR-137. The TLR4/NF-κB pathway was inhibited, subsequently reducing HIF-1α and repressing the transcription of HK2, PKM2 and LDHA involved in glycolysis. Pharmacological inhibition of glycolysis and TLR4 attenuated microglial activation and lactate production, ultimately improved autism-like behaviors of BTBR mice. In conclusion, our results indicated that miR-137 could alleviate autism-like behaviors by HIF-1α-mediated adaptive metabolic changes in glycolysis and neuroinflammation.
研究领域:
神经科学
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分子生物学
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医学
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DOI
PubMed
高影响因子
AQUATIC TOXICOLOGY
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2018
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IF 3.884
Jinfeng Liu,Chenyan Xiang,Wenhao Huang,Jingyi Mei,Limei Sun,Yuhang Ling,Caihong Wang,Xuedong Wang,Randy A. Dahlgren,Huili Wang
Triclosan (TCS) is a prevalent anthropogenic contaminant in aquatic environments and its chronic exposure can lead to a series of neurotoxic effects in zebrafish. Both qRT-PCR and W-ISH identified that TCS exposure resulted in significant up-regulation of miR-137, but downregulation of its regulatory genes ( bcl11aa , MAPK6 and Runx1 ). These target genes are mainly associated with neurodevelopment and the MAPK signaling pathway, and showed especially high expression in the brain. After overexpression or knockdown treatments by manual intervention of miR-137, a series of abnormalities were induced, such as ventricular abnormality, bent spine, yolk cyst, closure of swim sac and venous sinus hemorrhage. The most sensitive larval toxicological endpoint from intervened miR-137 expression was impairment of the central nervous system (CNS), ventricular abnormalities and notochord curvature. Microinjection of microRNA mimics or inhibitors of miR-137 both caused zebrafish malformations. The posterior lateral line neuromasts became obscured and decreased in number in intervened miR-137 groups and TCS-exposure groups. Up-regulation of miR-137 led to more severe neurotoxic effects than its down-regulation. Behavioral observations demonstrated that both TCS exposure and miR-137 over-expression led to inhibited hearing or vision sensitivity. HE staining indicated that hearing and vision abnormalities induced by long-term TCS exposure originated from CNS injury, such as reduced glial cells and loose and hollow fiber structures. The findings of this study enhance our mechanistic understanding of neurotoxicity in aquatic animals in response to TCS exposure. These observations provide theoretical guidance for development of early intervention treatments for nervous system diseases.
研究领域:
毒理学
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神经科学
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水生生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Translational Medicine
·
2024
·Vol. 22
·期 1
·1-19
·
IF 6.1
Qin Qian,Shan Zhiyan,Xing Lei,Jiang Yutong,Li Mengyue,Fan Linlin,Zeng Xin,Ma Xinrui,Zheng Danyang,Wang Han,Wang Hui,Liu Hao,Liang Shengjun,Wu Lijie,Liang Shuang
Autism spectrum disorder (ASD) is a multifaceted neurodevelopmental disorder predominant in childhood. Despite existing treatments, the benefits are still limited. This study explored the effectiveness of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) loaded with miR-137 in enhancing autism-like behaviors and mitigating neuroinflammation. Utilizing BTBR mice as an autism model, the study demonstrated that intranasal administration of MSC-miR137-EVs ameliorates autism-like behaviors and inhibits pro-inflammatory factors via the TLR4/NF-κB pathway. In vitro evaluation of LPS-activated BV2 cells revealed that MSC-miR137-EVs target the TLR4/NF-κB pathway through miR-137 inhibits proinflammatory M1 microglia. Moreover, bioinformatics analysis identified that MSC-EVs are rich in miR-146a-5p, which targets the TRAF6/NF-κB signaling pathway. In summary, the findings suggest that the integration of MSC-EVs with miR-137 may be a promising therapeutic strategy for ASD, which is worthy of clinical adoption.
研究领域:
神经科学
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干细胞生物学
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分子生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Reports
·
2024
·
IF 7.5
Zhu Li,Kexin Mao,Lin Liu,Shengyun Xu,Min Zeng,Yu Fu,Jintao Huang,Tingting Li,Guoan Gao,Zhao-Qian Teng,Qinmiao Sun,Dahua Chen,Ying Cheng
Microglia are versatile regulators in brain development and disorders. Emerging evidence links microRNA (miRNA)-mediated regulation to microglial function; however, the exact underlying mechanism remains largely unknown. Here, we uncover the enrichment of miR-137, a neuropsychiatric-disorder-associated miRNA, in the microglial nucleus, and reveal its unexpected nuclear functions in maintaining the microglial global transcriptomic state, phagocytosis, and inflammatory response. Mechanistically, microglial Mir137 deletion increases chromatin accessibility, which contains binding motifs for the microglial master transcription factor Pu.1. Through biochemical and bioinformatics analyses, we propose that miR-137 modulates Pu.1-mediated gene expression by suppressing Pu.1 binding to chromatin. Importantly, we find that increased Pu.1 binding upregulates the target gene Jdp2 (Jun dimerization protein 2) and that knockdown of Jdp2 significantly suppresses the impaired phagocytosis and pro-inflammatory response in Mir137 knockout microglia. Collectively, our study provides evidence supporting the notion that nuclear miR-137 acts as a transcriptional modulator and that this microglia-specific function is essential for maintaining normal adult brain function.
研究领域:
神经生物学
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分子生物学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）