作者: Dai, Shaobing ; Si, Xiaoli ; Zhao, Guohua ; Pu, Jiali ; Liu, Yi ; Li, Yaolin ; Song, Zhe ; Tang, Jiahui ; Chen, Ying ; Zhang, Baorong ; Wang, Zhiyun ; Fang, Yi

INTRODUCTION:

The glymphatic system offers a perivascular pathway for the clearance of pathological proteins and metabolites to optimize neurological functions. Glymphatic dysfunction plays a pathogenic role in Parkinson's disease (PD); however, the molecular mechanism of glymphatic dysfunction in PD remains elusive.

OBJECTIVE:

To explore whether matrix metalloproteinase-9 (MMP-9)-mediated β-dystroglycan (β-DG) cleavage is involved in the regulation of aquaporin-4 (AQP4) polarity-mediated glymphatic system in PD.

METHODS:

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD and A53T mice were used in this study. The glymphatic function was evaluated using ex vivo imaging. TGN-020, an AQP4 antagonist, was administered to investigate the role of AQP4 in glymphatic dysfunction in PD. GM6001, an MMP-9 antagonist, was administered to investigate the role of the MMP-9/β-DG pathway in regulating AQP4. The expression and distribution of AQP4, MMP-9, and β-DG were assessed using western blotting, immunofluorescence, and co-immunoprecipitation. The ultrastructure of basement membrane (BM)-astrocyte endfeet was detected using transmission electron microscopy. Rotarod and open-field tests were performed to evaluate motor behavior.

RESULTS:

Perivascular influx and efflux of cerebral spinal fluid tracers were reduced in MPTP-induced PD mice with impaired AQP4 polarization. AQP4 inhibition aggravated reactive astrogliosis, glymphatic drainage restriction, and dopaminergic neuronal loss in MPTP-induced PD mice. MMP-9 and cleaved β-DG were upregulated in both MPTP-induced PD and A53T mice, with reduced polarized localization of β-DG and AQP4 to astrocyte endfeet. MMP-9 inhibition restored BM-astrocyte endfeet-AQP4 integrity and attenuated MPTP-induced metabolic perturbations and dopaminergic neuronal loss.

CONCLUSION:

AQP4 depolarization contributes to glymphatic dysfunction and aggravates PD pathologies, and MMP-9-mediated β-DG cleavage regulates glymphatic function through AQP4 polarization in PD, which may provide novel insights into the pathogenesis of PD.

2022-08-01·American journal of orthodontics and dentofacial orthopedics : official publication of the American Association of Orthodontists, its constituent societies, and the American Board of Orthodontics2区 · 医学

Effects of local vs systemic administration of CXCR4 inhibitor AMD3100 on orthodontic tooth movement in rats

2区 · 医学

Article

作者: Hosomichi, Jun ; Ono, Takashi ; Li, Kai ; Ishida, Yuji ; Petdachai, Sirima ; Hatano-Sato, Kasumi ; Usumi-Fujita, Risa ; Ongprakobkul, Narubhorn ; Mahatumarat, Korapin

INTRODUCTION:

Chemokines play pivotal roles in orthodontic tooth movement (OTM) through osteoclast-mediated bone resorption, but the underlying mechanism remains unclear. We aimed to elucidate the effects of serial local vs systemic administration of the chemokine receptor CXCR4 antagonist AMD3100 on OTM.

METHODS:

The maxillary first molar (M1) of rats was moved mesially using a 10 g of force nickel-titanium coil spring. The injections were performed every other day with phosphate-buffered saline as a control, whereas local and systemic animals were injected with AMD3100 at the buccal palatal mucosa adjacent to M1 and subcutaneously, respectively. OTM distance and alveolar bone were examined by microcomputed tomography and histologic analysis. Osteoclast numbers were quantified using TRAP staining. Cathepsin K and stromal cell-derived factor-1 (SDF-1) were evaluated using immunohistochemistry. Reverse transcriptase polymerase chain reaction for cathepsin K, Runx2, SDF-1, CXCR4, RANKL, and OPG were also examined.

RESULTS:

OTM and osteoclast numbers were significantly decreased in the local and systemic groups compared with the control group, whereas there was no significant difference among the experimental groups. Local administration inhibited molar but not incisor movement. Trabecular thickness and trabecular spacing of the alveolar bone significantly increased, and trabecular number significantly decreased in the systemic group compared with the control group, whereas local injection also affected bone quality in the same tendency as a systemic injection. AMD3100 significantly downregulated the mRNA expression levels of cathepsin K, Runx2, SDF-1, RANKL, and RANKL/OPG ratio in both experimental groups.

CONCLUSIONS:

Local administration of AMD3100 can control initial OTM and diminish bone resorption processes during OTM via inhibition of the SDF-1/CXCR4 axis, similar to the systemic administration.

2022-05-01·Neurology(R) neuroimmunology & neuroinflammation1区 · 医学

Cell-Free DNA Derived From Neutrophils Triggers Type 1 Interferon Signature in Neuromyelitis Optica Spectrum Disorder

1区 · 医学

ArticleOA

作者: Shiraishi, Naoyuki ; Kumanogoh, Atsushi ; Koda, Toru ; Sugiyama, Yasuko ; Kinoshita, Makoto ; Tada, Satoru ; Beppu, Shohei ; Konaka, Hachiro ; Takamatsu, Hyota ; Murata, Hisashi ; Okuno, Tatsusada ; Yasumizu, Yoshiaki ; Mochizuki, Hideki ; Kihara, Keigo ; Motooka, Daisuke

Background and Objectives:

Recently accumulating evidence suggests the pivotal role of type 1 interferon (IFN-1) signature in the pathogenesis of neuromyelitis optica spectrum disorder (NMOSD). However, the mechanism of the initial trigger that augments IFN-1 pathway in the peripheral immune system of NMOSD has yet to be elucidated.

Methods:

Clinical samples were obtained from 32 patients with aquaporin-4 antibody–positive NMOSD and 23 healthy subjects. IFN-1 induction in peripheral blood mononuclear cells (PBMCs) by serum-derived cell-free DNA (cfDNA) was assessed in combination with blockades of DNA sensors in vitro. CfDNA fraction was analyzed for DNA methylation profiles by bisulfite sequencing, elucidating the cellular origin of cfDNA. The induction of neutrophil extracellular trap related cell death (NETosis) was further analyzed in NMOSD and control groups, and the efficacy of pharmacologic intervention of NETosis was assessed.

Results:

Enhanced IFN-1 induction by cfDNA derived from NMOSD was observed in PBMCs with cofactor of LL37 antimicrobial peptide. DNase treatment, cGAS inhibitor, and Toll-like receptor 9 antagonist efficiently inhibited IFN-1 production. DNA methylation pattern of cfDNA in patients with NMOSD demonstrated that the predominant cellular source of cfDNA was neutrophils. Whole blood transcriptome analysis also revealed neutrophil activation in NMOSD. In addition, enhanced NETosis induction was observed with NMOSD-derived sera, and efficient pharmacologic inhibition of NETosis with dipyridamole was observed.

Discussion:

Our study highlights the previously unrevealed role of cfDNA predominantly released by neutrophil in the induction of IFN-1 signature in NMOSD and further indicate a novel pharmacologic target in NMOSD.

100 项与 NR11/1943 (Norgine) 相关的药物交易

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