Author: Iguchi, Tomohiro ; Ogura, Kiyoshi ; Kikuchi, Norihito ; Yamamoto, Naomasa ; Maeda, Nobuaki ; Shimoda, Yasushi ; Kasahara, Kohji ; Fukuyama, Michiko ; Shimonaka, Motoyuki ; Takeda, Yasuo ; Komatsuya, Keisuke ; Sugiura, Nobuo ; Kawashima, Ikuo

AbstractPhosphacan, a chondroitin sulfate proteoglycan, is a repulsive cue of cerebellar granule cells. This study aims to explore the molecular mechanism. The glycosylphosphatidylinositol‐anchored neural adhesion molecule TAG‐1 is a binding partner of phosphacan, suggesting that the repulsive effect of phosphacan is possibly because of its interaction with TAG‐1. The repulsive effect was greatly reduced on primary cerebellar granule cells of TAG‐1‐deficient mice. Surface plasmon resonance analysis confirmed the direct interaction of TAG‐1 with chondroitin sulfate C. On postnatal days 1, 4, 7, 11, 15, and 20 and in adulthood, phosphacan was present in the molecular layer and internal granular layer, but not in the external granular layer. In contrast, transient TAG‐1 expression was observed exclusively within the premigratory zone of the external granular layer on postnatal days 1, 4, 7, and 11. Boyden chamber cell migration assay demonstrated that phosphacan exerted its repulsive effect on the spontaneous and brain‐derived neurotrophic factor (BDNF)‐induced migration of cerebellar granule cells. The BDNF‐induced migration was inhibited by MK‐2206, an Akt inhibitor. The pre‐treatment with a raft‐disrupting agent, methyl‐β‐cyclodextrin, also inhibited the BDNF‐induced migration, suggesting that lipid rafts are involved in the migration of cerebellar granule cells. In primary cerebellar granule cells obtained on postnatal day 7 and cultured for 7 days, the ganglioside GD3 and TAG‐1 preferentially localized in the cell body, whereas the ganglioside GD1b and NB‐3 localized in not only the cell body but also neurites. Pre‐treatment with the anti‐GD3 antibody R24, but not the anti‐GD1b antibody GGR12, inhibited the spontaneous and BDNF‐induced migration, and attenuated BDNF‐induced Akt activation. These findings suggest that phosphacan is responsible for the repulsion of TAG‐1‐expressing cerebellar granule cells via GD3 rafts to attenuate BDNF‐induced migration signaling.

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01 Jul 2021·Computers in Biology and MedicineQ3 · ENGINEERING & TECHNOLOGY

Binding mechanism of inhibitors to p38α MAP kinase deciphered by using multiple replica Gaussian accelerated molecular dynamics and calculations of binding free energies

Q3 · ENGINEERING & TECHNOLOGY

Article

Author: Sun, Haibo ; Chen, Jianzhong ; Pang, Laixue ; Wang, Wei ; Bao, Huayin

The p38α MAP Kinase has been an important target of drug design for treatment of inflammatory diseases and cancers. This work applies multiple replica Gaussian accelerated molecular dynamics (MR-GaMD) simulations and the molecular mechanics generalized Born surface area (MM-GBSA) method to probe the binding mechanism of inhibitors L51, R24 and 1AU to p38α. Dynamics analyses show that inhibitor bindings exert significant effect on conformational changes of the active helix α2 and the conserved DFG loop. The rank of binding free energies calculated with MM-GBSA not only agrees well with that determined by the experimental IC50 values but also suggests that mutual compensation between the enthalpy and entropy changes can improve binding of inhibitors to p38α. The analyses of free energy landscapes indicate that the L51, R24 and 1AU bound p38α display a DFG-out conformation. The residue-based free energy decomposition method is used to evaluate contributions of separate residues to the inhibitor-p38α binding and the results imply that residues V30, V38, L74, L75, I84, T106, H107, L108, M109, L167, F169 and D168 can be utilized as efficient targets of potent inhibitors toward p38α.

01 Jan 2021·American journal of translational research

miR-24 targets HMOX1 to regulate inflammation and neurofunction in rats with cerebral vasospasm after subarachnoid hemorrhage.

Article

Author: Zhang, Qi ; Liang, Chong ; Deng, Xiaodong ; Qian, Lei

OBJECTIVETo investigate the effects of miR-24 and HMOX1 on the inflammatory response and neurological function in rats with cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH).METHODSFifteen Sprague-Dawley rats were randomly assigned to the sham group (sham operation, treated with normal saline). Rat model of SAH-induced CVS was established in 90 rats, and these rats were randomly divided into the model, miR-24 NC (treated with miR-24-NC vector), miR-24 inhibitor (treated with miR-24 inhibitor vector), HMOX-NC (treated with HMOX1-NC vector), oe-HMOX1 (treated with HMOX1 overexpression vector), and miR-24 inhibitor + si-HMOX1 (treated with miR-24 inhibitor and si-HMOX1 vectors) groups. Adenoviral vectors containing the target sequences were injected into the hippocampus of the rats in the corresponding groups. Dual-luciferase reporter assay was conducted to verify the relationship between miR-24 and HMOX1. The learning and memory abilities, neurological function, cerebral edema, permeability of blood-brain barrier, myeloperoxidase activity, and levels of miR-24, HMOX1, interleukin-6, tumor necrosis factor-α, superoxide dismutase, and malondialdehyde in rats were examined.RESULTSmiR-24 could negatively regulate HMOX1 expression. SAH-induced CVS was accompanied with increased miR-24 expression and decreased HMOX1 expression. Inhibiting miR-24 expression or enhancing the expression of its down streaming target, HMOX1, could partly reverse the increased oxidation and inflammation as well as functional deficits in the rats. Moreover, the effects of miR-24 inhibitor could be reversed by inhibiting HMOX1 expression.CONCLUSIONmiR-24 downregulation can promote HMOX1 expression, thereby decreasing the inflammatory response and improving the neurological function of rats with CVS after SAH.

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Indication	Highest Phase	Country/Location	Organization	Date
Helicobacter pylori infection	Preclinical	CN	Shanghai United Cell Biotechnology Co. Ltd.	30 Nov 2022

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