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The Bu Shen Yi Sui Formula Promotes Axonal Regeneration via Regulating the Neurotrophic Factor BDNF/TrkB and the Downstream PI3K/Akt Signaling Pathway.

ABSTRACT: Axonal damage is recognized as an important pathological feature in the chronic progressive neurological disorder multiple sclerosis (MS). Promoting axonal regeneration is a critical strategy for the treatment of MS. Our clinical and experimental studies have shown that the Bu Shen Yi Sui formula (BSYS) promotes axonal regeneration in MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS, but the exact mechanism has not been thoroughly elucidated to date. In this study, we investigated the effects of BSYS and its two decomposed formulas-the Bu Shen formula (BS) and the Hua Tan Huo Xue formula (HTHX)-on brain-derived neurotrophic factor (BDNF)/TrkB and related signaling pathways to explore the mechanism by which axonal regeneration is promoted in vitro and in vivo. Damaged SH-SY5Y cells incubated with low serum were treated with BSYS-, BS-, and HTHX-containing serum, and EAE mice induced by the myelin oligodendrocyte glycoprotein (MOG)35-55 peptide were treated with BSYS. The results showed that the BSYS-containing serum markedly increased cell viability and increased the levels of growth associated protein (GAP)-43, phosphorylated (p)-cAMP-response element binding protein (CREB), BDNF, TrkB, and p-PI3K. The BS and HTHX treatments also induced the protein expression of GAP-43 and p-extracellular signal-regulated kinase (ERK) in the cells. Furthermore, the effects of BSYS on cell viability, GAP-43, p-CREB, and neurite outgrowth were clearly inhibited by LY294002, a specific antagonist of the PI3K signaling pathways. The addition of U0126 and U73122, antagonists of the ERK and PLC? pathway, respectively, significantly inhibited cell viability and GAP-43 protein expression. Moreover, BSYS treatment significantly increased the expression of the 68-, 160-, and 200-kDa neuro?laments (NFs) of proteins and the BDNF, TrkB, PI3K, and Akt mRNA and proteins in the brain or spinal cord of mice at different stages. These results indicated that BSYS promotes nerve regeneration, and its mechanism is mainly related to the upregulation of the BDNF/TrkB and PI3K/Akt signaling pathways. BS and HTHX also promoted nerve regeneration, and this effect involved the ERK pathway.

SUBMITTER: Zheng Q

PROVIDER: S-EPMC6650751 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The Bu Shen Yi Sui Formula Promotes Axonal Regeneration <i>via</i> Regulating the Neurotrophic Factor BDNF/TrkB and the Downstream PI3K/Akt Signaling Pathway.

Zheng Qi Q Liu Lei L Liu Haolong H Zheng Hong H Sun Hao H Ji Jing J Sun Yaqin Y Yang Tao T Zhao Hui H Qi Fang F Li Kangning K Li Junling J Zhang Nan N Fan Yongping Y Wang Lei L

Frontiers in pharmacology 20190717

Axonal damage is recognized as an important pathological feature in the chronic progressive neurological disorder multiple sclerosis (MS). Promoting axonal regeneration is a critical strategy for the treatment of MS. Our clinical and experimental studies have shown that the Bu Shen Yi Sui formula (BSYS) promotes axonal regeneration in MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS, but the exact mechanism has not been thoroughly elucidated to date. In this study, w ...[more]

PMID: 31379571

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Project description:MethodsThe potential active ingredients and corresponding potential targets of BSYS Capsule were obtained from the TCMSP, BATMAN-TCM, Swiss Target Prediction platform, and literature research. Disease targets of CNSD were explored through the GeneCards and the DisGeNET databases. The matching targets of BSYS in CNSD were identified from a Venn diagram. The protein-protein interaction (PPI) network was constructed using bioinformatics methods. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to predict the mechanisms of BSYS. Furthermore, the neuroprotective effects of BSYS were evaluated using a cell model of hydrogen peroxide- (H2O2-) induced cell death in OLN-93 cells.ResultsA total of 59 potential bioactive components of BSYS Capsule and 227 intersection targets were obtained. Topological analysis showed that AKT had the highest connectivity degrees in the PPI network. Enrichment analysis revealed that the targets of BSYS in the treatment of CNSD were the PI3K-Akt and MAPK signaling pathway, among other pathways. GO analysis results showed that the targets were associated with various biological processes, including apoptosis, reactive oxygen species metabolic process, and response to oxidative stress, among others. The experimental results demonstrated that BSYS drug-containing serum alleviated the H2O2-induced increase in LDH, MDA, and ROS levels and reversed the decrease in SOD and mitochondrial membrane potential induced by H2O2. BSYS treatment also decreased the number of TUNEL (+) cells, downregulated Bcl-2 expression, and upregulated Bax and c-caspase-3 expression by promoting Akt phosphorylation.ConclusionBSYS Capsule alleviated H2O2-induced OLN-93 cell injury by increasing Akt phosphorylation to suppress oxidative stress and cell apoptosis. Therefore, BSYS can be potentially used for CNSD treatment. However, the results of this study are only derived from in vitro experiments, lacking the validation of in vivo animal models, which is a limitation of our study. We will further verify the underlying mechanisms of BSYS in animal experiments in the future.

Project description:ObjectiveTo explore the mechanism of action of Bu-Fei-Yi-Shen formula (BFYSF) in treating chronic obstructive pulmonary disease (COPD) based on network pharmacology analysis and molecular docking validation.MethodsFirst of all, the pharmacologically active ingredients and corresponding targets in BFYSF were mined by the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, the analysis platform, and literature review. Subsequently, the COPD-related targets (including the pathogenic targets and known therapeutic targets) were identified through the TTD, CTD, DisGeNet, and GeneCards databases. Thereafter, Cytoscape was employed to construct the candidate component-target network of BFYSF in the treatment of COPD. Moreover, the cytoHubba plug-in was utilized to calculate the topological parameters of nodes in the network; then, the core components and core targets of BFYSF in the treatment of COPD were extracted according to the degree value (greater than or equal to the median degree values for all nodes in the network) to construct the core network. Further, the Autodock vina software was adopted for molecular docking study on the core active ingredients and core targets, so as to verify the above-mentioned network pharmacology analysis results. Finally, the Omicshare database was applied in enrichment analysis of the biological functions of core targets and the involved signaling pathways.ResultsIn the core component-target network of BFYSF in treating COPD, there were 30 active ingredients and 37 core targets. Enrichment analysis suggested that these 37 core targets were mainly involved in the regulation of biological functions, such as response to biological and chemical stimuli, multiple cellular life processes, immunity, and metabolism. Besides, multiple pathways, including IL-17, Toll-like receptor (TLR), TNF, and HIF-1, played certain roles in the effect of BFYSF on treating COPD.ConclusionBFYSF can treat COPD through the multicomponent, multitarget, and multipathway synergistic network, which provides basic data for intensively exploring the mechanism of action of BFYSF in treating COPD.

Project description:Background: Shen-sui-tong-zhi formula (SSTZF) has been used to treat osteoporosis for decades and shows excellent clinical efficacy. This article aims to explore the optimal anti-osteoporotic ingredient and its precise mechanisms in mice models. Methods: In this study, we first screened the optimal anti-osteoporosis fraction of SSTZF extract in vivo, and then further explored the mechanism of its effects both in vivo and in vitro. Ten-week-old female C57BL/6J mice were administrated with each fraction of SSTZF. At 10 weeks after ovariectomy (OVX), femurs were collected for tissue analyses, including histology, micro-CT, biomechanical tests, and immunohistochemistry for ALP, FABP4, and β-catenin. Additionally, we also evaluated the mRNA expression level of ALP and FABP4 and the protein expression level of β-catenin after being treated with SSTZF extract in C3H10T1/2 cells. Moreover, we investigated the anti-osteoporosis effect of SSTZF extract on mice with β-catenin conditional knockout in growth plate chondrocytes (β-catenin Gli1ER mice) through μCT, histology, and immunohistochemistry analyzes. Results: At 10 weeks after treatment, osteoporosis-like phenotype were significantly ameliorated in SSTZF n-butanol extract (SSTZF-NB) group mice, as indicated by increased trabecular bone area and ALP content, and decreased lipid droplet area and FABP4 content. No such improvements were observed after being treated with other extracts, demonstrating that SSTZF-NB is the optimal anti-osteoporosis fraction. Additionally, the elevated β-catenin was revealed in both OVX mice and C3H10T1/2 cells with SSTZF-NB administered. Furthermore, a significant osteoporosis-like phenotype was observed in β-catenin Gli1ER mice as expected. However, SSTZF-NB failed to rescue the deterioration in β-catenin Gli1ER mice, no significant re-upregulated ALP and downregulated FABP4 were observed after being treated with SSTZF-NB, demonstrating that SSTZF-NB prevents bone loss mainly via β-catenin signaling. Conclusion: SSTZF-NB enhances osteogenesis mainly via activation of β-catenin signaling in growth plate chondrocytes. SSTZF-NB is the optimal anti-osteoporosis fraction of SSTZF and it can be considered a salutary alternative therapeutic option for osteoporosis.

Dataset Information

The Bu Shen Yi Sui Formula Promotes Axonal Regeneration via Regulating the Neurotrophic Factor BDNF/TrkB and the Downstream PI3K/Akt Signaling Pathway.

Publications

The Bu Shen Yi Sui Formula Promotes Axonal Regeneration <i>via</i> Regulating the Neurotrophic Factor BDNF/TrkB and the Downstream PI3K/Akt Signaling Pathway.

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