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Bu-Shen-Yi-Sui Capsule, an Herbal Medicine Formula, Promotes Remyelination by Modulating the Molecular Signals via Exosomes in Mice with Experimental Autoimmune Encephalomyelitis.

ABSTRACT: Multiple sclerosis (MS) is a common inflammatory demyelinating disorder of the central nervous system. Bu-shen-yi-sui capsule (BSYSC) could significantly reduce the relapse rate, prevent the progression of MS, and enhance remyelination following neurological injury in experimental autoimmune encephalomyelitis (EAE), an established model of MS; however, the mechanism underlying the effect of BSYSC on remyelination has not been well elucidated. This study showed that exosomes carrying biological information are involved in the pathological process of MS and that modified exosomes can promote remyelination by modulating related proteins and microRNAs (miRs). Here, the mechanism by which BSYSC promoted remyelination via exosome-mediated molecular signals was investigated in EAE mice and oligodendrocyte progenitor cells (OPCs) in vitro. The results showed that BSYSC treatment significantly improved the body weight and clinical scores of EAE mice, alleviated inflammatory infiltration and nerve fiber injury, protected the ultrastructural integrity of the myelin sheath, and significantly increased the expression of myelin basic protein (MBP) in EAE mice. In an in vitro OPC study, BSYSC-containing serum, especially 20% BSYSC, promoted the proliferation and migration of OPCs and induced OPCs to differentiate into mature oligodendrocytes that expressed MBP. Furthermore, BSYSC treatment regulated the expression of neuropilin- (NRP-) 1 and GTX, downregulated the expression of miR-16, let-7, miR-15, miR-98, miR-486, and miR-182, and upregulated the level of miR-146 in serum exosomes of EAE mice. In conclusion, these results suggested that BSYSC has a neuroprotective effect and facilitates remyelination and that the mechanism underlying the effect of BSYSC on remyelination probably involves regulation of the NRP-1 and GTX proteins and miRs in serum exosomes, which drive promyelination.

SUBMITTER: Zhao PY

PROVIDER: S-EPMC7396036 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Bu-Shen-Yi-Sui Capsule, an Herbal Medicine Formula, Promotes Remyelination by Modulating the Molecular Signals via Exosomes in Mice with Experimental Autoimmune Encephalomyelitis.

Zhao Pei-Yuan PY Ji Jing J Liu Xi-Hong XH Zhao Hui H Xue Bin B Jin Liang-Yun LY Fan Yong-Ping YP Zhao Wen-Jing WJ Wang Lei L

Oxidative medicine and cellular longevity 20200722

Multiple sclerosis (MS) is a common inflammatory demyelinating disorder of the central nervous system. Bu-shen-yi-sui capsule (BSYSC) could significantly reduce the relapse rate, prevent the progression of MS, and enhance remyelination following neurological injury in experimental autoimmune encephalomyelitis (EAE), an established model of MS; however, the mechanism underlying the effect of BSYSC on remyelination has not been well elucidated. This study showed that exosomes carrying biological i ...[more]

PMID: 32774683

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Project description: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.

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:San-Huang-Yi-Shen capsule (SHYS) has been used in the treatment of diabetic nephropathy (DN) in clinic. However, the mechanisms of SHYS on DN remain unknown. In this study, we used a high-fat diet (HFD) combined with streptozotocin (STZ) injection to establish a DN rat model. Next, we used 16S rRNA sequencing and untargeted metabolomics to study the potential mechanisms of SHYS on DN. Our results showed that SHYS treatment alleviated the body weight loss, hyperglycemia, proteinuria, pathological changes in kidney in DN rats. SHYS could also inhibite the oxidative stress and inflammatory response in kidney. 16S rRNA sequencing analysis showed that SHYS affected the beta diversity of gut microbiota community in DN model rats. SHYX could also decrease the Firmicutes to Bacteroidetes (F to B) ratio in phylum level. In genus level, SHYX treatment affected the relative abundances of Lactobacillus, Ruminococcaceae UCG-005, Allobaculum, Anaerovibrio, Bacteroides and Candidatus_Saccharimonas. Untargeted metabolomics analysis showed that SHYX treatment altered the serum metabolic profile in DN model rats through affecting the levels of guanidineacetic acid, L-kynurenine, prostaglandin F1α, threonine, creatine, acetylcholine and other 21 kind of metabolites. These metabolites are mainly involved in glycerophospholipid metabolism, tryptophan metabolism, alanine, aspartate and glutamate metabolism, arginine biosynthesis, tricarboxylic acid (TCA) cycle, tyrosine metabolism, arginine and proline metabolism, arginine and proline metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, and D-glutamine and D-glutamate metabolism pathways. Spearman correlation analysis showed that Lactobacillus, Candidatus_Saccharimonas, Ruminococcaceae UCG-005, Anaerovibrio, Bacteroides, and Christensenellaceae_R-7_group were closely correlated with most of physiological data and the differential metabolites following SHYS treatment. In conclusion, our study revealed multiple ameliorative effects of SHYS on DN including the alleviation of hyperglycemia and the improvement of renal function, pathological changes in kidney, oxidative stress, and the inflammatory response. The mechanism of SHYS on DN may be related to the improvement of gut microbiota which regulates arginine biosynthesis, TCA cycle, tyrosine metabolism, and arginine and proline metabolism.

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

Bu-Shen-Yi-Sui Capsule, an Herbal Medicine Formula, Promotes Remyelination by Modulating the Molecular Signals via Exosomes in Mice with Experimental Autoimmune Encephalomyelitis.

Publications

Bu-Shen-Yi-Sui Capsule, an Herbal Medicine Formula, Promotes Remyelination by Modulating the Molecular Signals via Exosomes in Mice with Experimental Autoimmune Encephalomyelitis.

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