Matrine inhibits the Wnt3a/ß-catenin/TCF7L2 signaling pathway in experimental autoimmune encephalomyelitis.

Oligodendrocyte (OL) death and remyelination failure lead to progressive neurological deficits in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Matrine (MAT), a quinolizidine alkaloid component derived from the root of Sophora flavescens, has the capacity to effectively inhibit central nervous system (CNS) inflammation and to promote neuroregeneration. In the present study we explored its regulatory mechanism on the Wnt/ß-catenin/TCF7L2 pathway, a negative modulator for myelination, in MOG35--55 peptide-induced EAE. Our results clearly indicate that MAT treatment reduced the activation of Wnt3a and ß-catenin in the CNS of EAE mice, accompanied by the activation of GSK3ß and decreased expression of cyclin D1 and Axin2, two target genes of the Wnt3a/ß-catenin pathway. In addition, MAT increased OL maturation and myelination, as evidenced by the decreased number of NG2+Olig2+ cells and the increased numbers of MBP+ and CC1+Olig2+ cells. Taken together, these findings indicate that MAT treatment promoted the maturation of OLs and myelin repair, which is closely related to the modulation of the Wnt/ß-catenin/TCF7L2 signaling pathway.

Investigation on the hesitancy of COVID-19 vaccination among liver transplant recipients: A cross-sectional study in China.

Objectives: The hospitalization and mortality rate from COVID-19 appears to be higher in liver transplant recipients when compared with general populations. Vaccination is an effective strategy to reduce the risk during the COVID-19 pandemic. We aimed to evaluate COVID-19 vaccine hesitancy in liver transplant recipients. Methods: In April 2022, we conducted an online-based survey through WeChat platform to investigate the vaccination hesitancy among liver transplant recipients followed at Shanghai Renji Hospital and further explore possible influencing factors. Survey items included multiple choice, Likert-type rating scale and open-ended answers. Participants were classified as no hesitancy group and hesitancy group. Using univariate analysis, ROC curve analysis and multiple logistic regression to evaluate associations between baseline characteristics and COVID-19 vaccine hesitancy. Results: 449 liver transplant recipients participated in the survey with 299 (66.6%) of them being categorized as vaccine hesitancy. In no hesitancy group, 73 (48.7%) recipients had completed vaccination, while 77 (51.3%) were not yet but intended to be vaccinated. In contrast, 195 (65.2%) recipients in hesitancy group were hesitant to get vaccinated, while the remaining 104 (34.8%) refused. The most common side effect was injection arm pain (n = 9, 12.3%). The common reasons for vaccine willingness was trusted in the effectiveness of the vaccine and fear of contracting COVID-19. The most common reason for vaccination hesitancy is fear of side effects, and the most effective improvement was the support from the attending physician. Factors associated with vaccine hesitancy include female sex, influenza vaccination status, awareness of the importance and safety of vaccine, attitudes of doctors and others toward vaccine, medical worker source information of vaccine, relative/friend with medical background, total score of VHS (Vaccine Hesitancy Scale), accessibility of vaccine. Conclusion: For liver transplant recipients, COVID-19 vaccine is an important preventive measure. Identifying the factors influencing COVID-19 vaccine hesitancy is therefore critical to developing a promotion plan. Our study shows that more comprehensive vaccine knowledge popularization and relevant medical workers' training can effectively improve the acceptance of COVID-19 vaccine in this population.

Matrine treatment induced an A2 astrocyte phenotype and protected the blood-brain barrier in CNS autoimmunity.

Type 1 astrocytes (A1), which are highly proinflammatory and neurotoxic, are prevalent in multiple sclerosis (MS). In addition, in MS and its animal model, experimental autoimmune encephalomyelitis (EAE), immune cells must cross the blood-brain barrier (BBB) and infiltrate into the parenchyma of the central nervous system (CNS) in order to induce neurological deficits. We have previously reported that treatment of EAE with matrine (MAT), a quinazine alkaloid derived from Sophorae Flavescens, effectively inhibited CNS inflammation and promoted neuroregeneration. However, the impact of MAT treatment on astrocyte phenotype is not known. In the present study, we showed that MAT treatment inhibited the generation of neurotoxic A1 astrocytes and promoted neuroprotective A2 astrocytes in the CNS of EAE, most likely by inhibiting production of the A1-inducing cytokine cocktail. MAT also downregulated the expression of vascular endothelial growth factor-A (VEGF-A) and upregulated tight junction proteins Claudin 5 and Occludin, thus protecting the BBB from CNS inflammation-induced damage. Moreover, MAT treatment promotes the formation of astrocyte tight junctions at glia limitans, thereby limiting parenchymal invasion of the CNS by immune cells. Taken together, the inhibition of A1 astrogliogenesis, and the dual effects on the BBB and astrocytic glia limitans, may be the mechanisms whereby MAT significantly improves EAE clinical scores and neuroprotection.

Illumination of Molecular Pathways in Multiple Sclerosis Lesions and the Immune Mechanism of Matrine Treatment in EAE, a Mouse Model of MS.

The etiology of multiple sclerosis (MS) is not clear, and the treatment of MS presents a great challenge. This study aimed to investigate the pathogenesis and potential therapeutic targets of MS and to define target genes of matrine, a quinolizidine alkaloid component derived from the root of Sophorae flavescens that effectively suppressed experimental autoimmune encephalomyelitis (EAE), an animal model of MS. To this end, the GSE108000 gene data set in the Gene Expression Omnibus Database, which included 7 chronic active MS lesions and 10 control samples of white matter, was analyzed for differentially expressed genes (DEGs). X cell was used to analyze the microenvironmental differences in brain tissue samples of MS patients, including 64 types of immune cells and stromal cells. The biological functions and enriched signaling pathways of DEGs were analyzed by multiple approaches, including GO, KEGG, GSEA, and GSVA. The results by X cell showed significantly increased numbers of immune cell populations in the MS lesions, with decreased erythrocytes, megakaryocytes, adipocytes, keratinocytes, endothelial cells, Th1 cells and Tregs. In GSE108000, there were 637 DEGs, including 428 up-regulated and 209 down-regulated genes. Potential target genes of matrine were then predicted by the network pharmacology method of Traditional Chinese medicine, and 12 key genes were obtained by cross analysis of the target genes of matrine and DEGs in MS lesions. Finally, we confirmed by RT-PCR the predicted expression of these genes in brain tissues of matrine-treated EAE mice. Among these genes, 2 were significantly downregulated and 6 upregulated by matrine treatment, and the significance of this gene regulation was further investigated. In conclusion, our study defined several possible matrine target genes, which can be further elucidated as mechanism(s) of matrine action, and novel targets in the treatment of MS.

Modulation of the HMGB1/TLR4/NF-κB signaling pathway in the CNS by matrine in experimental autoimmune encephalomyelitis.

The inflammatory mediator high-mobility group box 1 (HMGB1)-induced signaling pathway has been shown to play an important role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Matrine (MAT), a quinolizidine alkaloid component derived from the root of Sophorae flavescens, has the capacity to effectively suppress EAE. However, the impact of MAT treatment on HMGB1-induced signaling is not known. In the present study, we show that MAT treatment alleviated disease severity of ongoing EAE, reduced inflammatory infiltration and demyelination, and reduced the production of inflammatory factors including TNF-α, IL-6, and IL-1ß in the CNS. Moreover, MAT administration significantly reduced the protein and RNA expression of HMGB1 and TLR4 in the spinal cord, particularly in astrocytes and microglia/infiltrating macrophages. The expression of MyD88 and TRAF6, and the phosphorylation of NF-κB p65, was also down-regulated after MAT treatment. In contrast, the level of IκB-α, an inhibitory molecule for NF-κB activation, was significantly increased. Furthermore, the direct inhibitory effect of MAT on HMGB1/TLR4/NF-κB signaling in macrophages was further confirmed in vitro. Taken together, these findings demonstrate that MAT treatment alleviated CNS inflammatory demyelination and activation of astrocytes and microglia/macrophages in EAE rats, and that the mechanism underlying these effects may be closely related to modulation of HMGB1/TLR4/NF-κB signaling pathway.

Matrine protects oligodendrocytes by inhibiting their apoptosis and enhancing mitochondrial autophagy.

Stressed oligodendrocytes (OLGs) activate microglia to produce an inflammatory response, and the impairment of mitochondria further aggravates OLG damage, which is the earliest pathological change in multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system. Matrine (MAT), a tetracyclic quinolizine alkaloid derived from the herb radix sophorae flavescentis, has been shown to effectively ameliorate clinical signs of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. However, the mechanisms underlying the effect of MAT treatment need to be further studied. In the present study, we show that MAT effectively suppressed ongoing EAE, and significantly reduced the expression of caspase-3 and alpha B-crystallin in OLGs, therefore lessen OLG apoptosis, microglial activation and inflammatory factors secretion. MAT treatment also reduced the content of cytochrome c and malondialdehyde, an oxidative stress marker, in the central nervous system. In contrast, the levels of autophagy-related proteins Beclin1, microtubule-associated protein l light chain 3 and glutathione peroxidase was upregulated, hence enhancing mitochondrial autophagy and alleviating the imbalance of the oxidation/antioxidation system caused by mitochondrial damage. Our research indicates that MAT is effective in treating EAE, at least in part, by protecting OLGs through inhibiting their apoptosis and enhancing mitochondrial autophagy.