Qinzhi Zhudan formula improves memory and alleviates neuroinflammation in vascular dementia rats partly by inhibiting the TNFR1-mediated TNF pathway

Objective: The Qinzhi Zhudan formula(QZZD) exhibits a prominent therapeutic effect in the treatment of vascular dementia(VaD). This study combined a network pharmacology approach and experimental validation to identify the underlying biological mechanism of QZZD against VaD.Methods: Male Wistar rats received bilateral common carotid artery occlusion(BCCAO) surgery, and after4 weeks of intragastric administration of QZZD, the therapeutic effect was assessed using the Morris water maze test and cerebral blood flow(CBF) assessment. Hematoxylin and eosin staining, Nissl staining, and electron microscopy were used to measure the histopathological changes in the neurons of rats. The effect of QZZD treatment on hippocampal neurotransmitters was assessed by high-performance liquid chromatography with electrochemical detection and liquid chromatography mass spectrometry.Immunofluorescence was used to observe VaD-induced microglia activation. The inflammatory cytokine levels were assessed by enzyme linked immunosorbent assay. Western blot was used to examine the TNFR1-mediated TNF pathway, which was screened out by network pharmacology analysis.Results: QZZD treatment alleviated pathological changes and neuronal damage in VaD rats and attenuated their cognitive impairment. In addition, QZZD increased CBF and the expression of acetylcholine and 5-hydroxytryptamine in the hippocampal region. Notably, QZZD inhibited microglial activation and the expression of IL-6 and TNF-a. Network pharmacology and western blot indicated that QZZD inhibited the levels of TNFR1, NF-κBp65, p-ERK, TNF-a, and IL-6, which are related to the TNFR1-mediated TNF signaling pathway.Conclusion: QZZD clearly improved learning and memory function, reduced brain pathological damage,elevated CBF and hippocampal neurotransmitter levels, and alleviated neuroinflammation of VaD rats partly by inhibiting the TNFR1-mediated TNF pathway, indicating its potential value in the clinical therapy of VaD.

High-throughput RNA sequencing reveals the anti-inflammatory mechanism of baicalin on Propionibacterium acnes-induced acne in rabbits

Objective:Propionibacterium acnes(P.acnes)plays an important role in the development of acne,an inflammatory skin disease with a high-incidence.In this study,we used high-throughput RNA sequencing(RNA-seq)to reveal the anti-inflammatory mechanism of baicalin on P.acnes-induced acne in rabbits.Methods:The Kligman method was used to induce acne in the ears of New Zealand rabbits.The effect of baicalin on the acne model was evaluated by the number of acne lesions and hematoxylin and eosin(H&E)staining of acne tissues.Enzyme-linked immunoabsorbent assay was used to measure the protein expression levels of tumor necrosis factor a(TNFA),interleukin-1 b(IL1B),IL6,and IL8 in the serum of rabbits.RNA-seq was performed to investigate the mechanism of anti-inflammatory activities of baicalin on acne.Immunohistochemical analysis and Western blot were used to validate the expression levels of related proteins in acne tissues.Results:Baicalin treatment significantly reduced the number of acne lesions and lesions of the ear as well as levels of serum inflammatory cytokines.RNA-seq data showed that baicalin treatment globally suppressed inflammation,especially the TNF signaling pathway and Staphylococcus aureus infection pathway,in the rabbit acne model.Conclusion: Baicalin effectively ameliorates P. acnes-induced acne in rabbits by suppressingthe inflammatory response in rabbits.

Study on possible synergistic anticancer cachexia effects of the main active compounds of Radix Sophorae flavescentis

Background:Cancer cachexia is a complex disease secondary to cancer,and no specific therapy for it has been found.The Chinese herb Kushen(Radix Sophorae flavescentis)is the dried root of Sophora flavescens Aiton,which has been widely applied in treating digestive and urinary inflammatory diseases.Matrine,one of the main components of Radix Sophorae flavescentis,can alleviate cancer cachexia.Methods:Compounds from Radix Sophorae flavescentis were screened using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform.The targets related to cancer cachexia were queried from the Therapeutic Target Database(http://db.idrblab.net),DisGeNET database(http://www.disgenet.org),and Search Tool for Interacting Chemicals database,related literature,and constructed cancer cachexia-protein network.Cancer cachexia-protein network was merged with compound-protein networks respectively using Cytoscape software as well as network topology data and key targets counting.Pathway enrichment analysis was conducted via the Database for Functional Annotation Bioinformatics Microarray Analysis.Protein crystal structures and compound structures were queried from RCSB and PubChem databases,respectively.Molecular docking was conducted using Discovery Studio software.Results:The anticancer cachexia compounds of Radix Sophorae flavescentis were screened as oxymatrine,matrine,and kurarinol,and targets such as BIRC2,TNF and STAT3 were found.The mechanisms of oxymatrine,matrine,and kurarinol have the characteristics of synergy and complementarity.Kurarinol has a mechanism similar to that of matrine,which includes the FoxO signaling pathway,insulin resistance and mTOR signaling pathway.TNF signaling pathway is a common signaling pathway of kurarinol,oxymatrine and matrine.Adipocytokine signaling pathway is the other common pathway of kurarinol and oxymatrine except for the TNF signaling pathway.Kurarinol can be successfully docked with CYCS,GPX2,BIRC7,etc.,and kushenol C can be successfully docked with IKBKB and PIK3CD.Conclusion:Kurarinol,matrine,oxymatrine,and kushenol C may be the key compounds of Radix Sophorae flavescentis treating cancer cachexia.Additionally,TNF signaling pathway is the key pathway for the synergistic action of kurarinol,matrine and oxymatrine.

Differences and similarities between mesenchymal stem cell and endothelial progenitor cell immunoregulatory properties against T cells

Bone-marrow-derived mesenchymal stem cells and endothelial progenitor cells have some interesting biological properties that make them unique for cell therapy of degenerative and cardiovascular disorders.Although both cell populations have been already studied and used for their regenerative potentials,recently their special immunoregulatory features have brought much more attention.Mesenchymal stem cells and endothelial progenitor cells have both proangiogenic functions and have been shown to suppress the immune response,particularly T cell proliferation,activation,and cytokine production.This makes them suitable choices for allogeneic stem cell transplantation.Nevertheless,these two cells do not have equal immunoregulatory activities.Many elements including their extraction sources,age/passage,expression of different markers,secretion of bioactive mediators,and some others could change the efficiency of their immunosuppressive function.However,to our knowledge,no publication has yet compared mesenchymal stem cells and endothelial progenitor cells for their immunological interaction with T cells.This review aims to specifically compare the immunoregulatory effect of these two populations including their T cell suppression,deactivation,cytokine production,and regulatory T cells induction capacities.Moreover,it evaluates the implications of the tumor necrosis factor alpha-tumor necrosis factor receptor 2 axis as an emerging immune checkpoint signaling pathway controlling most of their immunological properties.

Transcriptome sequencing and metabolome analysis reveal the mechanism of Shuanghua Baihe Tablet in the treatment of oral mucositis

Oral mucositis(OM) caused by cancer therapy is the most common adverse reaction in the radiotherapy of head and neck tumors. In severe cases, it can lead to the interruption of treatment, which affects the control of the disease and the quality of life.Shuanghua Baihe Tablet(SBT) is a traditional Chinese medicine(TCM) formula, which is administerd to treat OM in China. It has been clinically effective for more than 30 years, but the underlying mechanism is not completely understood. With the development of multiple omics, it is possible to explore the mechanism of Chinese herbal compound prescriptions. Based on transcriptomics and metabolomics, we explored the underlying mechanism of SBT in the treatment of OM. An OM model of rats was established by 5-FU induction, and SBT was orally administered at dosages of 0.75 and 3 g·kg;·d;. In order to search for SBT targets and related metabolites, the dysregulated genes and metabolites were detected by transcriptomics and metabolomics. Immune related indicators such as interleukin-17(IL-17) and tumor necrosis factor-α(TNF-α) were detected by ELISA. Treg cell disorders was analyzed by flow cytometry. Our results showed that SBT significantly alleviated the symptoms of OM rats and the inflammatory infiltration of ulcer tissues.After SBT administration, inflammatory related metabolic pathways including linoleic acid metabolism, valine, leucine and isoleucine biosynthesis were significantly altered. Furthermore, the production of proinflammatory factors like IL-17 and TNF-α, were also dramatically reduced after SBT administration. Besides, the infiltration degree of Treg cells in the spleen of OM modeling rats was significantly improved by SBT administration, thus maintaining the immune balance of the body. The current study demonstrates that SBT regulates inoleic acid metabolism, glycerophospholipid metabolism and amino acid metabolism, and inhibits IL-17/TNF signal transduction to restore Treg and Th17 cell homeostasis in OM rats, thereby alleviating chemotherapy-induced OM.