Xanthones from Securidaca inappendiculata Hassk. attenuate collagen-induced arthritis in rats by inhibiting the nicotinamide phosphoribosyltransferase/glycolysis pathway and macrophage polarization.

Securidaca inappendiculata (SI) Hassk. is a traditional medicine used to treat rheumatoid arthritis. Recent studies have reported that macrophages are the primary regulators of joint homeostasis and their polarization is closely related to their metabolic mode. Here, we aimed to investigate the relationship between the joint protective effect of SI's xanthone-rich fraction (XRF) on collagen-induced arthritis (CIA) in rats and the nicotinamide phosphoribosyltransferase (NAMPT)-glycolysis-polarization axis of macrophages. CIA model rats were treated with oral XRF and therapeutic efficacy was assessed based on arthritis score, degree of paw swelling, histological examination, and immunohistochemical analysis. Serum levels of cytokines, cellular metabolite concentrations, and protein and mRNA expression were determined by enzyme-linked immunosorbent assay (ELISA), western blotting (WB), and quantitative real-time PCR (RT-qPCR), respectively. The effects of dihydroxy-3,4-dimethoxyxanthone (XAN), a representative SI-derived compound, on RAW264.7 macrophages was analyzed in vitro using confocal laser scanning and flow cytometry. We found that XRF treatment significantly alleviated disease severity in CIA model rats. Levels of pro-inflammatory cytokines in the serum and M1 markers in synovium were reduced after XRF treatment, accompanied by an increase in the levels of anti-inflammatory cytokines and M2 markers. Further, XRF significantly suppressed synovial glycolysis by regulating NAMPT. In vitro studies further showed that XAN induced repolarization of lipopolysaccharide (LPS)-induced RAW264.7 macrophages with M1-M2 phenotype. Moreover, XAN negatively regulated glycolysis in the LPS-induced RAW264.7 macrophages in correlation with changes in NAMPT expression. Overall, the findings of this study suggest that the joint protective effects of XRF are achieved by inhibiting the NAMPT/glycolysis pathway and thereby regulating macrophage polarization.

Polyphenols from Securidaca inappendiculata alleviated acute lung injury in rats by inhibiting oxidative stress sensitive pathways.

Objective: Securidaca inappendiculata is a medicinal plant frequently used in the treatment of inflammatory diseases in south China. In this study, we aimed to explore its bioactive constituent which contributes to the anti-inflammatory activity. Methods: Polyphenol-enriched and polyphenol-deprived fractions (PRF and PDF, respectively) were separated from the ethanolic extract by HPD300 macroporous resin-based method, and their anti-inflammatory activities were investigated on a lipopolysaccharide (LPS)-induced acute lung injury (ALI) model in rats. The possible mechanism of action in alleviating acute inflammation was studied using RAW264.7 cells. Results: Both Folin-Ciocalteu and 1H nuclear magnetic resonance (NMR) analyses showed that polyphenolic content in PRF was approximately 10 times higher than that of PDF, and this observation reflected in their antioxidative capacities. PRF but not PDF significantly decreased the level of malondialdehyde, suppressed the expression of nicotinamide phosphoribosyltransferase (NAMPT) protein, and improved the severity of ALI in rats. PRF at 10 µg/mL effectively downregulated the expression of proteins NAMPT, HMGB1, TLR4, and p-p65, and scavenged the intracellular reactive oxygen species (ROS) in LPS-primed RAW264.7 cells. N-acetyl-L-cysteine exhibited similar inhibitory effects on ROS production and NAMPT-mediated TLR4/NF-κB activation in vitro, whereas nicotinamide mononucleotide antagonized all the changes induced by PRF during cotreatments. Conclusion: As an antioxidant, PRF exhibited potent anti-inflammatory activity under both in vivo and in vitro conditions by downregulating NAMPT and TLR4/NF-κB. Accordingly, polyphenols were identified as important bioactive constituents in S. inappendiculata targeting oxidative stress-sensitive pro-inflammatory pathways.

Polyphenols from Securidaca inappendiculata alleviated acute lung injury in rats by inhibiting oxidative stress sensitive pathways / 中草药·英文版

Objective: Securidaca inappendiculata is a medicinal plant frequently used in the treatment of inflammatory diseases in south China. In this study, we aimed to explore its bioactive constituent which contributes to the anti-inflammatory activity. Methods: Polyphenol-enriched and polyphenol-deprived fractions (PRF and PDF, respectively) were separated from the ethanolic extract by HPD300 macroporous resin-based method, and their anti-inflammatory activities were investigated on a lipopolysaccharide (LPS)-induced acute lung injury (ALI) model in rats. The possible mechanism of action in alleviating acute inflammation was studied using RAW264.7 cells. Results: Both Folin-Ciocalteu and

Chemical constituents from the stems of Securidaca inappendiculata Hassk.

Three new neolignan glycosides, (7R,8S)-4-hydroxy-3,3'-dimethoxy-8,4'-oxyneoligna-7,9,9'-triol-4-O-ß-d-glucopyranosyl-(1 → 4)-ß-D-glucopyranoside (1), (7R,8S)-4-hydroxy-3,5'-dimethoxy-4',7-epoxy-8,3'-neoligna-9,9'-diol-9'-O-ß-d-glucopyranosyl-4-O-[ß-d-glucopyranosyl-(1 → 4)]-ß-D-glucopyranoside (2), and (7R,8S)-4-hydroxy-3,5,5'-trimethoxy-4',7-epoxy-8,3'-neoligna-9,9'-diol-9'-O-ß-d-glucopyranosyl-4-O-[ß-d-glucopyranosyl-(1 → 4)]-ß-D-glucopyranoside (3), one new phenolic glycoside, securiphenoside B (4) and two new hemiterpene glycosides, securiterpenoside E-F (5-6) were isolated from the stems of Securidaca inappendiculata Hassk. Their structures were elucidated on the basis of 1D and 2D NMR, HRESIMS, CD and chemical evidence. Furthermore, compound 2 showed moderate hepatoprotective activity compared with bicyclol in vitro.

A new hemiterpene glycoside from rhizomes of Securidaca inappendiculata / 中草药

Objective To study the chemical constituents from the rhizomes of Securidaca inappendiculata. Methods The concrete exacted by 95% EtOH from the rhizomes of S. inappendiculata was isolated and purified by chromatography on macroporous resin, silica gel, MPLC, gel, preparative HPLC, etc. The structures of the chemical constituents were elucidated by means of physicochemical properties and spectroscopic analysis. Results Five compounds were isolated and identified as 2- methylene-butanoic acid 4-O-[(β-D-glucopyranosyl)oxy]-intramol-1,6’-ester (1), 3-methoxyl-4-O-β-D-glucopyranosyloxy-benzoic acid methyl ester (2), threo-4,7,9,9’-tetrahydroxy-3,3’-dimethoxy-8-O-4’-neolignan-4-O-β-D-glucopyranoside (3), eucomegastigside A (4), and acernikol-4″-O-β-D-glucopyranoside (5). Conclusion Compound 1 is a new hemiterpene glycoside named securiterpenoside D, and compounds 2-4 are isolated from Polygalaceae for the first time.

Reactive oxygen species mediated NF-κB/p38 feedback loop implicated in proliferation inhibition of HFLS-RA cells induced by 1,7-dihydroxy-3,4-dimethoxyxanthone.

1,7-Dihydroxy-3,4-dimethoxyxanthone (XAN) is a bioactive compound isolated from Securidaca inappendiculata Hassk. and exerts the inhibitory effects on fibroblast-like synoviocytes by targeting NF-κB and p38. This study was designed to elucidate mechanisms underlying the divergent regulation on the two pathways in HFLS-RA cells by XAN. Expressions of hallmark proteins and transcription of GADD45α mRNA were determined by Western-blot and RT-qPCR methods, respectively. Fluorescence staining was employed to evaluate intracellular oxidative stress. Effects of XAN and N-acetyl-l-cysteine (NAC) on the proliferation of cells were investigated by MTT assay, and pro-apoptotic effects of XAN were assessed by Annexin V-FITC/PI method. It was found XAN blocked NF-κB signaling in HFLS-RA cells shortly after treatment. Moreover, it up-regulated both transcription and expression of GADD45α, and subsequently activated p38 pathway. As time went on, XAN significantly promoted the generation of reactive oxygen species (ROS), which accompanied with sustained up-regulation of p-p38 and increased apoptosis. 48H later, dual-effects of XAN on NF-κB and p38 were reversed. As activation of p38 and increased apoptosis induced by XAN were antagonized by NAC, they were deemed as ROS mediated effects. Furthermore, the accumulated ROS should also account for the activation of NF-κB in the late stage of treatments via interfering in p38/MSK1/NF-κB feedback. Altogether, these findings suggested XAN-induced ROS contributed great importance to the proliferation inhibition of HFLS-RA cells by mediating NF-κB/p38 feedback loop and apoptosis, which provided us a panoramic view of potential target in the therapy of RA by XAN.

Chemical constituents from Securidaca inappendiculata / 中成药

AIM To study the chemical constituents from Securidaca inappendiculata Hassk..METHODS The dichloromethane and ethyl acetate fractions of S.inappendiculata 95％ ethanol extract were isolated and purified by silica,gel column and recrystallization,then the structures of obtained compounds were identified by physicochemical properties and spectral data.RESULTS Ten compounds were isolated and identified as 8-hydroxy-1,3,4-trimethoxyxanthone (1),1,2,7-trimethoxyxanth-one (2),4-hydroxy-3,5-dimethoxybenzaldehyde (3),sesamin (4),2-methoxy-3,4-methylenedioxybenzophenone (5),1,3,7-trihydroxy-4-methoxyxanthone (6),1,3,7-t-rihydroxy-2-methoxyxanthone (7),2-hydroxy-1,7-dimethoxyxanthone (8),3,8-dih-ydroxy-1,4-dimethoxyxanthone (9),oα-spinasterol (10).CONCLUSION Compound 1 is first found in the form of natural product,compounds 2-4 are isolated from genus Securidaca for the first time.

Chemical constituents of Securidaca inappendiculata Ⅱ / 中草药

Object To investigate the chemical constituents of Securidaca inappendiculata Hassk Methods Compounds of 95% alcohol extract from the stem of S inappendiculata were isolated by column chromatography and Medium Pressure Liquid Chromatography, respectively The structures of the compounds were elucidated by chemical and spectral (UV, IR, MS, 1HNMR adn 13 CNMR) analyses Results Six compounds were isolated and identified as: 4, 4′ dimethyl 1, 7 heptanedioic acid (Ⅰ), inositol (Ⅱ), stigmasterol (Ⅲ), vittadinoside (Ⅳ), rhamnose (Ⅴ), sucrose (Ⅵ) Conclusion For the first time, compound Ⅰ was obtained from the plant and other compounds were isolated from Securidaca Mill