Calycosin,Astragali Radix most prominent ingredient,has drawn more attention as a result of its ability to treat atherosclerosis(AS).However,the mechanism of action has not been fully elucidated.We investigated the ef...Calycosin,Astragali Radix most prominent ingredient,has drawn more attention as a result of its ability to treat atherosclerosis(AS).However,the mechanism of action has not been fully elucidated.We investigated the effects of calycosin on bile acid(BA)metabolism and gut microbiome in ApoE^(-/-)mice fed a high-fat diet(HFD).The data showed that the aorta of ApoE^(-/-)mice treated with HFD showed significant atheromatous plaque formation and lipid accumulation,and the levels of total cholesterol(TC),triglycerides(TG)and low-density lipoprotein cholesterol(LDL-C)were significantly increased,while the levels of high-density lipoprotein cholesterol(HDL-C)were significantly decreased.Calycosin can substantially regulate lipid levels,thereby alleviating liver lipid deposition induced by atherosclerosis.In addition,16S rRNA sequencing showed that calycosin treatment has reshaped the gut microbiota disturbed by HFD,in particular,increasing the ratio of Bacteroidetes/Firmicutes,and improving the relative abundance of Bilophila,Desulfovibrio,Bacteroides,Lactobacillus,etc.Meanwhile,targeted metabolomics analysis showed that calycosin treatment significantly modulated glycodeoxycholic acid(CDCA),taurocholic acids(TCA),lithocholic acid(LCA),deoxycholic acid(DCA),taurodeoxycholic acid(TDCA)and BA pool composition,which were associated with atherosclerotic plaque areas.In addition,calycosin treatment also down-regulated farnesoid X receptor(FXR)protein levels and up-regulated cytochrome P450 family 7 subfamily A member 1(CYP7A1)protein levels in the hepatic.At the same time,calycosin inhibits the ileum FXR/TGR5 signaling pathway,inhibits BA reabsorption,promotes BA excretion,and reduces hepatic cholesterol accumulation by enterohepatic circulation.In addition,we found that calycosin significantly promoted the expression of hepatic ATP-binding cassette transporter A1(ABCA1)and ABCG1 to mediate cholesterol efflux.Meanwhile,calycosin regulates gut microbiota,and Bacteroides,Alistipes,Desulfovibrio,Lactobacillus,Bilophila and Odoribacter are closely related to specific BAs.This enables us to further understand the relationship between BA metabolism and gut microbiota.Calycosin may reduce high-fat diet-induced hepatic cholesterol accumulation in ApoE^(-/-)mice through gut microbiota and BA metabolism,and play a role in treating AS.Finally,we confirmed that calycosin-altered gut microbiota by fecal microbiota transplantation was sufficient to alleviate atherosclerosis.Taken together,our findings provide important insights into the pharmacological mechanisms underlying the efficacy of calycosin on atherosclerosis.展开更多
The major pathological changes in Alzheimer＇s disease are beta amyloid deposits and cognitive impairment. Calycosin is a typical phy- toestrogen derived from radix astragali that binds to estrogen receptors to produc...The major pathological changes in Alzheimer＇s disease are beta amyloid deposits and cognitive impairment. Calycosin is a typical phy- toestrogen derived from radix astragali that binds to estrogen receptors to produce estrogen-like effects. Radix astragali Calycosin has been shown to relieve cognitive impairment induced by diabetes mellitus, suggesting calycosin may improve the cognitive function of Alzhei- mer＇s disease patients. The protein kinase C pathway is upstream of the mitogen-activated protein kinase pathway and exerts a neuropro- tective effect by regulating Alzheimer＇s disease-related beta amyloid degradation. We hypothesized that calycosin improves the cognitive function of a transgenic mouse model of Alzheimer＇s disease by activating the protein kinase C pathway. Various doses of calycosin （10, 20 and 40 mg/kg） were intraperitoneally injected into APP/PS1 transgenic mice that model Alzheimer＇s disease. Calycosin diminished hippocampal beta amyloid, Tau protein, interleukin-lbeta, tumor necrosis factor-alpha, acetylcholinesterase and malondialdehyde levels in a dose-dependent manner, and increased acetylcholine and glutathione activities. The administration of a protein kinase C inhibitor, cal- phostin C, abolished the neuroprotective effects of calycosin including improving cognitive ability, and anti-oxidative and anti-inflammato- ry effects. Our data demonstrated that calycosin mitigated oxidative stress and inflammatory responses in the hippocampus of Alzheimer＇s disease model mice by activating the protein kinase C pathway, and thereby improving cognitive function.展开更多
Cardiovascular disease is the main cause of mortality and morbidity in the world,especially in developing countries.Drug therapy is one of the main ways to treat cardiovascular diseases.Among them,great progress has b...Cardiovascular disease is the main cause of mortality and morbidity in the world,especially in developing countries.Drug therapy is one of the main ways to treat cardiovascular diseases.Among them,great progress has been made in the treatment of cardiovascular diseases with traditional Chinese medicine.In terms of experimental research,the mechanism of traditional Chinese medicine in the treatment of cardiovascular diseases has been thoroughly discussed in vitro and in vivo.In terms of clinical treatment,traditional Chinese medicine with flavonoids,saponins and alkaloids as the main effective components has a definite effect on the treatment of cardiovascular diseases such as arrhythmia,myocardial ischemia,angina pectoris and myocardial infarction,with high safety and good application prospects.With the further research on the effective ingredients,mechanism and adverse reactions of traditional Chinese medicine,it will be beneficial to the effectiveness of traditional Chinese medicine,reduce side effects and promote the modernization of traditional Chinese medicine.Calycosin and its derivatives,the main bioactive flavonoids in Astragalus membranaceus have multiple biological effects,such as antioxidant,pro-angiogenesis,anti-tumour,and anti-inflammatory effects.Based on the above biological effects,calycosin has been shown to have good potential for cardiovascular protection.The potent antioxidant effect of calycosin may play an important role in the cardiovascular protective potential.For injured cardiac myocytes,calycosin and its derivatives can alleviate the cell damage mainly marked by the release of myocardial enzymes and reduce the death level of cardiac myocytes mainly characterized by apoptosis through various mechanisms.For vascular endothelial cells,calycosin also has multiple effects and multiple mechanisms,such as promoting vascular endothelial cell proliferation,exerting vasodilating effect and directly affecting the synthesis function of endothelial cells.The present review will address the bioactivity of calycosin in cardiovascular diseases such as protective effects on cardiac myocytes and vascular endothelial cells and elucidate main mechanism of calycosin and its derivatives to exert the above biological effects.展开更多
BACKGROUND Acute lung injury(ALI)is a common and life-threatening complication of severe acute pancreatitis(SAP).There are currently limited effective treatment options for SAP and associated ALI.Calycosin(Cal),a bioa...BACKGROUND Acute lung injury(ALI)is a common and life-threatening complication of severe acute pancreatitis(SAP).There are currently limited effective treatment options for SAP and associated ALI.Calycosin(Cal),a bioactive constituent extracted from the medicinal herb Radix Astragali exhibits potent anti-inflammatory properties,but its effect on SAP and associated ALI has yet to be determined.AIM To identify the roles of Cal in SAP-ALI and the underlying mechanism.METHODS SAP was induced via two intraperitoneal injections of L-arg(4 g/kg)and Cal(25 or 50 mg/kg)were injected 1 h prior to the first L-arg challenge.Mice were sacrificed 72 h after the induction of SAP and associated ALI was examined histologically and biochemically.An in vitro model of lipopolysaccharide(LPS)-induced ALI was established using A549 cells.Immunofluorescence analysis and western blot were evaluated in cells.Molecular docking analyses were conducted to examine the interaction of Cal with HMGB1.RESULTS Cal treatment substantially reduced the serum amylase levels and alleviated histopathological injury associated with SAP and ALI.Neutrophil infiltration and lung tissue levels of neutrophil mediator myeloperoxidase were reduced in line with protective effects of Cal against ALI in SAP.Cal treatment also attenuated the serum levels and mRNA expression of pro-inflammatory cytokines tumor necrosis factor-α,interleukin-6,IL-1β,HMGB1 and chemokine(CXC motif)ligand 1 in lung tissue.Immunofluorescence and western blot analyses showed that Cal treatment markedly suppressed the expression of HMGB1 and phosphorylated nuclear factor-kappa B(NF-κB)p65 in lung tissues and an in vitro model of LPSinduced ALI in A549 cells suggesting a role for HGMB1 in the pathogenesis of ALI.Furthermore,molecular docking analysis provided evidence for the direct interaction of Cal with HGMB1.CONCLUSION Cal protects mice against L-arg-induced SAP and associated ALI by attenuating local and systemic neutrophil infiltration and inflammatory response via inhibition of HGMB1 and the NF-κB signaling pathway.展开更多
Calycosin is an important isoflavone compound in traditional Chinese medicine Astragali Radix.It not only has remarkable anti-oxidation,anti-inflammatory and anti-tumor functions,but also has the characteristics of sm...Calycosin is an important isoflavone compound in traditional Chinese medicine Astragali Radix.It not only has remarkable anti-oxidation,anti-inflammatory and anti-tumor functions,but also has the characteristics of small adverse reactions and low toxicity,so it has attracted wide attention of scholars and researchers.This paper reviewed the pharmacological effects and mechanisms of calycosin in recent years,in the hope of providing a theoretical basis for its clinical application.展开更多
BACKGROUND Bone marrow-derived mesenchymal stem cells(MSCs)show podocyte-protective effects in chronic kidney disease.Calycosin(CA),a phytoestrogen,is isolated from Astragalus membranaceus with a kidney-tonifying effe...BACKGROUND Bone marrow-derived mesenchymal stem cells(MSCs)show podocyte-protective effects in chronic kidney disease.Calycosin(CA),a phytoestrogen,is isolated from Astragalus membranaceus with a kidney-tonifying effect.CA preconditioning enhances the protective effect of MSCs against renal fibrosis in mice with unilateral ureteral occlusion.However,the protective effect and underlying mechanism of CA-pretreated MSCs(MSCsCA)on podocytes in adriamycin(ADR)-induced focal segmental glomerulosclerosis(FSGS)mice remain unclear.AIM To investigate whether CA enhances the role of MSCs in protecting against podocyte injury induced by ADR and the possible mechanism involved.METHODS ADR was used to induce FSGS in mice,and MSCs,CA,or MSCsCA were administered to mice.Their protective effect and possible mechanism of action on podocytes were observed by Western blot,immunohistochemistry,immunofluorescence,and real-time polymerase chain reaction.In vitro,ADR was used to stimulate mouse podocytes(MPC5)to induce injury,and the supernatants from MSC-,CA-,or MSCsCA-treated cells were collected to observe their protective effects on podocytes.Subsequently,the apoptosis of podocytes was detected in vivo and in vitro by Western blot,TUNEL assay,and immunofluorescence.Overexpression of Smad3,which is involved in apoptosis,was then induced to evaluate whether the MSCsCA-mediated podocyte protective effect is associated with Smad3 inhibition in MPC5 cells.RESULTS CA-pretreated MSCs enhanced the protective effect of MSCs against podocyte injury and the ability to inhibit podocyte apoptosis in ADR-induced FSGS mice and MPC5 cells.Expression of p-Smad3 was upregulated in mice with ADR-induced FSGS and MPC5 cells,which was reversed by MSCCA treatment more significantly than by MSCs or CA alone.When Smad3 was overexpressed in MPC5 cells,MSCsCA could not fulfill their potential to inhibit podocyte apoptosis.CONCLUSION MSCsCA enhance the protection of MSCs against ADR-induced podocyte apoptosis.The underlying mechanism may be related to MSCsCA-targeted inhibition of p-Smad3 in podocytes.展开更多
The iso fl avone calycosin-7-O-β-D-glucopyranoside(CG) is a principal constituent of Astragalus membranaceus(AR) and has been reported to inhibit osteoclast development in vitro and bone loss in vivo. The aim of this...The iso fl avone calycosin-7-O-β-D-glucopyranoside(CG) is a principal constituent of Astragalus membranaceus(AR) and has been reported to inhibit osteoclast development in vitro and bone loss in vivo. The aim of this study was to investigate the osteogenic effects of CG and its underlying mechanism in ST2 cells. The results show that exposure of cells to CG in osteogenic differentiation medium increases ALP activity, osteocalcin(Ocal) m RNA expression and the osteoblastic mineralization process. Mechanistically, CG treatment increased the expression of bone morphogenetic protein 2(BMP-2), p-Smad 1/5/8, β-catenin and Runx2, all of which are regulators of the BMP- or wingless-type MMTV integration site family(WNT)/β-catenin-signaling pathways. Moreover, the osteogenic effects of CG were inhibited by Noggin and DKK-1 which are classical inhibitors of the BMP and WNT/β-catenin-signaling pathways, respectively. Taken together, the results indicate that CG promotes the osteoblastic differentiation of ST2 cells through regulating the BMP/WNT signaling pathways. On this basis, CG may be a useful lead compound for improving the treatment of bone-decreasing diseases and enhancing bone regeneration.展开更多
目的基于中药超分子(supramolecules of traditional Chinese medicine,STCM)理论,系统探讨黄芪Astragali Radix-莪术Curcumae Rhizoma(AC)药对协同增效抗肝癌的物质基础,旨在揭示其配伍的科学内涵。方法采用离心-透析法对STCM进行分离...目的基于中药超分子(supramolecules of traditional Chinese medicine,STCM)理论,系统探讨黄芪Astragali Radix-莪术Curcumae Rhizoma(AC)药对协同增效抗肝癌的物质基础,旨在揭示其配伍的科学内涵。方法采用离心-透析法对STCM进行分离;并借助动态光散射(dynamic light scattering,DLS)技术和透射电子显微镜(transmission electron microscope,TEM)对其粒径、形貌进行表征,结合光谱技术分析其形成机制;进一步利用液相色谱-质谱联用(liquid chromatograph mass spectrometer,LC-MS)技术分析其化学成分;并对其体外抗肝癌活性进行评价。结果黄芪-莪术合煎液与物理混合液中均存在STCM,但黄芪-莪术合煎液中STCM(AC-STCM)的粒径更小、分布更均匀且稳定性更高;其自组装过程中可能由毛蕊异黄酮、芒柄花素、双去甲氧基姜黄素等成分通过氢键和π-π堆积作用共同驱动;AC-STCM对人肝癌HepG2细胞具有显著抑制作用(P<0.01),其体外抗肿瘤活性显著优于合煎液、物理混合STCM(Mix-STCM)(P<0.01),同时,合煎液本身的抗肿瘤效果亦优于物理混合液(P<0.01)。结论在煎煮过程中,黄芪-莪术药对通过非共价键实现成分的自组装,形成稳定的STCM体系,构成其协同增效抗肝癌作用的重要物质基础。首次从STCM的新视角阐释黄芪-莪术药对协同增效抗肝癌的科学内涵,为中药复方配伍理论的现代化研究提供理论依据与实验基础。展开更多
Background Ferroptosis,a pathologic state induced by lipid-driven oxidative stress,is associated with the development of human cancers.Calycosin,a natural compound with antioxidant and anti-inflammatory activities,has...Background Ferroptosis,a pathologic state induced by lipid-driven oxidative stress,is associated with the development of human cancers.Calycosin,a natural compound with antioxidant and anti-inflammatory activities,has promising antitumor effects.However,the ferroptosis-related mechanism of calycosin in the treatment of hepatic carcinoma has not been reported.Methods This study applied network pharmacology and bioinformatic approaches(including Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis)to investigate the pharmacologic targets and mechanism of action of calycosin in the treatment of hepatic carcinoma through targeting ferroptosis.By searching online databases including The Cancer Genome Atlas,FerrDb,GeneCards,SwissTargetPrediction,SuperPred,BindingDB,TargetNet,BATMAN-TCM,and Drugbank,we identified 13 ferroptosis-related putative target genes of calycosin against hepatic carcinoma including IL-6,PTGS2,SRC,HRAS,NQO1,NOX4,PGK1,G6PD,GPI,MIF,NOS2,ALDOA,and SQSTM1.Results Molecular docking analysis revealed that calycosin potentially binded directly with the target proteins IL-6,PTGS2,and SRC.Functional enrichment analysis of these proteins indicated that they were involved in gluconeogenesis and apoptosis through regulation of ERK1,ERK2,and MAPK activities(P<0.05).Conclusion Calycosin exerts antitumor effects in hepatic carcinoma by targeting ferroptosis through regulation of IL-6,PTGS2,and SRC.展开更多
Background Colorectal cancer(CRC)is a type of malignant gastroenteric tumors associated with a high mortal-ity rate worldwide.Calycosin,a natural phytoestrogen,possesses potent anti-cancer properties.We structurally m...Background Colorectal cancer(CRC)is a type of malignant gastroenteric tumors associated with a high mortal-ity rate worldwide.Calycosin,a natural phytoestrogen,possesses potent anti-cancer properties.We structurally modified calycosin to improve its physicochemical properties,and generated a novel small molecule termed CA028.Methods By using network pharmacology,followed by gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis and molecular docking,we aimed to predict and disclose the biological functions and mechanism of CA028 in the treatment of CRC through bioinformatic analyses.Results By searching the online Swiss Target Prediction and TargetNet databases,we identified 150 genes shared by CA028 and CRC.Using the Search Tool for the Retrieval of Interacting Genes(STRING)database and Cytoscape software,we identified 14 hub-functional genes,namely the FYN proto-oncogene,a Src family tyrosine kinase(F YN),mitogen-activated protein kinase 1(MAPK1),MAPK8,MAPK14,Rac family small GTPase 1(RAC1),epi-dermal growth factor receptor(EGFR),protein tyrosine kinase 2(PTK2),sphingosine-1-phosphate receptor 1(S1PR1),S1PR2,Janus kinase 1(JAK1),JAK2,the RELA proto-oncogene NF-𝜅B subunit(RELA),bradykinin re-ceptor B1(BDKRB1),and BDKRB2.Additionally,biological docking analysis using the Autodock Vina software revealed that FYN and MAPK1 were the main pharmacological proteins of CA028 against CRC.The gene ontol-ogy analysis using R-language packages further revealed the anti-CRC functions of CA028,including biological processes,cell components,and molecular pathways.Conclusion CA028 exhibits effective pharmacological activity against CRC by suppressing the proliferation of CRC cells and improving the tumor microenvironment.Importantly,certain predicted genes(e.g.,FYN and MAPK1)may be the pharmacological targets of CA028 in the treatment of CRC.展开更多
基金supported by Heilongjiang Postdoctoral Program(ZHY2022-114)General program of Heilongjiang Province(LBHZ22251)Young Elite Scientists Sponsorship Program(2022-QNRC1-27)。
文摘Calycosin,Astragali Radix most prominent ingredient,has drawn more attention as a result of its ability to treat atherosclerosis(AS).However,the mechanism of action has not been fully elucidated.We investigated the effects of calycosin on bile acid(BA)metabolism and gut microbiome in ApoE^(-/-)mice fed a high-fat diet(HFD).The data showed that the aorta of ApoE^(-/-)mice treated with HFD showed significant atheromatous plaque formation and lipid accumulation,and the levels of total cholesterol(TC),triglycerides(TG)and low-density lipoprotein cholesterol(LDL-C)were significantly increased,while the levels of high-density lipoprotein cholesterol(HDL-C)were significantly decreased.Calycosin can substantially regulate lipid levels,thereby alleviating liver lipid deposition induced by atherosclerosis.In addition,16S rRNA sequencing showed that calycosin treatment has reshaped the gut microbiota disturbed by HFD,in particular,increasing the ratio of Bacteroidetes/Firmicutes,and improving the relative abundance of Bilophila,Desulfovibrio,Bacteroides,Lactobacillus,etc.Meanwhile,targeted metabolomics analysis showed that calycosin treatment significantly modulated glycodeoxycholic acid(CDCA),taurocholic acids(TCA),lithocholic acid(LCA),deoxycholic acid(DCA),taurodeoxycholic acid(TDCA)and BA pool composition,which were associated with atherosclerotic plaque areas.In addition,calycosin treatment also down-regulated farnesoid X receptor(FXR)protein levels and up-regulated cytochrome P450 family 7 subfamily A member 1(CYP7A1)protein levels in the hepatic.At the same time,calycosin inhibits the ileum FXR/TGR5 signaling pathway,inhibits BA reabsorption,promotes BA excretion,and reduces hepatic cholesterol accumulation by enterohepatic circulation.In addition,we found that calycosin significantly promoted the expression of hepatic ATP-binding cassette transporter A1(ABCA1)and ABCG1 to mediate cholesterol efflux.Meanwhile,calycosin regulates gut microbiota,and Bacteroides,Alistipes,Desulfovibrio,Lactobacillus,Bilophila and Odoribacter are closely related to specific BAs.This enables us to further understand the relationship between BA metabolism and gut microbiota.Calycosin may reduce high-fat diet-induced hepatic cholesterol accumulation in ApoE^(-/-)mice through gut microbiota and BA metabolism,and play a role in treating AS.Finally,we confirmed that calycosin-altered gut microbiota by fecal microbiota transplantation was sufficient to alleviate atherosclerosis.Taken together,our findings provide important insights into the pharmacological mechanisms underlying the efficacy of calycosin on atherosclerosis.
基金supported by the a grant from China Postdoctoral Science Project,No.801161020425the Natural Science Foundation of China,No.8160010172
文摘The major pathological changes in Alzheimer＇s disease are beta amyloid deposits and cognitive impairment. Calycosin is a typical phy- toestrogen derived from radix astragali that binds to estrogen receptors to produce estrogen-like effects. Radix astragali Calycosin has been shown to relieve cognitive impairment induced by diabetes mellitus, suggesting calycosin may improve the cognitive function of Alzhei- mer＇s disease patients. The protein kinase C pathway is upstream of the mitogen-activated protein kinase pathway and exerts a neuropro- tective effect by regulating Alzheimer＇s disease-related beta amyloid degradation. We hypothesized that calycosin improves the cognitive function of a transgenic mouse model of Alzheimer＇s disease by activating the protein kinase C pathway. Various doses of calycosin （10, 20 and 40 mg/kg） were intraperitoneally injected into APP/PS1 transgenic mice that model Alzheimer＇s disease. Calycosin diminished hippocampal beta amyloid, Tau protein, interleukin-lbeta, tumor necrosis factor-alpha, acetylcholinesterase and malondialdehyde levels in a dose-dependent manner, and increased acetylcholine and glutathione activities. The administration of a protein kinase C inhibitor, cal- phostin C, abolished the neuroprotective effects of calycosin including improving cognitive ability, and anti-oxidative and anti-inflammato- ry effects. Our data demonstrated that calycosin mitigated oxidative stress and inflammatory responses in the hippocampus of Alzheimer＇s disease model mice by activating the protein kinase C pathway, and thereby improving cognitive function.
文摘Cardiovascular disease is the main cause of mortality and morbidity in the world,especially in developing countries.Drug therapy is one of the main ways to treat cardiovascular diseases.Among them,great progress has been made in the treatment of cardiovascular diseases with traditional Chinese medicine.In terms of experimental research,the mechanism of traditional Chinese medicine in the treatment of cardiovascular diseases has been thoroughly discussed in vitro and in vivo.In terms of clinical treatment,traditional Chinese medicine with flavonoids,saponins and alkaloids as the main effective components has a definite effect on the treatment of cardiovascular diseases such as arrhythmia,myocardial ischemia,angina pectoris and myocardial infarction,with high safety and good application prospects.With the further research on the effective ingredients,mechanism and adverse reactions of traditional Chinese medicine,it will be beneficial to the effectiveness of traditional Chinese medicine,reduce side effects and promote the modernization of traditional Chinese medicine.Calycosin and its derivatives,the main bioactive flavonoids in Astragalus membranaceus have multiple biological effects,such as antioxidant,pro-angiogenesis,anti-tumour,and anti-inflammatory effects.Based on the above biological effects,calycosin has been shown to have good potential for cardiovascular protection.The potent antioxidant effect of calycosin may play an important role in the cardiovascular protective potential.For injured cardiac myocytes,calycosin and its derivatives can alleviate the cell damage mainly marked by the release of myocardial enzymes and reduce the death level of cardiac myocytes mainly characterized by apoptosis through various mechanisms.For vascular endothelial cells,calycosin also has multiple effects and multiple mechanisms,such as promoting vascular endothelial cell proliferation,exerting vasodilating effect and directly affecting the synthesis function of endothelial cells.The present review will address the bioactivity of calycosin in cardiovascular diseases such as protective effects on cardiac myocytes and vascular endothelial cells and elucidate main mechanism of calycosin and its derivatives to exert the above biological effects.
文摘BACKGROUND Acute lung injury(ALI)is a common and life-threatening complication of severe acute pancreatitis(SAP).There are currently limited effective treatment options for SAP and associated ALI.Calycosin(Cal),a bioactive constituent extracted from the medicinal herb Radix Astragali exhibits potent anti-inflammatory properties,but its effect on SAP and associated ALI has yet to be determined.AIM To identify the roles of Cal in SAP-ALI and the underlying mechanism.METHODS SAP was induced via two intraperitoneal injections of L-arg(4 g/kg)and Cal(25 or 50 mg/kg)were injected 1 h prior to the first L-arg challenge.Mice were sacrificed 72 h after the induction of SAP and associated ALI was examined histologically and biochemically.An in vitro model of lipopolysaccharide(LPS)-induced ALI was established using A549 cells.Immunofluorescence analysis and western blot were evaluated in cells.Molecular docking analyses were conducted to examine the interaction of Cal with HMGB1.RESULTS Cal treatment substantially reduced the serum amylase levels and alleviated histopathological injury associated with SAP and ALI.Neutrophil infiltration and lung tissue levels of neutrophil mediator myeloperoxidase were reduced in line with protective effects of Cal against ALI in SAP.Cal treatment also attenuated the serum levels and mRNA expression of pro-inflammatory cytokines tumor necrosis factor-α,interleukin-6,IL-1β,HMGB1 and chemokine(CXC motif)ligand 1 in lung tissue.Immunofluorescence and western blot analyses showed that Cal treatment markedly suppressed the expression of HMGB1 and phosphorylated nuclear factor-kappa B(NF-κB)p65 in lung tissues and an in vitro model of LPSinduced ALI in A549 cells suggesting a role for HGMB1 in the pathogenesis of ALI.Furthermore,molecular docking analysis provided evidence for the direct interaction of Cal with HGMB1.CONCLUSION Cal protects mice against L-arg-induced SAP and associated ALI by attenuating local and systemic neutrophil infiltration and inflammatory response via inhibition of HGMB1 and the NF-κB signaling pathway.
基金the Heilongjiang Farms&Land Reclamation Administration Support Project for Key Scientific Research(HKKYZD190705)The Heilongjiang Bayi Agricultural University Support Program for"San Zong"(TDJH201905)Heilongjiang Touyan Innovation Team Program(2019HTY078).
文摘Calycosin is an important isoflavone compound in traditional Chinese medicine Astragali Radix.It not only has remarkable anti-oxidation,anti-inflammatory and anti-tumor functions,but also has the characteristics of small adverse reactions and low toxicity,so it has attracted wide attention of scholars and researchers.This paper reviewed the pharmacological effects and mechanisms of calycosin in recent years,in the hope of providing a theoretical basis for its clinical application.
基金the National Natural Science Foundation of China(General Program),No.82205002Science and Technology Project of Sichuan Province,No.2022YFS0621,No.21ZDYF0348,and No.2022NSFSC1459+1 种基金Luzhou-Southwest Medical University Science and Technology Strategic Cooperation Project,No.2021LZXNYD-P04Southwest Medical University of Affiliated Traditional Medicine Hospital Project,No.2022-CXTD-03.
文摘BACKGROUND Bone marrow-derived mesenchymal stem cells(MSCs)show podocyte-protective effects in chronic kidney disease.Calycosin(CA),a phytoestrogen,is isolated from Astragalus membranaceus with a kidney-tonifying effect.CA preconditioning enhances the protective effect of MSCs against renal fibrosis in mice with unilateral ureteral occlusion.However,the protective effect and underlying mechanism of CA-pretreated MSCs(MSCsCA)on podocytes in adriamycin(ADR)-induced focal segmental glomerulosclerosis(FSGS)mice remain unclear.AIM To investigate whether CA enhances the role of MSCs in protecting against podocyte injury induced by ADR and the possible mechanism involved.METHODS ADR was used to induce FSGS in mice,and MSCs,CA,or MSCsCA were administered to mice.Their protective effect and possible mechanism of action on podocytes were observed by Western blot,immunohistochemistry,immunofluorescence,and real-time polymerase chain reaction.In vitro,ADR was used to stimulate mouse podocytes(MPC5)to induce injury,and the supernatants from MSC-,CA-,or MSCsCA-treated cells were collected to observe their protective effects on podocytes.Subsequently,the apoptosis of podocytes was detected in vivo and in vitro by Western blot,TUNEL assay,and immunofluorescence.Overexpression of Smad3,which is involved in apoptosis,was then induced to evaluate whether the MSCsCA-mediated podocyte protective effect is associated with Smad3 inhibition in MPC5 cells.RESULTS CA-pretreated MSCs enhanced the protective effect of MSCs against podocyte injury and the ability to inhibit podocyte apoptosis in ADR-induced FSGS mice and MPC5 cells.Expression of p-Smad3 was upregulated in mice with ADR-induced FSGS and MPC5 cells,which was reversed by MSCCA treatment more significantly than by MSCs or CA alone.When Smad3 was overexpressed in MPC5 cells,MSCsCA could not fulfill their potential to inhibit podocyte apoptosis.CONCLUSION MSCsCA enhance the protection of MSCs against ADR-induced podocyte apoptosis.The underlying mechanism may be related to MSCsCA-targeted inhibition of p-Smad3 in podocytes.
基金supported by the National Natural Science Foundation of China, China (No. 31400304)the Natural Science Foundation of Hubei Province, China (No. 2012FFB00303)+1 种基金the Youth & Middle-aged Talent Project of Hubei Province (No. Q20111005)the Science and Technology Program of Shandong Province (No. J12LL07)
文摘The iso fl avone calycosin-7-O-β-D-glucopyranoside(CG) is a principal constituent of Astragalus membranaceus(AR) and has been reported to inhibit osteoclast development in vitro and bone loss in vivo. The aim of this study was to investigate the osteogenic effects of CG and its underlying mechanism in ST2 cells. The results show that exposure of cells to CG in osteogenic differentiation medium increases ALP activity, osteocalcin(Ocal) m RNA expression and the osteoblastic mineralization process. Mechanistically, CG treatment increased the expression of bone morphogenetic protein 2(BMP-2), p-Smad 1/5/8, β-catenin and Runx2, all of which are regulators of the BMP- or wingless-type MMTV integration site family(WNT)/β-catenin-signaling pathways. Moreover, the osteogenic effects of CG were inhibited by Noggin and DKK-1 which are classical inhibitors of the BMP and WNT/β-catenin-signaling pathways, respectively. Taken together, the results indicate that CG promotes the osteoblastic differentiation of ST2 cells through regulating the BMP/WNT signaling pathways. On this basis, CG may be a useful lead compound for improving the treatment of bone-decreasing diseases and enhancing bone regeneration.
文摘目的基于中药超分子(supramolecules of traditional Chinese medicine,STCM)理论,系统探讨黄芪Astragali Radix-莪术Curcumae Rhizoma(AC)药对协同增效抗肝癌的物质基础,旨在揭示其配伍的科学内涵。方法采用离心-透析法对STCM进行分离;并借助动态光散射(dynamic light scattering,DLS)技术和透射电子显微镜(transmission electron microscope,TEM)对其粒径、形貌进行表征,结合光谱技术分析其形成机制;进一步利用液相色谱-质谱联用(liquid chromatograph mass spectrometer,LC-MS)技术分析其化学成分;并对其体外抗肝癌活性进行评价。结果黄芪-莪术合煎液与物理混合液中均存在STCM,但黄芪-莪术合煎液中STCM(AC-STCM)的粒径更小、分布更均匀且稳定性更高;其自组装过程中可能由毛蕊异黄酮、芒柄花素、双去甲氧基姜黄素等成分通过氢键和π-π堆积作用共同驱动;AC-STCM对人肝癌HepG2细胞具有显著抑制作用(P<0.01),其体外抗肿瘤活性显著优于合煎液、物理混合STCM(Mix-STCM)(P<0.01),同时,合煎液本身的抗肿瘤效果亦优于物理混合液(P<0.01)。结论在煎煮过程中,黄芪-莪术药对通过非共价键实现成分的自组装,形成稳定的STCM体系,构成其协同增效抗肝癌作用的重要物质基础。首次从STCM的新视角阐释黄芪-莪术药对协同增效抗肝癌的科学内涵,为中药复方配伍理论的现代化研究提供理论依据与实验基础。
基金supported by the National Natural Science Foundation of Guangxi (Grant No.2020GXNSFBA159066).
文摘Background Ferroptosis,a pathologic state induced by lipid-driven oxidative stress,is associated with the development of human cancers.Calycosin,a natural compound with antioxidant and anti-inflammatory activities,has promising antitumor effects.However,the ferroptosis-related mechanism of calycosin in the treatment of hepatic carcinoma has not been reported.Methods This study applied network pharmacology and bioinformatic approaches(including Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis)to investigate the pharmacologic targets and mechanism of action of calycosin in the treatment of hepatic carcinoma through targeting ferroptosis.By searching online databases including The Cancer Genome Atlas,FerrDb,GeneCards,SwissTargetPrediction,SuperPred,BindingDB,TargetNet,BATMAN-TCM,and Drugbank,we identified 13 ferroptosis-related putative target genes of calycosin against hepatic carcinoma including IL-6,PTGS2,SRC,HRAS,NQO1,NOX4,PGK1,G6PD,GPI,MIF,NOS2,ALDOA,and SQSTM1.Results Molecular docking analysis revealed that calycosin potentially binded directly with the target proteins IL-6,PTGS2,and SRC.Functional enrichment analysis of these proteins indicated that they were involved in gluconeogenesis and apoptosis through regulation of ERK1,ERK2,and MAPK activities(P<0.05).Conclusion Calycosin exerts antitumor effects in hepatic carcinoma by targeting ferroptosis through regulation of IL-6,PTGS2,and SRC.
基金the National Natural Science Founda-tion of China(Grant Nos.81973574,82174082,and 82060736)Guangxi Natural Science Foundation(Grant Nos.2019GXNSFFA245001 and 2018GXNSFAA281334)Innovation Project of Guangxi Graduate Education(Grant No.YCSW2021253).
文摘Background Colorectal cancer(CRC)is a type of malignant gastroenteric tumors associated with a high mortal-ity rate worldwide.Calycosin,a natural phytoestrogen,possesses potent anti-cancer properties.We structurally modified calycosin to improve its physicochemical properties,and generated a novel small molecule termed CA028.Methods By using network pharmacology,followed by gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis and molecular docking,we aimed to predict and disclose the biological functions and mechanism of CA028 in the treatment of CRC through bioinformatic analyses.Results By searching the online Swiss Target Prediction and TargetNet databases,we identified 150 genes shared by CA028 and CRC.Using the Search Tool for the Retrieval of Interacting Genes(STRING)database and Cytoscape software,we identified 14 hub-functional genes,namely the FYN proto-oncogene,a Src family tyrosine kinase(F YN),mitogen-activated protein kinase 1(MAPK1),MAPK8,MAPK14,Rac family small GTPase 1(RAC1),epi-dermal growth factor receptor(EGFR),protein tyrosine kinase 2(PTK2),sphingosine-1-phosphate receptor 1(S1PR1),S1PR2,Janus kinase 1(JAK1),JAK2,the RELA proto-oncogene NF-𝜅B subunit(RELA),bradykinin re-ceptor B1(BDKRB1),and BDKRB2.Additionally,biological docking analysis using the Autodock Vina software revealed that FYN and MAPK1 were the main pharmacological proteins of CA028 against CRC.The gene ontol-ogy analysis using R-language packages further revealed the anti-CRC functions of CA028,including biological processes,cell components,and molecular pathways.Conclusion CA028 exhibits effective pharmacological activity against CRC by suppressing the proliferation of CRC cells and improving the tumor microenvironment.Importantly,certain predicted genes(e.g.,FYN and MAPK1)may be the pharmacological targets of CA028 in the treatment of CRC.
