Objective: Cinobufotalin (CINO), a cardiotonic steroid (CTS) or bufadienolide, is extracted from the skin secretions of giant toads and is utilized in traditional Chinese medicine (Chan Su). CINO has been used as a ca...Objective: Cinobufotalin (CINO), a cardiotonic steroid (CTS) or bufadienolide, is extracted from the skin secretions of giant toads and is utilized in traditional Chinese medicine (Chan Su). CINO has been used as a cardiotonic, diuretic and a hemostatic agent. Recently, CINO has been shown to inhibit lung cancer cell function and has been implicated in several other disease processes. In this study, we pursued the potential anticancer application of CINO using the ovarian tumor cell line SK-OV-3. Study Design: We evaluated the effect of CINO on cultures of SK-OV-3. Cells were treated with 0.1, 0.5, 1, 5, and 10 μM CINO. Cell proliferation, migration, invasion, and viability were measured using commercially available kits. Cell cycle progression was evaluated by a Cell Cycle Phase Determination Kit. Apoptosis was evaluated by an Apoptotic Blebs Assay Kit;cell cycle arrest and apoptotic signaling were determined by fluorescence-activated cell sorting (FACS) analysis. Results: CINO at ≥ 0.5 μM inhibited SKOV-3 cell proliferation, migration, and invasion (p < 0.05). There was a higher (p < 0.05) percentage of S phase cells in groups treated with CINO at 0.5 μM. CINO at ≥ 0.5 μM down regulated expression of Proliferating Cell Nuclear Antigen (PCNA) and caused cell death. Conclusion: This data demonstrates that CINO impairs SK-OV-3 cell function via cell cycle arrest and apoptotic signaling, suggesting CINO be further investigated as a novel anti-ovarian cancer agent.展开更多
Objective The aim of this study was to investigate the effect of cinobufotalin on apoptosis in renal cell carcinoma and its possible mechanism of action.Methods The expression levels of Notch1 in renal cancer cells,as...Objective The aim of this study was to investigate the effect of cinobufotalin on apoptosis in renal cell carcinoma and its possible mechanism of action.Methods The expression levels of Notch1 in renal cancer cells,as well as in adjacent and normal tissues were assessed in 64 patients with renal cellcarcinoma.The 769-P cells were treated with 0,10,20 and 40 mg/L cinobufotalin and the proliferation activity and apoptotic rate of the cells were measured.The expression levels of Notch1,Bcl-2,and Pro-caspase 3 were detected by RT-PCR and Western-blot.Results(1)The rates of Notch1 expression in renal cancer cells,adjacent tissues,and normal tissues were 75.0%,45.3%,and 9.4%,respectively.Notch1 expression had significant effects on tumor,node and metastasis(TNM)staging,Fuhrman grade,and tumor size in patients with renal cell carcinoma(P<0.05);(2)The inhibition rates of cinobufotalin on 769-P cells were 0%,6.85%,11.37%,and 16.33%at 24 h;0%,13.57%,20.14%,and 31.69%at 48 h;0%,19.97%,28.53%and 51.42%at 72 h.At 24 h,the apoptotic rates were 8.2±3.1%,19.8±5.6%,33.7±5.0%,and 51.5±6.8%.The effect of cinobufotalin on apoptosis of 769-P cells was dose-dependent;(3)RT-PCR assay showed that protein expression levels for Notch1,Bcl-2,and Pro-caspase 3 were significantly decreased with the increase of drug concentration.Western-blot analysis also showed that Notch1,Bcl-2 and Pro-caspase 3 protein levels showed a significant downward trend with the increase of drug concentration.Conclusion Cinobufotalin inhibits the growth of renal cancer cells and induces apoptosis in renal cell carcinoma,which may be related to the inhibition of Notch1 signal activation.展开更多
Background:Osteoporosis is a chronic bone disease characterized by bone loss and decreased bone strength.However,current anti-resorptive drugs carry a risk of various complications.The deep learning-based efficacy pre...Background:Osteoporosis is a chronic bone disease characterized by bone loss and decreased bone strength.However,current anti-resorptive drugs carry a risk of various complications.The deep learning-based efficacy prediction system(DLEPS)is a forecasting tool that can effectively compete in drug screening and prediction based on gene expression changes.This study aimed to explore the protective effect and potential mechanisms of cinobufotalin(CB),a traditional Chinese medicine(TCM),on bone loss.Methods:DLEPS was employed for screening anti-osteoporotic agents according to gene profile changes in primary osteoporosis.Micro-CT,histological and morphological analysis were applied for the bone protective detection of CB,and the osteogenic differentiation/function in human bone marrow mesenchymal stem cells(hBMMSCs)were also investigated.The underlying mechanism was verified using qRT-PCR,Western blot(WB),immunofluorescence(IF),etc.Results:A safe concentration(0.25mg/kg in vivo,0.05μM in vitro)of CB could effectively preserve bone mass in estrogen deficiency-induced bone loss and promote osteogenic differentiation/function of hBMMSCs.Both BMPs/SMAD and Wnt/β-catenin signaling pathways participated in CB-induced osteogenic differentiation,further regulating the expression of osteogenesis-associated factors,and ultimately promoting osteogenesis.Conclusion:Our study demonstrated that CB could significantly reverse estrogen deficiency-induced bone loss,further promoting osteogenic differentiation/function of hBMMSCs,with BMPs/SMAD and Wnt/β-catenin signaling pathways involved.展开更多
Glioblastoma(GBM)belongs to the deadliest primary malignancies with high mortality rate and poor prognosis.Over the past decades,less progress has been made to treat GBM,owing largely to the lack of effective chemothe...Glioblastoma(GBM)belongs to the deadliest primary malignancies with high mortality rate and poor prognosis.Over the past decades,less progress has been made to treat GBM,owing largely to the lack of effective chemotherapeutics and poor drug accumulation in the glioma tissue.In order to address this issue,we present an efficient biomimetic nanocomposite(Cu_(2−x)Se-CB@MEM,CCM),consisting of Cu_(2−x)Se nanoparticle core modified by cinobufotalin(CB),a toad venom extract,which is camouflaged with glioma cell Ln229 membrane.It is demonstrated that CB can decrease the protein activity of inosine monophosphate dehydrogenase 1(IMPDH1),a key target correlated with prognosis,through intermolecular hydrogen bonding with amino acid residues ARG-105 and ASP-77.The glioma cell membrane-camouflage endows the CCM with blood-brain barrier penetration and homology tumor-targeted ability.The optimized cinobufotalin based chemotherapy combining with the near-infrared-II(NIR-II)irradiation shows outstanding inhibition effect to glioma cells,by blocking cell cycle and inducing apoptosis.In vivo mice bearing orthotopic Ln229 GBM treated with CCM+NIR-II(CCM+L)have significantly suppressed tumor growth and extended survival,without side effect.The glioma cell membrane camouflaged nanocomposite of Cu_(2−x)Se and cinobufotalin with its significant anti-glioma property and well biosafety will provide novel alternatives for clinical treatment of GBM.展开更多
Objective: To find effective treatment with less side-effect for hepatocarcinoma.Methods: Seventy patients were divided into two groups, treated with cinobufotalin plus chemicals and chemicals alone by arterial perfus...Objective: To find effective treatment with less side-effect for hepatocarcinoma.Methods: Seventy patients were divided into two groups, treated with cinobufotalin plus chemicals and chemicals alone by arterial perfusion respectively. The symptoms, hematological picture, tumor size and viral marker of patients were observed and compared.Results: The treatment with cinobufotalin plus chemicals was more effective than that of chemicals alone in body weight increasing, pain relieving, liver function recovering and virus marker negative inversing.Conclusion: Cinobufotalin could improve the effect of chemo-embolization therapy of hepatocarcinoma.展开更多
文摘Objective: Cinobufotalin (CINO), a cardiotonic steroid (CTS) or bufadienolide, is extracted from the skin secretions of giant toads and is utilized in traditional Chinese medicine (Chan Su). CINO has been used as a cardiotonic, diuretic and a hemostatic agent. Recently, CINO has been shown to inhibit lung cancer cell function and has been implicated in several other disease processes. In this study, we pursued the potential anticancer application of CINO using the ovarian tumor cell line SK-OV-3. Study Design: We evaluated the effect of CINO on cultures of SK-OV-3. Cells were treated with 0.1, 0.5, 1, 5, and 10 μM CINO. Cell proliferation, migration, invasion, and viability were measured using commercially available kits. Cell cycle progression was evaluated by a Cell Cycle Phase Determination Kit. Apoptosis was evaluated by an Apoptotic Blebs Assay Kit;cell cycle arrest and apoptotic signaling were determined by fluorescence-activated cell sorting (FACS) analysis. Results: CINO at ≥ 0.5 μM inhibited SKOV-3 cell proliferation, migration, and invasion (p < 0.05). There was a higher (p < 0.05) percentage of S phase cells in groups treated with CINO at 0.5 μM. CINO at ≥ 0.5 μM down regulated expression of Proliferating Cell Nuclear Antigen (PCNA) and caused cell death. Conclusion: This data demonstrates that CINO impairs SK-OV-3 cell function via cell cycle arrest and apoptotic signaling, suggesting CINO be further investigated as a novel anti-ovarian cancer agent.
基金Supported by a grant from the Research Project of Jiangsu Provincial Health and Family Planning Commissioned in 2015(No.H201516).
文摘Objective The aim of this study was to investigate the effect of cinobufotalin on apoptosis in renal cell carcinoma and its possible mechanism of action.Methods The expression levels of Notch1 in renal cancer cells,as well as in adjacent and normal tissues were assessed in 64 patients with renal cellcarcinoma.The 769-P cells were treated with 0,10,20 and 40 mg/L cinobufotalin and the proliferation activity and apoptotic rate of the cells were measured.The expression levels of Notch1,Bcl-2,and Pro-caspase 3 were detected by RT-PCR and Western-blot.Results(1)The rates of Notch1 expression in renal cancer cells,adjacent tissues,and normal tissues were 75.0%,45.3%,and 9.4%,respectively.Notch1 expression had significant effects on tumor,node and metastasis(TNM)staging,Fuhrman grade,and tumor size in patients with renal cell carcinoma(P<0.05);(2)The inhibition rates of cinobufotalin on 769-P cells were 0%,6.85%,11.37%,and 16.33%at 24 h;0%,13.57%,20.14%,and 31.69%at 48 h;0%,19.97%,28.53%and 51.42%at 72 h.At 24 h,the apoptotic rates were 8.2±3.1%,19.8±5.6%,33.7±5.0%,and 51.5±6.8%.The effect of cinobufotalin on apoptosis of 769-P cells was dose-dependent;(3)RT-PCR assay showed that protein expression levels for Notch1,Bcl-2,and Pro-caspase 3 were significantly decreased with the increase of drug concentration.Western-blot analysis also showed that Notch1,Bcl-2 and Pro-caspase 3 protein levels showed a significant downward trend with the increase of drug concentration.Conclusion Cinobufotalin inhibits the growth of renal cancer cells and induces apoptosis in renal cell carcinoma,which may be related to the inhibition of Notch1 signal activation.
基金Beijing Natural Science Foundation,Grant/Award Number:L222145 and L222030Emerging Engineering Interdisciplinary Project and the Fundamental Research Funds for the Central Universities,Grant/Award Number:PKU2022XGK008Peking University Medicine Fund of Fostering Young Scholars’Scientific&Technological Innovation,Grant/Award Number:BMU2022PY010。
文摘Background:Osteoporosis is a chronic bone disease characterized by bone loss and decreased bone strength.However,current anti-resorptive drugs carry a risk of various complications.The deep learning-based efficacy prediction system(DLEPS)is a forecasting tool that can effectively compete in drug screening and prediction based on gene expression changes.This study aimed to explore the protective effect and potential mechanisms of cinobufotalin(CB),a traditional Chinese medicine(TCM),on bone loss.Methods:DLEPS was employed for screening anti-osteoporotic agents according to gene profile changes in primary osteoporosis.Micro-CT,histological and morphological analysis were applied for the bone protective detection of CB,and the osteogenic differentiation/function in human bone marrow mesenchymal stem cells(hBMMSCs)were also investigated.The underlying mechanism was verified using qRT-PCR,Western blot(WB),immunofluorescence(IF),etc.Results:A safe concentration(0.25mg/kg in vivo,0.05μM in vitro)of CB could effectively preserve bone mass in estrogen deficiency-induced bone loss and promote osteogenic differentiation/function of hBMMSCs.Both BMPs/SMAD and Wnt/β-catenin signaling pathways participated in CB-induced osteogenic differentiation,further regulating the expression of osteogenesis-associated factors,and ultimately promoting osteogenesis.Conclusion:Our study demonstrated that CB could significantly reverse estrogen deficiency-induced bone loss,further promoting osteogenic differentiation/function of hBMMSCs,with BMPs/SMAD and Wnt/β-catenin signaling pathways involved.
基金supported by the National Natural Science Foundation of China(Nos.81872064 and 82272879)the Natural Science Fund of Guangdong Province,China(No.2021A1515012465)+1 种基金Technology Program of Guangzhou(No.202206010068)Major Discipline and Academic Leader Training Program of Jiangxi Province(No.20225BCJ23001).
文摘Glioblastoma(GBM)belongs to the deadliest primary malignancies with high mortality rate and poor prognosis.Over the past decades,less progress has been made to treat GBM,owing largely to the lack of effective chemotherapeutics and poor drug accumulation in the glioma tissue.In order to address this issue,we present an efficient biomimetic nanocomposite(Cu_(2−x)Se-CB@MEM,CCM),consisting of Cu_(2−x)Se nanoparticle core modified by cinobufotalin(CB),a toad venom extract,which is camouflaged with glioma cell Ln229 membrane.It is demonstrated that CB can decrease the protein activity of inosine monophosphate dehydrogenase 1(IMPDH1),a key target correlated with prognosis,through intermolecular hydrogen bonding with amino acid residues ARG-105 and ASP-77.The glioma cell membrane-camouflage endows the CCM with blood-brain barrier penetration and homology tumor-targeted ability.The optimized cinobufotalin based chemotherapy combining with the near-infrared-II(NIR-II)irradiation shows outstanding inhibition effect to glioma cells,by blocking cell cycle and inducing apoptosis.In vivo mice bearing orthotopic Ln229 GBM treated with CCM+NIR-II(CCM+L)have significantly suppressed tumor growth and extended survival,without side effect.The glioma cell membrane camouflaged nanocomposite of Cu_(2−x)Se and cinobufotalin with its significant anti-glioma property and well biosafety will provide novel alternatives for clinical treatment of GBM.
文摘Objective: To find effective treatment with less side-effect for hepatocarcinoma.Methods: Seventy patients were divided into two groups, treated with cinobufotalin plus chemicals and chemicals alone by arterial perfusion respectively. The symptoms, hematological picture, tumor size and viral marker of patients were observed and compared.Results: The treatment with cinobufotalin plus chemicals was more effective than that of chemicals alone in body weight increasing, pain relieving, liver function recovering and virus marker negative inversing.Conclusion: Cinobufotalin could improve the effect of chemo-embolization therapy of hepatocarcinoma.
