In recent decades,cancer stem cells(CSCs)have been increasingly identified in many malignancies.CSC-related signaling pathways and their functions provide new strategies for treating cancer.The aberrant activation of ...In recent decades,cancer stem cells(CSCs)have been increasingly identified in many malignancies.CSC-related signaling pathways and their functions provide new strategies for treating cancer.The aberrant activation of related signaling pathways(e.g.,Wnt,Notch,and Hedgehog pathways)has been linked to multiple types of malignant tumors,which makes these pathways attractive targets for cancer therapy.CSCs display many characteristic features,such as self-renewal,differentiation,high tumorigenicity,and drug resistance.Therefore,there is an urgent need to develop new therapeutic strategies to target these pathways to control stem cell replication,survival,and differentiation.Notable crosstalk occurs among different signaling pathways and potentially leads to compensatory escape.Therefore,multitarget inhibitors will be one of the main methods to overcome the drug resistance of CSCs.Many small molecule inhibitors of components of signaling pathways in CSCs have entered clinical trials,and some inhibitors,such as vismodegib,sonidegib,and glasdegib,have been approved.Tumor cells are susceptible to sonidegib and vismodegib resistance due to mutations in the Smo protein.The signal transducers and activators of transcription 3(STAT3)inhibitor BBI608 is being evaluated in a phase III trial for a variety of cancers.Structural derivatives of BBI608 are the main focus of STAT3 inhibitor development,which is another strategy for CSC therapy.In addition to the potential pharmacological inhibitors targeting CSCrelated signaling pathways,other methods of targeting CSCs are available,such as nano-drug delivery systems,mitochondrion targeting,autophagy,hyperthermia,immunotherapy,and CSC microenvironment targeting.In addition,we summarize the latest advances in the clinical development of agents targeting CSC-related signaling pathways and other methods of targeting CSCs.展开更多
Although the appearance of Doxil alleviated the cardiotoxicity of DOX, the progression-free survival of patients was not prolonged compared with traditional medication regimens, and side effects such as hand-foot synd...Although the appearance of Doxil alleviated the cardiotoxicity of DOX, the progression-free survival of patients was not prolonged compared with traditional medication regimens, and side effects such as hand-foot syndrome has occurred. In order to solve this dilemma, we have designed a novel co-delivery strategy to construct a co-loaded liposome of berberine(BER) and doxorubicin(DOX), which was called Lipo Be Do. The optimal synergistic ratio of the two drugs was screened by cell cytotoxicity experiments in vitro, and the optimal attenuation ratio was further determined by in vivo cardiac H&E staining pathological sections. The optimal combination treatment caused a robust increase in apoptotic cells of 4T1, as compared to drug alone treatment. The prepared co-loaded liposome, Lipo Be Do, had high encapsulation efficiency and good stability. The nanoliposome carrier controlled the biological fate of the drugs and maintained a pre-defined optimal ratio in vivo. The Lipo Be Do significantly inhibited tumor growth in 4T1 murine mammary carcinoma model compared with Doxil(P < 0.05), and completely overcame the myocardial rupture toxicity caused by Doxil in mice. Our co-loaded liposome delivery platform technology provided a new direction for the clinical treatment of triple-negative breast cancer and the safe application of DOX.展开更多
The therapeutic efficiency of active targeting nanoparticulate drug delivery systems(nano-DDS)is highly compromised by the plasma proteins adsorption on nanoparticles(NPs)surface,which significantly hinders cell membr...The therapeutic efficiency of active targeting nanoparticulate drug delivery systems(nano-DDS)is highly compromised by the plasma proteins adsorption on nanoparticles(NPs)surface,which significantly hinders cell membrane receptors to recognize the designed ligands,and provokes the off-target toxicity and rapid clearance of NPs in vivo.Herein,we report a novel dihydroartemisinin(DHA)-decorating nano-DDS that in situ specifically recruits endogenous apolipoprotein E(apoE)on the NPs surface.The apoE-anchored corona is able to prolong PLGA-PEG2000-DHA(PPD)NPs circulation capability in blood,facilitate NPs accumulating in tumor cells by the passive enhanced permeability and retention(EPR)effect and low-density lipoprotein receptor(LDLr)-mediated target transport,and ultimately improve the in vivo antitumor activity.Our findings demonstrate that the strategy of in situ regulated apoE-enriched corona ensures NPs an efficient LDLr-mediated tumor-homing chemotherapy.展开更多
Genomic alterations are commonly found in the signaling pathways of fibroblast growth factor receptors(FGFRs). Although there is no selective FGFR inhibitors in market, several promising inhibitors have been investiga...Genomic alterations are commonly found in the signaling pathways of fibroblast growth factor receptors(FGFRs). Although there is no selective FGFR inhibitors in market, several promising inhibitors have been investigated in clinical trials, and showed encouraging efficacies in patients. By designing a hybrid between the FGFR-selectivity-enhancing motif dimethoxybenzene group and our previously identified novel scaffold, we discovered a new series of potent FGFR inhibitors, with the best one showing sub-nanomolar enzymatic activity. After several round of optimization and with the solved crystal structure, detailed structure–activity relationship was elaborated. Together with in vitro metabolic stability tests and in vivo pharmacokinetic profiling, a representative compound(35) was selected and tested in xenograft mouse model, and the result demonstrated that inhibitor 35 was effective against tumors with FGFR genetic alterations, exhibiting potential for further development.展开更多
In an attempt to develop potent antitumor agents,new rhodacyanine analogues containing the pyridinium ring(5a-5h),the isoquinolinium ring(6a-6c) and the quinolinium ring(7a-7e) linked to the rhodanine ring via N...In an attempt to develop potent antitumor agents,new rhodacyanine analogues containing the pyridinium ring(5a-5h),the isoquinolinium ring(6a-6c) and the quinolinium ring(7a-7e) linked to the rhodanine ring via N-N covalent bond were designed, synthesized and evaluated for antitumor activity against human lung cancer cell line(H460) by MTT assay in vitro.Most of the tested compounds showed enhanced antitumor activity with IC_(50) values ranging from 0.006 to 9.2 u,mol/L as compared to the lead compound MKT-077.Among them,the most promising compound 7d(IC_(50) = 0.006μmol/L) was 216.7 times more active than MKT-077(IC_(50) = 1.3μmol/L).The preliminary structure-activity relationship of the target compounds was discussed.展开更多
Adipose stem cells(ADSCs)have been reported to have multidirectional differentiation potential,and can promote cell proliferation and growth,and nerve regeneration function,which has become a promising treatment regim...Adipose stem cells(ADSCs)have been reported to have multidirectional differentiation potential,and can promote cell proliferation and growth,and nerve regeneration function,which has become a promising treatment regimen forwound repair.Exosomes derived from ADSCs(ADSCs-Exos)have excellenttissuerepairfunctions,including high vascular endothelial growth factor A,fibroblast growth factor_2,hepatocyte growth factor,platelet-derived growth factor subunit BB,and other importantwoundhealingfactors.l Supplementary Figure1,http:/links.lww.com/CM9/A828 is a simplified diagram of the exosome formation and release model.展开更多
A simple and efficient HPLC method was developed for quality analysis of flavonoids from Impatiens balsamina L.(IBL)flowers,which were collected from Xingjiang,Anhui,Henan,and Hubei provinces in China.The flavonoids s...A simple and efficient HPLC method was developed for quality analysis of flavonoids from Impatiens balsamina L.(IBL)flowers,which were collected from Xingjiang,Anhui,Henan,and Hubei provinces in China.The flavonoids substances in IBL were determined by HPLC through methyl alcohol ultrasonic extraction.A mixture of展开更多
A novel series of β-propanamide derivatives as inhibitors of cholesteryl ester transfer protein(CETP)were synthesized.Previously,H3(IC_(50) 2 μmol/L) was observed to inhibit CETP moderately(Xie et ah,2016).S...A novel series of β-propanamide derivatives as inhibitors of cholesteryl ester transfer protein(CETP)were synthesized.Previously,H3(IC_(50) 2 μmol/L) was observed to inhibit CETP moderately(Xie et ah,2016).Structural modifications based on H3 led to discovery of the successful CETP inhibitor,known as 1-methyl-4-arylpyrazole.Using a similar approach,compound Q08 was identified as a highly potent CETP inhibitor with an IC_(50) of 490 nmol/L in vitro.展开更多
Rocuronium bromide has been used as an aminosteroid non-depolarizing neuromuscular blocker and muscle relaxant.In this work,a new and efficient route for preparing a key intermediate 2β-(4-morpholinyl)-16β-(1-pyr...Rocuronium bromide has been used as an aminosteroid non-depolarizing neuromuscular blocker and muscle relaxant.In this work,a new and efficient route for preparing a key intermediate 2β-(4-morpholinyl)-16β-(1-pyrrolidinyl)-5α-androstan-3α,17β-diol(6) was developed through a ring-opening of epoxide followed by introducing and pyrrolidine.Compound 6 can easily provide rocuronium bromide and the overall yield of compound 6 in 5 steps increased to 57.8%,which was higher than currently reported methods.Extraordinarily,this method would avoid the generation of disubstituted impurities E and F which are difficult to remove.展开更多
Velvet antler is an important and precious traditional Chinese animal medicine,and was used for strengthening the kidney,anti-fatigue,improving sexual function and so on.But the evaluation methods of velvet antler and...Velvet antler is an important and precious traditional Chinese animal medicine,and was used for strengthening the kidney,anti-fatigue,improving sexual function and so on.But the evaluation methods of velvet antler and the scientific evidence for the use of antler is insufficient.Materials and Vacuum freeze drier was used for dehydration of the fresh antler at-60.,6 pa for 24 h.展开更多
基金Supported by Natural Science Foundation of Liaoning Province,No.201602707
文摘In recent decades,cancer stem cells(CSCs)have been increasingly identified in many malignancies.CSC-related signaling pathways and their functions provide new strategies for treating cancer.The aberrant activation of related signaling pathways(e.g.,Wnt,Notch,and Hedgehog pathways)has been linked to multiple types of malignant tumors,which makes these pathways attractive targets for cancer therapy.CSCs display many characteristic features,such as self-renewal,differentiation,high tumorigenicity,and drug resistance.Therefore,there is an urgent need to develop new therapeutic strategies to target these pathways to control stem cell replication,survival,and differentiation.Notable crosstalk occurs among different signaling pathways and potentially leads to compensatory escape.Therefore,multitarget inhibitors will be one of the main methods to overcome the drug resistance of CSCs.Many small molecule inhibitors of components of signaling pathways in CSCs have entered clinical trials,and some inhibitors,such as vismodegib,sonidegib,and glasdegib,have been approved.Tumor cells are susceptible to sonidegib and vismodegib resistance due to mutations in the Smo protein.The signal transducers and activators of transcription 3(STAT3)inhibitor BBI608 is being evaluated in a phase III trial for a variety of cancers.Structural derivatives of BBI608 are the main focus of STAT3 inhibitor development,which is another strategy for CSC therapy.In addition to the potential pharmacological inhibitors targeting CSCrelated signaling pathways,other methods of targeting CSCs are available,such as nano-drug delivery systems,mitochondrion targeting,autophagy,hyperthermia,immunotherapy,and CSC microenvironment targeting.In addition,we summarize the latest advances in the clinical development of agents targeting CSC-related signaling pathways and other methods of targeting CSCs.
基金the Career Development Program for Yong and Middle-aged Teachers in Shenyang Pharmaceutical University。
文摘Although the appearance of Doxil alleviated the cardiotoxicity of DOX, the progression-free survival of patients was not prolonged compared with traditional medication regimens, and side effects such as hand-foot syndrome has occurred. In order to solve this dilemma, we have designed a novel co-delivery strategy to construct a co-loaded liposome of berberine(BER) and doxorubicin(DOX), which was called Lipo Be Do. The optimal synergistic ratio of the two drugs was screened by cell cytotoxicity experiments in vitro, and the optimal attenuation ratio was further determined by in vivo cardiac H&E staining pathological sections. The optimal combination treatment caused a robust increase in apoptotic cells of 4T1, as compared to drug alone treatment. The prepared co-loaded liposome, Lipo Be Do, had high encapsulation efficiency and good stability. The nanoliposome carrier controlled the biological fate of the drugs and maintained a pre-defined optimal ratio in vivo. The Lipo Be Do significantly inhibited tumor growth in 4T1 murine mammary carcinoma model compared with Doxil(P < 0.05), and completely overcame the myocardial rupture toxicity caused by Doxil in mice. Our co-loaded liposome delivery platform technology provided a new direction for the clinical treatment of triple-negative breast cancer and the safe application of DOX.
基金Supported by Anhui University of Chinese Medicine Foundation(No.2019zrzd13)the Key Project of Anhui Province Department of Education(No.KJ2019A0471)+1 种基金the Key Project of Liaoning Province Department of Education(No.2017LZD03)the National Nature Science Foundation of China(Nos.81473164,81703451,81873019 and 81873351,U1608283).
文摘The therapeutic efficiency of active targeting nanoparticulate drug delivery systems(nano-DDS)is highly compromised by the plasma proteins adsorption on nanoparticles(NPs)surface,which significantly hinders cell membrane receptors to recognize the designed ligands,and provokes the off-target toxicity and rapid clearance of NPs in vivo.Herein,we report a novel dihydroartemisinin(DHA)-decorating nano-DDS that in situ specifically recruits endogenous apolipoprotein E(apoE)on the NPs surface.The apoE-anchored corona is able to prolong PLGA-PEG2000-DHA(PPD)NPs circulation capability in blood,facilitate NPs accumulating in tumor cells by the passive enhanced permeability and retention(EPR)effect and low-density lipoprotein receptor(LDLr)-mediated target transport,and ultimately improve the in vivo antitumor activity.Our findings demonstrate that the strategy of in situ regulated apoE-enriched corona ensures NPs an efficient LDLr-mediated tumor-homing chemotherapy.
基金financial support from the National Natural Science Foundation of China(Grants No.81661148046 and81773762,China)the "Personalized Medicines-Molecular Signature-based Drug Discovery and Development",Strategic Priority Research Program of the Chinese Academy of Sciences(Grants No.XDA12020317,China)+1 种基金the program for Innovative Research Team of the Ministry of Education(China)the program for Liaoning Innovative Research Team at Shenyang Pharmaceutical University(China)
文摘Genomic alterations are commonly found in the signaling pathways of fibroblast growth factor receptors(FGFRs). Although there is no selective FGFR inhibitors in market, several promising inhibitors have been investigated in clinical trials, and showed encouraging efficacies in patients. By designing a hybrid between the FGFR-selectivity-enhancing motif dimethoxybenzene group and our previously identified novel scaffold, we discovered a new series of potent FGFR inhibitors, with the best one showing sub-nanomolar enzymatic activity. After several round of optimization and with the solved crystal structure, detailed structure–activity relationship was elaborated. Together with in vitro metabolic stability tests and in vivo pharmacokinetic profiling, a representative compound(35) was selected and tested in xenograft mouse model, and the result demonstrated that inhibitor 35 was effective against tumors with FGFR genetic alterations, exhibiting potential for further development.
文摘In an attempt to develop potent antitumor agents,new rhodacyanine analogues containing the pyridinium ring(5a-5h),the isoquinolinium ring(6a-6c) and the quinolinium ring(7a-7e) linked to the rhodanine ring via N-N covalent bond were designed, synthesized and evaluated for antitumor activity against human lung cancer cell line(H460) by MTT assay in vitro.Most of the tested compounds showed enhanced antitumor activity with IC_(50) values ranging from 0.006 to 9.2 u,mol/L as compared to the lead compound MKT-077.Among them,the most promising compound 7d(IC_(50) = 0.006μmol/L) was 216.7 times more active than MKT-077(IC_(50) = 1.3μmol/L).The preliminary structure-activity relationship of the target compounds was discussed.
基金National Nature Science Foundation of China(Nos. 81873939 and 31970374)。
文摘Adipose stem cells(ADSCs)have been reported to have multidirectional differentiation potential,and can promote cell proliferation and growth,and nerve regeneration function,which has become a promising treatment regimen forwound repair.Exosomes derived from ADSCs(ADSCs-Exos)have excellenttissuerepairfunctions,including high vascular endothelial growth factor A,fibroblast growth factor_2,hepatocyte growth factor,platelet-derived growth factor subunit BB,and other importantwoundhealingfactors.l Supplementary Figure1,http:/links.lww.com/CM9/A828 is a simplified diagram of the exosome formation and release model.
文摘A simple and efficient HPLC method was developed for quality analysis of flavonoids from Impatiens balsamina L.(IBL)flowers,which were collected from Xingjiang,Anhui,Henan,and Hubei provinces in China.The flavonoids substances in IBL were determined by HPLC through methyl alcohol ultrasonic extraction.A mixture of
基金supported by the National Natural Science Foundation of China (No. 81373324)the program for Innovative Research Team of the Ministry of Education and Program for Liaoning Innovative Research Team in University
文摘A novel series of β-propanamide derivatives as inhibitors of cholesteryl ester transfer protein(CETP)were synthesized.Previously,H3(IC_(50) 2 μmol/L) was observed to inhibit CETP moderately(Xie et ah,2016).Structural modifications based on H3 led to discovery of the successful CETP inhibitor,known as 1-methyl-4-arylpyrazole.Using a similar approach,compound Q08 was identified as a highly potent CETP inhibitor with an IC_(50) of 490 nmol/L in vitro.
基金the National Natural Science Foundation of China (No. 81373259 & No. 81573286)
文摘Rocuronium bromide has been used as an aminosteroid non-depolarizing neuromuscular blocker and muscle relaxant.In this work,a new and efficient route for preparing a key intermediate 2β-(4-morpholinyl)-16β-(1-pyrrolidinyl)-5α-androstan-3α,17β-diol(6) was developed through a ring-opening of epoxide followed by introducing and pyrrolidine.Compound 6 can easily provide rocuronium bromide and the overall yield of compound 6 in 5 steps increased to 57.8%,which was higher than currently reported methods.Extraordinarily,this method would avoid the generation of disubstituted impurities E and F which are difficult to remove.
文摘Velvet antler is an important and precious traditional Chinese animal medicine,and was used for strengthening the kidney,anti-fatigue,improving sexual function and so on.But the evaluation methods of velvet antler and the scientific evidence for the use of antler is insufficient.Materials and Vacuum freeze drier was used for dehydration of the fresh antler at-60.,6 pa for 24 h.