The multidrug resistance P-glycoprotein (P-gp) expression and func-tion in hematopoietic stem/progenitor cells were studied to investigate whether the inhibition of hematopoietic cell P-gp function by multidrug resist...The multidrug resistance P-glycoprotein (P-gp) expression and func-tion in hematopoietic stem/progenitor cells were studied to investigate whether the inhibition of hematopoietic cell P-gp function by multidrug resistance reversal agent increases the cytotoxicity of chemotherapy drugs on the hematopoietic cells.The expression of P-gp on the surface of CD cells from healthy human marrow was examined by flow cytometry. The multidrug resistance reversal agent MS-209 was used to measure the effects of MS-209 on the Rhodamin-123 uptaking o fCD hematopoietic cells. By using methylcellulose semi-solid culture, normal human granulocyte-macrophage clonal formation unit (CFU-GM) was cultured. The changes in CFU-GM inhibitory rate caused by daunorubicin were determined in the presence or absence of MS-2O9. The results showed that the P-gp expression rate of bone marrow CDL cells was 13. 3 %. MS-209 obviously increased the Rhodamin-123 uptake of CD positive cells. The mean inhibitory rate of daunorubicin for CFU-GM was 29. 6 %, but it was increased to 43. 3 % in the presence of MS-209 with the difference being significant (P< 0. 05). It was concluded that hematopoietic cells expressed P-gp protein and possessed active function- MS-209could inhibit the membrane efflux pump and increase the cytotoxicity of chemotherapy drugs to the clonal growth of hematopoeitic stem cells, suggesting the side effects of these drugs on the hematopoietic system should be taken into consideration in the clinical use.展开更多
A novel class of molecules with structure N-（3-arylpropyl）-9,10-dihydro-9-oxoacridine-4-carboxamides （20- 29） were designed by generating a pharmacophore for potent MDR reversal activity using phase drug design so...A novel class of molecules with structure N-（3-arylpropyl）-9,10-dihydro-9-oxoacridine-4-carboxamides （20- 29） were designed by generating a pharmacophore for potent MDR reversal activity using phase drug design software. The designed molecules were synthesized by a novel synthesis route and evaluated for their inhibitory effects on the transport activity of P-glycoprotein （P-gp） by standard Hoechst 33342 assay method. Based on the pIC50 values of ten title compounds screened, three compounds exhibited better activity as compared to Verapamil used as standard.展开更多
Human immunodeficiency virus(HIV)-1 infection creates a persistent latent reservoir even after antiretroviral therapy,which is the main barrier to HIV cure.One of the most explored strategies is the use of latent reve...Human immunodeficiency virus(HIV)-1 infection creates a persistent latent reservoir even after antiretroviral therapy,which is the main barrier to HIV cure.One of the most explored strategies is the use of latent reversal agents(LRAs)to activate HIV latent reservoirs,followed by immunotherapy to remove infected cells.Immunomodulatory LRAs have the dual advantage of activating viral latency and promoting immune cell elimination of HIV-infected cells.The emergence of novel immunotherapies has also enhanced the possibility ofHIV clearance.Here we review the activity and potential mechanisms of immunomodulatory agonists and immunotherapies.The possible combinational strategies to achieve HIV functional cure and the problems encountered using this approach are discussed.展开更多
Reactivation of the latent viral reservoirs is crucial for a cure of HIV/AIDS.However,current latency reversing agents are inefficient,and the endogenous factors that have the potential to reactivate HIV in vivo remai...Reactivation of the latent viral reservoirs is crucial for a cure of HIV/AIDS.However,current latency reversing agents are inefficient,and the endogenous factors that have the potential to reactivate HIV in vivo remain poorly understood.To identify natural activators of latent HIV-1,we screened a comprehensive peptide/protein library derived from human hemofiltrate,representing the entire blood peptidome,using J-Lat cell lines harboring transcriptionally silent HIV-1 GFP reporter viruses.Fractions potently reactivating HIV-1 from latency contained human Retinol Binding Protein 4(RBP4),the carrier of retinol(Vitamin A).We found that retinol-bound holo-RBP4 but not retinol-free apo-RBP4 strongly reactivates HIV-1 in a variety of latently infected T cell lines.Functional analyses indicate that this reactivation involves activation of the canonical NF-κB pathway and is strengthened by JAK/STAT5 and JNK signalling but does not require retinoic acid production.High levels of RBP4 were detected in plasma from both healthy individuals and people living with HIV-1.Physiological concentrations of RBP4 induced significant viral reactivation in latently infected cells from individuals on long-term antiretroviral therapy with undetectable viral loads.As a potent natural HIV-1 latency-reversing agent,RBP4 offers a novel approach to activating the latent reservoirs and bringing us closer to a cure.展开更多
Multidrug resistance （MDR） is a major cause of cancer chemotherapy failure, and it is important to develop suitable reversal agents to overcome MDR. A majority of chemical reversal agents have acceptable reversal ef...Multidrug resistance （MDR） is a major cause of cancer chemotherapy failure, and it is important to develop suitable reversal agents to overcome MDR. A majority of chemical reversal agents have acceptable reversal effects. However, the toxicity and adverse reactions associated with these agents restricts their clinical use. Chinese medicines （CMs） have lower toxicities and adverse reactions and are associated with multiple components, multiple targets and reduced toxicity. CMs have several advantages and could reverse MDR, decrease drug dosage, enhance patient compliance and increase efficacy. This review summarizes the current progress of CM reversal agents..展开更多
Overexpression of ABCG2 transporter in cancer cells has been linked to the development of multidrug resistance(MDR), an obstacle to cancer therapy. Our recent study uncovered that the MET inhibitor,tepotinib, is a pot...Overexpression of ABCG2 transporter in cancer cells has been linked to the development of multidrug resistance(MDR), an obstacle to cancer therapy. Our recent study uncovered that the MET inhibitor,tepotinib, is a potent reversal agent for ABCB1-mediated MDR. In the present study, we reported for the first time that the MET inhibitor tepotinib can also reverse ABCG2-mediated MDR in vitro and in vivo by directly binding to the drug-binding site of ABCG2 and reversibly inhibiting ABCG2 drug efflux activity, therefore enhancing the cytotoxicity of substrate drugs in drug-resistant cancer cells. Furthermore, the ABCB1/ABCG2 double-transfected cell model and ABCG2 gene knockout cell model demonstrated that tepotinib specifically inhibits the two MDR transporters. In mice bearing drug-resistant tumors, tepotinib increased the intratumoral accumulation of ABCG2 substrate drug topotecan and enhanced its antitumor effect. Therefore, our study provides a new potential of repositioning tepotinib as an ABCG2 inhibitor and combining tepotinib with substrate drugs to antagonize ABCG2-mediated MDR.展开更多
Although the advent of combination antiretroviral therapy can efficiently suppress human immunodeficiency virus(HIV)replication,a complete cure for HIV infection cannot be achieved due to the existence of latent viral...Although the advent of combination antiretroviral therapy can efficiently suppress human immunodeficiency virus(HIV)replication,a complete cure for HIV infection cannot be achieved due to the existence of latent viral reservoirs.In recent years,investigation of HIV cure strategies has become a hot topic in the field.In this article,we review the major barriers to HIV cure,compare the progress and challenges of non-specific and specific latent reversal agents in curing HIV,and discuss possible solutions to the current problems.展开更多
文摘The multidrug resistance P-glycoprotein (P-gp) expression and func-tion in hematopoietic stem/progenitor cells were studied to investigate whether the inhibition of hematopoietic cell P-gp function by multidrug resistance reversal agent increases the cytotoxicity of chemotherapy drugs on the hematopoietic cells.The expression of P-gp on the surface of CD cells from healthy human marrow was examined by flow cytometry. The multidrug resistance reversal agent MS-209 was used to measure the effects of MS-209 on the Rhodamin-123 uptaking o fCD hematopoietic cells. By using methylcellulose semi-solid culture, normal human granulocyte-macrophage clonal formation unit (CFU-GM) was cultured. The changes in CFU-GM inhibitory rate caused by daunorubicin were determined in the presence or absence of MS-2O9. The results showed that the P-gp expression rate of bone marrow CDL cells was 13. 3 %. MS-209 obviously increased the Rhodamin-123 uptake of CD positive cells. The mean inhibitory rate of daunorubicin for CFU-GM was 29. 6 %, but it was increased to 43. 3 % in the presence of MS-209 with the difference being significant (P< 0. 05). It was concluded that hematopoietic cells expressed P-gp protein and possessed active function- MS-209could inhibit the membrane efflux pump and increase the cytotoxicity of chemotherapy drugs to the clonal growth of hematopoeitic stem cells, suggesting the side effects of these drugs on the hematopoietic system should be taken into consideration in the clinical use.
文摘A novel class of molecules with structure N-（3-arylpropyl）-9,10-dihydro-9-oxoacridine-4-carboxamides （20- 29） were designed by generating a pharmacophore for potent MDR reversal activity using phase drug design software. The designed molecules were synthesized by a novel synthesis route and evaluated for their inhibitory effects on the transport activity of P-glycoprotein （P-gp） by standard Hoechst 33342 assay method. Based on the pIC50 values of ten title compounds screened, three compounds exhibited better activity as compared to Verapamil used as standard.
基金funded by the Beijing Municipal Science and Technology Commission(No.D17110700050000).
文摘Human immunodeficiency virus(HIV)-1 infection creates a persistent latent reservoir even after antiretroviral therapy,which is the main barrier to HIV cure.One of the most explored strategies is the use of latent reversal agents(LRAs)to activate HIV latent reservoirs,followed by immunotherapy to remove infected cells.Immunomodulatory LRAs have the dual advantage of activating viral latency and promoting immune cell elimination of HIV-infected cells.The emergence of novel immunotherapies has also enhanced the possibility ofHIV clearance.Here we review the activity and potential mechanisms of immunomodulatory agonists and immunotherapies.The possible combinational strategies to achieve HIV functional cure and the problems encountered using this approach are discussed.
基金supported by the DFG(CRC 1279)the NIH(AI164570,P30 AI045008)+2 种基金the Robert I.Jacobs Fund of the Philadelphia Foundation(LM),and a Herbert Kean,M.D.,Family Professorship(LM)Additionally,we thank the Human Immunology Core(HIC)at the Perelman School of Medicine at the University of Pennsylvania for their support with the Simoa assay,with partial funding from NIH P30 AI045008 and P30 CA016520The HIC is also supported by NIH grants and is identified by RRID:SCR_022380.G.M.L.was supported by NIH U24AI143502.
文摘Reactivation of the latent viral reservoirs is crucial for a cure of HIV/AIDS.However,current latency reversing agents are inefficient,and the endogenous factors that have the potential to reactivate HIV in vivo remain poorly understood.To identify natural activators of latent HIV-1,we screened a comprehensive peptide/protein library derived from human hemofiltrate,representing the entire blood peptidome,using J-Lat cell lines harboring transcriptionally silent HIV-1 GFP reporter viruses.Fractions potently reactivating HIV-1 from latency contained human Retinol Binding Protein 4(RBP4),the carrier of retinol(Vitamin A).We found that retinol-bound holo-RBP4 but not retinol-free apo-RBP4 strongly reactivates HIV-1 in a variety of latently infected T cell lines.Functional analyses indicate that this reactivation involves activation of the canonical NF-κB pathway and is strengthened by JAK/STAT5 and JNK signalling but does not require retinoic acid production.High levels of RBP4 were detected in plasma from both healthy individuals and people living with HIV-1.Physiological concentrations of RBP4 induced significant viral reactivation in latently infected cells from individuals on long-term antiretroviral therapy with undetectable viral loads.As a potent natural HIV-1 latency-reversing agent,RBP4 offers a novel approach to activating the latent reservoirs and bringing us closer to a cure.
基金Supported by the National Natural Science Foundation of China(No.81272972,81472355)Hunan Provincial Science Department Program(No.2014FJ6006)Open-End Fund for the Valuable and Precision Instruments of Central South University(No.CSUZC201638)
文摘Multidrug resistance （MDR） is a major cause of cancer chemotherapy failure, and it is important to develop suitable reversal agents to overcome MDR. A majority of chemical reversal agents have acceptable reversal effects. However, the toxicity and adverse reactions associated with these agents restricts their clinical use. Chinese medicines （CMs） have lower toxicities and adverse reactions and are associated with multiple components, multiple targets and reduced toxicity. CMs have several advantages and could reverse MDR, decrease drug dosage, enhance patient compliance and increase efficacy. This review summarizes the current progress of CM reversal agents..
基金supported by the Key Research and Development Program of Jiangsu Province (BE2020637,China)Wuxi double hundred young and middle-aged medical and health top-notch talent project (No.202014,China)。
文摘Overexpression of ABCG2 transporter in cancer cells has been linked to the development of multidrug resistance(MDR), an obstacle to cancer therapy. Our recent study uncovered that the MET inhibitor,tepotinib, is a potent reversal agent for ABCB1-mediated MDR. In the present study, we reported for the first time that the MET inhibitor tepotinib can also reverse ABCG2-mediated MDR in vitro and in vivo by directly binding to the drug-binding site of ABCG2 and reversibly inhibiting ABCG2 drug efflux activity, therefore enhancing the cytotoxicity of substrate drugs in drug-resistant cancer cells. Furthermore, the ABCB1/ABCG2 double-transfected cell model and ABCG2 gene knockout cell model demonstrated that tepotinib specifically inhibits the two MDR transporters. In mice bearing drug-resistant tumors, tepotinib increased the intratumoral accumulation of ABCG2 substrate drug topotecan and enhanced its antitumor effect. Therefore, our study provides a new potential of repositioning tepotinib as an ABCG2 inhibitor and combining tepotinib with substrate drugs to antagonize ABCG2-mediated MDR.
基金supported by grants from Anhui Science and Technology Bureau(202104a07020032).
文摘Although the advent of combination antiretroviral therapy can efficiently suppress human immunodeficiency virus(HIV)replication,a complete cure for HIV infection cannot be achieved due to the existence of latent viral reservoirs.In recent years,investigation of HIV cure strategies has become a hot topic in the field.In this article,we review the major barriers to HIV cure,compare the progress and challenges of non-specific and specific latent reversal agents in curing HIV,and discuss possible solutions to the current problems.
