Objective:Mcl-1 overexpression confers acquired resistance to Bcl-2 inhibitors in non-small cell lung cancer(NSCLC),but no direct Mcl-1 inhibitor is currently available for clinical use.Thus,novel therapeutic strategi...Objective:Mcl-1 overexpression confers acquired resistance to Bcl-2 inhibitors in non-small cell lung cancer(NSCLC),but no direct Mcl-1 inhibitor is currently available for clinical use.Thus,novel therapeutic strategies are urgently needed to target Mcl-1 and sensitize the anti-NSCLC activity of Bcl-2 inhibitors.Methods:Cell proliferation was measured using sulforhodamine B and colony formation assays,and apoptosis was detected with Annexin V-FITC staining.Gene expression was manipulated using siRNAs and plasmids.Real-time PCR and Western blot were used to measure mRNA and protein levels.Immunoprecipitation and immunofluorescence were used to analyze co-localization o f dual specificity tyrosine-phosphorylation-regulated kinase 1A(DYRK1A)and Mcl-1.Results:Suppression of DYRK1A resulted in reduced Mcl-1 expression in NSCLC cells,whereas overexpression of DYRK1A significantly increased Mcl-1 expression.Suppression of DYRK1A did not alter Mcl-1 mRNA levels,but did result in an accelerated degradation o f Mcl-1 protein in NSCLC cells.Furthermore,DYRK1A mediated proteasome-dependent degradation o f Mcl-1 in NSCLC cells,and DYRK1A co-localized with Mcl-1 in NSCLC cells and was co-expressed with Mcl-1 in tumor samples from lung cancer patients,suggesting that Mcl-1 may be a novel DYRK1A substrate.We showed that combined therapy with harmine and Bcl-2 antagonists significantly inhibited cell proliferation and induced apoptosis in NSCLC cell lines as well as primary NSCLC cells.Conclusions:Mcl-1 is a novel DYRK1A substrate,and the role of DYRK1A in promoting Mcl-1 stability makes it an attractive target for decreasing Bcl-2 inhibitor resistance.展开更多
In the published paper1,errors appeared in Figure 1D on page 391.In Figure 1D,an incorrect gel image was shown for Bcl-xL in NCI-H1299 cells.Figure 1D has been updated to correct the mistake above.The errors do not af...In the published paper1,errors appeared in Figure 1D on page 391.In Figure 1D,an incorrect gel image was shown for Bcl-xL in NCI-H1299 cells.Figure 1D has been updated to correct the mistake above.The errors do not affect the conclusions of this article.We apologize for the errors and for any confusion that they may have caused.展开更多
In this work,the–catechol and–thiol modified starch was prepared by the esterification and amino condensation reaction,then a fully starch based hydrogel was prepared via the thiol-catechol Michael addition reaction...In this work,the–catechol and–thiol modified starch was prepared by the esterification and amino condensation reaction,then a fully starch based hydrogel was prepared via the thiol-catechol Michael addition reaction.The starch hydrogel gained shape memory behaviors by coordinate with Fe^(3+)ions at alkaline condition.1H-NMR had been used to character the structure of the starch derivatives and its character peaks.The hydrogel’s modulus had also been measured before and after coordinating with Fe^(3+)ions in linear area and the result showed that both the hydrogel’s storage modulus and loss modulus kept constant in linear area from 0.1 rad/s to 100 rad/s,which demonstrated a good network was formed inside the hydrogel.Furthermore,the shape memory behaviors had been tested by changing the pH value in solution.The result showed that the hydrogel can keep its temporary shape in high pH condition and recover to its original state after the shaped hydrogel immersed into acidic solution.This hydrogel might have great application prospects in the field of biomedical and engineering.展开更多
Mesenchymal stem cells(MSCs)are pluripotent stem cells isolated from human tissues.Due to their strong self-renewal capacity,pluripotency,and immunomodulatory properties,MSCs have garnered significant attention in cel...Mesenchymal stem cells(MSCs)are pluripotent stem cells isolated from human tissues.Due to their strong self-renewal capacity,pluripotency,and immunomodulatory properties,MSCs have garnered significant attention in cell therapy and tissue regeneration.However,cellular senescence induced by replication or external stimuli can impair MSC proliferation and differentiation,making it crucial to develop interventions that delay or reverse the senescence process.From a traditional Chinese medicine perspective,senescence stems from spleen and stomach deficiency,kidney deficiency,and related factors;thus,medicines that tonify the kidney and promote Qi and blood circulation play vital roles in anti-senescence therapy.Chinese medicine,characterized by low toxicity and multi-target,multi-functional properties,has become prominent in anti-senescence research.This paper examines the MSC senescence process by discussing its causes,characteristics,and mechanisms,then summarizes how active ingredients in herbal medicines and natural compounds reverse MSC senescence,facilitating the discovery of additional anti-senescence Chinese medicines and their effective components.展开更多
基金the National Natural Science Foundation of China(Grant Nos.81702887,81272473)the Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province(Grant No.2020E10021)+6 种基金the Key Medical Disciplines of Zhejiang Province(Grant No.2018-2-3)the Hangzhou Major Science and Technology Project(Grant No.20172016A01)the Zhejiang Provincial Foundation of Natural Science(Grant No.LY19H310004)the Scientific and Technological Developing Scheme of Hangzhou City(Grant No.20191203B49)the Science Research Foundation of Zhejiang Health Bureau(Grant No.2020RC026)the High-level Talents Coming Back from Abroad Innovation,the Entrepreneurship Program in Hangzhouand the Teachers Research Fund of Zhejiang University City College(Grant No.J-19006).
文摘Objective:Mcl-1 overexpression confers acquired resistance to Bcl-2 inhibitors in non-small cell lung cancer(NSCLC),but no direct Mcl-1 inhibitor is currently available for clinical use.Thus,novel therapeutic strategies are urgently needed to target Mcl-1 and sensitize the anti-NSCLC activity of Bcl-2 inhibitors.Methods:Cell proliferation was measured using sulforhodamine B and colony formation assays,and apoptosis was detected with Annexin V-FITC staining.Gene expression was manipulated using siRNAs and plasmids.Real-time PCR and Western blot were used to measure mRNA and protein levels.Immunoprecipitation and immunofluorescence were used to analyze co-localization o f dual specificity tyrosine-phosphorylation-regulated kinase 1A(DYRK1A)and Mcl-1.Results:Suppression of DYRK1A resulted in reduced Mcl-1 expression in NSCLC cells,whereas overexpression of DYRK1A significantly increased Mcl-1 expression.Suppression of DYRK1A did not alter Mcl-1 mRNA levels,but did result in an accelerated degradation o f Mcl-1 protein in NSCLC cells.Furthermore,DYRK1A mediated proteasome-dependent degradation o f Mcl-1 in NSCLC cells,and DYRK1A co-localized with Mcl-1 in NSCLC cells and was co-expressed with Mcl-1 in tumor samples from lung cancer patients,suggesting that Mcl-1 may be a novel DYRK1A substrate.We showed that combined therapy with harmine and Bcl-2 antagonists significantly inhibited cell proliferation and induced apoptosis in NSCLC cell lines as well as primary NSCLC cells.Conclusions:Mcl-1 is a novel DYRK1A substrate,and the role of DYRK1A in promoting Mcl-1 stability makes it an attractive target for decreasing Bcl-2 inhibitor resistance.
文摘In the published paper1,errors appeared in Figure 1D on page 391.In Figure 1D,an incorrect gel image was shown for Bcl-xL in NCI-H1299 cells.Figure 1D has been updated to correct the mistake above.The errors do not affect the conclusions of this article.We apologize for the errors and for any confusion that they may have caused.
基金This work was supported by the National Natural Science Foundation of China(Grant No.51673191)Wuyi University’s special fund(Grant No.5041700128).
文摘In this work,the–catechol and–thiol modified starch was prepared by the esterification and amino condensation reaction,then a fully starch based hydrogel was prepared via the thiol-catechol Michael addition reaction.The starch hydrogel gained shape memory behaviors by coordinate with Fe^(3+)ions at alkaline condition.1H-NMR had been used to character the structure of the starch derivatives and its character peaks.The hydrogel’s modulus had also been measured before and after coordinating with Fe^(3+)ions in linear area and the result showed that both the hydrogel’s storage modulus and loss modulus kept constant in linear area from 0.1 rad/s to 100 rad/s,which demonstrated a good network was formed inside the hydrogel.Furthermore,the shape memory behaviors had been tested by changing the pH value in solution.The result showed that the hydrogel can keep its temporary shape in high pH condition and recover to its original state after the shaped hydrogel immersed into acidic solution.This hydrogel might have great application prospects in the field of biomedical and engineering.
基金supported by Zhejiang Provincial Natural Science Foundation of China(No.LQ23H290006)the National Natural Science Foundation of China(No.82204781)+2 种基金the Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province(No.2020E10021)Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents(No.ZWB-2020-18)Zhejiang Provincial Traditional Chinese Medicine Science and Technology Project(No.2023ZR119).
文摘Mesenchymal stem cells(MSCs)are pluripotent stem cells isolated from human tissues.Due to their strong self-renewal capacity,pluripotency,and immunomodulatory properties,MSCs have garnered significant attention in cell therapy and tissue regeneration.However,cellular senescence induced by replication or external stimuli can impair MSC proliferation and differentiation,making it crucial to develop interventions that delay or reverse the senescence process.From a traditional Chinese medicine perspective,senescence stems from spleen and stomach deficiency,kidney deficiency,and related factors;thus,medicines that tonify the kidney and promote Qi and blood circulation play vital roles in anti-senescence therapy.Chinese medicine,characterized by low toxicity and multi-target,multi-functional properties,has become prominent in anti-senescence research.This paper examines the MSC senescence process by discussing its causes,characteristics,and mechanisms,then summarizes how active ingredients in herbal medicines and natural compounds reverse MSC senescence,facilitating the discovery of additional anti-senescence Chinese medicines and their effective components.
