[Objectives]To investigate whether Ailanthone(AIL)could reverse cisplatin resistance in non-small cell lung cancer(NSCLC)by modulating autophagy pathways in A549/DDP cells.[Methods]Cisplatin-resistant A549/DDP cells w...[Objectives]To investigate whether Ailanthone(AIL)could reverse cisplatin resistance in non-small cell lung cancer(NSCLC)by modulating autophagy pathways in A549/DDP cells.[Methods]Cisplatin-resistant A549/DDP cells were treated with AIL(0.6μmol/L),cisplatin(50μg/mL),or their combination.Cell proliferation was assessed by MTT,EdU and colony formation assays;migration by Transwell and wound healing assays;autophagy markers(P62,LC3B,Beclin1,ATG5)by Western blot;LC3B puncta by immunofluorescence;with rescue experiments using rapamycin.[Results]The AIL-cisplatin combination synergistically inhibited proliferation and migration,while downregulating P-gp and MVP.AIL significantly increased P62 accumulation while decreasing LC3B-II,Beclin1 and ATG5.Rapamycin reversed these effects,restoring viability and resistance markers.[Conclusions]AIL reverses cisplatin resistance in NSCLC by inhibiting autophagy through P62/LC3B regulation,offering a promising therapeutic strategy for refractory NSCLC.展开更多
Prostate cancer (PCa) is the most common male cancer [1, 2]. PCa initially depends on androgen receptor (AR) signaling for growth and survival. Androgen deprivation therapy causes a temporary reduction in PCa tumor bu...Prostate cancer (PCa) is the most common male cancer [1, 2]. PCa initially depends on androgen receptor (AR) signaling for growth and survival. Androgen deprivation therapy causes a temporary reduction in PCa tumor burden, but the tumor eventually develops into castrationresistant prostate cancer (CRPC) with the ability to grow again in the absence of androgens [3]. Mechanisms of CRPC progression include AR amplification and overexpression [4], AR gene rearrangement promoting synthesis of constitutively-active truncated AR splice variants (ARVs) [4], and induction of intracrine androgen metabolic enzymes [3]. Current anti-androgen therapies including MDV3100 (Enzalutamide) and abiraterone have focused on the androgen-dependent activation of AR through its ligand-binding domain (LBD), but do not provide a continuing clinical benefit for patients with CRPC and presumably fail due to multiple mechanisms including the expression of AR-Vs lacking the LBD [5]. These AR-Vs signal in the absence of ligand and are therefore resistant to LBD-targeting AR antagonists or agents that repress androgen biosynthesis [6].展开更多
African swine fever(ASF)is an acute,highly contagious and deadly viral disease in swine that jeopardizes the worldwide pig industry.Unfortunately,there are no authoritative vaccine and antiviral drug available for ASF...African swine fever(ASF)is an acute,highly contagious and deadly viral disease in swine that jeopardizes the worldwide pig industry.Unfortunately,there are no authoritative vaccine and antiviral drug available for ASF control.African swine fever virus(ASFV)is the etiological agent of ASF.Among the ASFV proteins,p72 is the most abundant component in the virions and thus a potential target for anti-ASFV drug design.Here,we con-structed a luciferase reporter system driven by the promoter of p72,which is transcribed by the co-transfected ASFV RNA polymerase complex.Using this system,we screened over 3200 natural product compounds and obtained three potent candidates against ASFV.We further evaluated the anti-ASFV effects and proved that among the three candidates,ailanthone(AIL)inhibits the replication of ASFV at the nanomolar concentration(IC_(50)=15 nmol/L).Our in vitro experiments indicated that the antiviral effect of AIL is associated with its inhibition of the HSP90-p23 cochaperone.Finally,we showed the antiviral activity of AIL on Zika virus and hepatitis B virus(HBV),which supports that AIL is a potential broad-spectrum antiviral agent.展开更多
Pulmonary fibrosis poses a significant health threat with very limited therapeutic options available.In this study,we reported the enhanced expression of mesenchymal homobox 1(MEOX1)in pulmonary fibrosis patients,espe...Pulmonary fibrosis poses a significant health threat with very limited therapeutic options available.In this study,we reported the enhanced expression of mesenchymal homobox 1(MEOX1)in pulmonary fibrosis patients,especially in their fibroblasts and endothelial cells,and confirmed MEOX1 as a central orchestrator in the activation of profibrotic genes.By high-throughput screening,we identified Ailanthone(AIL)from a natural compound library as the first small molecule capable of directly targeting and suppressing MEOX1.AIL demonstrated the ability to inhibit both the activation of fibroblasts and endothelial-to-mesenchymal transition of endothelial cells when challenged by transforming growth factor-b1(TGF-b1).In an animal model of bleomycin-induced pulmonary fibrosis,AIL effectively mitigated the fibrotic process and restored respiratory functions.Mechanistically,AIL acted as a suppressor of MEOX1 by disrupting the interaction between the transcription factor JUN and the promoter of MEOX1,thereby inhibiting MEOX1 expression and activity.In summary,our findings pinpointed MEOX1 as a cell-specific and clinically translatable target in fibrosis.Moreover,we demonstrated the potent anti-fibrotic effect of AIL in pulmonary fibrosis,specifically through the suppression of JUN-dependent MEOX1 activation.展开更多
基金Supported by National Natural Science Foundation of China(81703001)Key R&D Project of Hebei Province(19277783D)+1 种基金Natural Science Foundation of Hebei Province(H2021406021)Chengde Medical University Discipline Construction Funds.
文摘[Objectives]To investigate whether Ailanthone(AIL)could reverse cisplatin resistance in non-small cell lung cancer(NSCLC)by modulating autophagy pathways in A549/DDP cells.[Methods]Cisplatin-resistant A549/DDP cells were treated with AIL(0.6μmol/L),cisplatin(50μg/mL),or their combination.Cell proliferation was assessed by MTT,EdU and colony formation assays;migration by Transwell and wound healing assays;autophagy markers(P62,LC3B,Beclin1,ATG5)by Western blot;LC3B puncta by immunofluorescence;with rescue experiments using rapamycin.[Results]The AIL-cisplatin combination synergistically inhibited proliferation and migration,while downregulating P-gp and MVP.AIL significantly increased P62 accumulation while decreasing LC3B-II,Beclin1 and ATG5.Rapamycin reversed these effects,restoring viability and resistance markers.[Conclusions]AIL reverses cisplatin resistance in NSCLC by inhibiting autophagy through P62/LC3B regulation,offering a promising therapeutic strategy for refractory NSCLC.
基金partially supported by Major State Basic Research Development Program of China(Nos.2015CB910400 and 2012CB910400)National Natural Science Foundation of China(Nos.81472788 and 81272463)
文摘Prostate cancer (PCa) is the most common male cancer [1, 2]. PCa initially depends on androgen receptor (AR) signaling for growth and survival. Androgen deprivation therapy causes a temporary reduction in PCa tumor burden, but the tumor eventually develops into castrationresistant prostate cancer (CRPC) with the ability to grow again in the absence of androgens [3]. Mechanisms of CRPC progression include AR amplification and overexpression [4], AR gene rearrangement promoting synthesis of constitutively-active truncated AR splice variants (ARVs) [4], and induction of intracrine androgen metabolic enzymes [3]. Current anti-androgen therapies including MDV3100 (Enzalutamide) and abiraterone have focused on the androgen-dependent activation of AR through its ligand-binding domain (LBD), but do not provide a continuing clinical benefit for patients with CRPC and presumably fail due to multiple mechanisms including the expression of AR-Vs lacking the LBD [5]. These AR-Vs signal in the absence of ligand and are therefore resistant to LBD-targeting AR antagonists or agents that repress androgen biosynthesis [6].
基金the State Key R&D Project to Xu Tan(2022YFE0102200)the Department of Science and Technology of Hunan Province to Xiaofeng Zheng(2019RS1050 and 2021JJ30354)。
文摘African swine fever(ASF)is an acute,highly contagious and deadly viral disease in swine that jeopardizes the worldwide pig industry.Unfortunately,there are no authoritative vaccine and antiviral drug available for ASF control.African swine fever virus(ASFV)is the etiological agent of ASF.Among the ASFV proteins,p72 is the most abundant component in the virions and thus a potential target for anti-ASFV drug design.Here,we con-structed a luciferase reporter system driven by the promoter of p72,which is transcribed by the co-transfected ASFV RNA polymerase complex.Using this system,we screened over 3200 natural product compounds and obtained three potent candidates against ASFV.We further evaluated the anti-ASFV effects and proved that among the three candidates,ailanthone(AIL)inhibits the replication of ASFV at the nanomolar concentration(IC_(50)=15 nmol/L).Our in vitro experiments indicated that the antiviral effect of AIL is associated with its inhibition of the HSP90-p23 cochaperone.Finally,we showed the antiviral activity of AIL on Zika virus and hepatitis B virus(HBV),which supports that AIL is a potential broad-spectrum antiviral agent.
基金support from National Key R&D Program of China(2022YFE0209700)the National Natural Science Foundation of China(82070406,82000080,and 82304486)+1 种基金Guangdong Provincial Drug Administration Science and Technology Innovation Program(2023ZDZ05,2022ZDZ10,China)supported by a funding from the Department of Science and Technology of Guangdong to AS(2024A1515010574,China).
文摘Pulmonary fibrosis poses a significant health threat with very limited therapeutic options available.In this study,we reported the enhanced expression of mesenchymal homobox 1(MEOX1)in pulmonary fibrosis patients,especially in their fibroblasts and endothelial cells,and confirmed MEOX1 as a central orchestrator in the activation of profibrotic genes.By high-throughput screening,we identified Ailanthone(AIL)from a natural compound library as the first small molecule capable of directly targeting and suppressing MEOX1.AIL demonstrated the ability to inhibit both the activation of fibroblasts and endothelial-to-mesenchymal transition of endothelial cells when challenged by transforming growth factor-b1(TGF-b1).In an animal model of bleomycin-induced pulmonary fibrosis,AIL effectively mitigated the fibrotic process and restored respiratory functions.Mechanistically,AIL acted as a suppressor of MEOX1 by disrupting the interaction between the transcription factor JUN and the promoter of MEOX1,thereby inhibiting MEOX1 expression and activity.In summary,our findings pinpointed MEOX1 as a cell-specific and clinically translatable target in fibrosis.Moreover,we demonstrated the potent anti-fibrotic effect of AIL in pulmonary fibrosis,specifically through the suppression of JUN-dependent MEOX1 activation.
