Alveolar bone regeneration has been strongly linked to macrophage polarization.M1 macrophages aggravate alveolar bone loss,whereas M2 macrophages reverse this process.Berberine(BBR),a natural alkaloid isolated and ref...Alveolar bone regeneration has been strongly linked to macrophage polarization.M1 macrophages aggravate alveolar bone loss,whereas M2 macrophages reverse this process.Berberine(BBR),a natural alkaloid isolated and refined from Chinese medicinal plants,has shown therapeutic effects in treating metabolic disorders.In this study,we first discovered that culture supernatant(CS)collected from BBR-treated human bone marrow mesenchymal stem cells(HBMSCs)ameliorated periodontal alveolar bone loss.CS from the BBR-treated HBMSCs contained bioactive materials that suppressed the M1 polarization and induced the M2 polarization of macrophages in vivo and in vitro.To clarify the underlying mechanism,the bioactive materials were applied to different animal models.We discovered macrophage colony-stimulating factor(M-CSF),which regulates macrophage polarization and promotes bone formation,a key macromolecule in the CS.Injection of pure M-CSF attenuated experimental periodontal alveolar bone loss in rats.Colony-stimulating factor 1 receptor(CSF1R)inhibitor or anti-human M-CSF(M-CSF neutralizing antibody,Nab)abolished the therapeutic effects of the CS of BBR-treated HBMSCs.Moreover,AKT phosphorylation in macrophages was activated by the CS,and the AKT activator reversed the negative effect of the CSF1R inhibitor or Nab.These results suggest that the CS of BBR-treated HBMSCs modulates macrophage polarization via the M-CSF/AKT axis.Further studies also showed that CS of BBR-treated HBMSCs accelerated bone formation and M2 polarization in rat teeth extraction sockets.Overall,our findings established an essential role of BBR-treated HBMSCs CS and this might be the first report to show that the products of BBR-treated HBMSCs have active effects on alveolar bone regeneration.展开更多
Tuberculosis(TB)is one of the deadly diseases caused by Mycobacterium tuberculosis(Mtb),which presents a significant public health challenge.Treatment of TB relies on the combination of several anti-TB drugs to create...Tuberculosis(TB)is one of the deadly diseases caused by Mycobacterium tuberculosis(Mtb),which presents a significant public health challenge.Treatment of TB relies on the combination of several anti-TB drugs to create shorter and safer regimens.Therefore,new anti-TB agents working by different mechanisms are urgently needed.FtsZ,a tubulin-like protein with GTPase activity,forms a dynamic Z-ring in cell division.Most of FtsZ inhibitors are designed to inhibit GTPase activity.In Mtb,the function of Z-ring is modulated by SepF,a FtsZ binding protein.The FtsZ/SepF interaction is essential for FtsZ bundling and localization at the site of division.Here,we established a yeast twohybrid based screening system to identify inhibitors of FtsZ/SepF interaction in M.tuberculosis.Using this system,we found compound T0349 showing strong anti-Mtb activity but with low toxicity to other bacteria strains and mice.Moreover,we have demonstrated that T0349 binds specifically to SepF to block FtsZ/SepF interaction by GST pull-down,fluorescence polarization(FP),surface plasmon resonance(SPR)and CRISPRi knockdown assays.Furthermore,T0349 can inhibit bacterial cell division by inducing filamentation and abnormal septum.Our data demonstrated that FtsZ/SepF interaction is a promising anti-TB drug target for identifying agents with novel mechanisms.展开更多
Zika virus(ZIKV)is an emerging pathogen associated with neurological complications,such as Guillain–Barrésyndrome in adults and microcephaly in fetuses and newborns.This mosquito-borne flavivirus causes importan...Zika virus(ZIKV)is an emerging pathogen associated with neurological complications,such as Guillain–Barrésyndrome in adults and microcephaly in fetuses and newborns.This mosquito-borne flavivirus causes important social and sanitary problems owing to its rapid dissemination.However,the development of antivirals against ZIKV is lagging.Although various strategies have been used to study anti-ZIKV agents,approved drugs or vaccines for the treatment(or prevention)of ZIKV infections are currently unavailable.Repurposing clinically approved drugs could be an effective approach to quickly respond to an emergency outbreak of ZIKV infections.The well-established safety profiles and optimal dosage of these clinically approved drugs could provide an economical,safe,and efficacious approach to address ZIKV infections.This review focuses on the recent research and development of agents against ZIKV infection by repurposing clinical drugs.Their characteristics,targets,and potential use in anti-ZIKV therapy are presented.This review provides an update and some successful strategies in the search for anti-ZIKV agents are given.展开更多
In antiviral therapy of hepatitis B virus(HBV)infection,drug resistance remains a huge obstacle to the long-term effectiveness of nucleoside/tide analogs(NAs).Primary resistance mutation(rtM204V)contributes to lamivud...In antiviral therapy of hepatitis B virus(HBV)infection,drug resistance remains a huge obstacle to the long-term effectiveness of nucleoside/tide analogs(NAs).Primary resistance mutation(rtM204V)contributes to lamivudine(LAM)-resistance,and compensatory mutations(rtL180M and rtV173L)restore viral fitness and increase replication efficiency.The evaluation of new anti-viral agents against drug-resistant HBV is limited by the lack of available small-animal models.We established LAM-resistance HBV replication mice models based on clinical LAM-resistant HBV mutants.Double(rtM204VþrtL180M)or triple(rtM204VþrtL180MþrtV173L)lamivudine-resistant mutations were introduced into HBV expression vector,followed by hydrodynamic injection into tail vein of NOD/SCID mice.Viremia was detected on days 5,9,13 and 17 and liver HBV DNA was detected on day 17 after injection.The serum and liver HBV DNA levels in LAM-resistant model carrying triple mutations are the highest among the models.Two NAs,LAM and entecavir(ETV),were used to test the availability of the models.LAM and ETV inhibited viral replication on wild-type model.LAM was no longer effective on LAM-resistant models,but ETV retains a strong activity.Therefore,these models can be used to evaluate anti-viral agents against lamivudine-resistance,affording new opportunities to establish other drug-resistant HBV small-animal models.展开更多
基金supported by the CAMS Innovation Foundation for Medical Sciences(2016-I2M1-011)A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions(2018-87)+1 种基金Jiangsu Province Capability Improvement Project through Science,Technology and Education-Jiangsu Provincial Research Hospital Cultivation Unit(YJXYYJSDW4)Jiangsu Provincial Medical Innovation Center(CXZX202227)。
文摘Alveolar bone regeneration has been strongly linked to macrophage polarization.M1 macrophages aggravate alveolar bone loss,whereas M2 macrophages reverse this process.Berberine(BBR),a natural alkaloid isolated and refined from Chinese medicinal plants,has shown therapeutic effects in treating metabolic disorders.In this study,we first discovered that culture supernatant(CS)collected from BBR-treated human bone marrow mesenchymal stem cells(HBMSCs)ameliorated periodontal alveolar bone loss.CS from the BBR-treated HBMSCs contained bioactive materials that suppressed the M1 polarization and induced the M2 polarization of macrophages in vivo and in vitro.To clarify the underlying mechanism,the bioactive materials were applied to different animal models.We discovered macrophage colony-stimulating factor(M-CSF),which regulates macrophage polarization and promotes bone formation,a key macromolecule in the CS.Injection of pure M-CSF attenuated experimental periodontal alveolar bone loss in rats.Colony-stimulating factor 1 receptor(CSF1R)inhibitor or anti-human M-CSF(M-CSF neutralizing antibody,Nab)abolished the therapeutic effects of the CS of BBR-treated HBMSCs.Moreover,AKT phosphorylation in macrophages was activated by the CS,and the AKT activator reversed the negative effect of the CSF1R inhibitor or Nab.These results suggest that the CS of BBR-treated HBMSCs modulates macrophage polarization via the M-CSF/AKT axis.Further studies also showed that CS of BBR-treated HBMSCs accelerated bone formation and M2 polarization in rat teeth extraction sockets.Overall,our findings established an essential role of BBR-treated HBMSCs CS and this might be the first report to show that the products of BBR-treated HBMSCs have active effects on alveolar bone regeneration.
基金CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-I2M-1-026,2022-I2M-2-002,2021I2M-JB-011,China)National Natural Science Foundation of China(No.81773784)Beijing Key Laboratory of NonClinical Drug Metabolism and PK/PD study(Z141102004414062,China)。
文摘Tuberculosis(TB)is one of the deadly diseases caused by Mycobacterium tuberculosis(Mtb),which presents a significant public health challenge.Treatment of TB relies on the combination of several anti-TB drugs to create shorter and safer regimens.Therefore,new anti-TB agents working by different mechanisms are urgently needed.FtsZ,a tubulin-like protein with GTPase activity,forms a dynamic Z-ring in cell division.Most of FtsZ inhibitors are designed to inhibit GTPase activity.In Mtb,the function of Z-ring is modulated by SepF,a FtsZ binding protein.The FtsZ/SepF interaction is essential for FtsZ bundling and localization at the site of division.Here,we established a yeast twohybrid based screening system to identify inhibitors of FtsZ/SepF interaction in M.tuberculosis.Using this system,we found compound T0349 showing strong anti-Mtb activity but with low toxicity to other bacteria strains and mice.Moreover,we have demonstrated that T0349 binds specifically to SepF to block FtsZ/SepF interaction by GST pull-down,fluorescence polarization(FP),surface plasmon resonance(SPR)and CRISPRi knockdown assays.Furthermore,T0349 can inhibit bacterial cell division by inducing filamentation and abnormal septum.Our data demonstrated that FtsZ/SepF interaction is a promising anti-TB drug target for identifying agents with novel mechanisms.
基金This work was supported by CAMS Major Collaborative Innovation Project(No.2016-I2M-1-011)National Natural Science Foundation of China(No.81773784)+2 种基金Beijing Nova Program(No.Z181100006218075)Basic Scientific Research Program of CAMS(No.2018RC350005)Drug Innovation Major Project(No.2018ZX09711001-002-002).
文摘Zika virus(ZIKV)is an emerging pathogen associated with neurological complications,such as Guillain–Barrésyndrome in adults and microcephaly in fetuses and newborns.This mosquito-borne flavivirus causes important social and sanitary problems owing to its rapid dissemination.However,the development of antivirals against ZIKV is lagging.Although various strategies have been used to study anti-ZIKV agents,approved drugs or vaccines for the treatment(or prevention)of ZIKV infections are currently unavailable.Repurposing clinically approved drugs could be an effective approach to quickly respond to an emergency outbreak of ZIKV infections.The well-established safety profiles and optimal dosage of these clinically approved drugs could provide an economical,safe,and efficacious approach to address ZIKV infections.This review focuses on the recent research and development of agents against ZIKV infection by repurposing clinical drugs.Their characteristics,targets,and potential use in anti-ZIKV therapy are presented.This review provides an update and some successful strategies in the search for anti-ZIKV agents are given.
基金This work was supported by the Basic Scientific Research Program of Materia Medica,CAMS(2013ZD05)State Mega Programs(2012ZX09301002-003/006)+1 种基金the Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study(BZ0150)973 Project(2012CB911103).
文摘In antiviral therapy of hepatitis B virus(HBV)infection,drug resistance remains a huge obstacle to the long-term effectiveness of nucleoside/tide analogs(NAs).Primary resistance mutation(rtM204V)contributes to lamivudine(LAM)-resistance,and compensatory mutations(rtL180M and rtV173L)restore viral fitness and increase replication efficiency.The evaluation of new anti-viral agents against drug-resistant HBV is limited by the lack of available small-animal models.We established LAM-resistance HBV replication mice models based on clinical LAM-resistant HBV mutants.Double(rtM204VþrtL180M)or triple(rtM204VþrtL180MþrtV173L)lamivudine-resistant mutations were introduced into HBV expression vector,followed by hydrodynamic injection into tail vein of NOD/SCID mice.Viremia was detected on days 5,9,13 and 17 and liver HBV DNA was detected on day 17 after injection.The serum and liver HBV DNA levels in LAM-resistant model carrying triple mutations are the highest among the models.Two NAs,LAM and entecavir(ETV),were used to test the availability of the models.LAM and ETV inhibited viral replication on wild-type model.LAM was no longer effective on LAM-resistant models,but ETV retains a strong activity.Therefore,these models can be used to evaluate anti-viral agents against lamivudine-resistance,affording new opportunities to establish other drug-resistant HBV small-animal models.
