Objective:Neutrophils play an important role in the pathogenesis of rheumatoid arthritis (RA).In this study,we used the adjuvant-induced arthritis murine model to evaluate the efficacy of celastrol on neutrophil-media...Objective:Neutrophils play an important role in the pathogenesis of rheumatoid arthritis (RA).In this study,we used the adjuvant-induced arthritis murine model to evaluate the efficacy of celastrol on neutrophil-mediated inflammation in RA.Methods:Freund's complete adjuvant-induced arthritis was used as the murine model of RA.Celastrol was intraperitoneally administrated daily after onset of the disease.The joint diameter and inflammatory score were evaluated daily during the treatment period.Myeloperoxidase (MPO) and neutrophil elastase (NE) activities were evaluated by immunohistochemical analyses.Quantitative PCR and enzyme-linked immunoabsorbent assay were used to quantify the expression of cytokines.The expression of apoptosis-related proteins Bcl-2,Bax and caspase-3 were evaluated by western blot.Results:Celastrol suppressed inflammation in joints of arthritic mice and diminished the expression of MPO and NE in the joint tissue.Celastrol significantly inhibited the expression of TNFα and IL-6 induced by LPS in neutrophils in a dose-dependent manner in vitro.Moreover,celastrol induced apoptosis of LPS-stimulated neutrophils by increasing the expression of Bax and cleaved caspase-3 while decreasing Bcl-2 expression.Conclusion:Our findings show that celastrol significantly alleviates murine arthritis by modulating the inflammatory activities of neutrophils.These results indicate that celastrol could serve as an alternative or adjunct modality for the treatment of RA.展开更多
Background:Cantharidin (CTD),a natural toxin produced from Chinese blister beetles,has extensive anti-tumor activity.The present study investigated the effect of CTD on a human colon cancer cell line to elucidate pote...Background:Cantharidin (CTD),a natural toxin produced from Chinese blister beetles,has extensive anti-tumor activity.The present study investigated the effect of CTD on a human colon cancer cell line to elucidate potential new insights regarding the mechanism(s) through which CTD exerts its anti-tumor effects.Materials and methods:The inhibitory effect of CTD on human colon cancer HCT116 cells was evaluated using the IncuCyte ZOOMTM analyzer.Apoptotic cells were detected by Annexin V-FITC/PI assay and cell cycle was evaluated with flow cytometry following propidium iodide staining.Alterations in F-actin microfilaments were analyzed by FITC-phalloidin staining and morphological changes were evaluated with a laser scanning confocal microscope.Cell migration assay was carried out to investigate the effects of CTD on migration of HCT116 cells in vitro.Results:CTD exhibited a significant growth inhibitory effect on HCT116 cells accompanied by an increase in G2/M phase cells,without a significant effect on apoptosis.CTD-treated cells also exhibited a dramatic collapse in their microfilament network and a significant reduction in cell adhesion.Conclusion:CTD inhibits growth by increasing G2/M phase cells and decreasing S phase cells,revealing that CTD exerts a significant growth inhibitory effect primarily through an inhibition of cell cycle progression (a cytostatic effect).Moreover,a negative effect on cell migration may also constitute a contributing factor to its anti-tumor potential.These findings suggest the potential use for developing CTD as a novel anti-cancer therapy that targets metastasis Giving full play to CTD may inhibit tumor transfer.展开更多
Drug-induced liver injury(DILI)is a type of bizarre adverse drug reaction(ADR)damaging liver(L-ADR)which may lead to substantial hospitalizations and mortality.Due to the general low incidence,detection of L-ADR remai...Drug-induced liver injury(DILI)is a type of bizarre adverse drug reaction(ADR)damaging liver(L-ADR)which may lead to substantial hospitalizations and mortality.Due to the general low incidence,detection of L-ADR remains an unsolved public health challenge.Therefore,we used the data of 6.673 million of ADR reports from January 1st,2012 to December 31st,2016 in China National ADR Monitoring System to establish a new database of L-ADR reports for future investigation.Results showed that totally 114,357 ADR reports were retrieved by keywords searching of liver-related injuries from the original heterogeneous system.By cleaning and standardizing the data fields by the dictionary of synonyms and English translation,we resulted 94,593 ADR records reported to liver injury and then created a new database ready for computer mining.The reporting status of L-ADR showed a persistent 1.62-fold change over the past five years.The national population-adjusted reporting numbers of L-ADR manifested an upward trend with age increasing and more evident in men.The annual reporting rate of L-ADR in age group over 80 years old strikingly exceeded the annual DILI incidence rate in general population,despite known underreporting situation in spontaneous ADR reporting system.The percentage of herbal and traditional medicines(H/TM)L-ADR reports in the whole number was 4.5%,while 80.60%of the H/TM reports were new findings.There was great geographical disparity of reported agents,i.e.more cardiovascular and antineoplastic agents were reported in higher socio-demographic index(SDI)regions and more antimicrobials,especially antitubercular agents,were reported in lower SDI regions.In conclusion,this study presented a large-scale,unbiased,unified,and computer-minable L-ADR database for further investigation.Age-,sex-and SDI-related risks of L-ADR incidence warrant to emphasize the precise pharmacovigilance policies within China or other regions in the world.展开更多
Deficiencies in DNA damage response and repair not only can result in genome instability and cancer predisposition,but also can render the cancer cells intrinsically more vulnerable to certain types of DNA damage insu...Deficiencies in DNA damage response and repair not only can result in genome instability and cancer predisposition,but also can render the cancer cells intrinsically more vulnerable to certain types of DNA damage insults.Particularly,replication stress is both a hallmark of human cancers and a common instigator for genome instability and cell death.Here,we review our work based on the genetic knockout studies on Blm and Recql5,two members of the mammalian RecQ helicase family.These studies have uncovered a unique partnership between these two helicases in the implementation of proper mitigation strategies under different circum-stances to promote DNA replication and cell survival and suppress genome instability and cancer.In particular,current studies have revealed the presence of a novel Recql5/RECQL5-dependent mechanism for suppressing replication fork collapse in response to global replication fork stalling following exposure to camptothecin(CPT),a topoisomerase I inhibitor,and a potent inhibitor of DNA replication.The unique partnership between Blm and Recql5 in coping with the challenge imposed by replication stress is discussed.In addition,given that irinotecan and topotecan,two CPT derivatives,are currently used in clinic for treating human cancer patients with very promising results,the potential implication of the new findings from these studies in anticancer treatments is also discussed.展开更多
The low-hanging fruits in plant breeding were harvested a long time ago.Now is the time for optimizing the desired traits,which often requires minor but significant changes in quantitative traits.Quantitative traits c...The low-hanging fruits in plant breeding were harvested a long time ago.Now is the time for optimizing the desired traits,which often requires minor but significant changes in quantitative traits.Quantitative traits can be affected by slight changes in expression levels.However,genetic variation in gene-regulatory regions may be rare and difficult to identify(Rodríguez-Leal et al.,2017).Therefore,methods to induce gradual changes in gene expression are highly warranted.展开更多
基金the National Natural Science Foundation of China(Grant number 81430099)International S&T Cooperation Program of China(Grant number 2014DFA32950)Beijing Municipal Commission of Education(Grant number 521/0101312).
文摘Objective:Neutrophils play an important role in the pathogenesis of rheumatoid arthritis (RA).In this study,we used the adjuvant-induced arthritis murine model to evaluate the efficacy of celastrol on neutrophil-mediated inflammation in RA.Methods:Freund's complete adjuvant-induced arthritis was used as the murine model of RA.Celastrol was intraperitoneally administrated daily after onset of the disease.The joint diameter and inflammatory score were evaluated daily during the treatment period.Myeloperoxidase (MPO) and neutrophil elastase (NE) activities were evaluated by immunohistochemical analyses.Quantitative PCR and enzyme-linked immunoabsorbent assay were used to quantify the expression of cytokines.The expression of apoptosis-related proteins Bcl-2,Bax and caspase-3 were evaluated by western blot.Results:Celastrol suppressed inflammation in joints of arthritic mice and diminished the expression of MPO and NE in the joint tissue.Celastrol significantly inhibited the expression of TNFα and IL-6 induced by LPS in neutrophils in a dose-dependent manner in vitro.Moreover,celastrol induced apoptosis of LPS-stimulated neutrophils by increasing the expression of Bax and cleaved caspase-3 while decreasing Bcl-2 expression.Conclusion:Our findings show that celastrol significantly alleviates murine arthritis by modulating the inflammatory activities of neutrophils.These results indicate that celastrol could serve as an alternative or adjunct modality for the treatment of RA.
文摘Background:Cantharidin (CTD),a natural toxin produced from Chinese blister beetles,has extensive anti-tumor activity.The present study investigated the effect of CTD on a human colon cancer cell line to elucidate potential new insights regarding the mechanism(s) through which CTD exerts its anti-tumor effects.Materials and methods:The inhibitory effect of CTD on human colon cancer HCT116 cells was evaluated using the IncuCyte ZOOMTM analyzer.Apoptotic cells were detected by Annexin V-FITC/PI assay and cell cycle was evaluated with flow cytometry following propidium iodide staining.Alterations in F-actin microfilaments were analyzed by FITC-phalloidin staining and morphological changes were evaluated with a laser scanning confocal microscope.Cell migration assay was carried out to investigate the effects of CTD on migration of HCT116 cells in vitro.Results:CTD exhibited a significant growth inhibitory effect on HCT116 cells accompanied by an increase in G2/M phase cells,without a significant effect on apoptosis.CTD-treated cells also exhibited a dramatic collapse in their microfilament network and a significant reduction in cell adhesion.Conclusion:CTD inhibits growth by increasing G2/M phase cells and decreasing S phase cells,revealing that CTD exerts a significant growth inhibitory effect primarily through an inhibition of cell cycle progression (a cytostatic effect).Moreover,a negative effect on cell migration may also constitute a contributing factor to its anti-tumor potential.These findings suggest the potential use for developing CTD as a novel anti-cancer therapy that targets metastasis Giving full play to CTD may inhibit tumor transfer.
基金This work was financially supported by the National Natural Science Foundation of China(grant numbers Nos.82074112,81630100 and 81721002)the National Science and Technology Directorate Major Project(2015ZX09501-004-001-008,China)+3 种基金the National Industry Program of China(201507004-04)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(ZYYCXTD-C-202005,China)the Beijing Talent Youth Program(JQ21026,China)the Project of China PLA General Hospital(2019-JQPY-003 and 2019MBD-023).
文摘Drug-induced liver injury(DILI)is a type of bizarre adverse drug reaction(ADR)damaging liver(L-ADR)which may lead to substantial hospitalizations and mortality.Due to the general low incidence,detection of L-ADR remains an unsolved public health challenge.Therefore,we used the data of 6.673 million of ADR reports from January 1st,2012 to December 31st,2016 in China National ADR Monitoring System to establish a new database of L-ADR reports for future investigation.Results showed that totally 114,357 ADR reports were retrieved by keywords searching of liver-related injuries from the original heterogeneous system.By cleaning and standardizing the data fields by the dictionary of synonyms and English translation,we resulted 94,593 ADR records reported to liver injury and then created a new database ready for computer mining.The reporting status of L-ADR showed a persistent 1.62-fold change over the past five years.The national population-adjusted reporting numbers of L-ADR manifested an upward trend with age increasing and more evident in men.The annual reporting rate of L-ADR in age group over 80 years old strikingly exceeded the annual DILI incidence rate in general population,despite known underreporting situation in spontaneous ADR reporting system.The percentage of herbal and traditional medicines(H/TM)L-ADR reports in the whole number was 4.5%,while 80.60%of the H/TM reports were new findings.There was great geographical disparity of reported agents,i.e.more cardiovascular and antineoplastic agents were reported in higher socio-demographic index(SDI)regions and more antimicrobials,especially antitubercular agents,were reported in lower SDI regions.In conclusion,this study presented a large-scale,unbiased,unified,and computer-minable L-ADR database for further investigation.Age-,sex-and SDI-related risks of L-ADR incidence warrant to emphasize the precise pharmacovigilance policies within China or other regions in the world.
文摘Deficiencies in DNA damage response and repair not only can result in genome instability and cancer predisposition,but also can render the cancer cells intrinsically more vulnerable to certain types of DNA damage insults.Particularly,replication stress is both a hallmark of human cancers and a common instigator for genome instability and cell death.Here,we review our work based on the genetic knockout studies on Blm and Recql5,two members of the mammalian RecQ helicase family.These studies have uncovered a unique partnership between these two helicases in the implementation of proper mitigation strategies under different circum-stances to promote DNA replication and cell survival and suppress genome instability and cancer.In particular,current studies have revealed the presence of a novel Recql5/RECQL5-dependent mechanism for suppressing replication fork collapse in response to global replication fork stalling following exposure to camptothecin(CPT),a topoisomerase I inhibitor,and a potent inhibitor of DNA replication.The unique partnership between Blm and Recql5 in coping with the challenge imposed by replication stress is discussed.In addition,given that irinotecan and topotecan,two CPT derivatives,are currently used in clinic for treating human cancer patients with very promising results,the potential implication of the new findings from these studies in anticancer treatments is also discussed.
文摘The low-hanging fruits in plant breeding were harvested a long time ago.Now is the time for optimizing the desired traits,which often requires minor but significant changes in quantitative traits.Quantitative traits can be affected by slight changes in expression levels.However,genetic variation in gene-regulatory regions may be rare and difficult to identify(Rodríguez-Leal et al.,2017).Therefore,methods to induce gradual changes in gene expression are highly warranted.
