Objective:To investigate the antifibrotic effects of curcumin in a transverse aortic constriction(TAC)mouse model and elucidate its molecular mechanisms.Methods:Male C57BL/6 mice underwent TAC and received vehicle,low...Objective:To investigate the antifibrotic effects of curcumin in a transverse aortic constriction(TAC)mouse model and elucidate its molecular mechanisms.Methods:Male C57BL/6 mice underwent TAC and received vehicle,low-dose curcumin(50 mg/kg),high-dose curcumin(200 mg/kg),high-dose curcumin plus a scrambled control antagomir,or high-dose curcumin plus anti-miR-29b treatments.Cardiac function was assessed by echocardiography.Fibrosis was evaluated by histology,collagen volume fraction,and hydroxyproline content.Expression of miR-29b,HDAC4,and fibrosis-related markers(Col1a1,Col3a1,TGF-β1)was measured by quantitative RT-PCR and Western blotting assays.Myocardial procollagen type I carboxy-terminal propeptide was determined by ELISA,and HDAC4-specific enzymatic activity was assayed using a fluorogenic kit.Results:Curcumin improved cardiac function,reduced fibrosis,restored miR-29b expression,and suppressed HDAC4 expression and activity in a dose-dependent manner.Furthermore,curcumin decreased myocardial procollagen type I carboxy-terminal propeptide levels,confirming reduced collagen synthesis.Anti-miR-29b administration partially abrogated the antifibrotic and cardioprotective effects of curcumin.Conclusions:Curcumin attenuates pressure overload-induced cardiac fibrosis and dysfunction in a TAC mouse model via modulation of the miR-29b/HDAC4 axis and suppression of collagen synthesis.展开更多
Iron overload has been evidenced to contribute to obesity-associated metabolic disorders,including insulin resistance.Strategies to reduce iron levels might help manage the metabolic complications associated with obes...Iron overload has been evidenced to contribute to obesity-associated metabolic disorders,including insulin resistance.Strategies to reduce iron levels might help manage the metabolic complications associated with obesity.Here,it is demonstrated that the specific accumulation of oleic acid-modified polyoxovanadates(OPOVs)in adipose tissue leads to the reduction of iron concentrations in adipocytes in mice fed with a high-fat diet(HFD).Conjugation of oleic acids to polyoxovanadates enables tissue-specific depletion of iron from white adipose tissue(WAT)by OPOVs,protecting mice from HFD-induced obesity and obesity-associated metabolic deteriorations.Glucose tolerance and insulin sensitivity are improved in OPOV-treated mice,which demonstrates that the OPOV-induced iron depletion can reverse the metabolic degeneration caused by HFD-induced obesity.Furthermore,a decrease in expression of the marker genes of iron overload suggests the participation of OPOVs in maintaining iron homeostasis and a potential medical application of vanadium clusters in targeting the iron overload caused by obesity.These findings underscore the potential of vanadate-based clusters tailored to address the complex interplay between iron metabolism and metabolic health.展开更多
BACKGROUND Iron overload cardiomyopathy is a significant cause of morbidity and mortality in transfusion-dependent thalassemia patients.Standard iron chelation therapy is less efficient in alleviating iron accumulatio...BACKGROUND Iron overload cardiomyopathy is a significant cause of morbidity and mortality in transfusion-dependent thalassemia patients.Standard iron chelation therapy is less efficient in alleviating iron accumulation in many organs,especially when iron enters the cells via specific calcium channels.AIM To validate our hypothesis that adding amlodipine to the iron chelation regimen is more efficient in alleviating myocardial iron overload.METHODS Five databases,including PubMed,Cochrane Library,Embase,ScienceDirect,and ClinicalTrials.gov,were systematically searched,and three randomized controlled trials involving 144 pediatric patients with transfusion-dependent thalassemia were included in our meta-analysis based on the predefined eligibility criteria.The quality of the included studies was assessed based on the Cochrane collab-oration tool for bias assessment.The primary outcome assessed was myocardial-T2 and myocardial iron concentration,while the secondary results showed serum ferritin level,liver iron concentration,and treatment adverse outcomes.Weighted mean difference and odds ratio were calculated to measure the changes in the estimated treatment effects.RESULTS During the follow-up period,Amlodipine treatment significantly improved cardiac T2 by 2.79 ms compared to the control group[95%confidence interval(CI):0.34-5.24,P=0.03,I2=0%].Additionally,a significant reduction of 0.31 in myocardial iron concentration was observed with amlodipine treatment compared to the control group[95%CI:-0.38-(-0.25),P<0.00001,I2=0%].Liver iron concentration was slightly lower in the amlodipine group by-0.04 mg/g,but this difference was not statistically significant(95%CI:-0.33-0.24,P=0.77,I2=0%).Amlodipine also showed a non-significant trend toward a reduction in serum ferritin levels(-328.86 ng/mL,95%CI:-1212.34-554.62,P=0.47,I2=90%).Regarding safety,there were no significant differences between the groups in the incidence of gastrointestinal upset,hypotension,or lower limb edema.CONCLUSION Amlodipine with iron chelation therapy significantly improved cardiac parameters,including cardiac-T2 and myocardial iron,in patients with transfusion-dependent thalassemia without causing significant adverse events but enhancing the efficacy of iron chelation therapy.展开更多
Objective Iron overload resulting from chronic alcohol consumption may aggravate liver damage,and the potential mechanisms involving ferritinophagic flux and the role of naturally occurring quercetin in alcohol-induce...Objective Iron overload resulting from chronic alcohol consumption may aggravate liver damage,and the potential mechanisms involving ferritinophagic flux and the role of naturally occurring quercetin in alcohol-induced liver disease remain unclear.Methods Adult male C57BL/6J mice were iso-calorically pair-fed with ethanol-containing Lieber De Carli liquid diets according to a chronic-plus-binge ethanol feeding protocol with either quercetin(100 mg/kg.bw)or iron-rich/limited treatment for 12 weeks,and liver damage,as well as the underlying mechanisms of lysosome-dependent ferritinophagy,was explored,following the study of ethanol-incubated HepG2 cells with specific pharmacological reagents or gene regulation in vitro.Results Chronic-plus-binge ethanol feeding led to an increase in the hepatosomatic ratio,hepatic lipid accumulation and triglyceride(TG)content of the mice and induced the release of alanine aminotransferase(ALT),aspartate transaminase(AST),and serum TG levels,which were normalized partially by quercetin treatment or iron limitation but worsened by iron supplementation.Similar findings were observed in vitro.Moreover,quercetin intervention alleviated iron deposition,inhibited the upregulation of p62 and downregulation of nuclear receptor coactivator 4(NCOA4)and microtubule-associated protein 1 light chain 3(LC3)-II,and blocked the colocalization of NCOA4 and ferritin heavy chain and the nuclear translocation of forkhead box protein O1(FOXO1)induced by ethanol.These effects were also observed when the cells were subjected to iron limitation but were abolished by iron supplementation,NCOA4 transfection,or AS1842856,a FOXO1 inhibitor.Conclusion Quercetin ameliorates secondary iron overload and subsequent liver damage caused by alcohol abuse by maintaining ferritinophagic flux and lysosome function via the FOXO1-TFEB NCOA4 signaling pathway.展开更多
In air combat,one effective way to counter an incoming missile attacking an aircraft is to launch a defense missile compared with traditional passive defense strategies such as decoy and electronic countermeasures.To ...In air combat,one effective way to counter an incoming missile attacking an aircraft is to launch a defense missile compared with traditional passive defense strategies such as decoy and electronic countermeasures.To address this issue,this paper proposes a three-body cooperative active defense guidance law with overload constraints from the perspective of a small speed ratio.First,a cooperative guidance-oriented model for active defense is established and linearized to provide a foundation for the design of the guidance law.Then,the essential quantity known as Zero-Effort-Miss(ZEM)is analyzed during the engagement process.In order to minimize the influence of inaccurate estimates of remaining flight time in the ZEM,the concept of Zero-Effort-Velocity(ZEV)is introduced.Subsequently,utilizing the sliding mode control method,the guidance law is designed by selecting the ZEM and ZEV as sliding mode surfaces,combined with the fast power reaching law,and its finite-time stability is analyzed using the Lyapunov method.Furthermore,to quantitatively evaluate the performance of the proposed active defense guidance law,the interception rendezvous angle index is introduced.The proposed active defense guidance law considers integrating information from the incoming missile,aircraft,and defense missile with fewer simplifications and assumptions,and ensures that the aircraft is effectively protected with less overload required for the defense missile.Finally,simulation experiments demonstrate the effectiveness and adaptability of the proposed active defense guidance law.展开更多
When only a portion of the shield lining structures in a full-line tunnel are overloaded,their bearing and failure characteristics are significantly different from those in the full-line overloaded case.In existing st...When only a portion of the shield lining structures in a full-line tunnel are overloaded,their bearing and failure characteristics are significantly different from those in the full-line overloaded case.In existing studies,one or several segmental lining rings have been studied,with overload applied to selected lining rings to analyze the performance evolution of the lining structures;however,this approach fails to reveal the bearing and failure characteristics of shield lining rings under localized overload.To address this research gap,we employ 3D finite element modeling to investigate the mechanical performance and failure mechanisms of shield segmental linings under localized overload conditions,and compare the results with full-line overload scenarios.Additionally,the impact of reinforcing shield segmental linings with steel rings is studied to address issues arising from localized overloads.The results indicate that localized overloads lead to significant ring joint dislocation and higher stress on longitudinal bolts,potentially causing longitudinal bolt failure.Furthermore,the overall deformation of lining rings,segmental joint opening,and stress in circumferential bolts and steel bars is lower compared to full-line overloads.For the same overload level,the convergence deformation of the lining under full-line overload is 1.5 to 2.0 times higher than that under localized overload.For localized overload situations,a reinforcement scheme with steel rings spanning across two adjacent lining rings is more effective than installing steel rings within individual lining rings.This spanning ring reinforcement strategy not only enhances the structural rigidity of each ring,but also limits joint dislocation and reduces stress on longitudinal bolts,with the reduction in maximum ring joint dislocation ranging from 70%to 82%and the reduction in maximum longitudinal bolt stress ranging from 19%to 57%compared to reinforcement within rings.展开更多
Along with the progress of sciences and technologies, a lot of explorations are taken in many countries or organizations in succession. Lunar, the natural satellite of the earth, become a focus of the space discovery ...Along with the progress of sciences and technologies, a lot of explorations are taken in many countries or organizations in succession. Lunar, the natural satellite of the earth, become a focus of the space discovery again recently because of its abundant resource and high value in use. Lunar exploration is also one of the most important projects in China. A primary objective of the probe in lunar is to soft-land a manned spacecraft on the lunar surface. The soft-landing system is the key composition of the lunar lander. In the overall design of lunar lander, the analysis of touchdown dynamics during landing stage is an important work. The rigid-flexible coupling dynamics of a system with flexible cantilevers attached to the main lander is analyzed. The equations are derived from the subsystem method. Results show that the deformations of cantilevers have considerable effect on the overloading of the lunar lander system.展开更多
基金supported by China International Medical Foundation(Z-2019-42-1908-4)Natural Science Basic Research Program of Shaanxi Province(2019JM-440).
文摘Objective:To investigate the antifibrotic effects of curcumin in a transverse aortic constriction(TAC)mouse model and elucidate its molecular mechanisms.Methods:Male C57BL/6 mice underwent TAC and received vehicle,low-dose curcumin(50 mg/kg),high-dose curcumin(200 mg/kg),high-dose curcumin plus a scrambled control antagomir,or high-dose curcumin plus anti-miR-29b treatments.Cardiac function was assessed by echocardiography.Fibrosis was evaluated by histology,collagen volume fraction,and hydroxyproline content.Expression of miR-29b,HDAC4,and fibrosis-related markers(Col1a1,Col3a1,TGF-β1)was measured by quantitative RT-PCR and Western blotting assays.Myocardial procollagen type I carboxy-terminal propeptide was determined by ELISA,and HDAC4-specific enzymatic activity was assayed using a fluorogenic kit.Results:Curcumin improved cardiac function,reduced fibrosis,restored miR-29b expression,and suppressed HDAC4 expression and activity in a dose-dependent manner.Furthermore,curcumin decreased myocardial procollagen type I carboxy-terminal propeptide levels,confirming reduced collagen synthesis.Anti-miR-29b administration partially abrogated the antifibrotic and cardioprotective effects of curcumin.Conclusions:Curcumin attenuates pressure overload-induced cardiac fibrosis and dysfunction in a TAC mouse model via modulation of the miR-29b/HDAC4 axis and suppression of collagen synthesis.
基金supported by the National Natural Science Foundation of China(No.22101086)Guangzhou Basic and Applied Basic Research Project(No.202201010052)Guangdong Basic and Applied Basic Research Foundation(No.2023A1515140030).
文摘Iron overload has been evidenced to contribute to obesity-associated metabolic disorders,including insulin resistance.Strategies to reduce iron levels might help manage the metabolic complications associated with obesity.Here,it is demonstrated that the specific accumulation of oleic acid-modified polyoxovanadates(OPOVs)in adipose tissue leads to the reduction of iron concentrations in adipocytes in mice fed with a high-fat diet(HFD).Conjugation of oleic acids to polyoxovanadates enables tissue-specific depletion of iron from white adipose tissue(WAT)by OPOVs,protecting mice from HFD-induced obesity and obesity-associated metabolic deteriorations.Glucose tolerance and insulin sensitivity are improved in OPOV-treated mice,which demonstrates that the OPOV-induced iron depletion can reverse the metabolic degeneration caused by HFD-induced obesity.Furthermore,a decrease in expression of the marker genes of iron overload suggests the participation of OPOVs in maintaining iron homeostasis and a potential medical application of vanadium clusters in targeting the iron overload caused by obesity.These findings underscore the potential of vanadate-based clusters tailored to address the complex interplay between iron metabolism and metabolic health.
文摘BACKGROUND Iron overload cardiomyopathy is a significant cause of morbidity and mortality in transfusion-dependent thalassemia patients.Standard iron chelation therapy is less efficient in alleviating iron accumulation in many organs,especially when iron enters the cells via specific calcium channels.AIM To validate our hypothesis that adding amlodipine to the iron chelation regimen is more efficient in alleviating myocardial iron overload.METHODS Five databases,including PubMed,Cochrane Library,Embase,ScienceDirect,and ClinicalTrials.gov,were systematically searched,and three randomized controlled trials involving 144 pediatric patients with transfusion-dependent thalassemia were included in our meta-analysis based on the predefined eligibility criteria.The quality of the included studies was assessed based on the Cochrane collab-oration tool for bias assessment.The primary outcome assessed was myocardial-T2 and myocardial iron concentration,while the secondary results showed serum ferritin level,liver iron concentration,and treatment adverse outcomes.Weighted mean difference and odds ratio were calculated to measure the changes in the estimated treatment effects.RESULTS During the follow-up period,Amlodipine treatment significantly improved cardiac T2 by 2.79 ms compared to the control group[95%confidence interval(CI):0.34-5.24,P=0.03,I2=0%].Additionally,a significant reduction of 0.31 in myocardial iron concentration was observed with amlodipine treatment compared to the control group[95%CI:-0.38-(-0.25),P<0.00001,I2=0%].Liver iron concentration was slightly lower in the amlodipine group by-0.04 mg/g,but this difference was not statistically significant(95%CI:-0.33-0.24,P=0.77,I2=0%).Amlodipine also showed a non-significant trend toward a reduction in serum ferritin levels(-328.86 ng/mL,95%CI:-1212.34-554.62,P=0.47,I2=90%).Regarding safety,there were no significant differences between the groups in the incidence of gastrointestinal upset,hypotension,or lower limb edema.CONCLUSION Amlodipine with iron chelation therapy significantly improved cardiac parameters,including cardiac-T2 and myocardial iron,in patients with transfusion-dependent thalassemia without causing significant adverse events but enhancing the efficacy of iron chelation therapy.
基金supported by the National Natural Science Foundation of China(No.82273628).
文摘Objective Iron overload resulting from chronic alcohol consumption may aggravate liver damage,and the potential mechanisms involving ferritinophagic flux and the role of naturally occurring quercetin in alcohol-induced liver disease remain unclear.Methods Adult male C57BL/6J mice were iso-calorically pair-fed with ethanol-containing Lieber De Carli liquid diets according to a chronic-plus-binge ethanol feeding protocol with either quercetin(100 mg/kg.bw)or iron-rich/limited treatment for 12 weeks,and liver damage,as well as the underlying mechanisms of lysosome-dependent ferritinophagy,was explored,following the study of ethanol-incubated HepG2 cells with specific pharmacological reagents or gene regulation in vitro.Results Chronic-plus-binge ethanol feeding led to an increase in the hepatosomatic ratio,hepatic lipid accumulation and triglyceride(TG)content of the mice and induced the release of alanine aminotransferase(ALT),aspartate transaminase(AST),and serum TG levels,which were normalized partially by quercetin treatment or iron limitation but worsened by iron supplementation.Similar findings were observed in vitro.Moreover,quercetin intervention alleviated iron deposition,inhibited the upregulation of p62 and downregulation of nuclear receptor coactivator 4(NCOA4)and microtubule-associated protein 1 light chain 3(LC3)-II,and blocked the colocalization of NCOA4 and ferritin heavy chain and the nuclear translocation of forkhead box protein O1(FOXO1)induced by ethanol.These effects were also observed when the cells were subjected to iron limitation but were abolished by iron supplementation,NCOA4 transfection,or AS1842856,a FOXO1 inhibitor.Conclusion Quercetin ameliorates secondary iron overload and subsequent liver damage caused by alcohol abuse by maintaining ferritinophagic flux and lysosome function via the FOXO1-TFEB NCOA4 signaling pathway.
基金support provided by the National Natural Science Foundation of China(No.62173274)the National Key R&D Program of China(No.2019YFA0405300)+3 种基金the Natural Science Foundation of Hunan Province of China(No.2021JJ10045)Shanghai Aerospace Science and Technology Innovation Fund,China(No.SAST2020-004)Postdoctoral Fellowship Program of CPSF(No.GZB20240989)the Open Research Subject of State Key Laboratory of Intelligent Game,China(No.ZBKF-24-01).
文摘In air combat,one effective way to counter an incoming missile attacking an aircraft is to launch a defense missile compared with traditional passive defense strategies such as decoy and electronic countermeasures.To address this issue,this paper proposes a three-body cooperative active defense guidance law with overload constraints from the perspective of a small speed ratio.First,a cooperative guidance-oriented model for active defense is established and linearized to provide a foundation for the design of the guidance law.Then,the essential quantity known as Zero-Effort-Miss(ZEM)is analyzed during the engagement process.In order to minimize the influence of inaccurate estimates of remaining flight time in the ZEM,the concept of Zero-Effort-Velocity(ZEV)is introduced.Subsequently,utilizing the sliding mode control method,the guidance law is designed by selecting the ZEM and ZEV as sliding mode surfaces,combined with the fast power reaching law,and its finite-time stability is analyzed using the Lyapunov method.Furthermore,to quantitatively evaluate the performance of the proposed active defense guidance law,the interception rendezvous angle index is introduced.The proposed active defense guidance law considers integrating information from the incoming missile,aircraft,and defense missile with fewer simplifications and assumptions,and ensures that the aircraft is effectively protected with less overload required for the defense missile.Finally,simulation experiments demonstrate the effectiveness and adaptability of the proposed active defense guidance law.
基金supported by the National Natural Science Foundation of China(No.52008308).
文摘When only a portion of the shield lining structures in a full-line tunnel are overloaded,their bearing and failure characteristics are significantly different from those in the full-line overloaded case.In existing studies,one or several segmental lining rings have been studied,with overload applied to selected lining rings to analyze the performance evolution of the lining structures;however,this approach fails to reveal the bearing and failure characteristics of shield lining rings under localized overload.To address this research gap,we employ 3D finite element modeling to investigate the mechanical performance and failure mechanisms of shield segmental linings under localized overload conditions,and compare the results with full-line overload scenarios.Additionally,the impact of reinforcing shield segmental linings with steel rings is studied to address issues arising from localized overloads.The results indicate that localized overloads lead to significant ring joint dislocation and higher stress on longitudinal bolts,potentially causing longitudinal bolt failure.Furthermore,the overall deformation of lining rings,segmental joint opening,and stress in circumferential bolts and steel bars is lower compared to full-line overloads.For the same overload level,the convergence deformation of the lining under full-line overload is 1.5 to 2.0 times higher than that under localized overload.For localized overload situations,a reinforcement scheme with steel rings spanning across two adjacent lining rings is more effective than installing steel rings within individual lining rings.This spanning ring reinforcement strategy not only enhances the structural rigidity of each ring,but also limits joint dislocation and reduces stress on longitudinal bolts,with the reduction in maximum ring joint dislocation ranging from 70%to 82%and the reduction in maximum longitudinal bolt stress ranging from 19%to 57%compared to reinforcement within rings.
基金HI-tech Research and Development Program of China
文摘Along with the progress of sciences and technologies, a lot of explorations are taken in many countries or organizations in succession. Lunar, the natural satellite of the earth, become a focus of the space discovery again recently because of its abundant resource and high value in use. Lunar exploration is also one of the most important projects in China. A primary objective of the probe in lunar is to soft-land a manned spacecraft on the lunar surface. The soft-landing system is the key composition of the lunar lander. In the overall design of lunar lander, the analysis of touchdown dynamics during landing stage is an important work. The rigid-flexible coupling dynamics of a system with flexible cantilevers attached to the main lander is analyzed. The equations are derived from the subsystem method. Results show that the deformations of cantilevers have considerable effect on the overloading of the lunar lander system.
