Dysregulated inflammation and multi-organ failure are hallmarks of sepsis,a potentially fatal illness for which there are currently no effective treatments.Fatty acid-binding protein(A-FABP)has been identified in rece...Dysregulated inflammation and multi-organ failure are hallmarks of sepsis,a potentially fatal illness for which there are currently no effective treatments.Fatty acid-binding protein(A-FABP)has been identified in recent research as a crucial mediator of the inflammatory pathways underlying sepsis.In this study,we used a murine model of lipopolysaccharide(LPS)-induced endotoxemia to assess the therapeutic potential of 6H2,a monoclonal antibody that targets A-FABP.In comparison to untreated septic mice,6H2 treatment significantly increased survival rates,decreased histopathological damage in the liver,lungs,kidneys,and heart,and reduced systemic inflammation.According to biochemical analyses,6H2 treatment decreased circulating levels of A-FABP,and this was associated with a reduction in inflammatory markers.These results indicate that A-FABP inhibition is a potentially effective treatment approach for sepsis,with 6H2 demonstrating strong therapeutic efficacy.展开更多
Pathological cardiac hypertrophy is an early and significant cardiac structural characteristic that contributes to the onset and progression of heart failure(HF).Its mainly structural feature is the abnormally enlarge...Pathological cardiac hypertrophy is an early and significant cardiac structural characteristic that contributes to the onset and progression of heart failure(HF).Its mainly structural feature is the abnormally enlarged cardiomyocyte.Effective intervention targets for abnormally enlarged cardiomyocyte remain to be identified.Previous studies have shown that the cellular shape and size can be regulated by the actin related protein 2/3(Arp2/3)complex,which is an actin-binding protein complex involved in the actin nucleation and assembly.However,the roles of the Arp2/3 complex in cardiomyocyte hypertrophy remain unknown.Here our study identifies its novel roles in the occurrence and development of cardiomyocyte hypertrophy.We found that mRNA levels of all subunits from the Arp2/3 complex are significantly upregulated(P<0.05)in the angiotensin Ⅱ(Ang Ⅱ)-induced neonatal rat primary and H9c2 cardiomyocyte hypertrophy.Further studies showed that siRNA-directed ARPC 2 silencing inhibits the reactivation of fetal genes and enlargement of cardiomyocyte area induced by Ang Ⅱ in neonatal rat primary cardiomyocytes(NRCMs)and H9c2 cells(P<0.05).In addition,the upstream activators of the Arp2/3 complex including SH3 protein interacting with Nck,90 kD(SPIN90)and Ras-related C3 botulinum toxin substrate 1(Rac1)/WASp family Verprolin-homologous protein-2(WAVE-2)are upregulated(P<0.05)in Ang Ⅱ-induced neonatal rat primary and H9c2 cardiomyocyte hypertrophy,indicating the excessive activation of the Arp2/3 complex.We further show that CK666,a specific Arp2/3 complex inhibitor,prevents the reactivation of fetal genes and the enlargement of cardiomyocyte area induced by Ang Ⅱ in NRCMs and H9c2 cells(P<0.05).Our results reveal that the Arp2/3 complex plays a crucial role in Ang Ⅱ-induced cardiomyocyte hypertrophy,which is beneficial to further studies about the molecular mechanisms by which the Arp2/3 complex regulates pathological cardiac hypertrophy.展开更多
Objective:This study aimed to prepare doxorubicin hydrochloride liposomes and explore their application value in patients with liver cancer.Methods:Doxorubicin hydrochloride liposomes were prepared using the ammonium ...Objective:This study aimed to prepare doxorubicin hydrochloride liposomes and explore their application value in patients with liver cancer.Methods:Doxorubicin hydrochloride liposomes were prepared using the ammonium sulfate gradient method.Doxorubicin,as a broad-spectrum antitumor drug,has significant toxic and side effects after toxicological investigation.After preparing DOX-Lip,single-factor analysis was used to analyze the effects of solution pH,number of ultrafiltration,oil-water ratio,incubation temperature,and time on the encapsulation efficiency of doxorubicin hydrochloride liposomes.The process was optimized through orthogonal experiments and then applied clinically.110 patients with liver cancer were selected as the research subjects to verify the drug’s effectiveness.Results:The results of this study showed that under optimal process conditions,the prepared doxorubicin hydrochloride liposomes were evenly distributed,similar to spherical shapes,with an average particle size of 85–87 mm and a Zeta potential of 15–16 mV,indicating good encapsulation efficiency.The application of these liposomes to clinical treatment of liver cancer demonstrated good therapeutic effects and could effectively promote favorable patient prognosis.Conclusion:The doxorubicin hydrochloride liposomes prepared through process optimization exhibit strong stability and pronounced sustained-release characteristics,providing a solid foundation for the treatment of liver cancer.展开更多
文摘Dysregulated inflammation and multi-organ failure are hallmarks of sepsis,a potentially fatal illness for which there are currently no effective treatments.Fatty acid-binding protein(A-FABP)has been identified in recent research as a crucial mediator of the inflammatory pathways underlying sepsis.In this study,we used a murine model of lipopolysaccharide(LPS)-induced endotoxemia to assess the therapeutic potential of 6H2,a monoclonal antibody that targets A-FABP.In comparison to untreated septic mice,6H2 treatment significantly increased survival rates,decreased histopathological damage in the liver,lungs,kidneys,and heart,and reduced systemic inflammation.According to biochemical analyses,6H2 treatment decreased circulating levels of A-FABP,and this was associated with a reduction in inflammatory markers.These results indicate that A-FABP inhibition is a potentially effective treatment approach for sepsis,with 6H2 demonstrating strong therapeutic efficacy.
文摘Pathological cardiac hypertrophy is an early and significant cardiac structural characteristic that contributes to the onset and progression of heart failure(HF).Its mainly structural feature is the abnormally enlarged cardiomyocyte.Effective intervention targets for abnormally enlarged cardiomyocyte remain to be identified.Previous studies have shown that the cellular shape and size can be regulated by the actin related protein 2/3(Arp2/3)complex,which is an actin-binding protein complex involved in the actin nucleation and assembly.However,the roles of the Arp2/3 complex in cardiomyocyte hypertrophy remain unknown.Here our study identifies its novel roles in the occurrence and development of cardiomyocyte hypertrophy.We found that mRNA levels of all subunits from the Arp2/3 complex are significantly upregulated(P<0.05)in the angiotensin Ⅱ(Ang Ⅱ)-induced neonatal rat primary and H9c2 cardiomyocyte hypertrophy.Further studies showed that siRNA-directed ARPC 2 silencing inhibits the reactivation of fetal genes and enlargement of cardiomyocyte area induced by Ang Ⅱ in neonatal rat primary cardiomyocytes(NRCMs)and H9c2 cells(P<0.05).In addition,the upstream activators of the Arp2/3 complex including SH3 protein interacting with Nck,90 kD(SPIN90)and Ras-related C3 botulinum toxin substrate 1(Rac1)/WASp family Verprolin-homologous protein-2(WAVE-2)are upregulated(P<0.05)in Ang Ⅱ-induced neonatal rat primary and H9c2 cardiomyocyte hypertrophy,indicating the excessive activation of the Arp2/3 complex.We further show that CK666,a specific Arp2/3 complex inhibitor,prevents the reactivation of fetal genes and the enlargement of cardiomyocyte area induced by Ang Ⅱ in NRCMs and H9c2 cells(P<0.05).Our results reveal that the Arp2/3 complex plays a crucial role in Ang Ⅱ-induced cardiomyocyte hypertrophy,which is beneficial to further studies about the molecular mechanisms by which the Arp2/3 complex regulates pathological cardiac hypertrophy.
基金supported by the National Natural Science Foundation of China (No. 30393130, No. 30572086)the National Basic Research Development Program of China (No. 2006CB504100)the Special Foundation for Doctoral Point in High Educational Institute of China (No.20060089009)
文摘本研究旨在探讨并比较慢性间歇性低压低氧(intermittent hypobaric hypoxia,IHH)和慢性连续性低压低氧(continuous hypobaric hypoxia,CHH)对大鼠血液动力学作用的影响。40只成年Sprague-Dawley大鼠随机分为5组:对照组(CON),28天IHH处理组(IHH28),42天IHH处理组(IHH42),28天CHH组(CHH28)和42天CHH组(CHH42)。IHH大鼠于低压氧舱分别接受28或42天模拟5000m海拔高度低氧(11.1%O2)处理、每天6h。CHH处理大鼠生活在低压氧舱环境中,除每天半小时常氧供食、供水和清洁外,其余时间均分别接受时程为28或42天的模拟5000m海拔高度低氧(11.1%O2)处理。每周定时测定大鼠体重。通过导管法测定基础常氧和急性低氧状态下的血液动力学,包括平均动脉压(mean artery blood pressure,MAP)、心率(heart rate,HR)、左室收缩峰压(left ventricular systolic pressure,LVSP)、正负左室最大压力变化速率(maximum change rate of left ventricular pressure,±LVdP/dtmax)。通过生物化学方法测定大鼠心肌超氧化物岐化酶活性和丙二醛含量。并分别测定全心、左心室和右心室重量。结果显示:(1)CHH42大鼠基础HR和MAP低于CON,IHH和CHH28大鼠(P<0.05)。(2)IHH大鼠表现出明显的抗心肌缺氧/复氧损伤作用,表现为急性低氧状态下的HR、MAP、LVSP和±LVdP/dtmax改变明显低于CON大鼠(P<0.05);CHH大鼠表现出更为明显的抗急性低氧心脏保护作用,表现为急性低氧的HR、MAP、LVSP和±LVdP/dtmax改变明显低于CON和IHH大鼠(P<0.05),但出现复氧损伤作用,表现为复氧过程中血液动力学的恢复明显低于CON和IHH大鼠(P<0.05)。(3)与CON大鼠相比较,IHH和CHH大鼠心肌抗氧化能力明显增强(P<0.05,P<0.01)。(4)与IHH和CON大鼠相比较,CHH大鼠表现明显的右心室肥厚(P<0.01)。结果表明,IHH可诱导有效的心脏保护作用,而无明显的不良反应,因而具有潜在的实际应用价值。
基金This work was supported by the National Basic Research Priorities Programme of China (No. 2006CB503802)the National Natural Science Foundation of China (No. 30330250)
文摘在糖尿病性大血管病变的发病过程中,高血糖以及晚期糖基化终末产物(advanced glycation end products,AGEs)、脂质异常和高胰岛素血症的相互作用较其单独作用可能更重要。本研究采用糖基化白蛋白(glycated serum albumin,GSA)模拟AGEs,观察胰岛素和GSA对大鼠血管平滑肌细胞(vascular smooth muscle cells,VSMCs)的增殖是否存在协同作用,并初步探讨其作用机制。采用组织贴块法分离培养大鼠VSMCs。经过或不经过各种丝裂原激活蛋白激酶(mitogen-activated protein kinases,MAPKs)抑制剂和氧自由基清除剂N-acetylcysteine(NAC)处理后,加入不同浓度的胰岛素、GSA或GSA+胰岛素,用MTT法和细胞计数法检测VSMCs的增殖。采用Western blot检测p38 MAPK和C-Jun N-terminal kinase 1／2(JNK1/2)的磷酸化。结果显示, GSA和胰岛素联合作用促进p38MAPK的磷酸化,而对JNK1/2的磷酸化无明显影响。GSA和胰岛素均可促进VSMCs增殖,而且两者具有协同作用。p38 MAPK抑制剂SB203580和NAC可以抑制GSA和胰岛素联合作用引起的VSMCs增殖。以上结果提示,胰岛素和GSA对促进VSMCs增殖有协同作用,这可能是通过氧化应激敏感的p38 MAPK通路实现的。胰岛素和AGEs的协同作用在糖尿病性动脉粥样硬化和再狭窄的发病过程中可能起重要作用。
基金This works was supported by the Natural Science Foundation of Hubei Province (No. 2002AB128)the National Natural Science Foundation of China (No.30400153).
基金This work was supported by the National Natural Science Foundation of China (No. 30370571)the Natural Science Foundation of Hebei Province (No. 200400628)+2 种基金the Program for New Century Excellent Scholars Ministry of Eduction China (No. 04-0253)
文摘Objective:This study aimed to prepare doxorubicin hydrochloride liposomes and explore their application value in patients with liver cancer.Methods:Doxorubicin hydrochloride liposomes were prepared using the ammonium sulfate gradient method.Doxorubicin,as a broad-spectrum antitumor drug,has significant toxic and side effects after toxicological investigation.After preparing DOX-Lip,single-factor analysis was used to analyze the effects of solution pH,number of ultrafiltration,oil-water ratio,incubation temperature,and time on the encapsulation efficiency of doxorubicin hydrochloride liposomes.The process was optimized through orthogonal experiments and then applied clinically.110 patients with liver cancer were selected as the research subjects to verify the drug’s effectiveness.Results:The results of this study showed that under optimal process conditions,the prepared doxorubicin hydrochloride liposomes were evenly distributed,similar to spherical shapes,with an average particle size of 85–87 mm and a Zeta potential of 15–16 mV,indicating good encapsulation efficiency.The application of these liposomes to clinical treatment of liver cancer demonstrated good therapeutic effects and could effectively promote favorable patient prognosis.Conclusion:The doxorubicin hydrochloride liposomes prepared through process optimization exhibit strong stability and pronounced sustained-release characteristics,providing a solid foundation for the treatment of liver cancer.
