It is shown by the result of the dual-cultured experiment that the inhibitory rate of DZW-47 was 60.42%, and the inhibitory rates of R.solani by actinomyces ZLR-2 and ZLR-11 were 43.75% and 43.05%, lower than that of ...It is shown by the result of the dual-cultured experiment that the inhibitory rate of DZW-47 was 60.42%, and the inhibitory rates of R.solani by actinomyces ZLR-2 and ZLR-11 were 43.75% and 43.05%, lower than that of DZW-47. The inhibitory mycelia growth mechanism of different strains on R.solani was quite different, with DZW-3 mainly on the aspect of hyperparasitism, DZW-21 on the synergism of hyperparasitism and metabolite, DZW-47 on the synergism of nutrient competition and secondary metabolite, ZLR-2 and ZLR-11 on producing secondary metabolite. Controlling efficiency of seedling bed accorded basically with that of the broth. The controlling efficiency of DZW-47, ZLR-2, ZLR-11, DZW-21 and DZW-3 were 97.20%, 95.7%, 94.6%, 93.6% and 89.20%, respectively.展开更多
To improve antagonistic metabolites production of Bacillus subtilis strain BS501a, physical parameters of fermentation and metal inorganic salts in medium, namely initial pH value, culture temperature, fermentation ti...To improve antagonistic metabolites production of Bacillus subtilis strain BS501a, physical parameters of fermentation and metal inorganic salts in medium, namely initial pH value, culture temperature, fermentation time, concentrations of CaC12, FeSO4, ZnSO4, MnSO4 and MgSO4, were optimized using one-factor-at-a-time and orthogonal tests. The results show that the optimal physical parameters of fermentation are an initial pH of 7.0, a culture temperature of 30 ~C, and a fermentation time of 48 h. The optimal concentrations of metal inorganic salts in basal medium are 10.2 mmol/L CaCl2, 0.4 mmol/L FeSO4, 3.5 mmol/L ZnSO4, 0.6 mmol/L MnSO4 and 2.0 mmol/L MgSO4. Among the metal inorganic salts, MgSO4 and MnSO4 play important roles in the improvement of the antagonistic metabolites production of B. subtilis strain BS501a; especially, MgSO4 contributes a highly significant effect. The average diameter of inhibition zone of the BS501a filtered fermentation supernatant （FFS） cultured in the optimal fermentation conditions against Magnaporthe grisea DWBJ329 reaches 71.4 mm, and there is 2.4-fold increase in antifungal activity as compared with 21.2 mm under the pre-optimized conditions.展开更多
The antagonistic activity of Lactobacillus acidophilus KLDS1.0901, KLDS1.0902, KLDSI.1003 and NCFM against Escherichia coli O157 ： H7 were investigated in this study. The culture supematants of all the L. acidophilus...The antagonistic activity of Lactobacillus acidophilus KLDS1.0901, KLDS1.0902, KLDSI.1003 and NCFM against Escherichia coli O157 ： H7 were investigated in this study. The culture supematants of all the L. acidophilus stains showed high bacteriostatic activities against E. coli O 157 ： H7 and the bacteriostatic substances of their Cell-Free Supernatants （CFS） were preliminarily determined from organic acids. The bacteriostatic activity from CFS or viable L. acidophilus against E. coli O157 ： H7 was also assessed by using co-incubation methods, CFS had high bactericidal activity against E. coli O157 ： H7, no viable E. coli O157 ： H7 was detected when 5×10^7 CfU ofE. coli O157 ： H7 was added to 5 mL of CFS and incubated at 37℃ for 2 h. However, L. acidophilus themselves had no bacteriostatic activity after directly contacted with E. coli O157 ： H7. The inhibition E. coli O157 ： H7 adhesion and colonization of L. acidophilus were also investigated based on competition, exclusion and displacement assays. L. acidophilus KLDS1.0901, KLDSI.1003 and NCFM strains were effective to displace E. coli O157 ： H7 from a Caco-2 cell layer in competition and exclusion assays. However, in displacement assay, all of the strains showed no significant antagonistic activities. Meanwhile, the probiotic potential of L. acidophilus strains was investigated based on adhesion assay to Caco-2 cells and anti- inflammatory effects by IL-8 produced in Caco-2 cells. The adhesion ability and anti-inflammatory effects of L. acidophilus strains showed a strain-dependent manner. In general, L. acidophilus KLDS 1.0901 and NCFM showed better probiotic potential than KLDS1.0902 and KLDSI.1003. Thus, the use ofL. acidophilus KLDS1.0901 and NCFM to prevent or treat of diseases associated induced E. coli O157 ： H7 in vivo was suggested.展开更多
The quantitative structure-activity relationship(QSAR) of 2-alkyl-4-(biphenylylmethoxy) pyridine derivatives was studied.Three different alignment methods were used to get the models of the comparative molecular field...The quantitative structure-activity relationship(QSAR) of 2-alkyl-4-(biphenylylmethoxy) pyridine derivatives was studied.Three different alignment methods were used to get the models of the comparative molecular field analysis(CoMFA),the comparative molecular similarity indices analysis(CoMSIA),and the hologram quantitative structure?activity relationship(HQSAR).The statistical results from the established models show believable predictivity based on the cross-validated value(q2>0.5) and the non-validated value(r2>0.9),The analysis on contour maps of CoMFA and CoMSIA models suggests that hydrophobic and hydrogen-bond acceptor fields are important factors that affect the AT1 antagonistic activity of 2-alkyl-4-(biphenylylmethoxy) pyridine derivatives besides the steric and electrostatic fields,The structural modification information from different atom contributions in the HQSAR model is in agreement with that in the 3D-QSAR models.展开更多
Poly(phthalazinone ether sulfone ketone)(PPESK)is a new-generation high-performance thermoplastic resin that exhibits excellent thermal stability and mechanical properties.However,its damage and failure mechanisms und...Poly(phthalazinone ether sulfone ketone)(PPESK)is a new-generation high-performance thermoplastic resin that exhibits excellent thermal stability and mechanical properties.However,its damage and failure mechanisms under high-temperature and high-strain-rate coupling conditions remain unclear,significantly limiting the engineering applications of PPESK-based composites in extreme environments such as aerospace.To address this issue,in this study,a temperature-controlled split Hopkinson pressure bar experimental platform was developed for dynamic tensile/compressive loading scenarios.Combined with scanning electron microscopy and molecular dynamics simulations,the thermomechanical behavior and failure mechanisms of PPESK were systematically investigated over the temperature range of 293-473 K.The study revealed a novel"dynamic hysteresis brittle behavior"and its underlying"segmental activation±response lag antagonistic mechanism".The results showed that the strain-rate-induced response lag of polymer chain segments significantly weakened the viscous dissipation capacity activated by thermal energy at elevated temperatures.Although high-strain-rate conditions led to notable enhancement in the dynamic strength of the material(with an increase of 8%-233%,reaching 130%-330%at elevated temperatures),the fracture surface morphology tended to become smoother,and brittle fracture characteristics became more pronounced.Based on these findings,a temperature±strain rate hysteresis antagonistic function was constructed,which effectively captured the competitive relationship between temperature-driven relaxation behavior and strain-rateinduced hysteresis in thermoplastic resins.A multiscale damage evolution constitutive model with temperature±rate coupling was subsequently established and numerically implemented via the VUMAT user subroutine.This study not only unveils the nonlinear damage mechanisms of PPESK under combined service temperatures and dynamic/static loading conditions,but also provides a strong theoretical foundation and engineering guidance for the constitutive modeling and parametric design of thermoplastic resin-based materials.展开更多
OBJECTIVE To explore the antipost-traumatic-stress-disorder(PTSD) effects and its probable mechanism of YQA14,a dopamine D3 receptor antagonist.METHODS Two PTSD animal models,the rat single prolonged stress(SPS) model...OBJECTIVE To explore the antipost-traumatic-stress-disorder(PTSD) effects and its probable mechanism of YQA14,a dopamine D3 receptor antagonist.METHODS Two PTSD animal models,the rat single prolonged stress(SPS) model and the mouse pre-shock model,were used in this experiment.In the SPS model,adult male Sprague-Dawley(SD) rats were randomly divided into control group,model group,positive group and YQA14 groups with different dosages.In the mouse pre-chock model,dopamine D3 receptor knockout(KO) and wild type(WT) mice were randomly divided into control group,model group,positive group and YQA14 group.After the establishment of animal models,the saline,sertraline(ig) and YQA14(ip)were administered to the animals in the control,model,positive control and test groups respectively.The open field test(OFT) was used to evaluate the locomotor activity while the contextual freezing(CF) measurement and elevated plus maze(EPM) test were used to evaluate the PTSD-like behaviors.RESULTS In the rat SPS model,neither SPS nor drug treatment affected the locomotor activity in rats.However,SPS rats showed significant PTSD-like behaviors with enhanced freezing time in CF(P<0.01) and decreased percentage of entries into open arms and time spent in open arms in EPM(P<0.05,P<0.01).Moreover,compared with the model group,the repeated administration of YQA14(3.125,6.25 and 12.5 mg·kg-1)significantly reduced the freezing time(P<0.01)and increased the percentages of entries into open arms and time spent in open arms(P<0.05).In the mouse pre-shock model,when both model groups showed significant higher freezing time compared with the respective control groups(P<0.05,P<0.01),YQA14 selectively alleviated the freezing time on WT mice(P<0.05) while had no effect on KO mice.In the EPM tests,the WT mice model group showed a significant reduction in the percentage of entries into open arms and time spent in open arms(P<0.05) while D3 R KO mice model group didn′ t show any reduction,compared with respective control groups.Furthermore,daily administration of YQA14 at 12.5 mg·kg-1 both significantly reduced the percentages of entries into and time spent in open arms(P<0.05) but not D3 R KO mice.None of the locomotor activity were significantly affected.CONCLUSION YQA14 could significantly alleviate the PTSD-like behaviors in rodents and the effects were mediated by the blockade of brain D3 receptors.展开更多
Aim The preclinical studies of a novel angiotensin II receptor 1 antagonist 2-（4-（ （1,7＇-dimethyl-2＇- propyl-1H ,3 ＇H-2,5＇-bibenzo [ d ] imidazol-3＇-yl ） methyl） -1H-indol-l-yl ） benzoic acid （ intesartan ...Aim The preclinical studies of a novel angiotensin II receptor 1 antagonist 2-（4-（ （1,7＇-dimethyl-2＇- propyl-1H ,3 ＇H-2,5＇-bibenzo [ d ] imidazol-3＇-yl ） methyl） -1H-indol-l-yl ） benzoic acid （ intesartan ）. Methods The affinity to AT1 receptor of intesartan was tested through radioactive receptor binding assay by -y-counter. The anti-hypertensive activity in spontaneously hypertensive rats （SHRs） at different doses in vivo was tested by tail noninvasive arterial blood pressure measurement system. Pharmacokinetic parameters were analyzed by high per- formance liquid chromatography （HPLC） method. Besides, acute toxicity tests in ICR and Ames reverse mutation assay in tester strain （TA97, TA98, TA100 and TA102） was also detected. Results The binding assays sugges- ted that intesartan displayed high affinity to angiotensin II AT1 receptor with an ICs0 value of （0.36 ± 0. 18） nmol · L^-1. In vivo anti-hypertensive experiments showed that intesartan had an efficient and long-acting effect in reduc- ing blood pressure which could last more than 24 h at the doses of 2 mg· kg^-1, 5 mg · kg^-1 , and 10 mg · kg^-1 in spontaneously hypertensive rats. The minimum effective dose of it was 2 mg · kg^-1 and the T/P value was 54. 18%. Acute toxicity tests suggested that intesartan was safe with the LDs0 value of 526.20 mg · kg^-1. Ames assay proved that it would not cause the mutations of salmonella typhimurium. And the pharmacokinetic experiments showed that it could be absorbed efficiently and metabolized smoothly both in blood and in tissues in wistar rats. Conclusions Intesartan could be considered as a novel anti-hypertension candidate with efficient, long-acting and low toxicity chracteristics.展开更多
The study was to investigate the effect of reducing central sympathetic nervous tone with clonidine on cardiomyocyte contraction,and further to analyze the influence of reducing the central sympathetic nervous tone on...The study was to investigate the effect of reducing central sympathetic nervous tone with clonidine on cardiomyocyte contraction,and further to analyze the influence of reducing the central sympathetic nervous tone on response of β1 and β2-AR in aged ventricular myocytes.Sprague-Dawley rats were randomly divided into three groups:adult group,aged group and aged group with clonidine.展开更多
OBJECTIVE TNF-related apoptosis-inducing ligand(TRAIL)is a promising cancer therapeutic agent due to its minimal toxicity to normal tissues and remarkable apoptotic activity in tumors.However,most breast cancer cells ...OBJECTIVE TNF-related apoptosis-inducing ligand(TRAIL)is a promising cancer therapeutic agent due to its minimal toxicity to normal tissues and remarkable apoptotic activity in tumors.However,most breast cancer cells are resistant to TRAIL-induced apoptosis.Our objectives are to investigate the underlying molecular mechanisms and to develop strategies to overcome such resistance.METHODS To identify modulators of TRAIL-induced apoptosis,we carried out a genome wide si RNA screen.To validate the screening result,we either silenced or overexpressed the identified genes in various breast cancer cells and changes in growth and TRAIL-induced cell apoptosis were determined in vitro and in an orthotopic xenograft mouse model.Finally,we investigated whether small molecules targeting the identified genes improve the effectiveness of TRAIL-therapy.RESULTS We unexpectedly identified androgen receptor(AR)to be responsible for TRAIL resistance.While AR is classically viewed as the key factor in prostate cancer progression,we found that AR expression levels were markedly elevated in human invasive breast cancer specimens including triple-negative breast cancers(TNBC)that are highly aggressive with poor prognosis.Importantly,breast cancer cell lines express different levels of AR that correlated with their TRAIL resistance.AR overexpression in MDA-MB-231 and MDA-MB-436 cells suppressed the TRAIL sensitivity whereas knockdown of AR rendered MCF-7 and MDA-MB-453 cells sensitive to TRAIL-induced apoptosis.AR overexpression also induced TRAIL resistance in breast tumors in vivo.Further,we observed an upregulation of the TRAIL receptor,death receptor 5(DR5)in breast cancer cells,following the removal or inhibition of AR by its antagonists Casodex and MDV3100.Treatment with AR antagonists also enhanced TRAIL-induced breast cancer cell apoptosis.CONCLUSION AR signaling suppresses TRAIL-induced breast cancer cell apoptosis,in part,by suppressing DR5 expression,and a combination of AR antagonists together with TRAIL may be a novel and effective therapy for TNBC.展开更多
Macitentan (MAC) is a pulmonary arterial hypertension (PAH) drug marketed as a tablet and often has stability issues in the final dosage form. Quantitative determination of MAC and its associated impurities in tablet ...Macitentan (MAC) is a pulmonary arterial hypertension (PAH) drug marketed as a tablet and often has stability issues in the final dosage form. Quantitative determination of MAC and its associated impurities in tablet dosage form has not been previously reported. This study quantified impurities present in Macitentan tablets using a binary solvent-based gradient elution method using reversed phase-high performance liquid chromatography.The developed method w as validated per International Conference on Harmonization (ICH) guidelines and the drug product w as subjected to forced degradation studies to evaluate stability. The developed method efficiently separated the drug and impurities (48 min) w ithout interference from solvents,excipients,or other impurities. The developed method met all guidelines in all characteristics w ith recoveries ranging from 85%-115%,linearity w ith r 2≥0. 996 6,and substantial robustness. The stability-indicating nature of the method w as evaluated using stressed conditions (hydrolysis:1 N HCl at 80℃/15 min; 1 N NaOH at 25℃/45 min; humidity stress (90%relative humidity) at 25℃for 24 h,oxidation:at 6%(v/v) H2O2,80℃/15 min,thermolysis:at105℃/16 h and photolysis:UV light at 200 Wh/m2; Fluorescent light at 1. 2 million luxh). Forced degradation experiments show ed that the developed method w as effective for impurity profiling. All stressed samples w ere assayed and mass balance w as> 96%. Forced degradation results indicated that MAC tablets w ere sensitive to hydrolysis (acid and alkali) and thermal conditions. The developed method is suitable for both assay and impurity determination,w hich is applicable to the pharmaceutical industry.展开更多
基金Supported by Technological Department Momentous Item of Heilongjiang Province(GA06C101-07)
文摘It is shown by the result of the dual-cultured experiment that the inhibitory rate of DZW-47 was 60.42%, and the inhibitory rates of R.solani by actinomyces ZLR-2 and ZLR-11 were 43.75% and 43.05%, lower than that of DZW-47. The inhibitory mycelia growth mechanism of different strains on R.solani was quite different, with DZW-3 mainly on the aspect of hyperparasitism, DZW-21 on the synergism of hyperparasitism and metabolite, DZW-47 on the synergism of nutrient competition and secondary metabolite, ZLR-2 and ZLR-11 on producing secondary metabolite. Controlling efficiency of seedling bed accorded basically with that of the broth. The controlling efficiency of DZW-47, ZLR-2, ZLR-11, DZW-21 and DZW-3 were 97.20%, 95.7%, 94.6%, 93.6% and 89.20%, respectively.
基金Project(2010A210003) supported by Henan Province Natural Sciences Research PlanProject(0910SGYS34370-2) supported by Zhengzhou City Science and Technology Research PlanProject supported by the Youth Backbone Teacher of Universities in Henan Province Grants Plan
文摘To improve antagonistic metabolites production of Bacillus subtilis strain BS501a, physical parameters of fermentation and metal inorganic salts in medium, namely initial pH value, culture temperature, fermentation time, concentrations of CaC12, FeSO4, ZnSO4, MnSO4 and MgSO4, were optimized using one-factor-at-a-time and orthogonal tests. The results show that the optimal physical parameters of fermentation are an initial pH of 7.0, a culture temperature of 30 ~C, and a fermentation time of 48 h. The optimal concentrations of metal inorganic salts in basal medium are 10.2 mmol/L CaCl2, 0.4 mmol/L FeSO4, 3.5 mmol/L ZnSO4, 0.6 mmol/L MnSO4 and 2.0 mmol/L MgSO4. Among the metal inorganic salts, MgSO4 and MnSO4 play important roles in the improvement of the antagonistic metabolites production of B. subtilis strain BS501a; especially, MgSO4 contributes a highly significant effect. The average diameter of inhibition zone of the BS501a filtered fermentation supernatant （FFS） cultured in the optimal fermentation conditions against Magnaporthe grisea DWBJ329 reaches 71.4 mm, and there is 2.4-fold increase in antifungal activity as compared with 21.2 mm under the pre-optimized conditions.
基金Supported by the Agro-scientific Research of China(201203009)the Ministry of Agriculture,China
文摘The antagonistic activity of Lactobacillus acidophilus KLDS1.0901, KLDS1.0902, KLDSI.1003 and NCFM against Escherichia coli O157 ： H7 were investigated in this study. The culture supematants of all the L. acidophilus stains showed high bacteriostatic activities against E. coli O 157 ： H7 and the bacteriostatic substances of their Cell-Free Supernatants （CFS） were preliminarily determined from organic acids. The bacteriostatic activity from CFS or viable L. acidophilus against E. coli O157 ： H7 was also assessed by using co-incubation methods, CFS had high bactericidal activity against E. coli O157 ： H7, no viable E. coli O157 ： H7 was detected when 5×10^7 CfU ofE. coli O157 ： H7 was added to 5 mL of CFS and incubated at 37℃ for 2 h. However, L. acidophilus themselves had no bacteriostatic activity after directly contacted with E. coli O157 ： H7. The inhibition E. coli O157 ： H7 adhesion and colonization of L. acidophilus were also investigated based on competition, exclusion and displacement assays. L. acidophilus KLDS1.0901, KLDSI.1003 and NCFM strains were effective to displace E. coli O157 ： H7 from a Caco-2 cell layer in competition and exclusion assays. However, in displacement assay, all of the strains showed no significant antagonistic activities. Meanwhile, the probiotic potential of L. acidophilus strains was investigated based on adhesion assay to Caco-2 cells and anti- inflammatory effects by IL-8 produced in Caco-2 cells. The adhesion ability and anti-inflammatory effects of L. acidophilus strains showed a strain-dependent manner. In general, L. acidophilus KLDS 1.0901 and NCFM showed better probiotic potential than KLDS1.0902 and KLDSI.1003. Thus, the use ofL. acidophilus KLDS1.0901 and NCFM to prevent or treat of diseases associated induced E. coli O157 ： H7 in vivo was suggested.
基金Project(20876180) supported by the National Natural Science Foundation of China
文摘The quantitative structure-activity relationship(QSAR) of 2-alkyl-4-(biphenylylmethoxy) pyridine derivatives was studied.Three different alignment methods were used to get the models of the comparative molecular field analysis(CoMFA),the comparative molecular similarity indices analysis(CoMSIA),and the hologram quantitative structure?activity relationship(HQSAR).The statistical results from the established models show believable predictivity based on the cross-validated value(q2>0.5) and the non-validated value(r2>0.9),The analysis on contour maps of CoMFA and CoMSIA models suggests that hydrophobic and hydrogen-bond acceptor fields are important factors that affect the AT1 antagonistic activity of 2-alkyl-4-(biphenylylmethoxy) pyridine derivatives besides the steric and electrostatic fields,The structural modification information from different atom contributions in the HQSAR model is in agreement with that in the 3D-QSAR models.
基金supported by National Key Research and Development Program"Advanced Structures and Composite Materials"Special Project[Grant No.2024YFB3712800]the Fundamental Research Funds for the Central Universities[Grant No.DUT22-LAB605]Liaoning Province's"Unveiling the List and Leading the Way"Science and Technology Research and Development Special Project[Grant No.2022JH1/10400043]。
文摘Poly(phthalazinone ether sulfone ketone)(PPESK)is a new-generation high-performance thermoplastic resin that exhibits excellent thermal stability and mechanical properties.However,its damage and failure mechanisms under high-temperature and high-strain-rate coupling conditions remain unclear,significantly limiting the engineering applications of PPESK-based composites in extreme environments such as aerospace.To address this issue,in this study,a temperature-controlled split Hopkinson pressure bar experimental platform was developed for dynamic tensile/compressive loading scenarios.Combined with scanning electron microscopy and molecular dynamics simulations,the thermomechanical behavior and failure mechanisms of PPESK were systematically investigated over the temperature range of 293-473 K.The study revealed a novel"dynamic hysteresis brittle behavior"and its underlying"segmental activation±response lag antagonistic mechanism".The results showed that the strain-rate-induced response lag of polymer chain segments significantly weakened the viscous dissipation capacity activated by thermal energy at elevated temperatures.Although high-strain-rate conditions led to notable enhancement in the dynamic strength of the material(with an increase of 8%-233%,reaching 130%-330%at elevated temperatures),the fracture surface morphology tended to become smoother,and brittle fracture characteristics became more pronounced.Based on these findings,a temperature±strain rate hysteresis antagonistic function was constructed,which effectively captured the competitive relationship between temperature-driven relaxation behavior and strain-rateinduced hysteresis in thermoplastic resins.A multiscale damage evolution constitutive model with temperature±rate coupling was subsequently established and numerically implemented via the VUMAT user subroutine.This study not only unveils the nonlinear damage mechanisms of PPESK under combined service temperatures and dynamic/static loading conditions,but also provides a strong theoretical foundation and engineering guidance for the constitutive modeling and parametric design of thermoplastic resin-based materials.
基金National Key Research and DevelopmentProgram of China (2016YFC0800907)MedicalInnovation Program (16CXZ033)+2 种基金National KeyBasic Research Program (2015CB553504)National Natural Science Foundation of China(8157340581373385).
文摘OBJECTIVE To explore the antipost-traumatic-stress-disorder(PTSD) effects and its probable mechanism of YQA14,a dopamine D3 receptor antagonist.METHODS Two PTSD animal models,the rat single prolonged stress(SPS) model and the mouse pre-shock model,were used in this experiment.In the SPS model,adult male Sprague-Dawley(SD) rats were randomly divided into control group,model group,positive group and YQA14 groups with different dosages.In the mouse pre-chock model,dopamine D3 receptor knockout(KO) and wild type(WT) mice were randomly divided into control group,model group,positive group and YQA14 group.After the establishment of animal models,the saline,sertraline(ig) and YQA14(ip)were administered to the animals in the control,model,positive control and test groups respectively.The open field test(OFT) was used to evaluate the locomotor activity while the contextual freezing(CF) measurement and elevated plus maze(EPM) test were used to evaluate the PTSD-like behaviors.RESULTS In the rat SPS model,neither SPS nor drug treatment affected the locomotor activity in rats.However,SPS rats showed significant PTSD-like behaviors with enhanced freezing time in CF(P<0.01) and decreased percentage of entries into open arms and time spent in open arms in EPM(P<0.05,P<0.01).Moreover,compared with the model group,the repeated administration of YQA14(3.125,6.25 and 12.5 mg·kg-1)significantly reduced the freezing time(P<0.01)and increased the percentages of entries into open arms and time spent in open arms(P<0.05).In the mouse pre-shock model,when both model groups showed significant higher freezing time compared with the respective control groups(P<0.05,P<0.01),YQA14 selectively alleviated the freezing time on WT mice(P<0.05) while had no effect on KO mice.In the EPM tests,the WT mice model group showed a significant reduction in the percentage of entries into open arms and time spent in open arms(P<0.05) while D3 R KO mice model group didn′ t show any reduction,compared with respective control groups.Furthermore,daily administration of YQA14 at 12.5 mg·kg-1 both significantly reduced the percentages of entries into and time spent in open arms(P<0.05) but not D3 R KO mice.None of the locomotor activity were significantly affected.CONCLUSION YQA14 could significantly alleviate the PTSD-like behaviors in rodents and the effects were mediated by the blockade of brain D3 receptors.
文摘Aim The preclinical studies of a novel angiotensin II receptor 1 antagonist 2-（4-（ （1,7＇-dimethyl-2＇- propyl-1H ,3 ＇H-2,5＇-bibenzo [ d ] imidazol-3＇-yl ） methyl） -1H-indol-l-yl ） benzoic acid （ intesartan ）. Methods The affinity to AT1 receptor of intesartan was tested through radioactive receptor binding assay by -y-counter. The anti-hypertensive activity in spontaneously hypertensive rats （SHRs） at different doses in vivo was tested by tail noninvasive arterial blood pressure measurement system. Pharmacokinetic parameters were analyzed by high per- formance liquid chromatography （HPLC） method. Besides, acute toxicity tests in ICR and Ames reverse mutation assay in tester strain （TA97, TA98, TA100 and TA102） was also detected. Results The binding assays sugges- ted that intesartan displayed high affinity to angiotensin II AT1 receptor with an ICs0 value of （0.36 ± 0. 18） nmol · L^-1. In vivo anti-hypertensive experiments showed that intesartan had an efficient and long-acting effect in reduc- ing blood pressure which could last more than 24 h at the doses of 2 mg· kg^-1, 5 mg · kg^-1 , and 10 mg · kg^-1 in spontaneously hypertensive rats. The minimum effective dose of it was 2 mg · kg^-1 and the T/P value was 54. 18%. Acute toxicity tests suggested that intesartan was safe with the LDs0 value of 526.20 mg · kg^-1. Ames assay proved that it would not cause the mutations of salmonella typhimurium. And the pharmacokinetic experiments showed that it could be absorbed efficiently and metabolized smoothly both in blood and in tissues in wistar rats. Conclusions Intesartan could be considered as a novel anti-hypertension candidate with efficient, long-acting and low toxicity chracteristics.
文摘The study was to investigate the effect of reducing central sympathetic nervous tone with clonidine on cardiomyocyte contraction,and further to analyze the influence of reducing the central sympathetic nervous tone on response of β1 and β2-AR in aged ventricular myocytes.Sprague-Dawley rats were randomly divided into three groups:adult group,aged group and aged group with clonidine.
基金supported by National Institutes of Health(R21CA193271 and R01HL116849)National Natural Science Foundation of China(31100595 and 31300683)
文摘OBJECTIVE TNF-related apoptosis-inducing ligand(TRAIL)is a promising cancer therapeutic agent due to its minimal toxicity to normal tissues and remarkable apoptotic activity in tumors.However,most breast cancer cells are resistant to TRAIL-induced apoptosis.Our objectives are to investigate the underlying molecular mechanisms and to develop strategies to overcome such resistance.METHODS To identify modulators of TRAIL-induced apoptosis,we carried out a genome wide si RNA screen.To validate the screening result,we either silenced or overexpressed the identified genes in various breast cancer cells and changes in growth and TRAIL-induced cell apoptosis were determined in vitro and in an orthotopic xenograft mouse model.Finally,we investigated whether small molecules targeting the identified genes improve the effectiveness of TRAIL-therapy.RESULTS We unexpectedly identified androgen receptor(AR)to be responsible for TRAIL resistance.While AR is classically viewed as the key factor in prostate cancer progression,we found that AR expression levels were markedly elevated in human invasive breast cancer specimens including triple-negative breast cancers(TNBC)that are highly aggressive with poor prognosis.Importantly,breast cancer cell lines express different levels of AR that correlated with their TRAIL resistance.AR overexpression in MDA-MB-231 and MDA-MB-436 cells suppressed the TRAIL sensitivity whereas knockdown of AR rendered MCF-7 and MDA-MB-453 cells sensitive to TRAIL-induced apoptosis.AR overexpression also induced TRAIL resistance in breast tumors in vivo.Further,we observed an upregulation of the TRAIL receptor,death receptor 5(DR5)in breast cancer cells,following the removal or inhibition of AR by its antagonists Casodex and MDV3100.Treatment with AR antagonists also enhanced TRAIL-induced breast cancer cell apoptosis.CONCLUSION AR signaling suppresses TRAIL-induced breast cancer cell apoptosis,in part,by suppressing DR5 expression,and a combination of AR antagonists together with TRAIL may be a novel and effective therapy for TNBC.
基金the management of Sinotherapeutics Inc. for supporting this study
文摘Macitentan (MAC) is a pulmonary arterial hypertension (PAH) drug marketed as a tablet and often has stability issues in the final dosage form. Quantitative determination of MAC and its associated impurities in tablet dosage form has not been previously reported. This study quantified impurities present in Macitentan tablets using a binary solvent-based gradient elution method using reversed phase-high performance liquid chromatography.The developed method w as validated per International Conference on Harmonization (ICH) guidelines and the drug product w as subjected to forced degradation studies to evaluate stability. The developed method efficiently separated the drug and impurities (48 min) w ithout interference from solvents,excipients,or other impurities. The developed method met all guidelines in all characteristics w ith recoveries ranging from 85%-115%,linearity w ith r 2≥0. 996 6,and substantial robustness. The stability-indicating nature of the method w as evaluated using stressed conditions (hydrolysis:1 N HCl at 80℃/15 min; 1 N NaOH at 25℃/45 min; humidity stress (90%relative humidity) at 25℃for 24 h,oxidation:at 6%(v/v) H2O2,80℃/15 min,thermolysis:at105℃/16 h and photolysis:UV light at 200 Wh/m2; Fluorescent light at 1. 2 million luxh). Forced degradation experiments show ed that the developed method w as effective for impurity profiling. All stressed samples w ere assayed and mass balance w as> 96%. Forced degradation results indicated that MAC tablets w ere sensitive to hydrolysis (acid and alkali) and thermal conditions. The developed method is suitable for both assay and impurity determination,w hich is applicable to the pharmaceutical industry.
