OBJECTIVE Leukotriene B4(LTB4)biosynthesis and subsequently neutrophilic inflammation may provide a potential strategy for the treatment of acute lung injury(ALI)or idiopathic pulmonary fibrosis(IPF).To provide a pote...OBJECTIVE Leukotriene B4(LTB4)biosynthesis and subsequently neutrophilic inflammation may provide a potential strategy for the treatment of acute lung injury(ALI)or idiopathic pulmonary fibrosis(IPF).To provide a potential strategy for the treatment of ALI or IPF,we identified potent inhibitors of Leukotriene A4 hydrolase(LTA4H),a key enzyme in the biosynthesis of LTB4.METHODS In this study,we identified two known histone deacetylase(HDAC)inhibitors,suberanilohydroxamic acid(SAHA)and its analogue 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide(M344),as effective inhibitors of LTA4H using enzymatic assay,thermofluor assay,and X-ray crystallographic investigation.We next tested the effect of SAHA and M344 on endogenous LTB4 biosynthesis in neutrophils by ELISA and neutrophil migration by transwell migration assay.A murine experimental model of ALI was induced by lipopolysaccharide(LPS)inhalation.Histopathological analysis of lung tissue using H&E staining revealed the serious pulmonary damage caused by LPS treatment and the effect of the SAHA.We next examined m RNA and protein levels of pro-inflammatory cytokines in lung tissue and bronchoalveolar lavage fluid using q RT-PCR and ELISA to further investigate the underlying mechanisms of anti-inflammatory activities by SAHA.We also investigated the effects of SAHA and M344 on a murine experimental model of bleomycin(BLM)-induced IPF model.RESULTS The results of enzymatic assay and X-ray crystallography showed that both SAHA and M344 bind to LTA4H,significantly decrease LTB4 levels in neutrophil,and markedly diminish early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose.CONCLUSION Collectively,SAHA and M344 would provide promising agents with well-known clinical safety for potential treatment in patients with ALI and IPF via pharmacologically inhibiting LAT4H and blocking LTB4 biosynthesis.展开更多
Aim Head and neck cancers are the eighth most common cancer worldwide. Despite significant ad- vances in the delivery of treatment and surgical reconstruction, the mortality rates for this disease have not improved in...Aim Head and neck cancers are the eighth most common cancer worldwide. Despite significant ad- vances in the delivery of treatment and surgical reconstruction, the mortality rates for this disease have not improved in the past 4 decades. Our previous study has shown that HIV protease inhibitors （HIV PIs） induce cell apoptosis via activating endoplasmic reticulum （ER） stress. It also has been reported that a few HIV PIs are able to radio- sensitize tumor cells. However, the underlying cellular mechanisms remain to be identified. The aim of this study was to examine whether HIV PIs activate the ER stress response and sensitize human head and neck carcinoma cells to radiation. Methods Human SQ20B and Fadu cells and the most commonly used HIV PIs, lopinavir and ritona- vir, were used in this study. The mRNA and protein levels of ER stress-related genes （ CHOP, ATF4, XBP-1, and GRP78 ） were detected by real time RT-PCR and Western blot, respectively. Cell viability and apoptosis were ana- lyzed using Cellometer Vision CBA. After treatment with HIV PIs, cells were irradiated at a dose of 2G or 4G. Col- onies were stained and counted 10 days after irradiation. Results HIV PIs significantly induced activation of ER stress and apoptosis. Treatment of HIV PIs inhibited Akt phosphorylation, induced cell cycle arrest in G1 phase and increased tumor cell sensitivity to irradiation-induced cell death. Conclusion HIV PIs sensitize human head and neck carcinoma cells to radiation by activating ER stress.展开更多
OBJECTIVE Selective serotonin reuptake inhibitors(SSRIs) bind 5-HT transporters,leading to the accumulation of 5-HT and amelioration of depression.Although different mouse strain showed different sensitivity to SSRIs ...OBJECTIVE Selective serotonin reuptake inhibitors(SSRIs) bind 5-HT transporters,leading to the accumulation of 5-HT and amelioration of depression.Although different mouse strain showed different sensitivity to SSRIs in mouse models of depression,the reason for these strain differences remains unclear.Here,therefore,in the present study,we examined immobility time and locomotor activity in two mouse strains,namely,C57BL/6 J and DBA/2 J mice,and the effects of the SSRIs fluoxetine.Furthermore,we analyzed 5-HT transporter binding and reuptake inhibition in both strains to explore their relationship with the immobility and locomotor activity effects of the three SSRIs in these two mouse strains.METHODS Strain differences in SSRI effects in the tail suspension test(TST) and forced swimming test(FST).To initiate our studies,we sought to confirm that SERT strain variation did not alter SERT protein expression,5-HT recognition,or uptake activity when expressed in C57BL/6 J and DBA/2 J mice.Radioligand binding assays were conducted to determine the affinity of the SSRIs for the 5-HT transporters in the two mouse strains.RESULTS SSRI citalopram dose-dependently reduced immobility time in both the FST and TST in DBA/2 J but not C57BL/6 J mouse strains,whereas fluoxetine showed opposite results.Paroxetine reduced immobility time similarly in both strains.The affinity of citalopram for the 5-HT transporter in DBA/2 J mice was 700-fold higher than that for in C57BL/6 J mice,whereas the affinity of fluoxetine in C57BL/6 J mice was 100-fold higher than that in the DBA/2 J mouse.Furthermore,High citalopram concentrations were required to [3 H]5-HT uptake in C57BL/6 J but not DBA/2 J mouse cortical synaptosomes,whereas fluoxetine also showed opposite results.CONCLUSION Immobility duration depends on 5-HT transporter binding levels,leading to apparent strain differences in immobility time in FST and TST.Furthermore,differences in 5-HT transporter binding may cause variations in SSRI responses on behaviors.SERT mutation mice maintained sensitivity to paroxetine,an antidepressant that is unaffected by the mouse mutation.Therefore,the background strain of these mice likely contributes to the acute behavioral actions of SSRIs in immobility time.These differences may help to explain some of the discrepancies in studies that used these strains of mice to examine the role of 5-HT in mouse models of depression.Future studies should investigate additional neural substrates and molecular mechanisms underlying strain variations in mouse models of depression to help identify genetic predispositions to this disorder in humans.展开更多
The inhibition ability of 4-amino-5-phenyl-4H-1, 2, 4-trizole-3-thiol （APTT）, ethylenediaminetetra-acetic acid （EDTA） and thiourea （TU） for mild steel corrosion in 1.0 moFL HC1 solution at 30 ℃ was investigated...The inhibition ability of 4-amino-5-phenyl-4H-1, 2, 4-trizole-3-thiol （APTT）, ethylenediaminetetra-acetic acid （EDTA） and thiourea （TU） for mild steel corrosion in 1.0 moFL HC1 solution at 30 ℃ was investigated. Tafel polarization and electrochemical impedance spectroscopy （EIS） were used to investigate the influence of these organic compounds as corrosion inhibitors of mild steel in 1.0 mol/L HC1 solution at 30 ℃. The inhibition mechanism was discussed in terms of Langrnuir isotherm model. Results obtained from Tafel polarization and impedance measurements are in a good agreement. The inhibition efficiency increases with the increase of the inhibitor concentration. The adsorption of the inhibitors on the mild steel surface follows Langmuir adsorption isotherm and the free energy of adsorption AGads indicates that the adsorption of APTT, EDTA, and TU molecules is a spontaneous process and a typical chemisorption.展开更多
Aim Nicotinamide phosphoribosyltransferase （NAMPT） plays an important role in cardiocerebro-vascu- lar physiopathological process. It is also a promising anticancer target. It is highly desirable to discover novel N...Aim Nicotinamide phosphoribosyltransferase （NAMPT） plays an important role in cardiocerebro-vascu- lar physiopathological process. It is also a promising anticancer target. It is highly desirable to discover novel NAMPT inhibitors as anticancer drug candidates and understand their action mode. Methods We carried out a high throughput screening system on a chemical library of 24434 small-molecules. Anti-proliferative activity were further studied on active compounds. Isothermal titration calorimetry and cellular thermal shift assay were used to confirm the target specificity. Molecular modeling and site-directed mutagenesis studies were taken to investigate the binding mode of NAMPT inhibitor. Results Using high throughput screening system targeting NAMPT, we ob- tained a potent NAMPT inhibitor MS0 （China Patent ZL201110447488.9 ） with excellent in vitro activity （IC50 = 9.87 ± 1.15 nmol · L^-1 ） and anti-proliferative activity against multiple human cancer cell lines including stem-like cancer cells. Structure-activity relationship studies yielded several highly effective analogues. These inhibitors spe- cifically bound NAMPT, rather than downstream NMNAT. We provided the first chemical case using cellular ther- mal shift assay to explain the difference between in vitro and cellular activity; MS7 showed best in vitro activity （ IC50 = 0.93 ± 0.29 nmol · L^-1 ） but worst cellular activity due to poor target engagement in living cells. Site-di- rected mutagenesis studies identified important residues for NAMPT catalytic activity and inhibitor binding. Con- clusions The present study provides a class of novel NAMPT inhibitors for future development of anticancer a- gents. Our findings also contribute to deep understanding the action mode of NAMPT inhibitors and NAMPT basic research in cardiocerebro-vascular system.展开更多
An extract (G-INH) made from mature human granulocytes freshly isolated from normai blood causes human neutrophils to undergo apoptosis in vitro as shown by morphologic changes and by the typical ladder pattern of sma...An extract (G-INH) made from mature human granulocytes freshly isolated from normai blood causes human neutrophils to undergo apoptosis in vitro as shown by morphologic changes and by the typical ladder pattern of small DNA fragments noted on agarose gel electrophoresis of isolated DNA. Apoptosis occurs in from 20% to 30% of neutrophils over 24 hours of culture in vitro and the addition of G-INH to the medium causes a dose-related increase in the incidence of apoptosis. Heating G-INH at 60t for 30 minutes does not destroy its capacity to induce apoptosis but GM-CSF, G-CSF, and to a lesser extent IL-1β, antagonize this action. IL-3 does not diminish G-INH induced apoptosis of neutrophils. Substances, released from, mature neutrophils may participate in regulating the survival of other neutrophils, particularly in sites where the cells are in close proximity as in the marrow. Self destruction of post-mitotic neutrophils in marrow may thus represent an-other level at which regulation of cell production展开更多
OBJECTIVE To examine whether17 AAG and STA9090 have anticonvulsant activity in absence epilepsy.METHODS For the acute seizure study,each group of mice received VPA(dissolved in saline) 100 mg·kg-1,17 AAG(dissolve...OBJECTIVE To examine whether17 AAG and STA9090 have anticonvulsant activity in absence epilepsy.METHODS For the acute seizure study,each group of mice received VPA(dissolved in saline) 100 mg·kg-1,17 AAG(dissolved in 50 μL DMSO) 25 mg·kg-1 or STA9090(dissolved in 20 μL DMSO) 50 mg·kg-1 by oral gavage respectively.The control group received DMSO alone.Thirty minutes after oral gavage,PTZ 80 mg·kg-1 was intraperitoneal injected to induce acute seizures.The number of seizures refers to the total number of epileptic mice after PTZ application.Seizure latency was defined by the time elapsed from PTZ injection to the occurrence of the first seizure.The levels of Hsp90β,GLT-1,GFAP and 20 S proteasome β1 in the cortex and hippocampus were detected by Western blotting.RESULTS The mortality were60% for 17 AAG and 43% for STA9090,and the mortality of valproate group dropped to 20%which decreased by 33.3% compared to model group.Seizure latency of valproate group obviously prolonged compared to model group(P<0.05).But the results demonstrated that 17 AAG and STA9090 had no significant differences in seizure latency.The result of Western blotting has shown that inhibition of Hsp90β significantly reduced expressions of both membrane and cytosolic Hsp90β in the hippocampus and cortex of each group of mice.However,the expressions of GLT-1 and GFAP did not show the significant difference in the cortex and hippocampus.The expression of 20 S proteasome β1 had not been obviously changed in the cortex and hippocampus among the groups.CONCLUSION 17 AAG and STA9090 did not have anticonvulsant activity and did not increase the stability of GLT-1 by disrupting proteasome-dependent GLT-1 degradation in PTZ induced mice of absence epilepsy.展开更多
Urea,paracetamol and glutamine(based on the expired drugs)were selected as vapor-phase corrosion inhibitors(VCIs)to study their corrosion protection effect on red copper in simulated marine atmospheric environment by ...Urea,paracetamol and glutamine(based on the expired drugs)were selected as vapor-phase corrosion inhibitors(VCIs)to study their corrosion protection effect on red copper in simulated marine atmospheric environment by using weight loss,electrochemical measurement techniques(specially designed electrochemical testing device for simulating marine atmospheric environments)and surface morphology characterization analysis(SEM/EDS,XRD,RAMAN,XPS).Weight loss results show that the three corrosion inhibitors have good corrosion inhibition effect on red copper,and the corrosion inhibition efficiency in the order of glutamine(83.62%)>urea(68.46%)>paracetamol(61.47%).Surface morphology characterization analysis provides evidence of adsorption of corrosion inhibitors molecules on the red copper surface,thus forming a protective film that blocked the red copper surface from the aggressive chloride ion attack.展开更多
Background and objective EGFR-tyrosine kinase inhibitors(EGFR-TKIs) were used to treat non-small cell lung cancer(NSCLC) patients with EGFR mutation positive. This study aims to compare the effectiveness of first line...Background and objective EGFR-tyrosine kinase inhibitors(EGFR-TKIs) were used to treat non-small cell lung cancer(NSCLC) patients with EGFR mutation positive. This study aims to compare the effectiveness of first line TKIs;gefitinib, erlotinib, and afatinib in the treatment of advanced stage NSCLC patients with EGFR mutation positive in the Indonesian population.Methods A retrospective cohort study of 88 NSCLC patients with EGFR mutation positive treated with gefitinib(n=59), erlotinib(n=22), and afatinib(n=7) was performed in national cancer hospital in Indonesia.Inclusion criteria were stage IIIb or IV NSCLC with adenocarcinoma subtype. Subjects less than 18 years or with a history of other malignancy were excluded. Outcomes were treatment response, progression-free survival(PFS), and mortality rate. Results Complete response, partial response, and stable disease were shown in 1.1%, 35.2%, and 31.8% of subjects, respectively. There were 31.8% of subjects developed progressive disease during treatment. Regarding EGFR mutation positive profile, a total of 56.8% subjects had deletion in exon 19, 42% subjects had mutation in exon 21, and rare mutation in exon 18 was found in 3.4% of total subjects. Demography and clinical characteristics had no significant association with the risk of progressive disease. The median PFS of subjects was 11 months(95%CI: 6.8-15.2 months). There was no statistical difference of PFS between treatment groups.Conclusion Gefitinib, erlotinib, and afatinib have similar effectiveness in advanced stage NSCLC with EGFR mutation positive. Afatinib tends to be associated with longer PFS but further investigation is required.展开更多
The severe erosion and inadequate mechanical strength are prominent challenges for high-energy gun propellants.To address it,novel PTW@PDA composites was prepared by polydopamine(PDA)-modifying onto potassium titanate...The severe erosion and inadequate mechanical strength are prominent challenges for high-energy gun propellants.To address it,novel PTW@PDA composites was prepared by polydopamine(PDA)-modifying onto potassium titanate whisker(PTW,K_(2)Ti_(6)O_(13)),and after was incorporated into gun propellant as erosion-reducing and mechanical-reinforcing fillers.The interfacial characterizations results indicated that as-prepared PTW@PDA composites exhibits an enhanced surface compatible with propellant matrix,thereby facilitating their dispersion into propellants more effectively than raw PTW materials.Compared to original propellants,PTW@PDA-modified propellants exhibited significant less erosion,with a Ti-Kbased protective coating being detected on the eroded steel.And 0.5 wt%and 1.0 wt%addition of PTW@PDA significantly improved impact,compressive and tensile strength of propellants.Despite the inevitably reduction in relative force,PTW@PDA slightly increase propellant burning rate while exerting little adverse impact on propellant dynamic activity.This strategy can provide a promising alternative to develop high-energy gun propellant with less erosion and more mechanical strength.展开更多
Currently, accumulating studies indicated that upregulation of glycogen synthase kinase-3β （GSK3β） played an important role in depression pathogenesis. Our previous study demonstrated that ammoxetine, a novel se- ...Currently, accumulating studies indicated that upregulation of glycogen synthase kinase-3β （GSK3β） played an important role in depression pathogenesis. Our previous study demonstrated that ammoxetine, a novel se- rotonin and norepinephrine uptake inhibitor, displayed antidepressant activity more potent and faster than existing antidepressants, which may be clue to the increasing of hippocampal inhibitory serine-phosphorylation of glycogen synthase kinase-3 （GSK3）. The present study was to evaluate whether activation of PI3K/Akt signaling, one of the most important pathways regulating the phosphorylation of GSK3β, was required for ammoxetine induced antide- pressant effects and upregulation of pGSK3β. Behavioral results indicated that acute oral administration of ammoxe- tine at 10 mg/kg produced robust antidepressant effects in the forced swimming test and learned helpless test in mice, which were blocked totally by phosphatidylinositol （PI3）-kinase （PI3K） inhibitor LY294002. Then, West- ern blot results demonstrated that ammoxetine induced increasing of GSK3 β phosphorylation and activation of PI3 K/ Akt signaling can also be antagonized at the same testing time points by LY294002. These findings suggest that ac- tivation of PI3 K/Akt/GSK3[3 signaling is pivotal and necessary for the antidepressant effects of ammoxetine in the forced swimming test and learned helpless test in mice.展开更多
A significant reduction of trypsin inhibitory activity by selected bacterial proteolytic enzymes was demonstrated in vitro.Two trials were conducted to examine the capacity of the tested enzymes to inactivate soybean ...A significant reduction of trypsin inhibitory activity by selected bacterial proteolytic enzymes was demonstrated in vitro.Two trials were conducted to examine the capacity of the tested enzymes to inactivate soybean ANFs in vivo.In trial I,twenty four piglets weaned at four weeks of age were assigned in replicate groups of 4 piglets per pen to one of three dietary treatments:(1)control;(2)Enzyme 1 supplemented(E 1);(3)Enzyme 2 supplemented (E 2).In trial II,twenty piglets weaned at five weeks of age were alloted to five treatment diets:(1)contro,l:(2)0.1% P4 supplemented;(3)0.5% P4 supplemented;(4)0.1% P7 supplemented;(5)0.5% P7 supplemented.The optimum pH for hydrolysis was 8 for E ,9 11 for E 2,8.5 for P4 and nuctral for P7.After 17 days of the trial,daily gain of piglets on enzymes E 1 and E 2 was 36% and 18% more than that in the control group,although the difference was not significant.The animals on the treated groups had a tendency to have lighter heart(7.8 and 5.9%),spleen(11.1 and 7.4%) and pancreas(16.7 and 12.5% for E 1 and E 2 respectively)in relation to empty body weight than those in the control.The small intestine of pigs on the treated groups was significantly lighter(18.9 for E 1 and 7.7% for E 2) than that in the control(P<0.05).The stomach (26.4 and 24%,p=0.198) and cecum(21.9 and 9.4%,p=0.114) also showed the same pattern.The growth depression was attributed to reduced feed intake caused by antinutritional factors in soybeans.It is concluded that supplements of proteolytic enzymes E 1 or E 2 had a positive effect on growth and efficiency and caused much less reaction in the gut as manifested by the weight of the tract and of its accessory organs.Dietary saupplements of P4 or P7 had no significant effect on growth,but reduced reaction of soybean antinutritional factors in the gut,especialy P4 in dose of 0.5%.The growth depression was attributed to low feed intake caused by antinutritional factors in soybeans.展开更多
The capacity of five enzymes (P1-P5) to inactivate the trypsin inhibitory activity (TIA) and lectin in raw soybean (RS) and low temperature-extruded soybean (LTES) was examined. P1 is an acid fungal protease with pH o...The capacity of five enzymes (P1-P5) to inactivate the trypsin inhibitory activity (TIA) and lectin in raw soybean (RS) and low temperature-extruded soybean (LTES) was examined. P1 is an acid fungal protease with pH optimum of 5 and P2, P3, P4 and P5 are bacterial proteases with pH optima of 7, 10, 8 and 8 respectively. The results indicated that all enzymes could reduce TIA to a varying degree at their optimum pH. The sequence of effectiveness was P3>P4>P5>P1>P2. The most effective enzyme, P3, reduced TIA to 38% and chymotrypsim inhibitory activity (CIA) to 9% of the original values. After six hours incubation at 50℃, the lectin concentration of LTES and RS was reduced by 50 and 17% respectively by P3, and by 42 and 29% by P4. In the second study, the best enzymes, P3 and P4, were incubated with RS or LTEs at different doses of 0, 0.10, 0.50% or 1.00% (w/w), for periods of 1, 2, 3, 6 or 12 hours. After one hour incubation with P3 at 1.00%, TIA of RS was reduced from 36.60 to 13.30 mg·g -1 . The corresponding values for LTES were 24.50 and 1.90 mg·g -1 . When the incubation was extended to 12 hours, the remaining TIA was 0.90 for LTES and 1.20 mg·g -1 for RS. P4 was not as effective as P3 up to six-hour incubation, but after twelve hours it achieved a similar reduction in activity to that of P3. A kinetic analysis of data showed that the inactivation process of purified soyabean trypsin inhibitors by P3 followed first-order chemical kinetics (Ct=90.90 -0.0408t , r=0.99). The rate of denaturation was -0.0408 per minute. It is concluded that the use of selected enzymes for anti-nutritive factors (ANFs) is an exciting possibility, but still requires further development.展开更多
The potential of di-(m-Formylphenol)-1,2-cyclohexandiimine as an environmentally friendly corrosion inhibitor for steel was investigated in 1 mol/L HCl using potentiodynamic polarization, electrochemical impedance spe...The potential of di-(m-Formylphenol)-1,2-cyclohexandiimine as an environmentally friendly corrosion inhibitor for steel was investigated in 1 mol/L HCl using potentiodynamic polarization, electrochemical impedance spectroscopy and chronoamperometry measurements. All electrochemical measurements suggest that this compound is an excellent corrosion inhibitor for mild steel and the inhibition efficiency increases with the increase in inhibitor concentration. The effect of temperature on the corrosion behavior of mild steel with the addition of the Schiff base was studied in the temperature range from 25 °C to 65 °C. It is found that the adsorption of this inhibitor follows the Langmuir adsorption isotherms. The value of activation energy and the thermodynamic parameters such as ΔHads, ΔSads, Kads and ΔGads were calculated by the corrosion currents at different temperatures using the adsorption isotherm. The morphology of mild steel surface in the absence and presence of inhibitor was examined by scanning electron microscopy(SEM) images.展开更多
基金supported by National Natural Science Foundation of China(81402482,91313303)
文摘OBJECTIVE Leukotriene B4(LTB4)biosynthesis and subsequently neutrophilic inflammation may provide a potential strategy for the treatment of acute lung injury(ALI)or idiopathic pulmonary fibrosis(IPF).To provide a potential strategy for the treatment of ALI or IPF,we identified potent inhibitors of Leukotriene A4 hydrolase(LTA4H),a key enzyme in the biosynthesis of LTB4.METHODS In this study,we identified two known histone deacetylase(HDAC)inhibitors,suberanilohydroxamic acid(SAHA)and its analogue 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide(M344),as effective inhibitors of LTA4H using enzymatic assay,thermofluor assay,and X-ray crystallographic investigation.We next tested the effect of SAHA and M344 on endogenous LTB4 biosynthesis in neutrophils by ELISA and neutrophil migration by transwell migration assay.A murine experimental model of ALI was induced by lipopolysaccharide(LPS)inhalation.Histopathological analysis of lung tissue using H&E staining revealed the serious pulmonary damage caused by LPS treatment and the effect of the SAHA.We next examined m RNA and protein levels of pro-inflammatory cytokines in lung tissue and bronchoalveolar lavage fluid using q RT-PCR and ELISA to further investigate the underlying mechanisms of anti-inflammatory activities by SAHA.We also investigated the effects of SAHA and M344 on a murine experimental model of bleomycin(BLM)-induced IPF model.RESULTS The results of enzymatic assay and X-ray crystallography showed that both SAHA and M344 bind to LTA4H,significantly decrease LTB4 levels in neutrophil,and markedly diminish early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose.CONCLUSION Collectively,SAHA and M344 would provide promising agents with well-known clinical safety for potential treatment in patients with ALI and IPF via pharmacologically inhibiting LAT4H and blocking LTB4 biosynthesis.
文摘Aim Head and neck cancers are the eighth most common cancer worldwide. Despite significant ad- vances in the delivery of treatment and surgical reconstruction, the mortality rates for this disease have not improved in the past 4 decades. Our previous study has shown that HIV protease inhibitors （HIV PIs） induce cell apoptosis via activating endoplasmic reticulum （ER） stress. It also has been reported that a few HIV PIs are able to radio- sensitize tumor cells. However, the underlying cellular mechanisms remain to be identified. The aim of this study was to examine whether HIV PIs activate the ER stress response and sensitize human head and neck carcinoma cells to radiation. Methods Human SQ20B and Fadu cells and the most commonly used HIV PIs, lopinavir and ritona- vir, were used in this study. The mRNA and protein levels of ER stress-related genes （ CHOP, ATF4, XBP-1, and GRP78 ） were detected by real time RT-PCR and Western blot, respectively. Cell viability and apoptosis were ana- lyzed using Cellometer Vision CBA. After treatment with HIV PIs, cells were irradiated at a dose of 2G or 4G. Col- onies were stained and counted 10 days after irradiation. Results HIV PIs significantly induced activation of ER stress and apoptosis. Treatment of HIV PIs inhibited Akt phosphorylation, induced cell cycle arrest in G1 phase and increased tumor cell sensitivity to irradiation-induced cell death. Conclusion HIV PIs sensitize human head and neck carcinoma cells to radiation by activating ER stress.
文摘OBJECTIVE Selective serotonin reuptake inhibitors(SSRIs) bind 5-HT transporters,leading to the accumulation of 5-HT and amelioration of depression.Although different mouse strain showed different sensitivity to SSRIs in mouse models of depression,the reason for these strain differences remains unclear.Here,therefore,in the present study,we examined immobility time and locomotor activity in two mouse strains,namely,C57BL/6 J and DBA/2 J mice,and the effects of the SSRIs fluoxetine.Furthermore,we analyzed 5-HT transporter binding and reuptake inhibition in both strains to explore their relationship with the immobility and locomotor activity effects of the three SSRIs in these two mouse strains.METHODS Strain differences in SSRI effects in the tail suspension test(TST) and forced swimming test(FST).To initiate our studies,we sought to confirm that SERT strain variation did not alter SERT protein expression,5-HT recognition,or uptake activity when expressed in C57BL/6 J and DBA/2 J mice.Radioligand binding assays were conducted to determine the affinity of the SSRIs for the 5-HT transporters in the two mouse strains.RESULTS SSRI citalopram dose-dependently reduced immobility time in both the FST and TST in DBA/2 J but not C57BL/6 J mouse strains,whereas fluoxetine showed opposite results.Paroxetine reduced immobility time similarly in both strains.The affinity of citalopram for the 5-HT transporter in DBA/2 J mice was 700-fold higher than that for in C57BL/6 J mice,whereas the affinity of fluoxetine in C57BL/6 J mice was 100-fold higher than that in the DBA/2 J mouse.Furthermore,High citalopram concentrations were required to [3 H]5-HT uptake in C57BL/6 J but not DBA/2 J mouse cortical synaptosomes,whereas fluoxetine also showed opposite results.CONCLUSION Immobility duration depends on 5-HT transporter binding levels,leading to apparent strain differences in immobility time in FST and TST.Furthermore,differences in 5-HT transporter binding may cause variations in SSRI responses on behaviors.SERT mutation mice maintained sensitivity to paroxetine,an antidepressant that is unaffected by the mouse mutation.Therefore,the background strain of these mice likely contributes to the acute behavioral actions of SSRIs in immobility time.These differences may help to explain some of the discrepancies in studies that used these strains of mice to examine the role of 5-HT in mouse models of depression.Future studies should investigate additional neural substrates and molecular mechanisms underlying strain variations in mouse models of depression to help identify genetic predispositions to this disorder in humans.
基金Project(UKM-GUP-BTT-07-25-170) supported by Universiti Kebangsaan Malaysia
文摘The inhibition ability of 4-amino-5-phenyl-4H-1, 2, 4-trizole-3-thiol （APTT）, ethylenediaminetetra-acetic acid （EDTA） and thiourea （TU） for mild steel corrosion in 1.0 moFL HC1 solution at 30 ℃ was investigated. Tafel polarization and electrochemical impedance spectroscopy （EIS） were used to investigate the influence of these organic compounds as corrosion inhibitors of mild steel in 1.0 mol/L HC1 solution at 30 ℃. The inhibition mechanism was discussed in terms of Langrnuir isotherm model. Results obtained from Tafel polarization and impedance measurements are in a good agreement. The inhibition efficiency increases with the increase of the inhibitor concentration. The adsorption of the inhibitors on the mild steel surface follows Langmuir adsorption isotherm and the free energy of adsorption AGads indicates that the adsorption of APTT, EDTA, and TU molecules is a spontaneous process and a typical chemisorption.
文摘Aim Nicotinamide phosphoribosyltransferase （NAMPT） plays an important role in cardiocerebro-vascu- lar physiopathological process. It is also a promising anticancer target. It is highly desirable to discover novel NAMPT inhibitors as anticancer drug candidates and understand their action mode. Methods We carried out a high throughput screening system on a chemical library of 24434 small-molecules. Anti-proliferative activity were further studied on active compounds. Isothermal titration calorimetry and cellular thermal shift assay were used to confirm the target specificity. Molecular modeling and site-directed mutagenesis studies were taken to investigate the binding mode of NAMPT inhibitor. Results Using high throughput screening system targeting NAMPT, we ob- tained a potent NAMPT inhibitor MS0 （China Patent ZL201110447488.9 ） with excellent in vitro activity （IC50 = 9.87 ± 1.15 nmol · L^-1 ） and anti-proliferative activity against multiple human cancer cell lines including stem-like cancer cells. Structure-activity relationship studies yielded several highly effective analogues. These inhibitors spe- cifically bound NAMPT, rather than downstream NMNAT. We provided the first chemical case using cellular ther- mal shift assay to explain the difference between in vitro and cellular activity; MS7 showed best in vitro activity （ IC50 = 0.93 ± 0.29 nmol · L^-1 ） but worst cellular activity due to poor target engagement in living cells. Site-di- rected mutagenesis studies identified important residues for NAMPT catalytic activity and inhibitor binding. Con- clusions The present study provides a class of novel NAMPT inhibitors for future development of anticancer a- gents. Our findings also contribute to deep understanding the action mode of NAMPT inhibitors and NAMPT basic research in cardiocerebro-vascular system.
基金Rothrock Research Fund in Hematology, The authors appreclate the assistance of supervising technicina, Linda Russ.Ulrica Stenheimer-Caudle, Sandra Peffly, and Marie Hyde.
文摘An extract (G-INH) made from mature human granulocytes freshly isolated from normai blood causes human neutrophils to undergo apoptosis in vitro as shown by morphologic changes and by the typical ladder pattern of small DNA fragments noted on agarose gel electrophoresis of isolated DNA. Apoptosis occurs in from 20% to 30% of neutrophils over 24 hours of culture in vitro and the addition of G-INH to the medium causes a dose-related increase in the incidence of apoptosis. Heating G-INH at 60t for 30 minutes does not destroy its capacity to induce apoptosis but GM-CSF, G-CSF, and to a lesser extent IL-1β, antagonize this action. IL-3 does not diminish G-INH induced apoptosis of neutrophils. Substances, released from, mature neutrophils may participate in regulating the survival of other neutrophils, particularly in sites where the cells are in close proximity as in the marrow. Self destruction of post-mitotic neutrophils in marrow may thus represent an-other level at which regulation of cell production
基金CAMS Innovation Fund for Medical Sciences(2017-I2M-2-004).
文摘OBJECTIVE To examine whether17 AAG and STA9090 have anticonvulsant activity in absence epilepsy.METHODS For the acute seizure study,each group of mice received VPA(dissolved in saline) 100 mg·kg-1,17 AAG(dissolved in 50 μL DMSO) 25 mg·kg-1 or STA9090(dissolved in 20 μL DMSO) 50 mg·kg-1 by oral gavage respectively.The control group received DMSO alone.Thirty minutes after oral gavage,PTZ 80 mg·kg-1 was intraperitoneal injected to induce acute seizures.The number of seizures refers to the total number of epileptic mice after PTZ application.Seizure latency was defined by the time elapsed from PTZ injection to the occurrence of the first seizure.The levels of Hsp90β,GLT-1,GFAP and 20 S proteasome β1 in the cortex and hippocampus were detected by Western blotting.RESULTS The mortality were60% for 17 AAG and 43% for STA9090,and the mortality of valproate group dropped to 20%which decreased by 33.3% compared to model group.Seizure latency of valproate group obviously prolonged compared to model group(P<0.05).But the results demonstrated that 17 AAG and STA9090 had no significant differences in seizure latency.The result of Western blotting has shown that inhibition of Hsp90β significantly reduced expressions of both membrane and cytosolic Hsp90β in the hippocampus and cortex of each group of mice.However,the expressions of GLT-1 and GFAP did not show the significant difference in the cortex and hippocampus.The expression of 20 S proteasome β1 had not been obviously changed in the cortex and hippocampus among the groups.CONCLUSION 17 AAG and STA9090 did not have anticonvulsant activity and did not increase the stability of GLT-1 by disrupting proteasome-dependent GLT-1 degradation in PTZ induced mice of absence epilepsy.
基金Project(ZR2023ME063)supported by the Shandong Provincial Natural Science Foundation,ChinaProject(121311KYSB20210005)supported by the Overseas Science and Education Cooperation Center Deployment Project,ChinaProject supported by the Qingdao Expert Workstation for Intelligent Anticorrosion for Water Diversion Project,China。
文摘Urea,paracetamol and glutamine(based on the expired drugs)were selected as vapor-phase corrosion inhibitors(VCIs)to study their corrosion protection effect on red copper in simulated marine atmospheric environment by using weight loss,electrochemical measurement techniques(specially designed electrochemical testing device for simulating marine atmospheric environments)and surface morphology characterization analysis(SEM/EDS,XRD,RAMAN,XPS).Weight loss results show that the three corrosion inhibitors have good corrosion inhibition effect on red copper,and the corrosion inhibition efficiency in the order of glutamine(83.62%)>urea(68.46%)>paracetamol(61.47%).Surface morphology characterization analysis provides evidence of adsorption of corrosion inhibitors molecules on the red copper surface,thus forming a protective film that blocked the red copper surface from the aggressive chloride ion attack.
文摘Background and objective EGFR-tyrosine kinase inhibitors(EGFR-TKIs) were used to treat non-small cell lung cancer(NSCLC) patients with EGFR mutation positive. This study aims to compare the effectiveness of first line TKIs;gefitinib, erlotinib, and afatinib in the treatment of advanced stage NSCLC patients with EGFR mutation positive in the Indonesian population.Methods A retrospective cohort study of 88 NSCLC patients with EGFR mutation positive treated with gefitinib(n=59), erlotinib(n=22), and afatinib(n=7) was performed in national cancer hospital in Indonesia.Inclusion criteria were stage IIIb or IV NSCLC with adenocarcinoma subtype. Subjects less than 18 years or with a history of other malignancy were excluded. Outcomes were treatment response, progression-free survival(PFS), and mortality rate. Results Complete response, partial response, and stable disease were shown in 1.1%, 35.2%, and 31.8% of subjects, respectively. There were 31.8% of subjects developed progressive disease during treatment. Regarding EGFR mutation positive profile, a total of 56.8% subjects had deletion in exon 19, 42% subjects had mutation in exon 21, and rare mutation in exon 18 was found in 3.4% of total subjects. Demography and clinical characteristics had no significant association with the risk of progressive disease. The median PFS of subjects was 11 months(95%CI: 6.8-15.2 months). There was no statistical difference of PFS between treatment groups.Conclusion Gefitinib, erlotinib, and afatinib have similar effectiveness in advanced stage NSCLC with EGFR mutation positive. Afatinib tends to be associated with longer PFS but further investigation is required.
基金the support of the instrument and equipment fund of the Key Laboratory of Special Energy,Ministry of Education,Nanjing University of Science and Technology,China.
文摘The severe erosion and inadequate mechanical strength are prominent challenges for high-energy gun propellants.To address it,novel PTW@PDA composites was prepared by polydopamine(PDA)-modifying onto potassium titanate whisker(PTW,K_(2)Ti_(6)O_(13)),and after was incorporated into gun propellant as erosion-reducing and mechanical-reinforcing fillers.The interfacial characterizations results indicated that as-prepared PTW@PDA composites exhibits an enhanced surface compatible with propellant matrix,thereby facilitating their dispersion into propellants more effectively than raw PTW materials.Compared to original propellants,PTW@PDA-modified propellants exhibited significant less erosion,with a Ti-Kbased protective coating being detected on the eroded steel.And 0.5 wt%and 1.0 wt%addition of PTW@PDA significantly improved impact,compressive and tensile strength of propellants.Despite the inevitably reduction in relative force,PTW@PDA slightly increase propellant burning rate while exerting little adverse impact on propellant dynamic activity.This strategy can provide a promising alternative to develop high-energy gun propellant with less erosion and more mechanical strength.
文摘Currently, accumulating studies indicated that upregulation of glycogen synthase kinase-3β （GSK3β） played an important role in depression pathogenesis. Our previous study demonstrated that ammoxetine, a novel se- rotonin and norepinephrine uptake inhibitor, displayed antidepressant activity more potent and faster than existing antidepressants, which may be clue to the increasing of hippocampal inhibitory serine-phosphorylation of glycogen synthase kinase-3 （GSK3）. The present study was to evaluate whether activation of PI3K/Akt signaling, one of the most important pathways regulating the phosphorylation of GSK3β, was required for ammoxetine induced antide- pressant effects and upregulation of pGSK3β. Behavioral results indicated that acute oral administration of ammoxe- tine at 10 mg/kg produced robust antidepressant effects in the forced swimming test and learned helpless test in mice, which were blocked totally by phosphatidylinositol （PI3）-kinase （PI3K） inhibitor LY294002. Then, West- ern blot results demonstrated that ammoxetine induced increasing of GSK3 β phosphorylation and activation of PI3 K/ Akt signaling can also be antagonized at the same testing time points by LY294002. These findings suggest that ac- tivation of PI3 K/Akt/GSK3[3 signaling is pivotal and necessary for the antidepressant effects of ammoxetine in the forced swimming test and learned helpless test in mice.
文摘A significant reduction of trypsin inhibitory activity by selected bacterial proteolytic enzymes was demonstrated in vitro.Two trials were conducted to examine the capacity of the tested enzymes to inactivate soybean ANFs in vivo.In trial I,twenty four piglets weaned at four weeks of age were assigned in replicate groups of 4 piglets per pen to one of three dietary treatments:(1)control;(2)Enzyme 1 supplemented(E 1);(3)Enzyme 2 supplemented (E 2).In trial II,twenty piglets weaned at five weeks of age were alloted to five treatment diets:(1)contro,l:(2)0.1% P4 supplemented;(3)0.5% P4 supplemented;(4)0.1% P7 supplemented;(5)0.5% P7 supplemented.The optimum pH for hydrolysis was 8 for E ,9 11 for E 2,8.5 for P4 and nuctral for P7.After 17 days of the trial,daily gain of piglets on enzymes E 1 and E 2 was 36% and 18% more than that in the control group,although the difference was not significant.The animals on the treated groups had a tendency to have lighter heart(7.8 and 5.9%),spleen(11.1 and 7.4%) and pancreas(16.7 and 12.5% for E 1 and E 2 respectively)in relation to empty body weight than those in the control.The small intestine of pigs on the treated groups was significantly lighter(18.9 for E 1 and 7.7% for E 2) than that in the control(P<0.05).The stomach (26.4 and 24%,p=0.198) and cecum(21.9 and 9.4%,p=0.114) also showed the same pattern.The growth depression was attributed to reduced feed intake caused by antinutritional factors in soybeans.It is concluded that supplements of proteolytic enzymes E 1 or E 2 had a positive effect on growth and efficiency and caused much less reaction in the gut as manifested by the weight of the tract and of its accessory organs.Dietary saupplements of P4 or P7 had no significant effect on growth,but reduced reaction of soybean antinutritional factors in the gut,especialy P4 in dose of 0.5%.The growth depression was attributed to low feed intake caused by antinutritional factors in soybeans.
文摘The capacity of five enzymes (P1-P5) to inactivate the trypsin inhibitory activity (TIA) and lectin in raw soybean (RS) and low temperature-extruded soybean (LTES) was examined. P1 is an acid fungal protease with pH optimum of 5 and P2, P3, P4 and P5 are bacterial proteases with pH optima of 7, 10, 8 and 8 respectively. The results indicated that all enzymes could reduce TIA to a varying degree at their optimum pH. The sequence of effectiveness was P3>P4>P5>P1>P2. The most effective enzyme, P3, reduced TIA to 38% and chymotrypsim inhibitory activity (CIA) to 9% of the original values. After six hours incubation at 50℃, the lectin concentration of LTES and RS was reduced by 50 and 17% respectively by P3, and by 42 and 29% by P4. In the second study, the best enzymes, P3 and P4, were incubated with RS or LTEs at different doses of 0, 0.10, 0.50% or 1.00% (w/w), for periods of 1, 2, 3, 6 or 12 hours. After one hour incubation with P3 at 1.00%, TIA of RS was reduced from 36.60 to 13.30 mg·g -1 . The corresponding values for LTES were 24.50 and 1.90 mg·g -1 . When the incubation was extended to 12 hours, the remaining TIA was 0.90 for LTES and 1.20 mg·g -1 for RS. P4 was not as effective as P3 up to six-hour incubation, but after twelve hours it achieved a similar reduction in activity to that of P3. A kinetic analysis of data showed that the inactivation process of purified soyabean trypsin inhibitors by P3 followed first-order chemical kinetics (Ct=90.90 -0.0408t , r=0.99). The rate of denaturation was -0.0408 per minute. It is concluded that the use of selected enzymes for anti-nutritive factors (ANFs) is an exciting possibility, but still requires further development.
文摘The potential of di-(m-Formylphenol)-1,2-cyclohexandiimine as an environmentally friendly corrosion inhibitor for steel was investigated in 1 mol/L HCl using potentiodynamic polarization, electrochemical impedance spectroscopy and chronoamperometry measurements. All electrochemical measurements suggest that this compound is an excellent corrosion inhibitor for mild steel and the inhibition efficiency increases with the increase in inhibitor concentration. The effect of temperature on the corrosion behavior of mild steel with the addition of the Schiff base was studied in the temperature range from 25 °C to 65 °C. It is found that the adsorption of this inhibitor follows the Langmuir adsorption isotherms. The value of activation energy and the thermodynamic parameters such as ΔHads, ΔSads, Kads and ΔGads were calculated by the corrosion currents at different temperatures using the adsorption isotherm. The morphology of mild steel surface in the absence and presence of inhibitor was examined by scanning electron microscopy(SEM) images.
