Background Elevated N-terminal pro-brain natriuretic peptide(NT-pro-BNP)is a recognized predictor of poor prognosis in heart failure and infectious diseases.We aimed to investigate its predictive value for short-term ...Background Elevated N-terminal pro-brain natriuretic peptide(NT-pro-BNP)is a recognized predictor of poor prognosis in heart failure and infectious diseases.We aimed to investigate its predictive value for short-term mortality in patients with infective endocarditis(IE)complicated by sepsis.Methods A total of 416 consecutive patients diagnosed with IE and sepsis at Guangdong Provincial People's Hospital were enrolled.The patients were divided into three groups according to the tertiles of NT-pro-BNP level of the first blood collection within 24 hours after admission:<2000 pg/mL(n=138),2000-7167 pg/mL(n=140),and>7167 pg/mL(n=138).Univariate and multivariate regression analysis were used to explore the predictive value of NT-pro-BNP for short-term mortality,and the best cut-off value was determined by receiver operating characteristic(ROC)curve.Results In-hospital and 6-month death occurred in 65 and 94 patients,respectively.Higher in-hospital mortality was found in patients with higher serum NT-pro-BNP levels(9.4%vs.13.6%vs.23.9%,P=0.003).ROC curve analysis identified an optimal NT-pro-BNP cutoff level of 1357 pg/mL[area under curve(AUC):0.652,95%CI:0.588-0.717,P<0.001].Multivariate regression analysis showed that both log-transformed NT-pro-BNP(in-hospital mortality:OR:1.987,95%CI:1.045-3.778,P=0.036;6-month mortality:HR:1.714,95%CI:1.072-2.7400,P=0.025)and NT-pro-BNP>1357 pg/mL(in-hospital mortality:OR:8.059,95%CI:1.813-35.818,P=0.006;6-month mortality:HR:5.193,95%CI:1.806-14.938,P=0.002)were both independent risk factors for in-hospital and 6-month mortality.Conclusions Serum NT-pro-BNP could serve as an independent predictor of in-hospital and 6-month mortality in patients with IE complicated with sepsis.展开更多
Dopamine β-monooxygenase N-terminal(DOMON)domain-containing genes are present across all taxa and are critical in cell signaling and redox transport.Despite their significance,these genes remain understudied in plant...Dopamine β-monooxygenase N-terminal(DOMON)domain-containing genes are present across all taxa and are critical in cell signaling and redox transport.Despite their significance,these genes remain understudied in plant species.In this study,we identified 15 DOMON genes in rice and analyzed their phylogenetic relationships,conserved motifs,and cis-regulatory elements.Phylogenetic analysis revealed distinct clustering of OsDOMON genes in rice and other monocots,compared with Arabidopsis thaliana.Promoter analysis showed a higher abundance of stress-related regulatory elements in Tetep,a well-known blast and abiotic stress-tolerant cultivar,compared with Nipponbare and HP2216.OsDOMON genes displayed differential expression under biotic stress(Magnaporthe oryzae infection)and abiotic stresses(drought,heat,and salinity)in contrasting cultivars.Tetep exhibited significantly higher expression levels of specific OsDOMON genes during early blast infection stages,particularly OsDOMON6.1 and OsDOMON9.2,suggesting their roles in cell wall fortification and reactive oxygen species signaling.Under abiotic stress,genes like OsDOMON3.3,OsDOMON8.1,and OsDOMON9.2 showed higher expression in Tetep,indicating their involvement in stress tolerance mechanisms.This study provides a foundation for future functional studies of OsDOMON genes,paving the way for developing rice cultivars resistant to biotic and abiotic stresses.展开更多
Background: In cardiac surgery, the N-terminal pro-brain natriuretic peptide (NT-proBNP) level is reportedly correlated with the onset of postoperative complications. We examined the relationship between the NT-proBNP...Background: In cardiac surgery, the N-terminal pro-brain natriuretic peptide (NT-proBNP) level is reportedly correlated with the onset of postoperative complications. We examined the relationship between the NT-proBNP level and perioperative complications in thoracic surgery and elucidated the significance of NT-proBNP measurement. Methods: We evaluated 48 patients excluding hemodialysis patients who underwent lung resection from November 2015 to February 2016. NT-proBNP measurement was performed three times preoperatively on postoperative days 2 and 5. We examined the relationship between clinical background factors such as preoperative comorbidity and the development of postoperative complications. Based on established criteria for surgical complications (Clavien-Dindo classification), grade ≥ II was defined as a complications. We classified the patients into two groups (with or without complications) and compared and examined the background factors between the groups. Results: The study included 48 patients (33 male, 15 female) with an average age of 72 years (range, 35 - 86 years). Preoperative comorbidities included cardiovascular disease in five patients, diabetes mellitus in four, and chronic obstructive pulmonary disease in six. The average operation time was 163 (29 - 308) minutes, and the bleeding volume was 30 (10 - 620) ml. Early complications were confirmed in 11 patients, and late complications were confirmed in 7 patients. A high NT-proBNP level on postoperative day 5 was an independent risk factor for late complications. Conclusion: The perioperative NT-proBNP level is considered to be a predictor of complications. Its measurement is useful for predicting postoperative complications, and careful perioperative management is required for patients with high levels.展开更多
Glucagon-like peptide-1（GLP-1） is an endogenous insulinotropic hormone with excellent blood glucose-lowering activity, however, it is rapidly inactivated in the plasma mainly by dipeptidyl peptidase IV（DPP-IV）. To...Glucagon-like peptide-1（GLP-1） is an endogenous insulinotropic hormone with excellent blood glucose-lowering activity, however, it is rapidly inactivated in the plasma mainly by dipeptidyl peptidase IV（DPP-IV）. To overcome this problem, various N-terminal modifications of GLP-1 have been performed to prolong the in vivo biological activity, by improving the DPP-IV resistance while retaining receptor affinity and receptor activation. These studies have included modifications of His7, Ala8 or Glu9 at the N-terminus of GLP-1 and some other modifications. Among them, Ala8 substitutions with glycine（Gly8） and α-aminoisobutyric acid（Aib8） have been clinically applied in the development of diabetic therapy, such as Exenatide, Semaglutide, Albiglutide and Taspoglutide. In this review, we introduce N-terminal modifications of GLP-1 that have been reported, and discuss their potential and challenges for the treatment of type 2 diabetes.展开更多
Objective: To study the regulatory effect and molecular mechanism of juglone on apoptosis of cervical cancer Hela cells. Methods: Cervical cancer Hela cells were cultured and treated with different dosages of juglone ...Objective: To study the regulatory effect and molecular mechanism of juglone on apoptosis of cervical cancer Hela cells. Methods: Cervical cancer Hela cells were cultured and treated with different dosages of juglone (10, 20, and 40 pmol/L, respectively) and c-Jun N-terminal kinase (JNK) inhibitor SP600125 (10, 20, and 40 mu mol/L. respectively). Then cellular proliferative activity and the expression of JNK/c-Jun pathway molecule and apoptotic molecule in the cells were detected. Results: After 6, 12. 18 and 24 h of treatment, the value for proliferative activity of cells treated with juglone was significantly lower than that of control group (p<0.05), and the anti-proliferative effect was more significant as the treatment period and juglone dosage increased (P<0.05). The protein expressions of Box, CytC, Fas, FasL, Caspase-3, and p-c-Jun in cells treated with juglone were significantly higher than those of control group (P<0.05), and the protein expressions of Bax, CytC, Fas. FasL, Caspase-3, p-JNK and p-c-Jun increased more remarkably as the juglone dosage increased (P<0.05). In cells treated with 40 pmol/L juglone and SP600125, the protein expressions of Bax, CytC, Fas. Fast.. and Caspase-3 were significantly lower than those of cells treated with 40 pmol/L juglone (J<0.05), and the protein expressions of Bax, CytC, Fas, FasL and Caspase-3 reduced more remarkably as the SP600125 dosage increased (P<0.05). Conclusion: Juglone can increase the expression of apoptotic molecules in mitochondrial pathway and death receptor pathway by activating JNK/c-Jun pathway, thus inducing apoptosis of cervical cancer cells.展开更多
Background The neutrophil-to-lymphocyte （N/L） ratio has been associated with poor prognosis in patients with heart failure, but it has not been compared with N-terminal pro-brain natriuretic peptide （NT-proBNP） in...Background The neutrophil-to-lymphocyte （N/L） ratio has been associated with poor prognosis in patients with heart failure, but it has not been compared with N-terminal pro-brain natriuretic peptide （NT-proBNP） in elderly patients with chronic heart failure （CHF）. We sought to make this comparison. Methods A total of 1355 elderly patients with CHF were analyzed. A multivariate logistic regression model was used to analyze the variables associated with atrial fibrillation （AF）. Cox regression analysis was used to assess the multivariable rela- tionship between the N/L ratio, NT-proBNP level, and subsequent major cardiovascular events （MCE）. Results In the multiple logistic regression analysis, the N/L ratio was demonstrated as a risk factor for AF in elderly patients with CHF [odds ratio （OR）： 1.079, 95% confi- dence interval （CI）： 1.027-1.134, P = 0.003]. The median follow-up period was 18 months. In a multivariable model using tertiles of both variables, the highest tertile of the N/L ratio was significantly associated with MCE [hazard ratio （HR）： 1.407, 95% CI： 1.098-1.802, P = 0.007] compared with the lowest tertile. Similarly, the highest NT-proBNP tertile was also significantly associated with MCE （HR： 1.461, 95% CI： 1.104-1.934, P- 0.008）. Conclusions In elderly patients with CHF, the N/L ratio is one of the important risk factors for AF and it is an inexpensive and readily available marker with similar independent prognostic power to NT-proBNP. The risk of MCE increases 1.407-fold when the N/L ratio is elevated to the highest tertile.展开更多
Objective:To investigate the effect of atorvastatin on serum oxidative stress and N-terminal brain natriuretic peptide expression in rats.Methods:A total of 40 healthy male SD rats were randomly divided into the sham ...Objective:To investigate the effect of atorvastatin on serum oxidative stress and N-terminal brain natriuretic peptide expression in rats.Methods:A total of 40 healthy male SD rats were randomly divided into the sham group(Croup A,n=10,saline 5 mL/d),ischemia-reperfusion group(Group B,n=10,saline S mL/d),atorvastatin group(Group C,n=10.atorvastatin 20 mg/kg·d),atorvastatin + N-amino-arginine group(Group D,n=10,atorvastatin 20 mg/kg·d + N-amino arginine 15 mg/kg).Myocardial ischemia-reperfusion rat model was eslablished after 3 days of gavage.N-amino arginine 15 mg/kg was given by tail vein injection 15 min before ischemia.After reperfusion,enzymology indicators such us creatine kinase(CK) and lactate dehydrogenase and the oxidative stress parameters such as nitric oxide(NO),malondialdehyde(MDA) and total superoxide dismutase(TSOD),and n-terminal pro-brain natriuretic peptide(NT-proBNP)expression was detected by immunohistochemistry.Results:LDH and CK levels of group A were significantly lower than the outer three groups,and group B was the highest.There was significant difference between group B and group C(P<0.05),and no significant difference between group B and group D(P>0.05).MDA levels in group B were significantly higher than the other three groups.The lowest was group A,followed by group C,the difference among groups was significantly(P<0.05).TSOD and NO levels in group B was the lowest,the level in group A was the highest,followed by group C,the difference among groups was significant(P<0.05).NT-proBNP level in group B was significantly higher than the other three groups,the lowest was group A,followed by group C,the difference among groups was significant(P<0.05).Conclusions:Atorvastatin has a protective effect on the myocardial injury in the myocardial ischemia and reperfusion rats.It can increase NO synthesis and decrease MDA content,increase serum TSOD activity and the oxidative stress effect,meanwhile protect myocardial cells and reduce myocardial injury.展开更多
AIM: Most studies on the immune effect of gp96 were focused on its enhancement of CTLs. It is interesting to know whether gp96 could influence the humoral immune response, and whether the recombinant N-terminal fragme...AIM: Most studies on the immune effect of gp96 were focused on its enhancement of CTLs. It is interesting to know whether gp96 could influence the humoral immune response, and whether the recombinant N-terminal fragment of gp96 could substitute native gp96 to stimulate the immune system.METHODS: gp96 isolated from livers of normal mice and its N-terminal fragment (amino acid 22-355) expressed in E coli were used for immunization of BALb/c mice. Eight groups of mice received one of the following regiments subcutaneously in 100 μL phosphate buffered saline (PBS)at an interval of 3 wk. Group 1: PBS only; group 2:gp96 only; group 3: N-terminal fragment only; group 4: HBsAg only; group 5: HBsAg+gp96; group 6: HBsAg+N-terminalfragment; group 7: HBsAg+incomplete Freud's adjuvant; group 8: HBsAg+N-terminal fragment (95 ℃ heated for 30 min). Serum anti-HBsAg antibody levels were assayed by ELISA. CTL responses in splenocytes were analyzed by ELISPOT after the last vaccination.RESULTS: The average titer of serum anti-HBsAg antibodyin the mice immunized with HBsAg together with gp96 or its N-terminal fragment were much higher than those immunized with HBsAg alone detected by ELISA. The cellular immune response of the mice immunized with HBsAg together with gp96 or its N-terminal fragment was not different with those immunized with HBsAg alone measured by ELISPOT assay.CONCLUSION: gp96 or its N-terminal fragment greatly improved humoral immune response induced by HBsAg, but failed to enhance the CTL response, which demonstrated the potential of using gp96 or its N-terminal fragment as a possible adjuvant to augment humoral immune response against HBV infection.展开更多
Objective To investigate plasma N-terminal pro-brain natriuretic peptide (NT-BNP) levels and to assess their clinical significance in elderly patients with isolated diastolic dysfunction. Methods Plasma NT-BNP level w...Objective To investigate plasma N-terminal pro-brain natriuretic peptide (NT-BNP) levels and to assess their clinical significance in elderly patients with isolated diastolic dysfunction. Methods Plasma NT-BNP level were measured by electrochemiluminescence immunoassay in 34 symptomatic patients (Group 1), 34 asymptomatic patients (Group 2) with isolated diastolic dysfunction, and in 16 elderly healthy subjects (control group, Group 3), serving controls. Colored Doppler echocardiography was performed to evaluate the patients' cardiac structures and functions. Results The plasma NT-BNP level in Group 1 was significantly higher than those in Group 2 and Group 3 and increased with the severity of heart failure. There was no significant difference of plasma NT-BNP levels between Group 2 and Group 3 (p>0.05). A NT-BNP value of 102.75 pg/mL showed a sensitivity of 88.2%, a specificity of 87.5%, and an accuracy of 88.1% for diagnosing diastolic dysfunction. Patients with restrictive filling pattern on echocardiography had higher NT-BNP levels than those of impaired relaxation pattern (1961.2±304.9 versus 460.1±92.7pg/mL, p<0.001). Conclusion The elevation of plasma NT-BNP level in elderly patients with isolated diastolic dysfunction correlates with the severity of their diastolic abnormalities. The level of plasma NT-BNP has an important clinical value in the diagnosis of elderly patients with isolated diastolic dysfunction.展开更多
The role of androgen receptor （AR） in the initiation and progression of prostate cancer （PCa） is well established. Competitive inhibition of the AR ligand-binding domain （LBD） has been the staple of antiandrogen...The role of androgen receptor （AR） in the initiation and progression of prostate cancer （PCa） is well established. Competitive inhibition of the AR ligand-binding domain （LBD） has been the staple of antiandrogen therapies employed to combat the disease in recent years. However, their efficacy has often been limited by the emergence of resistance, mediated through point mutations, and receptor truncations. As a result, the prognosis for patients with malignant castrate resistant disease remains poor. The amino-terminal domain （NTD） of the AR has been shown to be critical for AR function. Its modular activation function （AF-1） is important for both gene regulation and participation in protein-protein interactions. However, due to the intrinsically disordered structure of the domain, its potential as a candidate for therapeutic intervention has been dismissed in the past. The recent emergence of the small molecule EPI-O01 has provided evidence that AR-NTD can be targeted therapeutically, independent of the LBD. Targeting of AR-NTD has the potential to disrupt multiple intermolecular interactions between AR and its coregulatory binding partners, in addition to intramolecular cross-talk between the domains of the AR. Therapeutics targeting these protein-protein interactions or NTD directly should also have efficacy against emerging AR splice variants which may play a role in PCa progression. This review will discuss the role of intrinsic disorder in AR function and illustrate how emerging therapies might target NTD in PCa.展开更多
Following acute and chronic liver injury,hepatic stellate cells (HSCs) become activated to undergo a phenotypic transformation into myofibroblast-like cells and lose their retinol content,but the mechanisms of retinoi...Following acute and chronic liver injury,hepatic stellate cells (HSCs) become activated to undergo a phenotypic transformation into myofibroblast-like cells and lose their retinol content,but the mechanisms of retinoid loss and its potential roles in HSCs activation and liver fibrosis are not understood.The influence of retinoids on HSCs and hepatic fibrosis remains controversial.The purpose of this study was to evaluate the effects of all-trans retinoid acid (ATRA) on cell proliferation,mRNA expression of collagen genes [procollagen α1 (Ⅰ),procollagen α1 (Ⅲ)],profibrogenic genes (TGF-β 1,CTGF,MMP-2,TIMP-1,TIMP-2,PAI-1),fibrolytic genes (MMP-3,MMP-13) and the upstream element (JNK and AP-1) in the rat hepatic stellate cell line (CFSC-2G).Cell proliferation was evaluated by measuring BrdU incorporation.The mRNA expression levels of collagen genes [procollagen α1 (Ⅰ),procollagen α1 (Ⅲ)],profibrogenic genes (TGF-β 1,CTGF,MMP-2,TIMP-1,TIMP-2,PAI-1),and fibrolytic genes (MMP-3,MMP-13) were quantitatively detected by using real-time PCR.The mRNA expression of JNK and AP-1 was quantified by RT-PCR.The results showed that ATRA inhibited HSCs proliferation and diminished the mRNA expression of collagen genes [procollagen α1 (Ⅰ),procollagen α1 (Ⅲ)] and profibrogenic genes (TGF-β 1,CTGF,MMP-2,TIMP-1,TIMP-2,PAI-1),and significantly stimulated the mRNA expression of MMP-3 and MMP-13 in HSCs by suppressing the mRNA expression of JNK and AP-1.These findings suggested that ATRA could inhibit proliferation and collagen production of HSCs via the suppression of active protein-1 and c-Jun N-terminal kinase signal,then decrease the mRNAs expression of profibrogenic genes (TGF-β 1,CTGF,MMP-2,TIMP-1,TIMP-2,PAI-1),and significantly induce the mRNA expression of MMP-3 and MMP-13.展开更多
AIM: To clarify the relationship between autophagy and lipotoxicity-induced apoptosis, which is termed "lipoapoptosis," in non-alcoholic steatohepatitis. METHODS: Male C57BL/6J mice were fed a high-fat diet(...AIM: To clarify the relationship between autophagy and lipotoxicity-induced apoptosis, which is termed "lipoapoptosis," in non-alcoholic steatohepatitis. METHODS: Male C57BL/6J mice were fed a high-fat diet(HFD) for 12 wk, after which the liver histology and expression of proteins such as p62 or LC3 were evaluated. Alpha mouse liver 12(AML12) cells treated with palmitate(PA) were used as an in vitro model. RESULTS: LC3-Ⅱ, p62, and Run domain Beclin-1 interacting and cysteine-rich containing(Rubicon) proteins increased in both the HFD mice and in AML12 cells in response to PA treatment. Rubicon expression was decreased upon c-Jun N-terminal kinase(JNK) inhibition at both the m RNA and the protein level in AML12 cells. Rubicon knockdown in AML12 cells with PA decreased the protein levels of both LC3-Ⅱ and p62. Rubicon expression peaked at 4 h of PA treatment in AML12, and then decreased. Treatment with caspase-9 inhibitor ameliorated the decrease in Rubicon protein expression at 10 h of PA and resulted in enlarged AML12 cells under PA treatment. The enlargement of AML12 cells by PA with caspase-9 inhibition was canceled by Rubicon knockdown.CONCLUSION: The JNK-Rubicon axis enhanced lipoapoptosis, and caspase-9 inhibition and Rubicon had effects that were cytologically similar to hepatocyte ballooning. As ballooned hepatocytes secrete fibrogenic signals and thus might promote fibrosis in the liver, the inhibition of hepatocyte ballooning might provide antifibrosis in the NASH liver.展开更多
Our previous results indicated that both the secreted and the intracellular form of full length and 1-97 N-terminal fragment of IGFBP-3 induce apoptosis in PC-3 human prostate cancer cells in an IGF-dependent and inde...Our previous results indicated that both the secreted and the intracellular form of full length and 1-97 N-terminal fragment of IGFBP-3 induce apoptosis in PC-3 human prostate cancer cells in an IGF-dependent and independent manner. This study was undertaken to delineate possible down-stream signaling pathways that are involved in this process. Intact IGFBP-3 and its N-terminal 1-97 fragments with or without a signal propeptide were fused to YFP and expressed in PC-3 human prostate cancer cells. In some cases, the putative IGF-binding site was presented in full length IGFBP-3 and its N-terminal fragment was also mutated. Extent of apoptosis was quantified using FACS. Up-regulation of total Stat-1 and activation of phospho-Stat-1 were shown by western blot. TGF-β signal was measured by luciferase reporter assay. Results from inhibitor studies indicated that both the Caspase 8 and caspase 9 pathways are involved in IGFBP-3 (non-secreted form) which induced apoptosis in PC-3 cells. Exogenous addition of IGFBP-3 to PC-3 cells increased Stat-1 protein expression/tyrosine phosphorylation. Interestingly, results also showed that knockdown of Stat-1 by siRNA potentiated the IGFBP-3 induced apoptosis in PC-3 cells. In addition, both full-length IGFBP-3 and its 1-97 Nterminal fragments inhibited TGF-β signaling in these cells. This is the first report that compares the signal transduction pathways involved in apoptotic pathways mediated by IGFBP-3 in PC-3 human prostate cancer cells. Non-secreted form of full length IGFBP-3 and its N-terminal fragments induced apoptosis in PC-3 cells via activation of caspase 8 and caspase 9. Although, only non-secreted form of IGFBP-3 is involved in inducing apoptosis in PC-3 cells via caspase 8 and caspase 9 activation pathways but both secreted and non-secreted forms of IGFBP-3 are involved in modulating Stat-1 and TGF-β pathways to induce apoptotic actions in PC-3 cells. Non-secreted intact IGFBP-3 and its N-terminal fragments induced apoptosis in PC-3 cells via activation of caspase 8 and caspase 9 pathways. Modulation in STAT-1 and TGF-β pathways may also be important for IGFBP-3 induced apoptosis in PC-3 cells in general. These studies clearly demonstrate that secreted and non-secreted FL and 1-97 N-terminal fragments induce apoptosis in PC-3 cells by regulating different mechanistic pathways.展开更多
AIM： To determine the role of c-Jun N-terminal kinase （JNK） activity in ethanol-induced apoptosis and the modulation of this signaling cascade by S-Adenosylmethionine （AdoMet）. METHODS： Primary hepatocyte cultur...AIM： To determine the role of c-Jun N-terminal kinase （JNK） activity in ethanol-induced apoptosis and the modulation of this signaling cascade by S-Adenosylmethionine （AdoMet）. METHODS： Primary hepatocyte cultures were pretreated with 100 IJmol/L SP600125, a selective JNK inhibitor, 1 mL/L DMSO or 4 mmol/L AdoMet and then exposed to 100 mmo/L ethanol. Hepatocyte apoptosis was determined by the TUNEL and DNA ladder assays. JNK activity and its inhibition by SP600125 and AdoMet were determined by Western blot analysis of c-jun phosphorylation and Bid fragmentation. SP600125 and AdoMet effects on the apoptotic signaling pathway were determined by Western blot analysis of cytochrome c release and pro-caspase 3 fragmentation. The AdoMet effect on glutathione levels was measured by EIIman＇s method and reactive oxygen species （ROS） generation by cell cytometry. RESULTS： The exposure of hepatocytes to ethanol induced JNK activation, c-jun phosphorylation, Bid fragmentation, cytochrome c release and pro-caspase 3 cleavage; these effects were diminished by SP600125, and caused a significant decrease in ethanol-induced apoptosis （P〈 0.05）. AdoMet exerted an antioxidant effect maintaining glutathione levels and decreasing ROS generation, without a significant effect on JNK activity, and prevented cytochrome c release and pro-caspase 3 cleavage.CONCLUSION： The JNK signaling cascade is a key component of the proapoptotic signaling pathway induced by ethanol. JNK activation may be independent from ROS generation, since AdoMet which exerted antioxidant properties did not have a significant effect on JNK activity. JNK pathway modulator agents and AdoMet may be components of promising therapies for alcoholic liver disease （ALD） treatment.展开更多
文摘Background Elevated N-terminal pro-brain natriuretic peptide(NT-pro-BNP)is a recognized predictor of poor prognosis in heart failure and infectious diseases.We aimed to investigate its predictive value for short-term mortality in patients with infective endocarditis(IE)complicated by sepsis.Methods A total of 416 consecutive patients diagnosed with IE and sepsis at Guangdong Provincial People's Hospital were enrolled.The patients were divided into three groups according to the tertiles of NT-pro-BNP level of the first blood collection within 24 hours after admission:<2000 pg/mL(n=138),2000-7167 pg/mL(n=140),and>7167 pg/mL(n=138).Univariate and multivariate regression analysis were used to explore the predictive value of NT-pro-BNP for short-term mortality,and the best cut-off value was determined by receiver operating characteristic(ROC)curve.Results In-hospital and 6-month death occurred in 65 and 94 patients,respectively.Higher in-hospital mortality was found in patients with higher serum NT-pro-BNP levels(9.4%vs.13.6%vs.23.9%,P=0.003).ROC curve analysis identified an optimal NT-pro-BNP cutoff level of 1357 pg/mL[area under curve(AUC):0.652,95%CI:0.588-0.717,P<0.001].Multivariate regression analysis showed that both log-transformed NT-pro-BNP(in-hospital mortality:OR:1.987,95%CI:1.045-3.778,P=0.036;6-month mortality:HR:1.714,95%CI:1.072-2.7400,P=0.025)and NT-pro-BNP>1357 pg/mL(in-hospital mortality:OR:8.059,95%CI:1.813-35.818,P=0.006;6-month mortality:HR:5.193,95%CI:1.806-14.938,P=0.002)were both independent risk factors for in-hospital and 6-month mortality.Conclusions Serum NT-pro-BNP could serve as an independent predictor of in-hospital and 6-month mortality in patients with IE complicated with sepsis.
基金supported by the Indian Council of Agricultural Research(ICAR)-Senior Research Fellowship from ICAR,India(Grant No.EDN/1/25/2015-Exam cell)ICAR-Centre for Agricultural Bioinformatics and National Institute for Plant Biotechnology,India(Grant No.1006456).
文摘Dopamine β-monooxygenase N-terminal(DOMON)domain-containing genes are present across all taxa and are critical in cell signaling and redox transport.Despite their significance,these genes remain understudied in plant species.In this study,we identified 15 DOMON genes in rice and analyzed their phylogenetic relationships,conserved motifs,and cis-regulatory elements.Phylogenetic analysis revealed distinct clustering of OsDOMON genes in rice and other monocots,compared with Arabidopsis thaliana.Promoter analysis showed a higher abundance of stress-related regulatory elements in Tetep,a well-known blast and abiotic stress-tolerant cultivar,compared with Nipponbare and HP2216.OsDOMON genes displayed differential expression under biotic stress(Magnaporthe oryzae infection)and abiotic stresses(drought,heat,and salinity)in contrasting cultivars.Tetep exhibited significantly higher expression levels of specific OsDOMON genes during early blast infection stages,particularly OsDOMON6.1 and OsDOMON9.2,suggesting their roles in cell wall fortification and reactive oxygen species signaling.Under abiotic stress,genes like OsDOMON3.3,OsDOMON8.1,and OsDOMON9.2 showed higher expression in Tetep,indicating their involvement in stress tolerance mechanisms.This study provides a foundation for future functional studies of OsDOMON genes,paving the way for developing rice cultivars resistant to biotic and abiotic stresses.
文摘Background: In cardiac surgery, the N-terminal pro-brain natriuretic peptide (NT-proBNP) level is reportedly correlated with the onset of postoperative complications. We examined the relationship between the NT-proBNP level and perioperative complications in thoracic surgery and elucidated the significance of NT-proBNP measurement. Methods: We evaluated 48 patients excluding hemodialysis patients who underwent lung resection from November 2015 to February 2016. NT-proBNP measurement was performed three times preoperatively on postoperative days 2 and 5. We examined the relationship between clinical background factors such as preoperative comorbidity and the development of postoperative complications. Based on established criteria for surgical complications (Clavien-Dindo classification), grade ≥ II was defined as a complications. We classified the patients into two groups (with or without complications) and compared and examined the background factors between the groups. Results: The study included 48 patients (33 male, 15 female) with an average age of 72 years (range, 35 - 86 years). Preoperative comorbidities included cardiovascular disease in five patients, diabetes mellitus in four, and chronic obstructive pulmonary disease in six. The average operation time was 163 (29 - 308) minutes, and the bleeding volume was 30 (10 - 620) ml. Early complications were confirmed in 11 patients, and late complications were confirmed in 7 patients. A high NT-proBNP level on postoperative day 5 was an independent risk factor for late complications. Conclusion: The perioperative NT-proBNP level is considered to be a predictor of complications. Its measurement is useful for predicting postoperative complications, and careful perioperative management is required for patients with high levels.
文摘Glucagon-like peptide-1（GLP-1） is an endogenous insulinotropic hormone with excellent blood glucose-lowering activity, however, it is rapidly inactivated in the plasma mainly by dipeptidyl peptidase IV（DPP-IV）. To overcome this problem, various N-terminal modifications of GLP-1 have been performed to prolong the in vivo biological activity, by improving the DPP-IV resistance while retaining receptor affinity and receptor activation. These studies have included modifications of His7, Ala8 or Glu9 at the N-terminus of GLP-1 and some other modifications. Among them, Ala8 substitutions with glycine（Gly8） and α-aminoisobutyric acid（Aib8） have been clinically applied in the development of diabetic therapy, such as Exenatide, Semaglutide, Albiglutide and Taspoglutide. In this review, we introduce N-terminal modifications of GLP-1 that have been reported, and discuss their potential and challenges for the treatment of type 2 diabetes.
基金supported by the Hainan Health Department(2002lx-12)
文摘Objective: To study the regulatory effect and molecular mechanism of juglone on apoptosis of cervical cancer Hela cells. Methods: Cervical cancer Hela cells were cultured and treated with different dosages of juglone (10, 20, and 40 pmol/L, respectively) and c-Jun N-terminal kinase (JNK) inhibitor SP600125 (10, 20, and 40 mu mol/L. respectively). Then cellular proliferative activity and the expression of JNK/c-Jun pathway molecule and apoptotic molecule in the cells were detected. Results: After 6, 12. 18 and 24 h of treatment, the value for proliferative activity of cells treated with juglone was significantly lower than that of control group (p<0.05), and the anti-proliferative effect was more significant as the treatment period and juglone dosage increased (P<0.05). The protein expressions of Box, CytC, Fas, FasL, Caspase-3, and p-c-Jun in cells treated with juglone were significantly higher than those of control group (P<0.05), and the protein expressions of Bax, CytC, Fas. FasL, Caspase-3, p-JNK and p-c-Jun increased more remarkably as the juglone dosage increased (P<0.05). In cells treated with 40 pmol/L juglone and SP600125, the protein expressions of Bax, CytC, Fas. Fast.. and Caspase-3 were significantly lower than those of cells treated with 40 pmol/L juglone (J<0.05), and the protein expressions of Bax, CytC, Fas, FasL and Caspase-3 reduced more remarkably as the SP600125 dosage increased (P<0.05). Conclusion: Juglone can increase the expression of apoptotic molecules in mitochondrial pathway and death receptor pathway by activating JNK/c-Jun pathway, thus inducing apoptosis of cervical cancer cells.
文摘Background The neutrophil-to-lymphocyte （N/L） ratio has been associated with poor prognosis in patients with heart failure, but it has not been compared with N-terminal pro-brain natriuretic peptide （NT-proBNP） in elderly patients with chronic heart failure （CHF）. We sought to make this comparison. Methods A total of 1355 elderly patients with CHF were analyzed. A multivariate logistic regression model was used to analyze the variables associated with atrial fibrillation （AF）. Cox regression analysis was used to assess the multivariable rela- tionship between the N/L ratio, NT-proBNP level, and subsequent major cardiovascular events （MCE）. Results In the multiple logistic regression analysis, the N/L ratio was demonstrated as a risk factor for AF in elderly patients with CHF [odds ratio （OR）： 1.079, 95% confi- dence interval （CI）： 1.027-1.134, P = 0.003]. The median follow-up period was 18 months. In a multivariable model using tertiles of both variables, the highest tertile of the N/L ratio was significantly associated with MCE [hazard ratio （HR）： 1.407, 95% CI： 1.098-1.802, P = 0.007] compared with the lowest tertile. Similarly, the highest NT-proBNP tertile was also significantly associated with MCE （HR： 1.461, 95% CI： 1.104-1.934, P- 0.008）. Conclusions In elderly patients with CHF, the N/L ratio is one of the important risk factors for AF and it is an inexpensive and readily available marker with similar independent prognostic power to NT-proBNP. The risk of MCE increases 1.407-fold when the N/L ratio is elevated to the highest tertile.
基金supported by Science and Technology Department General Project in Hunan Province(2012SK3127)
文摘Objective:To investigate the effect of atorvastatin on serum oxidative stress and N-terminal brain natriuretic peptide expression in rats.Methods:A total of 40 healthy male SD rats were randomly divided into the sham group(Croup A,n=10,saline 5 mL/d),ischemia-reperfusion group(Group B,n=10,saline S mL/d),atorvastatin group(Group C,n=10.atorvastatin 20 mg/kg·d),atorvastatin + N-amino-arginine group(Group D,n=10,atorvastatin 20 mg/kg·d + N-amino arginine 15 mg/kg).Myocardial ischemia-reperfusion rat model was eslablished after 3 days of gavage.N-amino arginine 15 mg/kg was given by tail vein injection 15 min before ischemia.After reperfusion,enzymology indicators such us creatine kinase(CK) and lactate dehydrogenase and the oxidative stress parameters such as nitric oxide(NO),malondialdehyde(MDA) and total superoxide dismutase(TSOD),and n-terminal pro-brain natriuretic peptide(NT-proBNP)expression was detected by immunohistochemistry.Results:LDH and CK levels of group A were significantly lower than the outer three groups,and group B was the highest.There was significant difference between group B and group C(P<0.05),and no significant difference between group B and group D(P>0.05).MDA levels in group B were significantly higher than the other three groups.The lowest was group A,followed by group C,the difference among groups was significantly(P<0.05).TSOD and NO levels in group B was the lowest,the level in group A was the highest,followed by group C,the difference among groups was significant(P<0.05).NT-proBNP level in group B was significantly higher than the other three groups,the lowest was group A,followed by group C,the difference among groups was significant(P<0.05).Conclusions:Atorvastatin has a protective effect on the myocardial injury in the myocardial ischemia and reperfusion rats.It can increase NO synthesis and decrease MDA content,increase serum TSOD activity and the oxidative stress effect,meanwhile protect myocardial cells and reduce myocardial injury.
基金Supported by the Major State Basic Research Development Program of China, Program 973, Grant No. 2001CB510001
文摘AIM: Most studies on the immune effect of gp96 were focused on its enhancement of CTLs. It is interesting to know whether gp96 could influence the humoral immune response, and whether the recombinant N-terminal fragment of gp96 could substitute native gp96 to stimulate the immune system.METHODS: gp96 isolated from livers of normal mice and its N-terminal fragment (amino acid 22-355) expressed in E coli were used for immunization of BALb/c mice. Eight groups of mice received one of the following regiments subcutaneously in 100 μL phosphate buffered saline (PBS)at an interval of 3 wk. Group 1: PBS only; group 2:gp96 only; group 3: N-terminal fragment only; group 4: HBsAg only; group 5: HBsAg+gp96; group 6: HBsAg+N-terminalfragment; group 7: HBsAg+incomplete Freud's adjuvant; group 8: HBsAg+N-terminal fragment (95 ℃ heated for 30 min). Serum anti-HBsAg antibody levels were assayed by ELISA. CTL responses in splenocytes were analyzed by ELISPOT after the last vaccination.RESULTS: The average titer of serum anti-HBsAg antibodyin the mice immunized with HBsAg together with gp96 or its N-terminal fragment were much higher than those immunized with HBsAg alone detected by ELISA. The cellular immune response of the mice immunized with HBsAg together with gp96 or its N-terminal fragment was not different with those immunized with HBsAg alone measured by ELISPOT assay.CONCLUSION: gp96 or its N-terminal fragment greatly improved humoral immune response induced by HBsAg, but failed to enhance the CTL response, which demonstrated the potential of using gp96 or its N-terminal fragment as a possible adjuvant to augment humoral immune response against HBV infection.
文摘Objective To investigate plasma N-terminal pro-brain natriuretic peptide (NT-BNP) levels and to assess their clinical significance in elderly patients with isolated diastolic dysfunction. Methods Plasma NT-BNP level were measured by electrochemiluminescence immunoassay in 34 symptomatic patients (Group 1), 34 asymptomatic patients (Group 2) with isolated diastolic dysfunction, and in 16 elderly healthy subjects (control group, Group 3), serving controls. Colored Doppler echocardiography was performed to evaluate the patients' cardiac structures and functions. Results The plasma NT-BNP level in Group 1 was significantly higher than those in Group 2 and Group 3 and increased with the severity of heart failure. There was no significant difference of plasma NT-BNP levels between Group 2 and Group 3 (p>0.05). A NT-BNP value of 102.75 pg/mL showed a sensitivity of 88.2%, a specificity of 87.5%, and an accuracy of 88.1% for diagnosing diastolic dysfunction. Patients with restrictive filling pattern on echocardiography had higher NT-BNP levels than those of impaired relaxation pattern (1961.2±304.9 versus 460.1±92.7pg/mL, p<0.001). Conclusion The elevation of plasma NT-BNP level in elderly patients with isolated diastolic dysfunction correlates with the severity of their diastolic abnormalities. The level of plasma NT-BNP has an important clinical value in the diagnosis of elderly patients with isolated diastolic dysfunction.
文摘The role of androgen receptor （AR） in the initiation and progression of prostate cancer （PCa） is well established. Competitive inhibition of the AR ligand-binding domain （LBD） has been the staple of antiandrogen therapies employed to combat the disease in recent years. However, their efficacy has often been limited by the emergence of resistance, mediated through point mutations, and receptor truncations. As a result, the prognosis for patients with malignant castrate resistant disease remains poor. The amino-terminal domain （NTD） of the AR has been shown to be critical for AR function. Its modular activation function （AF-1） is important for both gene regulation and participation in protein-protein interactions. However, due to the intrinsically disordered structure of the domain, its potential as a candidate for therapeutic intervention has been dismissed in the past. The recent emergence of the small molecule EPI-O01 has provided evidence that AR-NTD can be targeted therapeutically, independent of the LBD. Targeting of AR-NTD has the potential to disrupt multiple intermolecular interactions between AR and its coregulatory binding partners, in addition to intramolecular cross-talk between the domains of the AR. Therapeutics targeting these protein-protein interactions or NTD directly should also have efficacy against emerging AR splice variants which may play a role in PCa progression. This review will discuss the role of intrinsic disorder in AR function and illustrate how emerging therapies might target NTD in PCa.
文摘Following acute and chronic liver injury,hepatic stellate cells (HSCs) become activated to undergo a phenotypic transformation into myofibroblast-like cells and lose their retinol content,but the mechanisms of retinoid loss and its potential roles in HSCs activation and liver fibrosis are not understood.The influence of retinoids on HSCs and hepatic fibrosis remains controversial.The purpose of this study was to evaluate the effects of all-trans retinoid acid (ATRA) on cell proliferation,mRNA expression of collagen genes [procollagen α1 (Ⅰ),procollagen α1 (Ⅲ)],profibrogenic genes (TGF-β 1,CTGF,MMP-2,TIMP-1,TIMP-2,PAI-1),fibrolytic genes (MMP-3,MMP-13) and the upstream element (JNK and AP-1) in the rat hepatic stellate cell line (CFSC-2G).Cell proliferation was evaluated by measuring BrdU incorporation.The mRNA expression levels of collagen genes [procollagen α1 (Ⅰ),procollagen α1 (Ⅲ)],profibrogenic genes (TGF-β 1,CTGF,MMP-2,TIMP-1,TIMP-2,PAI-1),and fibrolytic genes (MMP-3,MMP-13) were quantitatively detected by using real-time PCR.The mRNA expression of JNK and AP-1 was quantified by RT-PCR.The results showed that ATRA inhibited HSCs proliferation and diminished the mRNA expression of collagen genes [procollagen α1 (Ⅰ),procollagen α1 (Ⅲ)] and profibrogenic genes (TGF-β 1,CTGF,MMP-2,TIMP-1,TIMP-2,PAI-1),and significantly stimulated the mRNA expression of MMP-3 and MMP-13 in HSCs by suppressing the mRNA expression of JNK and AP-1.These findings suggested that ATRA could inhibit proliferation and collagen production of HSCs via the suppression of active protein-1 and c-Jun N-terminal kinase signal,then decrease the mRNAs expression of profibrogenic genes (TGF-β 1,CTGF,MMP-2,TIMP-1,TIMP-2,PAI-1),and significantly induce the mRNA expression of MMP-3 and MMP-13.
文摘AIM: To clarify the relationship between autophagy and lipotoxicity-induced apoptosis, which is termed "lipoapoptosis," in non-alcoholic steatohepatitis. METHODS: Male C57BL/6J mice were fed a high-fat diet(HFD) for 12 wk, after which the liver histology and expression of proteins such as p62 or LC3 were evaluated. Alpha mouse liver 12(AML12) cells treated with palmitate(PA) were used as an in vitro model. RESULTS: LC3-Ⅱ, p62, and Run domain Beclin-1 interacting and cysteine-rich containing(Rubicon) proteins increased in both the HFD mice and in AML12 cells in response to PA treatment. Rubicon expression was decreased upon c-Jun N-terminal kinase(JNK) inhibition at both the m RNA and the protein level in AML12 cells. Rubicon knockdown in AML12 cells with PA decreased the protein levels of both LC3-Ⅱ and p62. Rubicon expression peaked at 4 h of PA treatment in AML12, and then decreased. Treatment with caspase-9 inhibitor ameliorated the decrease in Rubicon protein expression at 10 h of PA and resulted in enlarged AML12 cells under PA treatment. The enlargement of AML12 cells by PA with caspase-9 inhibition was canceled by Rubicon knockdown.CONCLUSION: The JNK-Rubicon axis enhanced lipoapoptosis, and caspase-9 inhibition and Rubicon had effects that were cytologically similar to hepatocyte ballooning. As ballooned hepatocytes secrete fibrogenic signals and thus might promote fibrosis in the liver, the inhibition of hepatocyte ballooning might provide antifibrosis in the NASH liver.
文摘Our previous results indicated that both the secreted and the intracellular form of full length and 1-97 N-terminal fragment of IGFBP-3 induce apoptosis in PC-3 human prostate cancer cells in an IGF-dependent and independent manner. This study was undertaken to delineate possible down-stream signaling pathways that are involved in this process. Intact IGFBP-3 and its N-terminal 1-97 fragments with or without a signal propeptide were fused to YFP and expressed in PC-3 human prostate cancer cells. In some cases, the putative IGF-binding site was presented in full length IGFBP-3 and its N-terminal fragment was also mutated. Extent of apoptosis was quantified using FACS. Up-regulation of total Stat-1 and activation of phospho-Stat-1 were shown by western blot. TGF-β signal was measured by luciferase reporter assay. Results from inhibitor studies indicated that both the Caspase 8 and caspase 9 pathways are involved in IGFBP-3 (non-secreted form) which induced apoptosis in PC-3 cells. Exogenous addition of IGFBP-3 to PC-3 cells increased Stat-1 protein expression/tyrosine phosphorylation. Interestingly, results also showed that knockdown of Stat-1 by siRNA potentiated the IGFBP-3 induced apoptosis in PC-3 cells. In addition, both full-length IGFBP-3 and its 1-97 Nterminal fragments inhibited TGF-β signaling in these cells. This is the first report that compares the signal transduction pathways involved in apoptotic pathways mediated by IGFBP-3 in PC-3 human prostate cancer cells. Non-secreted form of full length IGFBP-3 and its N-terminal fragments induced apoptosis in PC-3 cells via activation of caspase 8 and caspase 9. Although, only non-secreted form of IGFBP-3 is involved in inducing apoptosis in PC-3 cells via caspase 8 and caspase 9 activation pathways but both secreted and non-secreted forms of IGFBP-3 are involved in modulating Stat-1 and TGF-β pathways to induce apoptotic actions in PC-3 cells. Non-secreted intact IGFBP-3 and its N-terminal fragments induced apoptosis in PC-3 cells via activation of caspase 8 and caspase 9 pathways. Modulation in STAT-1 and TGF-β pathways may also be important for IGFBP-3 induced apoptosis in PC-3 cells in general. These studies clearly demonstrate that secreted and non-secreted FL and 1-97 N-terminal fragments induce apoptosis in PC-3 cells by regulating different mechanistic pathways.
文摘AIM： To determine the role of c-Jun N-terminal kinase （JNK） activity in ethanol-induced apoptosis and the modulation of this signaling cascade by S-Adenosylmethionine （AdoMet）. METHODS： Primary hepatocyte cultures were pretreated with 100 IJmol/L SP600125, a selective JNK inhibitor, 1 mL/L DMSO or 4 mmol/L AdoMet and then exposed to 100 mmo/L ethanol. Hepatocyte apoptosis was determined by the TUNEL and DNA ladder assays. JNK activity and its inhibition by SP600125 and AdoMet were determined by Western blot analysis of c-jun phosphorylation and Bid fragmentation. SP600125 and AdoMet effects on the apoptotic signaling pathway were determined by Western blot analysis of cytochrome c release and pro-caspase 3 fragmentation. The AdoMet effect on glutathione levels was measured by EIIman＇s method and reactive oxygen species （ROS） generation by cell cytometry. RESULTS： The exposure of hepatocytes to ethanol induced JNK activation, c-jun phosphorylation, Bid fragmentation, cytochrome c release and pro-caspase 3 cleavage; these effects were diminished by SP600125, and caused a significant decrease in ethanol-induced apoptosis （P〈 0.05）. AdoMet exerted an antioxidant effect maintaining glutathione levels and decreasing ROS generation, without a significant effect on JNK activity, and prevented cytochrome c release and pro-caspase 3 cleavage.CONCLUSION： The JNK signaling cascade is a key component of the proapoptotic signaling pathway induced by ethanol. JNK activation may be independent from ROS generation, since AdoMet which exerted antioxidant properties did not have a significant effect on JNK activity. JNK pathway modulator agents and AdoMet may be components of promising therapies for alcoholic liver disease （ALD） treatment.
