Objective Recent researches find that endoplasmic reticulum is a new target for the treatment of cardiovascular disease and its stress response plays an important role in the hypertension-induced cardiovascular remodeling.The study built up the apoptosis model of endoplasmic reticulum stress ( ERS) in human umbilical vein endothelial cells ( HUVECs) and investigated the im-pact of 17β-estradiol ( E2) on the ERS apoptosis of HUVECs induced by tunicamycinand(TM)/dithiothreitol(DTT). Methods HUVECs incubated for 10 h in 10μmol/L TM or 8 h in 2 mmol/L DTT were the best concentration and time for ERS apoptosis.E2 of 10-8 mol/L was prominent in protecting ERS.According to the application of TM/DTT, E2, estrogen antagonists (ICI182, 780 and G15), there were 6 groups:control group, TM/DTT group, TM/DTT+E2 group, TM/DTT+E2 +G15 group, TM/DTT+E2 +ICI+G15 group.Western blot was applied to detect the expressions of biomarkers for ERS in-duced apoptosis (GRP78, cleaved caspase-12 and CHOP).Hochest staining was used to observe the changes of the apoptosis cell number. Results Compared with control group, the expressions of GRP78, caspase-12 and CHOP significantly increased(P<0.05).In comparison with TM group, the expressions of GRP78, caspase-12 and CHOP in TM+E2 group significantly decreased (6.80 ±1.07 vs 4.01 ±0.46, 1.54 ±0.32 vs 0.88 ±0.10, 1.91 ±0.37 vs 0.91 ± 0.02, P<0.05).In comparison with TM +E2 group, the CHOP expression in TM +E2 +ICI group increased(0.91 ±0.02 vs 0.96 ±0.02, P<0.05), and the expressions of GRP78 and caspase-12 in TM+E2 +G15 group increased(4.01 ±0.46 vs 5.25 ± 0.80, 0.88 ±0.10 vs 1.02 ±0.07, P<0.05), and the expressions of GRP78, caspase-12 and CHOP in TM+E2 +ICI+G15 group increased (P<0.05).Compared with DTT group, the expressions of GRP78 and CHOP in DTT+E2 group decreased (1.81 ± 0.08 vs 1.30 ±0.14, 1.00 ±0.13 vs 0.51 ±0.01, P<0.05).In comparison with DTT+E2 group, the expressions of GRP78 and CHOP in DTT+E2 +ICI group decreased(P <0.05), and the expression of GPR78 in DTT+E2 +G15 group increased(P<0.05), and the expressions of GRP78, caspase-12 and CHOP in DTT+E2 +ICI+G15 group increased(P<0.05).The change of the apop-tosis cell number observed by hochest staining was in consistence with the result of western blot. Conclusion E2 can protect human endothelial cells from ERS induced apoptosis caused by TM and DTT.Estrogen maintains homeostasis by regulating ERS estrogen re-ceptors, thereby protecting the cardiovascular system.

Objective To explore the optimal timing of liver transplantation for acute liver failure,and analyze relative risk factors affecting patients' prognosis.Methods We retrospectively analyze perioperative clinical data of 50 patients suffering from acute liver failure who underwent liver transplantation between March 2005 and June 2010 in Organ Transplantation Center,the First Affiliated Hospital of Sun Yat-sen University.Patients were divided into survival group and death group.Clinical data before operation were collected and analyzed by univariate and multivariate analysis,respectively.Risk factors influencing the perioperative mortality were selected and were used to direct the operation time.Results There were 50 patients who underwent liver transplantation and 11 cases died during perioperative phase.Five patients died of respiratory infection,three of acute renal failure,one of digestive tract hemorrhage,one of primary allograft failure and one of multiple organ failure.The perioperative,one-year and three-year survival rate were 78％,74％ and 72％ respectively.In the univariate analysis,age,bilirubin level,prothrombin time,creatinine level,grade of encephalopathy and MELD score were found to be significantly different between survival group and death group.The multivariate analysis revealed that age≥65 y,INR ≥3.5,creatinine level ≥ 2.5 mg/dl and MELD score ≥ 40 were independent risk factors affecting survival.Conclusions Liver transplantation is an effective treatment of choice for acute liver failure.Appropriate timing of transplantation helps achieve a high survival rate.

Aim To investage the regulatory effect of alizarin on renal interlobar arterial smooth muscle cells. Method The effect of alizarin on BKCa channels was observed by whole-cell patch clamp recording tech-nique. Results Selective BKCa channel blocker ibTX inhibited alizarin-induced outward current(P<0. 05);single smooth muscle cells were incubated in extracel-lular fluid with no Ca2+ 30 minutes, selective L-Ca2+channel blocker nimodipine, selective calcium ion che-lating agent BAPTA-AM and ryanodine inhibited the a-lizarin-induced BKCa channels current, too ( P <0. 05 ) . Conclusion Alizarin relaxes renales interlobar arterial smooth muscle via activation of L-Ca2+ channel firstly, which lead to Ca2+ flowed into cytoplam, and rising of Ca2+ in cytoplam ryanodine receptor indirect-ly, and BKCa is activated at last.

Objective To investigate the feasibility of serum cardiac troponin T(cTnT) as a marker of cardiovascular events and hemodialysis (HD) adequacy in maintainence hemodialysis (MHD) patients.Methods Forty-seven cases of MHD patients were randomly divided into two groups (group A and group B).Group A received intermittent HD 4 h thrice one week,and group B received intermittent HD 4 h twice one week plus high-flux hemodiafiltration(HDF) 4 h once one week.Serum examination for blood biochemical indicator,cTnT and echocardiogram was performed every three months and at the time of recruitment.All the patients were followed up until the occurrence of death or cardiovascular events.Results After 3 months treatment,serum cTnT deceased significantly in group B compared with group A,and maintained the lower levels throughout the follow-up.E/A and LVEF had been reduced since 3 months treatment in group A,but stable in group B,E/A was lower in group A after 18 months treatment than that in group B,LVEF was lower in group A after 12 months treatment than that in group B.There were positive correlations between cTnT and E/A or LVEF in 42 cases who accomplished the follow-up of 12 months (r =0.54,0.66,P ＜0.05).Kaplan-Meier survival curve showed that the occurrence of cardiovascular events in patients with cTnT≥0.1μ g/L was higher than that with cTnT ＜0.1 μg/L in (28.5 ± 9.7) months' follow- up (Log-rank test: P =0.02).Both survival analysis and Cox analysis indicated that serum cTnT was a predictor of cardiovascular events in MHD patients.Conclusions Serum level of cTnT can be used as a marker of HD adequacy,and it is a predictor of cardiac events in MHD patients.Regular high-flux HDF increases the adequacy of HD treatment and improves the quality of life in MHD patients.

BACKGROUND:MicroRNA plays an important role in the process of growth and aging of living body. To know the role of let-7d in inducing bone marrow mesenchymal stem celldifferentiation into neurons can promote the stem celltransplantation. OBJECTIVE:To investigate the role of let-7d in inducing bone marrow mesenchymal stem celldifferentiation into neurons. METHODS:(1) The lentiviral vector of let-7d was constructed and transfected into rat bone marrow mesenchymal stem cells. The cells were divided into non-transfected group, negative control group (transfected with FU-RNAi-NC-LV), transfected enhancement group (transfected with let-7d-LV), transfected inhibition group ( transfected with let-7d-inhibition-LV). (2) Rat bone marrow mesenchymal stem cells were treated with fasudil as an inducer for triggering the cells to differentiate into neurons. The expression of neuron-specific markers, neuron-specific enolase and microtubule-associated protein 2, were measured by immunocytochemical method. The mRNA expression of microtubule-associated protein 2 was detected by RT-PCR. The viability of bone marrow mesenchymal stem cells was determined by MTT method. RESULTS AND CONCLUSION:Under inverted fluorescence microscope, the cells were successful y transfected with let-7d. Fasudil induced bone marrow mesenchymal stem cells to differentiate into neurons. The transfection efficiency and expression levels of neuron-specific enolase and microtubule-associated protein 2 in transfected enhancement group were higher than those in the negative control group (P<0.05);while in the inhibition group, they were lower than those in the negative control group (P<0.05). These findings indicate that let-7d can promote the differentiation of bone marrow mesenchymal stem cells into neurons induced by fasudil, and by control ing the expression of let-7d we can influence the differentiation efficiency from bone marrow mesenchymal stem cells to neurons.

This study was aimed to investigate the diuretic effect ofMori Cortex and to identify effective fractions inM. Cortex. Metabolic cages were used to firstly observe the diuretic effect ofM. Cortex aqueous extracts on rats. Medications were continuously given for 5 days to screen for the best dosage of diuretic effect. Picric acid assays were used to detect creatinine levels in serum and urine after 5-day medication. Then, the diuretic effect of each chemical split fraction inM. Cortex was studied in order to indentify the effective parts. The results showed that after administration ofM. Cortex aqueous extracts for 3 to 5 days, compared with the control group, there was a significant diuretic effect on rats (P<0.05 orP<0.01). And the medium-dose ofM. Cortex aqueous extracts showed the best effect (P<0.01). However,M. Cortex aqueous extracts had no significant effect on creatinine levels in serum and urine. Assays of diuretic effect of chemical split fractions ofM.Cortex indicated that compared with the control group, 30% ethanol fraction and fatty oil fraction had the best diuretic effect (P<0.01). It was concluded thatM.Cortex aqueous extracts had a significant diuretic effect. And the chemical fractions contributed mostly to this effect were mainly existed in the 30% ethanol fraction and fatty oil fraction.

Objective:To explore the relationship between mobile phone addiction and perceived stress, negative emotion, social support and psychological capital in college students, especially to clarify the internal mechanism of these variables.Methods:A total of 836 college students were investigated with mobile phone addiction index scale, positive psychological capital questionnaire, stress perception scale, positive and negative emotion scale and perceived social support scale.SPSS 22.0 software was used for correlation analysis and SPSS-PROCESS was used to analyze the mediating effect and moderating effect.Results:(1)The scores of psychological capital and perceived stress were(123.38±17.96)and(38.76±6.39)respectively, and the scores of negative emotion, social support and mobile phone addiction were(22.46±6.45), (63.36±12.40)and(39.31±10.01)respectively.Psychological capital was negatively correlated with perceived stress, negative emotion and mobile phone addiction( r=-0.66, -0.37, -0.28, all P<0.01).Perceived stress was positively correlated with negative emotion and mobile phone addiction( r=0.50, 0.38, both P<0.01).Social support was positively correlated with psychological capital( r=0.50, P<0.01), while negatively correlated with perceived stress, negative emotion and mobile phone addiction( r=-0.41, -0.30, -0.12, all P<0.01).(2)Psychological capital influenced mobile phone addiction by the mediating effect of perceived stress( β=-0.20, SE=0.03, 95% CI: -0.27--0.13).In addition, psychological capital influenced mobile phone addiction through the chain mediating effect of perceived stress and negative emotion( β=-0.04, SE=0.01, 95% CI: -0.06--0.01).Moreover, the mediating effect of psychological capital on stress perception was moderated by social support. Conclusion:Perceived stress and negative emotion are important mediations between psychological capital and mobile phone addiction.Social support can moderate the effect of psychological capital on perceived stress.

Tacrolimus exhibits varied individual pharmacokinetic and a narrow therapeutic window, resulting in difficulties in personalized medication.In order to improve the safety of tacrolimus in clinical application and its efficiency and rationality in clinical practice, many countries and regions in the world have issued a number of guidelines for tacrolimus application.However, these guidelines generally aim at particular disease and race, and have certain limitation.In this article, the guidelines were explicated and analyzed in detail.Moreover, an individual tacrolimus medication recommendation for Chinese population was summarized based on the latest research of tacrolimus pharmacogenomics and therapeutic drug monitoring so as to provide assistance for the rational use of tacrolimus.

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment landscape for chronic myeloid leukemia (CML). However, TKI resistance poses a significant challenge, leading to treatment failure and disease progression. Resistance mechanisms include both BCR::ABL1-dependent and BCR::ABL1-independent pathways. The mechanisms underlying BCR::ABL1 independence remain incompletely understood, with CML cells potentially activating alternative signaling pathways, including the AKT/mTOR and JAK2/STAT5 pathways, to compensate for the loss of BCR::ABL1 kinase activity. This study explored tumoral VISTA (encoded by VSIR) as a contributing factor to TKI resistance in CML patients and identified elevated tumoral VISTA levels as a marker of resistance and poor survival. Through in vitro and in vivo analyses, we demonstrated that VSIR knockdown and the application of NSC-622608, a novel VISTA inhibitor, significantly impeded CML cell proliferation and induced apoptosis by attenuating the AKT/ mTOR and JAK2/STAT5 pathways, which are crucial for CML cell survival independent of BCR::ABL1 kinase activity. Moreover, VSIR overexpression promoted TKI resistance in CML cells. Importantly, the synergistic effect of NSC-622608 with TKIs offers a potent therapeutic avenue against both imatinib-sensitive and imatinib-resistant CML cells, including those harboring the challenging T315I mutation. Our findings highlight the role of tumoral VISTA in mediating TKI resistance in CML, suggesting that inhibition of VISTA, particularly in combination with TKIs, is an innovative approach to enhancing treatment outcomes in CML patients, irrespective of BCR::ABL1 mutation status. This study not only identified a new pathway contributing to TKI resistance but also revealed the possibility of targeting tumoral VISTA as a means of overcoming this significant clinical challenge.

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment landscape for chronic myeloid leukemia (CML). However, TKI resistance poses a significant challenge, leading to treatment failure and disease progression. Resistance mechanisms include both BCR::ABL1-dependent and BCR::ABL1-independent pathways. The mechanisms underlying BCR::ABL1 independence remain incompletely understood, with CML cells potentially activating alternative signaling pathways, including the AKT/mTOR and JAK2/STAT5 pathways, to compensate for the loss of BCR::ABL1 kinase activity. This study explored tumoral VISTA (encoded by VSIR) as a contributing factor to TKI resistance in CML patients and identified elevated tumoral VISTA levels as a marker of resistance and poor survival. Through in vitro and in vivo analyses, we demonstrated that VSIR knockdown and the application of NSC-622608, a novel VISTA inhibitor, significantly impeded CML cell proliferation and induced apoptosis by attenuating the AKT/ mTOR and JAK2/STAT5 pathways, which are crucial for CML cell survival independent of BCR::ABL1 kinase activity. Moreover, VSIR overexpression promoted TKI resistance in CML cells. Importantly, the synergistic effect of NSC-622608 with TKIs offers a potent therapeutic avenue against both imatinib-sensitive and imatinib-resistant CML cells, including those harboring the challenging T315I mutation. Our findings highlight the role of tumoral VISTA in mediating TKI resistance in CML, suggesting that inhibition of VISTA, particularly in combination with TKIs, is an innovative approach to enhancing treatment outcomes in CML patients, irrespective of BCR::ABL1 mutation status. This study not only identified a new pathway contributing to TKI resistance but also revealed the possibility of targeting tumoral VISTA as a means of overcoming this significant clinical challenge.