Effects of Ionic Liquids on Piezoelectric Properties of Electrospun Poly(L-lactic acid) Nanofiber Membranes.

The development of environmentally friendly, degradable piezoelectric materials is of great significance for the environment. Poly(L-lactic acid) (PLLA) is a promising piezoelectric material as a degradable material. Here, we have introduced a series of ionic liquids (ILs) into PLLA spinning solution, and the PLLA/IL composite nanofiber membranes are prepared by electrospinning method. When the conductivity of the spinning solution is below 400 µS·cm-1, the addition of ILs, especially [EMIm][PF6], can significantly improve the morphology and piezoelectric properties of the PLLA/IL composite nanofiber membrane with the output voltage of 2.3 V under the pressure of 5 N, which is 4 times that of the PLLA nanofiber membrane. The improvement of the piezoelectric properties of PLLA/IL nanofiber membrane may be due to the high dipole moment generated by the C=O dipole after the interaction between the O atom in C=O on the PLLA molecular chain and the [EMIm]+ cation in the IL. This work has elucidated the effects of ILs on the properties of spinning solution and the piezoelectric properties of PLLA, which can provide a theoretical basis for the selection of the preparation system of piezoelectric polymer and inspire the development of environmentally friendly flexible piezoelectric materials.

A systematic review and meta-analysis of sex differences in clinical outcomes of hypertrophic cardiomyopathy.

Background: Hypertrophic cardiomyopathy (HCM) is recognized as the most prevalent form of genetic cardiomyopathy, and recent investigations have shed light on the existence of sex disparities in terms of clinical presentation, disease progression, and outcomes. Objectives: This study aimed to systematically review the literature and perform a meta-analysis to comprehensively compare the clinical outcomes between female and male patients with HCM. Methods: A thorough search was conducted in databases including PubMed, Embase, Cochrane Library, and Web of Science, encompassing literature from inception until June 2023. The primary endpoints examined were: (1) all-cause mortality; (2) an arrhythmic endpoint comprising sudden cardiac death (SCD), sustained ventricular tachycardia, ventricular fibrillation, or aborted SCD; and (3) a composite endpoint incorporating either (1) or (2), in addition to hospitalization for heart failure or cardiac transplantation. Pooled estimates were derived using a random-effects meta-analysis model. Results: The analysis encompassed a total of 29 observational studies, involving 44,677 patients diagnosed with HCM, of which 16,807 were female. Baseline characteristics revealed that the female group exhibited an advanced age [55.66 ± 0.04 years vs. 50.38 ± 0.03 years, pooled mean difference (MD) = 0.31, 95% CI: 0.22-0.40, p = 0.000, I2 = 88.89%], a higher proportion of New York Heart Association class III/IV patients [pooled odds ratio (OR) = 1.94, 95% CI: 1.55-2.43, p = 0.000, I2 = 85.92%], and a greater prevalence of left ventricular outflow tract gradient greater than or equal to 30 mmHg (pooled OR = 1.48, 95% CI: 1.27-1.73, p = 0.000, I2 = 68.88%) compared to the male group. The female group were more likely to have a positive genetic test (pooled OR = 1.27, 95% CI: 1.08-1.48, p = 0.000, I2 = 42.74%) and to carry the myosin heavy chain beta 7 mutation (pooled OR = 1.26, 95% CI: 1.04-1.54, p = 0.020, I2 = 0.00%) compared to the male group. Female sex exhibited a significant association with increased risks of all-cause mortality (pooled OR = 1.62, 95% CI: 1.38-1.89, p = 0.000, I2 = 72.78%) and the composite endpoint (pooled OR = 1.47, 95% CI: 1.20-1.79, p = 0.000, I2 = 84.96%), while no substantial difference was observed in the arrhythmic endpoint (pooled OR = 1.08, 95% CI: 0.87-1.34, p = 0.490, I2 = 55.48%). Conclusions: The present findings suggest that female patients with HCM tend to experience poorer clinical outcomes. It is imperative to critically reevaluate disease definitions and enhance awareness to mitigate delays in the diagnosis and treatment of HCM in women, thereby fostering equitable healthcare practices. Systematic Review Registration: https://www.crd.york.ac.uk/, PROSPERO (CRD42023431881).

Cobalt-Catalyzed Chemoselective Reduction of N-Heteroaryl Ketones with N,N-Dimethylformamide as a Hydride Source.

A method for chemoselective reduction of 2-pyridyl ketones and related N-heteroaryl compounds catalyzed by cobalt stearate using DMF as a hydride source is developed. The ketone substrate is activated by chelation with cobalt, which makes the present method highly chemoselective. A possible reaction mechanism is proposed on the basis of control experiments.

Reductive Hydrodehalogenation of Halogenated Carboxylic Acid Derivatives Using a DMSO/HCOONa·2H2O System.

A practical and operationally simple hydrodehalogenation of halogenated carboxylic acid derivatives using a DMSO/HCOONa·2H2O system is developed. This protocol avoids the involvement of light irradiation, electrochemical apparatus, transition metals, radical initiators, strong bases, and other additional additives. Control experiments suggest that HCOONa might function as a hydride donor in the reduction process via nucleophilic substitution or addition to achieve the hydrodehalogenation.

Factors associated with the elasticity of asymptomatic carotid plaques in hypertension Tibetan population.

AIMS: Hypertension is a major risk factor for coronary, cerebrovascular, and the greatest cause of stroke. Half of stroke events are the result of cerebrovascular atherosclerosis, including carotid plaques. It is of major importance to detect which plaques are vulnerable, even though not yet ruptured. Due to the particularity of the Tibetan population, this study evaluated the elasticity of asymptomatic carotid plaques in Tibetan hypertension patients using shear wave elastography (SWE) and explored associated risk factors. METHODS: A total of 91 Tibetan patients were divided into normotension, grade 1-2, and grade 3 hypertension groups based on the level of blood pressure. All subjects underwent common duplex ultrasonic examination and SWE evaluation for carotid plaques. Elasticity of carotid plaque was assessed by Young's modulus. RESULTS: The final analysis included 126 plaques as representative plaques according to Total Plaque Risk Score. The mean and maximum Young's modulus in the grade 3 hypertension group were smaller, and more plaques with irregularity surface compared with the other two groups (p < 0.05). Multivariate regression analysis showed drinking butter tea (ß = -0.220, p = 0.009; ß = -0.240, p = 0.004, respectively) was the independent factor associated with mean and maximum Young's modulus. CONCLUSIONS: SWE is feasible for measurement of Young's modulus of carotid plaques. Plaques in the grade 3 hypertension group were more likely to become vulnerable ones. In hypertension Tibetan patients, drinking butter tea was an independent factor associated with mean and maximum Young's modulus of asymptomatic carotid plaque.

Cardiac adaptation to high altitudes after short- and long-term exposure among Chinese Han lowlanders.

BACKGROUND: Short-term, high altitude (HA) exposure raises pulmonary artery systolic pressure (PASP) and decreases left ventricular volumes. However, relatively little is known of the long-term cardiac consequences of prolonged exposure in Chinese Han lowlanders, a highly adapted HA population. AIMS: We studied cardiac structure and function by echocardiography to investigate short-term adaptation and potential long-term cardiac remodeling. METHODS: This study included 301 healthy subjects of short-term exposure (STE), acclimatized Chinese Han lowlanders (AL) at HA, native Tibetans (NT), and sea level residents (SLR) with 75, 77, 69, and 80 participants, respectively. All groups underwent standard echocardiography. RESULTS: Compared with SLR, systolic blood pressure (SBP) and heart rate of STE and AL did not significantly increase following HA exposure, but SBP in STE was lower than AL. In lowlanders, HA exposure enlarged right heart and pulmonary artery (PA), reduced left ventricular (LV) diastolic function. This decrease in LV diastolic function increased with exposure time. Compared with SLR, ejection fraction did not change significantly in STE, but decreased in AL. Interventricular septal end-diastolic thickness (IVSd) increased both in STE and AL compared with SLR. Compared with NT, AL population had higher SBP and the greater diameter of PA. CONCLUSIONS: In Chinese Han lowlanders, exposure to HA enlarged right ventricle and decreased the diastolic function of LV. LV systolic function was preserved after short-term HA exposure but decreased after long-term HA exposure. It was possible to speculate that ethnicity contributed to the observed difference in heart.

[High frequency oscillatory ventilation and conventional mechanical ventilation in the treatment of infants with severe respiratory syncytial virus pneumonia: a randomized controlled trial].

OBJECTIVE: To compare the clinical efficacy of high frequency oscillatory ventilation (HFOV) and conventional mechanical ventilation (CMV) in the treatment of infants with severe respiratory syncytial virus (RSV) pneumonia. METHODS: A prospective randomized controlled trial was conducted. The infants with severe RSV pneumonia who received invasive mechanical ventilation admitted to intensive care unit (ICU) of Children's Hospital Affiliated to Capital Institute of Pediatrics from January 2018 to December 2019 were enrolled. According to the order of admission, each infant was assigned to HFOV group or CMV group by random number table. The basic data, pediatric critical score, blood gas analysis, ventilator parameters, oxygenation index [OI, OI = mean airway pressure (Pmean)×fraction of inspired oxygen (FiO2)/arterial partial pressure of oxygen (PaO2)×100], duration of mechanical ventilation, length of ICU stay, complications, prognosis, use of muscle relaxants and vasoactive drugs and other clinical indicators of the two groups were recorded. RESULTS: A total of 28 infants were enrolled in the analysis, including 15 infants receiving CMV and 13 infants receiving HFOV. There were no significant differences in age, body weight, pediatric critical score and OI before enrollment, type II respiratory failure, multiple organ dysfunction, basic diseases and laboratory examination indexes before enrollment between the two groups. Six hours after enrollment, compared with CMV group, heart rate (HR), respiratory rate (RR), case of transcutaneous oxygen saturation (SpO2) decrease, case of HR decrease, case of cardiopulmonary resuscitation (CPR) and OI in HFOV group were significantly decreased [HR (bpm): 130 (125, 138) vs. 144 (140, 160), RR (times/min): 35 (34, 38) vs. 40 (35, 45), SpO2 decrease (case: 1 vs. 10), HR decrease (case: 0 vs. 6), CPR (case: 0 vs. 4), OI: 6.5 (4.4, 8.9) vs. 9.3 (8.0, 12.8)], while case of use of muscle relaxants (case: 3 vs. 0) and volume of 7-day positive fluid balance [mL/kg: 167.1 (113.8, 212.6) vs. 90.8 (57.8, 112.7)] were significantly higher, the differences were statistically significant (all P < 0.05). There was no use of blood purification treatment, no severe complications such as pneumothorax and intracranial hemorrhage, and no death within 28 days in the two groups. CONCLUSIONS: Compared with CMV, HFOV in the treatment of infants with severe RSV pneumonia can improve the oxygenation level and clinical physiological indexes earlier, reduce the incidence of adverse events such as HR, SpO2 decrease and CPR, increase the use of muscle relaxants and the positive fluid balance, and do not increase the incidence of severe complications such as pneumothorax and intracranial hemorrhage, so its clinical application is safe.

Judicious fabrication of bifunctionalized graphene oxide/MnFe2O4 magnetic nanohybrids for enhanced removal of Pb(II) from water.

Novel ternary nanohybrids, bifunctionalized graphene oxide/MnFe2O4 magnetic nanoparticles (PEHA-Phos-GO/MnFe2O4), were prepared by a facile method and applied for the removal of Pb(II) from aqueous solution. Attributing to the numerous amino and phosphate groups on the bifunctionalized GO nanosheets as well as the magnetic nanoparticles of MnFe2O4, PEHA-Phos-GO/MnFe2O4 demonstrated high removal efficiency of Pb(II) and rapid magnetic separation. The 366.4 mg/g maximum adsorption capacity of Pb(II) on PEHA-Phos-GO/MnFe2O4 was obtained at the optimal adsorption pH of 5.5, much higher than that on GO (212.1 mg/g). The kinetics and isotherm data indicated that the adsorption processes can be well described by the pseudo-second-order kinetics and the Langmuir model. For the adsorption of Pb(II) on PEHA-Phos-GO/MnFe2O4, thermodynamic studies revealed the endothermic nature of the spontaneous adsorption process. The exhibited adsorption capacity, easy magnetic separation and reusability make the PEHA-Phos-GO/MnFe2O4 nanohybrids very promising adsorbents for efficacious removal of heavy metals from aqueous solutions in environmental pollution cleanup.

Effects of a Reactive Phosphorus-Sulfur Containing Flame-Retardant Monomer on the Flame Retardancy and Thermal and Mechanical Properties of Unsaturated Polyester Resin.

A novel reactive phosphorus and sulfur-containing monomer (bis(acryloxyethyldiphenylphosphate)sulfone, BADPS) was synthesized to enhance the comprehensive performance of unsaturated polyester resin (UPR),and corresponding flame-retardant unsaturated polyester resins (FR-UPRs) with various amounts of BADPS were prepared by radical bulk polymerization. The flame retardancy and thermal and mechanical properties of the UPR samples were investigated by limiting oxygen index (LOI) measurements, cone calorimetry, differential scanning calorimetry (DSC),a thermogravimetric analysis (TGA), and a tension test. The results showed that the introduction of BADPS remarkably enhanced the flame resistance and high-temperature stability, as well as the tensile performance of UPR. Scanning electron microscopy (SEM),Fourier transform infrared (FTIR), and Raman spectroscopy studies revealed that BADPS can efficaciously promote the formation of UPR char residue with an improved microstructure and increased graphitization degree, which enhancedthe high-temperature stability and char yield of UPR. Additionally, a thermogravimetry-Fourier transform infrared (TG-FTIR) analysis corroborated that the evolution of combustible volatiles from UPR decomposition was substantially restrained by the incorporation of BADPS, which is beneficial for the suppression of fire hazards in UPR.

The long noncoding RNA MIR210HG promotes tumor metastasis by acting as a ceRNA of miR-1226-3p to regulate mucin-1c expression in invasive breast cancer.

BACKGROUND: Long noncoding RNAs have been known to be involved in multiple types of malignancies, including invasive breast cancer (IBC). This study aimed to explore the role of long noncoding RNAs in IBC and elucidate the potential molecular mechanisms. METHODS: Using TCGA microarray data analysis, we identified a long noncoding RNA, MIR210HG, highly expressed in IBC. Kaplan-Meier method and the log-rank test were used for survival analysis. The gain-of-function experiments were performed to assess the function of MIR210HG in IBC invasion and migration in both in vitro and in vivo settings. Bioinformatic analysis as well as luciferase reporter assay, rescue experiments and western blot assay revealed the mode of action of MIR210HG. RESULTS: The aberrantly enhanced MiR210HG expression predicted poor prognosis and lower survival rate. Knockdown of MiR210HG suppressed IBC cell invasion and metastasis both in vitro and in vivo. MiR-1226-3p was identified and validated to be the target miRNA of MiR210HG. Furthermore, MiR210HG functions as a competing endogenous RNAs (ceRNA) which sponges miR-1226-3p, therefore upregulates the expression of mucin1 (MUC1-C). CONCLUSIONS: Our study demonstrated that MiR210HG sponges miR-1226-3p to facilitate invasive breast cancer cell invasion and metastasis by regulating mucin-1c and EMT pathway, revealing the oncogenic role of MiR210HG in IBC cells.

Changes in left ventricular function in patients with aortic regurgitation 12 months after transapical transcatheter aortic valve implantation.

Transcatheter aortic valve implantation (TAVI) is an established treatment for high surgical risk aortic stenosis patients; in recent years, it has also been used in patients with pure/dominant aortic regurgitation (AR). This study aimed to determine the impact of transapical TAVI on left ventricle myocardial mechanics in AR patients. Thirty AR patients (70% men; mean age, 72.8 ± 4.3 years) were enrolled. Conventional echocardiography was performed on all patients before and 12 months after TAVI. Three-dimensional speckle tracking was accomplished in 20 AR patients for the evaluation of global longitudinal strain, global circumferential strain, twist, torsion, apical rotation and basal rotation. Preoperative left ventricular ejection fraction (LVEF), global longitudinal strain (GLS), global circumferential strain (GCS), twist, torsion and apical rotation were impaired in AR patients compared with controls. Mean left ventricular (LV) end-diastolic diameter (from 62.9 ± 7.3 to 52.0 ± 6.8 mm, p < 0.001), LV end-diastolic volume (from 199.4 ± 55.0 to 130.1 ± 48.9 mL, p < 0.001), and LV mass index (179.8 ± 52.2-134.4 ± 42.5 g/m2, p = 0.001) decreased 12 months after TAVI. Interestingly, GLS (from - 17.2 ± 3.2 to - 18.9 ± 3.7, p = 0.007) and GCS (from - 23.9 ± 4.9 to - 25.7 ± 5.0, p = 0.008) improved significantly, but LVEF did not significantly improve. In terms of the rotational mechanics, twist, rotation and basal rotation remained almost unchanged, whereas apical rotation (from 7.4 ± 4.0 to 5.5 ± 3.9, p = 0.009) was significantly impaired after transapical TAVI. Our results indicate that LV function was improved in terms of myocardial deformation but worsened in terms of apical rotation 12 months after TAVI in AR patients. Three-dimensional speckle tracking echocardiography appears to be a sensitive method for detecting subtle cardiac remodeling after TAVI.

Novel ternary nanohybrids of tetraethylenepentamine and graphene oxide decorated with MnFe2O4 magnetic nanoparticles for the adsorption of Pb(II).

Novel ternary nanohybrids, consisting of tetraethylenepentamine (TEPA), graphene oxide (GO) and manganese ferrite magnetic nanoparticles (TEPA-GO/MnFe2O4), were prepared by a facile hydrothermal method and utilized to remove Pb(II) from aqueous solution effectively. The adsorbents were characterized by SEM, TEM, XRD, FTIR, zeta potential analysis, magnetization hysteresis loop, BET and XPS. These nanoparticles exhibited superparamagnetic behavior as well as high removal efficiency for Pb(II). Moreover, numerous amino groups of the functionalized pendant TEPA on GO coupled with the porous structure of TEPA-GO/MnFe2O4 contribute to high Pb(II) adsorption capacity. The maximum Pb(II) adsorption capacity of TEPA-GO/MnFe2O4 was determined to be 263.2 mg/g at the optimized solution pH of 5.5, much higher than that of GO/MnFe2O4 (133.3 mg/g) and GO (196.1 mg/g). The kinetics and isotherm data fitted well with the pseudo-second-order kinetics and the Langmuir isotherm model, respectively. Thermodynamic studies revealed that the Pb(II) adsorption of TEPA-GO/MnFe2O4 was a endothermic and spontaneous process. The experimental results corroborated that TEPA-GO/MnFe2O4 can be efficaciously reused after washed with HCl, indicative of its potential applications in environmental cleanup.

[Quantitative Measurements on the Blood Flow Fields of Left Atrial Appendage using Vector Flow Mapping in Patients with Nonvalvular Atrial Fibrillation].

OBJECTIVE: To quantify the hemodynamic characteristics of patients with nonvalvular atrial fibrillation. METHODS: Twenty patients with paroxysmal atrial fibrillation and 15 patients with persistent atrial fibrillation enrolled in this study,while 12 patients with sinus rhythms served as controls. The hemodynamic characteristics of the patients in left atrial appendage were measured by transesophageal echocardiography (TEE) and vector flow mapping (VFM) using indicators such as vectors,vortex and energy loss (EL). RESULTS: ① Significant differences appeared between the patients with atrial fibrillation and the controls in heart rate,size of left atrium,size of left atrial appendage (LAA),and velocities of LAA filling and emptying. ② Regular vectors in LAA in early systole and late diastole were found in the patients with paroxysmal atrial fibrillation and the controls; whereas,irregular vectors with direction alternating were visualized in the whole cardiac cycle in the patients with persistent atrial fibrillation. ③ Small vortexes were observed at the opening of the left atrial appendage in late diastole in the patients with paroxysmal atrial fibrillation and the controls. ④ Peak EL values occurred in early systole and late diastole in the patients with paroxysmal atrial fibrillation and the controls. But the patients with persistent atrial fibrillation had increased EL values over the whole cardiac cycle. CONCLUSION: VFM can visualize and quantify the hemodynamics of LAA in patients with different heart rhythms. It may provide a new method for assessing atrial fibrillation.

Arrhythmogenic Right Ventricular Cardiomyopathy with Multiple Thrombi and Ventricular Tachycardia of Atypical Left Branch Bundle Block Morphology.

A 61-year-old male patient was admitted to our hospital with recurrent palpitations and syncope. Electrocardiography, echocardiography, and contrast-enhanced computed tomography were performed. The patient was diagnosed with arrhythmogenic right ventricular cardiomyopathy (ARVC) complicated by multiple thrombi, and ventricular tachycardia (VT) without typical left bundle branch block (LBBB) morphology. This case suggests that VT is not always the sole contributor to syncope and death in patients with ARVC, and pulmonary embolism should be considered. Furthermore, VT with typical LBBB morphology is not an absolute necessity as a major criterion for the diagnosis of ARVC when the right heart is extremely enlarged.

[Application of Echocardiography to Support Transapical Transcatheter Aortic Valve Implantation in Patients with Aortic Regurgitation].

OBJECTIVE: To explore the role of echocardiography in pre-procedural,peri-procedural and post-procedural stages of transapical transcatheter aortic valve implantation (TAVI) in patients with aortic regurgitation (AR). METHODS: 31 patients with pure/dominant AR at a high risk on surgery were enrolled in this study. The degree of their aortic regurgitation was evaluated before TAVI,as well as the related diameters of aortic root and the left ventricular systolic function measured by transthoracic echocardiography (TTE). TEE was used to reevaluate the valve pathology after general anesthesia. TEE in combination with fluoroscopy provided accurate position of the prosthetic valve for implantation. TEE was also used to monitor complications and to evaluate immediate post-procedure paravalvular regurgitation. The post TAVI follow-up included valve heamodynamic status,complications,left ventricular systolic function and left ventricular mass index (LVMI) measured by TEE. RESULTS: Transapical TAVI was successful in 29 of the 31 patients: 23 experienced no or little paravalvular regurgitation; 6 had mild paravalvular regurgitation. The left ventricular end-diastolic diameter (LVDd) and left ventricular mass index (LVMI) of the patients decreased significantly one week after TAVI,which progressed until one month later ( P<0.05) . The left ventricular ejection (EF) of the patients also decreased one week after TAVI ( P<0.05) ,but it resumed to the pre-procedural level one month later. CONCLUSION: Transapical TAVI is a potentially safe and effective therapy for patients with pure/dominant AR at a high risk on open-heart surgery. Echocardiography plays an important role in pre-procedural evaluation,peri-procedural monitoring and post-procedural follow-up in TAVI.

Two new amides from a halotolerant fungus, Myrothecium sp. GS-17.

Two new amides, named N-acetyl-2,4,10,17-tetrahydroxyheptadecylamine (1) and N-acetyl-3,5,11,18-tetrahydroxyoctadecyl-2-amine (2), were isolated from a halotolerant fungus, Myrothecium sp. GS-17. Their structures were identified on the basis of spectroscopic characteristics. The cancer cell cytotoxicities of two compounds were evaluated, and compound 2 exhibited weak cytotoxicity in HL-60 cell line.

Synthesis and biological evaluation of novel indoline-2,3-dione derivatives as antitumor agents.

A new series of 1,5-disubstituted indolin-2,3-diones was synthesized and their inhibition of the growth of a human acute promyelocytic leukemia (HL-60) cell line was evaluated. These compounds had promising inhibition of HL-60 cell growth in vitro. Results indicated that compounds with a benzyl substituent at the N-1 position on the indolin-2,3-dione ring had more potent antiproliferative activity than those with a (4-fluorobenzyl) amino-2-oxoethyl substituent at the N-1 position. Among the compounds synthesized, compound 8l inhibited half of cell growth at a concentration of 0.07 µM and compound 8p did so at a concentration of 0.14 µM. These compounds may serve as lead compounds for further optimization in order to develop novel anticancer agents.

Ethacrynic acid oxadiazole analogs induce apoptosis in malignant hematologic cells through downregulation of Mcl-1 and c-FLIP, which was attenuated by GSTP1-1.

Ethacrynic acid, a diuretic, inhibits glutathione S-transferase P1-1 (GSTP1-1) activity and induces cell death in malignant cells at high concentrations. To improve ethacrynic acid activity, ethacrynic acid oxadiazole analogs 6s and 6u were synthesized. Although both compounds have greater antiproliferative effects than ethacrynic acid in human HL-60 cells, 6u has a reduced ability to inhibit GSTP1-1 activity. The mechanisms of both 6s- and 6u-induced cell death as well as the role of GSTP1-1 in their actions were studied. Both 6s and 6u equally induced apoptosis in HL-60 cells due to the activation of caspase-3, -9, and -8, which was correlated with the downregulation of antiapoptotic proteins c-FLIP, Mcl-1, and XIAP. The caspase inhibitor Z-VAD-FMK blocked the reduction of XIAP, but not of c-FLIP and Mcl-1, in 6s-treated cells. The reduction of c-FLIP and Mcl-1 by 6s was not blocked by the proteasomal inhibitor MG132, but was correlated with inhibition of the phosphorylation of extracellular signal-regulated kinase (ERK) and eIF4E. Both 6s and 6u decreased the intracellular glutathione (GSH) levels. N-acetylcysteine blocked reduction in the levels of Mcl-1, c-FLIP, and intracellular GSH as well as apoptosis in HL-60 cells treated by either compound. Silencing of GSTP1-1 in K562 cells sensitized, but overexpression of GSTP1-1 in Raji cells blocked, apoptosis induction by either compound. GSH conjugation at the methylene group abrogated the ability of inducing apoptosis. These data suggest that the methylene group plays an important role in the downregulation of c-FLIP and Mcl-1 proteins and apoptosis induction, which is inactivated by GSTP1-1 by forming GSH conjugates.

2-(2-Methylfuran-3-carboxamido)-3-phenylpropanoic acid, a potential CYP26A1 inhibitor to enhance all-trans retinoic acid-induced leukemia cell differentiation based on virtual screening and biological evaluation.

To develop new CYP26A1 inhibitors, a three-cycle virtual screening was carried out based on the constructed homology model of human CYP26A1 using Dock, Fred, Gold and AutoDock. Twenty-two compounds exhibited high scores and reasonable binding modes in molecular docking were purchased from Specs Company. Eighteen compounds were tested their abilities to enhance ATRA-induced differentiation in human acute promyelocytic leukemia NB4 cells. Eight of them enhanced the ability of ATRA to induce differentiation at concentrations of 0.5 and 1 µM. Among these compounds, 2-(2-methylfuran-3-carboxamido)-3-phenylpropanoic acid (S8) is of most effective in blocking ATRA breaking down in NB4 cells based on the LC-MS/MS assay.

Synthesis of spirolactone-type diterpenoid derivatives from kaurene-type oridonin with improved antiproliferative effects and their apoptosis-inducing activity in human hepatoma Bel-7402 cells.

A series of novel spirolactone-type diterpenoid derivatives of oridonin (12a-j) were designed and synthesized. All the target compounds showed improved anti-proliferative activity against a panel of human cancer cell lines and the most effective compound 12j was more potent than positive control Taxol in K562 and Bel-7402 cells with IC(50) values of 0.39 µM and 1.39 µM, respectively. The cellular mechanisms showed that compound 12j induced apoptosis at low micromolar concentrations in human hepatoma Bel-7402 cells. These results demonstrate that the spirolactone-type diterpenoid derivatives of oridonin have optimized growth inhibitory activity against cancer cells and interesting apoptosis-inducing ability.