Search

Chemoresistance is the most significant reason for the failure of cancer treatment following radical cystectomy. The response rate to the first-line chemotherapy of cisplatin and gemcitabine does not exceed 50%. In our previous research, elevated BMI1 (B-cell specific Moloney murine leukemia virus integration region 1) expression in bladder cancer conferred poor survival and was associated with chemoresistance. Herein, via analysis of The Cancer Genome Atlas database and validation of clinical samples, BMI1 was elevated in patients with bladder cancer resistant to cisplatin and gemcitabine, which conferred tumor relapse and progression. Consistently, BMI1 was markedly increased in the established cisplatin- and gemcitabine-resistant T24 cells (T24/DDP&GEM). Functionally, BMI1 overexpression dramatically promoted drug efflux, enhanced viability and decreased apoptosis of bladder cancer cells upon treatment with cisplatin or gemcitabine, whereas BMI1 downregulation reversed this effect. Mechanically, upon interaction with p53, BMI1 was recruited on the promoter of miR-3682-3p gene concomitant with an increase in the mono-ubiquitination of histone H2A lysine 119, leading to transcription repression of miR-3682-3p gene followed by derepression of ABCB1 (ATP binding cassette subfamily B member 1) gene. Moreover, suppression of P-glycoprotein by miR-3682-3p mimics or its inhibitor XR-9576, could significantly reverse chemoresistance of T24/DDP&GEM cells. These results provided a novel insight into a portion of the mechanism underlying BMI1-mediated chemoresistance in bladder cancer.

Ketoreductases have shown considerable potential as biocatalysts in the asymmetric synthesis of chiral alcohols. However, compared to the widely studied ketoreductases for chiral alcohols, limited knowledge is available about ketoreductases for efficient dynamic reductive kinetic resolution (DYRKR) of bulky α-amino β-keto esters. In this study, structure-guided rational direct evolution was applied to a ketoreductase (WTEA) from Exiguobacterium sp. F42 for the asymmetric reduction of bulky α-amino β-keto esters. A number of mutants were then obtained with remarkably improved activity toward various bulky α-amino β-keto esters with excellent stereoselectivity by performing structure-guided rational design. In particular, mutant M30 (W82L/F88V/V121A/A138L/R142M/A190V/S193A/Y201F/N204A) exhibited excellent stereoselectivity (>99% dr, >99% de) and high conversion (>99%) for six α-amino β-keto esters. Furthermore, novel and practical chemoenzymatic routes were developed for the synthesis of chloramphenicol and florfenicol, which featured the application of enzymatic DYRKR to establish the two stereocenters of amino alcohols 4-NO2-substituted (2S, 3R)-5b and 4-SO2Me-substituted (2S, 3R)-8b with > 99% dr, > 99% de and >99% conversion from 100 g L−1 α-amino β-keto esters 5a and 8a (highest substrate loading reported), respectively. Crystal structure and molecular dynamics studies revealed the potential molecular basis for activity improvement and the stereoselectivity control mechanism at the atomic level. These results provide important insights into the evolution of ketoreductases for the asymmetric synthesis of chiral vicinal amino alcohols and establish a solid foundation for further large-scale industrial applications in the future.

We first developed a novel and efficient chemoenzymatic process to prepare (S)-1-(pyridin-4-yl)-1,3-propanediol, a vital HepDirect prodrug intermediate, from inexpensive and commercially available ...

(S)-2-Chloro-1-(2,4-dichlorophenyl) ethanol (3) is a chiral intermediate in the synthesis of luliconazole ((R)-E-1). Here, we report a novel biopreparation of 3 by bioreduction of 2-chloro-1-(2,4-d...

Nitrogen (N) enrichment has great consequences on several fundamental ecological processes through its impacts on plant nutrition traits (i.e. nutrient concentration and stoichiometric ratios); however, the extent to which the effects of N enrichment depend on phosphorus (P) availability are less well understood. While there is mounting evidence for the species-specific responses of plant nutrition traits to nutrient enrichment, we know little about the changes at the community-level. Here, we measured community-level biomass weighted (CWM) and non-weighted (CM) plant N and P concentrations and N:P ratio in a temperate meadow steppe after four years factorial N and P addition, with biomass and nutrition traits of each species in each plot being recorded. Nitrogen addition significantly increased community-level N concentration, decreased P concentration, and enhanced community N:P ratio. Phosphorus addition had no impacts on community-level N concentration, significantly increased P concentration, and reduced community N:P ratio. The impacts of N addition on community nutrition traits were not dependent on P addition and the community-level nutrition trait responses to N and P additions were primarily driven by intraspecific trait variation (ITV) rather than by species turnover. Community-level nutrition traits in the temperate meadow steppe were sensitive to the projected N and P enrichment. While nutrient enrichment had substantially changed community composition, its impacts on community nutrition traits were driven by ITV. Nitrogen deposition would result in imbalance of N and P in plant community, as indicated by the substantial increase in community-level N:P, which was not affected by increased P availability.

Two new hybrid compounds with chemical formulas [Co(L1)2(H2O)2]2[SiW12O40]·6H2O (1) and [Cu2(C9H22 N)2(L2)2][SiW12O40]·2H2O (2) (L1 = 3,3′-diamino-5,5′-bis(1H-1,2,4-triazole), L2 = 1,2-bis(3-(2-pyridyl)pyrazole-1-ylmethyl)benzene, C9H22 N = tripropylamine) were prepared in a hydrothermal reaction system containing Keggin-type polyoxometalates (POMs), transition metal (TM) salts (cobalt salts and copper salts), and chelate L1/L2 ligands. X-ray structural analysis reveals that 1 and 2 possess 3-D supramolecular host frameworks with large cavities and the polyoxoanions SiW12 reside in these cavities as the guest templates. The photocatalytic activities of 1 and 2 were investigated. Both compounds show efficient catalytic activity for degradation of RhB with 1 > 2. The loading amount of the POM units and the structural features of these POM-based organic-inorganic hybrid compounds may be necessary factors that affect the activity of catalysts in the photocatalytic degradation.

Two new polyoxometalate(POM)-based entangled coordination networks with chemical formula of [Mn2(H2O)2(BBPTZ)5][SiW12O40] (1) and [Ni2(H2O)2(BBPTZ)5][SiMo12O40]·6H2O (2) (BBPTZ = 4.4′-bis(1,2,4-triazol-1-ylmethyl)biphenyl), were prepared in a hydrothermal reaction system. Compounds 1–2 were characterized by elemental analyses, IR spectroscopy, thermogravimetric analysis, powder X-ray diffraction and single-crystal X-ray diffraction. In compound 1, dangling arms thread in quadrangular window of the adjacent 2-D layers, thus resulting in a rare 2-D → 3-D polythreading motif. Compound 2 exhibits a rare 2-D → 3-D zipper-closing motif. Using the degradation of methylene blue (MB) as the model, the photocatalytic activities of compounds 1–2 were investigated. Both compounds show efficient catalytic activity for the degradation of MB with the order of 2 > 1. It is found that the POM species of compounds 1–2 play the main role in the photocatalytic degradation process.

Our preliminary results show that huperzine A, an acetylcholinesterase inhibitor used to treat Alzheimer's disease (AD) patients in China, exhibits different pharmacokinetic features in elderly and young healthy subjects. However, its pharmacokinetic data in elderly subjects remains unavailable to date. Thus, we developed a population pharmacokinetic (PPK) model of huperzine A in elderly Chinese people, and identified the covariate affecting its pharmacokinetics for optimal individual administration.A total of 341 serum huperzine A concentration records was obtained from 2 completed clinical trials (14 elderly healthy subjects in a phase I pharmacokinetic study; 35 elderly AD patients in a phase II study). Population pharmacokinetic analysis was performed using the non-linear mixed-effect modeling software Phoenix NLME1.1.1. The effects of age, gender, body weight, height, creatinine, endogenous creatinine clearance rate as well as drugs administered concomitantly were analyzed. Bootstrap and visual predictive checks were used simultaneously to validate the final population pharmacokinetics models.The plasma concentration-time profile of huperzine A was best described by a one-compartment model with first-order absorption and elimination. Age was identified as the covariate having significant influence on huperzine A clearance. The final PPK model of huperzine A was: CL (L/h)=2.4649(*)(age/86)((-3.3856)), Ka=0.6750 h(-1), V (L)=104.216. The final PPK model was demonstrated to be suitable and effective by the bootstrap and visual predictive checks.A PPK model of huperzine A in elderly Chinese subjects is established, which can be used to predict PPK parameters of huperzine A in the treatment of elderly AD patients.

Polyimide (PI) nanocomposites with different proportions of Al2O3 were prepared via two-step reaction. Silicon nitride (Si3N4) was deposited on PI composite films by a RF magnetron sputtering system and used as a gas barrier to investigate the water vapor transmission rate (WVTR). The thermal stability and mechanical properties of a pure PI film can be improved obviously by adding adequate content of Al2O3. At lower sputtering pressure (4 mTorr), the PI/Al2O3 hybrid film deposited with Si3N4 barrier film exhibits denser structure and lower root mean square (RMS) surface roughness (0.494 nm) as well as performs better in preventing the transmission of water vapor. The lowest WVTR value was obtained from the sample, 4 wt.%Al2O3–PI hybrid film deposited with Si3N4 barrier film with the thickness of 100 nm, before and after bending test. The interface bonding, Al–N and Al–O–Si, was confirmed with the XPS composition-depth profile.

The physiological indices of Chinese cabbage(Brassica chinensis L.) grown under different intercropping systems used for this study included total soluble protein content, soluble sugar content, reducing sugar content, nitrate content, and pigment concentration. The objective of the present study is to discover the physiological level changes in Chinese cabbage in intercropping systems. The intercropping systems studied involved Chinese cabbage- garlic (Allium sativum L.) (CG), and Chinese cabbage-lettuce (Lactuca sativa L.) (CL). Chinese cabbage monoculture served as control (CK). Overall, higher mean soluble protein content and nitrate content were found in Chinese cabbage grown in the intercropping systems than those in CK. Significantly higher chlorophyll a content was found in cabbages from CL than CK during the latter half of the growing season. No significant difference in soluble sugar concentrations was found in CG and CL, as compared with CK. Reducing sugar content varied over the growing period of the Chinese cabbage in CG and CL. These results suggest that Chinese cabbage intercropped with noncrucifer plants increase the plant nutrient content.

The reduction of benzylidenemalononitrile by 1-benzyl-1,4-dihydronicotinamide undergoes via a one-step hydride transfer mechanism rather than a multistep mechanism involving initial electron transfer.

The use of magnetic micro- and nanoparticles for the removal of pollutants from wastewater is gaining increasing attention. Here, amine-functionalized magnetic microparticles (AFMMs) and carboxylic-functionalized magnetic microparticles (CFMMs) were synthesized by modifying the surface of Fe3O4 with amino and carboxyl groups for fast and efficient removal of textile dyes from aqueous solution. The functionalized magnetic microparticles were characterized by TEM, SEM, FTIR, and VSM. The adsorption experiments were carried out by varying the regulating parameters like solution pH and adsorbent dosage and analyzed in terms of kinetic and isotherm models. It was demonstrated that simple electrostatic interactions between functionalized magnetic microparticles and adsorbates played a dominating role in the adsorption of textile dyes. The positively charged AFMMs adsorbed the negatively charged dyes vat blue (VB) and direct violet (DV) at pH 6 with the maximum removal percentages of 95.72 and 97.29 %, respectively. The maximum removal percentages of cationic dyes methylene blue (MB) and azure A chloride (AA) on the negatively charged CFMMs were 92.28 and 92.22 % at pH 11, respectively. Moreover, the adsorbed dyes could be desorbed completely from the surface of CFMMs at a lower pH, and AFMMs also allowed rapid removal of VB and DV in different water samples. All the results in the present work demonstrated that the functionalized magnetic microparticles as efficient, magnetically separable adsorbents are attractive for the removal of dye pollutants.

Objective: To evaluate the relationship between flow cytometric DNA ploidy, biological features and prognosis in patients with Stage II colorectal cancer. Methods: Nuclear DNA content, proliferation index and S-phase fraction were measured in a prospective series of 45 patients with curatively resected Stage II colorectal adenocarcinomas by means of flow cytometry using frozen tumor samples. Results: Of the 45 samples examined, 17 tumors (38%) were diploid and 28 (62%) aneuploid. The diploid tumors were significantly more common in the proximal colon than in the distal colon (67% vs. 23%; P 0.05). The proliferation index and S-phase fraction in the distal tumors were higher than those in the proximal tumors, but the difference was not significant (P>0.05). When the 5-year survival rate of patients with Stage II colorectal cancer was compared by the log rank test, a significant relationship between DNA ploidy status and disease free survival was observed in the group of all patients. Patients with DNA diploid tumors had a better disease free survival than those with DNA aneuploid tumors (P

The mechanism of reduction of 1,1-diphenyl-2,2-dinitroethylene (DPDN) by 1-benzyl-1,4-dihydronicotinamide (BNAH) in acetonitrile has been investigated. Based on product analysis, isotopic tracing and electrochemical analysis, the reaction takes place by a hydride transfer mechanism giving 1,1-diphenyl-2,2-dinitroethane (DPDNH). Single crystal X-ray analysis shows that DPDN conforms to idealized C2 symmetry, but steric repulsions between the bulky substituents result in an appreciable twist about the central bond, such that the phenyl rings make a dihedral angle of 77.7°and the planar C–NO2 fragments make a dihedral angle of 68.5°. A small kinetic H/D isotope effect was obtained, that we propose is due to steric hindrance. Reaction in oxygen-saturated acetonitrile produced DPDNH and benzophenone in the ratio of 59.2∶22.0 as the final products with a total yield of 68.6% by GC. Control experiments were performed, by stirring a solution of DPDN or DPDNH alone in oxygen-saturated acetonitrile, or by stirring a solution of DPDN or DPDNH alone in aqueous acetonitrile containing a small amount of hydrochloric acid or in acetonitrile containing triethylamine. These produced no benzophenone. The results clearly indicate the trapping of a radical species by oxygen in the reaction. A curve-crossing model for the reaction projects that the transition state has partial diradical and partial covalent bonding character. As DPDN has a low-lying π* orbital (LUMO), the radical anion DPDN−· is a stabilized radical. It is known that the reaction of alkyl and benzyl radicals with oxygen is exothermic with a rate close to the diffusion-controlled limit. Thus, with use of More O’Ferrall’s two-dimensional potential energy diagram, the results are rationalized by a mechanistic change induced by steric hindrance so that the transition state collapses in two directions leading to the formation of DPDNH (polar pathway) and benzophenone (ET pathway), respectively.

Thermal and photoinduced reduction of ethyl (Z)-α-cyano-β-bromomethylcinnamate (1) by coenzyme NAD(P)H model 1-benzyl-1,4-dihydronicotinamide (BNAH, 2) gives ethyl (E)-1-cyano-2-phenylcyclopropane-1-carboxylate (3) in the former case, and the (E)-4 and (Z)-5 isomers of ethyl α-cyano-β-methylcinnamate with the (E)-isomer as the major product in the latter case. The results are rationalized in terms of direct hydride transfer and electron transfer–debromination–hydrogen abstraction mechanism, respectively.

1-Benzyl-1, 4-dihydronicotinamide (1) and KCN reacted with 2-(o-bromomethyl)-benzylidene-1, 3-indandione (2) to give 7, 12-dihydro-1-oxoindeno[3, 2-c][2]benzooxepine (3) and 1′-cyano-3′-hydro-2, 2′-spirobi[2H-indene]-1, 3-dione (4), respectively, and the selectivity of O-alkylation and C-alkylation is discussed.

1-Benzyl-1, 4-dihydronicotinamide (1) and KCN reacted with 2-( o-bromomethyl)-benzylidene-1, 3-indandione (2) to give 7, 12-dihydro-1-oxoindeno[3, 2-c][2]benzooxepine (3) and 1′-cyano-3′-hydro-2, 2′-spirobi[2H-indene]-1, 3-dione (4), respectively, and the selectivity of O-alkylation and C-alkylation is discussed.

Although Stat5a and Stat5b exhibit some non-redundant functional properties, their distinct contributions to carcinogenesis are not clearly defined. Here we report that Stat5a expression is selectively inhibited by DNA methylation of the Stat5a gene promoter region in cells expressing an oncogenic tyrosine kinase NPM/ALK. The DNA methylation is induced by NPM/ALK itself by employing its key effector Stat3, and is associated with binding to the promoter of MeCP2 capping protein and lack of binding of the Stat5a transcription activator Sp-1. Reversal of the methylation by DNA methyltransferase inhibitor, 5′-aza-2-deoxycytidine, restores the Sp-1 binding and Stat5a expression. Strikingly, the induced or exogenously expressed Stat5a binds to enhancer and exon 14 of the NPM/ALK gene and triggers selective suppression of NPM/ALK expression. These results demonstrate that NPM/ALK induces epigenetic silencing of Stat5a and that Stat5a can act as key tumor suppressor by reciprocally inhibiting expression of NPM/ALK.