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Bromo-containing binuclear Schiff base copper(II) complex, CuL(OAc), with an alkoxo/acetato-bridged moiety was employed as a model of carboxylesterases to promote the hydrolytic cleavage of p-nitrophenyl picolinate (PNPP). Furthermore, the reactivity of a mononuclear complex (CuHL) was evaluated for comparing it with that of binuclear one. The results reveal that the as-prepared binuclear CuL(OAc) efficiently accelerated the hydrolysis of PNPP, giving rise to excess four orders of magnitude rate enhancement in contrast to the un-catalyzed reaction. CuL(OAc) represented an enzyme-like bell-shaped pH-responsive kinetic behavior. Moreover, the binuclear one is more reactive than its mononuclear analogue (CuHL) by two orders of magnitude. The total efficiency of CuL(OAc) is about 61-fold than that of its mononuclear analogue, CuHL. In addition, a contrast experiment reveals that binuclear CuL(OAc) displayed good activity in the hydrolysis of PNPP as well another active ester, i.e., S-2-benzothiazolyl 2-amino-alpha-(methoxyimino)-4-thiazolethiolacetate (AE-active ester). Noteworthyly, it was found that mononuclear one inspired more obvious rate enhancement in the hydrolysis of AE-active ester relative to PNPP hydrolysis. The estimated p K of bound water on the binuclear CuL(OAc) using second derivative method (SDM) is relatively smaller than that for CuHL by a gap of about 0.8 pK unit, which facilitates the hydrolysis of PNPP. Graphical Abstract: Four orders of magnitude rate enhancement was observed for the catalytic hydrolysis of p-nitrophenyl picolinate (PNPP) by one μ-alkoxide/acetato-bridged binuclear copper(II) complex under physiological conditions. Substrate specificity of the resulting binuclear complexes was observed for the hydrolysis of PNPP and AE-active ester. [ABSTRACT FROM AUTHOR]

Two alkoxo/hydroxide-bridged dinuclear copper(II) complexes (CuL1 and CuL2) were prepared for evaluating their activity towards the hydrolysis of p-nitrophenyl picolinate (PNPP). Importantly, this work investigated the effects of varied micelles of four surfactants, e.g., cationic gemini 16-2-16 and 16-6-16, single-chain CTAB (hexadecyltrimethylammonium bromide), and LSS ( n-lauroylsarcosine sodium), on the PNPP hydrolysis by the as-prepared copper(II) complexes. The experimental results indicate that at neutral pH both of complexes exhibited much better activity by excess four-order of magnitude rate enhancement. For instant, rate constants of PNPP hydrolysis by CuL1 and bromo-containing CuL2 are approximate 49,569.6- and 31,123.5-fold than that of PNPP spontaneous hydrolysis. In addition, the hydrolytic reactivity of the bromo-containing CuL2 is subordinate to that one without bromine, CuL1. Moreover, it is found that the micellar solution of gemini 16-6-16 is proved to be the best medium, and whereas LSS micellar solution is the worst one. Particularly, the p K values of the Cu(II)-bound HO are determined by a new methodology which is correlative to second derivatives. [ABSTRACT FROM AUTHOR]

One new hydroxyl-functionalized imidazole derivative (L) was synthesized and characterized. Further, the related mononuclear zinc(II) and cobalt(II) complexes were prepared and used as mimic hydrolases to catalyze the hydrolytic cleavage of p-nitrophenyl picolinate (PNPP) in buffered aqueous solution and a micellar solution of cetyltrimethylammonium bromide (CTAB). Observations show that for all of catalytic systems, the hydrolysis of PNPP was pH-dependent in the pH range of 7.00-8.20. Besides, hydrolysis rates of PNPP displayed a constant increase with the increasing concentration of substrate. In the case of CoL-containing system, moreover, much greater acceleration for PNPP hydrolysis was observed in comparison with the ZnL-containing system. However, micellar effect of CTAB micelle aggregates on the PNPP hydrolysis was not obvious only showing 1.0 ∼ 1.3 folds rate difference in contrast to buffered aqueous solution. [ABSTRACT FROM AUTHOR]

Two μ-alkoxide/acetate-bridged small molecule binuclear copper(II) complexes were synthesized, and used to promote the hydrolysis of a classic carboxylic acid ester, p-nitrophenyl picolinate (PNPP). Both binuclear complexes exhibited good hydrolytic reactivity, giving rise to ca. 15547- and 17462-fold acceleration over background value for PNPP hydrolysis at neutral conditions, respectively. For comparing, activities of the other two mononuclear analogues were evaluated, revealing that binuclear complexes show approximately 150- and 171-fold kinetic advantage over their mononuclear analogues. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

To assess the role of the p53 tumor suppressor gene in skin carcinogenesis by UV radiation, mice constitutively lacking one or both copies of the functional p53 gene were compared to wild-type mice for their susceptibility to UV carcinogenesis. Heterozygous mice showed greatly increased susceptibility to skin cancer induction, and homozygous p53 knockout mice were even more susceptible. Accelerated tumor development in the heterozygotes was not associated with loss of the remaining wild-type allele of p53, as reported for tumors induced by other carcinogens, but in many cases was associated with UV-induced mutations in p53. Tumors arose on the ears and dorsal skin of mice of all three genotypes, and homozygous knockout mice also developed ocular tumors, mainly melanomas. Skin tumors in the p53 knockout mice were predominately squamous cell carcinomas and were associated with premalignant lesions resembling actinic keratoses, whereas those in the heterozygous and wild-type mice were mainly sarcomas. These results demonstrate the importance of p53 in protecting against UV-induced cancers, particularly in the eye and epidermis. [ABSTRACT FROM AUTHOR]

Two novel bis-tridentate imidazole derivatives were conveniently synthesized using a 'one-pot' method. Their dinuclear (Cu2L1Cl4, Cu2L2Cl4) and mononuclear (CuL1Cl2, CuL2Cl2∙H2O) copper (II) complexes were synthesized to comparably evaluate their reactivities in the hydrolytic cleavage of 2-hydroxypropyl p-nitrophenyl phosphate (HPNP) as a classic RNA model. Single crystals of Cu2L1Cl4 and Cu2L2Cl4 indicate that both of them are centrosymmetric, and each central copper ion is penta-coordinated. Regarding the transesterification of HPNP, both of dinuclear ones exhibited excess one order of magnitude rate enhancement in contrast with auto-hydrolysis reaction. Under comparable conditions, dinuclear complexes displayed no more than twofold increase in activity over their mononuclear analogues, which verifies the lack of binuclear cooperation effect due to long Cu-to-Cu space. [ABSTRACT FROM AUTHOR]

Explores the nature of antigen-specific T-cell responses in chronic myelogenous leukemia. Principles of antigen recognition; Various methods in determining the nature of target antigens of the graft-versus leukemia effect; Expression of myeloid-restricted proteins in leukemia; Correlation of PR1-cytotoxic T-cell with cytogenetic remission.

Background: A biosimilar needs to demonstrate its similarity to the originator reference product (RP) in terms of structural and functional properties as well as nonclinical and clinical outcomes. Objectives: The aim was to assess the analytical similarity between the trastuzumab biosimilar HLX02 and Europe-sourced Herceptin® (EU-Herceptin®) and China-sourced Herceptin® (CN-Herceptin®) following a quality-by-design (QbD) quality study and tier-based quality attribute evaluation. Methods: A panel of highly sensitive and orthogonal methods, including a novel Fc gamma receptor IIIa (FcγRIIIa) affinity chromatography technique that enables quantitative comparison of glycan effects on effector function, was developed for the assessment. To ensure the full product variability was captured, ten batches of HLX02 were compared with 39 RP batches with expiry dates from August 2017 to March 2021. Results: The extensive three-way similarity assessment demonstrated that HLX02 is highly similar to the RPs. Furthermore, the %afucose, %galactose, and FcγRIIIa affinity of the RPs were observed to first decrease and then return to the original level in relation to their expiry dates, and the RP batches can be subgrouped by their FcγRIIIa affinity chromatograms. HLX02 is demonstrated to be more similar to the RPs of the high FcγRIIIa affinity group. Conclusion: Besides having an overall high analytical similarity to both EU-Herceptin® and CN-Herceptin®, HLX02 is more similar to Herceptin® with high FcγRIIIa affinity, a result that demonstrates the power of the novel FcγRIIIa affinity chromatography technology in biosimilarity evaluation. [ABSTRACT FROM AUTHOR]

The detailed degradation mechanism of an insensitive explosive, 2,4-dinitroanisole (DNAN), in advanced oxidation processes (AOPs) was investigated computationally at the M06-2X/6-311 + G(d,p)/SMD level of theory. Results obtained show that the addition-elimination reaction is the dominant mechanism. The phenol products formed can continue to be oxidized to benzoquinone radicals that are often detected by experiments and may be the initial reactants of ring-opening reactions. The H-abstraction reaction is an unavoidable competing mechanism; the intermediate generated can also undergo the process of addition-elimination reaction. The nitro departure reaction involves not only hydroxyl radical (•OH), but also other active substances (such as •H). More importantly, we found that AOP technology can easily degrade DNAN, similar to TNT and DNT. Thus, this method is worth trying in experiments. The conclusions of this work provide theoretical support for such experimental research.Possible pathways of degradation by •OH radicals in advanced oxidation processes (AOPs) of the typical insensitive explosive 2,4-dinitroanisole (DNAN) were investigated by density functional theory (DFT) methods. Based on the Gibbs free energy barriers and intermediates, the dominant reaction mechanism was determined. The conclusions will be helpful in utilizing AOP technology to remove DNAN pollution [ABSTRACT FROM AUTHOR]

Titania (TiO)-based photocatalysts decorated with different amounts of indium oxide (InO) were prepared by a pore impregnating method and characterized by the Brunauer-Emmett-Teller (BET) method, X-ray diffraction (XRD), UV-Vis diffuse reflectance spectroscopy (DRS), and X-ray photoelectron spectroscopy (XPS). The separation efficiency of photogenerated charges was investigated using benzoquinone (BQ) as scavenger. The activities of the photocatalysts were evaluated by decolorization of methyl orange (MO) aqueous solution under ultraviolet-light irradiation. Compared to TiO, InO/TiO composites show improved photocatalytic performance due to the coupling effect of TiO and InO, which greatly improves the separation of photogenerated electrons and holes. [ABSTRACT FROM AUTHOR]

Recent studies have shown that the treatment of nonmetastatic K-1735 murine melanoma cells with cytokines induces the production of nitric oxide (NO) and hence cell death. The purpose of this study was to determine the mechanism of this cytokine-induced NO-mediated apoptosis. Incubation of nonmetastatic K-1735 cells with interleukin-1 alpha (IL-1α) and interferon-gamma (IFN-γ) induced high NO production, Bcl-2 downregulation, and apoptotic cell death. In contrast, incubation of metastatic K-1735 cells with IL-1α and IFN-γ did not induce significant production of NO, downregulation of Bcl-2, or cell death. The exposure to exogenous NO derived from the NO donors, sodium nitroprusside (SNP), or GEA5024 produced a dose-dependent apoptotic cell death in both the metastatic and nonmetastatic K-1735 cells, which was associated with downregulation of Bcl-2 at the mRNA level and, to a lesser extent, at the protein level. Nonmetastatic and metastatic K-1735 cells transfected with the Bcl-2 gene were more resistant to apoptosis mediated by both endogenous and exogenous NO. Subsequent to intravenous injection, the tumor cells transfected with the Bcl-2 gene had an increased survival rate in the lungs of nude mice and produced a higher number of experimental lung metastases. These data suggest that NO-induced apoptosis in K-1735 melanoma cells is associated with downregulation of Bcl-2. [ABSTRACT FROM AUTHOR]