Identification of the ortho-Benzoquinone Intermediate of 5-O- Caffeoylquinic Acid In Vitro and In Vivo: Comparison of Bioactivation under Normal and Pathological Situations □ S

ABSTRACT: 5-O-Caffeoylquinic acid (5-CQA) is one of the major bioactive ingredients in some Chinese herbal injections. Occasional anaphylaxis has been reported for these injections during their clinical use, possibly caused by reactive metabolites of 5-CQA. This study aimed at characterizing the bioactivation pathway(s) of 5-CQA and the metabolic enzyme(s) involved. After incubating 5-CQA with GSH and NADPH-supplemented human liver microsomes, two types of GSH conjugates were characterized: one was M1-1 from the 1,4-addition of GSH to ortho-benzoquinone intermediate; the other was M2-1 and M2-2 from the 1,4-addition of GSH directly to the ␣,␤-unsaturated carbonyl group of the parent. The formation of M1-1 was cytochrome P450 (P450)-mediated, with 3A4 and 2E1 as the principal catalyzing enzymes, whereas the formation of M2-1 and M2-2 was independent of NADPH and could be accelerated by cytosolic glutathione transferase. In the presence of cumene hydroperoxide, M1-1 formation increased 6-fold, indicating that 5-CQA can also be bioactivated by P450 peroxidase under oxidizing conditions. Furthermore, M1-1 could be formed by myeloperoxidase in activated human leukocytes, implying that 5-CQA bioactivation is more likely to occur under inflammatory conditions. This finding was supported by experiments on lipopolysaccharideinduced inflammatory rats, where a greater amount of M1-1 was detected. In S-adenosyl methionine-and GSH-supplemented human S9 incubations, M1-1 formation decreased by 80% but increased after tolcapone-inhibited catechol-O-methyltransferase (COMT) activity. In summary, the high reactivities of the orthobenzoquinone metabolite and ␣,␤-unsaturated carbonyl group of 5-CQA to nucleophiles have been demonstrated. Different pathological situations and COMT activities in patients may alter the bioactivation extent of 5-CQA

Paeoniflorin inhibits the growth of bladder carcinoma via deactivation of STAT3

Bladder cancer (BCa) is one of the most common urinary cancers. The present study aims to investigate whether Paeoniflorin (Pae) can exert inhibitory effects on BCa. The results showed that Pae inhibited proliferation of human BCa cell lines in a concentration- and time-dependent manner. Pae and cisplatin (Cis) synergistically inhibited the growth of tumours in RT4-bearing mice. Pae treatment neutralized the body loss induced by Cis. Moreover, Pae induced apoptosis in RT4 cells and increased the activities of caspase3, caspase8 and caspase9. Western blotting and immunohistochemical analysis revealed that the phosphorylated signal transducer and activator of transcription-3 (p-STAT3) level were decreased in Pae-treated RT4 cells and Pae-treated tumour-bearing mice. Furthermore, STAT3 transcriptional target B-cell lymphoma-2 was decreased in Pae-treated RT4 cells. Interestingly, Pae prevented translocation of STAT3 to the nucleus in RT4 cells. Collectively, Pae inhibits the growth of BCa, at least in part, via a STAT3 pathway

N-(4-Chloro­phen­yl)-4-meth­oxy-3-(propanamido)­benzamide cyclo­hexane hemisolvate

The title compound, C17H17ClN2O3·0.5C6H12, was prepared by the condensation reaction of 4-meth­oxy-3-(propanamido)­benzoic acid with 4-chloro­aniline. The Cl atom, the propionyl CH3 group and the cyclo­hexyl CH2 group are disordered over two sets of sites of equal occupancy in both mol­ecules. The cyclo­hexane solvent mol­ecule is disordered over two orientations which were modelled with relative occupancies of 0.484 (4) and 0.516 (4). In the crystal, there are a number of N—H⋯O hydrogen bonds, forming layers perpendicular to (001)

DESCN: Deep Entire Space Cross Networks for Individual Treatment Effect Estimation

Causal Inference has wide applications in various areas such as E-commerce and precision medicine, and its performance heavily relies on the accurate estimation of the Individual Treatment Effect (ITE). Conventionally, ITE is predicted by modeling the treated and control response functions separately in their individual sample spaces. However, such an approach usually encounters two issues in practice, i.e. divergent distribution between treated and control groups due to treatment bias, and significant sample imbalance of their population sizes. This paper proposes Deep Entire Space Cross Networks (DESCN) to model treatment effects from an end-to-end perspective. DESCN captures the integrated information of the treatment propensity, the response, and the hidden treatment effect through a cross network in a multi-task learning manner. Our method jointly learns the treatment and response functions in the entire sample space to avoid treatment bias and employs an intermediate pseudo treatment effect prediction network to relieve sample imbalance. Extensive experiments are conducted on a synthetic dataset and a large-scaled production dataset from the E-commerce voucher distribution business. The results indicate that DESCN can successfully enhance the accuracy of ITE estimation and improve the uplift ranking performance. A sample of the production dataset and the source code are released to facilitate future research in the community, which is, to the best of our knowledge, the first large-scale public biased treatment dataset for causal inference.Comment: Accepted by SIGKDD 2022 Applied Data Science Trac

Tetra­aqua­bis(2-methyl­benzimidazolium-1,3-diacetato-κO)zinc(II) tetra­hydrate

The asymmetric unit of the title compound, [Zn(C12H11N2O4)2(H2O)4]·4H2O, contains one-half of the complex mol­ecule and two uncoordin­ated water mol­ecules. The four water O atoms in the equatorial plane around the ZnII centre ( symmetry) form a distorted square-planar arrangement, while the distorted octa­hedral coordination geometry is completed by the O atoms of the zwitterionic 2-methyl­benzimidazolium-1,3-diacetate ligands in the axial positions. The benzimidazole ring system is planar, with a maximum deviation of 0.041 (3) Å. Intra­molecular O—H⋯O hydrogen bonding results in the formation of a non-planar six-membered ring. In the crystal structure, strong intra- and inter­molecular O—H⋯O hydrogen bonds link the mol­ecules into a three-dimensional network. π–π contacts between benzimidazole rings [centroid–centroid distance = 3.899 (1) Å] may further stabilize the structure

{μ-trans-N,N′-Bis[(diphenyl­phosphan­yl)meth­yl]benzene-1,4-diamine-κ2 P:P′}bis­{(acetonitrile-κN)[dipyrido[3,2-a:2′,3′-c]phenazine-κ2 N 4,N 5]copper(I)} bis­(tetra­fluoridoborate)

In the centrosymmetric dinuclear title compound, [Cu2(C2H3N)2(C18H10N4)2(C32H30N2P2)](BF4)2, the CuI centre is coordinated by two N atoms from a dipyridophenazine ligand, one P atom from an N,N′-bis­[(diphenyl­phosphan­yl)meth­yl]benzene-1,4-diamine (bpbda) ligand, and one N atom from an acetonitrile mol­ecule in a distorted tetra­hedral geometry. The bpbda ligand, lying on an inversion center, bridges two CuI centres into a Z-shaped complex. Intra­molecular π–π inter­actions between the dipyridophenazine ligand and the benzene ring of the bpbda ligand are observed [centroid–centroid distance = 3.459 (3) Å]. The crystal structure also involves inter­molecular π–π inter­actions between the dipyridophenazine ligands [centroid–centroid distance = 3.506 (3) Å], which lead to a one-dimensional supra­molecular structure

PSME2 identifies immune-hot tumors in breast cancer and associates with well therapeutic response to immunotherapy

Breast cancer (BrCa) is a heterogeneous disease, which leads to unsatisfactory prognosis in females worldwide. Previous studies have proved that tumor immune microenvironment (TIME) plays crucial roles in oncogenesis, progression, and therapeutic resistance in Breast cancer. However, biomarkers related to TIME features have not been fully discovered. Proteasome activator complex subunit 2 (PSME2) is a member of proteasome activator subunit gene family, which is critical to protein degradation mediated by the proteasome. In the current research, we comprehensively analyzed the expression and immuno-correlations of Proteasome activator complex subunit 2 in Breast cancer. Proteasome activator complex subunit 2 was significantly upregulated in tumor tissues but associated with well prognosis. In addition, Proteasome activator complex subunit 2 was overexpressed in HER2-positive Breast cancer but not related to other clinicopathological features. Interestingly, Proteasome activator complex subunit 2 was positively related to immune-related processes and identified immuno-hot TIME in Breast cancer. Specifically, Proteasome activator complex subunit 2 was positively correlated with immunomodulators, tumor-infiltrating immune cells (TIICs), immune checkpoints, and tumor mutation burden (TMB) levels. Moreover, the positive correlation between Proteasome activator complex subunit 2 and PD-L1 expression was confirmed in a tissue microarray (TMA) cohort. Furthermore, in an immunotherapy cohort of Breast cancer, patients with pathological complete response (pCR) expressed higher Proteasome activator complex subunit 2 compared with those with non-pathological complete response. In conclusion, Proteasome activator complex subunit 2 is upregulated in tumor tissues and correlated with the immuno-hot tumor immune microenvironment, which can be a novel biomarker for the recognition of tumor immune microenvironment features and immunotherapeutic response in Breast cancer

New function for Escherichia coli xanthosine phophorylase (xapA): genetic and biochemical evidences on its participation in NAD+ salvage from nicotinamide

BACKGROUND: In an effort to reconstitute the NAD(+) synthetic pathway in Escherichia coli (E. coli), we produced a set of gene knockout mutants with deficiencies in previously well-defined NAD(+)de novo and salvage pathways. Unexpectedly, the mutant deficient in NAD(+)de novo and salvage pathway I could grow in M9/nicotinamide medium, which was contradictory to the proposed classic NAD(+) metabolism of E. coli. Such E. coli mutagenesis assay suggested the presence of an undefined machinery to feed nicotinamide into the NAD(+) biosynthesis. We wanted to verify whether xanthosine phophorylase (xapA) contributed to a new NAD(+) salvage pathway from nicotinamide. RESULTS: Additional knockout of xapA further slowed down the bacterial growth in M9/nicotinamide medium, whereas the complementation of xapA restored the growth phenotype. To further validate the new function of xapA, we cloned and expressed E. coli xapA as a recombinant soluble protein. Biochemical assay confirmed that xapA was capable of using nicotinamide as a substrate for nicotinamide riboside formation. CONCLUSIONS: Both the genetic and biochemical evidences indicated that xapA could convert nicotinamide to nicotinamide riboside in E. coli, albeit with relatively weak activity, indicating that xapA may contribute to a second NAD(+) salvage pathway from nicotinamide. We speculate that this xapA-mediated NAD(+) salvage pathway might be significant in some bacteria lacking NAD(+)de novo and NAD(+) salvage pathway I or II, to not only use nicotinamide riboside, but also nicotinamide as precursors to synthesize NAD(+). However, this speculation needs to be experimentally tested