Photochemical Nickel-Catalyzed Reductive Migratory Cross-Coupling of Alkyl Bromides with Aryl Bromides

A novel method to access 1,1-diarylalkanes from readily available, nonactivated alkyl bromides and aryl bromides via visible-light-driven nickel and iridium dual catalysis, wherein diisopropylamine (^<i>i</i>Pr₂NH) is used as the terminal stoichiometric reductant, is reported. Both primary and secondary alkyl bromides can be successfully transformed into the migratory benzylic arylation products with good selectivity. Additionally, this method showcases tolerance toward a wide array of functional groups and the presence of bases

Residue-specific free energy analysis in ligand bindings to JAK2

<p>Janus kinase 2 (JAK2) has vital importance on the regulation of proliferation, survival and differentiation of a variety of cells by the activation of JAK-STAT pathway. In this study, we employ a new approach to quantitatively calculate residue-specific binding free energies to identify hot-spots in ligand bindings to JAK2 using computational alanine scanning technique combined with the interaction entropy method for entropic change in binding free energies. This combined approach allows one to quantitatively analyse important protein–ligand binding interactions, and in addition, provides a new method for more accurate computation of total protein–ligand binding free energy. In this report, we computed a total of 14 JAK2–ligand binding systems, all with crystal structures and experimentally measured binding data. Key residues are identified with L983 being the quantitatively dominant residue in binding free energy contributions to the ligands. The values of the computed total JAK2–ligand binding free energies are in much closer agreement with experimentally measured data than those obtained by using the standard MM/GBSA approach. Our study thus provided new insights into specific binding mechanisms in ligand binding to JAK2.</p

Ligand-Controlled Nickel-Catalyzed Reductive Relay Cross-Coupling of Alkyl Bromides and Aryl Bromides

1,1-Diarylalkanes are important structural frameworks which are widespread in biologically active molecules. Herein, we report a reductive relay cross-coupling of alkyl bromides with aryl bromides by nickel catalysis with a simple nitrogen-containing ligand. This method selectively affords 1,1-diarylalkane derivatives with good to excellent yields and regioselectivity

Manganese-Doped Ag₂S-ZnS Heteronanostructures

Doping semiconductor nanocrystals and integrating disparate components together are two effective ways for modulating the optical properties of semiconductor nanocrystals. For the first time, we successfully synthesized Mn-doped Ag₂S-ZnS heteronanostructures (HNSs) by combining these two strategies together. The obtained Mn-doped Ag₂S-ZnS HNSs exhibit multicolor emissions of blue, orange, and near-infrared (NIR), in which the blue emission originates from ZnS trap state, the orange emission is induced by the ⁴T₁–⁶A₁ transition in Mn²⁺ dopant, and the NIR emission is attributed to the band gap emission of Ag₂S. Reaction temperature-dependent and Mn²⁺ dopant concentration-dependent optical properties, as well as the growth kinetics of Ag₂S-ZnS HNSs during doping process, were systemically studied to achieve the desirable optical properties and preserve well-defined HNSs simultaneously. We expect that the prepared Mn-doped Ag₂S-ZnS HNSs with tunable multicolor emissions will create numerous opportunities for potential applications in bioimaging and optoelectronic devices, and the facile methodology modulating Ag₂S-ZnS HNSs with desirable properties will be general and be ready to other complex semiconductor nanostructures

Proteomic Characterization of Peritoneal Extracellular Vesicles in a Mouse Model of Peritoneal Fibrosis

Peritoneal fibrosis progression is regarded as a significant cause of the loss of peritoneal function, markedly limiting the application of peritoneal dialysis (PD). However, the pathogenesis of peritoneal fibrosis remains to be elucidated. Tissue-derived extracellular vesicles (EVs) change their molecular cargos to adapt the environment alteration, mediating intercellular communications and play a significant role in organ fibrosis. Hence, we performed, for the first time, four-dimensional label-free quantitative liquid chromatography–tandem mass spectrometry proteomic analyses on EVs from normal peritoneal tissues and PD-induced fibrotic peritoneum in mice. We demonstrated the alterations of EV concentration and protein composition between normal control and PD groups. A total of 2339 proteins containing 967 differentially expressed proteins were identified. Notably, upregulated proteins in PD EVs were enriched in processes including response to wounding and leukocyte migration, which participated in the development of fibrosis. In addition, EV proteins of the PD group exhibited unique metabolic signature compared with those of the control group. The glycolysis-related proteins increased in PD EVs, while oxidative phosphorylation and fatty acid metabolism-related proteins decreased. We also evaluated the effect of cell-type specificity on EV proteins, suggesting that mesothelial cells mainly cause the alterations in the molecular composition of EVs. Our study provided a useful resource for further validation of the key regulator or therapeutic target of peritoneal fibrosis

Plasma Metabolomic Profiling to Reveal Antipyretic Mechanism of <i>Shuang-Huang-Lian</i> Injection on Yeast-Induced Pyrexia Rats

<div><p><i>Shuang-huang-lian</i> injection (<i>SHLI</i>) is a famous Chinese patent medicine, which has been wildly used in clinic for the treatment of acute respiratory tract infection, pneumonia, influenza, etc. The existing randomized controlled trial (RCT) studies suggested that <i>SHLI</i> could afford a certain anti-febrile action. However, seldom does research concern the pharmacological mechanisms of <i>SHLI</i>. In the current study, we explored plasma metabolomic profiling technique and selected potential metabolic markers to reveal the antipyretic mechanism of <i>SHLI</i> on yeast-induced pyrexia rat model using UPLC-Q-TOF/MS coupled with multivariate statistical analysis and pattern recognition techniques. We discovered a significant perturbance of metabolic profile in the plasma of fever rats and obvious reversion in <i>SHLI</i>-administered rats. Eight potential biomarkers, i.e. 1) 3-hydeoxybutyric acid, 2) leucine, 3) 16∶0 LPC, 4) allocholic acid, 5) vitamin B₂, 6) Cys-Lys-His, 7) 18∶2 LPC, and 8) 3-hydroxychola-7, 22-dien-24-oic acid, were screened out by OPLS-DA approach. Five potential perturbed metabolic pathways, i.e. 1) valine, leucine, and isoleucine biosynthesis, 2) glycerophospholipid metabolism, 3) ketone bodies synthesis and degradation, 4) bile acid biosynthesis, and 5) riboflavin metabolism, were revealed to relate to the antipyretic mechanisms of <i>SHLI</i>. Overall, we investigated antipyretic mechanisms of <i>SHLI</i> at metabolomic level for the first time, and the obtained results highlights the necessity of adopting metabolomics as a reliable tool for understanding the holism and synergism of Chinese patent drug.</p></div

The results of S-plots of OPLS-DA models.

<p>(A) At positive ion mode. (B) At negative ion mode. Note: NC (▴), M (•) and SHLI (▪).</p

Typical base peak intensity (BPI) chromatograms ofplasma samples from each groups.

<p>(A) NC at positive ion mode. (B) M at positive ion mode (C) <i>SHLI</i> treatment at positive mode (Blue arrows show drug induced components).</p

Metabolites selected by OPLS-DA with VIP >1 and significant test <i>P</i><0.05 between the pyretic model group and the normal control group.

<p>Note: ^aMetabolites were identified based on database information in METLIN, Lipid MAPs or HMDB; ↑showed up-regulated metabolites and ↓showed down-regulated metabolites; ^#<i>p<0.05</i>, ^{# #}<i>p<0.01</i>, ^{# # #}<i>p<0.001</i> Model vs. normal control; *<i>p<0.05</i>, **<i>p<0.01</i>, ***<i>p<0.001</i> SHLI vs. Model.</p

Summary of pathway analysis with MetPA.

<p>Note: 1. Valine, leucine and isoleucine biosynthesis. 2. Glycerophospholipid metabolism. 3. Synthesis and degradation of ketone bodies. 4. Riboflavin metabolism. 5. Butanoate metabolism. 6. Valine, leucine and isoleucine degradation. 7. Aminoacyl-tRNA biosynthesis.</p