Neutrophil ALDH2 is a new therapeutic target for the effective treatment of sepsis-induced ARDS.

Acetaldehyde dehydrogenase 2 (ALDH2) mutations are commonly found in a subgroup of the Asian population. However, the role of ALDH2 in septic acute respiratory distress syndrome (ARDS) remains unknown. Here, we showed that human subjects carrying the ALDH2rs671 mutation were highly susceptible to developing septic ARDS. Intriguingly, ALDH2rs671-ARDS patients showed higher levels of blood cell-free DNA (cfDNA) and myeloperoxidase (MPO)-DNA than ALDH2WT-ARDS patients. To investigate the mechanisms underlying ALDH2 deficiency in the development of septic ARDS, we utilized Aldh2 gene knockout mice and Aldh2rs671 gene knock-in mice. In clinically relevant mouse sepsis models, Aldh2-/- mice and Aldh2rs671 mice exhibited pulmonary and circulating NETosis, a specific process that releases neutrophil extracellular traps (NETs) from neutrophils. Furthermore, we discovered that NETosis strongly promoted endothelial destruction, accelerated vascular leakage, and exacerbated septic ARDS. At the molecular level, ALDH2 increased K48-linked polyubiquitination and degradation of peptidylarginine deiminase 4 (PAD4) to inhibit NETosis, which was achieved by promoting PAD4 binding to the E3 ubiquitin ligase CHIP. Pharmacological administration of the ALDH2-specific activator Alda-1 substantially alleviated septic ARDS by inhibiting NETosis. Together, our data reveal a novel ALDH2-based protective mechanism against septic ARDS, and the activation of ALDH2 may be an effective treatment strategy for sepsis.

Synthesis, Structures and Photophysical Properties of Asymmetric Fulvene-[b]-fused BODIPYs.

Herein, we developed a one-pot procedure to synthesize novel fulvene-[b]-fused BODIPYs from α-(2-alkynylphenyl)-pyrrole and acylpyrrole, using 5-exo cyclization as the key transformation. Compared to benzene-[b]-fused BODIPYs, although they have similar chemical compositions, their structures and properties significantly differ from each other, which can be attributed to the less aromaticity of the fulvene linker than benzene. Notably, fulvene-[b]-fused BODIPY 1 b exhibits helical-twisted core skeleton, intensified red-shifted absorption, and peak fluorescence. In addition, the pathway of this one-pot reaction and the mechanism of POCl3 mediated 5-exo cyclization have been proposed by a combining experimental and computational study.

AIEgen-Enabled Multicolor Visualization for the Formation of Supramolecular Polymer Networks.

Extensive reports on the use of supramolecular polymer networks (SPNs) in self-healing materials, controlled release system and degradable products have led more researchers to tap their potential owing to the unique properties. Yet, the attendant efforts in the visualization through conventional luminescence methods during the formation of SPNs have been met with limited success. Herein, we designed a special type of SPNs prepared by PPMU polymer chains containing pyrene benzohydrazonate (PBHZ) molecules as AIEgens for the multicolor visualization with naked eyes. The complete detection of the formation process of the networks relied on the PBHZ molecules with aggregation-induced ratiometric emission (AIRE) effect, which enabled the fluorescence of the polymer networks transits from blue to cyan, and then to green with the increasing crosslinking degree derived from the hydrogen bonds between 2-ureido-4-pyrimidone (UPy) units of the polymer chains. Additionally, we certificated the stimuli-responsiveness of the obtained SPNs, and the fluorescence change, as well as observing the morphology transition. The AIEgen-enabled multicolor visualization of the formation of SPNs may provide better understanding of the details of the crosslinking interactions in the microstructural evolution, giving more inspiration for the multifunctional products based on SPNs.

Synthesis and evaluation of new 2-chloro-4-aminopyrimidine and 2,6-dimethyl-4-aminopyrimidine derivatives as tubulin polymerization inhibitors.

Eighteen new 2-chloro-4-aminopyrimidine and 2,6-dimethyl-4-aminopyrimidine derivatives were synthesized and evaluated as tubulin polymerization inhibitor for the treatment of cancer. Among them, compounds 10, 17, 20 and 21 exhibited potent antiproliferative activities against five human cancer cell lines. Microtubule dynamics assay showed that compound 17 could effectively inhibit tubulin polymerization. Molecular docking studies were also carried out to understand the binding pattern. Further mechanism studies revealed that 17 could induce G2/M phase arrest, disrupt the organization of the cellular microtubule network and induce cell apoptosis and mitochondrial dysfunction.

Synthesis and Biological Evaluation of Selenium-Containing 4-Anilinoquinazoline Derivatives as Novel Antimitotic Agents.

Twenty-eight novel selenium-containing 4-anilinoquinazoline derivatives were designed, synthesized, and evaluated as antiproliferative agents. Most of them had significant in vitro activities, particularly for compounds 23a, 25a, and 25d, which also exhibited the most potent antitumor activities against cisplatin-resistant cell lines and the doxorubicin-resistant cell lines, good selectivity toward normal cells, and obvious inhibitory effect on migration of A549 cell lines. Further mechanistic studies revealed that 23a, 25a, and 25d induce G2/M phase arrest and apoptosis in A549 cells, which was associated with a collapse of the mitochondrial membrane potential, alterations in the expression of some cell cycle-related and apoptosis-related proteins, and increasing the intracellular ROS level. Finally, compounds 23a, 25a, and 25d also effectively inhibited the tumor growth in the A549 xenograft model without obvious hints of toxicity. Taken together, these in vitro and in vivo results suggest that 23a, 25a, and 25d may be promising microtubule-stabilizing agents and can be used as a promising lead for the development of new antitumor agents.

Enantioselective bioreduction of benzo-fused cyclic ketones with engineered Candida glabrata ketoreductase 1 - a promising synthetic route to ladostigil (TV3326).

Biocatalysis has been recently emerging as a promising alternative to traditional chemical synthesis because of its "green" characteristics and comparable selectivities, which accord with the concept of sustainable development and demand for asymmetric synthesis. In this study, whole-cell biocatalysts containing glucose dehydrogenase (GDH) and Candida glabrata ketoreductase 1 (CgKR1) variants were constructed. These biocatalysts were applied to the reduction of benzo-fused cyclic ketones and showed good to high activities and enantioselectivities. Particularly, CgKR1 variants displayed high activities (90.6%-98.4% conversions) and enantioselectivities (>99.9% ee) towards 5a, a key intermediate of ladostigil (TV3326). Based on these results, a chemoenzymatic synthesis of (S)-5b was developed by using biocatalytic asymmetric reduction as a key step, giving the product with a total yield of 34.0% and 99.9% ee.

High-Rate and Cycling-Stable Nickel-Rich Cathode Materials with Enhanced Li(+) Diffusion Pathway.

The nickel-rich LiNi0.7Co0.15Mn0.15O2 material was sintered by Li source with the Ni0.7Co0.15Mn0.15(OH)2 precursor, which was prepared via hydrothermal treatment after coprecipitation. The intensity ratio of I(110)/I(108) obtained from X-ray diffraction patterns and high-resolution transmission electronmicroscopy confirm that the particles have enhanced growth of (110), (100), and (010) surface planes, which supply superior inherent Li(+) deintercalation/intercalation. The electrochemical measurement shows that the LiNi0.7Co0.15Mn0.15O2 material has high cycling stability and rate capability, along with fast charge and discharge ability. Li(+) diffusion coefficient at the oxidation peaks obtained by cyclic voltammogram measurement is as large as 10(-11) (cm(2) s(-1)) orders of magnitude, implying that the nickel-rich material has high Li(+) diffusion capability.

[Studies on the triterpenoids constituents from Phyllodium elegans].

OBJECTIVE: To study the chemical constituents of Phyllodium elegans. METHODS: The compounds were isolated and purified by extraction, chromatography on silica gel and recrystallization. Their structures were elucidated on the basis of physicochemical properties and spectra analysis. RESULTS: Three triterpenoids were isolated and identified as lupenone (1), lupeol (2), betulin (3). CONCLUSION: Compound 2 is obtained from the genus for the first time, Compounds 1-3 are isolated from this plant for the first time.

[Studies on the chemical constituents from Cissus pteroclada].

OBJECTIVE: To study the chemical constituents of Yao Medicine Cissus pteroclada. METHODS: The compounds were isolated and purified by column chromatography with silica gel, TLC and recrystallization. Their structures were elucidated on the basis of physicochemical properties and spectra analysis. RESULTS: Six compounds were isolated and identified as beta-sitosterol (I), bergenin (II), 11-O-galloylbergenin (III), 11-O-(4-hydroxy benzoyl) bergenin (IV), gallic acid (V), daucosterol (VI). CONCLUSION: Compounds III and NIV are obtained from the genus for the first time. All the compounds are isolated from this plant for the first time except the compound II.

Production of monoclonal antibodies for detecting marine fungal polysaccharide isolated from the Phoma herbarum YS4108.

Seven monoclonal antibodies (MAbs) specific for marine fungal polysaccharide YCP isolated from the Phoma herbarum YS4108 were obtained after immunization of BALB/c mice with the conjugate of YCP coupled to bovine serum albumin (BSA). Their epitope mapping and binding specificity characterized by blocking and inhibition Enzyme-linked immunosorbent assay (ELISA) indicated that these specific MAbs have similar binding patterns. An immuno-capture ELISA has been developed on the basis of employing the MAbs N(3)F and P(12)B specific for YCP as the capture antibody and the detecting antibody, respectively. The working range for YCP in aqueous solution was 1-10,000 ng/ml with a good reproducibility (relative standard deviation