Pyroptosis of syncytia formed by fusion of SARS-CoV-2 Spike and ACE2 expressing cells

SARS-Cov-2 infected cells fused with the ACE2-positive neighboring cells forming syncytia. However, the effect of syncytia in disease development is largely unknown. We established an in vitro cell-cell fusion system and used it to mimic the fusion of SARS-CoV-2 infected cells with ACE2-expressing cells to form syncytia. We found that Caspase-9 was activated after syncytia formation, and Caspase-3/7 was activated downstream of Caspase-9, but it triggered GSDME-dependent pyroptosis rather than apoptosis. What is more, single cell RNA-sequencing data showed that both ACE2 and GSDME were expression in alveolar type 2 cells in human lung. We propose that pyroptosis is the fate of syncytia formed by SARS-CoV-2 infected host cells and ACE2-positive cells, which indicated that lytic death of syncytia may contribute to the excessive inflammatory responses in severe COVID-19 patients.

Multi-substituted N-phenyl-2, 2-dichloroacetamide analogues as anti-cancer drugs: design, synthesis and biological evaluation / 药学学报

Our earlier research has shown that mono-substituted N-phenyl-2, 2-dichloroacetamide exhibited much higher anti-cancer activity than the lead compound sodium dichloroacetate (DCA). In this paper, a variety of multi-substituted N-phenyl-2, 2-dichloroacetamides were synthesized and biologically evaluated. The results showed that 3, 5-disubstituted N-phenyl-2, 2-dichloroacetamide analogues had satisfactory potency. Among them, N-(3, 5-diiodophenyl)-2, 2-dichloroacetamide had an IC50 of 2.84 micromol x L(-1) against non-small cell lung cancer cell line A549 and could induce cancer cell apoptosis.

Prioritization of charge over geometry in transition state analogues of a dual specificity protein kinase.

The direct observation of a transition state analogue (TSA) complex for tyrosine phosphorylation by a signaling kinase has been achieved using (19)F NMR analysis of MEK6 in complex with tetrafluoroaluminate (AlF(4)(-)), ADP, and p38α MAP kinase (acceptor residue: Tyr182). Solvent-induced isotope shifts and chemical shifts for the AlF(4)(-) moiety indicate that two fluorine atoms are coordinated by the two catalytic magnesium ions of the kinase active site, while the two remaining fluorides are liganded by protein residues only. An equivalent, yet distinct, AlF(4)(-) complex involving the alternative acceptor residue in p38α (Thr180) is only observed when the Tyr182 is mutated to phenylalanine. The formation of octahedral AlF(4)(-) species for both acceptor residues, rather than the trigonal bipyramidal AlF(3)(0) previously identified in the only other metal fluoride complex with a protein kinase, shows the requirement of MEK6 for a TSA that is isoelectronic with the migrating phosphoryl group. This requirement has hitherto only been demonstrated for proteins having a single catalytic magnesium ion.

Anticancer Efficacy of Concurrent Capecitabine and Radiation Therapy for Cervical Adenocarcinoma in Nude Mice / 中国医科大学学报

Objective To observe the therapeutic effect of the new plan of concurrent capecitabine (CAP) and radiation therapy for hu-man cervical adenocarcinoma in nude mice. Methods The nude mice were injected with CAC-1 cells for the modelization of cervical ade-nocarcinoma. Before treatment,all mice with tumors were randomly divided into control group,CAP group,5-FU group,radiation group,CAP+ radiation group,5-FU+radiation group. According to the tumor size,mice were furtherly divided into large-size and small-size groups in the control group,CAP group,radiation group, CAP+radiation group. The change of tumor size,tumor growth percentage and the delay time of tu-mor growth were evaluated. Results The therapeutic effect of combining 2/3MTD CAP with 6 Gy radiation or fractionation 2 Gy × 8 times radiation was better than that of the control group,chemotherapy group and the radiation group. The difference was significant (P < 0.05). The restraint effect of the combining 2/3MTD CAP with 6 Gy radiotherapy was better than that of the combining 2/3MTD 5-FU with 6 Gy radiotherapy. Combining 2/3MTD CAP with fractionation 2 Gyx8 times radiation therapy was more efficient than Combining 2/3MTD CAP with fractionation 6 Gy radiation therapy. In combining therapy groups,the response of large-size tumors was more significant than that of the small-size tumors (P < 0.05),which had almost no obvious response. Conclusion Concurrent CAP and radiation therapy has obvious restraint effect on CAC-1 cervix adenocarcinoma in nude mice. The CAP and radiation therapy can promote the therapeutic effect to each oth-er. The therapeautic effect of the concurrent CAP and radiation therapy is affected by the radiation dose, radiation method and the tumor size.

Synthesis of phenyloxyisobutyric acid derivatives and their antidiabetic activity in vitro / 药学学报

Aim To design and synthesize new phenyloxyisobutyric acid analogues as antidiabetic compounds. Methods Eight new target compounds were synthesized by combination of lipophilic moieties and acidic moiety with nucleophilic replacement or Mitsunobu condensation. The eight compounds were confirmed by 1H NMR, 13C NMR, IR and MS. Results In vitro insulin-sensitizing activity (3T3-L1adipocyte) demonstrated, that the cultured glucose concentration of up-clear solution detected with GODpioglitazone, compounds A and B were added to the insulin-resistant system. Conclusion In vitro insulin-sensitizing activity of target compound A is in between that of rosiglitazone and pioglitazone, and activity of target compound B is slightly less than that of pioglitazone.