<div>Abstract<p>Aberrant N-linked glycosylation is a prominent feature of cancers. Perturbance of oligosaccharide structure on cell surfaces directly affects key processes in tumor development and progression. In spite of the critical role played by N-linked glycans in tumor biology, the discovery of small molecules that specifically disturbs the N-linked glycans is still under investigation. To identify more saccharide-structure-perturbing compounds, a repurposed drug screen by using a library consisting of 1530 FDA-approved drugs was performed. Interestingly, an antipsychotic drug, penfluridol, was identified as being able to decrease cell surface wheat germ agglutinin staining. In the presence of penfluridol, cell membrane glycoproteins programmed death-ligand 1 (PD-L1) shifted to a lower molecular weight. Further studies demonstrated that penfluridol treatment caused an accumulation of high-mannose oligosaccharides, especially Man<sub>5–7</sub>GlcNAc<sub>2</sub> glycan structures. Mechanistically, this effect is due to direct targeting of MAN1A1 mannosidase, a Golgi enzyme involved in N-glycan maturation. Moreover, we found that altered glycosylation of PD-L1 caused by penfluridol disrupted interactions between programmed cell death protein 1 and PD-L1, resulting in activation of T-cell tumor immunity. In a mouse xenograft and glioma model, penfluridol enhanced the antitumor effect of the anti–PD-L1 antibody <i>in vivo</i>. Overall, these findings revealed an important biological activity of the antipsychotic drug penfluridol as an inhibitor of glycan processing and proposed a repurposed use of penfluridol in antitumor therapy through activation of T-cell immunity.</p></div>
<p>(a) qPCR analysis of the GRP78 and CHOP expression in MDA-MB-231 cells after the treatment with the indicated concentrations for 6 hours. (b) Western blot analysis of Integrin β1 expression pattern in MDA-MB-231 cells after indicated drugs treatment for 24 hours. (c) Western blot analysis of protein expression pattern of Integrin β1 in MDA-MB-231 cells treated with the indicated siRNA.</p>
<p>(a) Western blot analysis of glycoprotein patterns in MDA-MB-231 cells after treatment with the indicated concentrations of penfluridol for 24 hours. Red arrowhead, immature glycoproteins. (b) Western blot analysis of protein expression pattern of ACE2 in HEK293T cells after treatment with the indicated concentrations of penfluridol for 24 hours. (c) In HEK293T cells, FLAG-tagged ACE2 was treated for 24 hours, collected by immunoprecipitation, subjected to SDS-PAGE, and analyzed by western blot. (d) Pearson correlation coefficient of three independent groups of (c) through N-glycan profiling.</p>
The NLRP3 inflammasome is the most characterized inflammasome activated by cellular infection or stress, which is responsible for the maturation of proinflammatory cytokines IL-1β and IL-18. The precise molecular mechanism for negative regulation of NLRP3 inflammasome activation needs to be further defined. Here we identify leucine-rich repeat Fli-I-interacting protein 2 (LRRFIP2) as an NLRP3-associated protein and an inhibitor for NLRP3 inflammasome activation. LRRFIP2 binds to NLRP3 via its N terminus upon NLRP3 inflammasome activation, and also interacts with Flightless-I, a pseudosubstrate of caspase-1, via its Coil motif. Knockdown of Flightless-I significantly promotes NLRP3 inflammasome activation. LRRFIP2 enhances the interaction between Flightless-I and caspase-1, facilitating the inhibitory effect of Flightless-I on caspase-1 activation. Furthermore, silencing of Flightless-I abrogates the inhibitory effect of LRRFIP2 on NLRP3 inflammasome. These data demonstrate that LRRFIP2 inhibits NLRP3 inflammasome activation by recruiting the caspase-1 inhibitor Flightless-I, thus outlining a new mechanism for negative regulation of NLRP3 inflammasome.
<p>(a) qPCR analysis of the GRP78 and CHOP expression in MDA-MB-231 cells after the treatment with the indicated concentrations for 6 hours. (b) Western blot analysis of Integrin β1 expression pattern in MDA-MB-231 cells after indicated drugs treatment for 24 hours. (c) Western blot analysis of protein expression pattern of Integrin β1 in MDA-MB-231 cells treated with the indicated siRNA.</p>
Paraoxonase(PON) is the first enzyme identified as a protective barrier against organophosphorus poisoning.PON acts as an important antioxidant enzyme against nerve system damage.The enzyme has been implicated in the pathogenesis of a number of disorders including diabetes,cardiovascular diseases,et al.After painstaking research spanning the last three decades,the knowledge about this enzyme and the role in diabetic patients has increased immensely.This article attempts to elaborate the characteristics of PON-1 in bionomics as well as the activity and the role of enzyme in diabetic ocular complications involving diabetic retinopathy and diabetic cataract.A better understanding of the molecular mechanism of PON-1 may act as a new target of therapy for diabetic retinopathy and diabetic cataract.
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