ABSTRACT
The NLRP3 inflammasome is a multiprotein complex that plays a crucial role in the pathophysiology of multiple inflammation-related diseases. In this study, we designed and synthesized a series of novel 2,3-dihydro-1H-indene-5-sulfonamide analogues as NLRP3 inflammasome inhibitors, and then identified compound 15z as a potent and specific inhibitor (IC50: 0.13 µM) with low toxicity. Mechanistic studies indicate that 15z binds directly to NLRP3 protein (KD: 102.7 nM), blocking the assembly and activation of the NLRP3 inflammasome and effectively inhibiting cell pyroptosis. Given the notable distribution of 15z in the colon, the DSS-induced colitis model was employed to evaluate its in vivo effectiveness. 15z significantly impacted NLRP3 inflammasome activation and relieved inflammatory bowel disease symptoms in this model. Acute and subacute toxicity studies suggested that 15z has a favorable safety profile. Our results indicate that 15z has great potential to be further developed as a candidate for the treatment of inflammatory bowel disease.
Subject(s)
Colitis , Inflammatory Bowel Diseases , Animals , Mice , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Colitis/chemically induced , Colitis/drug therapy , Colitis/metabolism , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/metabolism , Sulfanilamide/adverse effects , Mice, Inbred C57BL , Dextran SulfateABSTRACT
As "Michael acceptors" may induce promiscuous responses in mammalian cells by reacting with various proteins, we modified the cinnamamide of our previous hydrazide-based HDAC inhibitors (HDACIs) to deactivate the Michael reaction. Representative compound 11h is 2-5 times more potent than lead compound 17 in both HDAC inhibitory activity (IC50 = 0.43-3.01 nM) and cell-based antitumor assay (IC50 = 19.23-61.04 nM). The breakthrough in the pharmacokinetic profile of 11h (oral bioavailability: 112%) makes it a lead-in-class oral active agent, validated in the in vivo anti-AML study (4 mg/kg p.o., TGI = 78.9%). Accumulated AcHH3 and AcHH4 levels in tumor tissue directly correlate with the in vivo efficacy, as panobinostat with lower AcHH3 and AcHH4 levels than 11h displays limited activity. To the best of our knowledge, this work contributes the first report of in vivo antitumor activity of hydrazide-based HDACIs. The outstanding pharmacokinetic/pharmacodynamic and antitumor activity of 11h could potentially extend the clinical application of current HDACIs.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Histone Deacetylase Inhibitors/pharmacology , Hydrazines/chemistry , Leukemia, Myeloid, Acute/drug therapy , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Apoptosis , Cell Proliferation , Female , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylase Inhibitors/pharmacokinetics , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Docking Simulation , Structure-Activity Relationship , Tissue Distribution , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
The article Dietary protein intake and subsequent risk of type 2 diabetes: a dose-response meta-analysis of prospective cohort studies written by Jianhong Ye, Qixin Yu, Weihua Mai, Peiling Liang, Xiaoxia Liu, Yunnan Wang was originally published electronically on the publisher's internet portal (currently SpringerLink) on 30 March 2019 with open access. With the author(s)' decision to step back from Open Choice, the copyright of the article changed on 30 May 2019 to © Springer-Verlag Italia S.r.l., part of Springer Nature 2019 and the article is forthwith distributed under the terms of copyright.
ABSTRACT
AIMS: Dietary proteins, including those obtained from animal and plant sources, have inconsistently been correlated with type 2 diabetes mellitus (T2DM) risk. Therefore, a meta-analysis was conducted to evaluate the association between dietary proteins and the risk of T2DM. METHODS: Prospective cohort studies published until November 2018 were systematically searched in PubMed, Embase, and the Cochrane library. The pooled relative risks (RRs) were calculated with 95% confidence intervals (CIs) using the random-effects model. RESULTS: Ten articles involving a total of 21 cohorts were included in the final meta-analysis. A total of 487,956 individuals were recruited in these studies and 38,350 T2DM cases were reported. Analysis of the pooled RRs indicated that high total protein intake was associated with an increased risk of T2DM (RR 1.10; P = 0.006), whereas moderate total protein intake was not significantly associated with T2DM risk (RR 1.00; P = 0.917). Moreover, a higher risk of T2DM was observed with high animal protein intake (RR 1.13; P = 0.013), whereas moderate animal protein intake had little or no effect on T2DM risk (RR 1.06; P = 0.058). Finally, high intake of plant protein did not affect T2DM risk (RR 0.93; P = 0.074), whereas moderate intake was associated with a reduced risk of T2DM (RR 0.94; P < 0.001). CONCLUSIONS: The results of this study indicate that high total protein and animal protein intakes are associated with an increased risk of T2DM, whereas moderate plant protein intake is associated with a decreased risk of T2DM.
