HDAC 3-selective inhibitor RGFP966 demonstrates anti-inflammatory properties in RAW 264.7 macrophages and mouse precision-cut lung slices by attenuating NF-κB p65 transcriptional activity

AbstractThe increasing number of patients suffering from chronic obstructive pulmonary disease (COPD) represents a major and increasing health problem. Therefore, novel therapeutic approaches are needed. Class I HDACs 1, 2 and 3 play key roles in the regulation of inflammatory gene expression with a particular pro-inflammatory role for HDAC 3. HDAC 3 has been reported to be an important player in inflammation by deacetylating NF-κB p65, which has been implicated in the pathology of COPD. Here, we applied the pharmacological HDAC 3-selective inhibitor RGFP966, which attenuated pro-inflammatory gene expression in models for inflammatory lung diseases. Consistent with this, a robust decrease of the transcriptional activity of NF-κB p65 was observed. HDAC 3 inhibition affected neither the acetylation status of NF-κB p65 nor histone H3 or histone H4. This indicates that HDAC 3 inhibition does not inhibit NF-κB p65 transcriptional activity by affecting its deacetylation but rather by inhibiting enzymatic activity of HDAC 3. Taken together, our findings indicate that pharmacological HDAC 3-selective inhibition by inhibitors such as RGFP966 may provide a novel and effective approach toward development of therapeutics for inflammatory lung diseases

HDAC1-3 inhibitor MS-275 enhances IL10 expression in RAW264.7 macrophages and reduces cigarette smoke-induced airway inflammation in mice

Chronic obstructive pulmonary disease (COPD) constitutes a major health burden. Studying underlying molecular mechanisms could lead to new therapeutic targets. Macrophages are orchestrators of COPD, by releasing pro-inflammatory cytokines. This process relies on transcription factors such as NF-κB, among others. NF-κB is regulated by lysine acetylation; a post-translational modification installed by histone acetyltransferases and removed by histone deacetylases (HDACs). We hypothesized that small molecule HDAC inhibitors (HDACi) targeting class I HDACs members that can regulate NF-κB could attenuate inflammatory responses in COPD via modulation of the NF-κB signaling output. MS-275 is an isoform-selective inhibitor of HDAC1-3. In precision-cut lung slices and RAW264.7 macrophages, MS-275 upregulated the expression of both pro- and anti-inflammatory genes, implying mixed effects. Interestingly, anti-inflammatory IL10 expression was upregulated in these model systems. In the macrophages, this was associated with increased NF-κB activity, acetylation, nuclear translocation, and binding to the IL10 promoter. Importantly, in an in vivo model of cigarette smoke-exposed C57Bl/6 mice, MS-275 robustly attenuated inflammatory expression of KC and neutrophil influx in the lungs. This study highlights for the first time the potential of isoform-selective HDACi for the treatment of inflammatory lung diseases like COPD

Olive oil intake and cancer risk: A systematic review and meta-analysis

Background Research evidence has established the beneficial effects of diet in cancer prevention; various epidemiological studies have suggested that olive oil component could play a role in decreasing cancer risk. This systematic review and meta-analysis aims to investigate the association between olive oil consumption, cancer risk and prognosis. Methods A systematic search was conducted in PubMed, EMBASE and Google Scholar databases (end-of-search: May 10, 2020). Pooled relative risk (RR) and 95% confidence intervals (95% CIs) were estimated with random-effects (DerSimonian-Laird) models. Subgroup analyses, sensitivity analyses and meta-regression analysis were also performed. Results 45 studies were included in the meta-analysis; 37 were case-control (17,369 cases and 28,294 controls) and 8 were cohort studies (12,461 incident cases in a total cohort of 929,771 subjects). Highest olive oil consumption was associated with 31% lower likelihood of any cancer (pooled RR = 0.69, 95%CI: 0.62–0.77), breast (RR = 0.67, 95%CI: 0.52–0.86), gastrointestinal (RR = 0.77, 95%CI: 0.66–0.89), upper aerodigestive (RR = 0.74, 95% CI: 0.60–0.91) and urinary tract cancer (RR = 0.46, 95%CI: 0.29–0.72). Significant overall effects spanned both Mediterranean and non-Mediterranean participants, studies presenting a multivariate and a univariate analysis and all subgroups by study quality. Conclusions Olive oil consumption seems to exert beneficial actions in terms of cancer prevention. Additional prospective cohort studies on various cancer types and survivors, as well as large randomized trials, seem desirable. © 2022 Markellos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Opportunities for Lipid-Based Probes in the Field of Immunology

Lipids perform a wide range of functions inside the cell, ranging from structural building block of membranes and energy storage to cell signaling. The mode of action of many signaling lipids has remained elusive due to their low abundance, high lipophilicity, and inherent instability. Various chemical biology approaches, such as photoaffinity or activity-based protein profiling methods, have been employed to shed light on the biological role of lipids and the lipid-protein interaction profile. In this review, we will summarize the recent developments in the field of chemical probes to study lipid biology, especially in immunology, and indicate potential avenues for future research.Molecular Physiolog