Cancer therapy reduces tumor burden by killing tumor cells, yet it simultaneously creates tumor cell debris that may stimulate inflammation and tumor growth. Sulciner et al. demonstrate that specific resolvins (RvD1, RvD2, and RvE1) inhibit tumor growth and enhance cancer therapy through the clearance of tumor cell debris.
Severe coronavirus disease is characterized by pulmonary hyper-inflammation and potentially life-threatening "cytokine storms". Controlling the local and systemic inflammatory response in COVID-19 may be as important as anti-viral therapies. Endogenous lipid autacoid mediators, referred to as eicosanoids, play a critical role in the induction of inflammation and pro-inflammatory cytokine production. SARS-CoV-2 may trigger a cell death ("debris")-induced "eicosanoid storm", including prostaglandins and leukotrienes, which in turn initiates a robust inflammatory response. A paradigm shift is emerging in our understanding of the resolution of inflammation as an active biochemical process with the discovery of novel endogenous specialized pro-resolving lipid autacoid mediators (SPMs), such as resolvins. Resolvins and other SPMs stimulate macrophagemediated clearance of debris and counter pro-inflammatory cytokine production, a process called inflammation resolution. SPMs and their lipid precursors exhibit anti-viral activity at nanogram doses in the setting of influenza without being immunosuppressive. SPMs also promote anti-viral B cell antibodies and lymphocyte activity, highlighting their potential use in the treatment of COVID-19. Soluble epoxide hydrolase (sEH) inhibitors stabilize arachidonic acid-derived epoxyeicosatrienoic acids (EETs), which also stimulate inflammation resolution by promoting the production of pro-resolution mediators, activating anti-inflammatory processes, and preventing the cytokine storm. Both resolvins and EETs also attenuate pathological thrombosis and promote clot removal, which is emerging as a key pathology of COVID-19 infection. Thus, both SPMs and sEH inhibitors may promote the resolution of inflammation in COVID-19, thereby reducing acute respiratory distress syndrome (ARDS) and other life-threatening complications associated with robust viral-induced inflammation. While most COVID-19 clinical trials focus on "anti-viral" and "anti-inflammatory" strategies, stimulating inflammation resolution is a novel host-centric therapeutic avenue. Importantly, SPMs and sEH inhibitors are currently in clinical trials for other inflammatory diseases and could be rapidly translated for the management of COVID-19 via debris clearance and inflammatory cytokine suppression. Here, we discuss using pro-resolution mediators as a potential complement to current anti-viral strategies for COVID-19.
Inflammation in the tumor microenvironment is a strong promoter of tumor growth. Substantial epidemiologic evidence suggests that aspirin, which suppresses inflammation, reduces the risk of cancer. The mechanism by which aspirin inhibits cancer has remained unclear, and toxicity has limited its clinical use. Aspirin not only blocks the biosynthesis of prostaglandins, but also stimulates the endogenous production of anti-inflammatory and proresolving mediators termed aspirin-triggered specialized proresolving mediators (AT-SPMs), such as aspirin-triggered resolvins (AT-RvDs) and lipoxins (AT-LXs). Using genetic and pharmacologic manipulation of a proresolving receptor, we demonstrate that AT-RvDs mediate the antitumor activity of aspirin. Moreover, treatment of mice with AT-RvDs (e.g., AT-RvD1 and AT-RvD3) or AT-LXA 4 inhibited primary tumor growth by enhancing macrophage phagocytosis of tumor cell debris and counter-regulating macrophage-secreted proinflammatory cytokines, including migration inhibitory factor, plasminogen activator inhibitor-1, and C-C motif chemokine ligand 2/monocyte chemoattractant protein 1. Thus, the pro-resolution activity of AT-resolvins and AT-lipoxins may explain some of aspirin's broad anticancer activity. These AT-SPMs are active at considerably lower concentrations than aspirin, and thus may provide a nontoxic approach to harnessing aspirin's anticancer activity. metabolomics | eicosanoids | resolvins | inflammation | metastasis M ore than 80 million aspirin tablets are consumed every year (1). Epidemiologic evidence suggests that the nonsteroidal anti-inflammatory drug (NSAID) aspirin reduces the risk and incidence of cancer and also prolongs survival when administered postdiagnosis (2). While initial studies have focused on colorectal cancers, low-dose aspirin has also demonstrated consistent antitumor activity in other cancers, including lung, breast, prostate, and metastatic cancers (3,4). Studies have also identified survival and chemopreventive benefits of low-dose aspirin following cytotoxic therapy (e.g., radiation, chemotherapy) or surgical tumor resection (5, 6). Compelling evidence of aspirin's anticancer activity stems from patients receiving low-dose aspirin for cardioprevention, in which a substantial fraction (20-30%) benefits from a decrease in cancer incidence (7). In contrast, several studies show that neither nonaspirin NSAIDs nor acetaminophen are associated with a reduced risk of cancer or chemopreventive activity (8,9). While the known anti-inflammatory activity of aspirin offers a generic rationale, the unique antitumor mechanisms of aspirin compared with other NSAIDs remain poorly understood. Importantly, the use of low-dose aspirin in cancer patients is limited by adverse side effects, such as gastrointestinal bleeding and hemorrhagic stroke, that necessitate hospitalization (10).The study of anti-inflammatory mechanisms in cancer has traditionally focused on the suppression of proinflammatory mediators, such as cytokines, eicosanoids, and enzymes (2). Cycloo...
BIDMC has filed patents on behalf of DP and VPS on the use of selective COX-1/TXA2 antagonists for preventing cancer recurrence. VPS is a consultant and equity holder in MitraBiotech, Berg, GMDx, and Victa Biotherapeutics. MB is an equity holder at Anxome, BiomaRx, Canomiks, and GMDx. MWK's current position at Bristol-Myers Squibb is not related to this work.
Severe coronavirus disease 2019 (COVID-19) symptoms, including systemic inflammatory response and multisystem organ failure, are now affecting thousands of infected patients and causing widespread mortality. Coronavirus infection causes tissue damage, which triggers the endoplasmic reticulum stress response and subsequent eicosanoid and cytokine storms. Although proinflammatory eicosanoids, including prostaglandins, thromboxanes, and leukotrienes, are critical mediators of physiological processes, such as inflammation, fever, allergy, and pain, their roles in COVID-19 are poorly characterized. Arachidonic acidederived epoxyeicosatrienoic acids could alleviate the systemic hyperinflammatory response in COVID-19 infection by modulating endoplasmic reticulum stress and stimulating the resolution of inflammation. Soluble epoxide hydrolase (sEH) inhibitors, which increase endogenous epoxyeicosatrienoic acid levels, exhibit potent anti-inflammatory activity and inhibit various pathologic processes in preclinical disease models, including pulmonary fibrosis, thrombosis, and acute respiratory distress syndrome. Therefore, targeting eicosanoids and sEH could be a novel therapeutic approach in combating COVID-19. In this review, we discuss the predominant role of eicosanoids in regulating the inflammatory cascade and propose the potential application of sEH inhibitors in alleviating COVID-19 symptoms. The host-protective action of omega-3 fatty acidederived epoxyeicosanoids and specialized proresolving mediators in regulating anti-inflammation and antiviral response is also discussed. Future studies determining the eicosanoid profile in COVID-19 patients or preclinical models are pivotal in providing novel insights into coronavirus-host interaction and inflammation modulation.
BackgroundAutogenous cis-regulators of ribosomal protein synthesis play a critical role in maintaining the stoichiometry of ribosome components. Structured portions within an mRNA transcript typically interact with specific ribosomal proteins to prevent expression of the entire operon, thus balancing levels of ribosomal proteins across transcriptional units. Three distinct RNA structures from different bacterial phyla have demonstrated interactions with S15 to regulate gene expression; however, these RNAs are distributed across a small fraction of bacterial diversity.ResultsWe used comparative genomics in combination with analysis of existing transcriptomic data to identify three novel putative RNA structures associated with the S15 coding region in microbial genomes. These structures are completely distinct from those previously published and encompass potential regulatory regions including ribosome-binding sites. To validate the biological relevance of our findings, we demonstrate that an example of the Alphaproteobacterial RNA from Rhizobium radiobacter specifically interacts with S15 in vitro, and allows in vivo regulation of gene expression in an E. coli reporter system. In addition, structural probing and nuclease protection assays confirm the predicted secondary structure and indicate nucleotides required for protein interaction.ConclusionsThis work illustrates the importance of integrating comparative genomic and transcriptomic approaches during de novo ncRNA identification and reveals a diversity of distinct natural RNA regulators that support analogous biological functions. Furthermore, this work indicates that many additional uncharacterized RNA regulators likely exist within bacterial genomes and that the plasticity of RNA structure allows unique, and likely independently derived, solutions to the same biological problem.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-657) contains supplementary material, which is available to authorized users.
Bioactive lipids are essential components of human cells and tissues. As discussed in this review, the cancer lipidome is diverse and malleable, with the ability to promote or inhibit cancer pathogenesis. Targeting lipids within the tumor and surrounding microenvironment may be a novel therapeutic approach for treating cancer patients. Additionally, the emergence of a novel super-family of lipid mediators termed specialized pro-resolving mediators (SPMs) has revealed a new role for bioactive lipid mediators in the resolution of inflammation in cancer biology. The role of SPMs in cancer holds great promise in our understanding of cancer pathogenesis and can ultimately be used in future cancer diagnostics and therapy.
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