The inflammation is the protective response of the body against various harmful stimuli; however, the aberrant and inappropriate activation tends to become harmful. The acute inflammatory response tends to resolved once the offending agent is subside but this acute response becomes chronic in nature when the body is unable to successfully neutralized the noxious stimuli. This chronic inflammatory microenvironment is associated with the release of various pro-inflammatory and oncogenic mediators such as nitric oxide (NO), cytokines [IL-1β, IL-2, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)], growth factor, and chemokines. These mediators make the inflammatory microenvironment more vulnerable toward tumorigenesis. The pro-inflammatory mediators released during the chronic inflammation tends to induce several molecular signaling cascades such as nuclear factor kappa B, MAPKinase, nuclear factor erythroid 2-related factor 2, phosphoinositide-3-kinase, Janus kinases/STAT, Wnt/B-catenin, and cyclic AMP response element binding protein. The immune system and its components have a pleiotropic effect on inflammation and cancer progression. Immune components such as T cells, natural killer cells, macrophages, and neutrophils either inhibit or enhance tumor initiation depending on the type of tumor and immune cells involved. Tumor-associated macrophages and tumor-associated neutrophils are pro-tumorigenic cells highly prevalent in inflammation-mediated tumors. Similarly, presence of T regulatory (Treg) cells in an inflammatory and tumor setting suppresses the immune system, thus paving the way for oncogenesis. However, Treg cells also inhibit autoimmune inflammation. By contrast, cytotoxic T cells and T helper cells confer antitumor immunity and are associated with better prognosis in patients with cancer. Cytotoxic T cells inflict a direct cytotoxic effect on cells expressing oncogenic markers. Currently, several anti-inflammatory and antitumor therapies are under trials in which these immune cells are exploited. Adoptive cell transfer composed of tumor-infiltrating lymphocytes has been tried for the treatment of tumors after their ex vivo expansion. Mediators released by cells in a tumorigenic and inflammatory microenvironment cross talk with nearby cells, either promoting or inhibiting inflammation and cancer. Recently, several cytokine-based therapies are either being developed or are under trial to treat such types of manifestations. Monoclonal antibodies directed against TNF-α, VEGF, and IL-6 has shown promising results to ameliorate inflammation and cancer, while direct administration of IL-2 has been shown to cause tumor regression.

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The Microrchidia (MORC) family of ATPases are required for transposable element (TE) silencing and heterochromatin condensation in plants and animals, and C. elegans MORC-1 has been shown to topologically entrap and condense DNA. In Arabidopsis thaliana, mutation of MORCs has been shown to reactivate silent methylated genes and transposons and to decondense heterochromatic chromocenters, despite only minor changes in the maintenance of DNA methylation. Here we provide the first evidence localizing Arabidopsis MORC proteins to specific regions of chromatin and find that MORC4 and MORC7 are closely co-localized with sites of RNA-directed DNA methylation (RdDM). We further show that MORC7, when tethered to DNA by an artificial zinc finger, can facilitate the establishment of RdDM. Finally, we show that MORCs are required for the efficient RdDM mediated establishment of DNA methylation and silencing of a newly integrated FWA transgene, even though morc mutations have no effect on the maintenance of preexisting methylation at the endogenous FWA gene. We propose that MORCs function as a molecular tether in RdDM complexes to reinforce RdDM activity for methylation establishment. These findings have implications for MORC protein function in a variety of other eukaryotic organisms.

Continued oxidative stress can lead to chronic inflammation, which in turn could mediate most chronic diseases including cancer. Nuclear factor erythroid 2-related factor (Nrf2), a critical transcriptional activator for antioxidative responses, has envolved to be an attractive drug target for the treatment or prevention of human diseases. In the present study, we investigated the effects and mechanisms of betulin on Nrf2 activation and its involvement in the lipopolysaccharide (LPS)-triggered inflammatory system. In macrophages, betulin activated the Nrf2 signaling pathway and increased Nrf2-targeted antioxidant and detoxifying enzymes, including NADPH, quinine oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), γ-glutamyl cysteine synthetase catalytic subunit (GCLC) and modifier subunit (GCLM) in a dose and time dependent manner. Importantly, we found betulin-induced activation of Nrf2 is AMPK/AKT/GSK3β dependent, as pharmacologically inactivating AMPK blocked the activating effect of betulin on AKT, GSK3β and Nrf2. Furthermore, betulin attenuated LPS-induced inflammatory mediators (iNOS and COX-2) and MAPK inflammatory signaling pathway. The effect of betulin on HO-1 and NQO1 upregulation, iNOS and COX-2 the downregulation, and survival time extension was largely weakened when Nrf2 was depleted in vitro and in vivo. Our results demonstrate that the AMPK/AKT/Nrf2 pathways are essential for the anti-inflammatory effects of betulin in LPS-stimulated macrophages and endotoxin-shocked mice.