[신간의 별자리x] 우리/미술, 그리고 ‘슬픔의 박물관’

CA : A Cancer Journal for Clinicians

Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis after stroke

Autophagy is an intracellular bulk degradation system that is highly conserved in eukaryotes. The discovery of autophagy-related ('ATG') proteins in the 1990s greatly advanced the mechanistic understanding of autophagy and clarified the fact that autophagy serves important roles in various biological processes. In addition, studies have revealed other roles for the autophagic machinery beyond autophagy. In this Review, we introduce advances in the knowledge of the roles of autophagy and its components in immunity, including innate immunity, inflammatory responses and adaptive immunity.

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Autophagy and autophagy-related proteins in the immune system

Targeting calcium signaling in cancer therapy.

Nonresolving inflammation in the intestine predisposes individuals to the development of colitis-associated cancer (CAC). Inflammasomes are thought to mediate intestinal homeostasis, and their dysregulation contributes to inflammatory bowel diseases and CAC. However, few agents have been reported to reduce CAC by targeting inflammasomes. Here we show that the small molecule andrographolide (Andro) protects mice against azoxymethane/dextran sulfate sodium-induced colon carcinogenesis through inhibiting the NLRP3 inflammasome. Administration of Andro significantly attenuated colitis progression and tumor burden. Andro also inhibited NLRP3 inflammasome activation in macrophages both in vivo and in vitro, as indicated by reduced expression of cleaved CASP1, disruption of NLRP3-PYCARD-CASP1 complex assembly, and lower IL1B secretion. Importantly, Andro was found to trigger mitophagy in macrophages, leading to a reversed mitochondrial membrane potential collapse, which in turn inactivated the NLRP3 inflammasome. Moreover, downregulation of the PIK3CA-AKT1-MTOR-RPS6KB1 pathway accounted for Andro-induced autophagy. Finally, Andro-driven inhibition of the NLRP3 inflammasome and amelioration of murine models for colitis and CAC were significantly blocked by BECN1 knockdown, or by various autophagy inhibitors. Taken together, our findings demonstrate that mitophagy-mediated NLRP3 inflammasome inhibition by Andro is responsible for the prevention of CAC. Our data may help guide decisions regarding the use of Andro in patients with inflammatory bowel diseases, which ultimately reduces the risk of CAC.

Small molecule-driven mitophagy-mediated NLRP3 inflammasome inhibition is responsible for the prevention of colitis-associated cancer

Plant cyclopeptide RA-V kills human breast cancer cells by inducing mitochondria-mediated apoptosis through blocking PDK1–AKT interaction

Background IL-10 is known as a negative regulator for inflammatory diseases, including contact dermatitis. However, only a few drug candidates are reported to induce endogenous IL-10. Objective We sought to elucidate a new mechanism underlying the immunosuppressive properties of astilbin through negative cytokine regulation in comparison with the effective pattern with cyclosporin A. Methods Contact hypersensitivity was induced in mice with picryl chloride. Lymph node cells were isolated for adoptive transfer and cytokine assays. Results Astilbin significantly inhibited contact hypersensitivity when given in the elicitation phase but not in the sensitization phase, whereas cyclosporin A inhibited both phases. Lymph node cells from donor mice administered astilbin failed to adoptively transfer the hypersensitivity. Astilbin in vivo remarkably induced IL-10 expression in lymph node cells at an earlier time and decreased TNF-α and IFN-γ expression at a later time. Furthermore, the in vivo neutralization of IL-10 significantly impaired the effect of astilbin on contact hypersensitivity. In the isolated lymphocytes sensitized with picryl chloride in vivo and challenged with trinitrobenzene–sulfonic acid in vitro , astilbin did not affect the cell proliferation but modulated the above cytokine profiles as its in vivo effect in a concentration-dependent manner and furthermore significantly enhanced the expressions of suppressor of cytokine signaling 1 and 3. On the other hand, cyclosporin A strongly inhibited proinflammatory cytokine production but influenced neither IL-10 nor downstream suppressor of cytokine signaling 1 and 3 expression. Conclusion Astilbin alleviates contact hypersensitivity through a unique mechanism involving a negative cytokine regulation through stimulating IL-10, which is distinct from the immunosuppressant cyclosporin A.

https://www.jacionline.org/article/S0091-6749(05)01918-4/pdf

Astilbin inhibits contact hypersensitivity through negative cytokine regulation distinct from cyclosporin A.

The side effects of current immunosuppressive drugs have impeded the development of therapies for immune diseases. Selective regulation of STAT signaling is an attractive strategy for treating immune disorders. In this study, we used a small-molecule compound to explore possible means of targeting STAT1 for the treatment of Th1-mediated inflammation. Selective regulation of STAT1 signaling in T cells from C57BL/6 mice was accomplished using fusaruside, a small-molecule compound that triggers the tyrosine phosphorylation of Src homology 2-containing protein tyrosine phosphatase 2 (SHP-2). The interaction of tyrosine phosphorylated SHP-2 (pY-SHP-2) with cytosolic STAT1 prevented the recruitment of STAT1 to IFN-γR and specifically inhibited STAT1 signaling, resulting in a reduction in Th1 cytokine production and an improvement in 2, 4, 6-trinitrobenzene sulfonic acid-induced colitis in mice. Blocking the pY-SHP-2-STAT1 interaction, with SHP-2 inhibitor NSC-87877 or using T cells from conditional SHP-2 knockout mice, reversed the effects of fusaruside, resulting in STAT1 activation and worsened colitis. The fusaruside-induced ability of pY-SHP-2 to selectively sequestrate STAT1 from recruitment to the receptor is independent of its function as a phosphatase, demonstrating a novel role for SHP-2 in regulating both STAT1 signaling and Th1-type immune responses. These findings could lead to increased options for the treatment of Crohn's disease and other Th1-mediated inflammatory diseases.

/pdf/selective-sequestration-of-stat1-in-the-cytoplasm-via-54eyfmci1v.pdf

Selective Sequestration of STAT1 in the Cytoplasm via Phosphorylated SHP-2 Ameliorates Murine Experimental Colitis

The p38 MAPK signaling pathway plays a pivotal role in inflammation. Targeting p38 MAPK may be a potential strategy for the treatment of inflammatory diseases. In the present study, we show that a novel chromone derivative, DCO-6, significantly reduced lipopolysaccharide (LPS)-induced production of nitric oxide, IL-1β and IL-6, decreased the levels of iNOS, IL-1β and IL-6 mRNA expression in both RAW264.7 cells and mouse primary peritoneal macrophages, and inhibited LPS-induced activation of p38 MAPK but not of JNK, ERK. Moreover, DCO-6 specifically inhibited TLR4-dependent p38 activation without directly inhibiting its kinase activity. LPS-induced production of intracellular reactive oxygen species (ROS) was remarkably impaired by DCO-6, which disrupted the formation of the TRAF6-ASK1 complex. Administering DCO-6 significantly protected mice from LPS-induced septic shock in parallel with the inhibition of p38 activation and ROS production. Our results indicate that DCO-6 showed anti-inflammatory properties through inhibition of ROS-dependent activation of TRAF6-ASK1-p38 pathway. Blockade of the upstream events required for p38 MAPK action by DCO-6 may provide a new therapeutic option in the treatment of inflammatory diseases.

/pdf/a-novel-chromone-derivative-with-anti-inflammatory-property-4p9rqzhkvu.pdf

Xuefeng Wu

Papers

Small molecule-driven mitophagy-mediated NLRP3 inflammasome inhibition is responsible for the prevention of colitis-associated cancer

Plant cyclopeptide RA-V kills human breast cancer cells by inducing mitochondria-mediated apoptosis through blocking PDK1–AKT interaction

Astilbin inhibits contact hypersensitivity through negative cytokine regulation distinct from cyclosporin A.

Selective Sequestration of STAT1 in the Cytoplasm via Phosphorylated SHP-2 Ameliorates Murine Experimental Colitis

A Novel Chromone Derivative with Anti-Inflammatory Property via Inhibition of ROS-Dependent Activation of TRAF6-ASK1-p38 Pathway