cardamonin and Colitis

Necroptosis, a new form of programmed cell death, is involved in the pathogenesis of ulcerative colitis (UC). Inhibition of necroptosis represents an attractive strategy for UC therapy. Herein, cardamonin, a natural chalcone isolated from Zingiberaceae family, was firstly identified as a potent necroptosis inhibitor. In vitro, cardamonin significantly inhibited necroptosis in TNF-α plus Smac mimetic and z-VAD-FMK (TSZ)-, cycloheximide plus TZ (TCZ)-, or lipopolysaccharide plus SZ (LSZ)-stimulated HT29, L929, or RAW264.7 cell lines. Furthermore, TSZ-induced elevated population of necrotic cells, release of LDH and HMGB1 also could be inhibited by cardamonin in HT29 cells. Cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) assay combined with molecular docking demonstrated that cardamonin interacted with RIPK1/3. Furthermore, cardamonin blocked the phosphorylation of RIPK1/3, thereby disrupting RIPK1-RIPK3 necrosome formation and MLKL phosphorylation. In vivo, orally administration of cardamonin attenuated dextran sulfate sodium (DSS)-induced colitis, which mainly manifested as mitigated intestinal barrier damage, suppressed necroinflammation, and reduced phosphorylation of MLKL. Taken together, our findings revealed that dietary cardamonin is a novel necroptosis inhibitor and has great potential for UC therapy by targeting RIPK1/3 kinases.

Topics: Chalcone; Chalcones; Colitis; Colitis, Ulcerative; Dextran Sulfate; Humans; Molecular Docking Simulation; Necroptosis; Receptor-Interacting Protein Serine-Threonine Kinases

Cardamonin is a naturally occurring chalcone, majorly from the Zingiberaceae family, which includes a wide range of spices from India. Herein, we investigated the anti-inflammatory property of cardamonin using different in vitro and in vivo systems. In RAW 264.7 cells, treatment with cardamonin showed a reduced nitrous oxide production without affecting the cell viability and decreased the expression of iNOS, TNF-α, and IL-6, and inhibited NF-kB signaling which emphasizes the role of cardamonin as an anti-inflammatory molecule. In a mouse model of dextran sodium sulfate (DSS)-induced colitis, cardamonin treatment protected the mice from colitis. Subsequently, we evaluated the therapeutic potential of this chalcone in a colitis-associated colon cancer model. We performed microRNA profiling in the different groups and observed that cardamonin modulates miRNA expression, thereby inhibiting tumor formation. Together, our findings indicate that cardamonin has the potential to be considered for future therapy against colorectal cancer.

Topics: Animals; Anti-Inflammatory Agents; Azoxymethane; Cell Proliferation; Cell Survival; Chalcones; Colitis; Colorectal Neoplasms; Dextran Sulfate; Disease Models, Animal; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Mice; MicroRNAs; Nitrous Oxide; RAW 264.7 Cells; Sequence Analysis, RNA; Signal Transduction; THP-1 Cells

Cardamonin (CAD) is a member of the aromatic ketones family that is closely related to anti-bacterial, anti-inflammatory and anti-cancer effects. Nevertheless, the physiological function of cardamonin in chronic colitis and colon cancer has not been well verified. We found that cardamonin treatment alleviates intestinal disease, including recurring colitis and colitis-associated tumorigenesis, along with the reduced secretion of IL-1β and TNF-α. Further, cardamonin inhibits cell viability and inflammation factors of colorectal cancer cells in vitro. In tumor cells, the inhibitory effect of cardamonin on cell proliferation is closely related to decreased phosphorylation of signal transducers and activators of transcription (STAT) signals. This study reveals the crucial role of cardamonin in sustaining gastrointestinal homeostasis and offers a new strategy for colon cancer therapy.

Topics: Animals; Carcinogenesis; Cell Survival; Chalcones; Colitis; Colon; Colonic Neoplasms; Dextran Sulfate; Disease Models, Animal; HT29 Cells; Humans; Inflammation; Interleukin-1beta; Neoplasm Recurrence, Local; NF-kappa B; Signal Transduction; STAT Transcription Factors; Tumor Necrosis Factor-alpha

Cardamonin is a naturally occurring chalcone with strong anti-inflammatory activity. However, the direct effect of cardamonin on intestinal inflammation remains elusive. In the present study, we found that cardamonin markedly ameliorated dextran sulfate sodium-induced mouse body weight loss, diarrhea, colon shortening, spleen swelling, and histological damage, which correlated with a decline in the activity of myeloperoxidase and the production of nitric oxide, tumor necrosis factor-α and interleukin-6 in the colon. The upregulation of toll-like receptor 4 after dextran sulfate sodium treatment was associated with an increase in the activation of myeloid differentiation factor 88, interleukin-1 receptor-associated kinase-1, nuclear factor-κB (NF-κB) p65, inhibitor κBα, and inhibitor κB kinase-α/β, as well as the mitogen-activated protein kinase molecules of extracellular signal-regulated kinase and c-Jun NH2-terminal kinase, and this upregulation was reversed by cardamonin administration. Moreover, cardamonin blocked the nuclear translocation of NF-κB p65, inhibited NF-κB-luciferase activity, and downregulated NF-κB target genes expression. The present study clearly demonstrates a beneficial effect of cardamonin on experimental inflammatory bowel disease via a mechanism associated with suppression of toll-like receptor 4 expression and inactivation of NF-κB and mitogen-activated protein kinase pathways. This study may give insight into the further evaluation of the therapeutic potential of cardamonin or its derivatives for human inflammatory bowel disease.

Topics: Animals; Anti-Inflammatory Agents; Cell Line; Chalcones; Colitis; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Female; Fluorescent Antibody Technique; Genes, Reporter; Humans; Immunoblotting; Interleukin-1 Receptor-Associated Kinases; Mice; Mice, Inbred C57BL; NF-kappa B; Polymerase Chain Reaction; Signal Transduction; Toll-Like Receptor 4