Background: Dehydrodiisoeugenol (DEH), a novel lignan component extracted from nutmeg, which is the seed of Myristica fragrans Houtt, displays noticeable anti-inflammatory and anti-allergic effects in digestive system diseases. However, the mechanism of its anticancer activity in gastrointestinal cancer remains to be investigated. Methods: In this study, the anticancer effect of DEH on human colorectal cancer and its underlying mechanism were evaluated. Assays including MTT, EdU, Plate clone formation, Soft agar, Flow cytometry, Electron microscopy, Immunofluorescence and Western blotting were used in vitro. The CDX and PDX tumor xenograft models were used in vivo. Results: Our findings indicated that treatment with DEH arrested the cell cycle of colorectal cancer cells at the G1/S phase, leading to significant inhibition in cell growth. Moreover, DEH induced strong cellular autophagy, which could be inhibited through autophagic inhibitors, with a rction in the DEH-induced inhibition of cell growth in colorectal cancer cells. Further analysis indicated that DEH also induced endoplasmic reticulum (ER) stress and subsequently stimulated autophagy through the activation of PERK/eIF2α and IRE1α/XBP-1 s/CHOP pathways. Knockdown of PERK or IRE1α significantly decreased DEH-induced autophagy and retrieved cell viability in cells treated with DEH. Furthermore, DEH also exhibited significant anticancer activities in the CDX- and PDX-models. Conclusions: Collectively, our studies strongly suggest that DEH might be a potential anticancer agent against colorectal cancer by activating ER stress-induced inhibition of autophagy.

During the last few years, mitochondrial DNA has attained much attention as a modulator of immune responses. Due to common evolutionary origin, mitochondrial DNA shares various characteristic features with DNA of bacteria, as it consists of a remarkable number of unmethylated DNA as 2′-deoxyribose cytidine-phosphate-guanosine (CpG) islands. Due to this particular feature, mitochondrial DNA seems to be recognized as a pathogen-associated molecular pattern by the innate immune system. Under the normal physiological situation, mitochondrial DNA is enclosed in the double membrane structure of mitochondria. However, upon pathological conditions, it is usually released into the cytoplasm. Growing evidence suggests that this cytosolic mitochondrial DNA induces various innate immune signaling pathways involving NLRP3, toll-like receptor 9, and stimulator of interferon genes (STING) signaling, which participate in triggering downstream cascade and stimulating to produce effector molecules. Mitochondrial DNA is responsible for inflammatory diseases after stress and cellular damage. In addition, it is also involved in the anti-viral and anti-bacterial innate immunity. Thus, instead of entire mitochondrial importance in cellular metabolism and energy production, mitochondrial DNA seems to be essential in triggering innate anti-microbial immunity. Here, we describe existing knowledge on the involvement of mitochondrial DNA in the anti-microbial immunity by modulating the various immune signaling pathways.

Melanoma, the most aggressive and deadliest form of skin cancer, has attracted increased attention due to its increasing incidence worldwide. The Cortex Mori (CM) has long been used as a classical traditional Chinese medicine (TCM) to treat various diseases, including cancer. The bioactive components and underlying mechanisms, however, remain largely unknown. The current study aims to investigate the anti-melanoma effects of CM and potential mechanisms through combined network pharmacology and bioinformatic analyses, and validated by in vitro and in vivo experiments. We report here that CM has anti-melanoma activity both in vitro and in vivo. Furthermore, 25 bioactive compounds in CM were found to share 142 melanoma targets, and network pharmacology and enrichment analyses suggested that CM inhibits melanoma through multiple biological processes and signaling pathways, particularly the PI3K-AKT signaling inhibition and activation of apoptotic pathways, which were further confirmed by biochemical and histological examinations. Finally, partial CM-derived bioactive compounds were found to show anti-melanoma effects, validating the anti-melanoma potential of bioactive ingredients of CM. Taken together, these results reveal bioactive components and mechanisms of CM in inhibiting melanoma, providing them as potential anti-cancer natural products for the treatment of melanoma.