Odor-preferences are usually influenced by life experiences. However, the neural circuit mechanisms remain unclear. The medial olfactory tubercle (mOT) is involved in both reward and olfaction, whereas the ventral tegmental area (VTA) dopaminergic (DAergic) neurons are considered to be engaged in reward and motivation. Here, we found that the VTA (DAergic)-mOT pathway could be activated by different types of naturalistic rewards as well as odors in DAT-cre mice. Optogenetic activation of the VTA-mOT DAergic fibers was able to elicit preferences for space, location and neutral odor, while pharmacological blockade of the dopamine receptors in the mOT fully prevented the odor-preference formation. Furthermore, inactivation of the mOT-projecting VTA DAergic neurons eliminated the previously formed odor-preference and strongly affected the Go-no go learning efficiency. In summary, our results revealed that the VTA (DAergic)-mOT pathway mediates a variety of naturalistic reward processes and different types of preferences including odor-preference in mice.

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Six new pairs of bibenzyl-based meroterpenoid enantiomers, (±)-rasumatranin A-D (1-4) and (±)-radulanin M and N (5 and 6), and six known compounds were isolated from the adnascent Chinese liverwort, Radula sumatrana. Their structures were elucidated based on spectroscopic data and chiral phase HPLC-ECD analyses. The structures of 1 and 7 were also confirmed by single-crystal X-ray diffraction analysis. Cytotoxicity tests of the isolated compounds showed that 6-hydroxy-3-methyl-8-phenylethylbenzo[b]oxepin-5-one (8) showed activity against the human cancer cell lines MCF-7, PC-3, and SMMC-7721, with IC values of 3.86, 6.60, and 3.58 μM, respectively, and induced MCF-7 cell death through a mitochondria-mediated apoptosis pathway.

Reactive oxygen species (ROS) induction is an effective mechanism to kill cancer cells for many chemotherapeutics, while resettled redox homeostasis induced by the anticancer drugs will promote cancer chemoresistance. Natural ent -kaurane diterpenoids have been found to bind glutathione (GSH) and sulfhydryl group in antioxidant enzymes covalently, which leads to the destruction of intracellular redox homeostasis. Therefore, redox resetting destruction by ent -kaurane diterpenoids may emerge as a viable strategy for cancer therapy. In this study, we isolated 30 ent -kaurane diterpenoids including 20 new samples from Chinese liverworts Jungermannia tetragona Lindenb and studied their specific targets and possible application in cancer drug resistance through redox resetting destruction. 11 β -hydroxy- ent -16-kaurene-15-one ( 23 ) possessed strong inhibitory activity against several cancer cell lines. Moreover, compound 23 induced both apoptosis and ferroptosis through increasing cellular ROS levels in HepG2 cells. ROS accumulation induced by compound 23 was caused by inhibition of antioxidant systems through targeting peroxiredoxin I/II (Prdx I/II) and depletion of GSH. Furthermore, compound 23 sensitized cisplatin (CDDP)-resistant A549/CDDP cancer cells in vitro and in vivo by inducing apoptosis and ferroptosis. Thus, the ent -kaurane derivative showed potential application for sensitizing CDDP resistance by redox resetting destruction through dual inhibition of Prdx I/II and GSH in cancer chemotherapy.