| 1 | A distinct D1-MSN subpopulation down-regulates dopamine to promote negative emotional state显示文摘Dopamine(DA)level in the nucleus accumbens(NAc)is critical for reward and aversion encoding.DA released from the ventral mesencephalon(VM)DAergic neurons increases the excitability of VM-projecting D1-dopamine receptor-expressing medium spiny neurons(D1-MSNs)in the NAc to enhance DA release and augment rewards.However,how such a DA positive feedback loop is regulated to maintain DA homeostasis and reward-aversion balance remains elusive.Here we report that the ventral pallidum(VP)projection of NAc D1-MSNs(D1^(NAc-VP))is inhibited by rewarding stimuli and activated by aversive stimuli.In contrast to the VM projection of D1-MSN(D1^(NAc-VM)),activation of D1^(NAc-VP) projection induces aversion,but not reward.D1^(NAc-VP) MSNs are distinct from the D1^(NAc-VM) MSNs,which exhibit conventional functions of D1-MSNs.Activation of D1^(NAc-VP) projection stimulates VM GABAergic transmission,inhibits VM DAergic neurons,and reduces DA release into the NAc.Thus,D1^(NAc-VP) and D1^(NAc-VM) MSNs cooperatively control NAc dopamine balance and reward-aversion states. | Zhiyuan Liu Qiumin Le Yanbo Lv Xi Chen Jian Cui Yiming Zhou Deqin Cheng Chaonan Ma Xiujuan Su Lei Xiao Ruyi Yang Jiayi Zhang Lan Ma Xing Liu | 2022 | Cell Research2022，32，2： | 2 |
| 2 | Anticarin-β shows a promising antiosteosarcoma effect by specifically inhibiting CCT4 to impair proteostasis显示文摘Unlike healthy, non-transformed cells, the proteostasis network of cancer cells is taxed to produce proteins involved in tumor development. Cancer cells have a higher dependency on molecular chaperones to maintain proteostasis. The chaperonin T-complex protein ring complex(TRiC) contains eight paralogous subunits(CCT1-8), and assists the folding of as many as 10% of cytosolic proteome.TRiC is essential for the progression of some cancers, but the roles of TRiC subunits in osteosarcoma remain to be explored. Here, we show that CCT4/TRiC is significantly correlated in human osteosarcoma,and plays a critical role in osteosarcoma cell survival. We identify a compound anticarin-β that can specifically bind to and inhibit CCT4. Anticarin-β shows higher selectivity in cancer cells than in normal cells. Mechanistically, anticarin-β potently impedes CCT4-mediated STAT3 maturation. Anticarin-β displays remarkable antitumor efficacy in orthotopic and patient-derived xenograft models of osteosarcoma.Collectively, our data uncover a key role of CCT4 in osteosarcoma, and propose a promising treatment strategy for osteosarcoma by disrupting CCT4 and proteostasis. | Gan Wang Min Zhang Ping Meng Chengbo Long Xiaodong Luo Xingwei Yang Yunfei Wang Zhiye Zhang James Mwangi Peter Muiruri Kamau Zhi Daic Zunfu Ke Yi Zhang Wenlin Chen Xudong Zhao Fei Ge Qiumin Lv Mingqiang Rong Dongsheng Li Yang Jin Xia Sheng Ren Lai | 2022 | Acta Pharmaceutica Sinica B2022，12，5： | 1 |
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