Cannabidiol modulates expression of type I IFN response genes and HIV infection in macrophages.

Cannabis (Cannabis sativa) is a widely used drug in the United States and the frequency of cannabis use is particularly high among people living with HIV (PLWH). One key component of cannabis, the non-psychotropic (-)-cannabidiol (CBD) exerts a wide variety of biological actions, including anticonvulsive, analgesic, and anti-inflammatory effects. However, the exact mechanism of action through which CBD affects the immune cell signaling remains poorly understood. Here we report that CBD modulates type I interferon responses in human macrophages. Transcriptomics analysis shows that CBD treatment significantly attenuates cGAS-STING-mediated activation of type I Interferon response genes (ISGs) in monocytic THP-1 cells. We further showed that CBD treatment effectively attenuates 2'3-cGAMP stimulation of ISGs in both THP-1 cells and primary human macrophages. Interestingly, CBD significantly upregulates expression of autophagy receptor p62/SQSTM1. p62 is critical for autophagy-mediated degradation of stimulated STING. We observed that CBD treated THP-1 cells have elevated autophagy activity. Upon 2'3'-cGAMP stimulation, CBD treated cells have rapid downregulation of phosphorylated-STING, leading to attenuated expression of ISGs. The CBD attenuation of ISGs is reduced in autophagy deficient THP-1 cells, suggesting that the effects of CBD on ISGs is partially mediated by autophagy induction. Lastly, CBD decreases ISGs expression upon HIV infection in THP-1 cells and human primary macrophages, leading to increased HIV RNA expression 24 hours after infection. However, long term culture with CBD in infected primary macrophages reduced HIV viral spread, suggesting potential dichotomous roles of CBD in HIV replication. Our study highlights the immune modulatory effects of CBD and the needs for additional studies on its effect on viral infection and inflammation.

Reconstructing the tumor architecture into organoids.

Cancer remains a leading health burden worldwide. One of the challenges hindering cancer therapy development is the substantial discrepancies between the existing cancer models and the tumor microenvironment (TME) of human patients. Constructing tumor organoids represents an emerging approach to recapitulate the pathophysiological features of the TME in vitro. Over the past decade, various approaches have been demonstrated to engineer tumor organoids as in vitro cancer models, such as incorporating multiple cellular populations, reconstructing biophysical and chemical traits, and even recapitulating structural features. In this review, we focus on engineering approaches for building tumor organoids, including biomaterial-based, microfabrication-assisted, and synthetic biology-facilitated strategies. Furthermore, we summarize the applications of engineered tumor organoids in basic cancer research, cancer drug discovery, and personalized medicine. We also discuss the challenges and future opportunities in using tumor organoids for broader applications.