Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to have devastating consequences worldwide. Recently, great efforts have been made to identify SARS-CoV-2 host factors, but the regulatory mechanisms of these host molecules, as well as the virus per se, remain elusive. Here we report a role of RNA G-quadruplex (RG4) in SARS-CoV-2 infection. Combining bioinformatics, biochemical and biophysical assays, we demonstrate the presence of RG4s in both SARS-CoV-2 genome and host factors. The biological and pathological importance of these RG4s is then exemplified by a canonical 3-quartet RG4 within Tmprss2, which can inhibit Tmprss2 translation and prevent SARS-CoV-2 entry. Intriguingly, G-quadruplex (G4)-specific stabilizers attenuate SARS-CoV-2 infection in pseudovirus cell systems and mouse models. Consistently, the protein level of TMPRSS2 is increased in lungs of COVID-19 patients. Our findings reveal a previously unknown mechanism underlying SARS-CoV-2 infection and suggest RG4 as a potential target for COVID-19 prevention and treatment.

Plant-derived extracellular vesicles (PDEVs) are nanoscale vesicles released from plant cells into the extracellular space.

5‐Hydroxytryptamine (5‐HT), a neurotransmitter and vasoactive factor, has been reported to promote proliferation of serum‐deprived hepatocellular carcinoma (HCC) cells but the detailed intracellular mechanism is unknown. As Wnt/β‐catenin signalling is highly dysregulated in a majority of HCC, this study explored the regulation of Wnt/β‐catenin signalling by 5‐HT. The expression of various 5‐HT receptors was studied by quantitative real‐time polymerase chain reaction (qPCR) in HCC cell lines as well as in 33 pairs of HCC tumours and corresponding adjacent non‐tumour tissues. Receptors 5‐HT1D (21/33, 63.6%), 5‐HT2B (12/33, 36.4%) and 5‐HT7 (15/33, 45.4%) were overexpressed whereas receptors 5‐HT2A (17/33, 51.5%) and 5‐HT5 (30/33, 90.1%) were reduced in HCC tumour tissues. In vitro data suggests 5‐HT increased total β‐catenin, active β‐catenin and decreased phosphorylated β‐catenin protein levels in serum deprived HuH‐7 and HepG2 cells compared to control cells under serum free medium without 5‐HT. Activation of Wnt/β‐catenin signalling was evidenced by increased expression of β‐catenin downstream target genes, Axin2, cyclin D1, dickoppf‐1 (DKK1) and glutamine synthetase (GS) by qPCR in serum‐deprived HCC cell lines treated with 5‐HT. Additionally, biochemical analysis revealed 5‐HT disrupted Axin1/β‐catenin interaction, a critical step in β‐catenin phosphorylation. Increased Wnt/β‐catenin activity was attenuated by antagonist of receptor 5‐HT7 (SB‐258719) in HCC cell lines and patient‐derived primary tumour tissues in the presence of 5‐HT. SB‐258719 also reduced tumour growth in vivo. This study provides evidence of Wnt/β‐catenin signalling activation by 5‐HT and may represent a potential therapeutic target for hepatocarcinogenesis.

The Akt/mTORC1 pathway plays a central role in the activation of Warburg effect in cancer. Here, we present for the first time that halofuginone (HF) treatment inhibits colorectal cancer (CRC) growth both in vitro and in vivo through regulation of Akt/mTORC1 signaling pathway. Halofuginone treatment of human CRC cells inhibited cell proliferation, induced the generation of reactive oxygen species and apoptosis. As expected, reduced level of NADPH was also observed, at least in part due to inactivation of glucose-6-phosphate dehydrogenase in pentose phosphate pathway upon HF treatment. Given these findings, we further investigated metabolic regulation of HF through Akt/mTORC1-mediated aerobic glycolysis and found that HF downregulated Akt/mTORC1 signaling pathway. Moreover, metabolomics delineated the slower rates in both glycolytic flux and glucose-derived tricarboxylic acid cycle flux. Meanwhile, both glucose transporter GLUT1 and hexokinase-2 in glycolysis were suppressed in CRC cells upon HF treatment, to support our notion that HF regulates Akt/mTORC1 signaling pathway to dampen glucose uptake and glycolysis in CRC cells. Furthermore, HF retarded tumor growth in nude mice inoculated with HCT116 cells, showing the anticancer activity of HF through metabolic regulation of Akt/mTORC1 in CRC.

Halofuginone and artemisinin synergistically arrest cancer cells at the G1/G0 phase by upregulating p21 Cip1 and p27 Kip1