In face of the everlasting battle toward COVID-19 and the rapid evolution of SARS-CoV-2, no specific and effective drugs for treating this disease have been reported until today. Angiotensin-converting enzyme 2 (ACE2), a receptor of SARS-CoV-2, mediates the virus infection by binding to spike protein. Although ACE2 is expressed in the lung, kidney, and intestine, its expressing levels are rather low, especially in the lung. Considering the great infectivity of COVID-19, we speculate that SARS-CoV-2 may depend on other routes to facilitate its infection. Here, we first discover an interaction between host cell receptor CD147 and SARS-CoV-2 spike protein. The loss of CD147 or blocking CD147 in Vero E6 and BEAS-2B cell lines by anti-CD147 antibody, Meplazumab, inhibits SARS-CoV-2 amplification. Expression of human CD147 allows virus entry into non-susceptible BHK-21 cells, which can be neutralized by CD147 extracellular fragment. Viral loads are detectable in the lungs of human CD147 (hCD147) mice infected with SARS-CoV-2, but not in those of virus-infected wild type mice. Interestingly, virions are observed in lymphocytes of lung tissue from a COVID-19 patient. Human T cells with a property of ACE2 natural deficiency can be infected with SARS-CoV-2 pseudovirus in a dose-dependent manner, which is specifically inhibited by Meplazumab. Furthermore, CD147 mediates virus entering host cells by endocytosis. Together, our study reveals a novel virus entry route, CD147-spike protein, which provides an important target for developing specific and effective drug against COVID-19.

The dorsal medial prefrontal cortex (dmPFC) has been recognized as a key cortical area for nociceptive modulation. However, the underlying neural pathway and the function of specific cell types remain largely unclear. Here, we showed that lesions of the dmPFC induced an algesic and anxious state. By using multiple tracing methods including rabies-based transsynaptic tracing method, an excitatory descending neural pathway from the dmPFC to the ventrolateral periaqueductal gray (vlPAG) was outlined. Specific activation of the dmPFC-vlPAG neural pathway by an optogenetic manipulation, produced analgesic and anxiolytic effects in a chronic pain mice model. Inhibitory neurons in the dmPFC were specifically activated by using a chemogenetic approach, which logically produced an algesic and anxious state under both normal and chronic pain conditions. Antagonists of GABAAR or mGluR1 were applied to the dmPFC, which produced analgesic and anxiolytic effects. In summary, the present results suggest that the dmPFC-vlPAG neural pathway might participate in the maintenance of pain thresholds and anxiolytic behaviors under normal conditions, while silencing or suppressing the dmPFC-vlPAG pathway might be involved in the initial stages and maintenance of chronic pain and the emergence of anxiety-like behaviors.

The probability of suffering the mood disorder depression is up to 30% in women and 15% in men during their life span. Pharmacological options for depression are limited: conventional antidepressants have low efficacy and a delayed onset of action (several weeks). Here we investigate the antidepressant actions of inhibitors of monoacylglycerol lipase (MAGL), the major degradative enzyme of the endocannabinoid 2-arachidonoylglycerol. A low-dose of MAGL inhibitors produces antidepressant effects on acute stress-exposed mice, through glutamatergic synaptic long-term depression (LTD), without significant effects on chronic corticosterone-exposed mice. In contrast, a high-dose of MAGL inhibitors produces pro- or antidepressant effects on acute stress- or chronic corticosterone-exposed mice, respectively, through GABAergic synaptic disinhibition. In the hippocampus, in vivo inhibition of MAGL induces a CB1 cannabinoid receptor (CB1R)-dependent suppression of inhibitory GABAergic synapses and an in vivo LTD of excitatory glutamatergic synapses. LTD induction requires CB1R in astroglial cells (but not in GABAergic or glutamatergic neurons) and postsynaptic glutamate receptors. The conventional antidepressant fluoxetine produces rapid or delayed antidepressant effects in acute stress- or chronic corticosterone-exposed mice, respectively. We propose that depression-like behavior of animals in response to acute stress is the normal behavioral response, and thus, MAGL inhibitors, which produce antidepressant effects in chronic corticosterone-exposed animals through GABAergic synaptic disinhibition, represent a new class of rapidly-acting and long-lasting antidepressants.

No abstract

This study was designed to investigate the tumor-inhibitory effects of quercetin (Que) and its water-soluble metabolites, quercetin-3'-sulfate (Q3'S) and quercetin-3-glucuronide (Q3G), as well as to make the molecular mechanism and structure-antitumor relationship clear. It was found that Que, Q3'S, and Q3G could inhibit the growth of human breast cancer MCF-7 cells in a dose-dependent manner, with the IC values of 23.1, 27.6, and 73.2 μM, respectively, and their anticancer effect was ranked as Que > Q3'S > Q3G. Furthermore, flow cytometric assay revealed that Que, Q3'S, and Q3G mediated the cell-cycle arrest principally at the S phase and decreased the number of G0/G1 and G2/M after a 48 h treatment with human breast MCF-7 cells. Moreover, it was found that 70.8%, 58.2%, and 48.0% of MCF-7 cancer cells entered the early phase of apoptosis when treated with 100 μM Que, Q3'S, and Q3G for 48 h, respectively. In addition, induction of apoptosis by Que, Q3'S, and Q3G was accompanied by marginal generation of intracellular reactive oxygen species (ROS) in the MCF-7 cancer cells. Overall, these results demonstrate that Que, Q3'S, and Q3G possess strong antitumor effects through induction of an ROS-dependent apoptosis pathway in MCF-7 cells.