SLC38A9 regulates SARS-CoV-2 viral entry.

SARS-CoV-2 viral entry into host cells depends on the cleavage of spike (S) protein into S1 and S2 proteins. Such proteolytic cleavage by furin results in the exposure of a multibasic motif on S1, which is critical for SARS-CoV-2 viral infection and transmission; however, how such a multibasic motif contributes to the infection of SARS-CoV-2 remains elusive. Here, we demonstrate that the multibasic motif on S1 is critical for its interaction with SLC38A9, an endolysosome-resident arginine sensor. SLC38A9 knockdown prevents S1-induced endolysosome de-acidification and blocks the S protein-mediated entry of pseudo-SARS-CoV-2 in Calu-3, U87MG, Caco-2, and A549 cells. Our findings provide a novel mechanism in regulating SARS-CoV-2 viral entry; S1 present in endolysosome lumen could interact with SLC38A9, which mediates S1-induced endolysosome de-acidification and dysfunction, facilitating the escape of SARS-CoV-2 from endolysosomes and enhancing viral entry.

Activation of V1a vasopressin receptors excite subicular pyramidal neurons by activating TRPV1 and depressing GIRK channels.

Arginine vasopressin (AVP) is a nonapeptide that serves as a neuromodulator in the brain and a hormone in the periphery that regulates water homeostasis and vasoconstriction. The subiculum is the major output region of the hippocampus and an integral component in the networks that processes sensory and motor cues to form a cognitive map encoding spatial, contextual, and emotional information. Whereas the subiculum expresses high densities of AVP-binding sites and AVP has been shown to increase the synaptic excitability of subicular pyramidal neurons, the underlying cellular and molecular mechanisms have not been determined. We found that activation of V1a receptors increased the excitability of subicular pyramidal neurons via activation of TRPV1 channels and depression of the GIRK channels. V1a receptor-induced excitation of subicular pyramidal neurons required the function of phospholipase Cß, but was independent of intracellular Ca2+ release. Protein kinase C was responsible for AVP-mediated depression of GIRK channels, whereas degradation of phosphatidylinositol 4,5-bisphosphate was involved in V1a receptor-elicited activation of TRPV1 channels. Our results may provide one of the cellular and molecular mechanisms to explain the physiological functions of AVP in the brain.

Edaravone decreases paraquat toxicity in a549 cells and lung isolated mitochondria.

Edaravone, an antioxidant and radical scavenger, showed protective effects against oxidative stress-like condition. Paraquat (PQ) is toxic herbicide considerable evidence suggests that oxidative stress and mitochondrial dysfunction contribute to PQ toxicity. In this study, protective effect of edaravone against PQ induced toxicity and reactive oxygen species (ROS) generation in A549 cells and lung isolated mitochondria were evaluated. A549 cells and lung isolated mitochondria were divided into control group, PQ group, edaravone group and PQ plus edaravone-pretreated group. Cellular and mitochondrial viability assayed using MTT test and ROS generations in both cellular and mitochondrial fraction were determined by fluorometry using DCFH-DA as indicator. Our results showed that edaravone (5-100 µM) prevented PQ (500 µM) induced cytotoxicity in A549 cells that the best protective effect was observed at concentration of 50 µM of edaravone. In addition, PQ-induced ROS generation in A549 cells significantly inhibited by edaravone. Moreover, PQ decreased mitochondria viability and also increased ROS generation in lung isolated mitochondria that edaravone (25-400 µM) markedly inhibited these toxic effects. In overall, the results of this study suggest that lung mitochondria maintenance is essential for maintaining PQt cytotoxicity and Edaravone is a protective drug against PQ toxicity in-vitro.