Varespladib mitigates acute liver injury via suppression of excessive mitophagy on Naja atra envenomed mice by inhibiting PLA2.

Snakebite envenomation often leads to severe visceral injuries, including acute liver injury (ALI). However, the toxicity mechanism remains unclear. Moreover, varespladib can directly inhibit phospholipase A2 (PLA2) in snake venom, but its protective effect on snakebite-induced ALI and the mechanism have not been clarified. Previous studies have shown that snake venom PLA2 leads to neuron cell death via reactive oxygen species (ROS), one of the initial factors related to the mitophagy pathway. The present study group also found that ROS accumulation occurred after Naja atra envenoming. Hematoxylin and eosin (H/E) staining and immunohistochemistry (IHC) were performed to identify the expression of inflammatory factors in the liver tissue, and flow cytometry and immunofluorescence were used to detect ROS levels and mitochondrial function. Immunofluorescence and western blotting were also used for detecting mitophagy pathway-related proteins. The results showed that N. atra bite induced ALI by activating mitophagy and inducing inflammation and that varespladib had a protective effect. Collectively, these results showed the pathological mechanism of ALI caused by N. atra bite and revealed the protective effect of varespladib.

A317491 relieved HIV gp120-associated neuropathic pain involved in P2X3 receptor in dorsal root ganglia.

Glycoprotein 120 (gp120) is an HIV envelope glycoprotein. Gp120 can directly stimulate the primary sensory afferent neurons and cause hyperalgesia. The P2X3 receptor in dorsal root ganglia (DRG) is involved in the transmission of pain. In this study, we aimed to explore the role of the P2X3 receptor in gp120-induced neuropathic pain. Our data showed that mechanical and thermal hyperalgesia in rats treated with gp120 were increased compared to those in the control group. The expression levels of the P2X3 mRNA and protein in rats treated with gp120 were higher than those in the control group. The P2X3 antagonist A317491 decreased mechanical hyperalgesia and thermal hyperalgesia and the up-regulated expression levels of P2X3 mRNA and protein in rats treated with gp120. A317491 decreased ERK1/2 phosphorylation levels in the gp120-treated rat DRG. In addition, P2X3 agonist α,ß-methylene ATP (α,ß-meATP)-activated currents in DRG neurons cultured with gp120 were higher than those in control neurons. The inhibitory effect of A317491 on α,ßme-ATP-induced currents in DRG neurons from the gp120-treated neurons was larger than that for control neurons. Molecular docking data showed that A317491 may be acted in the gp120 protein to inhibit the gp120 initiated the P2X3 activation, decrease the sensitizing DRG primary afferents and reduce the signal transmission of neuropathic pain in gp120-treated rats. Therefore, the inhibition of the P2X3 receptor in rat DRG neurons relieved gp120-induced mechanical hyperalgesia.

Ontogenic expression profiles and oxaliplatin regulation of leptin expression in mice dorsal root ganglion.

Leptin is widely distributed in many tissues, including the nervous system. However, the ontogeny of leptin expression in the dorsal root ganglion (DRG) is unclear. Recent studies have shown that leptin is involved in the regulation of neuropathic pain induced by nerve injury. Our previous results showed that exogenous leptin administration alleviated the pain behaviors induced by chronic constriction sciatic nerve injury. In the present study, the ontogenic expression of leptin was detected in the DRG of the mouse embryo at days 15.5 (E15.5), E17.5, and E19.5 of gestation and in the postnatal mouse at days 5 (P5), P15, and P25, and in the adult mouse. Leptin immunoreactivity and mRNA were not found in DRG at E15.5. The percentage of leptin immunopositive (leptin) neurons was about 27% at E17.5. It continued to increase to about 70% at P5. From P5 to P15, there was no significant change. The proportion of DRG neurons positive for leptin decreased after P15 and there were about 41% leptin neurons in adults. The expression profile of leptin mRNA is similar to leptin immunoreactivity. Oxaliplatin (OXA) is an effective platinum-based drug used as first-line chemotherapy for advanced colorectal cancer. However, it may induce neuropathic pain. In the current study, we found that the expression of leptin was increased in the lumbar 4-6 DRG of OXA-treated mice. These results indicate that leptin is involved in the regulation of DRG development and OXA-induced neuropathic pain.