Toll-Like Receptor 9 Is Required for Opioid-Induced Microglia Apoptosis

Opioids have been widely applied in clinics as one of the most potent pain relievers for centuries, but their abuse has deleterious physiological effects beyond addiction. However, the underlying mechanism by which microglia in response to opioids remains largely unknown. Here we show that morphine induces the expression of Toll-like receptor 9 (TLR9), a key mediator of innate immunity and inflammation. Interestingly, TLR9 deficiency significantly inhibited morphine-induced apoptosis in microglia. Similar results were obtained when endogenous TLR9 expression was suppressed by the TLR9 inhibitor CpGODN. Inhibition of p38 MAPK by its specific inhibitor SB203580 attenuated morphine-induced microglia apoptosis in wild type microglia. Morphine caused a dramatic decrease in Bcl-2 level but increase in Bax level in wild type microglia, but not in TLR9 deficient microglia. In addition, morphine treatment failed to induce an increased levels of phosphorylated p38 MAPK and MAP kinase kinase 3/6 (MKK3/6), the upstream MAPK kinase of p38 MAPK, in either TLR9 deficient or μ-opioid receptor (μOR) deficient primary microglia, suggesting an involvement of MAPK and μOR in morphine-mediated TLR9 signaling. Moreover, morphine-induced TLR9 expression and microglia apoptosis appears to require μOR. Collectively, these results reveal that opioids prime microglia to undergo apoptosis through TLR9 and μOR as well. Taken together, our data suggest that inhibition of TLR9 and/or blockage of μOR is capable of preventing opioid-induced brain damage

Toll-Like Receptor 9 Is Required for Opioid-Induced Microglia Apoptosis

Opioids have been widely applied in clinics as one of the most potent pain relievers for centuries, but their abuse has deleterious physiological effects beyond addiction. However, the underlying mechanism by which microglia in response to opioids remains largely unknown. Here we show that morphine induces the expression of Toll-like receptor 9 (TLR9), a key mediator of innate immunity and inflammation. Interestingly, TLR9 deficiency significantly inhibited morphine-induced apoptosis in microglia. Similar results were obtained when endogenous TLR9 expression was suppressed by the TLR9 inhibitor CpGODN. Inhibition of p38 MAPK by its specific inhibitor SB203580 attenuated morphine-induced microglia apoptosis in wild type microglia. Morphine caused a dramatic decrease in Bcl-2 level but increase in Bax level in wild type microglia, but not in TLR9 deficient microglia. In addition, morphine treatment failed to induce an increased levels of phosphorylated p38 MAPK and MAP kinase kinase 3/6 (MKK3/6), the upstream MAPK kinase of p38 MAPK, in either TLR9 deficient or µ-opioid receptor (µOR) deficient primary microglia, suggesting an involvement of MAPK and µOR in morphine-mediated TLR9 signaling. Moreover, morphine-induced TLR9 expression and microglia apoptosis appears to require μOR. Collectively, these results reveal that opioids prime microglia to undergo apoptosis through TLR9 and µOR as well. Taken together, our data suggest that inhibition of TLR9 and/or blockage of µOR is capable of preventing opioid-induced brain damage

Post-marketing surveillance for the safety of the 9-valent human papillomavirus vaccine: a retrospective real-world study in China

Background The 9-valent human papillomavirus (9vHPV) vaccine was introduced in China in 2018. This study was conducted to monitor the occurrence of new-onset autoimmune diseases (AIs) in Chinese women vaccinated with the 9vHPV vaccine and adverse pregnancy outcomes in infants born to mothers with inadvertent pregnancy exposure. Research design and methods Women who received the first dose of the 9vHPV vaccine at age 16–26 years in Ningbo between January 2019 and March 2021 were monitored in the Ningbo Regional Health Information Platform. New-onset cases of seven pre-specified AIs diagnosed within six months after vaccination were collected. Cases of stillbirth and 23 major congenital anomalies diagnosed within three months of birth in target infants were collected. Results A total of 102,670 doses of the 9vHPV vaccine were administered to 41,609 women who had received no other HPV vaccine. New-onset AIs were diagnosed in 36 women, comprising 21 Hashimoto’s, 11 Graves’, and 4 uveitis disease cases. Among 50 women with maternal vaccination exposure, no stillbirths were observed. One case of microtia was observed. Conclusions In this first post-marketing surveillance of the 9vHPV vaccine in China, no safety signals were identified when putting the results in context to published data

Three-Dimensional Nanoporous Polyethylene-Reinforced PVDF-HFP Separator Enabled by Dual-Solvent Hierarchical Gas Liberation for Ultrahigh-Rate Lithium Ion Batteries

High-power lithium ion batteries (LIBs) have extensive applications ranging from electronic devices to electric vehicles. The composition and structure of separators largely impact the rate performances of LIBs. Here, a three-dimensional (3D) nanoporous poly­(vinylidenefluoride-hexafluoropropylene) (PVDF-HFP)- polyethylene (PE) composite separator is obtained through solvent liberation. The composite separator owns a high ionic conductivity of 1.01 mS·cm lithium ion batteries (LIBs) have extensive applications ranging from electronic devices to electric vehicles. The composition and structure of separators largely impact the rate performances of LIBs. Here, a three-dimensional (3D) nanoporous poly­(^–1 at room temperature due to the high porosity up to 95.6% and the uniform 3D pore distribution. LiFePO₄/Li half-cells with the composite separator deliver record rate capacities of 97 mAh·g^–1 at 10 C and 57 mAh·g^–1 at 20 C. PE in the composite separator significantly enhances the mechanical strength and thermal stability of the separator. Theoretical calculations show that the difference in the absorption energy between acetone and NMP solvent on PVDF-HFP is the major driving force for the formation of the inter-island structure, which provides massive Li⁺ transport channels during high-rate battery cycling

Inhibition of p38 MAPK by SB203580 attenuates morphine-induced microglia apoptosis.

<p>WT microglial cells and TLR9 deficient microglial cells were pretreated with 10 µM SB203580 (SB) for 1 hr and then exposed to morphine at 10 µM for 24 hr. Apoptotic cells were determined as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0018190#pone-0018190-g003" target="_blank">Fig. 3</a>. (A). Representative light microscopic images showed TUNEL-positive microglia (red arrow head). Magnification 200×. Results represent mean ± SD from three independent experiments. * <i>p</i><0.01 compared with indicated groups. (B). Apoptotic cells were analyzed by flow cytometry. Three experiments were performed with similar results.</p