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Antiviral Effects of Menthol on Coxsackievirus B.
薄荷醇对柯萨奇 B 病毒的抗病毒作用
- 影响因子:4.03
- DOI:10.3390/v12040373
- 作者列表:"Taylor DJR","Hamid SM","Andres AM","Saadaeijahromi H","Piplani H","Germano JF","Song Y","Sawaged S","Feuer R","Pandol SJ","Sin J
- 发表时间:2020-03-28
Abstract
Coxsackievirus B (CVB) is a common human enterovirus that causes systemic infection but specifically replicates to high titers in the pancreas. It was reported that certain viruses induce mitochondrial fission to support infection. We documented that CVB triggers mitochondrial fission and blocking mitochondrial fission limits infection. The transient receptor potential channels have been implicated in regulating mitochondrial dynamics; namely, the heat and capsaicin receptor transient receptor potential cation channel subfamily V member 1 (TRPV1) contributes to mitochondrial depolarization and fission. When we transiently warmed HeLa cells to 39 °C prior to CVB exposure, infection was heightened, whereas cooling cells to 25 °C reduced infection. Inducing "cold" by stimulating transient receptor potential cation channel subfamily M member 8 (TRPM8) with menthol led to reduced infection and also resulted in lower levels of mitochondrial fission during infection. Additionally, menthol stabilized levels of mitochondrial antiviral signaling (MAVS) which is known to be tied to mitochondrial dynamics. Taken together, this highlights a novel pathway wherein CVB relies on TRPV1 to initiate proviral mitochondrial fission, which may contribute to the disruption of antiviral immunity. TRPM8 has been shown to antagonize TRPV1, and thus we hypothesize that stimulating TRPM8 blocks TRPV1-mediated mitochondrial fragmentation following CVB exposure and attenuates infection.
摘要
柯萨奇 B 病毒 (Coxsackievirus B,CVB) 是一种常见的人类肠病毒,可引起全身性感染,但在胰腺中特异性复制为高滴度。据报道,某些病毒诱导线粒体分裂以支持感染。我们记录了 CVB 触发线粒体分裂并阻断线粒体裂变极限感染。瞬时受体电位通道参与调节线粒体动力学; 即热和辣椒素受体瞬时受体电位阳离子通道亚家族 V 成员 1 (TRPV1) 有助于线粒体去极化和分裂。当我们在 CVB 暴露前将 HeLa 细胞短暂加热至 39 ℃ 时,感染加剧,而将细胞冷却至 25 ℃ 则减少感染。用薄荷醇刺激瞬时受体电位阳离子通道亚家族 M 成员 8 (TRPM8) 诱导 “冷” 导致感染减少,也导致感染过程中线粒体分裂水平降低。此外,薄荷醇稳定了已知与线粒体动力学相关的线粒体抗病毒信号 (MAVS) 的水平。总之,这突出了一个新的途径,其中 CVB 依赖 TRPV1 启动前病毒线粒体分裂,这可能有助于破坏抗病毒免疫。TRPM8 已被证明可拮抗 TRPV1,因此我们假设刺激 TRPM8 可阻断 CVB 暴露后 TRPV1-mediated 线粒体断裂并减弱感染。
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METHODS:PURPOSE:To quantify the effects of absorbed radiation dose on healthy liver parenchyma following radioembolisation (RE) using [99mTc]TcMebrofenin to analyse both global and regional liver function. METHODS:Patients having RE to treat hepatic disease underwent a [99mTc]TcMebrofenin hepatobilliary scintigraphy (HBS) study at both baseline and 8 weeks following treatment. Changes in global liver uptake rate were compared with healthy liver absorbed dose measures derived from the post-treatment 90Y PET/CT, including average dose, minimum dose to 70% of the volume (D70) and volume receiving at least 50 Gy (V50). Changes in functional burden associated with treatment and spared liver volumes in patients receiving lobar RE were also assessed, as were changes experienced by regional volumes corresponding to various dose ranges. Standard liver function pathology tests (LFTs) (bilirubin, albumin, ALP, AST, ALT and GGT) were examined for changes between baseline and post-treatment. RESULTS:Thirty-five patients were included in the study, of which, 9 had lobar treatment. A significant linear correlation was found between both baseline global liver uptake rate (negative) and D70 with change in global liver uptake rate. Patients undergoing lobar treatments demonstrated a shift in functional burden, and a significant difference was seen between the mean dose corresponding to liver volumes that increased their functional burden (9 Gy) and those that decreased their functional burden (35 Gy). No baseline LFTs predicted a decrease in global liver function; however, D70 demonstrated a linear correlation with changes in bilirubin and GGT. CONCLUSIONS:Given the significant negative relationship between baseline and change in global liver uptake rate, baseline HBS studies should not be used alone to disqualify patients considered for RE. In terms of treatment planning and evaluation, D70 may be the most appropriate metric of dose, with values greater than 15 Gy indicative of a likely drop in global liver function. The evidence of increasing functional burden in spared liver volumes suggests that patients at risk of complications could benefit from a lobar approach to treatment.
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