青蒿琥酯抗炎与抗菌增敏作用在其保护细菌脓毒症模型小鼠中的作用及机制研究
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摘要
目的:
脓毒症(Sepsis)是由感染因素引起的全身失控性炎症反应综合症(Systemic inflammatory response sydrome, SIRS),由其导致的脓毒症休克和多器官功能障碍综合症(multiple organ dysfuction syndrome, MODS)是死亡的重要原因,病死率高达50%-80%,至今尚无有效的治疗手段。
目前认为,菌体成分如细菌基因组DNA和存在于革兰阴性细菌外膜的脂多糖/内毒素(lipopolysaccharide/endotoxin,LPS)等是诱导脓毒症发生的主要致病因子。虽然抗菌药物可抑制细菌的增殖,达到治疗感染性疾病的目的,但已有大量实验表明,许多抗菌药物尤其是β-内酰胺类抗生素在杀死细菌的同时,能促使内毒素从细菌胞膜的释放而加重感染。因此,寻找具有治疗细菌脓毒症的药物对提高感染性疾病的治疗效果具有重要意义。
我们实验室前期的工作已证实:青蒿素对LPS、CpG ODN、热灭活大肠埃希菌攻击小鼠具有显著的保护作用;其与β-内酰胺类抗生素同时使用可对活大肠埃希菌攻击小鼠具有显著保护作用。但是,由于青蒿素不溶于水或油,仅能口服给药,不适宜于重症脓毒症病人的抢救。
青蒿素的4种衍生物包括双氢青蒿素、蒿甲醚、蒿乙醚及青蒿琥酯,均可静脉、肌肉给药,剂型适合重症患者使用。鉴于与青蒿素相似的化学结构,推测它们可能具有治疗脓毒症的效果。为此,本课题拟通过体外细胞因子实验筛选出对不同致炎成分诱导的细胞因子释放有较强抑制作用的青蒿素衍生物;在上述工作基础上,采用不同脓毒症模型研究该青蒿素衍生物防治细菌脓毒症的作用并探讨其可能的作用机制,为寻找有效的治疗细菌脓毒症的药物并拓宽青蒿素及其衍生物的临床适应症提供实验依据。
方法:
一、双氢青蒿素、青蒿琥酯、蒿甲醚抑制炎性细胞因子释放的活性筛选:ELISA法观察三种衍生物对不同刺激物诱导的小鼠原代腹腔巨噬细胞和传代巨噬细胞系RAW264.7细胞释放TNF-α、IL-6的影响
二、青蒿琥酯对细菌脓毒症模型小鼠的保护作用:分别建立热灭活大肠埃希菌攻击脓毒症小鼠模型、活大肠埃希菌攻击脓毒症小鼠模型和CLP脓毒症小鼠模型,观察青蒿琥酯对不同脓毒症模型小鼠的保护作用。
三、青蒿琥酯对细菌脓毒症模型小鼠保护作用的分子机制研究
(一)青蒿琥酯的抗炎作用分子机制研究
1.生物传感器技术研究青蒿琥酯与LPS/lipid A或CpG ODN的直接结合作用;
2.鲎试剂动态浊度法检测青蒿琥酯对内毒素的体外中和作用;
3.流式细胞术观察青蒿琥酯对CpG ODN在RAW264.7细胞表面结合及细胞内聚集的影响;
4. RT-PCR观察青蒿琥酯对TLR4 mRNA、TLR9 mRNA表达的影响;免疫荧光技术检测青蒿琥酯对TLR9蛋白表达的影响;
5. ELISA法检测青蒿琥酯对NF-κB活化的影响;
(二)青蒿琥酯抗菌增敏作用及其机制研究
1.采用微孔稀释法观察青蒿琥酯和不同抗菌药物的MIC、青蒿琥酯和不同抗菌药物联合使用时对大肠埃希菌国际标准株ATCC35218和临床分离株MICs的影响;
2.采用动态生长曲线法观察青蒿琥酯和不同抗菌药物联合使用时对大肠埃希菌ATCC35218和大肠埃希菌临床分离株的体外协同抗菌作用;
3.采用激光共聚焦、荧光分光光度法观察青蒿琥酯对柔红霉素在大肠埃希菌ATCC35218内聚集的影响;
4.透射电镜技术观察青蒿琥酯对大肠埃希菌ATCC35218胞膜通透性的影响。
结果:
一、双氢青蒿素、青蒿琥酯、蒿甲醚抑制炎性细胞因子释放的活性筛选三种青蒿素衍生物中,青蒿琥酯抑制炎性细胞因子释放的作用最强;
二、青蒿琥酯对细菌脓毒症模型小鼠的保护作用
1.青蒿琥酯能明显延迟热灭活大肠埃希菌攻击模型小鼠的死亡时间,降低脓毒症小鼠的死亡率,其保护作用可能与其降低热灭活大肠埃希菌攻击小鼠血清内毒素和TNF-α的水平有关;
2.青蒿琥酯与庆大霉素、舒氨西林联合使用对活大肠埃希菌攻击脓毒症模型小鼠具有协同保护作用;
3.青蒿琥酯与舒氨西林联合使用对CLP脓毒症模型小鼠具有协同保护作用。
三、青蒿琥酯对脓毒症模型小鼠保护作用的分子机制研究
(一)青蒿琥酯的抗炎作用的机制研究
1.青蒿琥酯在体外不能直接结合LPS和CpG ODN,对LPS无中和作用;
2.青蒿琥酯对CpG ODN表面的结合,但增加CpG ODN在细胞内的聚集;
3.青蒿琥酯可抑制热灭活大肠埃希菌、LPS和CpG ODN诱导的RAW264.7细胞TLR4 mRNA和TLR9 mRNA高表达和TLR9蛋白的表达;
4.青蒿琥酯可抑制热灭活大肠埃希菌诱导的RAW264.7细胞NF-κB的活化。
(二)青蒿琥酯的抗菌增敏作用及机制研究
1.青蒿琥酯单独使用几乎没有抗菌作用,但与不同抗生素联合使用时对大肠埃希菌可产生明显的抗菌增敏作用;
2.青蒿琥酯可增加柔红霉素在细菌内聚集,呈显著的量效和时效关系;
3.一定浓度的青蒿琥酯预处理可破坏大肠埃希菌细胞膜结构的完整性,其抗菌增敏作用机制可能与青蒿琥酯增加抗菌药物在细菌内的聚集有关。
结论:
1.双氢青蒿素、青蒿琥酯、蒿甲醚3种青蒿素衍生物中,青蒿琥酯抑制炎性细胞因子释放的作用最强;
2.青蒿琥酯对热灭活大肠埃希菌攻击脓毒症模型小鼠具有显著的保护作用,青蒿琥酯与抗菌药物联合使用对活大肠埃希菌攻击脓毒症和CLP脓毒症模型小鼠均具有协同保护作用;
3.青蒿琥酯的抗炎作用机制可能与抑制TLR4、TLR9表达和抑制NF-κB活性,从而减少致炎细胞因子TNF-α、IL-6的释放有关;
4.青蒿琥酯的抗菌增敏作用机制可能与增加抗菌药物在细菌内的聚集有关;
5.鉴于青蒿琥酯的抗炎作用与抗菌增敏作用、对细菌脓毒症模型动物具有明显的保护作用,深入研究青蒿琥酯具有重要意义。
Objective:
Sepsis is systemic inflammatory response syndrome (SIRS) caused by infection. This condition may result in septic shock, multiple organ dysfunction syndrome (MODS) and ultimately death. The mortality is as high as to 50~80%. There have been few effective therapeutic method.
At present, sepsis is found to be triggered by the presence of invasive bacteria and bacterial components, such as bacterial genomic DNA (bDNA) and lipopolysaccharide (LPS [endotoxin]), etc. Although antibacterial agents could inhibit bacterial growth and treat infectious disease, there are reports that many antibacterial agents, especiallyβ-lactam antibiotics, could induce LPS release from bacterial membrance during killing bacteria and enhance infection. Therefore, it is very important to search drugs to treat bacterail sepsis. In our previous study, we have confirmed that artemisinin (ART) could protect mice against lethal heat-killed E. coli challenge and synergize with antibiotics to protect animals against lethal live E. coli challenge. However, ART is poorly soluble in oil and water and can only be administered orally, which is disadvantageous for treating critically ill patients.
There are four derivates of ART; they are dihydroartemisinine (DHA), artemether(AM), arteether and artesunate(AS). The derivates of ART could be administered by intravescular and intramuscular injection, which is suitabl for critically ill patients. Based on their similar chemical structure, we suppose four derivates of ART possibly play role to treat sepsis as well as ART.
With these considerations in mind, we undertook the current study to find most effective derivate by screening the effects of their inhibitons on inflammatory cytokines release induced by bacteria and bacterial component. And then, the protection of this derivate on different sepsis model mice and its possible molecular mechanisms will be investigated in orde to search for effective anti-sepsis drug and broaden indications.
Methods:
1. Screening of inhibitory effect of DHA, AS and AM on TNF-αand IL-6 releases from mice primary peritoneal macrophages and macrophage cell line RAW264.7 cells stimulated by different stimulators using ELISA method.
2. The protective effect of AS on bacterial sepsis model mice. Sepsis mice model challenged with heat killed E.coli, live E.coli and CLP model were established. The protective effects of AS were observed.
3. The molecular mechanisms of AS on sepsis model mice
(1) Mechanism of AS’anti-inflammatory effect The ability of AS to neutralize LPS in vitro was assayed using the LAL test. The direct binding ability of AS to CpG ODN or LPS/lipid A was observed using affinity biosensor technology.
Cell-surface binding and accumulation of 6-FAM CpG ODN in RAW264.7 cell lines treated with AS were observed using flow cytometry. TLR4 and TLR9 mRNA expression down-regulated by AS was tested using RT-PCR method; TLR9 expression at protein level within the cells was observed using immunofluorescence assay. Inhibition of AS on NF-κB activation was observed using ELISA assay.
(2) Mechanisms of AS as antibacterial potentiator
①MICs of AS and different antibacterial agents on E.coli ATCC 35218 and clinical separated strains were observed using micropore dilution, and effects of AS with antibiotics on above strains were observed,too.
②Synergistic effect of AS with antibacterial agents on E.coli ATCC35218 and clinical separated strains were observed using dynamic growth curve assay.
③Accumulation of daunorubicin within bacteria treated with AS was using confocal scanning microscopy and fluorospectrophotometry.effect of AS on bacterial membrance permeability was observed using transmission electron microscope.
Results:
1. Among three derivates of ART, AS produced most marked inhibition on inflammatory cytokines release.
2. The protective effect of AS on different sepsis model mice.
①AS could delay the death time and decrease the mortality of sepsis mice challenged with heat-killed E.coli. This protection was associated with reductions in serum TNF-αand measurable endotoxin levels.
②The administration of AS together with gentamycin or a complex of ampicillin and sulbactam decreased sepsis mice mortality challenged by lethal live E.coli. The administration of AS together with a complex of ampicillin and sulbactam decreased CLP sepsis model mice mortality.
3. The molecular mechanisms of AS on sepsis model mice
(1) Mechanism of AS’anti-inflammatory effect
①AS could not directly bind to LPS or CpG ODN. AS could not neutralize LPS in vitro. AS could not change CpG ODN-binding to the cell-surface of RAW264.7 cells but could promote CpG ODN’s accumulation within.
③AS down-regulated TLR4 mRNA and TLR9 mRNA expressions up-regulated by LPS, CpG ODN or heat-killed E. coli. AS also down-regulated TLR9 at protein level, too.
④AS inhibited heat-killed E. coli-induced NF-κB activation.
(2) Mechanisms of AS as antibacterial potentiator
①AS had no antibacterial effect, but AS could produce synergistic effect if it with antibacterial agents to E.coli.
②AS could increase accumulation of daunomycin within E.coli ATCC35218 in a dose-dependent and time-dependent manners.
③AS could destroy the integrity of E.coli cell membrance. The mechanism of AS as antibacterial potentiator was tightly related to increased accumulation of antibacterial agents within bacteria.
Conclusions:
①Among three derivates of ART, AS produced most marked inhibition on inflammatory cytokines release.
②AS could protect sepsis mice challenged with heat-killed E.coli. The administration of AS together with antibacterial agents could produce synergistic protection for sepsis model mice.
③AS-mediated anti-inflammatory effect was associated with a reduction of TNF-αand IL-6 releases via a decrease in TLR4 and TLR9 expressions and NF-κB activation.
④Antibacterial potentiator’s effect of AS was related to increased drug accumulation within bacteria.
⑤Based on anti-inflammatory effect and antibacterial potentiator’s effect of AS, and its protection for sepsis model mice, it is significant to further investigate AS.
脓毒症(Sepsis)是由感染因素引起的全身失控性炎症反应综合症(Systemic inflammatory response sydrome, SIRS),由其导致的脓毒症休克和多器官功能障碍综合症(multiple organ dysfuction syndrome, MODS)是死亡的重要原因,病死率高达50%-80%,至今尚无有效的治疗手段。
目前认为,菌体成分如细菌基因组DNA和存在于革兰阴性细菌外膜的脂多糖/内毒素(lipopolysaccharide/endotoxin,LPS)等是诱导脓毒症发生的主要致病因子。虽然抗菌药物可抑制细菌的增殖,达到治疗感染性疾病的目的,但已有大量实验表明,许多抗菌药物尤其是β-内酰胺类抗生素在杀死细菌的同时,能促使内毒素从细菌胞膜的释放而加重感染。因此,寻找具有治疗细菌脓毒症的药物对提高感染性疾病的治疗效果具有重要意义。
我们实验室前期的工作已证实:青蒿素对LPS、CpG ODN、热灭活大肠埃希菌攻击小鼠具有显著的保护作用;其与β-内酰胺类抗生素同时使用可对活大肠埃希菌攻击小鼠具有显著保护作用。但是,由于青蒿素不溶于水或油,仅能口服给药,不适宜于重症脓毒症病人的抢救。
青蒿素的4种衍生物包括双氢青蒿素、蒿甲醚、蒿乙醚及青蒿琥酯,均可静脉、肌肉给药,剂型适合重症患者使用。鉴于与青蒿素相似的化学结构,推测它们可能具有治疗脓毒症的效果。为此,本课题拟通过体外细胞因子实验筛选出对不同致炎成分诱导的细胞因子释放有较强抑制作用的青蒿素衍生物;在上述工作基础上,采用不同脓毒症模型研究该青蒿素衍生物防治细菌脓毒症的作用并探讨其可能的作用机制,为寻找有效的治疗细菌脓毒症的药物并拓宽青蒿素及其衍生物的临床适应症提供实验依据。
方法:
一、双氢青蒿素、青蒿琥酯、蒿甲醚抑制炎性细胞因子释放的活性筛选:ELISA法观察三种衍生物对不同刺激物诱导的小鼠原代腹腔巨噬细胞和传代巨噬细胞系RAW264.7细胞释放TNF-α、IL-6的影响
二、青蒿琥酯对细菌脓毒症模型小鼠的保护作用:分别建立热灭活大肠埃希菌攻击脓毒症小鼠模型、活大肠埃希菌攻击脓毒症小鼠模型和CLP脓毒症小鼠模型,观察青蒿琥酯对不同脓毒症模型小鼠的保护作用。
三、青蒿琥酯对细菌脓毒症模型小鼠保护作用的分子机制研究
(一)青蒿琥酯的抗炎作用分子机制研究
1.生物传感器技术研究青蒿琥酯与LPS/lipid A或CpG ODN的直接结合作用;
2.鲎试剂动态浊度法检测青蒿琥酯对内毒素的体外中和作用;
3.流式细胞术观察青蒿琥酯对CpG ODN在RAW264.7细胞表面结合及细胞内聚集的影响;
4. RT-PCR观察青蒿琥酯对TLR4 mRNA、TLR9 mRNA表达的影响;免疫荧光技术检测青蒿琥酯对TLR9蛋白表达的影响;
5. ELISA法检测青蒿琥酯对NF-κB活化的影响;
(二)青蒿琥酯抗菌增敏作用及其机制研究
1.采用微孔稀释法观察青蒿琥酯和不同抗菌药物的MIC、青蒿琥酯和不同抗菌药物联合使用时对大肠埃希菌国际标准株ATCC35218和临床分离株MICs的影响;
2.采用动态生长曲线法观察青蒿琥酯和不同抗菌药物联合使用时对大肠埃希菌ATCC35218和大肠埃希菌临床分离株的体外协同抗菌作用;
3.采用激光共聚焦、荧光分光光度法观察青蒿琥酯对柔红霉素在大肠埃希菌ATCC35218内聚集的影响;
4.透射电镜技术观察青蒿琥酯对大肠埃希菌ATCC35218胞膜通透性的影响。
结果:
一、双氢青蒿素、青蒿琥酯、蒿甲醚抑制炎性细胞因子释放的活性筛选三种青蒿素衍生物中,青蒿琥酯抑制炎性细胞因子释放的作用最强;
二、青蒿琥酯对细菌脓毒症模型小鼠的保护作用
1.青蒿琥酯能明显延迟热灭活大肠埃希菌攻击模型小鼠的死亡时间,降低脓毒症小鼠的死亡率,其保护作用可能与其降低热灭活大肠埃希菌攻击小鼠血清内毒素和TNF-α的水平有关;
2.青蒿琥酯与庆大霉素、舒氨西林联合使用对活大肠埃希菌攻击脓毒症模型小鼠具有协同保护作用;
3.青蒿琥酯与舒氨西林联合使用对CLP脓毒症模型小鼠具有协同保护作用。
三、青蒿琥酯对脓毒症模型小鼠保护作用的分子机制研究
(一)青蒿琥酯的抗炎作用的机制研究
1.青蒿琥酯在体外不能直接结合LPS和CpG ODN,对LPS无中和作用;
2.青蒿琥酯对CpG ODN表面的结合,但增加CpG ODN在细胞内的聚集;
3.青蒿琥酯可抑制热灭活大肠埃希菌、LPS和CpG ODN诱导的RAW264.7细胞TLR4 mRNA和TLR9 mRNA高表达和TLR9蛋白的表达;
4.青蒿琥酯可抑制热灭活大肠埃希菌诱导的RAW264.7细胞NF-κB的活化。
(二)青蒿琥酯的抗菌增敏作用及机制研究
1.青蒿琥酯单独使用几乎没有抗菌作用,但与不同抗生素联合使用时对大肠埃希菌可产生明显的抗菌增敏作用;
2.青蒿琥酯可增加柔红霉素在细菌内聚集,呈显著的量效和时效关系;
3.一定浓度的青蒿琥酯预处理可破坏大肠埃希菌细胞膜结构的完整性,其抗菌增敏作用机制可能与青蒿琥酯增加抗菌药物在细菌内的聚集有关。
结论:
1.双氢青蒿素、青蒿琥酯、蒿甲醚3种青蒿素衍生物中,青蒿琥酯抑制炎性细胞因子释放的作用最强;
2.青蒿琥酯对热灭活大肠埃希菌攻击脓毒症模型小鼠具有显著的保护作用,青蒿琥酯与抗菌药物联合使用对活大肠埃希菌攻击脓毒症和CLP脓毒症模型小鼠均具有协同保护作用;
3.青蒿琥酯的抗炎作用机制可能与抑制TLR4、TLR9表达和抑制NF-κB活性,从而减少致炎细胞因子TNF-α、IL-6的释放有关;
4.青蒿琥酯的抗菌增敏作用机制可能与增加抗菌药物在细菌内的聚集有关;
5.鉴于青蒿琥酯的抗炎作用与抗菌增敏作用、对细菌脓毒症模型动物具有明显的保护作用,深入研究青蒿琥酯具有重要意义。
Objective:
Sepsis is systemic inflammatory response syndrome (SIRS) caused by infection. This condition may result in septic shock, multiple organ dysfunction syndrome (MODS) and ultimately death. The mortality is as high as to 50~80%. There have been few effective therapeutic method.
At present, sepsis is found to be triggered by the presence of invasive bacteria and bacterial components, such as bacterial genomic DNA (bDNA) and lipopolysaccharide (LPS [endotoxin]), etc. Although antibacterial agents could inhibit bacterial growth and treat infectious disease, there are reports that many antibacterial agents, especiallyβ-lactam antibiotics, could induce LPS release from bacterial membrance during killing bacteria and enhance infection. Therefore, it is very important to search drugs to treat bacterail sepsis. In our previous study, we have confirmed that artemisinin (ART) could protect mice against lethal heat-killed E. coli challenge and synergize with antibiotics to protect animals against lethal live E. coli challenge. However, ART is poorly soluble in oil and water and can only be administered orally, which is disadvantageous for treating critically ill patients.
There are four derivates of ART; they are dihydroartemisinine (DHA), artemether(AM), arteether and artesunate(AS). The derivates of ART could be administered by intravescular and intramuscular injection, which is suitabl for critically ill patients. Based on their similar chemical structure, we suppose four derivates of ART possibly play role to treat sepsis as well as ART.
With these considerations in mind, we undertook the current study to find most effective derivate by screening the effects of their inhibitons on inflammatory cytokines release induced by bacteria and bacterial component. And then, the protection of this derivate on different sepsis model mice and its possible molecular mechanisms will be investigated in orde to search for effective anti-sepsis drug and broaden indications.
Methods:
1. Screening of inhibitory effect of DHA, AS and AM on TNF-αand IL-6 releases from mice primary peritoneal macrophages and macrophage cell line RAW264.7 cells stimulated by different stimulators using ELISA method.
2. The protective effect of AS on bacterial sepsis model mice. Sepsis mice model challenged with heat killed E.coli, live E.coli and CLP model were established. The protective effects of AS were observed.
3. The molecular mechanisms of AS on sepsis model mice
(1) Mechanism of AS’anti-inflammatory effect The ability of AS to neutralize LPS in vitro was assayed using the LAL test. The direct binding ability of AS to CpG ODN or LPS/lipid A was observed using affinity biosensor technology.
Cell-surface binding and accumulation of 6-FAM CpG ODN in RAW264.7 cell lines treated with AS were observed using flow cytometry. TLR4 and TLR9 mRNA expression down-regulated by AS was tested using RT-PCR method; TLR9 expression at protein level within the cells was observed using immunofluorescence assay. Inhibition of AS on NF-κB activation was observed using ELISA assay.
(2) Mechanisms of AS as antibacterial potentiator
①MICs of AS and different antibacterial agents on E.coli ATCC 35218 and clinical separated strains were observed using micropore dilution, and effects of AS with antibiotics on above strains were observed,too.
②Synergistic effect of AS with antibacterial agents on E.coli ATCC35218 and clinical separated strains were observed using dynamic growth curve assay.
③Accumulation of daunorubicin within bacteria treated with AS was using confocal scanning microscopy and fluorospectrophotometry.effect of AS on bacterial membrance permeability was observed using transmission electron microscope.
Results:
1. Among three derivates of ART, AS produced most marked inhibition on inflammatory cytokines release.
2. The protective effect of AS on different sepsis model mice.
①AS could delay the death time and decrease the mortality of sepsis mice challenged with heat-killed E.coli. This protection was associated with reductions in serum TNF-αand measurable endotoxin levels.
②The administration of AS together with gentamycin or a complex of ampicillin and sulbactam decreased sepsis mice mortality challenged by lethal live E.coli. The administration of AS together with a complex of ampicillin and sulbactam decreased CLP sepsis model mice mortality.
3. The molecular mechanisms of AS on sepsis model mice
(1) Mechanism of AS’anti-inflammatory effect
①AS could not directly bind to LPS or CpG ODN. AS could not neutralize LPS in vitro. AS could not change CpG ODN-binding to the cell-surface of RAW264.7 cells but could promote CpG ODN’s accumulation within.
③AS down-regulated TLR4 mRNA and TLR9 mRNA expressions up-regulated by LPS, CpG ODN or heat-killed E. coli. AS also down-regulated TLR9 at protein level, too.
④AS inhibited heat-killed E. coli-induced NF-κB activation.
(2) Mechanisms of AS as antibacterial potentiator
①AS had no antibacterial effect, but AS could produce synergistic effect if it with antibacterial agents to E.coli.
②AS could increase accumulation of daunomycin within E.coli ATCC35218 in a dose-dependent and time-dependent manners.
③AS could destroy the integrity of E.coli cell membrance. The mechanism of AS as antibacterial potentiator was tightly related to increased accumulation of antibacterial agents within bacteria.
Conclusions:
①Among three derivates of ART, AS produced most marked inhibition on inflammatory cytokines release.
②AS could protect sepsis mice challenged with heat-killed E.coli. The administration of AS together with antibacterial agents could produce synergistic protection for sepsis model mice.
③AS-mediated anti-inflammatory effect was associated with a reduction of TNF-αand IL-6 releases via a decrease in TLR4 and TLR9 expressions and NF-κB activation.
④Antibacterial potentiator’s effect of AS was related to increased drug accumulation within bacteria.
⑤Based on anti-inflammatory effect and antibacterial potentiator’s effect of AS, and its protection for sepsis model mice, it is significant to further investigate AS.
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