Exploring the effective materials of flavonoids-enriched extract from Scutellaria baicalensis roots based on the metabolic activation in influenza A virus induced acute lung injury.
- 作者列表："Zhi H","Jin X","Zhu H","Li H","Zhang Y","Lu Y","Chen D
:Flavonoids-enriched extract from Scutellaria baicalensis roots (FESR) ameliorated influenza A virus (IAV) induced acute lung injury (ALI) in mice by inhibiting the excessive activation of complement system in vivo. However, FESR had no anti-complementary activity in vitro. In order to reveal the effective materials of FESR for the treatment of IAV-induced ALI, the present research explored the metabolic process of FESR both in nomal and IAV infected mice by the method of UHPLC-ESI-LTQ/MS, as well as the metabolic activating mechanism. The results showed that the inactive flavonoid glycosides of FESR were partly metabolized into anti-complementary aglycones in vivo, mainly including 5,7,4'-trihydroxy-8-methoxy-flavone, norwogonin, baicalein, wogonin, oroxylin A and chrysin. Moreover, compared with the normal mice, IAV-induced ALI mice exhibited more efficient on producing and absorbing these active metabolites, with AUC0-t and Cmax in plasma and concentrations in lungs and intestines markedly elevated in the IAV treated groups (P < 0.05). Interestingly, the intestinal bacteria from IAV-induced ALI mice showed stronger -glucuronidase activity and also had higher efficiency on transforming FESR to the flavonoid aglycones. These findings suggested that the anti-complementary aglycones produced by metabolic activation in vivo should be the potential effective materials of FESR against IAV infections, and intestinal bacteria might play an important role on the higher bioavailability of FESR in IAV infected mice. Additionally, the animals under the pathological state are more suitable for the metabolic study of traditional Chinese medicine.
黄芩黄酮提取物 (FESR) 通过抑制补体系统的过度激活，改善甲型流感病毒 (IAV) 诱导的小鼠急性肺损伤 (ALI)。然而，FESR 在体外没有抗互补活性。为了揭示 FESR 治疗 IAV 诱导的 ALI 的有效材料,本研究采用 UHPLC-ESI-LTQ/MS 方法，探讨了 FESR 在正常和 IAV 感染小鼠体内的代谢过程，以及代谢激活机制。结果表明，FESR 的无活性黄酮苷在体内部分代谢成抗互补苷元，主要包括 5,7 、 4 '-trihydroxy-8-methoxy-flavone 、去甲汉黄芩素、 oroxylin A 和白杨素。此外，与正常小鼠相比，IAV 诱导的 ALI 小鼠表现出更有效的产生和吸收这些活性代谢物,IAV 治疗组血浆 AUC0-t 和 Cmax 及肺和肠组织中 Cmax 浓度显著升高 (p <0.05)。有趣的是，来自 IAV 诱导的 ALI 小鼠的肠道细菌表现出更强的-葡萄糖醛酸酶活性，并且在将 FESR 转化为黄酮苷元方面也具有更高的效率。这些发现提示体内代谢激活产生的抗互补苷元应该是 FESR 抗 IAV 感染的潜在有效物质,肠道细菌可能在 IAV 感染小鼠高 FESR 生物利用度中起重要作用。此外，病理状态下的动物更适合传统的代谢研究 中医。
METHODS:BACKGROUND:From 2015/16 through 2017/18, injectable, trivalent inactivated influenza vaccines (IIV3) and a nasal spray, tetravalent live-attenuated influenza vaccine (LAIV4) were used in parallel in Finland. To understand how well vaccination with each vaccine type protected children against influenza under real-life conditions, vaccine effectiveness in two-year-olds was estimated for all three seasons. METHODS:Each season, a nationwide register-based cohort study was conducted. The study population comprised 60,088 children in 2015/16, 60,860 children in 2016/17 and 60,345 children in 2017/18. Laboratory-confirmed influenza was the study outcome. Seasonal influenza vaccination with either LAIV4 or IIV3 was the time-dependent exposure of interest. Vaccine effectiveness was defined as 1 minus the hazard ratio comparing vaccinated with unvaccinated children. RESULTS:From 2015/16 through 2017/18, the effectiveness of LAIV4 against influenza of any virus type was estimated at 54.2% (95% confidence interval, 32.2%-69.0%), 20.3% (-12.7% to 43.6%) and 30.5% (10.9%-45.9%); the corresponding effectiveness of IIV3 was 77.2% (48.9%-89.8%), 24.5% (-29.8% to 56.1%) and -20.1% (-61.5% to 10.7%). Neither of the influenza vaccines clearly excelled in protecting children. The LAIV4 effectiveness against type B was greater than against type A and greater than the IIV3 effectiveness against type B. CONCLUSIONS:To understand how influenza vaccines could be improved, vaccine effectiveness must be analyzed by vaccine and virus type. Effectiveness estimates expressing also overall protection levels are needed to guide individual and programmatic decision-making processes. Supported by this analysis, the vaccination program in Finland now recommends LAIV4 and injectable, tetravalent inactivated influenza vaccines replacing IIV3.
METHODS::Intranasally administered influenza vaccines could be more effective than injected vaccines, since intranasal vaccination can induce virus-specific IgA antibodies in the upper respiratory tract, which is the initial site of infection. In the current study, immune responses elicited by an intranasal inactivated H5 influenza vaccine were evaluated in healthy H5 influenza virus-naive individuals. Three doses of intranasal inactivated whole-virion H5 influenza vaccine induced strong neutralizing nasal IgA and serum IgG antibodies. In addition, a mucoadhesive excipient, carboxy-vinyl polymer (CVP), had a notable impact on the induction of nasal IgA antibody responses but not serum IgG antibody responses. The nasal hemagglutinin (HA)-specific IgA antibody responses clearly correlated with mucosal neutralizing antibody responses, indicating that measurement of nasal HA-specific IgA titers could be used as a surrogate for the mucosal antibody response. Furthermore, increased numbers of plasma cells and vaccine antigen-specific helper T (Th) cells in the peripheral blood were observed after vaccination, suggesting that peripheral blood biomarkers may also be used to evaluate the intranasal vaccine-induced immune response. However, peripheral blood immune cell responses correlated with neutralizing antibody titers in serum samples but not in nasal wash samples. Thus, analysis of the peripheral blood immune response could be a surrogate for the systemic immune response to intranasal vaccination but not for the mucosal immune response. The current study suggests the clinical potential of intranasal inactivated vaccines against H5 influenza viruses and highlights the need to develop novel means to evaluate intranasal vaccine-induced mucosal immune responses. This article is protected by copyright. All rights reserved.
METHODS:BACKGROUND:Influenza is an important public health problem and existing vaccines are not completely protective. New vaccines that protect by alternative mechanisms are needed to improve efficacy of influenza vaccines. In 2015, we did a phase 1 trial of an oral influenza vaccine, VXA-A1.1. A favourable safety profile and robust immunogenicity results in that trial supported progression of the vaccine to the current phase 2 trial. The aim of this study was to evaluate efficacy of the vaccine in a human influenza challenge model. METHODS:We did a single-site, placebo-controlled and active-controlled, phase 2 study at WCCT Global, Costa Mesa, CA, USA. Eligible individuals had an initial A/California/H1N1 haemagglutination inhibition titre of less than 20 and were aged 18-49 years and in good health. Individuals were randomly assigned (2:2:1) to receive a single immunisation of either 1011 infectious units of VXA-A1.1 (a monovalent tablet vaccine) orally, a full human dose of quadrivalent inactivated influenza vaccine (IIV) via intramuscular injection, or matched placebo. Randomisation was done by computer-generated assignments with block size of five. An unmasked pharmacist provided the appropriate vaccines and placebos to the administrating nurse. Individuals receiving the treatments, investigators, and staff were all masked to group assignments. 90 days after immunisation, individuals without clinically significant symptoms or signs of influenza, an oral temperature of higher than 37·9°C, a positive result for respiratory viral shedding on a Biofire test, and any investigator-assessed contraindications were challenged intranasally with 0·5 mL wild-type A/CA/like(H1N1)pdm09 influenza virus. The primary outcomes were safety, which was assessed in all immunised participants through 365 days, and influenza-positive illness after viral challenge, which was assessed in individuals that received the viral challenge and the required number of assessments post viral challenge. This trial is registered with ClinicalTrials.gov, number NCT02918006. RESULTS:Between Aug 31, 2016, and Jan 23, 2017, 374 individuals were assessed for eligibility, of whom 179 were randomly assigned to receive either VXA-A1.1 (n=71 [one individual did not provide a diary card, thus the solicited events were assessed in 70 individuals]), IIV (n=72), or placebo (n=36). Between Dec 2, 2016, and April 26, 2017, 143 eligible individuals (58 in the VXA-A1.1 group, 54 in the IIV group, and 31 in the placebo group) were challenged with influenza virus. VXA-A1.1 was well tolerated with no serious or medically significant adverse events. The most prevalent solicited adverse events for each of the treatment groups after immunisation were headache in the VXA-A1.1 (in five [7%] of 70 participants) and placebo (in seven [19%] of 36 participants) groups and tenderness at injection site in the IIV group (in 19 [26%] of 72 participants) Influenza-positive illness after challenge was detected in 17 (29%) of 58 individuals in the VXA-A1.1 group, 19 (35%) of 54 in the IIV group, and 15 (48%) of 31 in the placebo group. INTERPRETATION:Orally administered VXA-A1.1 was well tolerated and generated protective immunity against virus shedding, similar to a licensed intramuscular IIV. These results represent a major step forward in developing a safe and effective oral influenza vaccine. FUNDING:Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, and Biomedical Advanced Research and Development Authority.