Management of the Virulent Influenza Virus Infection by Oral Formulation of Nonhydrolized Carnosine and Isopeptide of Carnosine Attenuating Proinflammatory Cytokine-Induced Nitric Oxide Production
Management of the Virulent Influenza Virus Infection by Oral Formulation of Nonhydrolized Carnosine and Isopeptide of Carnosine Attenuating Proinflammatory Cytokine-Induced Nitric Oxide Production
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DOI：
10.1097/mjt.0b013e3181dcf589
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发表时间：
2012-01-01
影响因子：
4.2
通讯作者：
Deyev, Anatoly I.
中科院分区：
文献类型：
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作者：
Babizhayev, Mark A.;Deyev, Anatoly I.
诱导型一氧化氮合酶(INOS)在炎症反应中起重要作用。在我们的研究中，我们发现与140名健康人相比，150名甲型流感病毒感染患者的血清样本中iNOS衍生的NO显著增加。在人肺上皮细胞中，感染甲型流感病毒或用聚(I：C)+干扰素-γ刺激导致IL-32和iNOS的mRNA和蛋白水平增加，随后释放NO。激活的巨噬细胞也是一氧化氮(NO)的来源，一氧化氮主要由iNOS对促炎细胞因子做出反应而产生。在这篇综述文章中，提出的研究结果对理解甲型H1N1流感病毒的发病机制、预防和治疗具有重要意义。病毒的直接细胞毒性(称为细胞病变效应)只是病毒感染引起的几种类型事件中的一小部分。甲型流感病毒(包括甲型H1N1流感病毒)感染的宿主菌体产生大量的一氧化氮和超氧阴离子(O-2(-中心点))等氧自由基，这些分子物种被认为是强有力的病原体。NO与O-2(-中心点)的相互作用导致过氧亚硝酸盐的形成在流感病毒肺炎的致病机制中起作用。过量产生的氧自由基的毒性和反应性介导了宿主对病毒复制的器官或组织的过度反应，这可能解释了在各种类型的流感病毒感染中观察到的组织损伤的机制。作者揭示了肌肽及其生物可用非水解物形式对过氧亚硝酸盐损伤和其他类型的病毒损伤的保护作用，这些损伤通常涉及免疫相互作用。肌肽(β-丙氨酰-L-组氨酸)显示了药物对NO释放的细胞内纠正作用，这可能是自然免疫控制甲型流感病毒感染初期(抑制病毒复制)和病毒诱导的细胞因子基因表达的重要因素之一。口服非水解型肌肽的保护作用至少包括与一氧化氮的直接相互作用，抑制细胞毒性NO诱导的促炎状态，以及减弱可对炎症细胞产生深刻影响的细胞因子和趋化因子的作用。这些数据与以下假设一致，即天然产品，如富含肌肽及其衍生安丝氨酸(β-丙氨酰-1-甲基-L-组氨酸)的鸡汤和鸡胸肉提取物，可能有助于流感病毒感染和感冒的发病和预防，但由于口服商品鸡肉提取物后对二肽与血清肌氨酸酶的酶解和尿液排泄的敏感性而具有局限性。作者开发并申请专利的消化道和血液非水解型天然肌肽和异肽(γ-谷氨酰肌肽)制剂在甲型H1N1流感病毒感染疾病控制和预防中具有广阔的应用前景。
Inducible nitric oxide synthase (iNOS) plays an important role in mediating inflammation. In our studies, we found that iNOS-derived NO was significantly increased in the serum samples of 150 patients infected with influenza A virus in comparison with samples of 140 healthy individuals. In human lung epithelial cells, infection with influenza A virus or stimulation with poly(I:C) + interferon-gamma resulted in increased mRNA and protein levels of both interleukin-32 and iNOS, with subsequent release of NO. Activated macrophages are also a source of nitric oxide (NO), which is largely produced by iNOS in response to proinflammatory cytokines. In this review article, the presented findings have many important implications for understanding the Influenza A (H1N1) viral pathogenesis, prevention, and treatment. The direct viral cytotoxicity (referred cytopathic effect) is only a fraction of several types of events induced by virus infection. Nitric oxide and oxygen free radicals such as superoxide anion (O-2(-center dot)) are generated markedly in influenza A (including H1N1) virus-infected host boosts, and these molecular species are identified as the potent pathogenic agents. The mutual interaction of NO with O-2(-center dot) resulting in formation of peroxynitrite is operative in the pathogenic mechanism of influenza virus pneumonia. The toxicity and reactivity of oxygen radicals, generated in excessive amounts mediate the overreaction of the host's immune response against the organs or tissues in which viruses are replicating, and this may explain the mechanism of tissue injuries observed in influenza virus infection of various types. The authors revealed the protection that carnosine and its bioavailable nonhydrolized forms provide against peroxynitrite damage and other types of viral injuries in which immunologic interactions are usually involved. Carnosine (beta-alanyl-L-histidine) shows the pharmacologic intracellular correction of NO release which might be one of the important factors of natural immunity in controlling the initial stages of influenza A virus infection (inhibition of virus replication) and virus-induced regulation of cytokine gene expression. The protective effects of orally applied nonhydrolized formulated species of carnosine include at least direct interaction with nitric oxide, inhibition of cytotoxic NO-induced proinflammatory condition, and attenuation of the effects of cytokines and chemokines that can exert profound effects on inflammatory cells. These data are consistent with the hypothesis that natural products, such as chicken soup and chicken breast extracts rich in carnosine and its derivative anserine (beta-alanyl-1-methyl-L-histidine) could contribute to the pathogenesis and prevention of influenza virus infections and cold but have a limitation due to susceptibility to enzymatic hydrolysis of dipeptides with serum carnosinase and urine excretion after oral ingestion of a commercial chicken extract. The developed and patented by the authors formulations of nonhydrolized in digestive tract and blood natural carnosine peptide and isopeptide (gamma-glutamyl-carnosine) products have a promise in the Influenza A (H1N1) virus infection disease control and prevention.