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回答: “万能”受体适配器--新冠S蛋白 4 由 苦难与荣耀 于 2023-09-07 9:55
由于帖子长度的限制，一些最新的补充内容无法加入主帖。以下是有关章节的最新完整内容，它们与主帖对应内容的区别是，添加了与部分中文描述对照的论文原文。 6park.com- 6park.com8、Hepcidin（铁调素） 6park.com- 6park.com论文依据四 6park.comIron and iron-related proteins in COVID-19
COVID-19中的铁和铁相关蛋白
https://link.springer.com/article/10.1007/s10238-022-00851-y 6park.comPublished: 18 July 2022 6park.com论文回顾了铁和铁（代谢）相关的各种蛋白、多肽在COVID-19中的状态（升高、降低，不同严重程度患者间的差异），全面总结、介绍了已报告的SARS-CoV-2感染引起的铁和铁相关蛋白、多肽可能的状态改变，相应的临床检测数据、结果和研究结论，探讨、解析了铁代谢相关蛋白、多肽在COVID-19中的相互作用、相互关联、相互影响，它们的临床数据之间间关系和互动。 6park.com论文考察的参与COVID-19病理机制的铁代谢相关蛋白、多肽包括：铁蛋白（Ferritin）、铁调素（Hepcidin）、转铁蛋白（Transferrin）、转铁蛋白受体（transferrin receptor）、乳铁蛋白（Lactoferrin）、血红蛋白（Hemoglobin）、脂质运载蛋白-2（Lipocalin-2）。 6park.com下面是论文的总结综述图： 6park.com6park.com论文两次提到SARS-CoV-2 Spike的铁调素模仿，有关内容摘录如下： 6park.com高水平的循环铁调素可抑制肠道铁吸收，并通过降解细胞铁转运蛋白（ferroportin）将铁锁定在铁储存和铁回收细胞内。这可以防止（血液）循环中铁水平的升高。因此，炎症诱导的铁调素增加（inflammation-induced hepcidin increment）导致全身性低铁血症（低铁血指低血清铁水平，low serum iron levels）。此外，发现了SARS-CoV-2 Spike蛋白与铁调素之间的结构相似性，据推测，病毒（SARS-CoV-2）Spike蛋白可能具有铁调素模拟作用（hepcidin-mimetic action）并诱导铁转运蛋白阻断（ferroportin blockage）。如果这一推测正确，那么这将进一步促进细胞内铁潴留并加剧全身性低铁血症（systemic hypoferremia）。 6park.comHigh levels of circulatory hepcidin inhibit intestinal iron absorption and lock iron within the iron-storing and iron-recycling cells by degrading the cellular-iron transporter ferroportin. This prevents iron entry and subsequent iron elevation in the circulation [111]. Thus, inflammation-induced hepcidin increment leads to systemic hypoferremia (low serum iron levels) [112]. In addition, structural similarity has been identified between hepcidin and SARS‐CoV‐2 spike protein. It has been hypothesized that the viral spike protein may have a hepcidin-mimetic action and induce ferroportin blockage [81]. If correct, then this can further promote intracellular iron retention and contribute to systemic hypoferremia. 6park.com。。。 6park.com低铁血症（hypoferremia）也可能由铁调素升高以外的原因引起。例如，可能由SARS-CoV-2 Spike蛋白推定的铁调素模拟作用（the putative hepcidin-mimetic action）引起，它将阻断铁转运蛋白（ferroportin），减少铁进入（血液）循环，导致低铁血症。另一个可能的原因是血清铁蛋白（serum ferritin）升高。正如在COVID-19中观察到的那样，除了提升血清铁调素外，炎症还提升铁蛋白（ferritin）水平。铁蛋白可以螯合（sequester）大量铁离子（iron ions），并且，相比转铁蛋白（transferrin，Tf），铁与铁蛋白和乳铁蛋白（lactoferrin ，Lf）的结合亲和力更高（在COVID-19 中转铁蛋白水平降低），铁蛋白对铁的大量螯合也可能导致低铁血症（hypoferremia）。 6park.comIn such cases, hypoferremia may be caused due to reasons other than hepcidin elevation. For example, this could be due to the putative hepcidin-mimetic action of the viral protein [81], which would block ferroportin and thereby reduce iron entry into the circulation leading to hypoferremia. Another reason could be elevated serum ferritin. In addition to elevating serum hepcidin, inflammation elevates ferritin levels, as observed in COVID-19 (Table 1). Ferritin can sequester a large number of iron ions, and the higher affinity of iron to ferritin and lactoferrin than transferrin (although transferrin levels are reduced in COVID-19) may assist in this sequestration process and contribute to hypoferremia. 6park.com论文依据五 6park.comThe Relationship Between Hepcidin-Mediated Iron Dysmetabolism and COVID-19 Severity: A Meta-Analysis
总结综述图：铁代谢相关因子在COVID-19中的状态，它们之间的相互关联、相互影响，在COVID-19病理机制中的角色。
铁调素介导的铁代谢异常与COVID-19严重程度的关系：一项荟萃分析
https://www.frontiersin.org/articles/10.3389/fpubh.2022.881412/full 6park.comFront. Public Health, 26 April 2022 6park.com论文旨在评估铁调素相关的铁代谢因子（蛋白、多肽）和相关参数，探讨铁调素参与的铁代谢异常（iron dysmetabolism）与COVID-19 严重程度之间的关系。论文考察了477名不同严重程度的COVID-19患者，这些患者的临床检测数据表明：重症COVID-19病例血清铁调素（serum hepcidin）铁蛋白（serum ferritin）水平较高，血清铁（serum iron）水平较低，但转铁蛋白饱和度（transferrin saturation）无显着差异。论文认为，需要进一步的研究来验证铁调素介导的铁代谢轴（iron metabolism axis）在COVID-19病理和治疗中的（确切）作用。 6park.com关于SARS-CoV-2 Spike蛋白的铁调素模仿，论文指出： 6park.comEhsani（“论文依据二”的作者）强调了SARS-CoV-2 Spike糖蛋白和铁调素多肽之间氨基酸序列的惊人相似性，这一观察结果为SARS-CoV-2的疫苗设计和生物工程抗体开发提供了思路。SARS-CoV-2的铁调素模拟作用（Hepcidin-mimetic action of SARS-CoV-2）可能会显着增加循环铁蛋白和组织铁蛋白（circulating and tissue ferritin），同时诱导SI（serum iron）缺乏。然而，SARS-CoV-2是否利用细胞膜上的铁转运蛋（ferroportin）作为侵入宿主细胞的另一种Spike结合受体，还需要进一步分析。此外，SARS-CoV-2是否通过模仿铁调素直接降解铁转运蛋白（whether SARS-CoV-2 directly degrades ferroportin through mimicking hepcidin），或通过炎症间接上调铁调素以介导铁代谢障碍，也需要仔细研究。 6park.comEhsani highlighted the striking similarity between the amino acid sequence of the SARS-CoV-2 spike glycoprotein and the hepcidin protein (37). This observation provides ideas for vaccine design and bioengineered antibody development for SARS-CoV-2. Hepcidin-mimetic action of SARS-CoV-2 may markedly increase circulating and tissue ferritin, while inducing SI deficiency (32, 33). However, whether SARS-CoV-2 utilizes ferroportin on the cell membrane as another binding receptor for the spike protein to invade host cells requires further analysis. Moreover, whether SARS-CoV-2 directly degrades ferroportin through mimicking hepcidin or indirectly upregulates hepcidin through inflammation to mediate iron dysmetabolism also needs to be carefully investigated. 6park.com论文依据六 6park.comSciELO - Brazil - SARS-CoV-2 association with hemoglobin and iron metabolism
SARS-CoV-2与血红蛋白和铁代谢的关联
https://www.scielo.br/j/ramb/a/Mb65VBcXPsgS5z6Y86zwjjm/ 6park.comMed. Bras. • Sept 2021 6park.com论文全面回顾了人体铁代谢机制、铁调素在铁代谢中的调节作用，考察、探讨了SARS-CoV-2感染引发的多种并发症，包括功能障碍性血红蛋白病、铁调素水平升高、氧化应激和（细胞）铁死亡、全身性低氧血症和高铁蛋白血症的内在机制，分析、指出了SARS-CoV-2感染对铁调素的影响，SARS-CoV-2的铁调素模仿这两方面的因素与这些并发症的可能的内在关联。 6park.com关于SARS-CoV-2 Spike蛋白的铁调素模仿，论文指出：
Esaki（就是“论文依据二”的作者Ehsani）指出，冠状病毒Spike蛋白的氨基酸序列与铁调素相同（应为相似），铁调素是铁代谢的主要系统调节剂。冠状病毒Spike蛋白与铁调素之间的这种相似性能够导致模仿效应（mimetic effect），这（或许）意味着SARS-CoV-2可以增加血清铁调素（或其模拟物），然后增加铁蛋白（ferritin），并引起高铁蛋白血症综合症（hyperferritinemic syndrome）。 6park.comEsaki demonstrated that the amino acid sequence of the coronavirus spike protein is identical to hepcidin, a protein that acts as the main systemic regulator of iron metabolism. Therefore, this similarity between hepcidin and coronavirus spike protein can lead to a mimetic effect, suggesting that SARS-CoV-2 can increase serum hepcidin and then ferritin, and cause hyperferritinemic syndrome5. 6park.com因此，功能障碍性血红蛋白病（dysfunctional hemoglobinopathy）与SARS-CoV-2相关的高铁蛋白血症（SARS-CoV-2-related hyperferritinemia）之间的关联可能影响红细胞的氧运输能力，导致缺氧；同时，非转铁蛋白结合铁（non-transferrin bound iron，NTBI，未与转铁蛋白结合的铁）导致组织损伤，并在炎症部位释放自由基（free radicals）。 6park.comTherefore, the association between dysfunctional hemoglobinopathy and SARS-CoV-2-related hyperferritinemia may affect the oxygen transport capacity of erythrocytes, thereby leading to hypoxia, while causing tissue damage due to non-transferrin bound iron (NTBI), and subsequently releasing free radicals at the inflammation sites6. 6park.com。。。 6park.com铁毒性（iron toxicity）在COVID-19病理生理学中的角色与SARS-CoV-2的铁调素模拟效应（the hepcidin mimetic effect of SARS-CoV-2）有关，铁转运蛋白（ferroportin）在胃肠道和网状内皮系统中的内化（internalization），导致SF（Serum ferritin，血清铁蛋白）的可用性受阻，这进而导致贫血（anemia）和高铁蛋白血症（hyperferritinemia），并最终造成细胞铁死亡（ferroptosis）。 6park.comThe role of iron toxicity in the pathophysiology of COVID-19 is related to the hepcidin mimetic effect of SARS-CoV-2, with consequent internalization of ferroportin, both in the gastrointestinal tract and reticuloendothelial system, thereby causing a blockage in the availability of SF, which leads to anemia and hyperferritinemia, and ultimately ferroptosis5,17. 6park.com通过模仿铁调素的作用（Through mimicking the action of hepcidin），SARS-CoV-2过度增加组织内（例如肝脏、脾脏、骨髓和肌肉）铁蛋白（ferritin）的浓度，同时减少SF（Serum ferritin）的可用性，从而减少红细胞的产生。循环红细胞（circulating erythrocytes）的减少导致持续性的全身低氧血症（systemic hypoxemia），并阻碍组织氧合（tissue oxygenation），进而引发损伤性的急性呼吸综合症（acute respiratory syndrome）。 6park.comThrough mimicking the action of hepcidin, SARS-CoV-2 exaggeratedly increases the concentration of intratissue (e.g., liver, spleen, bone marrow, and muscles)ferritin, while there is a reduction in the availability of SF, and consequently, a reduction in erythrocyte production. This decrease in circulating erythrocytes perpetuates systemic hypoxemia and hinders tissue oxygenation, which is already impaired in patients with acute respiratory syndrome. 6park.com论文依据七 6park.comCOVID-19 compromises iron homeostasis:Transferrin as a target of investigation
COVID-19损害铁稳态：转铁蛋白作为研究目标
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9694355/
https://linkinghub.elsevier.com/retrieve/pii/S0946-672X(22)00189-4
https://pubmed.ncbi.nlm.nih.gov/36509021/ 6park.comPublished online 2022 Nov 25 6park.com论文旨在评估、分析COVID-19患者的铁（iron）、铁蛋白（ferritin）和铁调素（hepcidin）水平以及转铁蛋白受体（transferrin receptor）基因表达。论文考察、研究了427名参与者的铁代谢标志物，其中218人在2020年6月至2020年9月间被诊断为COVID-19患者，另外209人未患有该疾病。 6park.com关于SARS-CoV-2的铁调素模仿，论文指出（以下内容顺序摘录自论文不同章节、段落）： 6park.com自COVID-19大流行开始以来，在患有这种疾病的个体中观察到了许多代谢改变（numerous metabolic alterations）。众所周知，SARS-CoV-2能够模仿铁调素的作用（SARS-CoV-2 can mimic the action of hepcidin），改变细胞内铁代谢（altering intracellular iron metabolism），但关于（SARS-CoV-2）对铁循环（iron cycle）其他途径可能造成的后果，仍然存在认识分歧。 6park.comSince the beginning of the COVID-19 pandemic, numerous metabolic alterations have been observed in individuals with this disease. It is known that SARS-CoV-2 can mimic the action of hepcidin, altering intracellular iron metabolism, but gaps remain in the understanding of possible outcomes in other pathways involved in the iron cycle. 6park.com。。。 6park.comCOVID-19导致多种铁循环途径（iron cycle pathways）发生改变，铁和铁蛋白（ferritin）水平是反映感染状态、演变（进展）以及疾病预后的标志物。转铁蛋白受体（transferrin receptor）基因表达增加表明铁内化增加（increased iron internalization），并且，SARS-CoV-2对铁调素作用的模仿（the mimicry of hepcidin action by SARS-CoV-2）减少了经由铁转运蛋白的铁输出（iron export via ferroportin），这可以解释由细胞内铁捕获（intracellular trapping）引起的低铁循环水平（low circulating levels of iron）。 6park.comCOVID-19 causes changes in several iron cycle pathways, with iron and ferritin levels being markers that reflect the state and evolution of infection, as well as the prognosis of the disease. The increased expression of the transferrin receptor gene suggests increased iron internalization and the mimicry of hepcidin action by SARS-CoV-2, reduces iron export via ferroportin, which would explain the low circulating levels of iron by intracellular trapping. 6park.com。。。 6park.com此外，由于（SARS-CoV-2）病毒的多重交互攻击，COVID-19会发生一系列生化途径失衡（biochemical pathway imbalances），例如铁代谢障碍（iron dysmetabolism）。据推测，这是因为SARS-CoV-2模仿了铁调素的作用（SARS-CoV-2 mimics the action of hepcidin），铁调素与铁转运蛋白（ferroportin）相互作用，导致该复合物（指ferroportin-hepcidin complex）内化和降解（causing the internalization and degradation of this complex），减少了细胞内铁的输出，进而引发高铁蛋白血症（hyperferritinemia）和铁死亡（ferroptosis）。 6park.comFurthermore, due to the multiple interactive levels of viral attack, a set of several biochemical pathway imbalances such as iron dysmetabolism occurs in COVID-19. This is supposedly because SARS-CoV-2 mimics the action of hepcidin [5], which interacts with ferroportin, causing the internalization and degradation of this complex, favoring iron entry into the cell and decreasing its export from the interior of cells [6], hyperferritinemia and ferroptosis develop [5]. 6park.com。。。 6park.com除了增加铁蛋白外，有研究（还）指出了SARS-CoV-2模仿铁调素作用，增加循环和组织铁蛋白的能力（the ability of SARS-CoV-2 to mimic the action of hepcidin, increasing circulating and tissue ferritin）。这导致血清铁缺乏（serum iron deficiency）并降低血红蛋白（lowered hemoglobin）。过量的铁与氧分子相互作用产生活性氧（reactive oxygen），导致不同器官诸如肺、肝、肾和心脏的氧化损伤（oxidative damage），这会导致（细胞）铁死亡（ferroptosis）。在细胞外环境方面（Regarding the extracellular environment），血红蛋白病（hemoglobinopathy）和铁代谢异常（iron dysmetabolism）共同损害红细胞运输O2的能力，导致缺氧。从生理上讲，贫血性缺氧（anemic hypoxia）诱导肺血管收缩（pulmonary vasoconstriction）并增加微血管内纤维蛋白的形成（fibrin formation within this microvasculature）。因此，铁调素和铁转运蛋白的失调化相互作用（the dysregulated interaction of hepcidin and ferroportin）能够通过平滑肌增殖（through smooth muscle proliferation） 导致肺动脉高压（pulmonary artery hypertension），这可能有助于阐明COVID-19患者因呼吸衰竭而死亡的病理机制（which perhaps helps elucidate death from respiratory failure in these COVID-19 patients）。 6park.comIn addition to increased ferritin, studies point to the ability of SARS-CoV-2 to mimic the action of hepcidin, increasing circulating and tissue ferritin. This induces serum iron deficiency and lowered hemoglobin [5]. Excess iron interacts with molecular oxygen generating reactive oxygen species, which contributes to oxidative damage in different organs, such as the lungs, liver, kidneys and heart, which can lead to ferroptosis [7]. Regarding the extracellular environment, the combination of hemoglobinopathy and iron dysmetabolism impairs the ability of erythrocytes to transport O2, resulting in hypoxia. Physiologically, anemic hypoxia induces pulmonary vasoconstriction and increased fibrin formation within this microvasculature. Thus, the dysregulated interaction of hepcidin and ferroportin can lead to pulmonary artery hypertension through smooth muscle proliferation [5], which perhaps helps elucidate death from respiratory failure in these COVID-19 patients. 6park.com。。。 6park.com关于铁和铁蛋白，本研究可以说支持了这样的假设：SARS-CoV-2，通过模仿铁调素的作用（by mimicking the action of hepcidin），增加铁蛋白的流通（increases circulation of ferritin），同时诱导血清铁和血红蛋白水平缺乏（inducing serum iron and hemoglobin level deficiency）。在这一动态中，患者会出现贫血状态（state of anemia），即使他们有高铁蛋白血症（hyperferritinemic）。（SARS-CoV-2）病毒（Spike）蛋白对铁调素的模拟作用（The mimetic action of the viral protein on hepcidin）能够导致铁转运蛋白阻断（ferroportin blockade）、细胞内铁捕获（intracellular iron trapping）和低铁血症（hypoferremia）。有证据表明，炎症期间，细胞内铁的积累（the accumulation of intracellular iron）也会增加铁蛋白，进一步增加细胞内铁的浓度，（与之有关的铁）代谢失调可导致早期多细胞铁死亡（early multicellular ferropoptosis）。 6park.comConsidering the results of the present study, in relation to iron and ferritin, it can be said they support the hypothesis that SARS-CoV-2, by mimicking the action of hepcidin, increases the circulation of ferritin while inducing serum iron and hemoglobin level deficiency. In this dynamic, the patient develops a state of anemia, even though they are hyperferritinemic [5]. The mimetic action of the viral protein on hepcidin can lead to ferroportin blockade causing intracellular iron trapping and hypoferremia. There is evidence that during inflammation, the accumulation of intracellular iron also increases ferritin, further increasing the concentration of intracellular iron, evidencing metabolic dysregulation that can lead to early multicellular ferropoptosis [9]. 6park.com- 6park.com9、ferroportin（铁转运蛋白） 6park.com- 6park.com相关论文三 6park.comHepcidin agonists as therapeutic tools
铁调素激动剂作为治疗工具
https://ashpublications.org/blood/article/131/16/1790/36820/Hepcidin-agonists-as-therapeutic-tools 6park.comBLOOD SPOTLIGHT| April 19, 2018 6park.com这篇论文设计的小铁调素与前面的minihepcidins 很相似。 6park.com论文“Utilizing hepcidin pathway to treat iron overload disorders”（利用铁调素途径治疗铁过载疾病）小节中说： 6park.com。。。这些遗传研究促使人们探索其他方法来增加铁调素缺乏的铁超载患者的循环铁调素。 全长铁调素的合成效率相对较低，而且由于肾脏清除速度快，铁调素在循环中的半衰期很短。为了克服这些限制，（其它研究已经）设计了几种分子来模拟铁调素活性或刺激内源性铁调素产生。我们开发了小铁调素，这是一种基于铁调素7-9 N端氨基酸片段的短肽。我们首先表明，hepcidin的这个N末端片段足以在体外诱导FPN-1（ferroportin-1，铁转运蛋白-1）内化和降解。然后，我们对这些肽进行了改造以延长其半衰期和效力，实验证明，给小鼠施用的这些（改造后的）小铁调素肽模拟了内源性铁调素对铁（释放）的限制作用。 6park.comThese genetic studies prompted the exploration of other approaches to increasing circulating hepcidin in iron-overloaded patients with hepcidin deficiency. Synthesis of full-length hepcidin is relatively inefficient, and the half-life of hepcidin in circulation is short because of rapid renal clearance.36 To overcome these limitations, several molecules have been designed to mimic hepcidin activity or stimulate endogenous hepcidin production.2,37 We developed minihepcidins (MHs), short peptides based on the 7-9 N-terminal amino acid segment of hepcidin. We first showed that this N-terminal segment of hepcidin is sufficient to induce FPN-1 internalization and degradation in vitro.38 We then engineered these peptides to increase their half-life and potency, and demonstrated that administration of MHs to mice mimics the iron-restrictive effect of endogenous hepcidin. 6park.com论文“Utilizing hepcidin agonists to treat siderophilic infections”（利用铁调素激动剂治疗嗜铁菌感染）小节还提到： 6park.com已经开发了多种其他策略来模拟铁调素活性或增加内源性铁调素的产量。其中包括合成全长人铁调素、另一种基于肽的铁调素模拟物、小分子FPN-1抑制剂、或通过体内靶向和降解Tmprss6信使RNA来对Tmprss6进行药理学抑制，在铁调素缺乏症的临床前模型中（上述方法）均显示出相似的有益效果。。。 6park.comMultiple other strategies have been developed to mimic hepcidin activity or increase production of endogenous hepcidin. These include synthetic full-length human hepcidin,45 another peptide-based hepcidin mimetic,46 small molecule FPN-1 inhibitors,47 or pharmacologic inhibition of Tmprss6 by in vivo targeting and degradation of Tmprss6 messenger RNA,48,49 all displaying similar beneficial effects in preclinical models of hepcidin deficiency. 6park.com笔者也未考察SARS-CoV-2 Spike尾部区域/Covidin片断与该论文开发的小铁调素肽氨基酸序列的相似、关联性。
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