Xyrox
2022-04-11T14:35:19+00:00
主要期刊：biomaterials，bioactive materials等
物质：EGCG 表没食子儿茶素没食子酸酯
作用: 抗菌、抗病毒、抗氧化、抗动脉硬化、抗血栓形成、抗血管增生、抗炎以及抗肿瘤作用
来源：绿茶茶多酚
中医古籍：
《本草纲目》略
《神农本草经》 轻身、耐老
《本草经集注》轻身，耐老，耐饥寒，高气不老
support
现代中医就是现代医学一部分，由传统医学而来，西医指的是西方社会在科学医学之前的主要医学，主要有放血治疗(至少干掉2位君主)，动物粪便，祈祷咒语+圣水(主要功绩在于延续了欧洲300年左右黑死病，使得西部欧洲快速跳出马尔萨斯陷阱)
中医在现代医学中有相当一部分重叠，当然中叠部分也有很多内容被证错，如脉搏这个和心律，血压的研究是比较科学的，此外，问诊这方面基本上是完全重合的。最主要的战场在植物提取药，植物提取药最早的辉煌并不是在中国，而是在日本，早期有大量日本研究关于植物提取药。
中医理论或者西医很多东西不过是换了一个说法而已，很多理论来源于早期研究不足，比如女性随着年龄增长容易骨质疏松，其实主要原因是卵巢功能的退化，或者糖尿病对于糖的摄取，实际上食用糖只会对II糖尿病影响。
植物提取药主要是有2个特征使得其成为现代医学
1.浓缩，提高强度以对抗病症
2.单一，能够确定某个成分对于具体病症的治疗机理
科学程度：
目前植物提取药物或者其他药物对于实际使用的情况还是很复杂的，靶向药绝大多数还是束之高阁的研究产物，而且对于传统医学的植物药来说，多种物质，如茶多酚和黄酮素等，其协同作用，和对于身体综合影响是无法准确估计的，目测按照现在科学逻辑也是无法满足的。比如黄酮素十几种，机制基本重复很高。
换句话说，目前大多数药物还是无法明确确切机理的经验产品(实际上经验科学广泛存在于所有实际发展的行业，且相当重要)，即便是某些表征被认为是可以确定的，但是往往在发展中被推翻或者拓展。
其他药物：
主要是化学，化工产品，有机化学的结果，如医药巨头拜耳曾经就是搞化工品的，大多数植物提取药被拆分然后重新组合，或者人工合成，如白藜芦醇。其中drugs的发展阶段就是，植物提取(大麻)到半化学合成(海洛因)再到合成(冰毒)。
医学药物的科学发展：
实际上和医学的发展一样，如1950s，英国医学界认为同性恋是病症，需要服用激素类药物(最知名人物为 图灵)，美国外科手术治疗精神疾病采用的是切除脑部部分，日本或者德国美国科学家药物治疗精神疾病，如1970s越战，制备了现代大多数硬毒品，包括美国一直到1980s依然在争论香烟是否有害健康，19030s之后，香烟一直被认为是治疗的药物。
所以从历史上来说，科学永远是不科学的。这是马原基本理论之一：真理绝对性和相对性，真理和实践之间不断的发展。从这个道理来看，学好哲学比科学更重要，不然博士为什么都叫phd呢？
编辑：
1.修补手速过快少掉的i，疫情在家家里老键盘按英文总少，又检查了一下，应该没啥问题。
2.关于doi，感到疑惑，因为EGCG是研究了相当长时间的药物，相关药物研究更多，作为关键词能在xmol或者webofscience搜索出一大堆，不是很明白其中逻辑，如果表达有期刊号自己能看，为何出现关键词却没有搜索能力？
3.phd原因是因为博士是上升到理论研究的学位，是学术研究，科学没有证伪之前其哲学逻辑是可以存在的，如医学和心理学社会学等一大群学科都可以研究对抗精神类疾病，其中部分学科为自然学科。
4.传统西医，传统中医都是现代医学的一部分。
5.如果反对某一个东西，但是无法体系的证伪，这个理论依然可以存在，甚至理论可以缩小其应用范围而合理存在，这才是科学。
那就更新一个时髦的：图文摘取，主要防止一些人DOI打不开。[s:ac:哭笑]
复旦大学附属肿瘤医院，罗格斯大学的21年的作品，Trends in Food Science & Technology：(顺便有个疑问哈，没有别的意思，一口一个doi自己会看，能力超群，但是好像关键词都有哈，好像检索也挺方便的哈，1秒就全出)
[img]https://img.nga.178.com/attachments/mon_202204/18/-7Q17p-7f8dK2rT3cSj5-ex.jpg[/img]
Highlights
•EGCG may impede SARS-CoV-2 infection by activating Nrf2 which downregulates ACE2 and TMPRSS2.
•EGCG may suppress SARS-CoV-2 replication via inhibiting SARS-CoV-2 main protease, mitochondrial ROS and ER-resident GRP78.
•EGCG may protect against ROS burst inflicted by SARS-CoV-2 induced neutrophil extracellular traps.
•EGCG may decrease SARS-CoV-2 triggered cytokine storm, sepsis, thrombosis and lung fibrosis.
•EGCG may prevent diabetes comorbidity risk in COVID-19 patients.
节选一段：
EGCG, with eight phenolic groups, provides multiple electron acceptors and donors for hydrogen bonding to a variety of molecules, especially to proteins. This is one of the reasons why EGCG has been shown to bind to many different proteins with high affinity and inhibit their activities. In studies in cell free systems, this is especially true as the inhibitory activity is stronger when lower concentrations of proteins are used in the assay. Without detailed characterization of the specificity or reversibility of the binding, these types of studies may result in the false identification of proteins as being “targets” for EGCG. The different activities and low bioavailability of EGCG makes extrapolation of results from in vitro studies to in vivo situations difficult.
With these chemical reactivities, EGCG has been shown to have many different biological effects, including anti-viral activities and these have been reviewed (Kaihatsu et al., 2018; Steinmann et al., 2013; Xu, Xu, & Zheng, 2017). EGCG has been shown to possess a broad spectrum of antiviral activities against RNA viruses such as hepatitis C virus, human immunodeficiency virus, Ebola virus and influenza virus, Zika virus, Dengue virus, West Nile viruses, Chikungunya virus, human porcine reproductive and respiratory virus; as well as DNA viruses such as herpes simplex virus, human papillomavirus, and hepatitis B virus. The structure-activity relationship of different catechins has been studied; EGCG has the highest activity, and the 3-galloyl and 5′-OH groups of EGCG appear crucial for the anti-viral activity (Kaihatsu et al., 2018).
EGCG mainly inhibits the early stages of viral infection, such as attachment, entry, and membrane fusion, by interfering with either viral membrane proteins or host cellular proteins or both. EGCG-fatty acid monoesters, which bind more effectively to viral and cellular membranes, have been shown to improve the anti-viral activity of EGCG against influenza and other viruses (Kaihatsu et al., 2018; Mhatre et al., 2020; Steinmann et al., 2013; Xu, Xu, & Zheng, 2017). Most of these studies were conducted in vitro under conditions that may be very different from those situations in humans, and these results should be interpreted with caution.
Many attempts have been made in developing EGCG into a therapeutic drug. Of note is that Veregen, a green tea polyphenol ornament preparation with EGCG as the major constituent, has been approved by the Food and Drug Administration (FDA) and European Medicine Agent (EMA) as a drug for topical treatment of external genital and anal warts caused by papillomavirus (Hara, 2011). The key reason of the success is topical application. How to deliver an effective dose of EGCG to the site of anti-viral action is a challenging issue in therapeutic application.
Dose and safety issues of EGCG for COVID-19 prevention and treatment
The biological activities and toxic effects of EGCG in mice have been extensively studied. Generally, the effect of an i.p. dose approximates that of a 10-fold oral dose. For example, 5575 mg/kg (i.p.) or 600 mg/kg (i.g.) for five consecutive days caused hepatoxicity and elevated hepatic Nrf2 response, while one dose of 200 mg/kg (i.p.) or 2000 mg/kg (i.g.) caused lethal consequence associated with suppression of hepatic Nrf2, in the same mouse species (Wang, Wang, Wan, Yang, & Zhang, 2015). The maximum non-toxic dose of EGCG by i.p. injection was 45 mg/kg (Wang, Wang, et al., 2015; Wang, Wei, et al., 2015; Wang, Wang, et al., 2019; Wang, Yang, et al., 2019) or 400450 mg/kg by i.g. administration in mice (Lambert et al., 2010). Accordingly, the non-toxic doses of EGCG at 1040 mg/kg (i.p.) or 100400 mg/kg (orally) are extensively used for elucidating functions of EGCG in mice (Bose et al., 2008; Gan et al., 2015; Kumazoe et al., 2013; Siddiqui et al., 2009; Yan, Zhao, Suo, Liu, & Zhao, 2012).
To prevent SARS-CoV-2 infection, the key step is to prevent the binding of viral spike proteins to cellular receptors (ACE2) and to inhibit cell host proteases (TMPRSS2). The activation of Nrf2 by EGCG at non-toxic doses, which has been demonstrated in animal models (Dong et al., 2016; Na et al., 2008; Sun et al., 2017; Yang et al., 2018), may reach a magnitude that can downregulate both ACE2 and TMPRSS2. However, these remain to be demonstrated. As described above, many studies in rodent models have demonstrated that EGCG at a non-toxic daily dose (under 30 mg/kg, i.p. or 300 mg/kg, i.g.) in mice can ameliorate hypoxia-induced oxidative stress, cytokine storm, and diabetes comorbidity as well as decrease GRP78 expression/activity, ER stress, thrombosis, sepsis, and lung fibrosis. These activities, if could be manifested in humans, would be beneficial in the prevention or alleviation of COVID-19 and associated syndromes.
The rodent dose can be converted to a human equivalent dose based on body weight divided by conversion factor of 12.9, because the mouse has a larger body surface area and higher metabolic rate per unit body weight (Reagan-Shaw, Nihal, & Ahmad, 2008). The above describes effective concentration of oral 300 mg/kg EGCG in mice is equal to 1392 mg EGCG daily for an adult with body weight of 60 kg. It was reported recently that daily 600 mg EGCG given orally to patients with idiopathic pulmonary fibrosis reversed profibrotic biomarkers in their diagnostic biopsies and serum samples, while FDA-approved drugs showed no beneficial effects (Chapman et al., 2020).
Two to 4 h following oral administrator of green tea polyphenols at a dose of 500 mg/kg in mice, the serum level of polyphenols reaches maximum value at 910 μg/mL (Yang et al., 1998). This level is higher than the IC50 (2.8 μg of green tea extract per mL) for the inhibition of Mpro activity of SARS-CoV-2 in vitro (Zhu & Xie, 2020). The inhibition of Mpro activity of SARS-CoV-2 by EGCG shows an IC50 of 7.5 μM (Zhu & Xie, 2020). In human studies, after ingesting 375 to 1200 mg of EGCG (as green tea extract or Polyphenon E) under fasting conditions, the maximum levels of EGCG were 4.35.6 μM (Chow et al., 2005; Nakagawa, Okuda, & Miyazawa, 1997). These human blood levels of EGCG approach, but are still lower than, the effective inhibitory concentration of EGCG against Mpro observed in vivo. There is also a possibility that some products formed from EGCG oxidation in vivo can inhibit Mpro activity of SARS-CoV-2 (Jang et al., 2020). The extrapolation of results from studies in vitro to situations in vivo, and the translation of animal studies to humans, are challenging issues. More studies on the dose response relationship of EGCG in humans are needed.
Following ingestion of tea catechins, the concentration of EGCG and other catechins can be rather high in the oral cavity. For example, in a study with volunteers, after each drinking 200 mL of warm tea (containing 1,200 mg of green tea extracts), followed by rinsing the mouth rigorously 10 times, the initial salivary concentrations of EGCG were 1050 μM with elimination t1/2 values of 1020 min. EGC and EC, were present in slightly higher concentrations (Yang, Lee, & Chen, 1999). In a second experiment, after subjects holding 96 mg EGCG in 60 mL in the mouth for 2 min, the saliva samples (collected similarly) initially contained 120300 μM EGCG and decreased to 2565 μM after 30 min. These results suggest that after drinking or gargling tea, the levels of EGCG and other catechins in the oral/nasal/pharyngeal cavity could be high enough to protect against viral infection. It has been shown in Japan that daily gargling a tea catechin solution significantly lowered the incidence of influenza infection in elderly (Yamada, Takuma, Daimon, & Hara, 2006). In a randomized double-blind trial of 200 healthcare workers, consumption of catechin capsules for 5 months had a protective effect against influenza virus compared to the placebo group (Matsumoto, Yamada, Takuma, Niino, & Sagesaka, 2011). These interesting studies need to be repeated in studies with more subjects and extended to other anti-viral studies in humans.
更新，有人说biomaterials是组装工程没半点关系，一下找了一篇纳米药制备的：
Hyaluronic acid-green tea catechin micellar nanocomplexes: Fail-safe cisplatin nanomedicine for the treatment of ovarian cancer without off-target toxicity
新加坡生物工程纳米研究所
[img]https://img.nga.178.com/attachments/mon_202204/18/-7Q17p-jjuuZrT3cSlp-p0.jpg[/img]
顺便更新bioactive materials：
ROS-responsive capsules engineered from EGCG-Zinc networks improve therapeutic angiogenesis in mouse limb ischemia
(treatment of limb ischemia requires that promote angiogenesis)
Peking Union Medical College
[img]https://img.nga.178.com/attachments/mon_202204/18/-7Q17p-vedZcT3cSsg-ba.jpg[/img]
The previous studies indicate that the 3′-OH4′-OH moieties are the most likely binding sites of the polyphenols for metals [27]. In order to verify the successful coordination between EGCG and zinc in this EGCG/Zn Ps delivery system, several different detection methods, such as FTIR, XPS were adopted, which were strongly recommended by literatures [15,28]. First, the acidic nature of the galloyl groups in EGCG cause zeta potential shift between EGCG and zinc. Second, FTIR show the peaks at 1425 cm−1 and 1145 cm−1 were attributed to the saturated phenolic hydroxyl group of EGCG, which were buried in the EGCG/Zn Ps indicating the phenolic groups coordinated with metal ions. Third, the peak at 533.3 eV and 531.7 eV were corresponded to HOC and Cdouble bondO groups of EGCG [28]. After chelation with zinc ions, the O1s peak corresponding to the HOC group shifted from 533.3 eV to lower binding energy of 532.9 eV, which suggested electron transfer from zinc ions to EGCG [29]. All these results were in accordance to the previous reports that the iron shift between phenolic and metals [16,28]. From our data, the release speed is a bit rapider in H2O2 than PBS, which may indicate that EGCG was oxidized by H2O2 to form benzoquinone species and the capsule decomposed consequently. Therefore, the mechanism of the Zn2+ release may due to the degradation of EGCG/Zn Ps. Besides, CaCO3 was selected as the temporary template for its good biocompatibility.
As excess of extracellular Zn2+ is toxic, which could induce cell death [30]. Our findings were generally consistent with previous studies that the toxic concentration of Zn2+ various from 100 μM to 600 μM for different cells [31,32]. Meanwhile, compared to Zn(NO3)2, EGCG/Zn Ps showed much lower toxicity and better cell migration and VEGF expression, which was mainly attributed to the sustained release of zinc ions. Zn2+ has been reported to promote the expression of vascular endothelial growth factor (VEGF) [33]. Sustained release ion could exert better property with less toxic [34,35]. Besides, EGCG was reported to accelerate reepithelialization and angiogenesis [[36], [37], [38]]. Therefore, it may be reasonable to explain that the EGCG/Zn Ps could exert the better result by combining the advantages of EGCG and Zn2+ sustain-release. In intro experiment, EGCG/Zn Ps has also been proved exerting antioxidant by eliminating H2O2 and showed a dose-dependent effect in the suppression of TNF-α and IL-6 expressions. These results were in accordance to previous studies [21,39].
The concentration of zinc to exert angiogenesis in the mouse model of limb ischemic is less well known. Attia reported that 30 μM of zinc-containing fluid had significantly improve the wound healing [40]. According to our in vitro experiment, the optimum concentration of zinc ions for cell migration and VEGF expression was 25 μM. So that 25 μM was chosen for in vivo study. Meanwhile, the injection interval of 1, 3 and 5 days were adopted for following two reason. First, the ROS level increased most obviously in the early stage of limb acute ischemia, so that is the best time for EGCG/Zn Ps to improvement the microenvironment [41]. Second, according to the release kinetic test, there was around 80% zinc ions release within the first 48 h and interval injection benefit to guarantee the dynamic stability of the zinc concentration. Besides, 14-day time point was selected because the angiogenesis was shown to be transient as blood vessels regressed with time [42]. It would be more valuable if we could demonstrate that the newly formed blood vessels are indeed mature and remain functional for more long time, but we mainly focus on demonstrating that EGCG/Zn Ps could exert angiogenesis in the present study. Long-term exploration worth further investigate.
Pipinos et al. reported that a high level of ROS generated in the ischemia hindlimb causes oxidative stress that contributes to inflammation in PAD and suppresses angiogenesis [43]. Kwon reported that H2O2-responsive antioxidant polymeric nanoparticles as therapeutic agents for peripheral arterial disease [44]. Therefore, reduce ROS stress might be a promising approach to promote angiogenesis and relieve symptoms of ischemia [45,46]. Urao N has reported that angiogenesis and recovery of blood perfusion required an appropriate range of ROS because both too much and too little ROS were detrimental to cell viability and functions [47]. Therefore, in our study, no obvious ischemia improvement was observed from EGCG group, which might due to excessively clear of ROS. However, EGCG/Zn Ps enable to eliminate ROS in a more moderate way and keep ROS in proper level benefit for angiogenesis. In addition, our study confirmed that zinc could promote the expression of the hypoxia response factor HIF-1α, in accordance with previous reports [48], which was surely benefit from the sustained release of the EGCG/Zn Ps system. Therefore, it is reasonable that EGCG/Zn Ps could significantly improve angiogenesis in vivo, which were widely demonstrated by limb ischemic score, limb temperature, histological results as well as LDPI and micro-CTA evaluation. Certainly, more deeper mechanism worth further study.
EGCG/Zn Ps, a new delivery system with angiogenesis property, was developed based on green tea polyphenolmetal networks. The biocompatible EGCG/Zn Ps could not only achieve sustained release of Zn2+ resulting in reduced toxicity and enhancive angiogenesis but also improve microenvironment by scavenging excess ROS and inhibiting inflammatory cytokine via EGCG. Moreover, this study demonstrate a safe and promising approach to combine the merit of Zn2+ and EGCG, thus enabling it as a potential medical therapy to treat CLI.
物质：EGCG 表没食子儿茶素没食子酸酯
作用: 抗菌、抗病毒、抗氧化、抗动脉硬化、抗血栓形成、抗血管增生、抗炎以及抗肿瘤作用
来源：绿茶茶多酚
中医古籍：
《本草纲目》略
《神农本草经》 轻身、耐老
《本草经集注》轻身，耐老，耐饥寒，高气不老
support
现代中医就是现代医学一部分，由传统医学而来，西医指的是西方社会在科学医学之前的主要医学，主要有放血治疗(至少干掉2位君主)，动物粪便，祈祷咒语+圣水(主要功绩在于延续了欧洲300年左右黑死病，使得西部欧洲快速跳出马尔萨斯陷阱)
中医在现代医学中有相当一部分重叠，当然中叠部分也有很多内容被证错，如脉搏这个和心律，血压的研究是比较科学的，此外，问诊这方面基本上是完全重合的。最主要的战场在植物提取药，植物提取药最早的辉煌并不是在中国，而是在日本，早期有大量日本研究关于植物提取药。
中医理论或者西医很多东西不过是换了一个说法而已，很多理论来源于早期研究不足，比如女性随着年龄增长容易骨质疏松，其实主要原因是卵巢功能的退化，或者糖尿病对于糖的摄取，实际上食用糖只会对II糖尿病影响。
植物提取药主要是有2个特征使得其成为现代医学
1.浓缩，提高强度以对抗病症
2.单一，能够确定某个成分对于具体病症的治疗机理
科学程度：
目前植物提取药物或者其他药物对于实际使用的情况还是很复杂的，靶向药绝大多数还是束之高阁的研究产物，而且对于传统医学的植物药来说，多种物质，如茶多酚和黄酮素等，其协同作用，和对于身体综合影响是无法准确估计的，目测按照现在科学逻辑也是无法满足的。比如黄酮素十几种，机制基本重复很高。
换句话说，目前大多数药物还是无法明确确切机理的经验产品(实际上经验科学广泛存在于所有实际发展的行业，且相当重要)，即便是某些表征被认为是可以确定的，但是往往在发展中被推翻或者拓展。
其他药物：
主要是化学，化工产品，有机化学的结果，如医药巨头拜耳曾经就是搞化工品的，大多数植物提取药被拆分然后重新组合，或者人工合成，如白藜芦醇。其中drugs的发展阶段就是，植物提取(大麻)到半化学合成(海洛因)再到合成(冰毒)。
医学药物的科学发展：
实际上和医学的发展一样，如1950s，英国医学界认为同性恋是病症，需要服用激素类药物(最知名人物为 图灵)，美国外科手术治疗精神疾病采用的是切除脑部部分，日本或者德国美国科学家药物治疗精神疾病，如1970s越战，制备了现代大多数硬毒品，包括美国一直到1980s依然在争论香烟是否有害健康，19030s之后，香烟一直被认为是治疗的药物。
所以从历史上来说，科学永远是不科学的。这是马原基本理论之一：真理绝对性和相对性，真理和实践之间不断的发展。从这个道理来看，学好哲学比科学更重要，不然博士为什么都叫phd呢？
编辑：
1.修补手速过快少掉的i，疫情在家家里老键盘按英文总少，又检查了一下，应该没啥问题。
2.关于doi，感到疑惑，因为EGCG是研究了相当长时间的药物，相关药物研究更多，作为关键词能在xmol或者webofscience搜索出一大堆，不是很明白其中逻辑，如果表达有期刊号自己能看，为何出现关键词却没有搜索能力？
3.phd原因是因为博士是上升到理论研究的学位，是学术研究，科学没有证伪之前其哲学逻辑是可以存在的，如医学和心理学社会学等一大群学科都可以研究对抗精神类疾病，其中部分学科为自然学科。
4.传统西医，传统中医都是现代医学的一部分。
5.如果反对某一个东西，但是无法体系的证伪，这个理论依然可以存在，甚至理论可以缩小其应用范围而合理存在，这才是科学。
那就更新一个时髦的：图文摘取，主要防止一些人DOI打不开。[s:ac:哭笑]
复旦大学附属肿瘤医院，罗格斯大学的21年的作品，Trends in Food Science & Technology：(顺便有个疑问哈，没有别的意思，一口一个doi自己会看，能力超群，但是好像关键词都有哈，好像检索也挺方便的哈，1秒就全出)
[img]https://img.nga.178.com/attachments/mon_202204/18/-7Q17p-7f8dK2rT3cSj5-ex.jpg[/img]
Highlights
•EGCG may impede SARS-CoV-2 infection by activating Nrf2 which downregulates ACE2 and TMPRSS2.
•EGCG may suppress SARS-CoV-2 replication via inhibiting SARS-CoV-2 main protease, mitochondrial ROS and ER-resident GRP78.
•EGCG may protect against ROS burst inflicted by SARS-CoV-2 induced neutrophil extracellular traps.
•EGCG may decrease SARS-CoV-2 triggered cytokine storm, sepsis, thrombosis and lung fibrosis.
•EGCG may prevent diabetes comorbidity risk in COVID-19 patients.
节选一段：
EGCG, with eight phenolic groups, provides multiple electron acceptors and donors for hydrogen bonding to a variety of molecules, especially to proteins. This is one of the reasons why EGCG has been shown to bind to many different proteins with high affinity and inhibit their activities. In studies in cell free systems, this is especially true as the inhibitory activity is stronger when lower concentrations of proteins are used in the assay. Without detailed characterization of the specificity or reversibility of the binding, these types of studies may result in the false identification of proteins as being “targets” for EGCG. The different activities and low bioavailability of EGCG makes extrapolation of results from in vitro studies to in vivo situations difficult.
With these chemical reactivities, EGCG has been shown to have many different biological effects, including anti-viral activities and these have been reviewed (Kaihatsu et al., 2018; Steinmann et al., 2013; Xu, Xu, & Zheng, 2017). EGCG has been shown to possess a broad spectrum of antiviral activities against RNA viruses such as hepatitis C virus, human immunodeficiency virus, Ebola virus and influenza virus, Zika virus, Dengue virus, West Nile viruses, Chikungunya virus, human porcine reproductive and respiratory virus; as well as DNA viruses such as herpes simplex virus, human papillomavirus, and hepatitis B virus. The structure-activity relationship of different catechins has been studied; EGCG has the highest activity, and the 3-galloyl and 5′-OH groups of EGCG appear crucial for the anti-viral activity (Kaihatsu et al., 2018).
EGCG mainly inhibits the early stages of viral infection, such as attachment, entry, and membrane fusion, by interfering with either viral membrane proteins or host cellular proteins or both. EGCG-fatty acid monoesters, which bind more effectively to viral and cellular membranes, have been shown to improve the anti-viral activity of EGCG against influenza and other viruses (Kaihatsu et al., 2018; Mhatre et al., 2020; Steinmann et al., 2013; Xu, Xu, & Zheng, 2017). Most of these studies were conducted in vitro under conditions that may be very different from those situations in humans, and these results should be interpreted with caution.
Many attempts have been made in developing EGCG into a therapeutic drug. Of note is that Veregen, a green tea polyphenol ornament preparation with EGCG as the major constituent, has been approved by the Food and Drug Administration (FDA) and European Medicine Agent (EMA) as a drug for topical treatment of external genital and anal warts caused by papillomavirus (Hara, 2011). The key reason of the success is topical application. How to deliver an effective dose of EGCG to the site of anti-viral action is a challenging issue in therapeutic application.
Dose and safety issues of EGCG for COVID-19 prevention and treatment
The biological activities and toxic effects of EGCG in mice have been extensively studied. Generally, the effect of an i.p. dose approximates that of a 10-fold oral dose. For example, 5575 mg/kg (i.p.) or 600 mg/kg (i.g.) for five consecutive days caused hepatoxicity and elevated hepatic Nrf2 response, while one dose of 200 mg/kg (i.p.) or 2000 mg/kg (i.g.) caused lethal consequence associated with suppression of hepatic Nrf2, in the same mouse species (Wang, Wang, Wan, Yang, & Zhang, 2015). The maximum non-toxic dose of EGCG by i.p. injection was 45 mg/kg (Wang, Wang, et al., 2015; Wang, Wei, et al., 2015; Wang, Wang, et al., 2019; Wang, Yang, et al., 2019) or 400450 mg/kg by i.g. administration in mice (Lambert et al., 2010). Accordingly, the non-toxic doses of EGCG at 1040 mg/kg (i.p.) or 100400 mg/kg (orally) are extensively used for elucidating functions of EGCG in mice (Bose et al., 2008; Gan et al., 2015; Kumazoe et al., 2013; Siddiqui et al., 2009; Yan, Zhao, Suo, Liu, & Zhao, 2012).
To prevent SARS-CoV-2 infection, the key step is to prevent the binding of viral spike proteins to cellular receptors (ACE2) and to inhibit cell host proteases (TMPRSS2). The activation of Nrf2 by EGCG at non-toxic doses, which has been demonstrated in animal models (Dong et al., 2016; Na et al., 2008; Sun et al., 2017; Yang et al., 2018), may reach a magnitude that can downregulate both ACE2 and TMPRSS2. However, these remain to be demonstrated. As described above, many studies in rodent models have demonstrated that EGCG at a non-toxic daily dose (under 30 mg/kg, i.p. or 300 mg/kg, i.g.) in mice can ameliorate hypoxia-induced oxidative stress, cytokine storm, and diabetes comorbidity as well as decrease GRP78 expression/activity, ER stress, thrombosis, sepsis, and lung fibrosis. These activities, if could be manifested in humans, would be beneficial in the prevention or alleviation of COVID-19 and associated syndromes.
The rodent dose can be converted to a human equivalent dose based on body weight divided by conversion factor of 12.9, because the mouse has a larger body surface area and higher metabolic rate per unit body weight (Reagan-Shaw, Nihal, & Ahmad, 2008). The above describes effective concentration of oral 300 mg/kg EGCG in mice is equal to 1392 mg EGCG daily for an adult with body weight of 60 kg. It was reported recently that daily 600 mg EGCG given orally to patients with idiopathic pulmonary fibrosis reversed profibrotic biomarkers in their diagnostic biopsies and serum samples, while FDA-approved drugs showed no beneficial effects (Chapman et al., 2020).
Two to 4 h following oral administrator of green tea polyphenols at a dose of 500 mg/kg in mice, the serum level of polyphenols reaches maximum value at 910 μg/mL (Yang et al., 1998). This level is higher than the IC50 (2.8 μg of green tea extract per mL) for the inhibition of Mpro activity of SARS-CoV-2 in vitro (Zhu & Xie, 2020). The inhibition of Mpro activity of SARS-CoV-2 by EGCG shows an IC50 of 7.5 μM (Zhu & Xie, 2020). In human studies, after ingesting 375 to 1200 mg of EGCG (as green tea extract or Polyphenon E) under fasting conditions, the maximum levels of EGCG were 4.35.6 μM (Chow et al., 2005; Nakagawa, Okuda, & Miyazawa, 1997). These human blood levels of EGCG approach, but are still lower than, the effective inhibitory concentration of EGCG against Mpro observed in vivo. There is also a possibility that some products formed from EGCG oxidation in vivo can inhibit Mpro activity of SARS-CoV-2 (Jang et al., 2020). The extrapolation of results from studies in vitro to situations in vivo, and the translation of animal studies to humans, are challenging issues. More studies on the dose response relationship of EGCG in humans are needed.
Following ingestion of tea catechins, the concentration of EGCG and other catechins can be rather high in the oral cavity. For example, in a study with volunteers, after each drinking 200 mL of warm tea (containing 1,200 mg of green tea extracts), followed by rinsing the mouth rigorously 10 times, the initial salivary concentrations of EGCG were 1050 μM with elimination t1/2 values of 1020 min. EGC and EC, were present in slightly higher concentrations (Yang, Lee, & Chen, 1999). In a second experiment, after subjects holding 96 mg EGCG in 60 mL in the mouth for 2 min, the saliva samples (collected similarly) initially contained 120300 μM EGCG and decreased to 2565 μM after 30 min. These results suggest that after drinking or gargling tea, the levels of EGCG and other catechins in the oral/nasal/pharyngeal cavity could be high enough to protect against viral infection. It has been shown in Japan that daily gargling a tea catechin solution significantly lowered the incidence of influenza infection in elderly (Yamada, Takuma, Daimon, & Hara, 2006). In a randomized double-blind trial of 200 healthcare workers, consumption of catechin capsules for 5 months had a protective effect against influenza virus compared to the placebo group (Matsumoto, Yamada, Takuma, Niino, & Sagesaka, 2011). These interesting studies need to be repeated in studies with more subjects and extended to other anti-viral studies in humans.
更新，有人说biomaterials是组装工程没半点关系，一下找了一篇纳米药制备的：
Hyaluronic acid-green tea catechin micellar nanocomplexes: Fail-safe cisplatin nanomedicine for the treatment of ovarian cancer without off-target toxicity
新加坡生物工程纳米研究所
[img]https://img.nga.178.com/attachments/mon_202204/18/-7Q17p-jjuuZrT3cSlp-p0.jpg[/img]
顺便更新bioactive materials：
ROS-responsive capsules engineered from EGCG-Zinc networks improve therapeutic angiogenesis in mouse limb ischemia
(treatment of limb ischemia requires that promote angiogenesis)
Peking Union Medical College
[img]https://img.nga.178.com/attachments/mon_202204/18/-7Q17p-vedZcT3cSsg-ba.jpg[/img]
The previous studies indicate that the 3′-OH4′-OH moieties are the most likely binding sites of the polyphenols for metals [27]. In order to verify the successful coordination between EGCG and zinc in this EGCG/Zn Ps delivery system, several different detection methods, such as FTIR, XPS were adopted, which were strongly recommended by literatures [15,28]. First, the acidic nature of the galloyl groups in EGCG cause zeta potential shift between EGCG and zinc. Second, FTIR show the peaks at 1425 cm−1 and 1145 cm−1 were attributed to the saturated phenolic hydroxyl group of EGCG, which were buried in the EGCG/Zn Ps indicating the phenolic groups coordinated with metal ions. Third, the peak at 533.3 eV and 531.7 eV were corresponded to HOC and Cdouble bondO groups of EGCG [28]. After chelation with zinc ions, the O1s peak corresponding to the HOC group shifted from 533.3 eV to lower binding energy of 532.9 eV, which suggested electron transfer from zinc ions to EGCG [29]. All these results were in accordance to the previous reports that the iron shift between phenolic and metals [16,28]. From our data, the release speed is a bit rapider in H2O2 than PBS, which may indicate that EGCG was oxidized by H2O2 to form benzoquinone species and the capsule decomposed consequently. Therefore, the mechanism of the Zn2+ release may due to the degradation of EGCG/Zn Ps. Besides, CaCO3 was selected as the temporary template for its good biocompatibility.
As excess of extracellular Zn2+ is toxic, which could induce cell death [30]. Our findings were generally consistent with previous studies that the toxic concentration of Zn2+ various from 100 μM to 600 μM for different cells [31,32]. Meanwhile, compared to Zn(NO3)2, EGCG/Zn Ps showed much lower toxicity and better cell migration and VEGF expression, which was mainly attributed to the sustained release of zinc ions. Zn2+ has been reported to promote the expression of vascular endothelial growth factor (VEGF) [33]. Sustained release ion could exert better property with less toxic [34,35]. Besides, EGCG was reported to accelerate reepithelialization and angiogenesis [[36], [37], [38]]. Therefore, it may be reasonable to explain that the EGCG/Zn Ps could exert the better result by combining the advantages of EGCG and Zn2+ sustain-release. In intro experiment, EGCG/Zn Ps has also been proved exerting antioxidant by eliminating H2O2 and showed a dose-dependent effect in the suppression of TNF-α and IL-6 expressions. These results were in accordance to previous studies [21,39].
The concentration of zinc to exert angiogenesis in the mouse model of limb ischemic is less well known. Attia reported that 30 μM of zinc-containing fluid had significantly improve the wound healing [40]. According to our in vitro experiment, the optimum concentration of zinc ions for cell migration and VEGF expression was 25 μM. So that 25 μM was chosen for in vivo study. Meanwhile, the injection interval of 1, 3 and 5 days were adopted for following two reason. First, the ROS level increased most obviously in the early stage of limb acute ischemia, so that is the best time for EGCG/Zn Ps to improvement the microenvironment [41]. Second, according to the release kinetic test, there was around 80% zinc ions release within the first 48 h and interval injection benefit to guarantee the dynamic stability of the zinc concentration. Besides, 14-day time point was selected because the angiogenesis was shown to be transient as blood vessels regressed with time [42]. It would be more valuable if we could demonstrate that the newly formed blood vessels are indeed mature and remain functional for more long time, but we mainly focus on demonstrating that EGCG/Zn Ps could exert angiogenesis in the present study. Long-term exploration worth further investigate.
Pipinos et al. reported that a high level of ROS generated in the ischemia hindlimb causes oxidative stress that contributes to inflammation in PAD and suppresses angiogenesis [43]. Kwon reported that H2O2-responsive antioxidant polymeric nanoparticles as therapeutic agents for peripheral arterial disease [44]. Therefore, reduce ROS stress might be a promising approach to promote angiogenesis and relieve symptoms of ischemia [45,46]. Urao N has reported that angiogenesis and recovery of blood perfusion required an appropriate range of ROS because both too much and too little ROS were detrimental to cell viability and functions [47]. Therefore, in our study, no obvious ischemia improvement was observed from EGCG group, which might due to excessively clear of ROS. However, EGCG/Zn Ps enable to eliminate ROS in a more moderate way and keep ROS in proper level benefit for angiogenesis. In addition, our study confirmed that zinc could promote the expression of the hypoxia response factor HIF-1α, in accordance with previous reports [48], which was surely benefit from the sustained release of the EGCG/Zn Ps system. Therefore, it is reasonable that EGCG/Zn Ps could significantly improve angiogenesis in vivo, which were widely demonstrated by limb ischemic score, limb temperature, histological results as well as LDPI and micro-CTA evaluation. Certainly, more deeper mechanism worth further study.
EGCG/Zn Ps, a new delivery system with angiogenesis property, was developed based on green tea polyphenolmetal networks. The biocompatible EGCG/Zn Ps could not only achieve sustained release of Zn2+ resulting in reduced toxicity and enhancive angiogenesis but also improve microenvironment by scavenging excess ROS and inhibiting inflammatory cytokine via EGCG. Moreover, this study demonstrate a safe and promising approach to combine the merit of Zn2+ and EGCG, thus enabling it as a potential medical therapy to treat CLI.