CHANGLELOG
All times refer to Australian Eastern Standard Time (AEST).
所有时间均以澳大利亚东部标准时间(AEST)为准。
•[Fri-22-Jan-2016]: Minor additions to 'Dietary Dosing' considerations
“膳食剂量”的小补充
•[Mon-28-Dec-2015]: Added partial 'Apoptotic Regulation' section
增加部分凋亡调节部分
•[Wed-16-Dec-2015]: Initial Publication
原始发布
Personal Motivation
个人动机
When I learnt how to apply coherence testing of acupuncture meridians to myself, I noticed that exogenous DHA would turn several points incoherent when consumed in excess. Over the 4 months from [Jul-2015] to [Oct-2015], I noted that:
当我学会如何将针灸经络的连贯性测试应用到自己身上时，我注意到外源性DHA过量摄入会导致几个点不连贯。在[2015年7月]至[2015年10月]的4个月中，我注意到:
I only needed to consume about 500mg of DHA once every 7 days
我只需要每7天摄取大约500毫克DHA
I would explicitly test incoherent in many of the Liver, Gallbladder, and Kidney points (and sometimes the Brain points) for the intervening days between DHA doses.
我会明确地测试肝胆肾点(有时是脑点)之间DHA剂量的不一致性。
This was independent of whether DHA came in supplemental pill form, or in seafood (indicating that the effect was likely due specifically to DHA and EPA)
这与DHA是否以补充药丸的形式存在或在海鲜中存在无关(表明这种影响可能是由DHA和EPA造成的)
Then in [Nov-2015] it basically reduced to where I wasn't testing or feeling well for almost any DHA consumption at all.
然后在[2015年11月]，它基本上减少到我不能测试或感觉良好几乎任何DHA消费。
I also had complaints sent my way from people who claimed to have bad digestion, which resolved after cutting excessive seafood amounts out of their diet. ie: eating seafood once a week instead of 4 times a week fixed digestive issues.
我还收到了一些人的投诉，他们声称自己消化不良，但在饮食中减少了过量的海鲜后，问题就解决了。例如:每周吃一次海鲜，而不是4次，解决消化问题。
Note: this is likely a function of poor liver function, which then cannot handle excess protein, fat, nor regulate DHA properly (details later in this article). According toa medical practitioner friend of mine, the incidence of poor liver function is just so high today (definitely the majority of his patients), that this is something to be considered a pathology that can break the entire system, and which must be addressed before using other measures.
注意:这可能是由于肝功能不佳造成的，肝功能不能够处理过多的蛋白质、脂肪，也不能适当地调节DHA(详见本文后文)。据我的一个医生朋友说，肝功能低下的发生率在今天非常高(肯定是他的大多数病人)，这被认为是一种病理，可以破坏整个系统，必须在使用其他措施之前解决这个问题。
From a practical standpoint, I didn't need to know any more than that. I would just test myself, and dose whatever DHA I needed. But digging into the mechanics at work regarding DHA inevitably bridges into all sorts of other topics, and helps elucidate even more mechanics.
从实际的角度来看，我不需要知道更多。我只会测试自己，然后给自己注射我需要的DHA。但深入挖掘与DHA相关的机制不可避免地会与其他各种主题联系在一起，并有助于阐明更多机制。
At best, I'd figure out a way to apply particular mechanics to people other than me, and at worst, I'd expose a whole bunch of shit that didn't work. And thus I decided to write this very long post.
在最好的情况下，我将想出一种方法将特定机制应用到其他人身上，而在最糟糕的情况下，我将暴露出一大堆不可行的东西。因此我决定写这篇很长的文章。
Practical Recommendations
实用的建议
My personal opinion on practical recommendations:
我个人对实际建议的看法:
•In pregnant and nursing women, DHA intake should be at least 60mg a day, and up to 200mg a day.
孕妇和哺乳期妇女每天的DHA摄入量应至少为60毫克，最多为200毫克。
•Infants should ideally be breastfed (for a multitude of reasons), and get whatever natural amounts of DHA are found in breast milk, with no exogeneous supplementation. Breast milk delivers about 100mg of a DHA a day, and this should be considered the safe threshold. Supplementation at the same dose as found in breast milk is needed if breast-feeding is not possible.
婴儿最好是母乳喂养(出于多种原因)，并从母乳中获得任何天然数量的DHA，而不是外来补充。母乳每天提供大约100毫克的DHA，这应该被认为是安全阈值。如果无法进行母乳喂养，则需要以母乳中发现的相同剂量补充。
•Beyond early development and pregnancy, DHA needs are likely very low. Minimisation of intake is preferred; there are many harmful effects of excess DHA.
在早期发育和怀孕之后，DHA的需求可能非常低。尽量减少摄入量为佳;DHA过量有很多有害的影响。
•Experimenting between small and more frequent doses of DHA and larger doses is probably recommended. For most, DHA from Seafood about 1 or 2 times a week is likely a safe dose.
可能建议在小剂量和更频繁的DHA和大剂量之间进行试验。对大多数人来说，每周从海鲜中摄取1到2次DHA可能是安全剂量。
•Endogenous regulation of DHA determines health outcomes, and not the amount of exogenous DHA consumption. Ensuring health of other systems (like the liver) ensures that DHA is put in the right places in the right amounts at the right times. Added exogenous DHA should be used if chronically deficient (eg: due to deficiency in early development), but beyond a “loading period” where DHA is consumed in higher amounts, added DHA becomes at best useless, and more likely harmful.
DHA的内源性调节决定健康结果，而不是外源性的DHA消耗量。确保其他系统(如肝脏)的健康，确保DHA在正确的时间、正确的数量被放在正确的地方。如果长期缺乏外源性DHA(例如:由于在早期发育中缺乏)，则应使用外源性DHA，但在“负荷期”(DHA以更高的量消耗)之后，添加的DHA充其量是无用的，更有可能是有害的。
•PUFA avoidance (especially Omega-6 PUFAs) is more important than DHA intake. DHA intake may help offset PUFA consumption, but this also places extra demands on the body. PUFA avoidance comes first and foremost.
避免PUFA多不饱和脂肪酸(特别是omega-6多不饱和脂肪酸)比DHA的摄入更重要。DHA的摄入可能有助于抵消不饱和脂肪酸的摄入，但这也会给身体带来额外的需求。最重要的是避免PUFA。
The reasoning for these opinions is explained in the article.
文章中解释了这些观点的原因。
Meta: citing other studies
引用其他研究
Personal pet peeve: Author makes #BoldClaim with tiny reference to a study in parens next to said BOLD Claim!!. RTFS yourself the link says ….
个人不喜欢的事:作者在#BoldClaim中，在括号中提到了一项研究，旁边是BOLD Claim!!RTFS自己的链接是….
Often times, I find too many bold claims without discussion of the mechanics being tested in the supposed supporting study, and thus is missing the contextual qualification needed for the claim to be useful at all.
很多时候，我发现太多大胆的主张没有讨论所谓的支持研究中所测试的机制，因此就失去了主张有用所需的背景资格。
In this article, I eschew that format, and when I link to a study, I try as much as possible to reproduce excerpts, fully qualify the experimental context, and discuss plausible mechanics which may be applicable to the topic at hand.
在本文中，我避开了这种格式，当我链接到一项研究时，我会尽可能地复制摘录，完全限定实验背景，并讨论可能适用于当前主题的合理机制。
My bias is always to figure out what NOT to do; via negativa, avoiding harm, and leaving anything that isn't harmful as fair game for personal experimentation. More often than not, you will find more questions than answers.
我的偏见总是弄清楚什么是不应该做的;通过消极，避免伤害，把任何没有害处的东西作为个人实验的公平游戏。通常情况下，你会发现更多的问题而不是答案。
Consequently, this article is long as fuck (and will become longer) and difficult to read. Deal with it :D. Use the Table of Contents to navigate.
因此，这篇文章很长(而且还会变得更长)，很难读。使用目录进行导航。
Preliminary Rant about studies not controlling for PUFA intake
对不控制多不饱和脂肪酸摄入量的研究的初步阐述
This deservers a section on it's own. The issue is that a lot of studies claiming to study the positive effects of DHA in a controlled and prospective fashion often like to compare it to a diet that is high in Omega-6 (n-6) fats, and oftentimes the high DHA diet is also high in n-6 fats.
这篇文章值得单独写一节。问题是，许多声称以可控的前瞻性方式研究DHA的积极作用的研究往往喜欢将其与富含-6 (n-6)脂肪的饮食进行比较，而通常高DHA饮食也富含n-6脂肪。
This is problematic, since:
这是一个问题，因为:
•n-6 fats are so harmful to begin with
n-6脂肪一开始就非常有害
•DHA and EPA can displace n-6 fats, and perceived benefit could be due to n-6 displacement instead of actual effects of DHA or EPA (although the n-3 fats obviously have effects as well)
DHA和EPA可以替代n-6脂肪，人们认为的益处可能是由于n-6取代DHA或EPA的实际作用(尽管n-3脂肪显然也有影响)
Arguably, it is still somewhat useful, since so many actual human beings over-consume n-6 fats to begin with, and thus testing the hypothesis “is DHA good in the context of a high PUFA diet in general?” has been done.
有争议的是，它仍然有一定的用处，因为许多实际的人类从一开始就过度消耗n-6脂肪，因此测试了“在普遍高不饱和脂肪酸饮食的背景下DHA是否有益?”的假设。
In a high PUFA context, DHA is probably the lesser of evils. However, the real goal should be PUFA minimisation of all kinds, DHA included.
在多不饱和脂肪酸含量高的情况下，DHA的危害可能较小。然而，真正的目标应该是减少所有种类的多不饱和脂肪酸，包括DHA。
An interesting study would be to test a nutrient-sufficient:
一项有趣研究测试了营养是否充足:
•PUFA-less diet where DHA is excluded
不含DHA的少PUFA饮食
•PUFA-less diet where DHA is included
含DHA的少PUFA饮食
•PUFA-rich diet where DHA is included
含DHA的多PUFA饮食
And then look at all the factors that have been discussed above.
然后看看上面已经讨论过的所有因素。
I'll be waiting for such studies …. In the meantime, bear in mind that this is a possible significant confounder which has not been tested.
我将等待这样的研究….与此同时，请记住，这可能是一个尚未经过测试的重要混杂因素。
DHA is Important, but how much do Humans need?
DHA很重要，但是人类需要多少呢?
I contend that the amount of DHA recommended by most sources far exceeds what the body needs on both an acute and chronic basis.
我认为，大多数来源推荐的DHA量远远超过了身体的急性和慢性需要。
How much DHA does/can the human body contain?
人体含有多少DHA?
DHA (and EPA) being just another fatty acid, can be stored in adipose tissue. 'Incorporation of dietary n-3 fatty acids into the fatty acids of human adipose tissue and plasma lipid classes' (Leaf et. al., 1995)
DHA(和EPA)只是另一种脂肪酸，可以储存在脂肪组织中。“将膳食n-3脂肪酸纳入人体脂肪组织和血浆脂类脂肪酸中”(Leaf等，1995年)
http://ajcn.nutrition.org/content/62/1/68.short
What is the limit? No clue, since I don't know of all possible regulatory processes, and add to that the relative ease of mobilisation of PUFAs from adipose stores.
极限是多少?不知道，因为我不知道所有可能的调控过程，而且从脂肪储存中调动多不饱和脂肪酸PUFA相对容易。
A more important question is how much of ingested DHA is:
一个更重要的问题是摄入多少DHA:
•Stored in adipose tissues where it is likely relatively inert (though we are not sure if stored DHA could affect something like Leptin secretion from an adipocyte)
储存在脂肪组织中的DHA可能是相对惰性的(尽管我们不确定储存的DHA是否会影响脂肪细胞的瘦素分泌)
•Oxidised to other harmful products before it can be processed (we'll get to these products in later sections)
在加工之前氧化成其他有害产品(我们将在后面的部分讨论这些产品)
•Used in various other tissues
用于其他各种组织
Regarding DHA content in other tissues, I have no clue what the absolute values are. There aren't many (if any) studies looking at how much DHA is contained in tissues like the skin, the GI tract, liver, spleen, etc … and if they have any functional roles in those tissues in humans.
至于DHA在其他组织中的含量，我不知道绝对值是多少。没有多少研究(如果有的话)关注皮肤、消化道、肝脏、脾脏等组织中含有多少DHA。如果它们在人类的这些组织中有任何功能作用。
In the brain, there is estimated to be only about 5g of total DHA, and brain turnover is only at most 5mg a day. (this point is elaborated on in later sections)
据估计，在大脑中只有大约5g DHA，大脑每天的周转量最多只有5毫克。(这一点将在后面的部分详细说明)
[TODO] Where is DHA found in the Brain? How do DHA levels vary over time?
DHA在大脑的哪个部位被发现?DHA水平如何随时间变化?
Breast Milk DHA Content
母乳DHA含量
We'll start off by looking at how much DHA there is in breast milk. The idea is that looking at the DHA needs during the time of development when brain growth.
我们将从母乳中含有多少DHA开始。想法是观察大脑发育期间DHA的需求。
How much DHA is there in breast milk? 'Docosahexaenoic and arachidonic acid concentrations in human breast milk worldwide' (Brenna et. al., 2007) – http://ajcn.nutrition.org/content/85/6/1457.full
母乳中含有多少DHA ?“全球母乳中二十二碳六烯酸和花生四烯酸的浓度”(Brenna et al.， 2007)
The best estimates of worldwide mean breast-milk DHA and AA concentrations (wt:wt) from the primary analysis group are 0.32 ± 0.22% for DHA and 0.47 ± 0.13% for AA.
初级分析组对全球母乳平均DHA和AA浓度(wt:wt)的最佳估计为DHA为0.32±0.22%，AA为0.47±0.13%
That's a high of 0.55% DHA as a percentage of all fatty acid content of breast milk.
这相当于母乳中所有脂肪酸含量的0.55%。
How much breast milk do infants drink per day? –
婴儿每天喝多少母乳?–
http://ajcn.nutrition.org/content/59/3/600.short
In infants exclusively breast-fed, mean milk intake was 781 and 855 mL/24 h at 2 and 4 mo, respectively, and correlated positively with the current weight of the infant and negatively with the amount of formula supplement given at the maternity ward.
在纯母乳喂养的婴儿中，在第2个月和第4个月时平均母乳摄入量分别为781和855 mL/24h，与婴儿当前体重呈正相关，与产科病房中配方奶粉的补充量呈负相关。
How much fat is there in breast milk? 'Macronutrient, mineral and trace element composition of breast milk from Japanese women' (Namiko Yamawaki et. al., 2005) – http://www.sciencedirect.com/science/article/pii/S0946672X05001008
母乳中有多少脂肪?“日本女性母乳的常量、矿物质和微量元素组成”
结果：
lipids, 3.46±1.49g/100 mL
This is from Japanese women, who generally have higher DHA concentrations in their breast milk.
这来自日本女性，她们的母乳中DHA含量通常较高。
So let's assume that 1,000mL of breast milk is consumed per day (over-estimate), and let's assume the high end of the fatty acid concentration of 3.46 + 1.49 = 4.95g/100mL breast milk.
因此，让我们假设每天消耗1000毫升母乳(过高估计)，让我们假设脂肪酸浓度的高端为3.46 + 1.49 = 4.95g/100mL母乳。
Total Infant MAX Daily DHA Consumption = 4.95 * 10 * 0.0055 = 0.272g = 272.2mg Average DHA Consumption = 3.46 * 8.55 * 0.0032 = 99.8mg
婴儿每日最大DHA总消耗量= 4.95 * 10 * 0.0055 = 0.272g = 272.2mg
平均DHA摄入量= 3.46 * 8.55 * 0.0032 = 99.8mg
This is when you are trying you darnest best to build a human brain, and that you need is 100-272mg of DHA. For context, 100g of sardines typically would deliver 500mg of DHA.
这是当你在尽最大努力构建人类大脑时，你需要100-272毫克DHA。另外，100克沙丁鱼通常可以提供500毫克的DHA。
Mini Rant about breast milk DHA studies
关于母乳DHA研究的碎碎念
I really dislike studies that specifically try to pick out fatty acid composition and its effects on immune function of the infant or child. Some example studies:
我真的不喜欢那些专门试图找出脂肪酸组成及其对婴儿或儿童免疫功能影响的研究。一些例子的研究:
•'Atopic Sensitization during the First Year of Life in Relation to Long Chain Polyunsaturated Fatty Acid Levels in Human Milk' (Duchen et. al., 1997) – http://www.nature.com/pr/journal/v44/n4/full/pr1998489a.html
“母乳中长链多不饱和脂肪酸水平与一岁时特应性致敏的关系”
•'Breast Milk Fatty Acids May Link Innate and Adaptive Immune Regulation: Analysis of Soluble CD14, Prostaglandin E2, and Fatty Acids' (Laitinen et. al., 2006) – http://www.nature.com/pr/journal/v59/n5/full/pr2006154a.html
母乳脂肪酸可能与先天免疫调节和适应性免疫调节有关:可溶性CD14、前列腺素E2和脂肪酸的分析
•'Breast milk fatty acids and allergic disease in preschool children: The Prevention and Incidence of Asthma and Mite Allergy birth cohort study' (Wijga et. al., 2006) – http://www.rima.org/web/medline_pdf/Breast_milk_allergy.pdf
“母乳脂肪酸与学龄前儿童过敏性疾病:哮喘和螨过敏的预防和发生率出生队列研究”
Singling out a single fatty acid like DHA is a nice way to skew the research in favour of financial interests invested in DHA supplementation. This misses all nuances of human immune function, and tries to attribute its modulation to a single compound.
挑出一种像DHA这样的单一脂肪酸是一种很好的方式，可以使研究偏向于投资于DHA补充的经济利益。这忽略了人类免疫功能的所有细微差别，并试图将其调节归于单一化合物。
I much prefer a balanced take which tries to examine all factors in Breast Milk and how they can potentially lead to immune function (and at least this study gives a hat tip to a Cesarean birth and how that can drastically affect the child's immune function):
我更喜欢一个平衡的方法，即尝试检查母乳中的所有因素，以及它们如何潜在地导致免疫功能(至少这项研究为剖宫产以及它如何严重影响孩子的免疫功能提供了一个提示):
•'Breast-Milk Characteristics Protecting Against Allergy' (Minniti et. al., 2014) – http://www.ingentaconnect.com/content/ben/emiddt/2014/00000014/00000001/art00003?crawler=true
“母乳特性防止过敏”
Personally, I think there are far too many factors involved in immunity other than DHA, to even begin to assign a significant role to DHA. I won't be discussing this topic any further in this article.
就我个人而言，我认为除了DHA，还有太多的因素与免疫有关，甚至不能开始赋予DHA一个重要的角色。在本文中，我不会进一步讨论这个主题。
Endogenous DHA Synthesis
内源性DHA合成
Clearly, the levels of DHA in breast are suitable for when CNS development as at its maximum possible rate. What about adults?
显然，当中枢神经系统发育达到最大可能速度时，乳房中的DHA水平是合适的。成年人呢?
First, how much DHA can we synthesize from ALA? 'Is docosahexaenoic acid synthesis from α-linolenic acid sufficient to supply the adult brain?' (Domenichiello et. al., 2015) – http://www.sciencedirect.com/science/article/pii/S0163782715000223
首先，我们可以从ALA中合成多少DHA ?“由α-亚麻酸合成的二十二碳六烯酸是否足以供应成人的大脑?”
Based on current estimates of ALA consumption in adult males of 1700 mg/day, the percent conversion of ALA to DHA would need to be 0.14–0.22% to match the brain DHA requirement.
根据目前成年男性每日1700毫克ALA摄入量估计，ALA转化为DHA的百分比需要为0.14-0.22%才能满足脑DHA的需求。
So 0.14% of 1700mg ALA is 2.38mg of DHA.
1700mg ALA的0.14%就是2.38mg DHA。
How much brain DHA is recycled on a daily basis? 'Docosahexaenoic Acid (DHA): An Ancient Nutrient for the Modern Human Brain ' (Joanne Bradbury, 2011) – http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257695/
每天有多少脑DHA被回收利用?二十二碳六烯酸(DHA):现代人类大脑的古老营养素
Sidenote: There are 2 similar studies which I won't go into here, but they basically got similar results:
旁注:有两项类似的研究，我在这里就不赘述了，但它们基本上得到了相似的结果:
•'Dietary intake and status of n−3 polyunsaturated fatty acids in a population of fish-eating and non-fish-eating meat-eaters, vegetarians, and vegans and the precursor-product ratio of α-linolenic acid to long-chain n−3 polyunsaturated fatty acids: results from the EPIC-Norfolk cohort' (Welch et. al., 2010) – http://ajcn.nutrition.org/content/92/5/1040.full
“食用鱼类和非食用鱼类的肉食者、素食者和纯素食者的饮食摄入量和n- 3多不饱和脂肪酸状况，以及α-亚麻酸与长链n- 3多不饱和脂肪酸的前体-产物比”
•'Long-chain n–3 polyunsaturated fatty acids in plasma in British meat-eating, vegetarian, and vegan men' (Rosell et. al., 2005) – http://ajcn.nutrition.org/content/82/2/327.full
“英国食肉者、素食者和纯素食者血浆中的长链n-3多不饱和脂肪酸”
This paper by Bradbury claims that brain DHA flux is about 3.8 ± 1.7 mg/day, with an estimated daily incorporation rate of 0.076% per day, and a 2.5 year half-life for DHA in the brain.
Bradbury的这篇论文声称，脑DHA流量约为3.8±1.7 mg/天，估计每日掺入率为0.076% /天，DHA在脑中的半衰期为2.5年。
This claim is based off of this paper, 'Imaging incorporation of circulating docosahexaenoic acid into the human brain using positron emission tomography'(Umhau et. al., 2009) – http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694326/#bib49
这一声明是基于这篇论文，“使用正电子发射断层扫描技术将循环二十二碳六烯酸成像到人类大脑中”
The calculation for daily DHA flux I consider pretty accurate.
我认为每日DHA流量的计算相当准确。
Umhau et. al. also want to know how much as a percentage of total DHA this turnover rate represents, and based the “5g total Brain DHA” on this paper, 'Abnormal profiles of polyunsaturated fatty acids in the brain, liver, kidney and retina of patients with peroxisomal disorders' (Martinez M., 1992) – http://www.ncbi.nlm.nih.gov/pubmed/1504825
Umhau等人还想知道这个周转率占总DHA的百分比，基于这篇论文的“5g总脑DHA”，“过氧化物酶体疾病患者的大脑、肝脏、肾脏和视网膜中多不饱和脂肪酸的异常分布”
This should be treated as an estimate, but it does gives us some perspective in dietary intake. For example, 100g (3.5oz) of Atlantic Salmon probably has anywhere from 400mg to 1,000mg of DHA. Compare that to the 5mg a day DHA turnover rate and 5g total DHA, and you can see that potential dietary intake far exceeds the capability of the brain to use that DHA.
这应该被视为一种估计，但它确实给了我们一些关于饮食摄入量的观点。例如，100克(3.5盎司)的大西洋鲑鱼可能含有400毫克到1000毫克的DHA。与每天5毫克的DHA流通率和5克的DHA总量相比，你可以看到，潜在的饮食摄入量远远超过大脑对DHA的利用能力。
It's fair to say that eating more DHA isn't better, and I will argue that excess DHA is in fact harmful.
公平地说，吃更多的DHA并不是更好，而且我认为过量的DHA实际上是有害的。
However, it is also important to note all the seemingly positive effect that supplemental DHA has shown in many different conditions. You can find many studies regarding positive effects of DHA (given the amount of money there is in that industry), so here's just one study, 'The benefit of docosahexaenoic acid for the adult brain in aging and dementia'(Salem et. al., 2015) – http://www.sciencedirect.com/science/article/pii/S0952327814001690
然而，还需要注意的是，补充DHA在许多不同的情况下都显示出了看似积极的效果。你可以找到许多关于DHA的积极作用的研究(考虑到该行业的资金规模)，所以这里只有一项研究，“二十二碳六烯酸对衰老和痴呆的成年人大脑的好处”
Quotes from various parts of the article (not in order presented in the actual paper):
文章各个部分的引用(不在实际论文中出现的顺序):
The ADCS AD trial found no benefit of DHA in the primary outcomes but found an intriguing benefit for cognitive score in ApoE4 negative allele patients.
ADCS的AD试验没有发现DHA对主要结果有好处，但发现ApoE4阴性等位基因患者的认知评分有让人感兴趣的好处。
The intervention was 900 mg of algal DHA/d vs. corn/soy oil placebo capsules over a 24 week period.
干预措施是在24周的时间内，用900毫克海藻DHA/d对比玉米油/豆油安慰剂胶囊。
The primary endpoint was the score in the Paired Associate Learning (PAL) test from CANTAB. This is a computer generated, objective test that is sensitive to early episodic memory changes.
主要终点是CANTAB的配对联想学习(PAL)测试得分，这是一种计算机生成的客观测试，对早期情景记忆变化很敏感。
Secondary endpoints included various tests of cognitive function, Activity of Daily Living (ADL) skills, plasma fatty acid analysis, safety and tolerability.
次要终点包括认知功能、日常生活活动(ADL)技能、血浆脂肪酸分析、安全性和耐受性等各项测试。
Subjects were >55 years of age and the population had a mean age of 70 years.
This was a randomized, controlled, multi-center trial of cognitive outcome in 485 healthy elderly patients.
受试者>55岁，人群平均年龄70岁。
这是一项对485名健康老年患者进行的认知结果的随机、对照、多中心试验。
The cut offs for these tests were as follows: subjects had an immediate (≤28) or delayed (≤15) recall score that was ≥1 standard deviation below the mean of younger subjects of 25–35 years, and also had an MMSE >26. Subjects were excluded who reported taking omega-3 supplements, consuming >200 mg/d DHA in their diets, used medications for AD, major anti-psychotic or anti-depressant medications, had major medical conditions or who abused alcohol or drugs.
这些测试的截断点如下:受试者的即时(≤28)或延迟(≤15)回忆得分比25-35岁的年轻受试者的平均值低≥1个标准差，MMSE >为26。排除了服用omega-3补充剂、饮食中摄入200mg /d DHA、服用AD药物、主要抗精神病或抗抑郁药物、有严重疾病或酗酒或滥用药物的受试者。
Good sample size, good screening procedures. Patients who already had existing cognitive issues.
好的样本量，好的筛选程序。已经有认知问题的患者。
Results were very good in this group. You can read the study for details.
这个组的结果很好。你可以阅读研究的细节。
They also discussed (in the 'Results' section) many other trails with varying populations in which DHA supplementation had no effect, and made the statement:
他们还讨论了(在“结果”部分)许多对不同人群进行的其他试验，在这些试验中补充DHA没有效果，并发表了以下声明:
It appears that benefits of DHA are best observed during aging where there is some decrement in cognition, e.g., a mild cognitive impairment or memory complaint or perhaps when a person is exposed to certain chronic physical or mental stressors. A limitation of the these interventional studies is that they can only address limited aspects of memory. In the case of the MIDAS study, the PAL task is considered to be a measure of episodic memory, one of many different aspects of the clinical construct of memory.
DHA的好处似乎在衰老过程中表现得最好，在这一过程中认知能力有所下降，例如轻度认知障碍或记忆障碍，或者当一个人暴露于某种慢性生理或心理压力时。这些介入性研究的一个局限性是，它们只能解决记忆的有限方面。在MIDAS研究中，PAL任务被认为是对情景记忆的测量，这是临床记忆构建的许多不同方面之一。
The rest of the study focused on the interactions between DHA and ApoE.
剩下的研究集中在DHA和载脂蛋白e之间的相互作用上。
However, the point that I wanted to make is that because both total brain DHA mass and DHA turover is so low compared to potential dietary intake, this hints that the effects of DHA on the brain are NOT due to direct regulation of uptake of / exit from the brain.Instead, it is the systemic effects that DHA has on regulatory processes which then go on to affect brain function that we should be focusing on.
但是,我想说明的一点是,因为大脑DHA总质量和DHA流通率如此之低与潜在的饮食摄入量相比,这暗示DHA对大脑的影响不是由于直接监管的吸收/退出大脑。相反，我们应该关注的是DHA在调节过程中产生的系统性影响，然后继续影响大脑功能。
This last study also used algal DHA, which is mostly likely consists largely of sn-1 DHA – not the type that is taken up by the brain (see section 'Brain DHA Regulatory Mechanisms'). Again, indicating that it is some correction of other systemic processes that then allow for better cognitive function.
最后一项研究也使用了海藻DHA，它很可能主要由sn-1 DHA组成，而不是被大脑吸收的那种DHA(见“大脑DHA调节机制”部分)。这再次表明，这是对其他系统过程的一些纠正，然后允许更好的认知功能。
Back to the Bradbury paper …. it cites numerous studies to show that you can get the minimum required dose for survival through ALA alone (based on clinical trials).
回到布拉德伯里的论文….它引用了大量的研究表明，你可以通过单靠ALA获得生存所需的最低剂量(基于临床试验)。
This is obviously a minimum, and is sub-optimal, but again, the body is not stupid, and will make it's own DHA to cover survival needs.
这显然是最低限度的，是次优的，但再次强调，身体并不愚蠢，它会制造自己的DHA来满足生存需要。
From the main text (Bradbury et. al.):The means and standard deviations of the estimated intakes of DHA in grams per day for male.
从主要文本(Bradbury等):男性每日DHA摄入量(以克计)的平均值及标准差。
•fish-eaters (n = 5952) was 0.16±0.22 g/day
•meat-eaters (n = 966) was 0.02±0.02 g/day
•vegetarians (n = 96) was 0.0007±0.004
•vegans (n = 12) was zero
•食鱼者(n = 5952)为0.16±0.22 g/d
•肉食者(n = 966) 0.02±0.02 g/d
•素食者(n = 96)为0.0007±0.004
•纯素食者(n = 12)为零
It should be noted, however, that EPA intakes were present in vegans at 0.01 ± 0.001 g/day in men and 0.002 ± 0.008 in women, and was overall in a similar range to those of vegetarians.
然而，值得注意的是，纯素食者的EPA摄入量在男性为0.01±0.001 g/天，女性为0.002±0.008，总体范围与素食者相似。
Although vegans had zero intake of preformed DHA, it was nevertheless present in blood phospholipids. In a subgroup of this sample, the means and standard deviations of the DHA in the blood phospholipids were measured in µmol/L:
虽然纯素食者没有摄入预先成型的DHA，但它仍然存在于血液磷脂中。在本样本的一个亚组中，以µmol/L测定血磷脂中DHA的均值和标准差:
•fish-eaters (n = 2257) were 239.7±106.2
•meat-eaters (n = 359) were 215.6±96.4
•vegetarians (n = 25) were 222.2±138.4
•vegans (n = 5) were 195.0±58.8
•鱼食用者(n = 2257)为239.7±106.2
•肉食者(n = 359)为215.6±96.4
•素食者(n = 25) 222.2±138.4
•纯素食者(n = 5)为195.0±58.8
Welch et al. [11] calculated the ratio of dietary precursor (ALA) to product (EPA + DHA). This ratio for:
Welch等人[11]计算了膳食前体(ALA)与产物(EPA + DHA)的比值。这一比率:
•fish-eaters (n = 2257) was 0.093±0.001 µmol/L
•meat-eaters (n = 359) was 0.101±0.004
•vegetarians (n = 25) was 0.108±0.012
•vegans (n = 5) was 0.199±0.027
•食鱼者(n = 2257)为0.093±0.001µmol/L
•肉食者(n = 359)为0.101±0.004
•素食者(n = 25)为0.108±0.012
•纯素食者(n = 5)为0.199±0.027
Thus the precursor/product ratio in vegans was twice that of fish-eaters. This finding suggests basal conversions from ALA to DHA that may be up-regulated by the absence of-and down-regulated by the presence of-dietary preformed DHA.
因此，纯素食者的前体/产品比例是吃鱼者的两倍。这一发现表明，从ALA到DHA的基础转化可能因膳食预制DHA的缺乏而上调，而因膳食预制DHA的存在而下调。
The difference in blood DHA content between vegans and fish-eaters was:
素食者和吃鱼者血液中DHA含量的差异如下:
•In the 最差worst case: 135mg 纯素食者vegan, 133mg 食鱼者fish-easter
•In the 最好best case: 255mg 纯素食者vegan, 345mg 食鱼者fish-eater
I like this best-vs-worst-case illustration, because it shows that by absolute levels, dietary DHA consumption is going to affect blood levels in different people in different ways.
我喜欢这个最好与最坏情况的例子，因为它表明，从绝对水平来看，饮食中DHA的摄入会以不同的方式影响不同人的血液水平。
Again, DHA regulation is probably liver-mediated, probably explains why some fish eaters still have low DHA (liver not good), and probably too complex for me to analyse further ….
此外，DHA的调节可能是由肝脏介导的，这可能解释了为什么一些吃鱼的人DHA仍然很低(肝脏不好)，而且可能太复杂了，我无法进一步分析….
This also means that the mean efficiency of ALA to DHA conversion stated by Domenichiello et. al. of 0.14-0.22% must not be correct when exogenous dietary DHA is low. Let's look into some details.
这也意味着当外源性DHA较低时，Domenichiello等人所说的ALA到DHA转化的平均效率为0.14-0.22%肯定是不正确的。让我们来看一些细节。
Some people may cite studies similar to this to claim that DHA supplement is necessary. 'Adolescents with or at ultra-high risk for bipolar disorder exhibit erythrocyte docosahexaenoic acid and eicosapentaenoic acid deficits: a candidate prodromal risk biomarker.' (McNamara et. al., 2015) – http://www.ncbi.nlm.nih.gov/pubmed/26486098
有些人可能会引用类似的研究，声称DHA补充剂是必要的。“患有双相情感障碍或具有超高风险的青少年表现出红细胞二十二碳六烯酸和二十碳五烯酸缺乏:一种候选前驱症状风险生物标志物。”
A paraphrased quote from the abstract:
Compared with Healthy Adolescents (61%), a greater percentage of High Risk Adolescents (77%, P = 0.02), Ultra High Risk Adolescents (80%, P = 0.005) and first-episode adolescent bipolar manic patients (97%, P = 0.001) subjects exhibited EPA + DHA levels of ≤4.0%
摘自摘要的一段话:
与健康青少年(61%)相比，高危青少年(77%，P = 0.02)、超高危险青少年(80%，P = 0.005)和首发青少年双相躁狂患者(97%，P = 0.001)中EPA + DHA≤4.0%的比例更高。
I do not dispute that DHA is important in the body. What I do question is whether we should be eating or supplementing a lot of it. (“A lot” meaning more than say an average of 150mg a day)
我不否认DHA对人体的重要性。我所质疑的是我们是否应该吃或补充大量的维生素c。(“很多”的意思是比平均每天150毫克要多)
We saw in the previous study above that vegan diets ramp up their ALA to DHA conversion efficiency to 0.199 ± 0.027 µmol/L (up from 0.093 ± 0.001 µmol/L in fish eaters), which is a 100% increase.
我们在前面的研究中看到，纯素饮食将ALA到DHA的转化效率提高到0.199±0.027µmol/L(从鱼食者的0.093±0.001µmol/L提高了100%)。
This suggests that in DHA deficient scenarios, the body synthesises more DHA, and in DHA excess scenarios, it shuttles down synthesis.
这表明，在DHA缺乏的情况下，身体会合成更多的DHA，而在DHA过量的情况下，身体会减慢合成。
If endogeneous systems are working, you actually don't need to consume a lot of DHA. Here is a study, 'High content of long-chain n-3 polyunsaturated fatty acids in red blood cells of Kenyan Maasai despite low dietary intake' (Knoll et. al., 2011) – http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179448/
如果内生性系统正常工作，你实际上不需要消耗大量的DHA。这是一项研究，“尽管饮食摄入量低，肯尼亚马赛人的红细胞中长链n-3多不饱和脂肪酸含量高”
Daily energy intake of the Maasai according to the 24-h recall constituted 7.6 ± 2.1 MJ per day and person (9.5 ± 2.3/7.0 ± 1.8 MJ/d, males/females.
The diet consisted of 56.2 ± 9.4% carbohydrates, 13.3 ± 2.0% protein, and 30.5 ± 7.9% fat. This corresponded to a daily intake of 242 ± 73 g carbohydrates, 58 ± 21 g protein, and 59 ± 26 g fat.
根据24小时回忆，马赛人每天的能量摄入量为7.6±2.1 MJ/d，人(9.5±2.3/7.0±1.8 MJ/d，男性/女性)
饲料中碳水化合物为56.2±9.4%，蛋白质为13.3±2.0%，脂肪为30.5±7.9%。这相当于每天摄入242±73克碳水化合物、58±21克蛋白质和59±26克脂肪。
The Masai consumed 7.6 MJ/day = 1,800kcal, of which 30% was fat (60g of fat), of which 0.15% was DHA. So about 90mg of DHA on average (120mg in the high case).
马赛人每天消耗7.6 MJ/天= 1800千卡，其中30%是脂肪(60克脂肪)，0.15%是DHA。平均约为90毫克DHA(最高为120毫克)。
Yet they maintained a RBC DHA which was 5.9% of all RBC fatty acids, higher.
但他们的红细胞DHA占所有红细胞脂肪酸的5.9%，更高。
Sidenote: while the authors claim that a total PUFA intake of 10% of all fats is “low”, there are studies to suggest that a lower PUFA intake is even more beneficial.
Another sidenote: in this study, the Maasai ate a near 50% carbohydrate diet. So much for the ketogenic Maasai.
注:虽然作者声称所有脂肪的10%的多不饱和脂肪酸摄入量是“低”的，但有研究表明，更低的多不饱和脂肪酸摄入量更有益。
另一个注:在这项研究中，马赛人的饮食中将近50%是碳水化合物。说马赛人生酮的到此为止。
So correlation studies like the bipolar study above need to be looked at as hypothesis generation tools at the very best. One needs to look at other factors concerning endogenous DHA production and regulation in bipolar teens. For example, we may discover that these teens have poor liver function to begin with, which basically screws up DHA handling.
因此，像上面的双相情感障碍研究这样的相关性研究，需要被视为最好的假设生成工具。我们需要研究双相情感障碍青少年的内源性DHA产生和调节的其他因素。例如，我们可能会发现这些青少年的肝功能很差，这基本上破坏了DHA的处理。
Of course, I single out the liver because it is such an important organ that is so often dysfunctional. However, the regulatory chain for DHA is so complex, and any failure along the chain can lead to DHA deficiency in the appropriate tissues. More on some of the pathways 2 sections below.
当然，我选择肝脏是因为它是一个如此重要的器官，而且经常功能失调。然而，DHA的调控链是如此复杂，这条链上的任何失败都可能导致相应组织中的DHA缺乏。下面将详细介绍一些途径。
Dietary Dosing
饮食定量
Because brain DHA turnover is so low, I asked myself: Does the way you dose DHA matter? Would it be more beneficial to have smaller doses more regularly, or larger doses (say 2g once a week).
因为脑内DHA的更替率很低，我问自己:你给DHA的方式重要吗?是经常服用小剂量还是大剂量(比如每周2g)更有益?
There is good reason to believe that endogenous conversion of stored DHA to DHA for nervous system use is the key limiting factor in adult humans. This is likely liver mediated, and we can ask if the liver burden of a large dose is a potential stressor.
有很好的理由相信，储存的DHA内源性转化为用于神经系统的DHA是成人的关键限制因素。这可能是肝脏介导的，我们可以问，大剂量的肝脏负担是否是一个潜在的应激源。
For example, given that DHA and EPA are unstable and prone to oxidation at high (body) temperatures, would a larger dose of such PUFAs at once lead to more breakdown of products before they get absorbed through the intestine? What sorts of compound-specific interactions would happen?
例如，DHA和EPA是不稳定的，而且在(人体)高温下容易氧化，那么，在通过肠道吸收之前，大量的不饱和不饱和脂肪酸会导致产品的分解吗?会发生什么样的化合物特异性相互作用?
For example, one study suggested and that there is significant DHA oxidisation (from raw minced mullet) under physiologic conditions. Polyphenols reduced the amount of oxidized products.
例如，一项研究表明，在生理条件下(从生切碎的鲻鱼中)有显著的DHA氧化。多酚降低了氧化产物的量。
•[Study]: 'Alterations in the Intestinal Assimilation of Oxidized PUFAs Are Ameliorated by a Polyphenol-Rich Grape Seed Extract in an In Vitro Model and Caco-2 Cells' (Masetre et. al., 2013) – http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3713019/
“在体外模型和Caco-2细胞中，富含多酚的葡萄籽提取物改善了肠道氧化PUFAs同化的改变”
Probably a good idea to have some Green Tea with your fish, but the complexity of interactions between foods is going to be too difficult to analyse.
也许在吃鱼的时候喝点绿茶是个好主意，但是食物之间相互作用的复杂性太难分析了。
This however, this somewhat support the idea that smaller doses are better. ie: A cup of green tea can only help with a limited amount of DHA at one time. It may also suggest that smaller DHA-containing meals, which transit more quickly through the GI tract, would suffer less oxidation before uptake into the bloodstream.
然而，这在一定程度上支持了小剂量效果更好的观点。例如:一杯绿茶一次只能提供有限的DHA。这也可能表明，少量含dha的食物通过胃肠道的速度更快，在进入血液之前遭受的氧化较少。
If you want to be precautious, then take your seafood / DHA supplements under conditions where digestion is quick (ie: not with or soon after a very large meal).
如果你想预防，那就在消化快的情况下服用海鲜/ DHA补充剂(例如:不要在一顿大餐后或一顿大餐后不久服用)。
Daily doses should probably be not much too higher than the daily requirement – say 50-100mg at a time, and at most 200-300mg at a time.
每天的剂量可能不应该比每天的需求量高太多——比如一次50-100毫克，最多一次200-300毫克。
In terms of sources, any whole food source would probably be preferred. A couple slices of raw fish with sushi, or a couple of good quality / free-range eggs (which usually have 100mg DHA in 2 eggs), would get the job done. Those sorts of doses anywhere from 3-5 times a week would likely be sufficient for an adult whom is not deficient in DHA.
就食物来源而言，任何天然食物来源都可能是首选。几片生鱼片配寿司，或者几个质量好的/散养的鸡蛋(通常两个鸡蛋中含有100毫克DHA)就可以了。对于不缺乏DHA的成年人来说，这种每周3-5次的剂量就足够了。
Note However, that I do consider it more than possible for healthy adults to deal with even lower doses than this. See my notes above about endogenous DHA synthesis and observed DHA levels in vegans.
注意:然而，我确实认为对健康的成年人来说，更低的剂量是不可能的。看我上面关于内源性DHA合成和观察纯素者DHA水平的笔记。
Brain DHA Regulatory Mechanisms: MFSD2A and LysoPC-DHA
脑DHA调节机制:MFSD2A和LysoPC-DHA
The low rate of brain DHA flux hints at tight endogenous regulatory processes for the amount of DHA in the brain. Too much DHA in the brain is probably as much a problem as too little DHA.
脑DHA的低通量暗示了大脑中DHA含量的内源性调节过程。大脑中太多的DHA可能和太少的DHA一样是个问题。
The entry of DHA into the brain is apparently very complex ….
DHA进入大脑显然是非常复杂的….
Firstly, all the DHA that gets into the brain is heavily regulated by the MFSD2A protein:
首先，所有进入大脑的DHA都受到MFSD2A蛋白质的严格控制:
•'Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid'(Nguyen et. al., 2014) – http://www.nature.com/nature/journal/v509/n7501/abs/nature13241.html
“Mfsd2a是必需的omega-3脂肪酸二十二碳六烯酸的转运体”
•'Blood-Brain Barrier: A Dual Life of MFSD2A?' (Zhen Zhao and Berislav V. Zlokovic, 2014) – http://www.sciencedirect.com/science/article/pii/S0896627314003985
“血脑屏障:MFSD2A的双重生活?”
To quote the authors of the last study:
Using cell-based assays and brain uptake studies in Mfsd2a−/− mice, they next show that Mfsd2a transports DHA and fatty acids into the brain across the BBB only in the form of esters with lysophosphatidylcholines (LPCs), but not as free unesterified fatty acids.
They also show that MSFD2A transport protein prefers long-chain fatty acids such as LPC-oleate and LPC-palmitate but does not transport LPCs with less than a 14-carbon acyl chain.
引用上一项研究的作者的话:
通过对Mfsd2a−/−小鼠的细胞分析和脑摄取研究，他们接下来表明，Mfsd2a仅以溶血磷脂酰胆碱酯(LPCs)的形式将DHA和脂肪酸转运到脑内，而不是以游离未酯化脂肪酸的形式。
他们还表明，MSFD2A转运蛋白更喜欢长链脂肪酸，如lpc-油酸酯和lpc-棕榈酸酯，但不转运少于14碳酰基链的lpc。
So DHA must be bound to lysophosphatidylcholine (LysoPC) to be taken up by the MFSD2A protein.
因此DHA必须与溶血磷脂酰胆碱(LysoPC)结合才能被MFSD2A蛋白摄取。
As an aside, it seems like Red Blood Cells also require DHA to be LysoPC for uptake, based on study 'Blood compartmental metabolism of docosahexaenoic acid (DHA) in humans after ingestion of a single dose of [13C]DHA in phosphatidylcholine'(Lemaitre-Delaunay et. al., 1999) – http://www.jlr.org/content/40/10/1867.full
说句题外话,似乎红细胞也为吸收需要LysoPC DHA,基于研究的血液区划的新陈代谢二十二碳六烯酸(DHA)在人类摄入一剂[13 c] DHA在磷脂酰胆碱。
Ordinary dietary DHA won't do. Quoting from this study 'Marine Omega-3 Phospholipids: Metabolism and Biological Activities' (Burri et. al., 2012) – http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3509649/
普通饮食中的DHA是不行的。引用这项研究“海洋-3磷脂:新陈代谢和生物活动”
According to this review, the most predominant PLs in marine sources such as salmon, tuna, rainbow trout and mackerel, is PC, whereas PE is shown to be the second most abundant. Phosphatidylinositol (PI), phosphatidylserine (PS), lysophosphatidylcholine (lyso-PC), and sphingomyelin are found in smaller amounts.
根据这篇综述，在海洋资源中，最主要的PLs是PC，如鲑鱼，金枪鱼，虹鳟和鲭鱼，而PE显示是第二丰富的。磷脂酰肌醇(PI)、磷脂酰丝氨酸(PS)、溶血磷脂酰胆碱(lyso-PC)和鞘磷脂含量较低。
Fish roe is probably an exception though, with “38%–75% of their lipids in the form of phospholipids, with phosphatidylcholine being the predominant lipid class”
鱼卵可能是个例外，“它们38%-75%的脂质是磷脂，磷脂酰胆碱是主要的脂类。”
So most of dietary DHA isn't bound to LysoPC, so that's a process that has to happen after ingestion of DHA.
所以大多数饮食中的DHA并没有与溶血蛋白结合，所以这是一个在摄入DHA后必须发生的过程。
For one, LysoPC is made in the liver, and I wouldn't be surprised if the amount of DHA that ends up in our transport system to begin with is regulated by the liver somehow (I have no proof of this though). Anecdotally, a lot of people with poor liver function don't seem to do well with a lot of DHA in their diet.
首先，溶血蛋白是在肝脏中产生的，如果我们运输系统中DHA的数量以某种方式受到肝脏的控制，我不会感到惊讶(尽管我没有证据)。有趣的是，很多肝功能不佳的人在饮食中摄入大量DHA时似乎效果不佳。
Then, we've got the distinction between sn-2 and non-sn-2 (sn-1 or sn-3) DHA.
然后，我们得到了sn-2和非sn-2 DHA (sn-1或sn-3)的区别。
sn-2 DHA seems to absorbed well in the Intestine. 'Intestinal absorption and lymphatic transport of eicosapentaenoic (EPA), docosahexaenoic (DHA), and decanoic acids: dependence on intramolecular triacylglycerol structure.'(Christensen et. al., 1995) – http://ajcn.nutrition.org/content/61/1/56.short
sn-2 DHA在肠内吸收良好。“二十碳五烯(EPA)、二十二碳六烯(DHA)和癸酸的肠道吸收和淋巴运输:依赖于分子内三酰基甘油结构。”
It's also likely better transported into the brain, 'Biological properties of a DHA-containing structured phospholipid (AceDoPC) to target the brain' (Lagarde et. al., 2014) – https://hal.archives-ouvertes.fr/file/index/docid/958127/filename/Lagarde_et_al._PLEFA_2013-2014.pdf
它也可能更好地传输到大脑，“含有dha的结构化磷脂(AceDoPC)的生物学特性，以靶向大脑”
One note though:
Although the lyso species was purified by HPLC immediately prior to acetylation, around 20% of 1-docosahexaenoyl,2-acetyl-PC was obtained, presumably due to DHA migration to the sn-1 position during the chemical process.
不过有一点要注意:
虽然溶酶体在乙酰化前立即被高效液相色谱纯化，但仍获得了约20%的1-二十二碳六烯基，2-乙酰- pc，可能是由于DHA在化学过程中迁移到sn-1位置。
So migration from the sn-2 position to the sn-1 or sn-3 position may offset some of the oxidative resilience seen at sn-2. 'Docosahexaenoic Acid is More Stable to Oxidation when Located at the sn-2 Position of Triacylglycerol Compared to sn-1(3)' (Wijesundera et. al., 2008) – http://link.springer.com/article/10.1007/s11746-008-1224-z
因此，从sn-2位点向sn-1或sn-3位点的迁移可能会抵消一些sn-2位点的氧化弹性。与sn-1相比，二十二碳六烯酸位于三酰基甘油的sn-2位置时更稳定的氧化(3)
As for dietary sources, Farmed Atlantic Salmon still has 80% of it's DHA in the sn-2 position according to 'Positional Distribution of Fatty Acids in Triacylglycerols and Phospholipids from Fillets of Atlantic Salmon (Salmo Salar) Fed Vegetable and Fish Oil Blends' (Ruiz-Lopez et. al., 2015) – http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4515615/
至于饮食来源，养殖大西洋鲑鱼仍然有80%的DHA在sn-2位置，根据“从用蔬菜和鱼油喂养的大西洋鲑鱼(Salmo Salar)鱼片中三酰基甘油和磷脂中脂肪酸的位置分布”
I think we can assume that seafood is a good source of sn-2 DHA.
我想我们可以假设海鲜是sn-2 DHA的良好来源。
Still, we've got a complex chain of regulation and control over DHA. It's definitely not a question about eating more of it to “get better brain function”.
尽管如此，我们对DHA还是有一个复杂的管理和控制链。这绝对不是一个吃更多咖啡来“改善大脑功能”的问题。
And of course, malfunctions anywhere along the chain, be it a stressed out liver, or malfunctioning MFSD2A, will lead to dys-regulation of the amount of DHA that can get to important tisuses like the brain.
当然，链条上任何地方的故障，无论是肝脏的压力过大，还是MFSD2A的故障，都会导致DHA数量的失调，而DHA可以到达大脑等重要组织。
Whole Food vs Supplements
天然食品vs补充剂
There is very little difference in plasma DHA levels regardless of the method of delivery based on 'Comparison of the effects of fish and fish-oil capsules on the n 3 fatty acid content of blood cells and plasma phospholipids.' (Harris WS et. al., 2007) – http://www.ncbi.nlm.nih.gov/pubmed/18065578
根据“比较鱼和鱼油胶囊对血细胞中n - 3脂肪酸含量和血浆磷脂的影响”的研究结果，无论使用哪种方式，血浆中DHA含量的差异都很小。
If brain DHA delivery is rate-limited in any case, then for practical measures, would it be “easier” for people to just take a good DHA supplement, while eating other foodstuffs?
如果脑内DHA的供给在任何情况下都是有限的，那么对于实际的措施来说，对人们来说，只吃一份好的DHA补充剂，而吃其他食物是否会“更容易”?
Of course, seafood generally contains a lot more nutrients than just DHA, so it's probably “better” in that sense. However, strictly in terms of DHA delivery, it's hard to make a direct case for seafood. Seafood also suffers simlar DHA oxidised.
当然，海鲜通常含有比DHA多得多的营养成分，所以从这个意义上说，它可能“更好”。然而，严格地说，就DHA的输送而言，很难对海鲜做出直接的解释。海鲜也遭受类似的DHA氧化。
Closing Rant: Preganancy and Early Developmental Needs do not Necessary Reflect other Contexts
结语:怀孕和早期发育需要不一定反映其他情况
It is clear that for Preganant and Breastfeeding mothers, as well as Infants, that no amount of endogneous DHA production is going to supply the needed amounts of DHA for development.
很明显，对于孕妇和哺乳期母亲以及婴儿来说，再多的内生DHA生产也不能满足发育所需的DHA。
However, once those developmental needs are met, can we really say that it is DHA deficiency that is the problem?
然而，一旦这些发育需要得到满足，我们真的能说DHA缺乏是问题所在吗?
This is going to be highly context dependent. For example, if a person was raised DHA deficient to begin with and is now 15 years old with neurological disorders, then yes, adding some DHA transiently is probably going to do well to create the DHA stores needed, which then need to be endogenously regulated and deposited in the right amounts in the right tissues.
这将是高度依赖上下文的。举个例子,如果一个人从小就开始DHA缺乏与神经障碍,现在15岁,那么是的,添加一些DHA是暂时性的DHA可能做好创建存储需要,然后需要从内部监管,把正确的数量在正确的组织。
Even in this case, it is not a simple matter of “eat more DHA and get fixed”. I will guarantee that keeping said sick teenager in a high nn-EMF with adequate DHA will get DHA into their tissues, but still leave them with the same (if not more) problems due to the failure of all other systems.
即使在这种情况下，也不是简单的“多吃DHA并得到修复”。我将保证，保持说生病的青少年在一个高nn-EMF与充足的DHA将DHA进入他们的组织，但仍然留给他们相同的(如果不是更多的)问题，由于所有其他系统的失败。
Or put differently, DHA is not a “stress-reliever” in any sense. It is a critical compound needed to get other critical compounds to the right places for critical function, and requires other critical systems to be working efficiently to perform its task.
或者换句话说，DHA在任何意义上都不是一种“减压剂”。它是一个关键化合物，需要其他关键化合物到正确的位置，以实现关键功能，并需要其他关键系统有效工作，以完成它的任务。
Now take the best case scenario, whereby you have a healthy person under low stress. Will this person benefit from DHA? Maybe 200mg of DHA a week is no problem. But beyond that? Brain requirements don't seem to be that high, and responses to stress seem to be made fragile by extra DHA (see later sections on immune and mitochondrial effects of DHA).
现在假设最好的情况，你有一个健康的人压力很低。这个人会从DHA中受益吗?也许一周200毫克的DHA没有问题。但除此之外呢?大脑的需求似乎没有那么高，额外的DHA似乎会使压力反应变得脆弱(见后面关于DHA的免疫和线粒体作用的部分)。
In any case, we cannot use “DHA is needed during development” to mean “DHA is always needed”. DHA is still critical for young humans, but the beneficial effects on older humans are dubious.
无论如何，我们不能用“DHA是在开发过程中需要的”来表示“DHA总是需要的”。DHA对年轻人仍然至关重要，但对老年人的有益影响值得怀疑。
PUFA considered harmful.
But DHA too?
PUFA被认为是有害的。但DHA也是吗?
Ray Peat proposes that an excess of any Polyunsaturated Fatty Acid (PUFA) is not a good thing –http://raypeat.com/articles/articles/fishoil.shtml
Ray Peat说多不饱和脂肪酸(PUFA)的过量不是一件好事
I like Giorgi's (haidut) summary too – https://raypeatforum.com/forum/viewtopic.php?t=8033
我也喜欢Giorgi的总结
I'm not going to discuss the rest of the PUFAs other than DHA and EPA. The reader can do an easy search for the harmful effects of excess PUFA – there is almost no way to spin a story supporting consumption of PUFAs beyond whatever minute quantities found in low-PUFA foods.
除了DHA和EPA，我不打算讨论其他的不饱和脂肪酸。读者可以很容易地搜索过量的多不饱和脂肪酸的有害影响——几乎没有办法编造一个故事来支持摄入多不饱和脂肪酸，超过低不饱和脂肪酸食品中的微量。
The next few sections deal with some issues of DHA.
下面几节将讨论DHA的一些问题。
Sidenote: DNL can provide a surprising amount of fatty acids.
旁注:DNL可以提供惊人数量的脂肪酸
In fact, you probably don't need any dietary PUFA at all except DHA. Apparent adipocytes can make all the fatty acids that the body needs via DNL. 'De novo lipogenesis in the differentiating human adipocyte can provide all fatty acids necessary for maturation' (Collins et. al., 2011) –http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3151688/
事实上，除了DHA，你可能根本不需要任何多不饱和脂肪酸。显然，脂肪细胞可以通过DNL制造身体所需的所有脂肪酸。“分化中的人类脂肪细胞的从头脂肪生成可以提供成熟所必需的所有脂肪酸”
This was basically a carbohydrate fueled metabolism:
In separate experiments, the following substrates were used: 1 mM [1-13C]acetate, D-[U-13C]glucose, 0.5 mM [U-13C]pyruvate, and 2 mM [U-13C]glutamine.
这基本上是碳水化合物驱动的新陈代谢:
在单独的实验中，使用以下底物:1 mM [1- 13c]醋酸酯、D-[U-13C]葡萄糖、0.5 mM [U-13C]丙酮酸酯和2 mM [U-13C]谷氨酰胺。
You basically got all the fatty acids you needed, including EPA. See figure 2 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3151688/figure/fig2/)
你基本上得到了你需要的所有脂肪酸，包括EPA。参见图2
DHA was not shown in the graph, but since it can be then used to make DHA, it is possible for full endogenous synthesis of DHA from the DNAL process. The efficiency is not known, though it must be somewhat significant to explain the relatively good levels of DHA in populations which do not consume any DHA.
DHA没有显示在图中，但由于它可以用来制造DHA，因此可以从DNAL过程中完全内源性合成DHA。这种功效目前还不清楚，但这一定对解释不摄入任何DHA的人群中DHA含量相对较高有一定意义。
As an aside, this could be a good explanation for why very low fat diets don't lead to health issues, as this article by Denise Minger discusses – http://rawfoodsos.com/2015/10/06/in-defense-of-low-fat-a-call-for-some-evolution-of-thought-part-1/
顺便说一句，这可以很好地解释为什么极低脂肪饮食不会导致健康问题，正如丹尼斯·明格尔(Denise Minger)的这篇文章所讨论的。
Isoprostanes and Neuroprostanes
8-异前列腺素和神经前列腺素
But back to DHA and possible toxicity, here are some of Peat's claims:
但回到DHA和可能的毒性，以下是peat的一些陈述:
EPA and DHA don't form ordinary prostaglandins, though the isoprostanes and neuroprostanes they produce during lipid peroxidation behave in many ways like the more common prostaglandins, and their enzymically formed eicosanoids have some functions similar to those of the common prostaglandins. The brain contains a very high concentration of these unstable fatty acids, and they are released in synapses by ordinary excitatory process.
EPA和DHA不能形成普通的前列腺素，尽管它们在脂质过氧化过程中产生的异前列腺素和神经前列腺素在许多方面的行为与更常见的前列腺素类似，而且它们通过酶的方式形成的二十烷类化合物具有与普通前列腺素类似的功能。大脑中含有非常高浓度的不稳定脂肪酸，它们通过普通的兴奋过程在突触中释放。
Well, here's one paper, 'Isoprostanes and Neuroprostanes as Biomarkers of Oxidative Stress in Neurodegenerative Diseases'(Miiler et. al., 2014) – http://www.hindawi.com/journals/omcl/2014/572491/
这里有一篇论文，“异前列腺素和神经前列腺素作为神经退行性疾病中氧化应激的生物标志物”
Excerpts and commentary follow.
The literature data indicate that in vivo or postmortem cerebrospinal fluid and brain tissue levels of F2-isoprostanes (F2-IsoPs) especially F4-neuroprotanes (F4-NPs) are significantly increased in some neurodegenerative diseases: multiple sclerosis, Alzheimer's disease, Huntington's disease, and Creutzfeldt-Jakob disease.
下面是摘录和评论：
文献资料表明，在体内或死后脑脊液和脑组织中，f2 -异前列腺素(F2-IsoPs)特别是f4 -神经蛋白(F4-NPs)水平在某些神经退行性疾病中显著升高，如多发性硬化、阿尔茨海默病、亨廷顿病、克雅氏病等。
This review focuses on the relationship between F2-IsoPs and F4-NPs as biomarkers of oxidative stress and neurodegenerative diseases. We summarize the knowledge of these novel biomarkers of oxidative stress and the advantages of monitoring their formation to better define the involvement of oxidative stress in neurological diseases.
本文就F2-IsoPs和F4-NPs作为氧化应激和神经退行性疾病的生物标志物之间的关系作一综述。我们总结了这些新的氧化应激生物标志物的知识，以及监测其形成的优势，以更好地界定氧化应激在神经系统疾病中的参与。
Fair enough. But how prone is DHA to degradation:
PUFAs are the most susceptible to free radical attack and, in general, oxidizability increases as the number of double bonds increases.
很好。但是DHA有多容易降解呢?
PUFAs最容易受到自由基的攻击，一般来说，氧化性随着双键数量的增加而增加。
So, the oxidizability of PUFAs can be estimated by the linear increase in the rate of oxidation with the increasing number of active methylene groups located between two bonds. From such correlation, the oxidizability of each PUFA is increased for about twofold for each active methylene group.
因此，PUFAs的可氧化性可以通过氧化速率随键间活性亚甲基数目的增加而线性增加来估计。从这种关联可以看出，每一个活性亚甲基使每一个PUFA的氧化性提高了约两倍。
Thus, the oxidizability of common fatty acids is as follows: linoleic acid (18:2) < arachidonic acid (20:4, n-6) < eicosapentaenoic acid (EPA, 20:5, n-3) < docosahexaenoic acid (DHA, 22:6, n-3)
因此，常见脂肪酸的氧化性如下:亚油酸(18:2)<花生四烯酸(20:4,n-6) <二十碳五烯酸(EPA, 20:5, n-3) <二十二碳六烯酸(DHA, 22:6, n-3)
So DHA is very easily oxidized.
所以DHA很容易被氧化。
By the peroxidation of the omega-3 PUFA, EPA and DHA, F-ring IsoPs have been generated. The IsoPs-like compounds generated from this acid are named NeuroPs.
通过n-3多不饱和脂肪酸、EPA和DHA的过氧化作用，生成f环IsoPs。由这种酸生成的类似isops的化合物被命名为NeuroPs。
F3-IsoPs are formed in abundance in vitro and in vivo from EPA nonenzymatically peroxidation, while DHA may be oxidized nonenzymatically into F4-, D4-, E4-, A4-, and J4-neuroprostanes (F4-, D4-, E4-, A4-, and J4-NeuroPs)
EPA在体外和体内通过非酶性过氧化大量形成F3-IsoPs，而DHA可被非酶氧化成F4-、D4-、E4-、A4-和j4 -神经前列腺素(F4-、D4-、E4-、A4-和j4 -神经前列腺素)。
Unlike AA, DHA is highly concentrated in neuronal membranes to the exclusion of other cell types. Moreover, F4-NeuroPs are by far the most abundant products of this pathway in the brain. The quantification of F4-NeuroPs provides a highly selective quantitative window for neuronal oxidative damage in vivo.
与AA不同的是，DHA在神经元膜中高度集中，排除了其他类型的细胞。此外，到目前为止，F4-NeuroPs是该通路在大脑中最丰富的产物。F4-NeuroPs的量化为体内神经元氧化损伤提供了一个高度选择性的定量窗口。
The rest of the paper just goes on to talk about how the Isoprostanes are likely suitable in vivo markers of Neurological conditions.
论文的其余部分将继续讨论异前列腺素是如何适用于神经系统疾病的体内标记物的。
I bring up that paper just to highlight that oxidised DHA is not good. This doesn't say anything about:
我提出那篇论文只是想强调氧化DHA是不好的。这并没有说:
•(a) if eating more DHA will lead to excess stores in tissues which are prone to oxidative damage.
多吃DHA是否会导致组织中储存过多的DHA，而这些组织容易受到氧化损伤。
•(b) if that stored DHA is going to get oxidised in the first place.
储存的DHA是否会首先被氧化。
It's more the case that if oxidative damage happens to occur where there is DHA present, then that DHA breaks down into substances we can measure.
更确切地说，如果氧化损伤发生在DHA存在的地方，那么DHA就会分解成我们可以测量的物质。
But Peat's perspective got me thinking:
但Peat的观点让我思考:
Another way of arguing for the use of fish oil or other omega-3 fats is to show a correlation between disease and a decreased amount of EPA, DHA, or arachidonic acid in the tissues, and to say “these oils are deficient, the disease is caused by a deficiency of essential fatty acids.”
另一种主张使用鱼油或其他ω- 3脂肪是指相关性疾病和减少数量的EPA, DHA,或组织中花生四烯酸,说“这些油不足,疾病是由于缺乏必需脂肪酸。”
Their “deficiency” in the tissues frequently corresponds to the intensity of oxidative stress and lipid peroxidation; it is usually their presence, rather than their deficiency, that created the disposition for the disease.
它们在组织中的“缺陷”往往与氧化应激和脂质过氧化的强度相对应;通常是它们的存在，而不是缺乏，造成了这种疾病的倾向。
So basically he's saying that the more DHA you have, the more prone that DHA is to oxidative damage, and to oxidative damage of the organism as a whole.
他的意思是DHA越多，DHA就越容易产生氧化损伤，对整个机体也越容易产生氧化损伤。
This is plausible, since DHA would be stored in adipose tissue like any other fatty acid, and would be mobilised like any other fatty acid (though some say that PUFAs are mobilised more readily than more saturated fatty acids).
这是有道理的，因为DHA会像其他脂肪酸一样储存在脂肪组织中，也会像其他脂肪酸一样被调动(尽管有人说不饱和脂肪酸比更多的饱和脂肪酸更容易调动)。
Free DHA in the serum would then be free to be oxidised in the serum (not good), transported to various places in the body (not good), used in mitochondrial ECT, with all the insulin sensitising effect and loss of ROS generation feedback loops (amoungst other bad effects).
血清中的游离DHA会在血清中被氧化(不好)，被运输到身体的各个地方(不好)，用于线粒体ECT，具有胰岛素增敏效应和ROS生成反馈回路的缺失(以及其他不好的影响)。
It does seem that Neuroprostanes are upregulated in Alzheimer's disease:
看来神经前列腺素在阿尔茨海默病中上调了:
'Formation of Isoprostane-like Compounds (Neuroprostanes) in Vivo from Docosahexaenoic Acid' (Jackson Roberts II et. al., 1998) – http://www.jbc.org/content/273/22/13605.full
二十二碳六烯酸在体内形成类异前列腺素化合物(神经前列腺素)
This study focused on the same F4 neuroprostanes (NP) and F2 Isoprostances (IsoPs) mentioned above.
本研究主要针对上述F4神经前列腺素(NP)和F2等前列腺素(IsoPs)。
It consisted of 3 different experiments:
它包括3个不同的实验:
•In vitro oxidation of equal molar amounts of DHA and Arachidonic Acid (AA) together using iron/ADP/ascorbate. 3.4 times more F4-NPs than F2-IsoPs were formed.
利用铁/ADP/抗坏血酸，在体外氧化等量DHA和花生四烯酸(AA)。形成的F4-NPs是F2-IsoPs的3.4倍。
•Measure levels of F4-NPs and F2-IsoPs in rat and pig brains.
F4-NPs dominate in pigs, and F2-IsoPs dominate in Rats. Mechanism for differences unknown, and sameple size was tiny.
Table 1 – http://www.jbc.org/content/273/22/13605/T1.expansion.html
测量大鼠和猪大脑中F4-NPs和F2-IsoPs的水平。
猪以F4-NPs为主，大鼠以F2-IsoPs为主。差异机制未知，相同大小很小。
•Examine F4-NP levels in cerebrospinal fluid obtained from four patients with Alzheimer’s disease and three age-matched control subjects.
检查从4名阿尔茨海默病患者和3名年龄匹配的对照组获得的脑脊液中F4-NP水平。
Quote:
F4-NPs were detected in 1–2 ml of cerebrospinal fluid from the control subjects at a level of 64 ± 8 pg/ml.
Concentrations measured in the patients with Alzheimer’s disease were significantly higher (110 ± 12 pg/ml) (p < 0.05)
引用:
对照组1-2 ml脑脊液中检测到F4-NPs，水平为64±8 pg/ml。
在阿尔茨海默病患者中检测到的浓度明显更高(110±12 pg/ml) (p < 0.05)。
Again, it is likely that DHA is “spontaenously” and non-enzymatically broken down to these compounds.
同样，DHA很可能是“自发的”和非酶分解为这些化合物。
A quote from the next study I'm about to mention:
Autooxidation of DHA occurs so readily that oxidation products are commonly found in DHA even after minimal handling
(based on 'Lipid peroxidation products are elevated in fish oil diets even in the presence of added antioxidants'. (Gonzalez MJ et. al, 1992))
And now on to yet another study …
我要引用的下一个研究:
DHA的自动氧化作用非常容易发生，即使在少量的处理后，氧化产物也普遍存在于DHA中
(基于“即使在添加抗氧化剂的情况下，鱼油饮食中的脂质过氧化产物也会升高”。(冈萨雷斯·乔丹等，1992))
现在来看另一项研究……
Neuroprostanes Mis-interpreted as Being “Good”
神经前列腺素被误解为“好”
One of the authors of that paper, Jason Morrow, followed up with proposed mechanisms of Neuroprostanes 10 years later in 'Electrophilic Cyclopentenone Neuroprostanes Are Anti-inflammatory Mediators Formed from the Peroxidation of the ω-3 Polyunsaturated Fatty Acid Docosahexaenoic Acid' (Musiek et. al., 2008) – http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2459280/
那篇论文的作者之一Jason Morrow在10年后的“亲电环戊酮神经前列腺素是ω-3多不饱和脂肪酸二十二碳六烯酸的过氧化形成的抗炎介质”中提出了神经前列腺素的机制。
This paper focused on A4-NPs and J4-NPs. Rat Macrophages (white blood cells) were used as the target.
本文重点研究了A4-NPs和J4-NPs。以大鼠巨噬细胞(白细胞)为靶点。
One class of endogenous NPs, the A4/J4-NPs, have been described, which are analogous in structure to the anti-inflammatory cyclopentenone PGs PGA2 and PGJ2.
已经描述了一类内源性NPs, A4/J4-NPs，其结构类似于抗炎环戊酮PGs PGA2和PGJ2。
These molecules contain an electrophilic α,β-unsaturated carbonyl moiety that readily forms adducts with cellular thiols via Michael addition.
这些分子包含亲电的α，β不饱和羰基部分，容易通过迈克尔加成与细胞硫醇形成加合物。
As the authors note, in vivo formation of such neuroprostanes occurs readily – 'Formation of highly reactive A-ring and J-ring isoprostane-like compounds (A4/J4-neuroprostanes) in vivo from docosahexaenoic acid' (Fam et. al., 2002)
作者指出，这种神经前列腺素在体内很容易形成——“在体内由二十二碳六烯酸形成高度反应的a环和j环类异前列腺素化合物(A4/ j4神经前列腺素)”(Fam et al.， 2002)。
They then claim:
Because of their structural similarities to anti-inflammatory cyclopentenone PGs and IsoPs, we hypothesize that A4/J4-NPs exert anti-inflammatory actions and may mediate some of the bioactivity of DHA.
然后他们说:
由于A4/J4-NPs与抗炎环戊酮PGs和IsoPs的结构相似，我们推测A4/J4-NPs具有抗炎作用，并可能介导DHA的一些生物活性。
Some of the results:
•A4-NP Inhibits LPS-induced iNOS and COX-2 Expression in RAW Macrophages.
0.5mM showed 25% inhibition. 1.0mM showed about 40% inhibition, 5mM showed almost 90% inhibition. Looks like we've got a linear effect going on here. More A4-NP, less iNOS and COX-2.
结果如下:
A4-NP抑制lps诱导的RAW巨噬细胞iNOS和COX-2表达。
0.5mM的抑制率为25%。1.0mM的抑制率约为40%，5mM的抑制率约为90%。看起来这里有一个线性效应。更多的A4-NP，更少的iNOS和COX-2。
•A4-NP Is an Inhibitor of the NF-κB Pathway.
A4-NP是NF-κB通路的抑制因子。
Quote:
A4-NP also completely blocked NF-κB activation induced by the pro-inflammatory cytokines TNFα and IL-1β (Fig. 3B)
LPS, TNFα, and IL-1β activate NF-κB via distinct receptors and signaling pathways, which converge at the level of IκB kinase complex (IKK) activation
This finding demonstrates that A4-NP-mediated inhibition of NF-κB signaling does not occur at the receptor level.
Inhibition of NF-κB Signaling by A4-NP Occurs at the Level of IKK Function.
引用:
A4-NP还完全阻断了促炎细胞因子TNFα和IL-1β诱导的NF-κB活化(图3B)
LPS、TNFα和IL-1β通过不同的受体和信号通路激活NF-κB，这些受体和信号通路集中于IκB激酶复合物(IKK)的激活水平。
这一发现表明，a4 - np介导的NF-κB信号抑制并不发生在受体水平。
在IKK功能水平上，A4-NP抑制NF-κB信号通路。
Quote:
NF-κB-mediated transcription requires translocation of p50/p65 heterodimers from the cytosol to the nucleus.
Immunostaining of RAW264.7 cells demonstrated NF-κB p65 confined to the cytoplasm, whereas LPS stimulation resulted in intense nuclear p65 accumulation after 30 min (Fig. 4A). Phosphorylation of IκBα at Ser-32 and -36 by IKK precedes its dissociation from p65/p50 and proteasomal degradation.
LPS caused pronounced IκBα phosphorylation at 10 min, which was almost completely abrogated by A4-NP (Fig. 4C). A4-NP also substantially inhibited IκBα phosphorylation after 20 min of LPS exposure.
These results, coupled with the ability of A4-NP to suppress NF-κB activation triggered by TNFα and IL-1β, suggest that A4-NP may inhibit NF-κB signaling at the level of the IKK complex.
Mutation of IKKβ Cysteine 179 Impairs the Ability of A4-NPs to Inhibit NF-κB Signaling.
引用:
NF-κ b介导的转录需要p50/p65异二聚体从胞质转位到细胞核。
RAW264.7细胞的免疫染色显示，NF-κB p65局限于细胞质，而LPS刺激在30分钟后导致核p65的强烈积累(图4A)。IKK可使IκBα在Ser-32和-36位点磷酸化，使其从p65/p50解离并降解蛋白酶体。
LPS可引起IκBα在10min时的显著磷酸化，而这一磷酸化几乎被A4-NP完全消除(图4C)。在LPS处理20分钟后，A4-NP也显著抑制IκBα磷酸化。
这些结果，再加上A4-NP抑制TNFα和IL-1β触发的NF-κB激活的能力，表明A4-NP可能在IKK复合物水平上抑制NF-κB信号通路。
IKKβ半胱氨酸179突变损害A4-NPs抑制NF-κB信号通路的能力。
Quote:
Cys-179 in IKKβ contains a thiol group susceptible to Michael adduction, and cyclopentenone PGs are known to inhibit NF-κB signaling via adduction of this residue.
Overexpression of WT or mutant C179A IKKβ caused a marked increase in NF-κB-luc reporter activity in HEK293 cells in the absence of LPS signaling. A4-NP suppressed this increase significantly by a mean of 62% in WT IKKβ cells (p < 0.05) but did not significantly decrease NF-κB activation in C179A mutant cells.
引用:
IKKβ中的Cys-179包含一个易受Michael内收的硫醇基团，环戊酮PGs已知可通过该残基的内收抑制NF-κB信号通路。
在缺乏LPS信号的情况下，过表达WT或突变C179A IKKβ可导致HEK293细胞NF-κB-luc报告因子活性的显著增加。在WT IKKβ细胞中，A4-NP显著抑制了这种增加，平均抑制率为62% (p < 0.05)，但在C179A突变细胞中NF-κB的活化没有显著降低。
•Oxidation of DHA Increases A4/J4-NP Content and Anti-inflammatory Potency in Parallel
DHA氧化可同时提高A4/J4-NP含量和抗炎效力
Quote:
As shown in Fig. 6A, treatment with unoxidized DHA did not affect LPS-induced nitrite production in RAW cells in the acute setting (30 min of preincubation), whereas oxidized DHA (which had been subjected to 10 h of oxidation with 5 mm AAPH) caused a dose-dependent inhibition of nitric oxide production.
oxDHA also inhibited LPS-stimulated NF-κB reporter activity at similar concentrations in immortalized murine macrophages (Fig. 6B)
oxDHA also inhibits NF-κB activation by IL-1β or TNFα (Fig. 3B).
oxDHA subjected to solid phase extraction on a C18 SepPak, which removes unoxidized DHA from the mixture but preserves A4/J4-NPs, retained its anti-inflammatory potency.
引用:
如图6所示,治疗未氧化的DHA并不影响LPS-induced原始细胞急性亚硝酸盐生产设置预孵化(30分钟),而氧化DHA(曾受到10 h与5毫米AAPH)氧化剂量依赖性抑制一氧化氮引起的生产。
在相同浓度下，oxDHA也能抑制lps刺激的NF-κB报告细胞活性(图6B)。
oxDHA还能抑制IL-1β或TNFα对NF-κB的激活(图3B)。
在C18 SepPak上进行固相萃取，从混合物中去除未氧化的DHA，但保留了A4/J4-NPs，保留了其抗炎效力。
•Bioactivity of Both A4-NPs and oxDHA Is Independent of PPARγ and Is Eliminated by Chemical Reduction or Conjugation to GSH.
4-nps和oxDHA的生物活性都不依赖于PPARγ，并通过化学还原或与GSH结合而消除。
Quote:
We observed that two molecularly distinct PPARγ receptor antagonists, GW9662 and T0070907, used at concentrations well above their respective IC50 values, failed to inhibit the anti-inflammatory effects of A4-NP (Fig. 7A), suggesting that PPARγ is not crucially involved
We also observed that PPARγ antagonists had no effect on the anti-inflammatory effect of oxDHA.
引用:
我们观察到，两种分子上截然不同的PPARγ受体拮抗剂，GW9662和T0070907，在其浓度远高于各自的IC50值时，未能抑制A4-NP的抗炎作用(图7A)，这表明PPARγ并不是关键因素
我们还观察到PPARγ拮抗剂对oxDHA的抗炎作用无影响。
•Activity not dependent on GSH
Quote (paraphrased):
Incubation of RAW cells with 10 μm A4-NP for 1 h also did not alter cellular levels of GSH (data not shown), demonstrating that A4-NPs mechanism of action is not reliant on the depletion of intracellular GSH
Taken together, these results suggest that the bioactivity of A4-NP is mediated largely by its chemical reactivity and ability to form thiol adducts with proteins,
This is consistent with a role for cyclopentenone NPs in the anti-inflammatory effect of oxDHA, although the inactivation of other reactive compounds present in the oxDHA mixture cannot be ruled out.
活动不依赖于谷胱甘肽
报价(转述):
用10 μm A4-NP孵育RAW细胞1小时也没有改变细胞内谷胱甘肽水平(数据未显示)，这表明A4-NP的作用机制并不依赖于细胞内谷胱甘肽的消耗。
综上所述，这些结果表明，A4-NP的生物活性主要是由其化学反应性和与蛋白质形成硫醇加合物的能力介导的，这与环戊酮NPs在oxDHA抗炎作用中的作用是一致的，尽管不能排除oxDHA混合物中存在的其他活性化合物的失活。
•A4/J4-NPs Are Found Abundantly in Human Brain Specimens from Patients with Alzheimer Disease
Quote:
We obtained frontal cortex brain samples from pathologically confirmed AD and age-matched control patients and examined levels of A4/J4-NPs by GC/MS.
As shown in Fig. 8, esterified levels of A4/J4-NPs were ∼3-fold greater in AD brain than controls. The average level of A4/J4-NPs in an AD brain sample was 295 ng/g brain tissue, which roughly converts to 950 nM A4/J4-NPs.
500 nM A4-NP exerted significant anti-inflammatory effects in our cell culture system, showing that A4/J4-NPs are found in biologically relevant concentrations in humans in vivo.
从阿尔茨海默病患者的大脑标本中大量发现A4/J4-NPs
引用:
我们从病理证实的AD患者和年龄匹配的对照组患者的额叶皮质脑样本中提取A4/J4-NPs，并用GC/MS检测A4/J4-NPs水平。
如图8所示，AD患者大脑中A4/J4-NPs的酯化水平比对照组高出约3倍。AD脑组织中A4/J4-NPs的平均水平为295 ng/g脑组织，大致转换为950 nM A4/J4-NPs。
500nm A4- np在我们的细胞培养体系中具有显著的抗炎作用，表明A4/ j4 - np在人体内存在生物学相关浓度。
OK, so that was a lot of details … but I only bring them up because I think they are exactly the details supporting why suppression of NF-kB and other “inflammatory” agents is a BAD thing. This is precisely why oxidised DHA and it's resultant products can be considered to be an “immune system suppressent”.
More details to follow.
好了，这就是很多细节……但我之所以提到它们，是因为我认为它们正是支持为什么抑制NF-kB和其他“炎症”因子是一件坏事的细节。这就是为什么氧化的DHA和它产生的产品可以被认为是“免疫系统抑制”。
更多细节在路上。
@“徐泾东八号出口”#p608 of the