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NF-κB Considered Useful NF -κB被认为是有用的

NF-κB is a key component in signalling, and shutting it down pre-emptively before the appropriate systemic response can occur is not a good thing. NF-κB是信号传递的关键组成部分，在适当的系统反应发生之前提前关闭它并不是一件好事。

Some studies: 一些研究： ?NF-kappaB activation within macrophages leads to an anti-tumor phenotype in a mammary tumor lung metastasis model&amp;apos; (Connelly et. al., 2011) 巨噬细胞内NF-kappaB激活导致乳腺肿瘤肺转移模型中的抗肿瘤表型”(Connelly等，2011年) http://www.breast-cancer-research.com/content/13/4/R83

Activation of NF-κB in macrophages during seeding leads to a reduction in lung metastases. The mechanism involved expression of inflammatory cytokines and reactive oxygen species, leading to apoptosis of tumor cells and preventing seeding in the lung. 播种期巨噬细胞NF-κB的激活导致肺转移的减少。其机制涉及炎性细胞因子和活性氧的表达，导致肿瘤细胞凋亡，防止在肺内播散。

This study actually studied live mice, bred differently to either activate NF-kB (IFKM mice) or inhibit NF-kB (DNFM mice). NOTE: &amp;quot;dox&amp;quot; is a transgene activator used to activate the genes needed for NF-kB expression. DNFM or IFKM mice do not have the NF-kB activating/inhibiting behaviour without this substance. 被研究的是活小鼠。它们要么被激活NF-kB (IFKM小鼠)，要么抑制NF-kB (DNFM小鼠)。 注:“dox”是一种转基因激活剂，用于激活NF-kB表达所需的基因。如果没有这种物质，DNFM或IFKM小鼠就没有NF-kB激活/抑制行为。 ?Almost no lung tumours with active NF-kB expression. Dox was administered throughout the experiment. See figure 2 (http://www.breast-cancer-research.com/content/13/4/R83/figure/F2). Note how Figure 2C shows high tumour counts with IFKM mice not fed dox, while tumour counts are almost non-existent with dox (and active NF-kB) 在NF-kB表达活跃下几乎没有产生肺肿瘤。在整个实验过程中都使用了Dox。参见图2 (http://www.breast-cancer-research.com/content/13/4/R83/figure/F2)。注意，图2C显示了未喂食dox的IFKM小鼠的高肿瘤计数，而dox小鼠(和活性NF-kB)的肿瘤计数几乎不存在。 ?This time, another test similar to the first one, except that Dox was stopped 2 days after tumour cells were injected. Almost no tumours from PyVT R221A cell. Much reduced tumour counts with PYG 129 cells. While the DNFM (low NF-kB) mice experienced more counts. See figure 3 (http://www.breast-cancer-research.com/content/13/4/R83/figure/F3). 这一次，另一项测试与第一次类似，除了阿霉素在注射肿瘤细胞2天后停止。PyVT R221A细胞几乎无肿瘤发生。PYG 129细胞大大减少了肿瘤计数。而DNFM(低NF-kB)小鼠的计数更多。参见图3 (http://www.breast-cancer-research.com/content/13/4/R83/figure/F3)。 ?Injecting dox 2 days after tumour cells were introduced led to no benefit. And thus: This suggests that activating NF-κB in macrophages &amp;quot;pre-educates&amp;quot; the IKFM lung environment to become anti-tumor, an effect that is achieved in control mice to a lesser degree only in response to tumor cells. 肿瘤细胞引入后2天注射dox没有任何益处。 因此: 这表明，在巨噬细胞中激活NF-κB“预先教育”IKFM肺环境成为抗肿瘤环境，这一效果仅在对照小鼠对肿瘤细胞的反应中达到，但程度较轻。 ?Increased clearing of tumor cells and apoptosis in IKFM lungs correlates with higher ROS levels and increased CXCL9 expression Quote: IKFM mice showed a significant increase in ROS levels as compared with controls (Figure 6d). This suggests that the lung environment in IKFM mice was more cytotoxic to tumor cells correlating with increased clearance and a reduction in final tumor counts. Fair enough. Tumour cells suck at dealing with oxidative stress, while I assume &amp;quot;normal&amp;quot; cells can deal with some oxidative load. IKFM肺中肿瘤细胞清除和凋亡的增加与更高的ROS水平和CXCL9表达增加相关 引用: 与对照组相比，IKFM小鼠的ROS水平显著升高(图6d)。这表明，IKFM小鼠的肺环境对肿瘤细胞更具细胞毒性，与清除增加和最终肿瘤计数减少相关。 很好。肿瘤细胞在处理氧化应激方面表现糟糕，而我认为“正常”细胞可以处理一些氧化负荷。 NOTE: It is important to remember that we are looking at mice lung tumours. Will this generalise to other tumours? Will this generalise to humans? 注意:重要的是要记住，我们观察的是小鼠的肺肿瘤。这是否也适用于其他肿瘤?或这是否也适用于人类?

The study above references other studies which show failures of macrophage defence in cancer, but like the authors note, it is most likely due to the nature of the NF-kB response. NF-kB needs to be elevated immediately upon tumour growth, and consistently elevated until what I assume is sufficient tumour apoptosis has occurred. This feels like simple redox balance to me, and shows a place where oxidative stress is a good thing. In that sense, keeping the metabolic rate high, whereby oxidative and reduction rates are high and in balance, is probably a good thing to both deal with existing oncogenic cells, and to prevent oncogenesis from occuring in the first place. If DHA suppresses that ability, then this is one place where DHA is not a good thing. As usual, I want to believe that if the body is allowed to endogenously regulate DHA distribution (and not being faced with consistent high exogenous load), then the appropriate macrophage NF-kB response will be allowed to continue (and stop once their role is complete). I have no way of proving this of course ;) 上述研究参考了其他研究，这些研究表明了巨噬细胞防御在癌症中的失败，但正如作者所指出的，这很可能是由于NF-kB反应的性质。NF-kB需要在肿瘤生长时立即升高，并持续升高，直到我认为发生了足够的肿瘤凋亡。 对我来说，这就像是简单的氧化还原平衡，表明氧化应激是一件好事。从这个意义上说，保持高代谢率，使氧化和还原率保持高和平衡，可能是一件好事，既可以处理现有的致癌细胞，又可以从一开始就防止肿瘤发生。 如果DHA抑制了这种能力，那么DHA就不是一件好事。和往常一样，我想相信，如果允许身体内源性调节DHA的分布(而不面临一致的高外源性负荷)，那么适当的巨噬细胞NF-kB反应将被允许继续(并在它们的作用完成后停止)。当然，我没有办法证明这一点;)

Still, we come back to the idea that transient bursts of oxidative stress to get rid of the cancer state is probably a good thing, and having stuff like NF-kB as stress response factors is also probably a good thing. Chronically elevated oxidation is not good. Chronically suppressing the oxidative stress cascade is also not good. 尽管如此，回到想法：氧化应激的短暂爆发来摆脱癌症状态可能是一件好事，有像NF-kB这样的应激反应因子可能也是一件好事。长期氧化升高是不好的。长期抑制氧化应激级联也是不好的。

How to determine this in a clinical context?You hear me talk about &amp;quot;woo woo&amp;quot; coherence testing of meridians, which is all I got. 如何在临床背景下确定这一点?听说过关于&amp;quot;我听了直呼nb&amp;quot;的经络一致性测试吧，这是我知道的全部。

?‘The complexity of NF-κB signaling in inflammation and cancer&amp;apos; (Bastian Hoesel and Johannes A Schmid, 2013) – http://molecular-cancer.biomedcentral.com/articles/10.1186/1476-4598-12-86

I don&amp;apos;t think I&amp;apos;m going to try and summarise this study. It gives a nice balanced take on all the nuances of NF-kB signalling, and all the complexities behind it (which frankly, I do not fully understand). Everything from fundamental signalling mechanics, different responses in different cell types, ROS/RNS interdependency (NF-kB depends on ROS/RNS and vice versa), RNA and DNA crosstalk as it applies to NF-kB, discussion of NF-kB inhibitors depending on stage of cancer, and a lot more … “炎症和癌症中NF-κB信号通路的复杂性”(Bastian Hoesel和Johannes A Schmid, 2013)—http://molecular-cancer.biomedcentral.com/articles/10.1186/1476-4598-12-86 我不打算总结这个研究。它对NF-kB信号的所有细微差别及其背后的所有复杂性(坦率地说，我不完全理解)给出了一个很好的平衡的看法。从基本的信号机制，不同细胞类型的不同反应，ROS/RNS的相互依赖性(NF-kB依赖于ROS/RNS，反之亦然)，RNA和DNA的串音，因为它适用于NF-kB, NF-kB抑制剂的讨论取决于癌症的阶段等等…

Definitely recommended reading! :D I tend to favour the metabolic model of cancer, whereby oncogenesis is just the culmination of poor metabolic function (likely at the Mitochondrial Complex I and TCA level, characterised by a low NAD+/NADH ratio). This is a continuum, whereby all the same inflammatory regulatory processes, including NF-kB signalling, need to constantly be working for redox balance in cells and organs. That is to say that the discussion on NF-kB with regards to cancer can just as well be applied to healthy cells, which teeter on the balance of &amp;quot;becoming concerous or not&amp;quot; on a minute to minute basis. 绝对推荐阅读!:D 我倾向于癌症的代谢模型，在这个模型中，肿瘤发生只是代谢功能差的顶点(可能是在线粒体复合物I和TCA水平，以低NAD+/NADH比率为特征)。这是一个连续体，所有相同的炎症调节过程，包括NF-kB信号，都需要在细胞和器官中为氧化还原平衡不断工作。 也就是说，关于NF-kB与癌症相关的讨论也同样适用于健康细胞，健康细胞在每分钟“是否变癌”的平衡上摇摆不定。

Back to the topic to DHA, does eating lots of DHA mean that you are constantly suppressing your immune system? The answer is obviously, &amp;quot;It depends on how well your body can regulate DHA&amp;apos;s distribution in tissues&amp;quot;. 回到DHA的话题，吃大量的DHA是否意味着你在不断地抑制你的免疫系统?答案很明显，“这取决于你的身体如何调节DHA在组织中的分布”。

That adds an even greater of complexity to clincal application, but if there are clear symptoms of the inability to process DHA, then I cannot advocate eating more of it. Example: if your liver is already screwed up, say you have some form of &amp;quot;Fatty Liver Disease&amp;quot;. Well, you should probably fix that liver first, and not eat more DHA to put added stress on your liver (just like you wouldn&amp;apos;t eat excess fructose, drinking alcohol, smoke cigarettes, perform heavy metal detox, try to lose weight, or eat other PUFAs if you had this condition). 这给临床应用增加了更大的复杂性，但如果有无法处理DHA的明显症状，那么我不能提倡多吃DHA。例如:如果你的肝脏已经坏了，就说你得了某种“脂肪肝病”。嗯，你可能应该首先修复你的肝脏，而不是吃更多的DHA给你的肝脏增加压力(就像你不会吃过量的果糖，饮酒，吸烟，进行重金属排毒，尝试减肥，或吃其他不饱和脂肪酸如果你有这种情况)。

One of the previous studies noted that A4-NPs are elevated in Alzheimer&amp;apos;s Disease. Some people would say, &amp;quot;plasma DHA is low in such a disease, and thus DHA supplementation is warranted&amp;quot;. Just because plasma DHA is low in the disease, does not imply that a lack of DHA is what caused the disease, and even less so that adding more DHA to a state where DHA breakdown is occurring so rapidly is going to fix the problem (with likely harmful effects directly attributed to DHA breakdown products). 之前的一项研究指出，阿兹海默症患者的A4-NPs水平升高。有些人会说，“这种病的血浆DHA含量很低，因此补充DHA是必要的”。仅仅因为等离子DHA是低的疾病,并不意味着缺乏DHA是什么导致了疾病,和更少,这样增加DHA DHA故障状态发生如此之快将解决这个问题(可能有害影响直接归因于DHA分解产物)。

In my opinion, addressing stressors that cause the disease comes first and foremost. I see measures like avoiding blue light at circadian inappropriate hours, avoid non-native EMF, and possibly eating a ketogenic diet to slow down disease progression, as far better ways to address the problem instead of eating more DHA (which could make the problem worse). Sidenote: Ray Peat would claim that eating some sugars can help with such cases. I can see some plausible mechanics, but that will have to be addressed in a future blog post. That said, it is still more than possible to consume say 30g of sugar on a ketogenic diet. 在我看来，解决导致疾病的压力源是最重要的。我认为，与摄入更多DHA(这会使问题变得更糟)相比，在昼夜节律不合适的时间避免蓝光、避免非原生电磁场、可能吃生酮饮食来减缓疾病进展等措施是解决问题的更好方法。 旁注:Ray Peat会声称吃一些糖可以帮助解决这种情况。我可以看到一些可行的机制，但这将在未来的博客文章中予以解决。也就是说，在生酮饮食中摄入30克糖仍然是不可能的。

I will also take this time to note that there are some people who absolutely need a strict carb-free keto diet. If carbs cause stupid brain-exploding symptoms, I don&amp;apos;t care for any plausible mechanics anymore. Just do what works. 我还想指出，有些人绝对需要严格的无碳水化合物生酮饮食。如果碳水化合物导致了愚蠢的精神飞翔症状，我就不再关心任何看似合理的机制了。只要做有用的事。 ?http://itsthewooo.blogspot.com/2015/10/i-tried-to-quit-keto-with-carbs-pt-1.html ?http://itsthewooo.blogspot.com/2015/10/i-tried-to-quit-keto-with-carbs-pt-2.html Macrophages Require Constitutive NF-κB Activation To Maintain A1 Expression and Mitochondrial Homeostasis&amp;apos; (Pagliari et. al., 2000) – http://www.ncbi.nlm.nih.gov/pmc/articles/PMC116114/ Quote: In the present study, we have demonstrated that the constitutive activation of NF-κB is necessary for the survival of both the murine macrophagelike cell line RAW 264.7 and human monocyte-derived macrophages. 巨噬细胞需要NF-κB激活来维持A1表达和线粒体稳态”(Pagliari et. al.， 2000)—http://www.ncbi.nlm.nih.gov/pmc/articles/PMC116114/ 引用: 在本研究中，我们证明了NF-κB的组成性激活对于小鼠巨噬细胞样细胞系RAW 264.7和人单核细胞来源的巨噬细胞的生存都是必要的。

I am going to assume here that DHA oxidation products do inhibit NF-kB based on the studies described prior (on Isoprostanes and Neuroprostanes), which also used similar Macrophages. This particular study has the strength of also using human macrophages. 根据之前的研究(关于异前列腺素和神经前列腺素)，我假设DHA氧化产物确实抑制NF-kB，这些研究也使用了类似的巨噬细胞。这项特别的研究也利用了人类巨噬细胞。 Figure 2 showed that inhibition of NF-kB using pyrrolidine dithiocarbamate (PDTC) for 15 hours reduced viable RAW 264.7 cells by 65% ± 13% (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC116114/figure/F2/) 图2显示，使用吡啶二硫代氨基甲酸酯(PDTC)抑制NF-kB 15小时使RAW 264.7活细胞减少65%±13% (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC116114/figure/F2/) Much more apoptosis in human macrophages too (&lt;10% in controls, &gt;60% with NF-kB inhibition): PDTC-treated primary macrophages exhibited a significant increase in cell death, measured by PI incorporation, at 72 h compared to control cells (Fig. ?(Fig.3A).3A) (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC116114/figure/F3/) Lots of DNA fragmentation, complete loss of delta psi (mitochondrial membrane potential), bad things for the macrophages in general. Interesting note: To determine if the collapse of ΔΨm in PDTC-treated macrophages was specifically due to NF-κB inhibition, primary macrophages were infected with AdIκBα and assessed for ΔΨm integrity. AdIκBα-infected macrophages displayed a time-dependent loss of ΔΨm (Rh123 decrease [Fig. 5A]) and subsequent increase in cell death (PI increase [Fig. 5A]) compared to Adβgal-infected cells. 人巨噬细胞也有更多的凋亡(对照&lt;10%，&gt;60%与NF-kB抑制): 通过PI掺入法测量，pdtc处理的原代巨噬细胞在72 h时，与对照组细胞相比，细胞死亡显著增加(图3a)。3a) (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC116114/figure/F3/) 大量的DNA片段，线粒体膜电位的完全丧失，对巨噬细胞来说都是坏事。 有趣的是: 为了确定在pdtc处理的巨噬细胞中ΔΨm的崩溃是否是由于NF-κB抑制所致，将原代巨噬细胞感染AdIκBα并评估ΔΨm完整性。adi κ b α感染的巨噬细胞表现出ΔΨm的时间依赖性损失(Rh123下降[图]。5A])，随后细胞死亡增加(PI增加[图（与ad βgal感染细胞相比） Parallel cultures revealed significant (P &lt; 0.02) DNA fragmentation at 12 h post-AdIκBα infection compared to Adβgal-infected cells (Fig. ?( 平行培养显示，与ad βgal感染细胞相比，adi κ b α感染后12 h DNA片段显著(P &lt; 0.02)。

The differences between the two methods of inhibiting NF-κB may be due to more effective inhibition of NF-κB by IκBα. Recall that the potentially-DHA-derived A4-NPs described earlier prevents phosphorylation of IκBα. Phosphorylation of IκBα is basically the &amp;quot;switch&amp;quot; that breaks IκBα apart from NF-kB, and allows for NF-kB activity. Same as saying that A4-NPs inhibit NF-kB. 两种抑制NF-κB方法的差异可能与IκBα对NF-κB的抑制作用更强有关。 回想一下，前面描述的潜在的dha衍生的A4-NPs可以阻止IκBα的磷酸化。IκBα磷酸化基本上是一个“开关”，将IκBα与NF-kB分离，并允许NF-kB活性。同理，A4-NPs抑制NF-kB。

The apoptotic mediator in the case of NF-kB is caspase 9, and you can read the full study to show how exactly they determined that. The exact mechanism isn&amp;apos;t too relevant for the purposes of this article. Finally, there is some mention of the B-cell lymphoma (Bcl) proteins, specifically Bcl-2, and found it unchanged in the face of DHA. This is not so important for our discussion of DHA. Just know that it is likely good that Bcl-2 levels remain unchanged, given than deficiency in Bcl expression (especially Bcl-2 and Bcl-6) are usually associated with excessive apoptosis in stressed cells. It is important to note that this discussion of NF-kB is for a specific type of cell. The constitutive activation of NF-κB is not essential for the survival of all cells types. In contrast to macrophages, fibroblasts, endothelial cells, and epithelial cells did not undergo apoptosis following NF-κB inhibition by PDTC or IκBα (data not shown and references 31, 60, and 66). 在NF-kB的情况下，凋亡介质是caspase 9，你可以阅读完整的研究，以显示他们是如何确定的。确切的机制与本文的目的不太相关。 最后，有一些提到b细胞淋巴瘤(Bcl)蛋白，特别是Bcl-2，并发现它在DHA面前没有变化。这对于我们讨论DHA并不是很重要。要知道，Bcl-2水平保持不变很可能是件好事情，因为在应激细胞中，Bcl-2(尤其是Bcl-2和Bcl-6)表达不足通常与过度凋亡有关。 值得注意的是，本文对NF-kB的讨论是针对一种特定类型的细胞。 NF-κB的组成性活化对所有类型的细胞的生存都不是必需的。与巨噬细胞相比，经PDTC或IκBα抑制NF-κB后，成纤维细胞、内皮细胞和上皮细胞不发生凋亡(数据未显示，参考文献31、60和66)。

It is relevant to immune cells though: However, similar to macrophages, other cells of the immune system, including both B and T lymphocytes, exhibited constitutive NF-κB activation (36, 47) and underwent apoptosis following NF-κB inhibition (3, 36, 67), although the responsible mechanisms have not been well characterized. However, I will have to say that there are plausible mechanics to Peat&amp;apos;s claim that &amp;quot;DHA and other Polyunsaturaed fats suppress the immune system&amp;quot;. 但它与免疫细胞有关: 然而，与巨噬细胞类似，免疫系统的其他细胞，包括B淋巴细胞和T淋巴细胞，表现出NF-κB的结构性激活(36,47)，并在NF-κB抑制后发生凋亡(3,36,67)，尽管相关机制尚未明确。 然而，我不得不说，“DHA和其他多不饱和脂肪抑制免疫系统”的说法似乎有道理。

Finally, sticking on the topic of NF-kB, &amp;apos;EPA and DHA reduce LPS-induced inflammation responses in HK-2 cells: Evidence for a PPAR-big gamma–dependent mechanism&amp;apos;(Li et. al., 2005) – http://www.nature.com/ki/journal/v67/n3/full/4495120a.html 最后，在NF-kB的话题上，“EPA和DHA降低脂多糖诱导的HK-2细胞炎症反应:ppar -大γ依赖机制的证据”(Li et. al.， 2005) http://www.nature.com/ki/journal/v67/n3/full/4495120a.html

This study used Human kidney-2 (HK-2) cells, which were &amp;quot;incubated with various concentrations of omega-3 PUFAs such as EPA and DHA in the presence or absence of lipopolysaccharide (LPS) for 24 hours&amp;quot;. Both EPA and DHA at 10 mumol/L and 100 mumol/L concentrations effectively decreased LPS-induced (10 mug/mL) NF-kappaB activation (Figure 1a).That result was to be expected, but the researchers also did some other interesting measurements. 这项研究使用了Human kidney-2 (HK-2)细胞，“将其与不同浓度的omega-3 PUFAs(如EPA和DHA)在有或无脂多糖(LPS)的条件下孵育24小时”。 EPA和DHA在10 mumol/L和100 mumol/L浓度下都能有效降低lps诱导的(10 mug/mL) NF-kappaB活化(图1a)。 这个结果在意料之中，但研究人员还做了一些其他有趣的测量。

They measure monocyte chemoattractant protein-1 (MCP-1) / chemokine (C-C motif) ligand 2 (CCL2), which is a cytokine involved in recruiting immune mediating cells to a site of injury. Both EPA and DHA effectively decreased LPS induced MCP-1 production in a dose-dependent manner (Figure 2a). LPS-induced MCP-1 mRNA was also suppressed by EPA and DHA Figure 2b.Suppression was very significant. about 50% suppression with EPA and &gt;80% suppression with DHA. This is more evidence for the statement, &amp;quot;DHA suppresses immune function&amp;quot;. 他们测量单核细胞趋化蛋白-1 (MCP-1) /趋化因子(C-C motif)配体2 (CCL2)，这是一种参与将免疫介导细胞招募到损伤部位的细胞因子。 EPA和DHA均以剂量依赖的方式有效降低LPS诱导的MCP-1生成(图2a)。lps诱导的MCP-1 mRNA也被EPA和DHA抑制 抑制非常显著。EPA抑制约50%，DHA抑制约80%。这为“DHA抑制免疫功能”的说法提供了更多的证据。

There was hugely increased PPAR-gamma expression: Both EPA and DHA increased PPAR-gamma mRNA expression Figure 3a. A two- to threefold increased binding of PPAR-gamma to PPRE was observed, with little difference between EPA and DHA Figure 3b. ppar - γ表达大幅增加: EPA和DHA都增加了PPAR-gamma mRNA的表达观察到PPAR-gamma与PPRE的结合增加了两到三倍，EPA和DHA之间几乎没有差异(图3b)。

It seems like it is PPAR-gamma activation that is responsible for the suppression of NF-kB and MCP-1: Next, we demonstrated that the PPAR-gamma antagonist BADGE abolished PPAR-gamma activation by EPA and DHA in HK-2 cells Figure 4a. BADGE (100 mumol/L) also removed the inhibitory effect of EPA and DHA on LPS-induced NF-kappaB activation in HK-2 cells Figure 4b. To further clarify the relationship between PPAR-gamma and NF-kappaB, PPAR-gamma was overexpressed in HK-2 cells by transient transfection Overexpression of PPAR-gamma further increased PPAR-gamma activation compared to the plasmid control in the presence of EPA or DHA Figure 5a. It also decreased LPS-induced NF-kappaB activation compared to the plasmid control Figure 5b. This activation was further decreased in the presence of EPA or DHA Figure 5b. 似乎是ppar - γ激活导致了NF-kB和MCP-1的抑制: 接下来，我们证明了PPAR-gamma拮抗剂BADGE在HK-2细胞中抑制了EPA和DHA对PPAR-gamma的激活(图4a)。BADGE (100 mumol/L)也可以消除EPA和DHA对lps诱导的HK-2细胞NF-kappaB激活的抑制作用(图4b)。 为了进一步阐明PPAR-gamma与NF-kappaB之间的关系，我们通过瞬时转染在HK-2细胞中过表达PPAR-gamma 与EPA或DHA存在的质粒对照相比，PPAR-gamma过表达进一步增加了PPAR-gamma激活(图5a)。 与质粒对照相比，它还降低了脂多糖诱导的NF-kappaB激活(图5b)。在EPA或DHA存在时，这种激活进一步降低(图5b)。

A little sidenote here: PPAR-gamma expression is often touted as a good thing. Note that this is usually in the context of cancer cells, whereby PPAR-gamma activation seems to cause apoptosis of the cancer cell. 这里有一点附注:PPAR-gamma表达式经常被吹捧为一件好事。注意，这通常是在癌细胞的情况下，ppar - γ激活似乎导致癌细胞凋亡。

We must distinguish this from healthy cells which are given an appropriate environment and metabolic substates. What may work once a cancer metabolism has already been establish is different from what a healthy cell needs. 我们必须将其与健康细胞区分开来，后者被给予适当的环境和代谢亚状态。一旦癌症新陈代谢已经建立起来，可能起作用的东西与健康细胞所需要的东西是不同的。

In fact, there is good reason to believe that DHA and other PUFAs may help cause a cancer metabolism (Complex 1 dysfunction). This is elaborated on in the &amp;apos;Mitochondrial Respiration&amp;apos; section later in the article. 事实上，有充分的理由相信DHA和其他不饱和脂肪酸可能有助于癌症代谢(复杂1功能障碍)。这将在本文后面的“线粒体呼吸”部分进行详细阐述。

PPARs and other related entities will be given a detailed treatment in a later section as well. ppar和其他相关实体也将在后面的部分中得到详细的处理。

For now, it is safe to say that DHA uniquely suppresses the immune function of the organism. Acutely high levels of inflammatory compounds are a necessity in order for the body to respond to insults. Suppressing any and all of such bursts by maintaining high tissue levels of DHA is likely to lead to a chronic suppression of these inflammation signals, and thus the body&amp;apos;s ability to respond to external threats. Again, just because chronic inflammation is bad, does not imply that acute inflammatory responses are also bad. 目前，可以有把握地说DHA独特地抑制机体的免疫功能。高水平的炎症化合物是身体对侮辱做出反应的必要条件。通过维持高水平的DHA来抑制任何和所有这些爆发可能会导致对这些炎症信号的慢性抑制，从而降低身体对外部威胁的反应能力。同样，仅仅因为慢性炎症是不好的，并不意味着急性炎症反应也是不好的。

There are practical consequences for this, and we shall get into some of those consequences in the next section. 这样做会产生一些实际的后果，我们将在下一节讨论其中一些后果。

DHA and Immune Function in the Gut, with a discussion of generic mechanisms DHA与肠道免疫功能和一般机制讨论

To look at more general immune function, we&amp;apos;ll look at this study, &amp;apos;Fish Oil Attenuates Omega-6 Polyunsaturated Fatty Acid-Induced Dysbiosis and Infectious Colitis but Impairs LPS Dephosphorylation Activity Causing Sepsis&amp;apos; (Ghosh et. al., 2013) – http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0055468 更一般的免疫功能,我们会在这项研究中,“鱼油变弱ω- 6系列多不饱和脂肪酸段生态失调和传染性结肠炎但损害有限合伙人去磷酸化活动导致脓毒症”(Ghosh等人,2013),http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0055468

This is a mice study, focusing on Ulcerative Colitis. Note that these are inbred C57BL/6 mice. Different mice will show different responses to intestinal sepsis, but in general the mechanisms are the same, so I think it is fair to use this study for mechanical analysis. It is not fair to say something like, &amp;quot;Look DHA makes sepsis worse in humans!!&amp;quot; right off the bat.This study used Citrobacter rodentium to induce colitis, which is fair methodology (instead of trying to do direct LPS-induced colitis, which doesn&amp;apos;t really work – http://www.ncbi.nlm.nih.gov/pubmed/25161013). 这是一项小鼠研究，重点是溃疡性结肠炎。请注意，这些是近亲繁殖的C57BL/6小鼠。不同的小鼠对肠脓毒症会有不同的反应，但一般机制是相同的，所以我认为用这个研究进行力学分析是公平的。 马上说“看，DHA会使人的败血症恶化!!”这样的话是不公平的。 这项研究使用啮齿柠檬酸杆菌诱导结肠炎，这是一种公平的方法(而不是尝试直接进行脂多糖诱导的结肠炎，这并不真正起作用——http://www.ncbi.nlm.nih.gov/pubmed/25161013)。

You have 3 groups: 3组 ?20% fat high高 omega-6 玉米油corn-oil diet饮食 ?20% fat 玉米油corn-oil + 鱼油fish oil diet ?5% fat 玉米油corn-oil diet

Some results: ω-6 PUFA rich diets enriched the microbiota with Enterobacteriaceae (Figure 1A), which are associated with IBD, and Segmented Filamentous Bacteria (SFB; Figure 1A), previously shown to induce responses that drive experimental colitis. ω-3 PUFA supplementation prevented these specific enrichments. Both high-fat diets increased Clostridia spp. compared to the low ω-6 PUFA control, the ω-3 PUFA supplemented group had reduced abundance compared to the ω-6 PUFA-rich diet The ω-3 PUFA supplemented group had fewer microbes from the Clostridium coccoides group (Figure 1B) which are opportunistic pathogens associated with IBD The ω-3 PUFA supplemented group also had enriched populations of the beneficial microbes Lactobacillus spp. and Bifidobacteria spp. ω-3 PUFA supplementation also induced Enterococcus faecium (Figure 1B) which has reported probiotic properties. 一些结果: ?富含ω-6 PUFA的饮食可富集与IBD相关的肠杆菌科(Enterobacteriaceae，图1A)和节段丝状菌(SFB;图1A)，先前显示的诱导反应驱动实验性结肠炎。 ?ω-3 PUFA的补充阻止了这些特异性富集。 ?与低ω-6 PUFA对照组相比，高脂饲粮均增加了梭菌丰度，而添加ω-3 PUFA组则降低了梭菌丰度。 ?添加ω-3 PUFA组来自球虫梭菌组的与IBD相关的条件致病菌较少(图1B) ?ω-3 PUFA添加组对乳酸菌和双歧杆菌有益菌群也有富集作用。 ?补充ω-3 PUFA也可诱导屎肠球菌(图1B)，有报道称其具有益生菌特性。

Pretty clear cut reduction in known pathological species of bacteria (in mice) with Omega-3 fatty acids. I emphasise the word &amp;quot;known&amp;quot; because there may be unknown species of bacteria, unique to humans, which prevent us from extrapolating this sort of analysis to humans. 非常明显地减少了已知病理性细菌种类(在老鼠身上)的Omega-3脂肪酸。我强调“已知”这个词，是因为可能存在人类所特有的未知细菌物种，这阻止了我们将这种分析推到人类身上。

Also, I&amp;apos;d love to see a near 0% PUFA control diet. ie: Replace the corn oil in 5% fat control diet with purified coconut oil or palm oil, or ideally some other tasteless saturaed fat. (coconut oil and palm oil have both thermogenic and gut protective capacities of their own) 此外，我希望看到接近0%的不饱和脂肪酸控制饮食。例如:用纯化的椰子油或棕榈油代替5%脂肪控制饮食中的玉米油，最好是其他一些无味的饱和脂肪。(椰子油和棕榈油本身也有产热和保护肠道的能力)

Interesting sidenote: &gt; In general, both high-fat diets reduced Bacteroides spp. (Figure 1C) a trend associated with obesity [27], and correspondingly both groups of mice were similarly obese There is enough research to hint at &amp;quot;More gut bacteria =&gt; more obesity&amp;quot; in rat models. I love ItsTheWooo!&amp;apos;s take on the nuances of human gut flora – http://itsthewooo.blogspot.com/2015/10/woos-gut-biome-experiments-background.html 有趣的旁注: 总的来说，两种高脂肪饮食都降低了拟杆菌属细菌(图1C)，这一趋势与肥胖相关，相应地，两组小鼠都是类似的肥胖。 有足够的研究表明，在大鼠模型中，“肠道细菌越多=肥胖越多”。我爱ItsTheWooo !他对人类肠道菌群细微差别的研究——http://itsthewooo.blogspot.com/2015/10/woos-gut-biome-experiments-background.html

It&amp;apos;s clear that omega-6 PUFAs are bad though: The normally resistant C57BL/6 mice fed ω-3 PUFA supplemented diets suffered increased mortality during infection where 30% of the mice had to be sacrificed by day 8 post-infection (p.i.; Figure 2A). While both low and high ω-6 PUFA diets resulted in similar weight changes during infection, the ω-3 PUFA supplemented group suffered the greatest weight loss throughout days 5–10 p.i. (Figure 2B) despite similar pre-infection body weights and caloric intake in mice fed both high-fat diets Yet during infection, the ω-3 PUFA fed mice displayed similar histopathological severity (based on mucodepletion, hyperplasia, immune cell infiltration, edema and epithelial integrity) as to the low ω-6 PUFA control (Figure 2C &amp; D). In contrast, ω-6 PUFA-rich fed mice displayed the most severe histopathology (Figure 2C–D) 很明显-6不饱和脂肪酸是有害的: 正常抗性C57BL/6小鼠在感染期间死亡率增加，感染后第8天必须处死30%的小鼠(p.i;图2 a)。 虽然低ω-6和高ω-6 PUFA饲料在感染期间产生了相似的体重变化，但ω-3 PUFA添加组在5-10 p.i期间的体重损失最大(图2B)，尽管两种高脂肪饲料在感染前小鼠的体重和热量摄入相似。 然而，在感染期间，喂食ω-3 PUFA的小鼠表现出与低ω-6 PUFA对照组相似的组织病理学严重程度(基于黏液衰竭、增生、免疫细胞浸润、水肿和上皮完整性)(图2C D)。 相比之下，ω-6富含pufa的喂养小鼠的组织病理学表现最为严重(图2C-D)。

The more PUFA, the worse the effect: Both high-fat diets induced cell death prior to acute colitis revealing that epithelial cell homeostasis was disrupted by high-fat aloneStill more bad effects on PUFA on immune response: We examined colonic neutrophil and macrophage cell infiltration (Figure 3A–B) and found that ω-6 PUFA rich diets increased infiltration of F4/80+ macrophages and MPO+ neutrophils compared to the low ω-6 PUFA group during infection. ω-3 PUFA supplementation restored immune cell infiltration similar to the low ω-6 PUFA control. We also examined the levels of PGE2, a key inflammatory marker in the gut, and found that mice fed ω-6 PUFA rich diets had the highest infection-induced levels of colonic PGE2. In contrast, ω-3 PUFA supplementation did not induce PGE2+ cell infiltration during infection, suggesting that these mice were impaired in mounting an inflammatory response to infection. PUFA越多，效果越差: 两种高脂肪饮食均在急性结肠炎前引起细胞死亡，表明仅高脂肪饮食就破坏了上皮细胞稳态 多不饱和脂肪酸对免疫反应的更坏影响: 我们检测了结肠中性粒细胞和巨噬细胞的浸润(图3A-B)，发现与低ω-6 PUFA组相比，富含ω-6 PUFA组在感染期间增加了F4/80+巨噬细胞和MPO+中性粒细胞的浸润。 与低ω-6 PUFA对照相似，添加ω-3 PUFA可恢复免疫细胞浸润 我们还检测了肠道中关键炎症标记物PGE2的水平，发现喂食富含ω-6 PUFA饲料的小鼠具有最高的结肠PGE2感染诱导水平 相反，ω-3 PUFA在感染过程中没有诱导PGE2+细胞浸润，表明这些小鼠对感染的炎症反应受到了损害。

I bold that last part because it is in agreement with some other studies, which I will discuss after this. The Omega-6 fed rats of BOTH high and low fat groups managed to mount an inflammatory response, but not so with the Omega-3 fed group: The ω-3 PUFA supplemented group was unable to induce such responses during infection evident by the lack of induction of IFN-γ, TNF-α, IL-17A, IL-22 and IL-23, as well as the chemokine Relm-β compared to pre-infection expression. Finally, we examined adiponectin since its impaired expression in mice fed ω-3 PUFA was shown to be responsible for increased colitis and mortality when exposed to dextran sodium sulfate (DSS). We found that infection reduced adiponectin expression similarly in both high-fat diets. 我大胆说出最后一部分，是因为它与其他一些研究是一致的，我将在这之后讨论这些研究。 高脂肪组和低脂肪组的老鼠都出现了炎症反应，但Omega-3组的老鼠却没有出现炎症反应: 与感染前相比，ω-3 PUFA添加组在感染期间无法诱导IFN-γ、TNF-α、IL-17A、IL-22和IL-23以及趋化因子Relm-β的表达，这一点很明显 最后，我们检测了脂联素，因为在喂食ω-3 PUFA的小鼠中，脂联素表达受损被证明是右旋糖酐硫酸钠(DSS)暴露导致结肠炎和死亡率增加的原因。我们发现，在两种高脂饮食中，感染同样降低了脂联素的表达。

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Then, another interesting note: ω-6 PUFA Rich Diets Resulted in Increased Translocation of γ-Proteobacteria We found the microbes deeply invading the crypts (100× magnification), and were observed in the submucosal region (600× magnification) of the colons from mice fed ω-6 PUFA-rich diets In contrast, the mice fed ω-3 PUFA supplemented diets were able to contain the pathogen at the top of the crypts and bacteria were not observed in the submucosal region. We examined the spleen and mesenteric lymph nodes (MLN) for C. rodentium colony forming units (CFU). We found an increase in CFU in the tissues from mice fed ω-6 PUFA rich diets, which was reduced following ω-3 PUFA supplementation (Figure 5B). 然后，另一个有趣的提示: 富含ω-6 PUFA的饲粮导致γ-变形菌易位增加 在100倍放大倍数下，我们发现微生物深入到隐窝，在600倍放大倍数下，在喂食富含ω-6 pufa饲料的小鼠结肠中，我们发现了微生物 结果表明，添加ω-3 PUFA的小鼠隐窝顶部均能检出病原菌，粘膜下未检出病原菌。 我们检查了小鼠脾脏和肠系膜淋巴结(MLN)，以确定小鼠的菌落形成单位(CFU)。我们发现，喂食富含ω-6 PUFA饲料的小鼠组织中CFU增加，而在添加ω-3 PUFA后CFU降低(图5B)。

I will throw out a couple of random theories here … Firstly, we saw above in the NF-kB section that all of DHA, EPA, and oxidative DHA products prevents Lipopolysaccharide (LPS) from activating NF-kB. This hints at a unique effect of the highly unsaturaed PUFAs to inhibit LPS activity. I assume this is a function of the number of C=C bonds. The IsoPs and NPs produced from oxidising DHA still contain 4 C=C bonds, which is more than the amount of any PUFAs found in corn oil. This is important because the cell membranes of Gram-negative bacteria like C. rodentium are filled with LPS. I assume that this compound is used heavily in extra-cellular signalling. 在这里我将抛出一些随机的理论… 首先，我们在上面的NF-kB部分看到，所有的DHA、EPA和氧化DHA产品都阻止了脂多糖(LPS)激活NF-kB。这提示高度不饱和的PUFAs具有抑制LPS活性的独特作用。我假设这是C=C键数的函数。氧化DHA产生的IsoPs和NPs仍然含有4c =C键，这比玉米油中发现的任何不饱和脂肪酸的数量都要多。 这是很重要的，因为革兰氏阴性细菌(如C.啮齿动物)的细胞膜充满了LPS。我认为这种化合物在细胞外信号中被大量使用。

I wonder what would happen if the rats were fed: * a high flaxseed oil diet, which contains a lot of Alpha-Linolenic Acid (ALA) with 3 C=C bonds * isolated Arachidonic Acid (AA), which has 4 C=C bonds That would tell us if there is a mechanism tying LPS inhibition and number of C=C bonds, and what the cut-off point is. eg: if ALA doesn&amp;apos;t give the same effects as DHA, but AA does, then 3 C=C bonds is the cut off point. 我想知道如果喂老鼠会发生什么: 高亚麻籽油饮食，其中含有大量的α -亚麻酸(ALA)与3c =C键 单独花生四烯酸(AA)，它有4个C=C键 这将告诉我们是否有一种机制将脂多糖抑制和C=C键的数量联系在一起，以及临界点是什么。如果ALA不能提供与DHA相同的效果，但是AA可以，那么3c =C键就是截止点。

Does this mean that the highly unsaturated PUFAs act at resisting gram-negative bacteria by virtue of these PUFAs apparent hate of LPS? What is the mechanism here? (It&amp;apos;s probably Electromagnetic) In any case, there has to be some electromagnetic mechanism to explain why the bacteria did not even enter the crypt tube (colonic crypts are described as being &amp;quot;test-tube shaped&amp;quot;). There has to be mechanical pressure preventing the bacteria from getting in. I&amp;apos;ll leave this as an open question for now until I can think of a plausible explanation, but the observations are there. 这是否意味着高度不饱和的欧法在抗革兰氏阴性细菌由于有限合伙人欧米明显恨?这里的机理是什么?(这可能是电磁) 无论如何，必须有某种电磁机制来解释为什么细菌甚至没有进入隐窝管(结肠隐窝被描述为“试管形状”)。必须有机械压力来阻止细菌进入。 在我能想出一个合理的解释之前，我将把这个问题作为一个开放的问题，但是观察结果是存在的。

So moving on, we get to the sepsis discussion: We examined sera for the presence of LPS binding protein (LBP), a clinical marker of sepsis. We found LBP in the sera of these [ω-6 fed] mice prior to infection (Figure 6A). In contrast, there was no induction of LBP in mice fed ω-3 PUFA supplements prior to infection but during infection LBP levels increased. Despite there being lower levels of pathogen in the spleen and MLN in the ω-3 PUFA supplemented group, these mice had the greatest induction of serum IL-15 and TNF-α. 接下来，我们开始讨论败血症 我们检测了血清中脂多糖结合蛋白(LBP)的存在，这是败血症的临床标志物。 我们在这些[ω-6喂养]小鼠的血清中发现了LBP(图6A)。相比之下，在感染前添加ω-3 PUFA的小鼠中，LBP水平没有诱导，但在感染期间LBP水平升高。 尽管添加ω-3 PUFA组小鼠脾脏中病原体和MLN水平较低，但这些小鼠血清中IL-15和TNF-α的诱导率最高。

The DHA-LPS interaction remains evident: We examined the expression of intestinal alkaline phosphatase (IAP), a key endogenous mucosal defense factor inducible by microbiota. IAP dephosphorylates LPS during infection preventing sepsis We found the greatest number of IAP+ cells infiltrating in the colonic submucosae from mice fed ω-6 PUFA rich diets (Figure 7A). In contrast, mice fed diets supplemented with ω-3 PUFA had fewer IAP+ cells Since IAP detoxifies LPS through dephosphorylation [34], we examined the ex vivo LPS dephosphorylation activity of colons from mice fed PUFA diets similar to Goldberg et al (2008) [34]. While both low and high ω-6 PUFA rich diets induced LPS-dephosphorylating activity during C. rodentium infection, the ω-3 PUFA supplemented diet resulted in an impaired ability to dephosphorylate LPS during infection (Figure 7B). As a result, any pathogen that escapes across the barrier in ω-3 PUFA supplemented mice may be more toxic leading to increased systemic inflammation associated with the increased mortality during C. rodentium infection. DHA-LPS的相互作用仍然很明显: 我们检测了肠道碱性磷酸酶(IAP)的表达，这是一种重要的内源性黏膜防御因子，可由微生物诱导。IAP在感染期间去磷酸化LPS，防止败血症。 我们发现，在喂食富含ω-6 PUFA饲料的小鼠中，结肠粘膜下浸润的IAP+细胞数量最多(图7A)。 与此相反，饲粮中添加ω-3 PUFA的小鼠IAP+细胞较少。 由于IAP通过去磷酸化[34]来解毒LPS，我们检测了饲喂与Goldberg等(2008)[34]相似的多不饱和脂肪酸饲料的小鼠结肠的体外LPS去磷酸化活性。 低和高富含ω-6 PUFA的饲粮均可诱导鼠牙鲆脂多糖脱磷酸化活性，但添加ω-3 PUFA的饲粮可导致鼠牙鲆脂多糖脱磷酸化能力受损(图7B)。 因此，在添加ω-3 PUFA的小鼠中，任何逃脱的病原体都可能具有更大的毒性，导致全身炎症增加，并增加了啮齿动物感染期间的死亡率。

NOTE: Dephosphorylation of LPS refers to removal of the phosphate group from Lipid A. 注意:LPS的去磷酸化是指从脂质A中去除磷酸基团。

So with Omega-3 supplementation, the bacteria don&amp;apos;t get incorporated into tissues as easily, but the LPS gets into serum, and puts inflammatory activity into overdrive. 所以通过补充Omega-3，细菌不会轻易进入组织，但LPS会进入血清，加速炎症活动。

Sidenote: Here&amp;apos;s a good paper on how LPS modulates Intestinal Tight Junctions to allow for increased intestinal permeability (&amp;quot;leaky gut&amp;quot;), &amp;apos;Lipopolysaccharide Causes an Increase in Intestinal Tight Junction Permeability in Vitro and in Vivo by Inducing Enterocyte Membrane Expression and Localization of TLR-4 and CD14&amp;apos; (Guo et. al., 2013) – http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3562736/ 旁注:这是一篇关于脂多糖如何调节肠道紧密连接以增加肠道通透性(“漏肠”)的好论文，“脂多糖通过诱导肠细胞膜表达和TLR-4和CD14定位，在体外和体内导致肠道紧密连接通透性增加”(Guo et. al.，2013)——http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3562736/。

If the NF-kB story holds true, then we likely also have the inability of macrophages to perform clean up (due to DHA oxidation product inhibition of IκBα phosphorylation, and thus inhibition of NF-kB). 如果NF-kB的说法成立，那么巨噬细胞可能也无法进行清理(由于DHA氧化产物抑制了IκBα磷酸化，从而抑制了NF-kB)。

It&amp;apos;s pretty clear from this study that Omega-3s specifically prevent gut dysbiosis, but also suppress immune function. 从这项研究中可以清楚地看到，omega -3脂肪酸可以防止肠道失调，但也会抑制免疫功能。

Retinal DHA 视网膜 DHA

The retina is technically part of the brain, and is one of the those tissues which requires a good deal of DHA to function. It is a tiny tissue in terms of mass, and DHA flux into that tissue is highly regulated. I&amp;apos;ll run through various studies, and come to the conclusion that again, you don&amp;apos;t need much DHA (absolute mass amount), and that the health of other systems to which DHA plays no role are more important for the function of the eye. 从技术上讲，视网膜是大脑的一部分，也是那些需要大量DHA才能发挥作用的组织之一。就质量而言，它是一个很小的组织，DHA进入组织的流量是高度调节的。 我将浏览各种研究，并得出结论，你不需要太多的DHA(绝对量)，DHA没有作用的其他系统的健康对眼睛的功能更重要。

Rat Studies 大鼠的研究 It is clear that in Rats, more DHA isn&amp;apos;t good for the retina: ?&amp;apos;Light damage in the rat retina: The effect of dietary deprivation of n-3 fatty acids on acute structural alterations&amp;apos; (Bush et. al., 1991) –http://www.sciencedirect.com/science/article/pii/001448359190109R ?&amp;apos;High levels of retinal membrane docosahexaenoic acid increase susceptibility to stress-induced degeneration&amp;apos; (Tanito et. al., 2008) – http://www.jlr.org/content/50/5/807.short 很明显，在大鼠身上，更多的DHA对视网膜没有好处: “大鼠视网膜的光损伤:饮食剥夺n-3脂肪酸对急性结构改变的影响”(Bush等人，1991)——http://www.sciencedirect.com/science/article/pii/001448359190109R “高水平的视网膜膜二十二碳六烯酸会增加压力诱导的变性的易感性”(Tanito等人，2008)——http://www.jlr.org/content/50/5/807.short

The first paper claims rod outer segment membrane damage in rats fed a higher DHA diet. Note that both groups were fed high PUFA diets, but only the group fed a higher DHA diet developed problems. It would make sense that only the extra DHA got incorporated into the eye, while Omega-6 fats were not. 第一篇论文声称，喂食高DHA饮食的老鼠的棒状外节膜损伤。注意，两组都饲喂高不饱和脂肪酸饲料，但只有饲喂高DHA饲料的一组出现问题。只有额外的DHA进入眼睛，而Omega-6脂肪没有进入眼睛，这就说得通了。

We saw higher Rhodopsin levels in the High DHA group, perhaps supporting Peat&amp;apos;s claim that &amp;quot;DHA increases sensitivity to light&amp;quot; (in a bad way). Second study is similar, feeding a similar high PUFA diet with and without DHA, and observing more apoptosis in Rod outer segments in the high DHA group. But those are rats, which are nocturnal to begin with. The testing methodology of what constitutes &amp;quot;Light Damage&amp;quot; is also a confounder. 我们发现高DHA组的视紫红质水平更高，这或许支持了Peat的说法“DHA增加对光的敏感性”(以一种不好的方式)。 第二项研究是类似的，在添加DHA和不添加DHA的情况下，饲喂类似的高不饱和脂肪酸饲料，在高DHA组中观察到更多的细胞凋亡。 但这些是老鼠，它们本来就是夜行动物。 构成“光损害”的测试方法也令人困惑。

The first study: Rats were maintained on a Full-size image (&lt;1 K) 12hr/12hr light/dark cycle in which the light level at the front of the cages was 5–10 lx Light damage was produced by exposing dark-adapted animals to diffuse white fluorescent light of 700–800 lx for 30 min followed by 90 min of darkness. In order to study recovery from light damage, additional groups of SFO and SO rats were returned to dim cyclic light for 27 hr following bright light exposure. The second study: Mice were born and raised under a cyclic light environment (&lt;30 lux, 12 h on/off, 7AM–7PM) in the Dean A. McGee Eye Institute vivarium … were exposed to 3,000 lux diffuse, cool, white fluorescent light for 24 h as described previously (42) with slight modifications. All light exposures began at 8:00 AM. Drinking water was supplied by a bottle attached to the side of a clear plastic cage with a wire top, so that there was no obstruction between the light and the animal. After light exposure [light (+) animals], the mice were kept under the cyclic light environment (&lt;30 lux, 12 h on/off, 7AM–7PM) for up to 1 wk, after which electroretinograms (ERGs) were recorded and eyes were enucleated for morphometric and biochemical analyses. 第一项研究: 大鼠维持全尺寸图像(&lt;1 K) 12hr/12hr的光/暗周期，其中笼子前部的光水平为5-10 lx 将适应黑暗的动物暴露在700-800 lx的漫射白色荧光灯下30分钟，然后在黑暗中90分钟，会产生光损伤。 为了研究光损伤后的恢复情况，将SFO和SO两组大鼠置于强光照射后的昏暗循环光照下27小时。 第二项研究: 小鼠在Dean a . McGee眼科研究所的试管内出生和成长，在循环光环境下(&lt;30勒克斯，12小时开关，7AM-7PM) 如前所述(42)，在3000勒克斯漫射，冷白色荧光灯下暴露24小时（稍加修改） 所有光线都是从早上八点开始照射的。饮用水由一个装在透明塑料笼子边上的瓶子提供，笼子顶部有电线，这样就不会有光线和动物之间的阻碍。 光暴露[光(+)动物]后，小鼠在循环光环境(&lt;30 lux, 7AM-7PM，开/关12小时)下保存1周，之后记录视网膜电图(ERGs)并摘除眼球进行形态学和生化分析。

That makes statements like these (from second study) dubious: In animals not exposed to light, the reduction in n-3 PUFA yielded no difference in the morphology of rod photoreceptor cells, as evidenced by the same number of photoreceptor nuclei in the ONL of all three groups in Balb/c (Fig. 3) and C57BL/6J (data not shown) strains. The rhodopsin content of the wt-SFO and fat-1-SFO in both strains was the same, and there were no apparent differences in the protein profiles as determined by SDS-PAGE and by Western blots (Fig. 7). This is in agreement with earlier studies showing that n-3 deficiency did not affect rhodopsin content (3, 10), but at odds with one study showing an increase in rhodopsin levels with n-3 deficiency (51). 这使得类似的声明(来自第二项研究)变得可疑: 在未暴露于光照下的动物中，n-3 PUFA的减少并未导致杆状光感受器细胞形态的差异，这可以从Balb/c(图3)和C57BL/6J(数据未显示)菌株中三组ONL的光感受器核数量相同得到证明。 wt-SFO和fat-1-SFO在两株菌株中的视紫红质含量相同，SDS-PAGE和Western blot检测的蛋白谱无明显差异(图7)。 这与早期的研究一致，即n-3缺乏不会影响视紫红质含量(3,10)，但与一项表明n-3缺乏会增加视紫红质含量(51)的研究不一致。

Difference in rhopdosin levels, which the authors try to explain as: As this latter study compared two different diets, it is possible that differences in rhodopsin levels resulted from a difference in the diets independent of n-3 deficiency. In the current experiments, mice were reared on the same diet so this variable is removed from our analyses. Thus, the dramatic changes in fatty acid composition were not accompanied by any measurable changes in retinal morphology or chemistry. 研究人员试图将其解释为: 由于后一项研究比较了两种不同的饲粮，因此有可能视紫红质水平的差异是由与n-3缺乏无关的饲粮差异造成的。在目前的实验中，老鼠被饲养在相同的饮食，所以这个变量被从我们的分析中删除了。因此，脂肪酸组成的显著变化并不伴随着视网膜形态或化学的任何可测量的变化。

Or maybe the methodology to create &amp;quot;Light Damage&amp;quot; is drastically different, and produces different levels of light damage ….. As an aside, I have a problem with using lux to measure harmful exposure in anything that is not human. The measurement of lux doesn&amp;apos;t measure total E/M radiation incidence to begin with, and is calibrated to the human visual spectrum via some supposedly accurate Luminosity function. Rats can see colors which we don&amp;apos;t see – they can see further into the UV range, and don&amp;apos;t perceive red light the same way we do since they don&amp;apos;t have red cones (overview –http://www.ratbehavior.org/RatVision.htm#NormalRatVision). 或者，创造“光伤害”的方法是截然不同的，并产生不同级别的光伤害….. 顺便说一句，我不太喜欢用勒克斯来测量非人类的有害物质。lux的测量一开始并不是测量总E/M辐射入射，而是通过一些被认为是精确的光度函数来校准人类的视觉光谱。 老鼠可以看到我们看不到的颜色——它们可以在紫外线范围内看得更远，也不能像我们一样感知红光，因为它们没有红色视锥细胞(概述- http://www.ratbehavior.org/RatVision.htm#NormalRatVision)。

There is also a big difference between the Fluorescent lighting used in such experiments, and other sources of light – http://www.newgradoptometry.com/everything-to-know-about-blue-light-crizal-prevencia/ . White fluorescent lights tend to peak in regions where the rats aren&amp;apos;t as sensitive to to begin with. Many confounders …. and we have to assume that the levels of light shone at these rats were damaging, based upon differential results (damage to the Rods). I hesitate to use rat studies of the retina for all the ambiguities listed above, and do not like arguments which rely on such studies. Let&amp;apos;s try some other animal model that more closely models the human eye. 在这种实验中使用的荧光灯和其他光源(http://www.newgradoptometry.com/everything-to-know-about-blue-light-crizal-prevencia/)之间也有很大的不同。白色荧光灯往往会在老鼠一开始不那么敏感的区域达到峰值。 许多混杂因素…根据不同的结果(杆状细胞受损)，我们必须假设照射在这些老鼠身上的光线是有害的。 对于上面列出的所有模棱两可的问题，我不愿使用老鼠的视网膜研究，也不喜欢依赖这些研究的论点。 让我们试试其他更接近人类眼睛的动物模型。

Monkey Studies 猴子研究

We&amp;apos;ll turn to Rhesus Monkeys. First question: Can the Rhesus monkey eye be used as a model for the human eye? ?&amp;apos;Color-detection thresholds in rhesus macaque monkeys and humans&amp;apos; (Gagin et. al., 2014) –http://jov.arvojournals.org/article.aspx?articleid=2194035#87556321 ?&amp;apos;Spectral sensitivity differences between rhesus monkeys and humans: implications for neurophysiology.&amp;apos; (Lindbloom-Brown et. al., 2014) – http://www.ncbi.nlm.nih.gov/pubmed/25253473 我们来看看恒河猴。 第一个问题:恒河猴的眼睛可以作为人类眼睛的模型吗? ?“恒河猴和人类的颜色检测阈值”(Gagin等人，2014)——http://jov.arvojournals.org/article.aspx?articleid=2194035#87556321 ?“恒河猴和人类光谱敏感度的差异:对神经生理学的影响。”(Lindbloom-Brown et al.， 2014)——http://www.ncbi.nlm.nih.gov/pubmed/25253473 Monkeys are a little bit more sensitive to blue and green light, meaning that they tend to perceive it better than us. &amp;quot;Better perception&amp;quot; doesn&amp;apos;t necessarily indicate the same receptivity to absolute levels of incoming E/M radiation, but the phisiology between the two are similar, and that&amp;apos;s the best we&amp;apos;ve got. Also, most of the ERG a-wave increase rates (used to measure Rod Recovery rate) in the studies that follow are within 5% of each other, so I will assume for now that the Rhesus Monkey model is suitably close to assessing how DHA affects the human eye. 猴子对蓝光和绿光更敏感，这意味着它们的感知能力比我们强。“更好的感知”并不一定意味着对入射E/M辐射的绝对接收能力相同，但两者之间的生理结构是相似的，这是我们得到的最好的结果。 此外，在接下来的研究中，大多数ERG a波增加率(用于测量棒恢复率)都在5%以内，所以我现在假设恒河猴模型非常接近于评估DHA对人眼的影响。

With that established, let&amp;apos;s look at 2 studies regarding rod photoreceptor response. First, &amp;apos;Biochemical and functional effects of prenatal and postnatal omega 3 fatty acid deficiency on retina and brain in rhesus monkeys&amp;apos; (Neuringer et. al., 1986) – http://www.ncbi.nlm.nih.gov/pmc/articles/PMC323657/ 在此基础上，让我们来看两项关于视杆细胞光感受器反应的研究。 首先，“出生前后omega 3脂肪酸缺乏对恒河猴视网膜和大脑的生化和功能影响”(Neuringer et. al.， 1986)——http://www.ncbi.nlm.nih.gov/pmc/articles/PMC323657/

This clearly shows a need for DHA during pregnancy and early development. We tested the effect of dietary omega 3 fatty acid deprivation during gestation and postnatal development upon the fatty acid composition of the retina and cerebral cortex and upon visual function. A control group of females and their infants received a semipurified diet supplying ample 18:3 omega 3. In near-term fetuses and newborn infants of the deficient group, the 22:6 omega 3 content of phosphatidylethanolamine was one-half of control values in the retina and one-fourth in cerebral cortex. By 22 months of age, the content of 22:6 omega 3 in these tissues approximately doubled in control monkeys, but it failed to increase in the deficient group. 这清楚地表明在怀孕和早期发育期间需要DHA。 我们测试了在妊娠期和出生后发育期间饮食中剥夺欧米茄3脂肪酸对视网膜和大脑皮层脂肪酸组成以及视觉功能的影响。 对照组的女性和她们的婴儿接受提供充足18:3欧米加3的半纯饮食。 在不足组的近期胎儿和新生儿中，视网膜中22:6 ω - 3的磷脂酰乙醇胺含量为对照值的一半，大脑皮层为对照值的四分之一。 到22个月大时，对照组的这些组织中22:6 ω - 3的含量大约增加了一倍，但在缺陷组中没有增加。

Again, you need adequate DHA intake during pregnancy and early development. These monkeys were clearly deficient, and it affected their eyesight in a negative manner: First, electroretinographic recordings, performed at 21 months of age, or within 1 month of the biochemical analyses, demonstrated an impairment in the recovery of the dark-adapted response to saturating flashes- i.e., those flashes sufficiently bright to elicit maximal response amplitudes. At long intervals (20 sec or more), responses were as large in deficient animals as in controls. However, the suppressive effect of shorter intervals was much greater in deficient animals (Fig. 4) 同样，在怀孕和早期发育期间，你需要摄入足够的DHA。这些猴子明显有缺陷，这对它们的视力造成了负面影响: 首先，在21个月大时或在生化分析后1个月内进行的视网膜电图记录显示，对饱和闪光的暗适应反应的恢复受到了损害——即，那些足够明亮的闪光能引起最大的反应幅度。 在很长一段时间内(20秒或更长)，缺陷动物的反应与对照组一样大。然而，在缺陷动物中，较短间隔的抑制作用要大得多(图4)。

We see &amp;quot;de-sensitisation&amp;quot; of the eye, and a laggard response to light stimuli in a dark environment. Being DHA deficient is probably not so good for spotting a jaguar at night. 我们看到眼睛“失敏”，以及在黑暗环境中对光刺激的滞后反应。缺乏DHA可能不太适合在夜间发现美洲虎。

The practical consequences are real: The second functional deficit was demonstrated by behavioral tests of visual acuity. Deficient infants had significantly higher visual acuity thresholds (that is, poorer acuity) at 4-12 weeks of age (Fig. 5).If you translate that to humans, it probably means poor visual awareness of their environment and thus reduced learning capabilities, which then has too many consequences to list (everything from recognising facial cues to spotting potential threats). Whatever the case, inadequate DHA during early development is definitely not good. 实际的后果是真实的: 第二种功能缺陷由视力行为测试证实。有缺陷的婴儿在4-12周龄时具有明显较高的视力阈值(即较差的视力)(图5)。 如果你把这句话翻译给人类，这可能意味着他们对环境的视觉意识差，从而降低了学习能力，然后有太多的后果可以列出(从识别面部线索到发现潜在的威胁)。 无论如何，在早期发育阶段DHA不足肯定是不好的。

Next study, &amp;apos;n-3 Fatty Acid Deficiency Alters Recovery of the Rod Photoresponse in Rhesus Monkeys&amp;apos; (Jeffrey et. al., 2002) –http://iovs.arvojournals.org/article.aspx?articleid=2123642 The final purpose of the study was to assess retinal function in adult rhesus monkeys fed lifelong diets differing in n-3 fatty acid content. Twenty-one rhesus monkeys (Macaca mulatta) were fed one of three semipurified diets (n = 7 per group) that were identical except for the source of dietary fat. ?The SOY diet (high ALA) contained 8% ALA (weight percentage of total fatty acids), with soybean oil as the sole dietary fat. ?The SAF diet (low ALA) contained less than 0.3% ALA; a 1:1 mixture of safflower and peanut oils was used to match the 54% linoleic acid (18:2n-6) content of the SOY diet. ?The dietary fat of the DHA diet consisted of a mixture of plant, animal, and fish oils that provided 0.6% DHA, 0.2% eicosapentaenoic acid (EPA, 20:5n-3), 0.2% ?arachidonic acid (AA, 20:4n-6) and 1.4% ALA. This diet was designed to match the fatty acid composition of rhesus milk. 下一项研究“n-3脂肪酸缺乏改变恒河猴杆光敏反应的恢复”(杰弗里等人，2002年)——http://iovs.arvojournals.org/article.aspx?articleid=2123642 这项研究的最终目的是评估成年恒河猴的视网膜功能，长期喂食不同的n-3脂肪酸含量的食物。 21只恒河猴(Macaca mulatta)被喂食三种半纯化饲料(n = 7每组)中的一种，这三种饲料除了膳食脂肪来源之外都是相同的。 ?高ALA的大豆饲粮中ALA(总脂肪酸的重量百分比)为8%，以大豆油为唯一脂肪。 ?SAF(低ALA)日粮中ALA含量低于0.3%;红花和花生油的1:1混合物用于匹配54%的亚油酸(18:2n-6)含量的大豆饲料。 ?DHA饲料由植物、动物和鱼油组成，提供0.6% DHA、0.2%二十碳五烯酸(EPA, 20:5n-3)、0.2%花生四烯酸(AA, 20:4n-6)和1.4% ALA。这种饮食被设计成与恒河鼠奶中的脂肪酸组成相匹配。

Good methodology, but again, I want to remind readers of my Preliminary PUFA rant. The n-6 to n-3 ratio for the SOY, SAF, and DHA diets were 180, 6.8, 9.0 respectively. It is important to note that the SAF diet contained no DHA, and 54% n-6 PUFAs (See Table 1 for details). Even the DHA diet had 20% n-6 PUFAs. ie: ALL the diets were high n-6 PUFA diets. This study is better interpreted as the beneficial of DHA in the context of a high n-6 PUFA diet. This context applies to most of the population on the planet, though I suggest that reduction of those dietary n-6 PUFAs is probably going to be a better plan. 很好的方法，但我想再次提醒读者我的初步PUFA文章。大豆、SAF和DHA日粮的n-6与n-3比值分别为180、6.8、9.0。值得注意的是，SAF饮食不含DHA，含54%的n-6 PUFAs(详见表1)。即使是DHA饮食也含有20%的n-6不饱和脂肪酸。即:所有饲料均为高n-6多不饱和脂肪酸饲料。 这项研究被更好地解释为在高n-6多不饱和脂肪酸饮食的背景下DHA的益处。这种情况适用于地球上大多数人，尽管我认为减少饮食中的n-6不饱和脂肪酸可能是一个更好的计划。

I would have liked to see 2 more groups: no DHA with Saturated fat only (no PUFAs whatsoever)with DHA and with rest of fat being Saturated (no n-6 PUFAs)Anyway, on to the methods. What the researchers did was to anesthesise the live monkeys, dilate their pupils, keep them in the dark for 30 minutes (to dark-adapt the eyes), and then flash them with 449nm blue light, while recording ERG response on the right eye. Two flashes allow the researchers to determine recovery time. You can read the study for all the details. The results section is also a hectic read, but the SOY and DHA monkeys basically had no difference in response, while the SAF monkeys suffered significantly delayed rod recovery times. 我希望看到另外两组: 不含DHA和饱和脂肪(不含不饱和脂肪酸) DHA和其余脂肪是饱和的(不含n-6不饱和脂肪酸) 好了，讲一下方法。研究人员所做的是麻醉活猴子，扩大它们的瞳孔，让它们在黑暗中呆30分钟(使眼睛适应黑暗)，然后用449nm蓝光向它们闪烁，同时记录右眼的ERG反应。 两次闪光可以让研究人员确定恢复时间。你可以阅读这项研究的所有细节。 结果部分也是令人兴奋的阅读，但大豆和DHA猴子的反应基本没有差异，而SAF猴子遭受了明显延迟的棒恢复时间。

Note that for Red Blood Cell DHA concentration: DHA was greatly elevated in the DHA group (8.8% ± 0.7% of total fatty acids, mean ± SD), almost absent in the SAF group (0.3% ± 0.1%), and intermediate in the SOY group (1.8% ± 0.6%)Is it fair to say that no DHA is bad, but a little bit of DHA is enough? Dunno, but it&amp;apos;s certainly plausible. The researchers did not manage to measure retinal DHA levels (because they had to kill the monkeys to do that), so we don&amp;apos;t know how much of that intermediate DHA amount gets incorporated into the retina. My hunch is that there would be no difference despite high DHA intake. Will humans respond the same way? Plausibly, given the studies I convered in the various Endogenous Production of DHA sections. 注意血红细胞DHA浓度: DHA组的DHA含量显著升高(总脂肪酸的8.8%±0.7%，平均±SD)，而SAF组的DHA含量几乎为零(0.3%±0.1%)，大豆组的DHA含量为中等(1.8%±0.6%)。 不吃DHA不好，吃一点就足够了，这样说是否公平?不知道，但肯定是有道理的。研究人员没有设法测量视网膜DHA水平(因为他们必须杀死猴子才能测量)，所以我们不知道有多少中间DHA进入视网膜。我的直觉是，尽管DHA摄入量很高，但不会有什么区别。 人类也会有同样的反应吗?听起来很有道理，根据我在各种内源性DHA生成部分所做的研究。

The study discussed some plausible mechanics, ranging from rhopdosin interactions to Ca2+ concentration control. Personally, I&amp;apos;ll focus on the empirical findings for now, which basically say that the retina isn&amp;apos;t as robust against transient blue light stress when DHA is chronically low. All we can say for now is that some DHA is needed, and saturating tissues with more DHA than can be used is not required. 该研究讨论了一些可能的机制，从罗普多素相互作用到Ca2+浓度控制。就我个人而言，我现在将重点放在实证研究结果上，这基本上说明，当DHA长期处于低水平时，视网膜对短暂的蓝光压力的抵抗力较差。 我们现在所能说的是，一些DHA是需要的，而饱和组织与更多的DHA可以使用是不需要的。

Xanthrophylls 叶黄素

Now on to 5 studies carried out by a similar group of researchers (most studies have Martha Neuringer, Robert M. Russell, Wolfgang Schalch, and D. Max Snodderly as authors). 现在，一个类似的研究小组进行了5项研究(大多数研究的作者是Martha Neuringer, Robert M. Russell, Wolfgang Schalch和D. Max Snodderly)。 ?‘Nutritional Manipulation of Primate Retinas, I: Effects of Lutein or Zeaxanthin Supplements on Serum and Macular Pigment in Xanthophyll-Free Rhesus Monkeys&amp;apos; 灵长类视网膜的营养操作，I:叶黄素或玉米黄质补充剂对无叶黄素恒河猴血清和黄斑色素的影响(Neuringer et. al., 2004) – https://www.researchgate.net/profile/Donald_Snodderly/publication/8386309_Nutritional_manipulation_of_primate_retinas_I_effects_of_lutein_or_zeaxanthin_supplements_on_serum_and_macular_pigment_in_xanthophyll-free_rhesus_monkeys/links/5407ca0b0cf2bba34c247148.pdf ?&amp;apos;Nutritional Manipulation of Primate Retinas, II: Effects of Age, n–3 Fatty Acids, Lutein, and Zeaxanthin on Retinal Pigment Epithelium&amp;apos; 灵长类视网膜的营养调控II:年龄的影响,n - 3脂肪酸,叶黄素和玉米黄质对视网膜色素上皮(Leung et. al., 2004) – https://www.researchgate.net/profile/Donald_Snodderly/publication/8386310_Nutritional_manipulation_of_primate_retinas_II_effects_of_age_n-3_fatty_acids_lutein_and_zeaxanthin_on_retinal_pigment_epithelium/links/5407ca0b0cf2bba34c247147.pdf ?&amp;apos;Nutritional Manipulation of Primate Retinas, III: Effects of Lutein or Zeaxanthin Supplementation on Adipose Tissue and Retina of Xanthophyll-Free Monkeys&amp;apos;灵长类视网膜的营养操纵，III:叶黄素或玉米黄质补充对无叶黄素猴子的脂肪组织和视网膜的影响(Johnson et. al., 2005) – http://iovs.arvojournals.org/Article.aspx?articleid=2123938 ?&amp;apos;Nutritional manipulation of primate retinas. IV. Effects of n?3 fatty acids, lutein, and zeaxanthin on S-cones and rods in the foveal region&amp;apos; 对灵长类视网膜的营养操纵。IV. n - 3脂肪酸、叶黄素和玉米黄质对中央凹区域s锥和杆状体的影响(Leung et. al., 2005) – http://www.sciencedirect.com/science/article/pii/S0014483505001016 ?&amp;apos;Nutritional Manipulation of Primate Retinas, V: Effects of Lutein, Zeaxanthin, and n–3 Fatty Acids on Retinal Sensitivity to Blue-Light–Induced Damage&amp;apos; 灵长类视网膜的营养操纵，V:叶黄素、玉米黄质和n-3脂肪酸对蓝光诱导的视网膜损伤敏感性的影响(Barker II et. al., 2011) – http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3175953/

First, these studies are looking at 2 different types of compounds – the xanthophylls (Lutein and Zeaxanthin), and DHA. I should make a quick note that we see similar dietary-induced increases in Lutein and Zeaxanthin in human supplementation trials, so I will assume similar changes to the human retina as compared to the Rhesus Monkey retina. [Study]: &amp;apos;Xanthophyll accumulation in the human retina during supplementation with lutein or zeaxanthin – the LUXEA (LUtein Xanthophyll Eye Accumulation) study&amp;apos; (Schalch et. al., 2007) –http://www.sciencedirect.com/science/article/pii/S0003986106003511 首先，这些研究着眼于两种不同类型的化合物——叶黄素(叶黄素和玉米黄质)和DHA。 我要简要说明一下，我们在人体补充试验中也看到了叶黄素和玉米黄质的类似的饮食诱导增加，所以我假设人类视网膜的变化与恒河猴视网膜的变化类似。[研究]:“补充叶黄素或玉米黄质时，人类视网膜中叶黄素的积累——LUXEA(叶黄素叶黄素眼积累)研究”(Schalch等人，2007年)——http://www.sciencedirect.com/science/article/pii/S0003986106003511

I&amp;apos;ll just summarise the findings of all the study in bullet points: Study (I) Not much needs to be said here. Lutein and Zeoxanthin needs to be obtained from the diet, and accumulation in tissues is rapidly restored to appropriate levels. Study (II) This was a nice study, which investigated Lutein and Zeoxanthin effects on both low and high DHA diets. The actual retina was extracted from monkeys (humanely) and then examined for Retinal Pigment Epithelium (RPE) cell density in the Fovea and Parafovea. As a quick aside: the RPE is where a lot of the important stuff in a eye happens, so studying it is worthwhile. Everything from absorbed incoming light, to being the site of rhopdosin enzymatic reactions, to regulating blood borne components to and from the eye. Anyway, what this study found is that: (a) &amp;quot;Foveal and parafoveal RPE cell densities increased with age&amp;quot;, which the researchers believe is a compensatory mechanism (need more cells to do the same work). But this finding is contracdicted by many other findings seeing decreased densities.(b) Lutein and Zeoxanthin are critical for maintaining normal fovea RPE cell density profiles© Lutein and Zeoxanthin + low DHA leads to assymetric increases and decreases in RPE cell density profile. Again, probably a compensatory mechanism, and likely hinting that DHA is the synergistic compound in whatever RPE cells need to get done.(d) Interesting result with Lutein and Zeoxanthin supplementation: &gt; It is striking that after supplementation (Table 4) RPE cell densities were higher in the inferior retina of the low n–3 animals but the asymmetry was reversed so that cell densities were higher in the superior retina of the adequate n–3 animals. These results imply an intricate interaction between the xanthophylls of the macular pigment and the n–3 fatty acids of the retina. 我将用要点来总结所有研究的发现: 研究(一） 这里不需要说太多。叶黄素和Zeoxanthin需要从饮食中获得，在组织中的积累迅速恢复到适当的水平。 研究(二) 这是一项很好的研究，研究叶黄素和Zeoxanthin在低DHA和高DHA饮食中的作用。从猴子的视网膜上(人道地)提取，然后检查中央凹和副中央凹的视网膜色素上皮(RPE)细胞密度。 顺便说一句:RPE是很多重要的东西发生的地方，所以研究它是值得的。从吸收进来的光线，到成为喜多酚酶反应的场所，到调节进出眼睛的血液成分。 不管怎样，这项研究发现: (a)“中央凹和副中央凹的RPE细胞密度随着年龄的增长而增加”，研究人员认为这是一种代偿机制(需要更多的细胞来完成同样的工作)。但这一发现与许多其他发现的密度下降相矛盾。 (b)叶黄素和Zeoxanthin对维持正常的中央凹RPE细胞密度剖面至关重要。 ©叶黄素和Zeoxanthin +低DHA导致RPE细胞密度剖面不对称增加或减少。同样，这可能是一种补偿机制，并可能暗示DHA是RPE细胞所需要的协同化合物。 (d)补充叶黄素和Zeoxanthin的有趣结果: 值得注意的是，在补充(表4)低n-3动物的下视网膜RPE细胞密度更高，但这种不对称性被逆转，在充足n-3动物的上视网膜细胞密度更高。这些结果表明黄斑色素的叶黄素和视网膜的n-3脂肪酸之间存在复杂的相互作用。

Clearly this is a highly dynamic system, which could very well fluctuate according to exposure stimuli given to the eye across a longer period of time. I cannot say anything other than the fact that at these these 3 compounds are important for maintaining adaptability of RPE cell density. What is the ideal density profile in these particular areas? No clue, and I suspect that there isn&amp;apos;t one. How much is it genetically determined? How &amp;quot;set in stone&amp;apos; is it based on early-life nutrition? How does this affect appropriate light exposure environments? etc, etc …. All questions that will likely remained unanswered. Maintaining adequate dietary amounts of early-life DHA intake, and then regular dietary Lutein and Zeoxanthin intake through life is probably a good idea, but we have no clue about optimal amounts. Again, with the adaptive behaviour triggered by Lutein and Zeoxanthin in this study, we can&amp;apos;t even say &amp;quot;more Xanthophylls are better&amp;quot;. 很明显，这是一个高度动态的系统，它可以很好地根据对眼睛的长期刺激而波动。 我只能说这三种化合物对于维持RPE细胞密度的适应性是很重要的。 在这些特定区域理想的密度分布是怎样的?不知道，我怀疑根本就没有。多少是由基因决定的?它是如何以早期生命营养为基础的?这对适当的光照环境有什么影响?等等,等等……所有的问题可能都还没有答案。 保持充足的饮食量DHA的早期摄入量，然后在一生中定期饮食叶黄素和Zeoxanthin的摄入量可能是一个好主意，但我们不知道最佳摄入量。在这项研究中，叶黄素和Zeoxanthin触发了适应性行为，我们甚至不能说“叶黄素越多越好”。

Study (III) This just demonstrated that Lutein and Zeaxanthin must be obtained from the diet in order to be accumulated in the body. Both can be stored in adipose tissue, presumably to be used in tissues like the retina at a later date. Study (IV) This study showed not much effect on S-cone or rod density profiles regardless of supplementation protocol. They do mention that: monkeys low in n?3 fatty acids had increased variability of S-cone density in the fovea and low density of foveal rod outer segments. The high variability suggests that the photoreceptors of some animals were resistant to the nutritional manipulations, while others may have been affected. Which supports the notion that there are many other regulatory systems at play. 研究(3) 这正好说明叶黄素和玉米黄质必须从饮食中获得才能在体内积累。两者都可以储存在脂肪组织中，估计以后会被用于视网膜等组织。 研究(4） 该研究表明，无论何种补充方案，对s锥或棒的密度剖面都没有太大影响。 他们确实提到: n - 3脂肪酸含量低的猴子中央凹s锥密度变异性增加，中央凹棒外节密度低。 高变异性表明，一些动物的光感受器对营养操纵有抵抗，而另一些可能受到了影响。 这支持了有许多其他监管体系在起作用的观点。

Study (5） This study is more interesting, because it looked at direct blue light stress to eyes. Regarding the methodology: Blue-light exposures were made with an argon laser (MF-2000; MIRA, Boston, MA) adjusted to deliver only the 476.5-nm line. The delivery beam was set for a nominal 150-μm spot size and was operated at a very low total power level of 2–7 mW. The exact power used for the exposure (which varied between 2 and 7 mW) was recorded and multiplied by the duration of that exposure (5–120 seconds) to obtain the total energy of the exposure. The range of exposure energies was chosen based on preliminary studies. Each test series was composed of four or five exposures of increasing duration designed to deliver energies (J) above and below the threshold for producing visible photochemical lesions. 研究(5） 这项研究更有趣，因为它观察了蓝光对眼睛的直接压力。 关于方法论: 用氩气激光器(MF-2000;MIRA，波士顿，MA)调整，只提供476.5 nm线。输出光束被设定为150 μm光斑大小，并在2-7 mW的非常低的总功率水平下工作。 记录曝光所用的准确功率(在2到7兆瓦之间)，并乘以曝光时间(5-120秒)，得到曝光的总能量。 在初步研究的基础上选择了暴露能量的范围。每个测试系列由4或5个持续时间不断增加的暴露组成，旨在提供能量(J)高于或低于产生可见光化学损伤的阈值。

Readers can go look at the exact results, which judge damage by the total lesion area, but the abstract really sums it up: In control animals, the fovea was less sensitive to blue-light–induced damage than the parafovea. Foveal protection was absent in xanthophyll-free animals but was evident after supplementation. In the parafovea, animals low in n–3 fatty acids showed greater sensitivity to damage than animals with adequate levels. In any case, you still need adequate Xanthophylls and DHA for protection against blue laser light. Now, is this an accurate damage model for real life scenarios? It&amp;apos;s definitely plausible for periods of acute very bright light exposure, but I would think that most people would be able to avoid that simply by closing their eyes and looking away. They wouldn&amp;apos;t be staring into a laser for even the minimum period of 5 seconds used in the experiment. The more important risk factor in the modern world is chronic low level blue light emission from artificial light sources like display screens. Does this study reflect the same risk factors? Probably not, but we will likely never know until a chronic exposure experiment is done. In any case, we see that it is not just DHA, but a combination of factors that affect eye health. I comment more in the Retinal Flux section below. 读者可以去看确切的结果，它根据损伤的总面积来判断损伤程度，但摘要真的总结了它: 在对照组动物中，中央凹对蓝光损伤的敏感性低于副中央凹。在无叶黄素的动物中没有中央凹的保护，但在补充叶黄素后很明显。在副凹中，n-3脂肪酸含量低的动物对损伤的敏感性高于脂肪酸含量充足的动物。 无论如何，你仍然需要足够的叶黄素和DHA来抵御蓝色激光。 这是真实情况下的精确损伤模型吗?对于剧烈的强光照射，这绝对是合理的，但我认为大多数人只要闭上眼睛，看向别处，就能避免这种情况。在实验中，他们甚至不会盯着激光看至少5秒。 在现代世界，更重要的风险因素是显示屏等人造光源长期发出的低水平蓝光。这项研究是否反映了同样的风险因素?可能不会，但我们可能永远不会知道，直到长期暴露实验完成。 无论如何，我们发现影响眼睛健康的不仅仅是DHA，而是多种因素的结合。我在下面的视网膜流量部分有更多的评论。

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tyw DHA（3）2015.12.16 Total Retina DHA Flux Unknown 视网膜总DHA通量未知 First off, you&amp;apos;ll see places which state that &amp;quot;DHA is 60% of the Retina&amp;apos;s lipis&amp;quot;. I honestly couldn&amp;apos;t find a study which supported that claim: 首先，你会看到“DHA占视网膜唇部的60%”。 老实说，我找不到任何研究支持这一说法: ?&amp;apos;Fatty acid composition of brain, retina, and erythrocytes in breast- and formula-fed infants.&amp;apos; (Makrides et. al., 1994) – http://www.ncbi.nlm.nih.gov/pubmed/7913291，Infant study, so I&amp;apos;d expect a lower DHA concentration. DHA is 12.3 +- 2.1% of total fatty acids by weight in the High DHA diet. ?&amp;apos;Fatty acid composition of the human macula and peripheral retina.&amp;apos; (F J van Kuijk and P Buck, 1992) – http://iovs.arvojournals.org/article.aspx?articleid=2178624 DHA 15.9% of total fatty acids in macular, 22.3% in the peripheral retina. ?&amp;apos;Lipids of human retina, retinal pigment epithelium, and Bruch&amp;apos;s membrane/choroid: comparison of macular and peripheral regions.&amp;apos; (Gülcan et. al., 1993) – http://iovs.arvojournals.org/article.aspx?articleid=2160942 ?In Phospholipids: DHA consists 8.4 +- 2.1% total lipids in the macular, 9.4 +- 2.0% ?in the peripheryIn Neutral Lipids: DHA consists 3.3 +- 2.5% total lipids in the macular, 2.6 +- 0.9% in the periphery. ?“母乳喂养和配方奶喂养的婴儿大脑、视网膜和红细胞的脂肪酸组成。(Makrides等，1994)——http://www.ncbi.nlm.nih.gov/pubmed/7913291，婴儿研究，所以我认为DHA浓度较低。在高DHA饮食中，DHA占总脂肪酸体重的12.3 +- 2.1%。 ?“人体黄斑和周围视网膜的脂肪酸组成。(F J van Kuijk and P Buck, 1992)——http://iovs.arvojournals.org/article.aspx?articleid=2178624 DHA占黄斑总脂肪酸的15.9%，占视网膜外周总脂肪酸的22.3%。 ?人类视网膜、视网膜色素上皮和Bruch膜/脉络膜的脂质:黄斑和周围区域的比较。(Gülcan等，1993)——http://iovs.arvojournals.org/article.aspx?articleid=2160942 ?在磷脂方面:DHA在黄斑中占总脂类的8.4±2.1%，在外围为9.4±2.0% ?在中性脂类中:DHA在黄斑中占总脂类的3.3 +- 2.5%，在外围2.6 +- 0.9% There are about 5 times as much Neutral Lipids compared to Phospholipids in the retina (Figure 3 in paper), so the total amount of DHA is more akin to (8.4 + 9.4) * 1/6 + (3.3 + 2.6) * 5/6 = 7.883% on average. The DHA content of the Retinal Pigment Epithelium and Bruch&amp;apos;s Membrane / Choroid are very low, less than 1% of total fatty acids in either of the Macula or Periphery. In any case, it&amp;apos;s not as high as purported, though 20+% of total lipids is still a lot. 视网膜中中性脂类的含量大约是磷脂的5倍(图3)，所以DHA的总量更接近(8.4 + 9.4)* 1/6 +(3.3 + 2.6)* 5/6 = 7.883%。 DHA在视网膜色素上皮和Bruch膜/脉络膜中的含量很低，在黄斑或周围的总脂肪酸中不到1%。 无论如何，这并不像传闻的那么高，尽管20%以上的总脂类仍然很多。 Much more important questions are: ?How much DHA does the entire eye contain (mass)? ?How much DHA gets recyled on a daily basis (mass)? We need to know answers to these questions, and the factors which influence the answers, to be able to say if endogenous DHA synthesis rates can meet retinal DHA demands (and therefore actually support the need for lower DHA intake), and to actually define DHA demands. 更重要的问题是: ?整个眼睛含有多少DHA(质量)? ?每天回收多少DHA(质量)? 我们需要知道这些问题的答案，以及影响这些答案的因素，从而能够说出内源性DHA合成率是否能够满足视网膜对DHA的需求(因此实际上支持低DHA摄入量的需求)，并确定DHA的需求。 The entire eye is probably something like 7.5g. And the retina is tiny … 1,094 mm^2 area with maximum thickness of 400 um, according to &amp;apos;Facts and Figures Concerning the Human Retina&amp;apos; (Helga Kolb, 2005) – http://www.ncbi.nlm.nih.gov/books/NBK11556/. 整个眼睛大概是7.5克左右。视网膜很小…根据“关于人类视网膜的事实和数据”(Helga Kolb, 2005)——http://www.ncbi.nlm.nih.gov/books/NBK11556/。 That is at best: 1094 * 10^-2 * 400 * 10^-4 = 0.4376 cm^3 of volume. (Assuming a uniformly thick retina, which it is not – average thickness will be less) I have no clue how much of this volume is lipid, and how much of it consists fatty acids, nor do I know what the density of said proteins and fatty acids are in the retina. But I would think that retina mass is mostly protein. Regardless, assuming a (more than generous) 1g/cm^3 density for fatty acids, and 50% of the retina volume as pure fatty acids (which it is not), and 20% of those fatty acids being DHA (high estimate), that&amp;apos;s 0.4376 * 0.5 * 0.2 * 1.0 = 0.04376g / 43.76mg of DHA. How much of it gets turned over every day? No clue. 这最多是:1094 * 10^-2 * 400 * 10^-4 = 0.4376 cm^3的体积。 (假设视网膜是均匀厚的，其实不是——平均厚度会小一些) 我不知道这个体积中有多少是脂质，有多少是脂肪酸，也不知道视网膜中蛋白质和脂肪酸的密度是多少。但我认为视网膜大部分是蛋白质。 无论如何，假设脂肪酸的密度是(非常高)1克/厘米^3，视网膜体积的50%是纯脂肪酸(其实不是)，而这些脂肪酸的20%是DHA(高估计)，那就是0.4376 * 0.5 * 0.2 * 1.0 = 0.04376克/ 43.76毫克DHA。 每天有多少被翻过来?没有线索。 I do not dispute that DHA is important for the eye in general. But focusing on something like DHA for eye health is missing all the other components of the human eye. Everything from the time light hits the cornea, to transversal the complex and not-well-understood optically active medium of the vitreous humour, to finally hitting the retine, and then the response to that signal, is all going to be equally important in &amp;quot;eye health&amp;quot;. And how aout looking at all those 3000+ proteins in &amp;apos;The proteome of human retina.&amp;apos;(Zhang et. al., 2015) – http://www.ncbi.nlm.nih.gov/pubmed/25407473 总的来说，我并不否认DHA对眼睛的重要性。但是，关注DHA等物质对眼睛健康的影响，就忽略了人眼的其他成分。从光线照射到角膜的时间，到穿过复杂的、不太了解的光学活性介质玻璃体，再到最后照射到视网膜，然后是对信号的反应，这一切对“眼睛健康”都将是同样重要的。 看看《人类视网膜的蛋白质组》里的3000多个蛋白质。(张等人，2015)——http://www.ncbi.nlm.nih.gov/pubmed/25407473 Clinical trials also don&amp;apos;t seem to show any improvement with DHA supplementation in sick eyes, &amp;apos;Lutein + Zeaxanthin and Omega-3 Fatty Acids for Age-Related Macular Degeneration. The Age-Related Eye Disease Study 2 (AREDS2) Randomized Clinical Trial&amp;apos; (The Age-Related Eye Disease Study 2 (AREDS2) Research Group, 2013) – http://jama.jamanetwork.com/article.aspx?articleid=1684847 In this large, multicenter, placebo-controlled clinical trial in people at high risk for progression to advanced AMD, daily supplementation with lutein + zeaxanthin, DHA + EPA, or lutein + zeaxanthin and DHA + EPA in addition to the original AREDS formulation showed no statistically significant overall effect on progression to advanced AMD or changes in visual acuity. Primary, secondary, and subgroup analyses demonstrated no beneficial or harmful effects of DHA + EPA for treatment of AMD. These null results may be attributable to the true lack of efficacy. 临床试验似乎也没有显示，补充DHA对患病眼睛的治疗效果有任何改善，叶黄素+玉米黄质和Omega-3脂肪酸对老年性黄斑变性的治疗效果也没有改善。年龄相关性眼病研究2 (AREDS2)随机临床试验“(年龄相关性眼病研究2 (AREDS2)研究组，2013)—http://jama.jamanetwork.com/article.aspx?articleid=1684847 在这项大型、多中心、安慰剂对照的临床试验中，研究对象是AMD进展的高危人群，每天补充叶黄素+玉米黄质DHA + EPA，或叶黄素+玉米黄质和DHA + EPA，除了原来的AREDS配方外，对进展到晚期AMD或视力变化没有统计上显著的整体影响。原发性、继发性和亚组分析显示DHA + EPA对AMD治疗无有益或有害影响。这些无效结果可能是由于真正缺乏疗效。 It&amp;apos;s more likely that these people were sick to begin with, and that dysfunction caused their eye issues, including a possible dysregulation of DHA delivery to the retina. It isn&amp;apos;t the lack of DHA that is the problem. It&amp;apos;s the regulatory mechanisms that are screwed (and which can&amp;apos;t be fixed simply by adding more DHA). 更有可能的是，这些人一开始就生病了，而功能障碍导致了他们的眼睛问题，包括可能的DHA输送到视网膜的失调。问题并不在于DHA的缺乏。这是调节机制被拧坏了(并不能简单地通过增加DHA来修复)。 Mitochondrial Respiration 线粒体呼吸 Good mitochondrial respiration is clearly very important. Ideally, you want your mitochodnria to be able to generate a lot of ATP and CO2, while making &amp;quot;correct&amp;quot; decisions in the face of nutrient excess, scarcity, or other stressors. A thorough discussion of mitochondrial mechanics deserves its own article, but it&amp;apos;s safe to assume that maximisation of the potential of forward electron flow Complex 1 activity is the goal (because in disease states like cancer ubiquitously, we see a failure of Complex 1). 良好的线粒体呼吸显然非常重要。理想情况下，你希望你的线粒体能够产生大量的ATP和CO2，同时在面对营养过剩、缺乏或其他压力源时做出“正确”的决定。 线粒体力学的全面讨论值得写一篇文章，但可以肯定的是，我们的目标是将前向电子流Complex 1活动的潜力最大化(因为在癌症等疾病的普遍状态下，我们看到Complex 1的失败)。 From that perspective, we can investigate if DHA and other PUFAs help or hurt this process, and by what mechanisms do they do so. In general, PUFAs are insulin sensitising when oxidised as fuel based on the FADH2:NADH ratio. Peter @ Hyperlipid gives you the details – http://high-fat-nutrition.blogspot.com/2012/08/protons-fadh2nadh-ratios-and-mufa.html , but it&amp;apos;s mainly a function of how much Complex 1 vs Complex 2 activity is taking place. PUFAs tend to support higher mitochodnrial membrane potential, greater insulin sensitivity, and lower superoxide levels. On a purely mitochondrial kinetic basis (ignoring all the other harmful effects of PUFAs), this is a bad thing in the context of a high fat diet (you want physiologic insulin resistance), and good in the context of a high carbohydrate diet. 从这个角度来看，我们可以研究DHA和其他不饱和脂肪酸是否有助于或损害这个过程，以及它们是通过什么机制起作用的。 一般来说，当PUFAs被氧化为燃料时，根据FADH2:NADH的比例，会使胰岛素增敏。彼得@ hyper血脂为您提供了详细信息，http://high-fat-nutrition.blogspot.com/2012/08/protons-fadh2nadh-ratios-and-mufa.html，但这主要是关于复合物1和复合物2的活动发生了多少的函数。 PUFAs倾向于支持更高的线粒体膜电位、更高的胰岛素敏感性和更低的超氧化物水平。在纯线粒体动力学的基础上(忽略PUFAs的所有其他有害影响)，这在高脂肪饮食的背景下是一件坏事(你想要生理胰岛素抵抗)，而在高碳水化合物饮食的背景下是一件好事。 Again, this is just a discussion of pure forward-flow mitochondrial mechanics with regard to PUFA. All the bad effects of PUFAs are good reason to avoid them as much as possible. As for DHA, we do not know how much DHA is put through beta-oxidation in a particular person, but if it is, then it will have a very low FADH2:NADH ratio, and consequently behave like any other PUFA put through Electron Chain Transport (ECT), and be very insulin sensitising. 再次强调，这只是关于多酚a的纯向前流线粒体力学的讨论。所有PUFAs的不良影响都是尽量避免使用的好理由。 至于DHA，我们不知道在一个特定的人体内有多少DHA通过β -氧化，但如果是，那么它将具有非常低的FADH2:NADH比率，并因此表现为通过电子链运输(ECT)的任何其他PUFA，并具有非常高的胰岛素敏感性。 DHA Membrane Incorporation DHA膜合并 The more interesting effects of DHA happen when it is incorporated into the mitochondrial membranes, which apparently happens readily in rats (and probably humans too), &amp;apos;Incorporation of marine lipids into mitochondrial membranes increases susceptibility to damage by calcium and reactive oxygen species: evidence for enhanced activation of phospholipase A2 in mitochondria enriched with n-3 fatty acids.&amp;apos;(Malis et. al., 1990) –http://www.pnas.org/content/87/22/8845.short The researches fed Sprague-Dawley rats fish oil or beef fat, and then performed respiratory experiments on isolated Renal corticol mitochondrial. 当DHA与线粒体膜结合时，会产生更有趣的效果，这在老鼠身上很容易发生(可能人类也会发生)。n-3脂肪酸丰富的线粒体磷脂酶A2活化增强的证据。(Malis et al.， 1990)——http://www.pnas.org/content/87/22/8845.short 研究人员给斯普拉格-道利大鼠喂食鱼油或牛肉脂肪，然后对分离的肾皮质线粒体进行呼吸实验。 The amount of DHA on mitochondrial membranes (no distinction between inner and outer membrane) was close to triple the amount in the fish oil fed rats, so obviously the amount of DHA being fed managed to make it into the mitochondria of the kidneys. DHA在线粒体膜上的含量(内膜和外膜没有区别)接近鱼油喂养大鼠的三倍，因此很明显，被喂养的DHA能够进入肾脏的线粒体。 Taking a look at the results, when DHA is high in the mitochondrial membranes, compared to when it is low: ?we see a slight drop in succinate driven respiration (Complex 2) ?a more significant drop in pyruvate/malate driven respiration (presumably representative of Complex 1 activity) [Figure 3] ?a very significant drop in respiration with pyruvate/malate upon exposure to Ca2+ and ypoxanthine (HX) xanthine oxidase (XO) (both generate reactive oxygen species) [Figure 3] ?a reduction in uncoupling with pyruvate/malate, especially when exposed to Ca2+ and ROS [Figure 4] ?an increase in uncoupling with succinate under any condition [Figure 4] 看看结果，当DHA在线粒体膜中含量高时，与DHA含量低时相比: ?琥珀酸驱动的呼吸略有下降(complex 2) ?丙酮酸/苹果酸驱动的呼吸作用更显著的下降(可能代表Complex 1的活性)[图3] ?在暴露于Ca2+和氧黄嘌呤(HX)黄嘌呤氧化酶(XO)时，丙酮酸/苹果酸的呼吸作用显著下降(两者都产生活性氧)[图3] ?丙酮酸盐/苹果酸盐解偶联减少，特别是当暴露于Ca2+和ROS时[图4] ?在任何条件下与琥珀酸解耦的增加[图4] Note that in general, high Ca2+ and ROS suppressed respiration in this experiment, but the high DHA mitochondria reacted with a larger suppression overall. Another note is that the DHA was likely oxidised by high ROS: Afterexposure to reactive oxygen species (HX/XO), A4Ach [20:4(n-6)], EPA [20:5(n-3)],and DHA [22:6(n-3)] content decreased significantly. That&amp;apos;s not surprising given the instability of PUFAs in general, and would produce harmful by-products as a result. 注意，在本实验中，一般来说，高Ca2+和ROS抑制呼吸，但高DHA线粒体的反应总体上有更大的抑制。 另一个值得注意的是DHA很可能被高ROS氧化: 活性氧(HX/XO)、A4Ach [20:4(n-6)]、EPA [20:5(n-3)]和DHA [22:6(n-3)]暴露后含量显著降低。 考虑到多不饱和脂肪酸的不稳定性，这并不奇怪，而且还会产生有害的副产品。 Looking at Table 1 and 2 shows much higher release of FFAs from the membranes of Fish-oil fed mice mitochondria after the experiments (as compared to the beef fat fed mice mitochondria). When compared with Fish Oil mitochondria, Beef Tallow mitochondria showed fewer changes in phospholipid fatty acid composition after the same level of exposure to Ca2+ and reactive oxygen species. 从表1和表2可以看出，实验结束后，鱼油喂养的小鼠线粒体膜释放的FFAs要比牛油喂养的小鼠线粒体高得多。 与鱼油线粒体相比，牛油线粒体在同样水平的Ca2+和活性氧暴露后磷脂脂肪酸组成变化较少。 They also look at Phospholipase A2 (PLA2) function, and found: We have reported (18) that dibucaine., a PLA2 inhibitor (23), protected mitochondria against functional defects induced by Ca2+ and reactive oxygen species. Dibucaine: (i) protected the electron transport chain, presumably at the level of NADH, CoQreductase; (ii) preserved Fl-ATPase and ADP translocaseactivity; and (iii) prevented complete uncoupling of mitochondrial respiration They then show a reduction in released 18:2, 20:4, and 20:5 FFAs during Ca2+ and ROS stress, but there was no change in apparent volatility of DHA. This was probably somewhat expected, given that DHA has the most number of double bonds, and is likely the &amp;quot;most reactive&amp;quot;. 他们还研究了磷脂酶A2 (PLA2)的功能，发现: 我们已经报道过(18)双布卡因。一种PLA2抑制剂(23)，保护线粒体免受Ca2+和活性氧诱导的功能缺陷。 双布卡因: (i)在NADH, CoQreductase水平上保护电子传递链; (ii)保留了Fl-ATPase和ADP转位酶活性;和 (iii)阻止线粒体呼吸完全解耦 然后，在Ca2+和ROS胁迫下，他们释放的18:2、20:4和20:5 FFAs减少，但DHA的表观挥发性没有变化。这在某种程度上可能是预料之中的，因为DHA拥有最多的双键，而且很可能是“最活跃的”。 The researchers claim: PLA2 activation is believed to contribute to tissue injury in a number of pathophysiological processes in kidney (17,24), brain (25), heart (26,27), and liver (28). We have suggested (18) that PLA2 activation played an important role in Ca2+ and reactive oxygen species-induced injury to mitochondria. and: Membranes enriched with high unsaturated n-3 fatty acids would be more susceptible to peroxidation by reactive oxygen species, with generation of toxic lipid hydroperoxides (29), propagating further damage. Peroxidized fatty acids may also potentiate activation of PLFA2 (7), which would amplify the injury. The increased levels of FFAs would in turn likely increase membrane permeability to Ca2+ (16), which might further activate PLA2. 研究人员声称: PLA2激活被认为在肾脏(17,24)、大脑(25)、心脏(26,27)和肝脏(28)的许多病理生理过程中导致组织损伤。我们认为(18)PLA2的激活在Ca2+和活性氧诱导的线粒体损伤中起重要作用。 和: 富含高不饱和n-3脂肪酸的膜更容易受到活性氧的过氧化作用，产生有毒的脂质氢过氧化物(29)，进一步传播损害。 过氧化物脂肪酸也可能增强PLFA2的激活(7)，这将放大损伤。 升高的FFAs水平可能会增加细胞膜对Ca2+的渗透性(16)，这可能会进一步激活PLA2。 That&amp;apos;s a vicious cascade of injurious events …. Excess DHA is not a good thing for mitochondria. On top of that you have increased proton permeability, and supposedly less ATP generation, specifically through defects at Complex 1. Again, not good. 这是一个恶性的连锁伤害事件….过量的DHA对线粒体来说不是好事。 最重要的是，你增加了质子渗透性，并且据说减少了ATP的生成，特别是通过复合物1的缺陷。再一次,不好。 Another study, &amp;apos;Complex I-Associated Hydrogen Peroxide Production Is Decreased and Electron Transport Chain Enzyme Activities Are Altered in n-3 Enriched fat-1 Mice&amp;apos; (Hagopian et. al., 2010) – http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0012696 Note that this study uses a specific type of transgenic mice: These mice express the fat-1 gene from C. elegans, which encodes a desaturase that uses n-6 fatty acids as a substrate for the formation of n-3 fatty acids [21]. Transgenic fat-1 mice express this gene ubiquitously and thus provide a model to investigate the effect of increasing tissue n-3 fatty acid levels without the need for dietary intervention to achieve this goal. This helps avoid the challenge of developing diets that truly differ only in the specific fatty acids of interest. 另一项研究“n-3强化脂肪-1小鼠中复合物i相关的过氧化氢生成减少，电子传递链酶活性改变”(Hagopian等，2010)——http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0012696 请注意，这项研究使用了一种特殊类型的转基因小鼠: 这些小鼠表达来自秀丽隐杆线虫的脂肪-1基因，该基因编码一种以n-6脂肪酸为底物形成n-3脂肪酸[21]的去饱和酶。转基因fat-1小鼠普遍表达该基因，因此提供了一个模型来研究在不需要饮食干预的情况下增加组织n-3脂肪酸水平的影响。 这有助于避免开发只在特定脂肪酸方面真正不同的饮食所面临的挑战。 In any case, it is the DHA on the mitochondria that that we are interested in, and from Table 2, we find that the liver mitochondria of the modified rats had about 22% more Phophatidylcholine (PC) DHA and 24% more phophatidylethanolamine (PE) DHA. There was no difference in coenzyme Q activity. 无论如何，我们感兴趣的是线粒体上的DHA，从表2中我们发现，转基因大鼠肝脏线粒体中磷脂酰胆碱(PC) DHA和磷脂酰乙醇胺(PE) DHA含量分别增加了22%和24%。 辅酶Q活性无差异。 Results: To investigate a system which also includes coenzyme Q, we also measured Complex I+III and Complex II+III activities. The activity of Complex I was decreased by 19% (p&lt;0.05) in the fat-1 compared to control mice. In contrast, the activities of Complex III and Complex IV were increased by 58% (p&lt;0.01) and 27% (p&lt;0.05), respectively, in liver mitochondria from the fat-1 mice. The decreased Complex I activity was not sufficient to cause an overall decrease in Complex I+III activity, and in fact there was a 19% increase (p&lt;0.05) in Complex I+III activity in the fat-1 animals. The activities of Complex II and Complex II+III were not significantly different between control and fat-1 mice. The activities of Complex I+III and II+III were lower than the activity of Complex III alone. This may reflect the fact that Complexes I and II are present at lower concentrations than Complex III in the mitochondrial membrane [22], [23], and coupling Complex III to other enzymes may blunt the “excess” capacity of this enzyme. 结果: 为了研究一个包含辅酶Q的系统，我们还测量了配合物I+III和配合物II+III的活性。 与对照组小鼠相比，fat-1小鼠复合物I的活性降低了19% (p&lt;0.05)。 相比之下，Complex III和Complex IV在fat-1小鼠肝脏线粒体中的活性分别提高了58% (p&lt;0.01)和27% (p&lt;0.05)。 复合物I活性的降低并不足以导致复合物I+III活性的整体下降，事实上，在脂肪-1动物中复合物I+III活性增加了19% (p&lt;0.05)。 Complex II和Complex +III活性在对照组和fat-1小鼠之间无显著差异。 复合物I+III和II+III的活性低于复合物III单独的活性。 这可能反映了复合物I和II在线粒体膜[22]，[23]中比复合物III的浓度低，复合物III与其他酶偶联可能会钝化该酶的“过剩”能力。 We see the same shift as in the previous experiment. Note that this was under conditions with not much added stress (unlike the previous experiment which added Ca2+ and ROS stress). 我们看到了与之前实验相同的变化。需要注意的是，这是在没有增加太多应激的条件下进行的(不像之前的实验增加了Ca2+和ROS应激)。 They then measured H2O2 production as a marker for ROS generation potential: Under substrate-only conditions, a significant decrease was observed in fat-1 H2O2 production in mitochondria respiring on succinate (p&lt;0.05) and succinate/glutamate/malate (p&lt;0.05). After addition of rotenone, fat-1 mitochondria respiring on succinate/glutamate/malate, glutamate/malate or pyruvate/malate produced significantly less H2O2 when compared to controls (p&lt;0.01). After addition of antimycin a, fat-1 H2O2 production was significantly decreased when succinate was the substrate (p&lt;0.001). However, with all other substrates, no significant differences in H2O2 production. The results indicate that H2O2 production was greatly decreased in fat-1 liver mitochondria under conditions of maximum ROS production from complex I by forward (rotenone with complex I linked substrates) or reverse (succinate or succinate with antimycin A) electron flow. 然后，他们测量了H2O2的产生，作为活性氧产生潜力的标记: 在只添加底物的条件下，琥珀酸(p&lt;0.05)和琥珀酸/谷氨酸/苹果酸(p&lt;0.05)对线粒体呼吸产生的脂肪-1 H2O2显著降低(p&lt;0.05)。 添加鱼藤酮后，琥珀酸/谷氨酸/苹果酸、谷氨酸/苹果酸或丙酮酸/苹果酸对脂肪-1线粒体呼吸产生的H2O2显著低于对照组(p&lt;0.01)。 添加抗霉素a后，以琥珀酸为底物时，脂肪-1 H2O2产量显著降低(p&lt;0.001)。然而，与其他基质相比，H2O2的产生没有显著差异。 结果表明，在复合物I通过正向(鱼藤酮与复合物I连接的底物)或反向(琥珀酸或琥珀酸与抗霉素A)电子流产生最大ROS的条件下，脂肪-1肝脏线粒体的H2O2产量大大降低。 Again, we see the same sorts of findings. Reduced ROS production along with reduced Complex 1 activity. There was no difference in proton leak (and thus ATP generation potential): There were no differences in maximal leak-dependent respiration and membrane potential (points farthest to the right in the graph) between the two groups of mice. 我们再次看到了相同的发现。活性氧生成减少，复合物1活性降低。 质子泄漏没有差异(因此ATP产生电位也没有差异): 两组小鼠的最大泄漏依赖呼吸和膜电位(图中最右边的点)没有差异。 The high DHA mitochondria are more prone to oxidative damage under &amp;quot;stressed&amp;quot; conditions, but not under regular basal metabolic conditions: A significant increase (P&lt;0.05) in mitochondrial membrane lipid peroxidation was observed in the fat-1 mice following stimulation of peroxidation with 2,2′-azobis(2-amidinopropane) (AAPH). This result indicates that the increase in membrane n-3 fatty acids in the fat-1 mice is associated with an increase in susceptibility to peroxidation when faced with an oxidative insult It was necessary next to determine if alterations in mitochondrial lipid peroxidation occurred in the fat-1 animals under basal conditions. Two methods, malondialdehyde (MDA) and 4-hydroxynonenal (HNE), were also used to provide an indication of basal levels of lipid peroxidation in mitochondria from the fat-1 mice (Figure 5A and 5B). In contrast to the AAPH results, no differences (P&gt;0.05) in MDA or HNE levels were observed in mitochondria from the two groups of mice. These results indicate that despite elevated n-3 levels, basal lipid peroxidation is not increased in mitochondria from 1 year old fat-1 mice. 高DHA线粒体在“压力”条件下更容易发生氧化损伤，但在常规的基础代谢条件下则不会: 2,2′-偶氮(2-脒基丙烷)(AAPH)刺激fat-1小鼠线粒体膜脂过氧化显著增加(P&lt;0.05)。这一结果表明，脂肪-1小鼠中膜n-3脂肪酸的增加与氧化损伤时过氧化敏感性的增加有关。 接下来有必要确定在基础条件下，脂肪-1动物线粒体脂质过氧化是否发生了改变。 两种方法，丙二醛(MDA)和4-羟基壬烯醛(HNE)，也被用来提供脂肪-1小鼠线粒体脂质过氧化基础水平的指示(图5A和5B)。 与AAPH结果相反，两组小鼠线粒体MDA和HNE水平无差异(P&gt;0.05)。这些结果表明，尽管n-3水平升高，但1岁大的fat-1小鼠线粒体的基础脂质过氧化没有增加。 Apoptotic Regulation 凋亡调控 Mitochondria send the signals which determine their own and their host cells&amp;apos; survival. Any change to respiration mechanics will change the autophagic and apoptotic signals and signalling contexts. 线粒体发出的信号决定了它们自己和宿主细胞的生存。呼吸机制的任何改变都会改变自噬和凋亡信号和信号传递环境。 Since the sections above showed reductions in respiration capacity with DHA incorporation, I want to infer that DHA increases the signal threshold required for autophagy and apoptosis (making these actions less likely). 由于上面的章节显示了DHA加入后呼吸能力的降低，我想推断DHA增加了自噬和凋亡所需的信号阈值(使这些行为不太可能发生)。 Cardiac Cells 心肌细胞 Well, the context seems to depend on the cell tested. First, cardiac mitochondria, &amp;apos;Improved Mitochondrial Function with Diet-Induced Increase in Either Docosahexaenoic Acid or Arachidonic Acid in Membrane Phospholipids&amp;apos; (Khairallah et. al., 2012) – http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0034402#pone.0034402-Khairallah1 Don&amp;apos;t be misled by the title; &amp;quot;improvements&amp;quot; is not the correct word to describe the changes observed (it requires context qualification to determine if the change is good or bad or inconsequential). 情况似乎取决于测试的细胞。首先，心脏线粒体，“通过饮食诱导膜磷脂中二十二碳六烯酸或花生四烯酸的增加，改善线粒体功能”(Khairallah等人，2012)——http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0034402#pone.0034402-Khairallah1 不要被标题所误导;“改进”不是描述观察到的更改的正确词汇(它需要上下文限定来确定更改是好是坏还是无关紧要)。 Firstly, this study used quite a fair bit of DHA supplementation (2.5% of total energy intake) on rats to induce DHA incorporation into cardiac mitochondria. This is a stupidly high intake (7g of DHA if you consume 2500kcal a day). Whether or sane consumption of DHA can achieve the same degree of DHA incorporation into cardiac mitochondria of humans is not known. This alone makes the study somewhat un-useful. 首先，本研究对大鼠进行了相当多的DHA补充(总能量摄入的2.5%)，诱导DHA进入心肌线粒体。这是一个愚蠢的高摄入量(7克DHA，如果你每天摄入2500千卡)。DHA的合理消耗是否能达到同样程度的DHA融入人类心脏线粒体尚不清楚。仅这一点就使这项研究有些无用。 In any case, let&amp;apos;s assume that this is possible, and DHA in cardiac mitochondrial membranes is doubled from 10% to 20% of total fatty acids like this study suggests. The results were that: Not much difference in State 3 and State 4 respiration; Substrate can still be used normally. Sidenote: cardiac mitochondria seem to be a little special in this way – that they can use up any form of substrate supplied to them. As we saw in the sections above, this sort of behaviou is not typical.Mitochondrial MPTP apoptotic threshold increased The authors clarify: Mitochondria can depolarize and trigger cell death through the opening of the mitochondrial permeability transition pore (MPTP). Results: Mitochondria from rats supplemented with DHA or ARA alone had significantly enhanced Ca2+ retention capacity compared to CTRL animals, as reflected by significantly lower. extramitochondrial [Ca2+] for a given cumulative Ca2+ load with all substrates except palmitoylcarnitine+malate. a large increase in either DHA or ARA in mitochondrial membrane phospholipids is associated with a significant increase in the mitochondrial capacity for Ca2+ retention, an index of MPTP opening. On the other hand, the extreme increase in the sum of ARA and DHA accompanied by depletion of linoleic acid that occurred with the DHA+ARA diet was associated with increased susceptibility to MPTP opening, and suggests that the combination of elevated DHA and ARA with low linoleic acid in membrane phospholipids is detrimental. 无论如何，让我们假设这是可能的，正如这项研究表明的那样，心脏线粒体膜中的DHA从总脂肪酸的10%翻倍到20%。 结果是: 状态3和状态4的呼吸差异不大;承印物仍可正常使用。 旁注:心脏线粒体似乎在这方面有一点特殊——它们可以消耗供给它们的任何形式的底物。正如我们在上面的章节中看到的，这种行为并不典型。 线粒体MPTP凋亡阈值升高 作者澄清: 线粒体可通过打开线粒体通透性过渡孔(MPTP)去极化并触发细胞死亡。 结果: 与对照组相比，单独添加DHA或ARA的大鼠的线粒体显著提高了Ca2+的保留能力， 表现为在给定的累积Ca2+负荷下，除棕榈肉碱+苹果酸外，所有底物的线粒体外[Ca2+]显著降低。 线粒体膜磷脂中DHA或ARA的大量增加与线粒体Ca2+保留能力的显著增加有关，这是MPTP开放的一个指标。 另一方面,极端ARA的总和和DHA伴随着损耗发生的亚油酸与DHA + ARA饮食与注射对MPTP药物增加有关,并表明,较低的高DHA和ARA亚油酸在膜磷脂是有害的。 All that is resonable, but even the authors admit that they assume a Ca2+ stressed state in this experiment, and state: A second important limitation is that lack of measurement of the initial mitochondrial [Ca2+], as dietary supplementation with DHA or ARA could affect the residual Ca2+ in the mitochondrial matrix following isolation. Decreased initial matrix [Ca2+] could increase mitochondrial Ca2+ uptake capacity and give the impression of delayed PTP opening in response to successive Ca2+ additions. Our main conclusion regarding mitochondrial Ca2+ retention is that dietary supplementation with docosahexaenoic acid or arachidonic acid are associated with a greater exogenous Ca2+ load required to induce MPTP opening. We know of no rationale to suggest there would be differences in the initial [Ca2+] among treatment groups, nevertheless there may be differences that could affect the capacity for Ca2+ retention. 所有这些都是合理的，但即使是作者也承认，他们在这个实验中假设了一个Ca2+压力状态，并说: 第二个重要的限制是缺乏对初始线粒体[Ca2+]的测量，因为在膳食中补充DHA或ARA可能会影响分离后线粒体基质中残留的Ca2+。降低初始基质[Ca2+]可增加线粒体Ca2+摄取能力，并在连续Ca2+添加的反应中给人延迟PTP开放的印象。 我们关于线粒体Ca2+保留的主要结论是，膳食中添加二十二碳六烯酸或花生四烯酸与诱导MPTP开放所需的更大的外源Ca2+负荷相关。 我们知道没有理由表明在初始[Ca2+]治疗组之间存在差异，尽管如此，可能存在影响Ca2+保留能力的差异。 Regardless of what model of the cell membrane you use (though I much prefer Gilbert Ling&amp;apos;s), Ca2+ is excluded by the membrane under normal conditions. The Ling model is appealing because it links ATP depletion directly to loss of membrane barrier function. In the Ling model, not enough ATP implies that proteins cannot maintain their extended conformation to create large sheaths of polarised water / EZ water, which is what naturally excludes various solutes (see the experimental work of Gerald Pollack). 不管你使用什么模型的细胞膜(尽管我更喜欢Gilbert Ling的)，Ca2+在正常情况下被膜排除在外。Ling模型之所以吸引人，是因为它将ATP耗尽直接与膜屏障功能的丧失联系起来。 在Ling模型中，没有足够的ATP意味着蛋白质不能维持其延伸的构象来产生大的极化水/ EZ水鞘，这自然排除了各种溶质(见Gerald Pollack的实验工作)。 Some may not favour these models, but regardless of what model you use, the lost of solute homeostasis empirically comes down to the lack of the ability to maintain barrier function due to energetic loss. All models will agree that ATP is the currency for energy. Lack of ATP =&gt; uncontrolled calcium infux. Let&amp;apos;s ignore direct insults to cell membranes for now, which can occur from any number of mechanical forces – from being sliced by a blade, to getting bombarded by high powered EMF. The types of damage we are concerned with are usually chronic, and metabolic in nature. 有些人可能不喜欢这些模型，但不管你使用什么模型，从经验上讲，溶质稳态的丧失归结为由于能量损失而缺乏维持屏障功能的能力。所有的模型都同意ATP是能量的货币。缺乏ATP =&gt;无控制的钙流入。 现在让我们先忽略对细胞膜的直接伤害，这可能来自任何数量的机械力——从被刀片划伤，到受到高能电磁场的轰击。我们所关心的损伤类型通常是慢性的，本质上是新陈代谢的。 In this regard, one can possibly come to the conclusion that there are multiple opposing forces at work here. ?(1) DHA can reduce Complex 1 activity and lead to lowered respiration and decreased ATP. This pre-disposes the cell to Ca2+ concentration dysregulation ?(2) DHA can increase the threshold for Ca2+ induced apoptosis In cardiac cells, DHA doesn&amp;apos;t affect (1) locally, so we have to look at non-local (wrt heart) means of Ca2+ influx excess. This is a very complex topic, with so many regulatory mechanisms which span all systems of the body – everything from direct dietary intake, to hypothalamic water regulation, to various excretion mechanics involving the liver and other oragns. 在这方面，人们可能会得出这样的结论:这里有多种相反的力量在起作用。 (1) DHA可降低Complex 1活性，导致呼吸降低，ATP减少。这使细胞易于Ca2+浓度失调 (2) DHA能提高Ca2+诱导的细胞凋亡阈值 在心脏细胞中，DHA不影响(1)局部，所以我们必须着眼于非局部(wrt心脏)Ca2+内流过量的方式。这是一个非常复杂的话题，有如此多的调节机制，跨越身体的所有系统——从直接饮食摄入，到下丘脑水的调节，到涉及肝脏和其他器官的各种排泄机制。 Trying to come to a conclusion that &amp;quot;DHA is good&amp;quot; based on such a study is not plausible. For one, we need the assume that all cells control MPTP-to-apoptosis regulation the same way as there specific cardiac mitochondria. Given that substrate effects are different, how can we be confident that MPTP behaves the same universally? How can we figure out what conditions induce Ca2+ damage? Is Ca2+ the most important signalling agent under those conditions? What about other &amp;quot;metabolic poisons&amp;quot; like Nitric Oxide which can lead to the same effects? Is apoptosis even a bad thing for the specific cell in question? I don&amp;apos;t know, and the likelihood of figuring such things out is basically close to 0%. Therefore, I will not use such information to make decisions about whether or not to consume more DHA (especially given the evidence against mitochondrial function). 试图根据这样的研究得出“DHA有益健康”的结论是不合理的。 首先，我们需要假设所有细胞控制mptp到凋亡的方式与特定的心肌线粒体相同。既然底物效应是不同的，我们怎么能确信MPTP的行为是普遍的呢? 我们怎么知道是什么条件导致Ca2+损伤?在这些条件下Ca2+是最重要的信号载体吗?那么其他的“代谢毒素”呢?比如一氧化氮，它也会导致同样的后果。细胞凋亡对特定的细胞来说是一件坏事吗? 我不知道，找出这些东西的可能性基本上接近于0%。因此，我不会使用这些信息来决定是否消耗更多的DHA(特别是考虑到线粒体功能的证据)。 Speculations and Practical Considerations 投机和实际考虑 We can speculate that having DHA incorporated into mitochondrial membranes signals a sort of &amp;quot;maintain the status quo&amp;quot; metabolism. Which is to say: ?reduce metabolic capacity in general, especially through Complex 1 ?prefer the use of fatty acids as a substrate for ATP generation ?reduce ROS generation and therefore the autophagic or apoptotic signal for existing mitochondria 我们可以推测，将DHA纳入线粒体膜是一种“维持现状”代谢的信号。 也就是说: 总体上降低代谢能力，特别是通过Complex 1 更喜欢使用脂肪酸作为生成ATP的底物 减少ROS的生成，从而抑制现有线粒体的自噬或凋亡信号。 Works great as a &amp;quot;hibernation strategy&amp;quot;, whereby external stressors and activity levels are probably low, while allowing the mitochondria to more readily feed off body fat stores. Probably not so good for a hard-charging athlete. Note however that we have no way to measure &amp;quot;excess DHA&amp;quot;. A person who has eaten a lot of DHA in the past may hold it in their adipose tissue, where it has no effect on said mitochondrial function, only to have them be liberated later on and become incorporated into mitochondrial membranes. 作为一种“冬眠策略”非常有效，外部压力源和活动水平可能很低，同时允许线粒体更容易消耗身体脂肪储备。对一个精力充沛的运动员来说可能不太好。 但是请注意，我们没有办法测量“多余的DHA”。 一个在过去吃了大量DHA的人可能会将其储存在脂肪组织中，而在脂肪组织中DHA对线粒体功能没有影响，只是在稍后它们被释放出来并并入线粒体膜。 Mitochondria also constantly get recycled, especially in tissues like the liver, so the state of membrane lipids is going to vary almost on a day to day basis (and definitely on a seasonal basis). This is a system in constant flux, and trying to predict the state of mitochondrial function can&amp;apos;t be measured in real time. We are left with using indirect measures of metabolism, and that is a whole different topic to discuss, and will not be discussed here. As for DHA, too much dietary DHA is obviously still bad. The ideal case would be to limit it to the minimum required. 线粒体也在不断被循环利用，特别是在肝脏这样的组织中，所以膜脂的状态几乎每天都在变化(当然还有季节性的变化)。 这是一个不断变化的系统，试图预测线粒体功能的状态是无法实时测量的。我们剩下的是使用间接的代谢测量，这是一个完全不同的话题，我们不会在这里讨论。 至于DHA，饮食中摄入过多的DHA显然还是不好的。理想的情况是将其限制在所需的最低限度。 Low-Level DHA Mechanics 低级DHA力学 This section is speculatory. It attempts to incorporate physical properties of atoms together with the most plausible model of membrane mechanics (Gilbert Ling&amp;apos;s) in an attempt to explain from a charge withdrawal / donation perspective, the physical mechanics of DHA. 这部分是推测性的。它试图将原子的物理性质与最合理的膜力学模型(Gilbert Ling的)结合在一起，试图从电荷提取/捐赠的角度来解释DHA的物理力学。 One thing that we do know is that DHA is probably not directly involved in any reaction (where charge transfer happens). It is so volatile to begin with, and if it were the site of energy transfer, so much of it would get degraded so quick that it&amp;apos;s utility would be nil. The most likely function of this compound, and why it has been preserved for biological use for so long, definitely has everything to do with it&amp;apos;s 6 C=C bonds, and the ability for it to create a specific environment on cell membranes just by its mere presence. While I say it is not a site of energy transfer, it can very well participate in attractive and repulsive behaviour with non-reactive compounds, which is obviously useful for biology to use as a &amp;quot;traffic director&amp;quot; for other molecules. 我们知道的一件事是DHA可能不直接参与任何反应(发生电荷转移)。它一开始就很不稳定，如果它是能量传递的场所，那么它的大部分会迅速降解，以至于它的效用将为零。 这种化合物最有可能的功能，以及为什么它能被保存这么长时间作为生物用途，肯定与它的6c =C键有关，以及它仅凭存在就能在细胞膜上创造特定环境的能力。 虽然我说它不是能量转移的场所，但它可以很好地参与非活性化合物的吸引和排斥行为，这显然是有用的，生物学上用作其他分子的“交通主管”。

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Edit:2021.08.23

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