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' (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: "dox" 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 "pre-educates" 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 "normal" 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 "woo woo" 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"我听了直呼nb"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' (Bastian Hoesel and Johannes A Schmid, 2013) – http://molecular-cancer.biomedcentral.com/articles/10.1186/1476-4598-12-86
I don't think I'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 "becoming concerous or not" 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, "It depends on how well your body can regulate DHA's distribution in tissues". 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 "Fatty Liver Disease". Well, you should probably fix that liver first, and not eat more DHA to put added stress on your liver (just like you wouldn'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's Disease. Some people would say, "plasma DHA is low in such a disease, and thus DHA supplementation is warranted". 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'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' (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 (<10% in controls, >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<10%，>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 < 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 < 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 "switch" 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'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's claim that "DHA and other Polyunsaturaed fats suppress the immune system". 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, 'EPA and DHA reduce LPS-induced inflammation responses in HK-2 cells: Evidence for a PPAR-big gamma–dependent mechanism'(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 "incubated with various concentrations of omega-3 PUFAs such as EPA and DHA in the presence or absence of lipopolysaccharide (LPS) for 24 hours". 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 >80% suppression with DHA. This is more evidence for the statement, "DHA suppresses immune function". 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 'Mitochondrial Respiration' 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'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'll look at this study, 'Fish Oil Attenuates Omega-6 Polyunsaturated Fatty Acid-Induced Dysbiosis and Infectious Colitis but Impairs LPS Dephosphorylation Activity Causing Sepsis' (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, "Look DHA makes sepsis worse in humans!!" 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'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 "known" 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'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: > 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 "More gut bacteria ⇒ more obesity" in rat models. I love ItsTheWooo!'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'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 & 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。
