ABCA1

本文为转化医学网原创，转载请注明出处 作者：Jerry 导读： 转移是结直肠癌(CRC)患者死亡的主要原因。本研究探讨了肿瘤相关巨噬细胞(tumor associated macrophages, tam)在结直肠癌转移中的调控作用。 2月22日，上海交通大学严东旺/赵倩研究团队在期刊《Clinical And Translational Medicine》上发表了研究文章，题为“Tumour-associated macrophage-derived DOCK7-enriched extracellular vesicles drive tumour metastasis in colorectal cancer via the RAC1/ABCA1 axis”。本研究结果表明，通过TAM-EVs传递的DOCK7可以通过RAC1/AKT/FOXO1/ABCA1轴调节CRC细胞中的胆固醇代谢和CRC细胞转移。 因此，DOCK7可能成为抑制CRC转移的新治疗靶点。 https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/full/10.1002/ctm2.1591 研究背景 01 结直肠癌(CRC)是消化系统最常见的恶性肿瘤，在癌症相关死亡中排名第二。转移是CRC治疗成功的主要障碍，主要发生在肝脏。大约20%的CRC患者在诊断时发现肝转移，甚至高达50%的患者在原位肿瘤完全切除后仍出现肝转移。目前的治疗方法，如全身化疗、靶向治疗和免疫治疗，对转移性CRC患者的治疗效果有限。因此，迫切需要确定CRC转移的关键机制和有效靶点。 在CRC微环境中，TAMs占据免疫细胞的主体，占所有免疫细胞的50%。TAMs通常有两种极化。M1-TAMs发挥促炎和抗肿瘤作用，而M2-TAMs与抗炎和抗肿瘤作用密切相关。许多研究表明，M2型巨噬细胞是肿瘤微环境(TME)中TAMs的最主要类型。越来越多的研究表明，TAMs可以显著调节肿瘤的恶性表型，如增殖、血管生成、运动和糖酵解。然而，TAMs是否以及如何调节CRC的转移尚未完全阐明。 研究进展 02 为了研究TAMs在CRC转移中的作用，研究人员收集了71例人类CRC标本和相应的临床病理资料。研究人员选择了典型的巨噬细胞标志物CD68和M2型TAM标志物CD163，通过免疫组化分析评估巨噬细胞和M2型TAMs的种群。结果显示，在转移性CRC组织中，巨噬细胞(CD68)和M2型TAMs(CD163)的招募比非转移性组织大。此外，CD163水平在III和IV期CRC组织中显著高于I和II期CRC组织，但CD68水平没有显著性差异。CRC患者肿瘤标本分化较差时，CD163表达也升高，但CD68表达无显著性差异。 研究发现 03 通过分析所选CRC患者的总生存期，研究人员发现，CD163水平高(IHC评分6-12)的患者比CD163水平低(IHC评分0-4)的患者生存期更差。虽然CD68表达与总生存期之间没有显著相关性，但研究人员发现，CD68lowCD163low组的患者比CD68highCD163high组的患者生存期更好。CRC最常见的转移部位是肝脏。为了进一步研究TAMs与CRC肝转移的相关性，研究人员验证了40例确诊为肝转移的CRC患者的CD163表达。免疫组化分析表明，在原发性CRC组织中观察到CD163的表达水平较高。 总的来说，这些发现表明CRC微环境中丰富的TAMs种群与转移和较差的预后相关。 TAMs与CRC转移相关 研究结论 04 总之，研究人员发现TAMs在CRC微环境中大量存在，并与转移相关。TAMs来源的EVs可以通过将DOCK7转移到CRC细胞中增加其迁移和侵袭能力。进一步的机制研究表明，TAM-EVs包裹的DOCK7可以激活CRC细胞中的RAC1，随后通过磷酸化AKT和FOXO1上调ABCA1的表达，最终调节胆固醇代谢，增加细胞膜流动性，从而调节CRC细胞的运动和侵袭能力。 本研究结果揭示了胆固醇代谢与CRC转移之间的新相互作用，它有望成为抑制CRC转移的新治疗靶点。 参考资料： https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/full/10.1002/ctm2.1591 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。 热门·直播/活动 🕓 上海｜3月01日-02日 ▶第三届长三角单细胞组学技术应用论坛暨空间组学前沿论坛将在上海召开，诚邀您的参与！ 点击对应文字 查看详情

*仅供医学专业人士阅读参考说起降脂，我们脑海里就会将其与动脉粥样硬化等心血管疾病连上线。实际上，异常的胆固醇积累和脂质代谢同样对我们的大脑造成深刻影响。 载脂蛋白E（ApoE）是大脑中最丰富的载脂蛋白，负责调节脂质和胆固醇的转运和代谢，在神经系统的正常功能和神经退行性疾病中起着关键作用。ApoE有3种主要异构体，为ApoE2、ApoE3和ApoE4，在阿尔茨海默病（AD）进展中扮演着不同的角色。其中，ApoE2与AD风险降低相关，ApoE4则被证明是迟发性阿尔茨海默病（LOAD）最强的遗传风险因子。 近日，美国圣路易斯华盛顿大学的David M. Holtzman、Gilbert Di Paolo及其同事们发现，ApoE4能够诱导Tau蛋白病理下的脑细胞发生脂质代谢紊乱、胆固醇酯异常积累，导致神经炎症反应增加。使用LXR激动剂或提高特定基因的表达，帮助脑细胞排出胆固醇酯，可以缓解小鼠的AD相关行为和大脑损伤。文章于近日发表在Neuron期刊上[1]。 “阿尔茨海默病中免疫细胞损害大脑的机制，与动脉粥样硬化病中免疫细胞损伤血管的机制极为相似，” David M. Holtzman表示[2]，“在这两种情况下，脂质都会在免疫细胞中发生积聚，导致其表现出高度炎症性特征并损害周围组织。消除脂质积累可能对我们的健康有双重好处！” 论文首页截图 神经元中的Tau蛋白过度磷酸化及其导致的神经原纤维缠结，是AD的核心病理特征之一。 此次，为了研究ApoE、脂质和脑损伤之间的联系，David M. Holtzman等人构建Tau蛋白病理的小鼠模型（P301S），这些小鼠更容易发生Tau蛋白积累，在6个月龄左右时出现神经退行性病变迹象，9.5月龄时大脑严重受损不再能进行筑巢等日常活动。另外，还结合遗传学技术使这些小鼠表达人类的ApoE4异构体（TE4）或者ApoE3异构体（TE3）。 结果显示，ApoE4与脑细胞脂质代谢紊乱有关。在9.5月龄大时，携带ApoE4的Tau蛋白病理小鼠大脑结构发生显著的神经退行性病变，在神经元、星形胶质细胞、小胶质细胞、少突胶质细胞等多种脑细胞中，超过181种脂质积累水平改变。尤其是星形胶质细胞和小胶质细胞，脂质水平增加幅度最大，以大量积累的胆固醇酯为特征。 脑细胞脂质代谢的这些变化依赖于ApoE4和Tau蛋白病理的同时存在，并且经检测，可能与溶酶体降解过程受损有关。相比之下，携带ApoE4的Tau蛋白病理小鼠，或者仅携带ApoE4的非Tau蛋白病理小鼠，脑细胞中脂质水平不会发生改变。 APOE4、Tau蛋白病理与脑细胞的异常脂质积累有关 星形胶质细胞和小胶质细胞可以说是大脑的护卫，一个负责维持血脑屏障的完整，一个担负着免疫细胞的职责，清除死亡的神经元或其它细胞碎片。这两种胶质细胞发生脂质异常积累与氧化应激，已被证明会导致神经炎症反应增加，进而促进神经退行性病变。 既然如此，如何消除由ApoE4与Tau蛋白病理合力引起的胶质细胞脂质代谢紊乱呢？ 于是，研究者们尝试帮助脑细胞“排脂”。 肝X受体（LXR）是一类核受体，能够调节胆固醇的代谢和外排。当细胞内胆固醇水平升高时，LXR被激活，进而促进胆固醇转运到细胞外，降低细胞内胆固醇水平。研究者们使用10mg/kg剂量的肝X受体（LXR）小分子激动剂GW3965，在小鼠6个月龄大时给予治疗。 结果确实有效。在9.5个月龄大时接受治疗、携带ApoE4的Tau蛋白病理小鼠，不仅“降脂”成功，星形胶质细胞和小胶质细胞的胆固醇酯等脂质积累、炎症性特征减少，而且AD病理特征得到缓解，病理性Tau蛋白聚集水平明显降低，神经炎症相关因子、T细胞浸润水平降低，突触损失减少；更直观的是，小鼠筑巢行为得到改善、神经退行性行为减少。 LXR激动剂排出胆固醇酯前后的胶质细胞[2]进一步研究发现，LXR激动剂是通过上调Abca1基因表达发挥作用。使用遗传学技术使小鼠过表达Abca1，可以得到与LXR激动剂相似的效果，表明Abca1可作为有潜力的治疗靶点。 总体来说，这项研究结果表明，清除脑细胞中异常积累的胆固醇酯，可作为改善ApoE4和Tau蛋白病理相关的神经退行性病变的治疗方法。但需要注意的是，以往研究表明LXR激动剂会影响肝脏中的脂质代谢，容易引起脂肪肝疾病，因此我们还需要找到更好的方式，来帮助脑细胞排出胆固醇酯等脂质。有趣的是，美国麻省理工学院的蔡立慧教授团队于去年在《细胞·干细胞》期刊上发表论文，揭示ApoE4会破坏小胶质细胞的脂质代谢能力，导致脂质分子，特别是胆固醇的积累。异常积累的胆固醇与神经元细胞膜中特定类型的钾离子通道结合后，抑制神经元放电，导致神经元兴奋性下降。同时，蔡立慧教授团队也指出新的研究方向，即恢复脂质稳态。结合这项研究来看，给脑细胞“降脂”的法子也许真的可行！参考文献：[1]https://www-cell-com.libproxy1.nus.edu.sg/neuron/fulltext/S0896-6273(23)00804-8[2]https://medicine.wustl.edu/news/lowering-a-form-of-brain-cholesterol-reduces-alzheimers-like-damage-in-mice/本文作者丨张艾迪

This review paper summarizes numerous research studies that address the role of kidney cholesterol and lipid accumulation in the development and progression of chronic kidney disease (CKD).ZyVersa’s Cholesterol Efflux Mediator™ VAR 200 is in development to reduce renal cholesterol and lipid accumulation that damages the kidneys' filtration system in patients with glomerular diseases, including diabetic kidney disease, focal segmental glomerulosclerosis, and Alport Syndrome. WESTON, Fla., Oct. 11, 2023 (GLOBE NEWSWIRE) -- ZyVersa Therapeutics, Inc. (Nasdaq: ZVSA, or “ZyVersa”), a clinical stage specialty biopharmaceutical company developing first-in-class drugs for treatment of renal and inflammatory diseases, announces publication of a paper in the peer-reviewed journal, Nature Reviews Nephrology, that summarizes data highlighting how lipid accumulation in the kidneys contributes to CKD development and disease progression. In the review paper titled, “Kidney lipid dysmetabolism and lipid droplet accumulation in chronic kidney disease,” the following key points were made: Lipids and lipid-related enzymes have a major role in modulating the function of the kidney’s filtration system, and lipid accumulation can drive CKD irrespective of circulating lipid levels and use of systemic lipid lowering drugs like statins.Although several lipid types, including cholesterol, triglycerides, fatty acids, and phospholipids, are dysregulated in the kidney and contribute to CKD progression, dysregulation of cholesterol metabolism is one of the hallmarks of kidney injury in CKD. Cholesterol accumulation occurs in association with impaired transport of cholesterol out of the kidney.Accumulation of fatty acids triggers kidney cell damage by promoting inflammation and fibrosis. The paper includes a brief overview of Cholesterol Efflux Mediator™ VAR 200 (hydroxy-propyl-beta-cyclodextrin), highlighting that it reduced cholesterol accumulation and cell death (apoptosis) in podocytes in vitro, and provided protection from kidney disease progression in mouse models of diabetic kidney disease, FSGS, and Alport Syndrome. The authors concluded this section by stating that VAR 200, which is in development for patients affected by several forms of kidney disease, provides therapeutic potential for diseases characterized by ABCA1 deficiency. To read the article, Click Here. “The numerous studies summarized in the paper published in Nature Reviews Nephrology reinforce the importance of addressing kidney accumulation of cholesterol and lipids to help attenuate progression of chronic kidney disease, which affects over 35 million adults in the United States,” commented Stephen C. Glover, ZyVersa’s Co-founder, Chairman, CEO, and President. “Currently, over 130,000 patients with kidney disease progress to renal failure each year, and more than 800,000 patients are living with renal failure requiring dialysis or transplant to sustain life. We are hopeful that protection against kidney injury, fibrosis, and disease progression seen with VAR 200 in animal models of diabetic kidney disease, FSGS, and Alport Syndrome will translate to humans. Our first clinical trial with VAR 200 in patients with diabetic kidney disease is planned to begin in early 2024.” To review a white paper summarizing the preclinical research with VAR 200, Click Here. About Cholesterol Efflux Mediator™ VAR 200 Cholesterol Efflux Mediator™ VAR 200 (2-hydroxypropyl-beta-cyclodextrin, 2HPβCD) is a phase 2a-ready drug in development to ameliorate renal lipid accumulation that damages the kidneys’ filtration system, leading to kidney disease progression. VAR 200 passively and actively removes excess lipids from the kidney. Preclinical studies with VAR 200 in animal models of FSGS, Alport syndrome, and diabetic kidney disease demonstrate that removal of excess cholesterol and lipids from kidney podocytes protects against structural damage and reduces excretion of protein in the urine (proteinuria). The lead indication for VAR 200 is orphan kidney disease focal segmental glomerulosclerosis (FSGS). VAR 200 has potential to treat other glomerular diseases, including orphan Alport syndrome and diabetic kidney disease. About ZyVersa Therapeutics, Inc. ZyVersa (Nasdaq: ZVSA) is a clinical stage specialty biopharmaceutical company leveraging advanced, proprietary technologies to develop first-in-class drugs for patients with renal and inflammatory diseases who have significant unmet medical needs. The Company is currently advancing a therapeutic development pipeline with multiple programs built around its two proprietary technologies – Cholesterol Efflux Mediator™ VAR 200 for treatment of kidney diseases, and Inflammasome ASC Inhibitor IC 100, targeting damaging inflammation associated with numerous CNS and other inflammatory diseases. For more information, please visit www.zyversa.com. Cautionary Statement Regarding Forward-Looking Statements Certain statements contained in this press release regarding matters that are not historical facts, are forward-looking statements within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended, and the Private Securities Litigation Reform Act of 1995. These include statements regarding management’s intentions, plans, beliefs, expectations, or forecasts for the future, and, therefore, you are cautioned not to place undue reliance on them. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. ZyVersa Therapeutics, Inc (“ZyVersa”) uses words such as “anticipates,” “believes,” “plans,” “expects,” “projects,” “future,” “intends,” “may,” “will,” “should,” “could,” “estimates,” “predicts,” “potential,” “continue,” “guidance,” and similar expressions to identify these forward-looking statements that are intended to be covered by the safe-harbor provisions. Such forward-looking statements are based on ZyVersa’s expectations and involve risks and uncertainties; consequently, actual results may differ materially from those expressed or implied in the statements due to a number of factors, including ZyVersa’s plans to develop and commercialize its product candidates, the timing of initiation of ZyVersa’s planned preclinical and clinical trials; the timing of the availability of data from ZyVersa’s preclinical and clinical trials; the timing of any planned investigational new drug application or new drug application; ZyVersa’s plans to research, develop, and commercialize its current and future product candidates; the clinical utility, potential benefits and market acceptance of ZyVersa’s product candidates; ZyVersa’s commercialization, marketing and manufacturing capabilities and strategy; ZyVersa’s ability to protect its intellectual property position; and ZyVersa’s estimates regarding future revenue, expenses, capital requirements and need for additional financing. New factors emerge from time-to-time, and it is not possible for ZyVersa to predict all such factors, nor can ZyVersa assess the impact of each such factor on the business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in any forward-looking statements. Forward-looking statements included in this press release are based on information available to ZyVersa as of the date of this press release. ZyVersa disclaims any obligation to update such forward-looking statements to reflect events or circumstances after the date of this press release, except as required by applicable law. This press release does not constitute an offer to sell, or the solicitation of an offer to buy, any securities. Corporate and IR Contact:Karen CashmereChief Commercial Officerkcashmere@zyversa.com786-251-9641 Media ContactsTiberend Strategic Advisors, Inc.Casey McDonaldcmcdonald@tiberend.com646-577-8520 Dave Schemeliadschemelia@tiberend.com609-468-9325