Hsp27

来自弗吉尼亚联邦大学等机构的科学家们通过研究发现了一种此前未知的蛋白质之间的相互作用，这种相互作用负责向肿瘤细胞提供能量，对于未来结肠癌疗法的开发具有非常重要的意义。 鞘脂（sphingolipids）在膜结构和细胞信号转导中发挥着关键作用，神经酰胺（ceramide）是鞘脂代谢的中心分子，在新生途径中能被神经酰胺合酶（CerS，ceramide synthases）所产生。近日，一篇发表在国际杂志Cell Reports上题为“The heat shock protein Hsp27 controls mitochondrial function by modulating ceramide generation”的研究报告中，来自弗吉尼亚联邦大学等机构的科学家们通过研究发现了一种此前未知的蛋白质之间的相互作用，这种相互作用负责向肿瘤细胞提供能量，对于未来结肠癌疗法的开发具有非常重要的意义。 研究者Can Senkal博士说道，这项研究令人非常兴奋，因为我们可以利用这些研究发现来帮助开发一种全新的癌症药物；潜在的答案或许就在于一类称之为神经酰胺的脂质化合物中，神经酰胺调节者多种重要的细胞功能，而且很多癌症药物都会刺激神经酰胺的产生从而帮助抵御疾病，当神经酰胺的产生被切断时，癌细胞就能更有效地存活并生长。研究者Senkal等人开始在实验室中广泛筛选细胞来识别哪些蛋白质能与产生神经酰胺的蛋白质有规律地发生相互作用从而确定可能值得进一步研究的潜在模式。 神经酰胺合酶是一种负责产生神经酰胺的酶类，其有6种不同的形式，即神经酰胺合酶1-6。首先研究人员观察到了第一种形式：神经酰胺合酶1（CerS1），其会与一种称之为热激蛋白27（Hsp27）的特定蛋白高度相互作用，热休克蛋白就好像其它蛋白的伴侣一样，能保持其全部功能，然而其过多的话就会导致天平失去平衡，从而就会阻断神经酰胺合酶发挥其正常功能。研究人员注意道，Hsp27的活性在很多结肠癌细胞中都较高，而与此同时CerS1的活性则明显较低，这或许就促使研究人员考虑是否其中一种的缺失与另一种的存在有关；研究者表示，这是一种阴阳关联，当然也给了我们遵循其的想法，Hsp27就好像一个坏人，其会阻碍名为CerS1的好人。 阻断特定蛋白的功能或能有效抑制结肠肿瘤的进展。 图片来源：Cell Reports (2023). DOI:10.1016/j.celrep.2023.113081 研究人员还识别出了Hsp27与结肠癌细胞中CerS1相互作用并抑制其功能的特定生物学机制，通过刻意地阻断这些细胞中Hsp27的活性，研究人员证实，Hsp27的减少会导致CerS1的再激活升高，从而就会驱动细胞中线粒体功能的降低。研究者Senkal说道，癌细胞依赖线粒体来获取繁殖的能量，如果没有线粒体的话，癌细胞就不再会维持其生存所需要的能量，随后就会死亡。通过阻断这些热激蛋白的功能，研究人员就能基本上重新激活细胞之手，从而拔掉与癌症相关的电源插头。 研究者认为，Hsp27或许是开发新型结肠癌疗法的主要靶点，研究者真的可以在不接触其它酶类的情况下，就能追踪这些蛋白质之间的相互作用从而精确地激活某些酶类。尽管这项研究在人类结肠癌研究中展现出了令人鼓舞的研究结果，但研究人员希望能将这项研究的范围扩大到已经观察到的Hsp27过表达的实体肿瘤中，包括肺癌、胰腺癌和前列腺癌。Senkal说道，我们希望在其它肿瘤中也能阐明这种关联，这或许就能更好地代表研究人员所纳入的患者群体。 综上，本文研究中，研究人员通过研究与Hsp27的蛋白-蛋白相互作用识别出了CerS1调节和CerS1所介导的有丝分裂的重要模式。（生物谷Bioon.com） 原始出处： Rowan A. Boyd，Saurav Majumder，Johnny Stiban, et al. The heat shock protein Hsp27 controls mitochondrial function by modulating ceramide generation, Cell Reports (2023). DOI:10.1016/j.celrep.2023.113081

Scientists discovered a previously unknown interaction between proteins that is responsible for supplying energy to tumor cells and could hold significant implications for the development of future treatments for colon cancer. Through study findings published Friday in Cell Reports, a team of scientists at VCU Massey Cancer Center discovered a previously unknown interaction between proteins that is responsible for supplying energy to tumor cells and could hold significant implications for the development of future treatments for colon cancer. "This study is really exciting because we may be able to use these findings to inform the development of an entirely new cancer drug right here at Massey," said study author Can Senkal, Ph.D., a member of the Cancer Biology research program at Massey and an assistant professor in the Department of Biochemistry and Molecular Biology at the VCU School of Medicine. The potential answer lies within a class of fatty compounds known as ceramides. Ceramides regulate a number of vital cellular functions, and many cancer drugs stimulate ceramide generation to help fend off disease. When that production of ceramide is cut off, cancer cells can survive and grow more efficiently. Senkal and his team began extensively screening cells in the lab to identify what proteins regularly interact with ceramide-producing proteins to identify potential patterns that could warrant further investigation. Ceramide synthases -- the enzymes responsible for the generation of ceramide -- come in a variety pack of six different flavors: Ceramide synthase 1-6. Through their research, Senkal's team observed that the first flavor, ceramide synthase 1 (CerS1), was highly interactive with a particular protein known as heat shock protein 27 (Hsp27). Heat shock proteins act like chaperones for other proteins to retain their full function; however, an overabundance of them can tip the scales and prevent ceramide synthases from doing their job. The researchers also noticed that Hsp27 activity was higher in many colon cancer cells while at the same time CerS1 activity was significantly lower, prompting Senkal and his team to consider if the absence of one was connected to the presence of the other. "There is this yin-yang kind of relationship, which gave us the idea to follow it," Senkal said. "Hsp27 is like the bad guy holding back the good guy, CerS1." Through the study, they identified a specific biological mechanism through which Hsp27 interacted with and inhibited the function of CerS1 in colon cancer cells. By deliberately blocking the activity of Hsp27 in these cells, the researchers confirmed the decreased presence of Hsp27 led to a heightened reactivation of CerS1, which in turn forced a reduction in mitochondrial function. "Cancer cells rely on mitochondria to have the energy to multiply. Without it, the cancer cells can no longer sustain the amount of energy they need and die," Senkal said. By blocking the function of these heat shock proteins, they were essentially able to reactivate the cellular hand that could pull the plug on the power source connected to the cancer, Senkal said. This revelation led the study authors to suggest that Hsp27 could be a primary target in the creation of novel therapies for colon cancer. "We can really go after these protein-protein interactions and precisely reactivate certain enzymes while we don't touch others," Senkal said. These findings are the result of a decade's worth of research by Senkal and his team, in an area which he noted isn't really being explored by anyone else. Senkal knows this won't be an overnight achievement, but hopes to collaborate with other scientists at Massey in a long-term effort to apply these findings to in-house novel drug development at the cancer center. Although this study showed encouraging results in colon cancer, they hope to broaden the scope of this research to additional solid tumors in which the overexpression of Hsp27 has been observed, including lung, pancreatic and prostate cancers. "We hope to demonstrate this connection in other tumors as well, which might better represent the patient population in Massey's catchment area," Senkal said. Massey was recently designated by the National Cancer Institute as a Comprehensive Cancer Center, the highest recognition available that reflects a center's scientific leadership, depth and breadth of research, effective community outreach and cancer research training and education. Collaborators on this study include Rowan Boyd, Sachin Kempelingaiah, Saurav Majumder, Ph.D., Grace Mavodza, Ph.D., Johnny Stiban, Ph.D. and Alexandra Straus of the VCU School of Medicine; and Yusuf Hannun, M.D., Lina Obeid, M.D., and Varun Reddy of Stony Brook University.

恒温生物对环境温度升高极度敏感。体温过高，体温调节无法保持机体恒温，则会损害各种器官的正常功能，甚至诱发多器官功能不全。如发生误诊漏诊、及对其严重程度估计不足、治疗方案实施不正确等情况，最终可能导致患者死亡。由热应激引起的疾病，俗称中暑，其中重度中暑尤为凶险，称为热射病。热射病病理生理热射病的病理生理学机制庞大而复杂，近年来，“双通道机制”被多数学者逐渐认同。第一通道即热暴露使核心温度升高造成的直接对各器官系统的损害 ；第二通道则是热暴露引起的热应激、内毒素血症，引起的全身炎性反应综合征 (SIRS)，免疫功能紊乱，这种病理过程被定义为热射病“类脓毒症反应”，造成患者多器官功能障碍，如不及时有效治疗，病死率可高达 60% 以上。目前认为热射病就是源于热暴露导致的直接细胞损害和全身炎症反应之间的复杂的相互作用，进而导致脏器损害或多器官功能障碍综合征（MODS）。（热射病急诊诊断与治疗专家共识）热应激激活免疫系统先天免疫和适应性免疫的不同组成部分均可能受到热应激的影响。热应激激活下丘脑-垂体-肾上腺（HPA）和交感神经-肾上腺-髓质（SAM）轴，以调节对应激源的反应，从而引发免疫反应的变化。Antibiotics 20211. 热休克蛋白热休克蛋白（HSP）构成热休克反应，作为应激刺激响应细胞功能障碍的信号。几种HSP的表达与热应激之间的关联，解释了这些蛋白质对细胞损伤的保护功能。热应激和氧化应激对蛋白质折叠有负面影响，改变其特定的生物学功能。热休克反应诱导HSP的表达，这有助于防止或逆转蛋白质错误折叠，并为正确折叠提供环境。热休克蛋白根据其分子量分为不同的家族，其中HSP90、HSP70和HSP27研究最多。热休克蛋白能够诱导免疫细胞(单核细胞、巨噬细胞和树突状细胞)NF-κB通路活化，释放促炎细胞因子(如TNF-α、IL-1β、IL-6和IL-12）。2. Toll样受体Toll样受体（TLRs）存在于动植物细胞中，通常在免疫细胞（例如巨噬细胞、中性粒细胞、树突状细胞和自然杀伤细胞）和非免疫细胞的细胞表面（TLR1-2、TLR4-6和TLR10-13）或内体（TLR3和TLR7-9）中表达。Toll样受体与对入侵微生物的先天防御有关，因为TLR可识别源自微生物的结构保守分子，例如细菌脂多糖（LPS）。此外，TLR通路响应于肠上皮中内源性HSP或染色质相关蛋白高迁移率组Box 1的结合而被激活。TLR途径的激活最终导致协调炎症反应和其他事件的基因上调或抑制。在热应激条件下，微生物内毒素可能进入肠道粘膜并激活TLR途径，触发细胞因子(TNF-α、IL-1β、IL-6和IL-12）的释放和促炎反应。3. 活性氧氧化还原稳态是生物体适应和控制氧化剂和抗氧化剂之间不平衡的能力。氧化剂有许多来源，例如线粒体、黄嘌呤氧化酶或其它氧化酶和过氧化物酶。一般来说，有利于氧化剂的不平衡，会导致氧化还原信号传导和控制的破坏，并最终可能导致分子和细胞功能障碍或损伤。活性氧（ROS）和细胞抗氧化防御系统之间的不平衡可能是急性热暴露导致氧化应激的主要后果之一。NO、O2和H2O2过度积累是由于细胞更新过程中细胞呼吸和嘌呤代谢的生化功能障碍，以及内脏组织向外周血液循环转移引起的肠缺氧引起的一氧化氮合酶活性。一项针对肠上皮细胞的体外研究表明，暴露于42◦C60分钟，会增加ROS浓度和线粒体功能障碍以及早期凋亡率。除了增加ROS产生外，热应激还会降低啮齿动物肠道组织中的抗氧化酶活性。补充硒和维生素E可缓解热应激猪的氧化应激。由于循环系统适应，热应激似乎会促进ROS的产生，但通过细胞代谢、分裂和免疫功能相关机制过度产生ROS可能会导致氧化态失衡，导致氧化应激和细胞损伤。后记热射病及其凶险，有相关症状要及时就医。中医药是祖先留给我们的宝贵财富，是中华民族的瑰宝，在热射病防治过程中，起到了不可或缺的重要作用。日常生活中常见的菊花、金银花、荷叶、薄荷、藿香和广藿香等都具有清热解暑的功效，不仅可以在一定程度上预防重症中暑的发生，也可以在发病的第一时间起到良好的治疗效果。中成药醒脑静注射液、痰热清注射液、安宫牛黄丸、复方麝香注射液等药具有清热解毒、祛风解痉、镇静醒神之效 ；现代药理学证实中药具有抗内毒素血症、抗氧化、清楚自由基、缓解感染危象、缩短高热时间、抑制脑损伤、降低器官衰竭等作用（热射病急诊诊断与治疗专家共识）。文章以科普为主目的，不构成任何医疗建议，有相关症状，请及时就医。参考资料全军热射病防治专家组  热射病急诊诊断与治疗专家共识组，热射病急诊诊断与治疗专家共识（2021版），中华急诊医学杂志 2021 年 11 月第 30 卷第 11 期 Chin J Emerg Med, November 2021, Vol. 30, No. 11Cantet, J.M.; Yu, Z.; Ríus, A.G. Heat Stress-Mediated Activation of Immune–Inflammatory Pathways. Antibiotics 2021, 10, 1285. https://doi-org.libproxy1.nus.edu.sg/10.3390/antibiotics10111285He, S.; Yu, Q.; He, Y.; Hu, R.; Xia, S.; He, J. Dietary resveratrol supplementation inhibits heat stress-induced high-activated innate immunity and inflammatory response in spleen of yellow-feather broilers. Poult. Sci. 2019, 98, 6378–6387. Bouchama A, Abuyassin B, Lehe C, et al. Classic and exertional heatstroke. Nat Rev DisPrimers.2022;8:8.·········点亮在看，传递信息♥