LPO

本文为转化医学网原创，转载请注明出处 作者：Rainbow 导读： 胶质瘤是一种侵袭性的脑肿瘤，占据中枢神经系统恶性肿瘤的80％。 12月4日，中国医科大学附属盛京医院刘静团队在期刊《Cell Death & Disease》上在线发表题为“HECW1 induces NCOA4-regulated ferroptosis in glioma through the ubiquitination and degradation of ZNF350”的研究论文， 本研究首次揭示了HECW1和ZNF350对胶质瘤的影响及它们在评估患者预后方面的潜在价值。研究人员探索并证明了HECW1/ZNF350/NCOA4通路在调节铁死亡中的作用和机制，并确定了胶质瘤治疗的新分子靶点。 https://www.nature.com/articles/s41419-023-06322-w 研究背景 01 胶质瘤的特点是其高度侵袭性和高死亡率。尽管手术干预和化放疗取得了重大进展，但胶质瘤患者的中位生存时间仍然很短，需要新的治疗策略来治疗胶质瘤。 铁死亡（ferroptosis）作为一种新型细胞死亡方式，已成为越来越受关注的研究课题。与其他细胞死亡机制不同，铁积累和活性氧（ROS）的产生，以及线粒体嵴的减少或消失是铁死亡的独特特征。核受体共激活因子4（NCOA4）与重链1的铁蛋白结合，并将其运输到溶酶体进行降解，从而能够在细胞中诱导铁死亡。越来越多的证据表明，铁死亡对肿瘤的生物过程具有复杂的调控作用。 泛素化（ubiquitination）是指真核生物中广泛存在的蛋白质后转录修饰，调控了许多生物过程。ATP、泛素活化酶(E1)、泛素连接酶(E2)和泛素连接酶(E3)对于蛋白质的泛素化和降解是不可或缺的。E3决定了泛素-底物结合的特异性，使其成为泛素化调控研究中的热门课题。含有HECT、C2和WW结构域的E3泛素蛋白连接酶1（HECW1）属于HECT家族，在脑肿瘤中首次被发现。 锌指蛋白350（ZNF350）是在对BRCA1（乳腺癌类型1易感蛋白）相关蛋白进行酵母双杂交分析时鉴定出的一个典型的含有KRAB结构域的锌指蛋白。ZNF350被确认为一个转录抑制因子，可以与其他蛋白形成复合物，或者以单因子形式发挥直接的转录抑制作用。因此，ZNF350在各种肿瘤的发展中起着重要作用。然而，ZNF350在胶质瘤中的潜在影响和机制尚未明确。 研究发现 02 在这项研究中，研究人员发现HECW1可以阻断胶质瘤细胞的进展，并增强铁积累和脂质过氧化（LPO），这是通过诱导NCOA4介导的铁死亡来实现的。通过筛选和验证，研究人员确认了ZNF350在HECW1对NCOA4的正调控中的介导作用。HECW1诱导的泛素化干扰了ZNF350的蛋白稳定性。ZNF350通过直接结合转录起始位点来抑制NCOA4的转录活性。在研究中，研究人员展示了HECW1/ZNF350/NCOA4通路在胶质瘤中对铁死亡的调控机制，这可能为胶质瘤治疗提供了一种新的策略。 HECW1通过诱导胶质瘤 细胞 铁 死亡发挥肿瘤抑制功能 03 为了揭示HECW1在癌症抑制中发挥作用的机制，研究人员使用不同的细胞死亡抑制剂处理了胶质瘤细胞。首先，研究人员通过Western Blot分析确定oeHECW1转染的细胞中HECW1的蛋白水平。HECW1的过表达显著降低了胶质瘤细胞的生长。这种效应被铁死亡抑制剂（Fer-1）所逆转。此外，HECW1的过表达明显增加了胶质瘤细胞的死亡，而这种效应在很大程度上被Fer-1处理所逆转。 在进一步的实验中，研究人员验证了HECW1的过表达显著提高了MDA、细胞内ROS（H2O2）和铁离子水平。接下来，研究人员揭示了HECW1沉默对铁死亡的影响。铁死亡诱导剂（erastin、RSL3）显著抑制了胶质瘤细胞的生长并加速了细胞死亡。然而，这种效应在HECW1沉默后很大程度上被抵消。三个铁死亡诱导剂也在HECW1沉默后显著降低。 结果表明，HECW1在胶质瘤细胞中引起铁积累、LPO和铁死亡。 研究结果 04 综上所述， 本研究首次揭示了HECW1和ZNF350对胶质瘤的影响及它们在评估患者预后方面的潜在价值。研究人员探索并证明了HECW1/ZNF350/NCOA4通路在调节铁死亡中的作用和机制，并确定了胶质瘤治疗的新分子靶点。 参考资料： https://www.nature.com/articles/s41419-023-06322-w 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 🕓 北京｜12月19日-20日 ▶第四届单细胞测序技术应用研讨会暨单细胞&空间组学研讨会（日程稍后公布） 点击对应文字 查看详情

肝癌是世界上第六大最常见的癌症，也是癌症相关死亡的第四大原因。其中，约90%为肝细胞癌。据估计，中国约占新诊断肝癌的55%，占肝癌相关死亡的45%。 肝癌是世界上第六大最常见的癌症，也是癌症相关死亡的第四大原因。其中，约90%为肝细胞癌。据估计，中国约占新诊断肝癌的55%，占肝癌相关死亡的45%。虽然治疗策略已有明显改善，但由于其恶性程度高，长期存活率仍然较低。 肝细胞癌常伴有肝硬变，其特征是必需蛋白质合成障碍。当确诊时，大多数患者已经处于相对较晚的阶段，肿瘤可能已经破坏了生理动态平衡。因此，肝细胞癌患者的营养状况通常较差，进而可能对预后产生不利影响。 图片来源：https://doi.org/10.1016/j.redox.2022.102538 近日，来自浙江省综合肿瘤学与智能医学重点实验室的研究者们在Redox Biology杂志上发表了题为“Multi-omics profiling reveals Chitinase-3-like protein 1 as a key mediator in the crosstalk between sarcopenia and liver cancer”的文章，该研究揭示了几丁质酶-3样蛋白1是少肌症和肝癌之间的关键介质。 少肌症在肝细胞癌患者中很普遍，并会对他们的预后产生不利影响。本研究旨在从多组学的角度探讨少肌症与肝细胞癌之间相互影响的关键机制。共有136例男性肝细胞癌患者入选。少肌症是肝移植后预后不良的独立危险因素。这些患者的炎性细胞因子和代谢组特征表明，血浆sTNF-R1/CHI3L1升高和脂代谢异常与肌萎缩症和肿瘤复发风险同时相关。 综合分析表明，CHI3L1与脂肪酸代谢密切相关。在小鼠腹腔注射H22细胞建立的恶病质模型中，萎缩的肌肉组织和循环中CHI3L1显著升高。在体外，CHI3L1在肌肉细胞中表达上调，通过肿瘤坏死因子-α/肿瘤坏死因子-R1信号通路保护自身免受炎性损伤。肌细胞分泌的CHI3L1促进共培养肝癌细胞的侵袭。 136名患者中73名患者的肿瘤组织转录组数据显示，CHI3L1可能调节脂肪酸代谢和氧化应激。在体外，CHI3L1可引起ROS和脂质堆积。靶向脂谱进一步证明CHI3L1能够激活花生四烯酸代谢，导致脂质过氧化(LPO)积累。同时，抑制LPO可拮抗CHI3L1显著的促癌作用。 机制总结图 图片来源：https://doi.org/10.1016/j.redox.2022.102538 综上所述，少肌症是影响肝细胞癌肝移植预后的独立危险因素。如示意图所示，CHI3L1是由骨骼肌上调和分泌的，通过肿瘤坏死因子-α/肿瘤坏死因子-R1信号保护肌肉细胞免受炎性损伤。反过来，CHI3L1通过促进脂质过氧化和脂肪酸氧化，有效地干扰脂质代谢，促进肝癌的进展。为了改善肝细胞癌患者的预后，综合治疗还应包括改善结节形成状况的新策略。（生物谷 Bioon.com） 参考文献 Di Lu et al. Multi-omics profiling reveals Chitinase-3-like protein 1 as a key mediator in the crosstalk between sarcopenia and liver cancer. Redox Biol. 2022 Dec;58:102538. doi: 10.1016/j.redox.2022.102538.

LOS ALTOS, Calif., Sept. 15, 2022 (GLOBE NEWSWIRE) -- BioJiva, a clinical-stage biopharmaceutical company focused on the development of novel, first-in-class therapies for degenerative diseases, today reported data from its completed multicenter, randomized, double-blind, placebo-controlled pilot Phase 2 clinical trial evaluating RT001, the company’s lead development candidate, in patients with amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease). The trial’s prespecified primary endpoint was change from baseline in the revised ALS Functional Rating Scale (ALSFRS-R) following 24 weeks of treatment. At 24 weeks, data demonstrated that patients treated with RT001 experienced less worsening (a 3.3-point reduction from baseline) in ALSFRS-R score as compared to greater worsening (4.6-point reduction from baseline) for the placebo group. Similarly, patients treated with RT001 experienced less worsening (a 13.3-point increase from baseline) in their score on the 40-item ALS assessment questionnaire (ALSAQ40) as compared to the placebo group (a 17.2-point increase from baseline). While suggesting a signal of directional improvement with RT001 treatment, these findings did not achieve statistical significance due to the small size of the study. This six-month randomized Phase 2 pilot study (NCT04762589), which was followed by a six-month open-label extension during which all patients received RT001, was conducted at four ALS Centers of Excellence in Europe. Investigators enrolled 43 patients with ALS who had symptom duration of less than three years. Enrolled patients had baseline ALSFRS-R scores ranging from 25 to 44, with a mean of 38.2 (+/-5.0.). Thirty-nine of the 43 enrolled subjects completed the initial 24-week randomized phase, with 32 of those also completing the open-label extension for a full year of treatment. At Week 24, patients receiving RT001 demonstrated a worsening from baseline in ALSFRS-R score of 3.3 points (from 38.2 to 34.9), as compared to a 4.6-point worsening from baseline for the placebo group (from 38.2 to 33.6). For patients who were enrolled with more severe disease (ALSFRS-R Data from the study’s 24-week open-label extension portion demonstrated that a signal of clinical benefit with RT001 treatment was also evident at 12 months. As no concurrent placebo was administered after 24 weeks, 12-month comparisons were made using data from the PRO ACT Database1, a validated and predictive historical control database of ALS progression. At 12 months, RT001-treated patients demonstrated a decrease in ALSFRS-R score of 7.2 +/- 6.7 points, whereas the PRO ACT Database shows an expected worsening on the ALSFRS score at 12 months of 10.1 points. For the study’s most severe patients that completed 12 months (ALSFRS-R “The promising signal of clinical benefit shown in this study with RT001 in a small group of ALS patients, combined with the continued demonstration of the well tolerated nature of the treatment, provides support for considering a larger clinical trial,” said Leonard H. van den Berg, M.D., Ph.D., professor of neurology at UMC Utrecht in the Netherlands, director of the Netherlands ALS Center, Chairman of TRICALS, an ALS clinical trial-focused European research initiative spanning 42 top research centers in 15 countries, and the principal investigator of the study. “Additionally, the study data suggest that patients with more severe ALS may have a higher likelihood of benefitting from RT001 treatment, which provides important context for considering the design and enrollment criteria for the next clinical trial.” “We conducted this trial with the dual goals of better understanding the manner in which RT001 may potentially impact the progression of ALS and detecting a signal of therapeutic benefit for patients receiving the treatment. While a small study that was not powered to demonstrate significance, we did see trends for RT001-treated patients compared to the placebo group that suggest the potential for RT001 to offer patients meaningful clinical benefit. The learnings from this study position us to continue development of RT001 for ALS, advancing next to a larger, statistically powered study focused on the more severe patient population that appears more likely to benefit from the treatment,” said Mark G. Midei, M.D., BioJiva’s vice president for medical affairs. About RT001 RT001 is a clinical stage isotopically stabilized, synthetic linoleic acid (LA) designed to combat the oxidative stress and cellular degeneration that arises from lipid peroxidation (LPO). While all healthy human tissues undergo this physiological process of cell degeneration and repair, it is well-established that a wide range of serious degenerative diseases are precipitated when the LPO process becomes out of balance. Polyunsaturated fatty acids (PUFAs), which make up cell and mitochondrial membranes throughout the body and are vital to healthy cellular function, are the target of the LPO process due to their inherent instability. Free radicals in the body exploit the instability of PUFAs to trigger chain reactions that drive LPO and the resulting breakdown of these vital PUFAs. Stabilized PUFAs, such as RT001, that become an integral part of all membranes are capable of down-regulating LPO to protect these membranes. About ALS Amyotrophic lateral sclerosis (ALS) is a rare, progressive neurodegenerative disease that primarily involves the nerve cells, or neurons, which are responsible for controlling voluntary muscle movements such as walking, talking and chewing. ALS and its related disorders are caused by the gradual degeneration of motor neurons, which are responsible for controlling communication between the brain and muscles responsible for voluntary movements. As these motor neurons deteriorate, communication between the brain and these muscles is impaired, leading to difficulty for patients in performing voluntary movements. As the disease progresses, voluntary muscle control becomes more difficult for patients, leading to an inability to breathe on their own and ultimately death. There is currently no cure for ALS and no effective treatment to halt, or reverse, the progression of the disease. About BioJiva BioJiva is a clinical-stage biopharmaceutical company focused on the development of first-in-class therapies for degenerative diseases ranging from orphan neurodegenerative indications to large market degenerative conditions. The company’s therapeutic pipeline consists of disease-modifying, isotopically stabilized synthetic versions of polyunsaturated fatty acids (PUFAs) that are designed to combat the oxidative stress and cellular degeneration by downregulation the lipid peroxidation (LPO) process. The company’s lead development candidate, RT001, is an isotopically stabilized, synthetic linoleic acid (LA) that is in clinical development for a range of orphan neurodegenerative diseases, including infantile neuroaxonal dystrophy (INAD), amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease) and progressive supranuclear palsy (PSP). In addition, the company is advancing its second development candidate, RT011, an isotopically stabilized, synthetic docosahexaenoic acid (DHA), toward the clinic for the treatment of dry age-related macular degeneration (AMD). BioJiva was founded in 2022 and is advancing the development assets formerly owned by Retrotope, which it purchased through a Delaware bankruptcy proceeding under Chapter 7. BioJiva is not a progression of Retrotope and BioJiva is not the former Retrotope. Several employees, advisors, and other service providers of Retrotope have joined BioJiva as part of the new company’s efforts to develop the previously Retrotope-owned assets.