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Early life adversities, psychopathologies and novel pharmacological strategies 早年的生活逆境、精神病理学和新型药理学策略。
IF 12 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-07-03 DOI: 10.1016/j.pharmthera.2024.108686
Annamaria Cattaneo , Veronica Begni , Valentina Zonca , Marco A. Riva

Exposure to adversities during early life stages (early life adversities - ELA), ranging from pregnancy to adolescence, represents a major risk factor for the vulnerability to mental disorders. Hence, it is important to understand the molecular and functional underpinning of such relationship, in order to develop strategies aimed at reducing the psychopathologic burden associated with ELA, which may eventually lead to a significant improvement in clinical practice. In this review, we will initially recapitulate clinical and preclinical evidence supporting the link between ELA and psychopathology and we will primarily discuss the main biological mechanisms that have been described as potential mediators of the effects of ELA on the psychopathologic risk, including the role for genetic factors as well as sex differences. The knowledge emerging from these studies may be instrumental for the development of novel therapeutic strategies aimed not only at correcting the deficits that emerge from ELA exposure, but also in preventing the manifestation of a full-blown psychopathologic condition. With this respect, we will specifically focus on adolescence as a key time frame for disease onset as well as for early therapeutic intervention. We believe that incorporating clinical and preclinical research data in the context of early life adversities can be instrumental to elucidate the mechanisms contributing to the risk for psychopathology or that may promote resilience. This will ultimately allow the identification of ‘at risk’ individuals who may benefit from specific forms of interventions that, by interfering with disease trajectories, could result in more benign clinical outcomes.

从怀孕到青春期的生命早期阶段(生命早期逆境--ELA)所遭遇的逆境是易患精神疾病的主要风险因素。因此,了解这种关系的分子和功能基础非常重要,这样才能制定出旨在减轻与 ELA 相关的精神病理负担的策略,从而最终显著改善临床实践。在本综述中,我们将首先回顾支持 ELA 与精神病理学之间联系的临床和临床前证据,并将主要讨论作为 ELA 对精神病理学风险影响的潜在介导因素的主要生物机制,包括遗传因素和性别差异的作用。从这些研究中获得的知识可能有助于开发新的治疗策略,其目的不仅在于纠正因暴露于 ELA 而出现的缺陷,而且还在于防止出现全面的精神病理状况。在这方面,我们将特别关注青少年时期,将其视为发病和早期治疗干预的关键时期。我们相信,将临床和临床前研究数据与早期生活逆境相结合,有助于阐明导致精神病理学风险或可能促进复原力的机制。这最终将有助于识别 "高危 "人群,他们可能会从特定形式的干预措施中获益,而这些干预措施通过干预疾病轨迹,可能会产生更加良性的临床结果。
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引用次数: 0
Spotlight on plasticity-related genes: Current insights in health and disease 聚焦可塑性相关基因:当前对健康和疾病的见解。
IF 12 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-07-03 DOI: 10.1016/j.pharmthera.2024.108687
Nicola Brandt , Franziska Köper , Jens Hausmann , Anja U. Bräuer

The development of the central nervous system is highly complex, involving numerous developmental processes that must take place with high spatial and temporal precision. This requires a series of complex and well-coordinated molecular processes that are tighly controlled and regulated by, for example, a variety of proteins and lipids. Deregulations in these processes, including genetic mutations, can lead to the most severe maldevelopments. The present review provides an overview of the protein family Plasticity-related genes (PRG1–5), including their role during neuronal differentiation, their molecular interactions, and their participation in various diseases. As these proteins can modulate the function of bioactive lipids, they are able to influence various cellular processes. Furthermore, they are dynamically regulated during development, thus playing an important role in the development and function of synapses. First studies, conducted not only in mouse experiments but also in humans, revealed that mutations or dysregulations of these proteins lead to changes in lipid metabolism, resulting in severe neurological deficits. In recent years, as more and more studies have shown their involvement in a broad range of diseases, the complexity and broad spectrum of known and as yet unknown interactions between PRGs, lipids, and proteins make them a promising and interesting group of potential novel therapeutic targets.

中枢神经系统的发育非常复杂,涉及众多发育过程,这些过程必须在空间和时间上高度精确。这需要一系列复杂而协调的分子过程,这些过程受到各种蛋白质和脂质等的严格控制和调节。这些过程的失调,包括基因突变,可导致最严重的发育不良。本综述概述了可塑性相关基因(PRG1-5)蛋白家族,包括它们在神经元分化过程中的作用、分子相互作用以及在各种疾病中的参与。由于这些蛋白可以调节生物活性脂质的功能,因此它们能够影响各种细胞过程。此外,它们在发育过程中受到动态调节,因此在突触的发育和功能中发挥着重要作用。不仅在小鼠实验中,而且在人类身上进行的首次研究显示,这些蛋白质的突变或失调会导致脂质代谢的变化,从而导致严重的神经功能缺陷。近年来,越来越多的研究表明,PRGs 参与了多种疾病的治疗,PRGs、脂质和蛋白质之间已知和未知相互作用的复杂性和广泛性使它们成为一组有希望的、有趣的潜在新型治疗靶点。
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引用次数: 0
HDL-based therapeutics: A promising frontier in combating viral and bacterial infections 基于高密度脂蛋白的疗法:抗击病毒和细菌感染的前景广阔。
IF 12 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-07-02 DOI: 10.1016/j.pharmthera.2024.108684
Alankrita Rani , Julia T. Stadler , Gunther Marsche

Low levels of high-density lipoprotein (HDL) and impaired HDL functionality have been consistently associated with increased susceptibility to infection and its serious consequences. This has been attributed to the critical role of HDL in maintaining cellular lipid homeostasis, which is essential for the proper functioning of immune and structural cells. HDL, a multifunctional particle, exerts pleiotropic effects in host defense against pathogens. It functions as a natural nanoparticle, capable of sequestering and neutralizing potentially harmful substances like bacterial lipopolysaccharides. HDL possesses antiviral activity, preventing viruses from entering or fusing with host cells, thereby halting their replication cycle. Understanding the complex relationship between HDL and the immune system may reveal innovative targets for developing new treatments to combat infectious diseases and improve patient outcomes. This review aims to emphasize the role of HDL in influencing the course of bacterial and viral infections and its and its therapeutic potential.

高密度脂蛋白(HDL)水平低和功能受损一直与感染及其严重后果的易感性增加有关。这归因于高密度脂蛋白在维持细胞脂质平衡方面的关键作用,而细胞脂质平衡对免疫细胞和结构细胞的正常运作至关重要。高密度脂蛋白是一种多功能微粒,在宿主抵御病原体的过程中发挥多种效应。它具有天然纳米颗粒的功能,能够封存和中和潜在的有害物质,如细菌脂多糖。高密度脂蛋白具有抗病毒活性,能阻止病毒进入宿主细胞或与宿主细胞融合,从而停止病毒的复制周期。了解高密度脂蛋白与免疫系统之间的复杂关系可为开发抗击传染病和改善患者预后的新疗法提供创新目标。本综述旨在强调高密度脂蛋白在影响细菌和病毒感染过程中的作用及其治疗潜力。
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引用次数: 0
Ion channel dysregulation and cellular adaptations to alpha-synuclein in stressful pacemakers of the parkinsonian brainstem 帕金森脑干应激性起搏器中的离子通道失调和细胞对α-突触核蛋白的适应。
IF 12 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-06-29 DOI: 10.1016/j.pharmthera.2024.108683
Wei-Hua Chiu , Nadine Wattad , Joshua A. Goldberg

Parkinson's disease (PD) is diagnosed by its cardinal motor symptoms that are associated with the loss of dopamine neurons in the substantia nigra pars compacta (SNc). However, PD patients suffer from various non-motor symptoms years before diagnosis. These prodromal symptoms are thought to be associated with the appearance of Lewy body pathologies (LBP) in brainstem regions such as the dorsal motor nucleus of the vagus (DMV), the locus coeruleus (LC) and others. The neurons in these regions that are vulnerable to LBP are all slow autonomous pacemaker neurons that exhibit elevated oxidative stress due to their perpetual influx of Ca2+ ions. Aggregation of toxic α-Synuclein (aSyn) – the main constituent of LBP – during the long prodromal period challenges these vulnerable neurons, presumably altering their biophysics and physiology. In contrast to pathophysiology of late stage parkinsonism which is well-documented, little is known about the pathophysiology of the brainstem during prodromal PD.

In this review, we discuss ion channel dysregulation associated with aSyn aggregation in brainstem pacemaker neurons and their cellular responses to them. While toxic aSyn elevates oxidative stress in SNc and LC pacemaker neurons and exacerbates their phenotype, DMV neurons mount an adaptive response that mitigates the oxidative stress. Ion channel dysregulation and cellular adaptations may be the drivers of the prodromal symptoms of PD. For example, selective targeting of toxic aSyn to DMV pacemakers, elevates the surface density of K+ channels, which slows their firing rate, resulting in reduced parasympathetic tone to the gastrointestinal tract, which resembles the prodromal PD symptoms of dysphagia and constipation. The divergent responses of SNc & LC vs. DMV pacemaker neurons may explain why the latter outlive the former despite presenting LBPs earlier. Elucidation the brainstem pathophysiology of prodromal PD could pave the way for physiological biomarkers, earlier diagnosis and novel neuroprotective therapies for PD.

帕金森病(Parkinson's disease,PD)的诊断依据是其主要的运动症状,而这些症状与黑质髓鞘(substantia nigra pars compacta,SNc)中多巴胺神经元的缺失有关。然而,帕金森病患者在确诊前数年会出现各种非运动症状。这些前驱症状被认为与路易体病变(LBP)在迷走神经背运动核(DMV)、脑小叶位置(LC)等脑干区域的出现有关。这些区域中易受枸杞多糖影响的神经元都是自主起搏的慢速神经元,它们会因持续流入 Ca2+ 离子而表现出氧化应激升高。枸杞多糖的主要成分--有毒的α-突触核蛋白(aSyn)在漫长的前驱期聚集,对这些脆弱的神经元构成挑战,可能会改变它们的生物物理学和生理学。帕金森病晚期的病理生理学已得到充分证实,但与之形成鲜明对比的是,人们对帕金森病前驱期脑干的病理生理学知之甚少。在本综述中,我们将讨论脑干起搏神经元中与 aSyn 聚集相关的离子通道失调及其细胞反应。毒性 aSyn 会增加 SNc 和 LC 起搏器神经元的氧化应激并加重其表型,而 DMV 神经元则会做出适应性反应,减轻氧化应激。离子通道失调和细胞适应可能是导致帕金森病前驱症状的驱动因素。例如,选择性地将毒性 aSyn 靶向 DMV 起搏器会提高 K+ 通道的表面密度,从而减慢其发射率,导致胃肠道副交感神经张力降低,这与吞咽困难和便秘等帕金森病前驱症状相似。SNc和LC起搏神经元与DMV起搏神经元的反应不同,这可能解释了为什么后者的寿命长于前者,而前者却更早出现枸杞多糖症。阐明前驱型帕金森病的脑干病理生理学可为帕金森病的生理生物标志物、早期诊断和新型神经保护疗法铺平道路。
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引用次数: 0
Matrikines in the skin: Origin, effects, and therapeutic potential 皮肤中的母树碱:起源、作用和治疗潜力。
IF 12 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-06-23 DOI: 10.1016/j.pharmthera.2024.108682
Jonathan P. Sirois, Andrea Heinz

The extracellular matrix (ECM) represents a complex multi-component environment that has a decisive influence on the biomechanical properties of tissues and organs. Depending on the tissue, ECM components are subject to a homeostasis of synthesis and degradation, a subtle interplay that is influenced by external factors and the intrinsic aging process and is often disturbed in pathologies. Upon proteolytic cleavage of ECM proteins, small bioactive peptides termed matrikines can be formed. These bioactive peptides play a crucial role in cell signaling and contribute to the dynamic regulation of both physiological and pathological processes such as tissue remodeling and repair as well as inflammatory responses. In the skin, matrikines exert an influence for instance on cell adhesion, migration, and proliferation as well as vasodilation, angiogenesis and protein expression. Due to their manifold functions, matrikines represent promising leads for developing new therapeutic options for the treatment of skin diseases. This review article gives a comprehensive overview on matrikines in the skin, including their origin in the dermal ECM, their biological effects and therapeutic potential for the treatment of skin pathologies such as melanoma, chronic wounds and inflammatory skin diseases or for their use in anti-aging cosmeceuticals.

细胞外基质(ECM)是一种复杂的多成分环境,对组织和器官的生物力学特性具有决定性影响。根据组织的不同,ECM 成分的合成和降解处于平衡状态,这种微妙的相互作用受到外部因素和内在衰老过程的影响,并经常在病理情况下受到干扰。当 ECM 蛋白质被蛋白酶裂解时,就会形成小的生物活性肽,即 matrikines。这些生物活性肽在细胞信号传导中起着至关重要的作用,有助于动态调节生理和病理过程,如组织重塑和修复以及炎症反应。例如,在皮肤中,消旋肽对细胞粘附、迁移、增殖以及血管扩张、血管生成和蛋白质表达都有影响。由于它们具有多方面的功能,母树蛋白是开发治疗皮肤病新疗法的有前途的线索。这篇综述文章全面概述了皮肤中的母树蛋白,包括它们在真皮 ECM 中的起源、生物效应以及在治疗黑色素瘤、慢性伤口和炎症性皮肤病等皮肤疾病或用于抗衰老药妆方面的治疗潜力。
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引用次数: 0
Bioactive lipids in the skin barrier mediate its functionality in health and disease 皮肤屏障中的生物活性脂质介导着皮肤屏障在健康和疾病中的功能。
IF 12 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-06-17 DOI: 10.1016/j.pharmthera.2024.108681
Anna Nicolaou , Alexandra C. Kendall

Our skin protects us from external threats including ultraviolet radiation, pathogens and chemicals, and prevents excessive trans-epidermal water loss. These varied activities are reliant on a vast array of lipids, many of which are unique to skin, and that support physical, microbiological and immunological barriers. The cutaneous physical barrier is dependent on a specific lipid matrix that surrounds terminally-differentiated keratinocytes in the stratum corneum. Sebum- and keratinocyte-derived lipids cover the skin's surface and support and regulate the skin microbiota. Meanwhile, lipids signal between resident and infiltrating cutaneous immune cells, driving inflammation and its resolution in response to pathogens and other threats. Lipids of particular importance include ceramides, which are crucial for stratum corneum lipid matrix formation and therefore physical barrier functionality, fatty acids, which contribute to the acidic pH of the skin surface and regulate the microbiota, as well as the stratum corneum lipid matrix, and bioactive metabolites of these fatty acids, involved in cell signalling, inflammation, and numerous other cutaneous processes. These diverse and complex lipids maintain homeostasis in healthy skin, and are implicated in many cutaneous diseases, as well as unrelated systemic conditions with skin manifestations, and processes such as ageing. Lipids also contribute to the gut-skin axis, signalling between the two barrier sites. Therefore, skin lipids provide a valuable resource for exploration of healthy cutaneous processes, local and systemic disease development and progression, and accessible biomarker discovery for systemic disease, as well as an opportunity to fully understand the relationship between the host and the skin microbiota. Investigation of skin lipids could provide diagnostic and prognostic biomarkers, and help identify new targets for interventions. Development and improvement of existing in vitro and in silico approaches to explore the cutaneous lipidome, as well as advances in skin lipidomics technologies, will facilitate ongoing progress in skin lipid research.

我们的皮肤保护我们免受紫外线辐射、病原体和化学物质等外部威胁,并防止表皮水分过度流失。这些不同的活动依赖于大量的脂质,其中许多脂质是皮肤独有的,它们支撑着物理、微生物和免疫屏障。皮肤的物理屏障依赖于一种特殊的脂质基质,这种基质包围着角质层中终末分化的角质细胞。由皮脂和角质形成的脂质覆盖在皮肤表面,支持并调节皮肤微生物群。同时,脂质在常驻和浸润的皮肤免疫细胞之间发出信号,推动炎症的发生和消退,以应对病原体和其他威胁。特别重要的脂质包括神经酰胺(对角质层脂质基质的形成至关重要,因此对物理屏障功能也至关重要)、脂肪酸(有助于皮肤表面酸性 pH 值的形成,并调节微生物群和角质层脂质基质)以及这些脂肪酸的生物活性代谢产物(参与细胞信号、炎症和许多其他皮肤过程)。这些多样而复杂的脂质维持着健康皮肤的平衡,并与许多皮肤疾病、具有皮肤表现的无关系统疾病以及衰老等过程有关。脂质还有助于形成肠道-皮肤轴,在两个屏障之间传递信号。因此,皮肤脂质为探索健康的皮肤过程、局部和全身性疾病的发生和发展、发现全身性疾病的生物标志物提供了宝贵的资源,也为全面了解宿主与皮肤微生物群之间的关系提供了机会。对皮肤脂质的研究可提供诊断和预后生物标志物,并有助于确定新的干预目标。开发和改进现有的体外和硅学方法以探索皮肤脂质体,以及皮肤脂质组学技术的进步将促进皮肤脂质研究的不断进步。
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引用次数: 0
UFMylation: An integral post-translational modification for the regulation of proteostasis and cellular functions UFMylation:调节蛋白稳态和细胞功能不可或缺的翻译后修饰。
IF 12 1区 医学 Q1 Medicine Pub Date : 2024-06-13 DOI: 10.1016/j.pharmthera.2024.108680
Xiaohui Wang , Xiaowei Lv , Jingjing Ma , Guoqiang Xu

Ubiquitin-fold modifier 1 (UFM1) is covalently conjugated to protein substrates via a cascade of enzymatic reactions, a process known as UFMylation. UFMylation orchestrates an array of vital biological functions, including maintaining endoplasmic reticulum (ER) homeostasis, facilitating protein biogenesis, promoting cellular differentiation, regulating DNA damage response, and participating in cancer-associated signaling pathways. UFMylation has rapidly evolved into one of the forefront research areas within the last few years, yet much remains to be uncovered. In this review, first, UFMylation and its cellular functions associated with diseases are briefly introduced. Then, we summarize the proteomic approaches for identifying UFMylation substrates and explore the impact of UFMylation on gene transcription, protein translation, and maintenance of ER homeostasis. Next, we highlight the intricate regulation between UFMylation and two protein degradation pathways, the ubiquitin-proteasome system and the autophagy-lysosome pathway, and explore the potential of UFMylation system as a drug target. Finally, we discuss emerging perspectives in the UFMylation field. This review may provide valuable insights for drug discovery targeting the UFMylation system.

泛素折叠修饰因子 1(UBiquitin-fold modifier 1,UFM1)通过一系列酶促反应与蛋白质底物共价结合,这一过程被称为 UFMylation。UFMylation 协调一系列重要的生物功能,包括维持内质网(ER)平衡、促进蛋白质生物生成、促进细胞分化、调节 DNA 损伤反应以及参与癌症相关信号通路。在过去的几年中,超频分化已迅速发展成为最前沿的研究领域之一,但仍有许多问题有待揭示。在这篇综述中,首先简要介绍了 UFMylation 及其与疾病相关的细胞功能。然后,我们总结了鉴定 UFMylation 底物的蛋白质组学方法,并探讨了 UFMylation 对基因转录、蛋白质翻译和维持 ER 平衡的影响。接下来,我们强调了 UFMylation 与两种蛋白质降解途径(泛素-蛋白酶体系统和自噬-溶酶体途径)之间错综复杂的调控关系,并探讨了其作为药物靶点的潜力。最后,我们讨论了 UFMylation 领域的新观点。本综述可为针对 UFMylation 系统的药物发现提供有价值的见解。
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引用次数: 0
Mechanistic insights into medulloblastoma relapse 髓母细胞瘤复发的机理启示
IF 12 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-06-08 DOI: 10.1016/j.pharmthera.2024.108673
Kendell Peterson , Maria Turos-Cabal , April D. Salvador , Isabel Palomo-Caturla , Ashley J. Howell , Megan E. Vieira , Sean M. Greiner , Thibaut Barnoud , Jezabel Rodriguez-Blanco

Pediatric brain tumors are the leading cause of cancer-related deaths in children, with medulloblastoma (MB) being the most common type. A better understanding of these malignancies has led to their classification into four major molecular subgroups. This classification not only facilitates the stratification of clinical trials, but also the development of more effective therapies. Despite recent progress, approximately 30% of children diagnosed with MB experience tumor relapse. Recurrent disease in MB is often metastatic and responds poorly to current therapies. As a result, only a small subset of patients with recurrent MB survive beyond one year. Due to its dismal prognosis, novel therapeutic strategies aimed at preventing or managing recurrent disease are urgently needed. In this review, we summarize recent advances in our understanding of the molecular mechanisms behind treatment failure in MB, as well as those characterizing recurrent cases. We also propose avenues for how these findings can be used to better inform personalized medicine approaches for the treatment of newly diagnosed and recurrent MB. Lastly, we discuss the treatments currently being evaluated for MB patients, with special emphasis on those targeting MB by subgroup at diagnosis and relapse.

小儿脑肿瘤是儿童癌症相关死亡的主要原因,其中髓母细胞瘤(MB)是最常见的类型。随着对这些恶性肿瘤的深入了解,人们将其分为四大分子亚组。这种分类不仅有助于临床试验的分层,还有助于开发更有效的疗法。尽管取得了最新进展,但约有 30% 的确诊为 MB 的儿童会出现肿瘤复发。MB 复发疾病通常是转移性的,对目前的疗法反应不佳。因此,只有一小部分复发的 MB 患者能存活一年以上。由于其预后不佳,迫切需要旨在预防或控制复发疾病的新型治疗策略。在这篇综述中,我们总结了最近在了解 MB 治疗失败背后的分子机制以及复发病例的分子机制方面取得的进展。我们还提出了如何利用这些发现更好地为治疗新诊断和复发性 MB 的个性化医学方法提供信息的途径。最后,我们讨论了目前正在评估的针对 MB 患者的治疗方法,特别强调了针对 MB 诊断和复发亚组的治疗方法。
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引用次数: 0
Mithramycin and its analogs: Molecular features and antitumor action 米曲霉毒素及其类似物:分子特征和抗肿瘤作用
IF 13.5 1区 医学 Q1 Medicine Pub Date : 2024-06-03 DOI: 10.1016/j.pharmthera.2024.108672
José Portugal

The antitumor antibiotic mithramycin A (MTA) binds to G/C-rich DNA sequences in the presence of dications. MTA inhibits transcription regulated by the Sp1 transcription factor, often enhanced during tumor development. It shows antitumor activity, but its clinical use was discontinued due to toxic side effects. However, recent observations have led to its use being reconsidered. The MTA biosynthetic pathways have been modified to produce mithramycin analogs (mithralogs) that encompass lower toxicity and improved pharmacological activity. Some mithralogs reduce gene expression in human ovarian and prostate tumors, among other types of cancer. They down-regulate gene expression in various cellular processes, including Sp1-responsive genes that control tumor development. Moreover, MTA and several mithralogs, such as EC-8042 (DIG-MSK) and EC-8105, effectively treat Ewing sarcoma by inhibiting transcription controlled by the oncogenic EWS-FLI1 transcription factor.

抗肿瘤抗生素米曲霉素 A(MTA)能在双阳离子存在的情况下与富含 G/C 的 DNA 序列结合。MTA 可抑制受 Sp1 转录因子调控的转录,而 Sp1 转录因子在肿瘤发展过程中往往会增强。它具有抗肿瘤活性,但由于其毒副作用而停止了临床应用。不过,最近的观察结果促使人们重新考虑其使用。人们对 MTA 的生物合成途径进行了改造,生产出了毒性更低、药理活性更强的米曲霉素类似物(mithralogs)。一些米曲霉素类似物可降低人类卵巢和前列腺肿瘤以及其他类型癌症的基因表达。它们能下调各种细胞过程中的基因表达,包括控制肿瘤发生的 Sp1 反应基因。此外,MTA 和几种 mithralogs,如 EC-8042 (DIG-MSK) 和 EC-8105,通过抑制由致癌 EWS-FLI1 转录因子控制的转录,有效治疗尤文肉瘤。
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引用次数: 0
Recent advances in the reciprocal regulation of m6A modification with non-coding RNAs and its therapeutic application in acute myeloid leukemia m6A 修饰与非编码 RNA 相互调控的最新进展及其在急性髓性白血病中的治疗应用。
IF 13.5 1区 医学 Q1 Medicine Pub Date : 2024-06-01 DOI: 10.1016/j.pharmthera.2024.108671
Jiawang Yang , Feng Liang , Fenglin Zhang , Hailong Zhao , Qihai Gong , Ning Gao

N6-methyladenosine (m6A) is one of the most common modifications of RNA in eukaryotic cells and is involved in mRNA metabolism, including stability, translation, maturation, splicing, and export. m6A also participates in the modification of multiple types of non-coding RNAs, such as microRNAs, long non-coding RNAs, and circular RNAs, thereby affecting their metabolism and functions. Increasing evidence has revealed that m6A regulators, such as writers, erasers, and readers, perform m6A-dependent modification of ncRNAs, thus affecting cancer progression. Moreover, ncRNAs modulate m6A regulators to affect cancer development and progression. In this review, we summarize recent advances in understanding m6A modification and ncRNAs and provide insights into the interaction between m6A modification and ncRNAs in cancer. We also discuss the potential clinical applications of the mechanisms underlying the interplay between m6A modifications and ncRNAs in acute myeloid leukemia (AML). Therefore, clarifying the mutual regulation between m6A modifications and ncRNAs is of great significance to identify novel therapeutic targets for AML and has great clinical application prospects.

N6-甲基腺苷(m6A)是真核细胞中最常见的 RNA 修饰之一,它参与了 mRNA 的代谢,包括稳定性、翻译、成熟、剪接和输出。m6A 还参与修饰多种类型的非编码 RNA,如 microRNA、长非编码 RNA 和环状 RNA,从而影响它们的代谢和功能。越来越多的证据表明,m6A 调节器(如书写器、擦除器和阅读器)对 ncRNA 进行依赖于 m6A 的修饰,从而影响癌症的进展。此外,ncRNA 还能调节 m6A 调节器,从而影响癌症的发生和发展。在这篇综述中,我们总结了了解 m6A 修饰和 ncRNA 的最新进展,并深入探讨了癌症中 m6A 修饰和 ncRNA 之间的相互作用。我们还讨论了急性髓性白血病(AML)中 m6A 修饰和 ncRNAs 相互作用的潜在临床应用机制。因此,厘清m6A修饰与ncRNA之间的相互调控关系对于发现急性髓性白血病的新型治疗靶点具有重要意义,并具有广阔的临床应用前景。
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引用次数: 0
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Pharmacology & Therapeutics
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