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The therapeutic potential of targeting the CHD protein family in cancer 针对癌症中 CHD 蛋白家族的治疗潜力
IF 13.5 1区 医学 Q1 Medicine Pub Date : 2024-02-15 DOI: 10.1016/j.pharmthera.2024.108610
Min Zhang , Kaiyuan Wu , Weijie Zhang , Xia Lin , Qi Cao , Lili Zhang , Kaifu Chen

Accumulating evidence indicates that epigenetic events undergo deregulation in various cancer types, playing crucial roles in tumor development. Among the epigenetic factors involved in the epigenetic remodeling of chromatin, the chromodomain helicase DNA-binding protein (CHD) family frequently exhibits gain- or loss-of-function mutations in distinct cancer types. Therefore, targeting CHD remodelers holds the potential for antitumor treatment. In this review, we discuss epigenetic regulations of cancer development. We emphasize proteins in the CHD family, delving deeply into the intricate mechanisms governing their functions. Additionally, we provide an overview of current therapeutic strategies targeting CHD family members in preclinical trials. We further discuss the promising approaches that have demonstrated early signs of success in cancer treatment.

越来越多的证据表明,在各种癌症类型中,表观遗传事件会发生失调,在肿瘤发生发展过程中起着至关重要的作用。在参与染色质表观遗传重塑的表观遗传因子中,染色质链螺旋酶 DNA 结合蛋白(CHD)家族在不同癌症类型中经常出现功能增益或缺失突变。因此,靶向 CHD 重塑者具有抗肿瘤治疗的潜力。在这篇综述中,我们将讨论癌症发展的表观遗传调控。我们强调 CHD 家族中的蛋白质,深入探讨支配其功能的复杂机制。此外,我们还概述了目前临床前试验中针对 CHD 家族成员的治疗策略。我们还进一步讨论了在癌症治疗中已显示出早期成功迹象的有希望的方法。
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引用次数: 0
Protein-rich foods, sea foods, and gut microbiota amplify immune responses in chronic diseases and cancers – Targeting PERK as a novel therapeutic strategy for chronic inflammatory diseases, neurodegenerative disorders, and cancer 富含蛋白质的食物、海产品和肠道微生物群可增强慢性疾病和癌症的免疫反应 - 将 PERK 作为治疗慢性炎症性疾病、神经退行性疾病和癌症的新策略。
IF 13.5 1区 医学 Q1 Medicine Pub Date : 2024-02-13 DOI: 10.1016/j.pharmthera.2024.108604
Fatma Saaoud , Yifan Lu , Keman Xu , Ying Shao , Domenico Praticò , Roberto I. Vazquez-Padron , Hong Wang , Xiaofeng Yang

The endoplasmic reticulum (ER) is a cellular organelle that is physiologically responsible for protein folding, calcium homeostasis, and lipid biosynthesis. Pathological stimuli such as oxidative stress, ischemia, disruptions in calcium homeostasis, and increased production of normal and/or folding-defective proteins all contribute to the accumulation of misfolded proteins in the ER, causing ER stress. The adaptive response to ER stress is the activation of unfolded protein response (UPR), which affect a wide variety of cellular functions to maintain ER homeostasis or lead to apoptosis. Three different ER transmembrane sensors, including PKR-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme-1 (IRE1), are responsible for initiating UPR. The UPR involves a variety of signal transduction pathways that reduce unfolded protein accumulation by boosting ER-resident chaperones, limiting protein translation, and accelerating unfolded protein degradation. ER is now acknowledged as a critical organelle in sensing dangers and determining cell life and death. On the other hand, UPR plays a critical role in the development and progression of several diseases such as cardiovascular diseases (CVD), metabolic disorders, chronic kidney diseases, neurological disorders, and cancer. Here, we critically analyze the most current knowledge of the master regulatory roles of ER stress particularly the PERK pathway as a conditional danger receptor, an organelle crosstalk regulator, and a regulator of protein translation. We highlighted that PERK is not only ER stress regulator by sensing UPR and ER stress but also a frontier sensor and direct senses for gut microbiota-generated metabolites. Our work also further highlighted the function of PERK as a central hub that leads to metabolic reprogramming and epigenetic modification which further enhanced inflammatory response and promoted trained immunity. Moreover, we highlighted the contribution of ER stress and PERK in the pathogenesis of several diseases such as cancer, CVD, kidney diseases, and neurodegenerative disorders. Finally, we discuss the therapeutic target of ER stress and PERK for cancer treatment and the potential novel therapeutic targets for CVD, metabolic disorders, and neurodegenerative disorders. Inhibition of ER stress, by the development of small molecules that target the PERK and UPR, represents a promising therapeutic strategy.

内质网(ER)是一种细胞器,在生理上负责蛋白质折叠、钙平衡和脂质生物合成。氧化应激、缺血、钙平衡失调、正常和/或折叠缺陷蛋白质的生成增加等病理刺激都会导致折叠错误的蛋白质在 ER 中积累,从而引起 ER 应激。对ER压力的适应性反应是激活未折叠蛋白反应(UPR),这种反应会影响多种细胞功能,以维持ER平衡或导致细胞凋亡。三种不同的ER跨膜传感器,包括PKR样ER激酶(PERK)、激活转录因子6(ATF6)和肌醇需要酶-1(IRE1),负责启动UPR。UPR 涉及多种信号转导途径,它们通过增强ER 驻留伴侣、限制蛋白质翻译和加速未折叠蛋白质降解来减少未折叠蛋白质的积累。ER是目前公认的感知危险和决定细胞生死的关键细胞器。另一方面,UPR 在心血管疾病(CVD)、代谢性疾病、慢性肾脏疾病、神经系统疾病和癌症等多种疾病的发生和发展过程中发挥着关键作用。在这里,我们批判性地分析了ER应激主调控作用的最新知识,特别是PERK通路作为条件性危险受体、细胞器串扰调控因子和蛋白质翻译调控因子的作用。我们强调,PERK 不仅是通过感知 UPR 和 ER 应激的 ER 应激调节器,还是肠道微生物群产生的代谢物的前沿传感器和直接感应器。我们的工作还进一步强调了 PERK 作为中心枢纽的功能,它导致代谢重编程和表观遗传修饰,从而进一步增强炎症反应和促进训练有素的免疫力。此外,我们还强调了ER应激和PERK在癌症、心血管疾病、肾脏疾病和神经退行性疾病等多种疾病的发病机制中的作用。最后,我们讨论了ER应激和PERK在癌症治疗中的治疗靶点,以及在心血管疾病、代谢性疾病和神经退行性疾病中潜在的新型治疗靶点。通过开发针对 PERK 和 UPR 的小分子药物来抑制 ER 应激是一种很有前景的治疗策略。
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引用次数: 0
The role of microglia heterogeneity in synaptic plasticity and brain disorders: Will sequencing shed light on the discovery of new therapeutic targets? 小胶质细胞异质性在突触可塑性和脑部疾病中的作用:测序能否发现新的治疗靶点?
IF 13.5 1区 医学 Q1 Medicine Pub Date : 2024-02-10 DOI: 10.1016/j.pharmthera.2024.108606
Yi You , Zhong Chen , Wei-Wei Hu

Microglia play a crucial role in interacting with neuronal synapses and modulating synaptic plasticity. This function is particularly significant during postnatal development, as microglia are responsible for removing excessive synapses to prevent neurodevelopmental deficits. Dysregulation of microglial synaptic function has been well-documented in various pathological conditions, notably Alzheimer's disease and multiple sclerosis. The recent application of RNA sequencing has provided a powerful and unbiased means to decipher spatial and temporal microglial heterogeneity. By identifying microglia with varying gene expression profiles, researchers have defined multiple subgroups of microglia associated with specific pathological states, including disease-associated microglia, interferon-responsive microglia, proliferating microglia, and inflamed microglia in multiple sclerosis, among others. However, the functional roles of these distinct subgroups remain inadequately characterized. This review aims to refine our current understanding of the potential roles of heterogeneous microglia in regulating synaptic plasticity and their implications for various brain disorders, drawing from recent sequencing research and functional studies. This knowledge may aid in the identification of pathogenetic biomarkers and potential factors contributing to pathogenesis, shedding new light on the discovery of novel drug targets. The field of sequencing-based data mining is evolving toward a multi-omics approach. With advances in viral tools for precise microglial regulation and the development of brain organoid models, we are poised to elucidate the functional roles of microglial subgroups detected through sequencing analysis, ultimately identifying valuable therapeutic targets.

小胶质细胞在与神经元突触相互作用和调节突触可塑性方面发挥着至关重要的作用。这一功能在出生后的发育过程中尤为重要,因为小胶质细胞负责清除过多的突触,以防止神经发育障碍。小胶质细胞突触功能失调已在各种病理情况中得到充分证实,尤其是阿尔茨海默病和多发性硬化症。最近,RNA 测序技术的应用为破译小胶质细胞的空间和时间异质性提供了一种强大而无偏见的方法。通过识别具有不同基因表达谱的小胶质细胞,研究人员定义了与特定病理状态相关的多个小胶质细胞亚群,包括疾病相关小胶质细胞、干扰素反应性小胶质细胞、增殖小胶质细胞和多发性硬化症中的炎性小胶质细胞等。然而,这些不同亚群的功能作用仍未得到充分描述。本综述旨在通过最近的测序研究和功能研究,完善我们目前对异质性小胶质细胞在调节突触可塑性方面的潜在作用及其对各种脑部疾病的影响的认识。这些知识有助于确定致病生物标志物和潜在的致病因素,为发现新的药物靶点提供新的启示。基于测序的数据挖掘领域正朝着多组学方法发展。随着用于精确调控小胶质细胞的病毒工具的进步和类脑器官模型的开发,我们有望阐明通过测序分析检测到的小胶质细胞亚群的功能作用,最终确定有价值的治疗靶点。
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引用次数: 0
Olea europaea L-derived secoiridoids: Beneficial health effects and potential therapeutic approaches 油橄榄 L-萃取琥珀酰糖苷:有益健康的作用和潜在的治疗方法
IF 13.5 1区 医学 Q1 Medicine Pub Date : 2024-02-01 DOI: 10.1016/j.pharmthera.2024.108595
Simone Filardo , Mattioli Roberto , Daniel Di Risola , Luciana Mosca , Marisa Di Pietro , Rosa Sessa

Over the years, health challenges have become increasingly complex and global and, at the beginning of the 21st century, chronic diseases, including cardiovascular, neurological, and chronic respiratory diseases, as well as cancer and diabetes, have been identified by World Health Organization as one of the biggest threats to human health. Recently, antimicrobial resistance has also emerged as a growing problem of public health for the management of infectious diseases. In this scenario, the exploration of natural products as supplementation or alternative therapeutic options is acquiring great importance, and, among them, the olive tree, Olea europaea L, specifically leaves, fruits, and oil, has been increasingly investigated for its health promoting properties. Traditionally, these properties have been largely attributed to the high concentration of monounsaturated fatty acids, although, in recent years, beneficial effects have also been associated to other components, particularly polyphenols. Among them, the most interesting group is represented by Olea europaea L secoiridoids, comprising oleuropein, oleocanthal, oleacein, and ligstroside, which display anti-inflammatory, antioxidant, cardioprotective, neuroprotective and anticancer activities. This review provides an overview of the multiple health beneficial effects, the molecular mechanisms, and the potential applications of secoiridoids from Olea europaea L.

多年来,健康挑战变得日益复杂和全球化,21 世纪初,慢性疾病,包括心血管、神经和慢性呼吸道疾病,以及癌症和糖尿病,已被世界卫生组织确定为人类健康的最大威胁之一。近来,抗菌药耐药性也已成为公共卫生中日益严重的传染病管理问题。在这种情况下,探索天然产品作为补充或替代疗法正变得越来越重要,其中,橄榄树(Olea europaea L),特别是叶子、果实和橄榄油,因其促进健康的特性而受到越来越多的研究。传统上,这些特性主要归功于高浓度的单不饱和脂肪酸,但近年来,其他成分,特别是多酚也产生了有益的影响。其中,最令人感兴趣的是油橄榄仲呋喃类化合物,包括油茶素、油茶醛、油茶甙和ligstroside,它们具有抗炎、抗氧化、保护心脏、保护神经和抗癌的作用。这篇综述概述了油橄榄中的呫吨类化合物对健康的多种益处、分子机制和潜在应用。
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引用次数: 0
Berberine prevents NAFLD and HCC by modulating metabolic disorders 小檗碱通过调节代谢紊乱预防非酒精性脂肪肝和肝癌
IF 13.5 1区 医学 Q1 Medicine Pub Date : 2024-02-01 DOI: 10.1016/j.pharmthera.2024.108593
Xinyue Lin , Juanhong Zhang , Yajun Chu , Qiuying Nie , Junmin Zhang

Non-alcoholic fatty liver disease (NAFLD) is a global metabolic disease with high prevalence in both adults and children. Importantly, NAFLD is becoming the main cause of hepatocellular carcinoma (HCC). Berberine (BBR), a naturally occurring plant component, has been demonstrated to have advantageous effects on a number of metabolic pathways as well as the ability to kill liver tumor cells by causing cell death and other routes. This permits us to speculate and make assumptions about the value of BBR in the prevention and defense against NAFLD and HCC by a global modulation of metabolic disorders. Herein, we briefly describe the etiology of NAFLD and NAFLD-related HCC, with a particular emphasis on analyzing the potential mechanisms of BBR in the treatment of NAFLD from aspects including increasing insulin sensitivity, controlling the intestinal milieu, and controlling lipid metabolism. We also elucidate the mechanism of BBR in the treatment of HCC. More significantly, we provided a list of clinical studies for BBR in NAFLD. Taking into account our conclusions and perspectives, we can make further progress in the treatment of BBR in NAFLD and NAFLD-related HCC.

非酒精性脂肪肝(NAFLD)是一种全球性代谢疾病,在成人和儿童中发病率都很高。重要的是,非酒精性脂肪肝正成为肝细胞癌(HCC)的主要病因。小檗碱(BBR)是一种天然植物成分,已被证实对多种代谢途径具有有利影响,并能通过导致细胞死亡和其他途径杀死肝肿瘤细胞。因此,我们可以推测和假设 BBR 在通过全面调节代谢紊乱来预防和抵御非酒精性脂肪肝和 HCC 方面的价值。在此,我们简要介绍了非酒精性脂肪肝和非酒精性脂肪肝相关的 HCC 的病因,并着重从提高胰岛素敏感性、控制肠道环境和控制脂质代谢等方面分析了 BBR 治疗非酒精性脂肪肝的潜在机制。我们还阐明了 BBR 治疗 HCC 的机制。更重要的是,我们提供了非酒精性脂肪肝中 BBR 的临床研究清单。考虑到我们的结论和展望,我们可以在非酒精性脂肪肝和非酒精性脂肪肝相关 HCC 的 BBR 治疗方面取得进一步进展。
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引用次数: 0
CDNF and ER stress: Pharmacology and therapeutic possibilities CDNF 和 ER 应激:药理学和治疗可能性
IF 13.5 1区 医学 Q1 Medicine Pub Date : 2024-02-01 DOI: 10.1016/j.pharmthera.2024.108594
Helike Lõhelaid , Mart Saarma , Mikko Airavaara

Cerebral dopamine neurotrophic factor (CDNF) is an endogenous protein in humans and other vertebrates, and it has been shown to have protective and restorative effects on cells in various disease models. Although it is named as a neurotrophic factor, its actions are drastically different from classical neurotrophic factors such as neurotrophins or the glial cell line-derived neurotrophic family of proteins. Like all secreted proteins, CDNF has a signal sequence at the N-terminus, but unlike common growth factors it has a KDEL-receptor retrieval sequence at the C-terminus. Thus, CDNF is mainly located in the ER. In response to adverse effects, such as ER stress, the expression of CDNF is upregulated and can alleviate ER stress. Also different from other neurotrophic factors, CDNF reduces protein aggregation and inflammation in disease models. Although it is an ER luminal protein, it can surprisingly directly interact with alpha-synuclein, a protein involved in the pathogenesis of synucleinopathies e.g., Parkinson's disease. Pleiotropic CDNF has therapeutic potential and has been tested as a recombinant human protein and gene therapy. The neuroprotective and neurorestorative effects have been described in a number of preclinical studies of Parkinson's disease, stroke and amyotrophic lateral sclerosis. Currently, it was successfully evaluated for safety in a phase 1/2 clinical trial for Parkinson's disease. Collectively, based on recent findings on the mode of action and therapeutic potential of CDNF, its use as a drug could be expanded to other ER stress-related diseases.

脑多巴胺神经营养因子(CDNF)是人类和其他脊椎动物体内的一种内源性蛋白质,已被证明在各种疾病模型中对细胞具有保护和修复作用。虽然它被命名为神经营养因子,但其作用与传统的神经营养因子(如神经营养素或神经胶质细胞系源性神经营养蛋白家族)截然不同。与所有分泌蛋白一样,CDNF 的 N 端有一个信号序列,但与普通生长因子不同的是,它的 C 端有一个 KDEL 受体检索序列。因此,CDNF 主要位于 ER 中。在应对ER压力等不利影响时,CDNF的表达会上调,并能缓解ER压力。与其他神经营养因子不同的是,CDNF 还能减少疾病模型中的蛋白质聚集和炎症。虽然它是一种ER管腔蛋白,但它竟然能与α-突触核蛋白直接相互作用,而α-突触核蛋白与突触核蛋白病(如帕金森病)的发病机制有关。多向性 CDNF 具有治疗潜力,已作为重组人蛋白和基因疗法进行了测试。对帕金森病、中风和肌萎缩性脊髓侧索硬化症的大量临床前研究都描述了其神经保护和神经恢复作用。目前,在一项针对帕金森病的 1/2 期临床试验中,它的安全性已得到成功评估。总之,根据最近对 CDNF 的作用模式和治疗潜力的研究结果,CDNF 作为药物的用途可扩展到其他与 ER 应激相关的疾病。
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引用次数: 0
Transformation or replacement - Effects of hormone therapy on cardiovascular risk 转变或替代 - 激素疗法对心血管风险的影响
IF 13.5 1区 医学 Q1 Medicine Pub Date : 2024-02-01 DOI: 10.1016/j.pharmthera.2024.108592
Julia Kielb , Süreyya Saffak , Jessica Weber , Leonard Baensch , Khatereh Shahjerdi , Aylin Celik , Nora Farahat , Sally Riek , Oscar Chavez-Talavera , Maria Grandoch , Amin Polzin , Malte Kelm , Lisa Dannenberg

Hormone therapy (HT) is important and frequently used both regarding replacement therapy (HRT) and gender affirming therapy (GAHT). While HRT has been effective in addressing symptoms related to hormone shortage, several side effects have been described. In this context, there are some studies that show increased cardiovascular risk. However, there are also studies reporting protective aspects of HT. Nevertheless, the exact impact of HT on cardiovascular risk and the underlying mechanisms remain poorly understood. This article explores the relationship between diverse types of HT and cardiovascular risk, focusing on mechanistic insights of the underlying hormones on platelet and leukocyte function as well as on effects on endothelial and adipose tissue cells.

激素疗法(HT)对于替代疗法(HRT)和性别平权疗法(GAHT)都很重要,也经常使用。虽然激素替代疗法能有效解决与激素短缺有关的症状,但也出现了一些副作用。在这方面,一些研究显示心血管风险增加。不过,也有研究报告称,激素替代疗法具有保护作用。然而,人们对激素对心血管风险的确切影响及其内在机制仍然知之甚少。本文探讨了各种类型的高血压与心血管风险之间的关系,重点是从机理上揭示潜在激素对血小板和白细胞功能的影响,以及对内皮细胞和脂肪组织细胞的影响。
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引用次数: 0
Multi-omics approaches for biomarker discovery in predicting the response of esophageal cancer to neoadjuvant therapy: A multidimensional perspective 预测食管癌对新辅助治疗反应的多组学生物标志物发现方法:多维视角
IF 13.5 1区 医学 Q1 Medicine Pub Date : 2024-02-01 DOI: 10.1016/j.pharmthera.2024.108591
Zhi Yang , Fada Guan , Lawrence Bronk , Lina Zhao

Neoadjuvant chemoradiotherapy (NCRT) followed by surgery has been established as the standard treatment strategy for operable locally advanced esophageal cancer (EC). However, achieving pathologic complete response (pCR) or near pCR to NCRT is significantly associated with a considerable improvement in survival outcomes, while pCR patients may help organ preservation for patients by active surveillance to avoid planned surgery. Thus, there is an urgent need for improved biomarkers to predict EC chemoradiation response in research and clinical settings. Advances in multiple high-throughput technologies such as next-generation sequencing have facilitated the discovery of novel predictive biomarkers, specifically based on multi-omics data, including genomic/transcriptomic sequencings and proteomic/metabolomic mass spectra. The application of multi-omics data has shown the benefits in improving the understanding of underlying mechanisms of NCRT sensitivity/resistance in EC. Particularly, the prominent development of artificial intelligence (AI) has introduced a new direction in cancer research. The integration of multi-omics data has significantly advanced our knowledge of the disease and enabled the identification of valuable biomarkers for predicting treatment response from diverse dimension levels, especially with rapid advances in biotechnological and AI methodologies. Herein, we summarize the current status of research on the use of multi-omics technologies in predicting NCRT response for EC patients. Current limitations, challenges, and future perspectives of these multi-omics platforms will be addressed to assist in experimental designs and clinical use for further integrated analysis.

新辅助化放疗(NCRT)后再手术已被确立为可手术局部晚期食管癌(EC)的标准治疗策略。然而,新辅助化疗获得病理完全反应(pCR)或接近pCR与生存率的显著改善密切相关,而pCR患者可通过主动监测来避免计划中的手术,从而有助于患者的器官保存。因此,在研究和临床环境中迫切需要改进的生物标志物来预测EC化疗反应。新一代测序等多种高通量技术的进步促进了新型预测性生物标志物的发现,特别是基于多组学数据(包括基因组/转录组测序和蛋白质组/代谢组质谱)的预测性生物标志物的发现。多组学数据的应用已显示出其在提高对欧共体 NCRT 敏感性/耐药性潜在机制的认识方面的优势。尤其是人工智能(AI)的显著发展为癌症研究引入了新的方向。特别是随着生物技术和人工智能方法学的快速发展,多组学数据的整合极大地推动了我们对疾病的认识,并使我们能够从不同维度识别出有价值的生物标志物来预测治疗反应。在此,我们总结了利用多组学技术预测心血管疾病患者 NCRT 反应的研究现状。我们将探讨这些多组学平台目前存在的局限性、面临的挑战和未来的展望,以协助实验设计和临床使用,进一步开展综合分析。
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引用次数: 0
A novel therapeutic target for kidney diseases: Lessons learned from starvation response 肾脏疾病的新型治疗靶点:从饥饿反应中汲取的经验教训
IF 13.5 1区 医学 Q1 Medicine Pub Date : 2024-02-01 DOI: 10.1016/j.pharmthera.2024.108590
Kosuke Yamahara, Mako Yasuda-Yamahara, Shinji Kume

The prevalence of chronic kidney disease (CKD) is increasing worldwide, making the disease an urgent clinical challenge. Caloric restriction has various anti-aging and organ-protective effects, and unraveling its molecular mechanisms may provide insight into the pathophysiology of CKD. In response to changes in nutritional status, intracellular nutrient signaling pathways show adaptive changes. When nutrients are abundant, signals such as mechanistic target of rapamycin complex 1 (mTORC1) are activated, driving cell proliferation and other processes. Conversely, others, such as sirtuins and AMP-activated protein kinase, are activated during energy scarcity, in an attempt to compensate. Autophagy, a cellular self-maintenance mechanism that is regulated by such signals, has also been reported to contribute to the progression of various kidney diseases. Furthermore, in recent years, ketone bodies, which have long been considered to be detrimental, have been reported to play a role as starvation signals, and thereby to have renoprotective effects, via the inhibition of mTORC1. Therefore, in this review, we discuss the role of mTORC1, which is one of the most extensively studied nutrient-related signals associated with kidney diseases, autophagy, and ketone body metabolism; and kidney energy metabolism as a novel therapeutic target for CKD.

慢性肾脏病(CKD)的发病率在全球范围内不断上升,使该疾病成为一项紧迫的临床挑战。热量限制具有多种抗衰老和器官保护作用,揭示其分子机制可能有助于深入了解慢性肾脏病的病理生理学。为应对营养状况的变化,细胞内营养信号通路会发生适应性变化。当营养物质丰富时,雷帕霉素复合体 1(mTORC1)等信号被激活,推动细胞增殖和其他过程。相反,其他信号,如sirtuins和AMP激活的蛋白激酶,则会在能量匮乏时被激活,试图进行补偿。自噬是一种受此类信号调控的细胞自我维护机制,也有报道称它是导致各种肾脏疾病恶化的原因之一。此外,近年来有报道称,长期以来一直被认为有害的酮体可作为饥饿信号发挥作用,从而通过抑制 mTORC1 发挥保护肾脏的作用。因此,在这篇综述中,我们将讨论 mTORC1 的作用(mTORC1 是与肾脏疾病、自噬和酮体代谢有关的营养相关信号中研究最为广泛的信号之一),以及肾脏能量代谢作为 CKD 新型治疗靶点的作用。
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引用次数: 0
Gene and stem cell therapy for inherited cardiac arrhythmias 遗传性心律失常的基因和干细胞疗法
IF 13.5 1区 医学 Q1 Medicine Pub Date : 2024-01-30 DOI: 10.1016/j.pharmthera.2024.108596
Zhong-He Zhang , Hector Barajas-Martinez , Hong Jiang , Cong-Xin Huang , Charles Antzelevitch , Hao Xia , Dan Hu

Inherited cardiac arrhythmias are a group of genetic diseases predisposing to sudden cardiac arrest, mainly resulting from variants in genes encoding cardiac ion channels or proteins involved in their regulation. Currently available therapeutic options (pharmacotherapy, ablative therapy and device-based therapy) can not preclude the occurrence of arrhythmia events and/or provide complete protection. With growing understanding of the genetic background and molecular mechanisms of inherited cardiac arrhythmias, advancing insight of stem cell technology, and development of vectors and delivery strategies, gene therapy and stem cell therapy may be promising approaches for treatment of inherited cardiac arrhythmias. Recent years have witnessed impressive progress in the basic science aspects and there is a clear and urgent need to be translated into the clinical management of arrhythmic events. In this review, we present a succinct overview of gene and cell therapy strategies, and summarize the current status of gene and cell therapy. Finally, we discuss future directions for implementation of gene and cell therapy in the therapy of inherited cardiac arrhythmias.

遗传性心律失常是一组易导致心脏骤停的遗传疾病,主要是由于编码心脏离子通道或参与其调节的蛋白质的基因发生变异所致。目前可用的治疗方案(药物治疗、消融治疗和基于设备的治疗)无法避免心律失常事件的发生和/或提供完全的保护。随着对遗传性心律失常的遗传背景和分子机制的了解不断加深,对干细胞技术的认识不断提高,以及载体和递送策略的发展,基因治疗和干细胞治疗可能成为治疗遗传性心律失常的有前途的方法。近年来,基础科学方面取得了令人瞩目的进展,但显然迫切需要将其转化为心律失常的临床治疗方法。在这篇综述中,我们简明扼要地概述了基因和细胞治疗策略,并总结了基因和细胞治疗的现状。最后,我们讨论了基因和细胞疗法在治疗遗传性心律失常方面的未来发展方向。
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Pharmacology & Therapeutics
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