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Aging and cancer hallmarks as therapeutic targets 衰老和癌症标志作为治疗靶点
Pub Date : 2023-01-01 DOI: 10.15212/amm-2023-0018
Jingchao Wang, Jonathan Wei, H. Inuzuka
The prevalence of age-related diseases has been progressively increasing worldwide. The pathogenesis of these disorders, including cancer, is closely associated with an age-dependent decline in cellular functions. There are multiple layers of crosstalk between aging processes and oncogenesis. Therefore, a better understanding of the interplay between aging and cancer will facilitate the development of novel therapeutic intervention strategies for malignancies at advanced ages. Recent review articles have concisely summarized and updated aging and cancer hallmark features and adequately discussed the interplays at both the cellular and molecular levels. Because aging and cancer share several key mechanisms that define the hallmarks, targeting shared features, such as cellular senescence, may be beneficial for cancer prevention and treatments. Notably, senolysis, an innovative therapeutic intervention for selectively removing senescent cells, holds great promise for developing new therapeutic approaches for cancers and other age-related diseases, such as viral infections and cardiovascular diseases. Herein we briefly summarize the recently updated knowledge on aging and cancer hallmarks, as well as the advances in senolysis for age-related conditions.
在世界范围内,与年龄有关的疾病的患病率逐渐增加。包括癌症在内的这些疾病的发病机制与细胞功能的年龄依赖性下降密切相关。在衰老过程和肿瘤发生之间存在多层的相互作用。因此,更好地了解衰老与癌症之间的相互作用将有助于开发针对高龄恶性肿瘤的新型治疗干预策略。最近的综述文章简明扼要地总结和更新了衰老和癌症的标志特征,并充分讨论了细胞和分子水平上的相互作用。因为衰老和癌症有几个共同的关键机制来定义标志,针对共同的特征,如细胞衰老,可能有利于癌症的预防和治疗。值得注意的是,senolysis是一种选择性去除衰老细胞的创新治疗干预,它为开发癌症和其他与年龄相关的疾病(如病毒感染和心血管疾病)的新治疗方法带来了巨大的希望。在这里,我们简要地总结了最近更新的知识老化和癌症的标志,以及在衰老相关的条件下的进展。
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引用次数: 1
Corrigendum to: Silybin has therapeutic efficacy against non-small cell lung cancer through targeting of Skp2 更正:水飞蓟宾通过靶向Skp2对非小细胞肺癌具有治疗效果
Pub Date : 2023-01-01 DOI: 10.15212/amm-2023-1001
Shi-Bing Zhang, Ming Hong, Xiao-Yang Sun, Da Huang, Dan-Hua He, Yu-Fei Chen, Yong Yuan, Yong-Qiang Liu
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引用次数: 1
Biological functions and therapeutic potential of acylation by histone acetyltransferases 组蛋白乙酰转移酶酰基化的生物学功能和治疗潜力
Pub Date : 2023-01-01 DOI: 10.15212/amm-2023-0010
Nan Li, Clark Hamor, Y. An, Licheng Zhu, Yusheng Gong, Y. Toh, Yusong R. Guo
Histone lysine acylation is a major class of histone post-translational modifications involved in essential biological activities, such as transcriptional regulation, DNA-damage repair, and cell-cycle progression. Abnormal acylation is strongly associated with various diseases, such as cancer. Thus, histone acetyltransferases (HATs), the “writers” that catalyze histone acylation, are promising targets for cancer treatment. Rapid developments in structural biology and artificial intelligence have facilitated the development of drugs targeting HATs. To provide new ideas for exploring novel HAT modifiers with high efficiency and selectivity, this article reviews the relationships between acylation and diseases, illustrates HAT catalytic mechanisms through structural biology, and summarizes research progress in HAT modifiers.
组蛋白赖氨酸酰化是一类主要的组蛋白翻译后修饰,涉及基本的生物活性,如转录调节、dna损伤修复和细胞周期进程。异常酰化与多种疾病密切相关,如癌症。因此,组蛋白乙酰转移酶(HATs),催化组蛋白酰化的“作者”,是癌症治疗的有希望的靶点。结构生物学和人工智能的快速发展促进了针对hat的药物的开发。本文综述了酰基化与疾病的关系,从结构生物学角度阐述了HAT的催化机制,并对HAT修饰剂的研究进展进行了总结,为探索高效、选择性的新型HAT修饰剂提供了新的思路。
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引用次数: 1
Cuproptosis-related MTF1 inhibits kidney renal clear cell carcinoma progression by suppressing proliferation and regulating immune cell infiltration 铜裂相关MTF1通过抑制增殖和调节免疫细胞浸润抑制肾透明细胞癌进展
Pub Date : 2023-01-01 DOI: 10.15212/amm-2023-0016
W. Mao, Z. Ding, Keyi Wang, Ming Chen
Cuproptosis is a newly identified specific form of programmed cell death. Our study aimed to identify cuproptosis-related genes (CRGs) in patients with kidney renal clear cell carcinoma (KIRC) from the The Cancer Genome Atlas database and to evaluate CRG biological functions. Using lasso regression, we identified four KIRC prognosis-associated CRGs and constructed an associated prognostic risk signature. Kaplan-Meier curves showed that patients with high-risk scores had significantly lower survival times than patients with low-risk scores. Multivariate Cox analysis identified MTF1 and FDX1 as two independent overall survival CRGs. Moreover, qRT-PCR showed that MTF1 and FDX1 expression was downregulated in KIRC and knockdown of MTF1 and FDX1 significantly promoted KIRC cell proliferation and migration ability. In addition, the MTF1 level was positively correlated with immune cell infiltration and knockdown of MTF1 promoted tumor growth in vivo. We developed a signature of prognostic risk-associated CRGs that accurately predicted the prognostic status of KIRC patients. MTF1 and FDX1 were shown to be key CRGs. MTF1 acts as a tumor suppressor, and may be involved in the progression of KIRC by inhibiting proliferation and regulating immune cell infiltration.
铜增生是一种新发现的程序性细胞死亡的特殊形式。本研究旨在从the Cancer Genome Atlas数据库中鉴定肾透明细胞癌(KIRC)患者的铜肾病相关基因(cuprotoisisrelated genes, CRGs),并评估CRG的生物学功能。使用套索回归,我们确定了四个与KIRC预后相关的crg,并构建了相关的预后风险特征。Kaplan-Meier曲线显示,高危评分患者的生存时间明显低于低危评分患者。多变量Cox分析发现MTF1和FDX1是两个独立的总生存CRGs。此外,qRT-PCR结果显示,KIRC中MTF1和FDX1的表达下调,MTF1和FDX1的下调显著促进了KIRC细胞的增殖和迁移能力。此外,MTF1水平与免疫细胞浸润呈正相关,体内MTF1敲低可促进肿瘤生长。我们开发了一种与预后风险相关的crg标记,可以准确预测KIRC患者的预后状况。MTF1和FDX1是关键的CRGs。MTF1作为肿瘤抑制因子,可能通过抑制增殖和调节免疫细胞浸润参与KIRC的进展。
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引用次数: 0
An intrinsic connection between COVID-19 and aging COVID-19与衰老之间存在内在联系
Pub Date : 2023-01-01 DOI: 10.15212/amm-2023-0030
Jingchao Wang, Jonathan Wei, Fabin Dang, Hiroyuki Inuzuka
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a rapidly spreading outbreak of coronavirus disease 2019 (the COVID-19 pandemic). COVID-19 has severely affected healthcare systems worldwide, as well as the global economy, and has significantly increased morbidity and mortality rates. The majority of COVID-19-related deaths occurred in older individuals, primarily among those with concomitant diseases, including metabolic, respiratory, and cardiovascular diseases. Aging hallmarks, such as cellular senescence, chronic inflammation, and genomic instability, partially explain the increased disease severity at the molecular level with advancing age. Other multifactorial considerations, including healthcare facilities, socioeconomic status, and dissemination of epidemic information, may help control morbidity in the elderly population. While the World Health Organization declared an end to the emergency status of COVID-19 in May 2023, physical and emotional impairments may persist after recovery from the virus. Precautions should therefore be taken to prevent future pandemics, and suitable emphasis should be placed on addressing persistent COVID-19 and preventing future pandemics.
严重急性呼吸综合征冠状病毒2 (SARS-CoV-2)引起了2019年冠状病毒病(COVID-19大流行)的迅速蔓延。COVID-19严重影响了世界各地的卫生保健系统和全球经济,并显著增加了发病率和死亡率。大多数与covid -19相关的死亡发生在老年人中,主要是伴有代谢、呼吸和心血管疾病等疾病的人。衰老的标志,如细胞衰老、慢性炎症和基因组不稳定,在分子水平上部分解释了随着年龄的增长疾病严重程度的增加。其他多因素考虑,包括保健设施、社会经济地位和流行病信息的传播,可能有助于控制老年人口的发病率。虽然世界卫生组织于2023年5月宣布COVID-19紧急状态结束,但从病毒中恢复后,身体和情绪障碍可能会持续存在。因此,应采取预防措施防止未来的大流行,并适当强调应对持续的COVID-19和预防未来的大流行。
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引用次数: 0
Latent herpes simplex virus type 1 reactivation increases the susceptibility of neurodegenerative diseases: intervention with traditional Chinese medicine 单纯疱疹潜伏病毒1型活化增加神经退行性疾病的易感性:中药干预
Pub Date : 2022-12-30 DOI: 10.15212/amm-2022-0043
Jie Sun, Chang-Yu Yan, Jie Niu, M. Pan, Zhuo Luo, Wen-Jun Duan, Wen Li, Yan-ping Wu, Wan-Yang Sun, Feng Huang, Fan-na Liu, Haizhi Liu, H. Kurihara, Yi-Fang Li, Rong-Rong He
Owing to environmental and lifestyle changes in modern society, physical and mental stress is on the rise among the population in attempting to compensate for the changes. Stress, defined as a series of non-specific responses to abnormal internal and external stimuli, has long been recognized to increase susceptibility to various diseases, including neurodegenerative diseases (NDs). Herpes simplex virus type 1 (HSV-1), a neurotropic herpes virus, establishes latent infections in the trigeminal ganglia for the lifetime of the host. Upon reactivation, the latent HSV-1 enters the lytic cycle, which not only causes a substantial production of reactive oxygen species (ROS) in the neurons, but also induces glial cells to produce inflammatory mediators, eventually resulting in neuronal damage and occurrence of NDs. Remarkably, both physical and psychological stress are common stimuli leading to latent HSV-1 reactivation. Acyclovir is a classic antiviral drug for the treatment of HSV-1 infection and recurrence, but acyclovir cannot reverse neuronal damage caused by HSV-1 reactivation. Recent studies have shown that traditional Chinese medicine (TCM) has advantages in the treatment of NDs. In addition, TCM is thought to prevent latent HSV-1 reactivation and NDs, which may involve regulation of the neuro-endocrine-immune network, treatment of emotional disorders, and modulation of oxidative stress. Understanding the mechanism underlying stress-induced reactivation of latent HSV-1 and the potential consequences of NDs is needed. TCM may be a promising alternative therapy for related diseases.
由于现代社会环境和生活方式的变化,为了弥补这些变化,人们的身心压力正在增加。压力被定义为对异常内外刺激的一系列非特异性反应,长期以来一直被认为会增加对各种疾病的易感性,包括神经退行性疾病。单纯疱疹病毒1型(HSV-1)是一种嗜神经性疱疹病毒,在宿主的一生中在三叉神经节中建立潜在感染。在重新激活时,潜伏的HSV-1进入裂解周期,这不仅导致神经元中大量产生活性氧(ROS),还诱导神经胶质细胞产生炎症介质,最终导致神经元损伤和NDs的发生。值得注意的是,生理和心理压力都是导致潜在HSV-1重新激活的常见刺激。阿昔洛韦是治疗HSV-1感染和复发的经典抗病毒药物,但阿昔洛韦不能逆转HSV-1再激活引起的神经元损伤。最近的研究表明,中医药在治疗NDs方面具有优势。此外,中医药被认为可以预防潜在的HSV-1再激活和NDs,这可能涉及神经内分泌免疫网络的调节、情绪障碍的治疗和氧化应激的调节。需要了解应激诱导的潜在HSV-1再激活的机制以及NDs的潜在后果。中医药可能是治疗相关疾病的一种很有前途的替代疗法。
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引用次数: 2
Mass spectrometry imaging advances and application in pharmaceutical research 质谱成像技术及其在药物研究中的应用
Pub Date : 2022-12-23 DOI: 10.15212/amm-2022-0046
Xiaowei Song, Chao Li, Yifan Meng
Mass spectrometry imaging (MSI) has been shown to be a valuable tool through nearly every stage of the preclinical drug research and development (R&D) pipeline, and even to the early phase of clinical pharmaceutical evaluation. MSI can specifically resolve distributions of a parent drug and its metabolic products across dosed specimens without loss of spatial information, thus facilitating the direct observation of a drug’s pharmacokinetic processes, such as absorption, distribution, metabolism, and excretion. MSI can simultaneously visualize hundreds of phenotype molecules, including proteins, glycans, metabolites, and lipids, which have unique distribution patterns and biofunctions across different physiologic regions. This featured specificity in the chemical and physical spaces empowers MSI as an ideal analytical technique in exploring a drug’s pharmacodynamic properties, including in vitro/in vivo efficacy, safety, potential toxicity, and possible molecular mechanism. The application of MSI in pharmaceutical research has also been expanded from the conventional dosed tissue analysis to the front end of the preclinical drug R&D pipeline, such as investigating the structure-activity relationship, high-throughput in vitro screening, and ex vivo studies on single cells, organoids, or tumor spheroids. This review summarizes MSI application in pharmaceutical research accompanied by its technical and methodologic advances serving this central demand.
质谱成像(MSI)已被证明是一种有价值的工具,几乎贯穿了临床前药物研究和开发(R&D)管道的每个阶段,甚至是临床药物评估的早期阶段。MSI可以在不丢失空间信息的情况下特异性地解析母体药物及其代谢产物在不同剂量样品中的分布,从而便于直接观察药物的药代动力学过程,如吸收、分布、代谢和排泄。MSI可以同时可视化数百种表型分子,包括蛋白质、聚糖、代谢物和脂质,它们在不同的生理区域具有独特的分布模式和生物功能。这种在化学和物理领域的特异性使MSI成为一种理想的分析技术,用于探索药物的药效学特性,包括体外/体内疗效、安全性、潜在毒性和可能的分子机制。MSI在药物研究中的应用也从传统的给药组织分析扩展到临床前药物研发管线的前端,如研究结构-活性关系、高通量体外筛选、单细胞、类器官或肿瘤球体的离体研究。本文综述了微信号在药物研究中的应用及其技术和方法上的进步,以满足这一核心需求。
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引用次数: 1
Cancer treatment: from traditional Chinese herbal medicine to the liposome delivery system 癌症治疗:从中药到脂质体输送系统
Pub Date : 2022-12-14 DOI: 10.15212/amm-2022-0035
Minhan Fu, Xueying Han, Bin Chen, Lingna Guo, Lei Zhong, Po Hu, Yang Pan, Min Qiu, P. Cao, J. Chen
Traditional Chinese herbal (TCH) medicines have emerged as a prospective and affordable method to treat various diseases with a broad range of biological activity; however, traditional preparations, like decoctions, are often associated with low bioavailability, thus resulting in limited efficacy against cancer. The drawbacks of active TCH components, including instability, poor permeability, high hydrophilicity or hydrophobicity, undesirable pharmacokinetic profiles, and off-target toxicity, also exist. Most TCH medicines are thus limited to a clinical alternative for the treatment of chronic diseases. A liposomal delivery system is the most common class of FDA-approved nanomedicines, which has improved pharmacokinetics, enhanced targetability, and reduced side effects. Therefore, we anticipate that liposomal delivery technology will help concentrate drugs inside tumors, and fully release the therapeutic potential and reduce the side effects of TCH medicines. The review provides a brief overview of several representative TCH components and related liposome delivery strategies for enhanced cancer therapy. Current challenges associated with liposomal targeting of TCH medicines are also discussed for interested researchers.
传统中草药已成为一种具有广泛生物活性的治疗各种疾病的前瞻性和负担得起的方法;然而,传统制剂,如煎剂,通常与低生物利用度有关,从而导致对癌症的疗效有限。活性TCH成分的缺点也存在,包括不稳定性、渗透性差、高亲水性或疏水性、不良的药代动力学特征和脱靶毒性。因此,大多数TCH药物仅限于治疗慢性病的临床替代药物。脂质体递送系统是美国食品药品监督管理局批准的最常见的纳米药物,它改善了药代动力学,增强了靶向性,减少了副作用。因此,我们预计脂质体递送技术将有助于将药物集中在肿瘤内,并充分释放TCH药物的治疗潜力和减少副作用。综述了几种具有代表性的TCH成分和相关脂质体递送策略在癌症强化治疗中的应用。感兴趣的研究人员还讨论了与TCH药物的脂质体靶向相关的当前挑战。
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引用次数: 7
Biothiol-triggered H2S release from a near-infrared fluorescent H2S donor promotes cutaneous wound healing 近红外荧光H2S供体生物硫醇触发的H2S释放促进皮肤伤口愈合
Pub Date : 2022-11-16 DOI: 10.15212/amm-2022-0032
Xinyue Zhao, Mengbin Ding, Lulu Ning, Fang Yuan, Jingchao Li, Yuan Guo, Y. Mu, Jianjian Zhang
Hydrogen sulfide (H2S) plays crucial roles in antioxidation, anti-inflammation, and cytoprotection. Despite substantial progress in the design and synthesis of activatable H2S donors, methods for high-precision detection and imaging of released H2S in living systems have been lacking. In this study, a biothiol-activated near-infrared (NIR) fluorescent H2S donor, PRO-ST, was developed for real-time visualization of H2S release. PRO-ST consists of a dicyanoisophorone-based NIR fluorescence moiety (TCOO), a biothiol-trigger moiety (4-isothiocyanate benzyl alcohol), and a sulfur-source group (thiophosgene). PRO-ST exhibits high NIR fluorescence enhancement (45-fold), outstanding H2S release efficiency (73%), controllable H2S release (60 min), and excellent cell compatibility. These distinctive features enable PRO-ST to be applied in visualizing H2S release in cells, zebrafish, and mice. Moreover, PRO-ST exhibits excellent performance in visualizing real-time anti-inflammation and wound healing enhancement in biological systems, as confirmed by in situ visualization of H2S release. Thus, PRO-ST provides a versatile and effective method to detect and visualize H2S release, elucidate the mechanisms underlying wound healing, or optimize interventional therapy.
硫化氢(H2S)在抗氧化、抗炎和细胞保护方面起着至关重要的作用。尽管在可活化H2S供体的设计和合成方面取得了实质性进展,但缺乏对活体系统中释放的H2S进行高精度检测和成像的方法。在本研究中,开发了一种生物硫醇激活的近红外(NIR)荧光H2S供体PRO-ST,用于H2S释放的实时可视化。PRO-ST由基于二氰基槐酮的近红外荧光部分(TCOO)、生物硫醇触发部分(4-异硫氰酸苄醇)和硫源基团(硫光气)组成。PRO-ST具有高的近红外荧光增强(45倍)、出色的H2S释放效率(73%)、可控的H2S释放(60分钟)和优异的细胞相容性。这些独特的特征使PRO-ST能够应用于观察细胞、斑马鱼和小鼠中H2S的释放。此外,PRO-ST在可视化生物系统中的实时抗炎和伤口愈合增强方面表现出优异的性能,H2S释放的原位可视化证实了这一点。因此,PRO-ST提供了一种检测和可视化H2S释放、阐明伤口愈合机制或优化介入治疗的通用有效方法。
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引用次数: 2
Structurally diverse polydopamine-based nanomedicines for cancer therapy 用于癌症治疗的结构多样的聚多巴胺基纳米药物
Pub Date : 2022-10-18 DOI: 10.15212/amm-2022-0023
Yu-Wen Zheng, Tao Cao, Xueying Han, Peng Cao, Qichen Zhan
Mussel-inspired polydopamine (PDA) has attracted substantial interest in materials synthesis, energy storage, environmental governance, and biomedical science since it was first reported in 2007. PDA, owing to its excellent biocompatibility and photothermal conversion efficiency (η), has been used in photothermal therapy alone and in combination with photodynamic therapy, chemotherapy, radiation therapy, immunotherapy, and gas therapy for cancer treatment. This review summarizes the methods for synthesizing structurally diverse PDA-based nanomedicines and their applications in cancer therapy, to provide perspectives to guide future studies in cancer treatment.
Mussel启发的聚多巴胺(PDA)自2007年首次报道以来,在材料合成、储能、环境治理和生物医学科学方面引起了极大的兴趣。PDA由于其良好的生物相容性和光热转换效率(η),已被单独用于光热治疗,并与光动力疗法、化学疗法、放射疗法、免疫疗法和气体疗法相结合用于癌症治疗。本文综述了结构多样的PDA基纳米药物的合成方法及其在癌症治疗中的应用,为癌症治疗的未来研究提供了指导。
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引用次数: 4
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Acta materia medica
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