Pub Date : 2024-02-15DOI: 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。
{"title":"The therapeutic potential of targeting the CHD protein family in cancer","authors":"Min Zhang , Kaiyuan Wu , Weijie Zhang , Xia Lin , Qi Cao , Lili Zhang , Kaifu Chen","doi":"10.1016/j.pharmthera.2024.108610","DOIUrl":"10.1016/j.pharmthera.2024.108610","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":13.5,"publicationDate":"2024-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139875925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-13DOI: 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。
{"title":"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","authors":"Fatma Saaoud , Yifan Lu , Keman Xu , Ying Shao , Domenico Praticò , Roberto I. Vazquez-Padron , Hong Wang , Xiaofeng Yang","doi":"10.1016/j.pharmthera.2024.108604","DOIUrl":"10.1016/j.pharmthera.2024.108604","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":13.5,"publicationDate":"2024-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139740068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-10DOI: 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.
{"title":"The role of microglia heterogeneity in synaptic plasticity and brain disorders: Will sequencing shed light on the discovery of new therapeutic targets?","authors":"Yi You , Zhong Chen , Wei-Wei Hu","doi":"10.1016/j.pharmthera.2024.108606","DOIUrl":"10.1016/j.pharmthera.2024.108606","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":13.5,"publicationDate":"2024-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139721090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01DOI: 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.
{"title":"Olea europaea L-derived secoiridoids: Beneficial health effects and potential therapeutic approaches","authors":"Simone Filardo , Mattioli Roberto , Daniel Di Risola , Luciana Mosca , Marisa Di Pietro , Rosa Sessa","doi":"10.1016/j.pharmthera.2024.108595","DOIUrl":"10.1016/j.pharmthera.2024.108595","url":null,"abstract":"<div><p>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, <em>Olea europaea</em> 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 <em>Olea europaea</em> 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 <em>Olea europaea</em> L.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":13.5,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0163725824000159/pdfft?md5=7f455e885308c9e62f77f01c0ce56257&pid=1-s2.0-S0163725824000159-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139577918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01DOI: 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.
{"title":"Berberine prevents NAFLD and HCC by modulating metabolic disorders","authors":"Xinyue Lin , Juanhong Zhang , Yajun Chu , Qiuying Nie , Junmin Zhang","doi":"10.1016/j.pharmthera.2024.108593","DOIUrl":"10.1016/j.pharmthera.2024.108593","url":null,"abstract":"<div><p>Non-alcoholic fatty liver disease (NAFLD) is a global metabolic disease<span><span> with high prevalence in both adults and children. Importantly, NAFLD is becoming the main cause of hepatocellular carcinoma (HCC). </span>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.</span></p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":13.5,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139659620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01DOI: 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。
{"title":"CDNF and ER stress: Pharmacology and therapeutic possibilities","authors":"Helike Lõhelaid , Mart Saarma , Mikko Airavaara","doi":"10.1016/j.pharmthera.2024.108594","DOIUrl":"10.1016/j.pharmthera.2024.108594","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":13.5,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139573748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01DOI: 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.
{"title":"Transformation or replacement - Effects of hormone therapy on cardiovascular risk","authors":"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","doi":"10.1016/j.pharmthera.2024.108592","DOIUrl":"10.1016/j.pharmthera.2024.108592","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":13.5,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139568703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01DOI: 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.
{"title":"Multi-omics approaches for biomarker discovery in predicting the response of esophageal cancer to neoadjuvant therapy: A multidimensional perspective","authors":"Zhi Yang , Fada Guan , Lawrence Bronk , Lina Zhao","doi":"10.1016/j.pharmthera.2024.108591","DOIUrl":"10.1016/j.pharmthera.2024.108591","url":null,"abstract":"<div><p>Neoadjuvant chemoradiotherapy<span> (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.</span></p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":13.5,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139568694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"A novel therapeutic target for kidney diseases: Lessons learned from starvation response","authors":"Kosuke Yamahara, Mako Yasuda-Yamahara, Shinji Kume","doi":"10.1016/j.pharmthera.2024.108590","DOIUrl":"10.1016/j.pharmthera.2024.108590","url":null,"abstract":"<div><p><span><span><span><span>The prevalence of chronic kidney disease<span> (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 </span></span>mechanistic target of rapamycin complex 1<span> (mTORC1) are activated, driving cell proliferation and other processes. Conversely, others, such as </span></span>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, </span>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, </span><em>via</em> 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.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":13.5,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139568758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-30DOI: 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.
{"title":"Gene and stem cell therapy for inherited cardiac arrhythmias","authors":"Zhong-He Zhang , Hector Barajas-Martinez , Hong Jiang , Cong-Xin Huang , Charles Antzelevitch , Hao Xia , Dan Hu","doi":"10.1016/j.pharmthera.2024.108596","DOIUrl":"10.1016/j.pharmthera.2024.108596","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":13.5,"publicationDate":"2024-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139644240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}