Pharmacology & Therapeutics最新文献

{"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 ,&nbsp;Yifan Lu ,&nbsp;Keman Xu ,&nbsp;Ying Shao ,&nbsp;Domenico Praticò ,&nbsp;Roberto I. Vazquez-Padron ,&nbsp;Hong Wang ,&nbsp;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":"255 ","pages":"Article 108604"},"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}

{"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 ,&nbsp;Zhong Chen ,&nbsp;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":"255 ","pages":"Article 108606"},"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}

{"title":"Olea europaea L-derived secoiridoids: Beneficial health effects and potential therapeutic approaches","authors":"Simone Filardo ,&nbsp;Mattioli Roberto ,&nbsp;Daniel Di Risola ,&nbsp;Luciana Mosca ,&nbsp;Marisa Di Pietro ,&nbsp;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":"254 ","pages":"Article 108595"},"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}

{"title":"CDNF and ER stress: Pharmacology and therapeutic possibilities","authors":"Helike Lõhelaid ,&nbsp;Mart Saarma ,&nbsp;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":"254 ","pages":"Article 108594"},"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}

{"title":"Berberine prevents NAFLD and HCC by modulating metabolic disorders","authors":"Xinyue Lin ,&nbsp;Juanhong Zhang ,&nbsp;Yajun Chu ,&nbsp;Qiuying Nie ,&nbsp;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":"254 ","pages":"Article 108593"},"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}

{"title":"Transformation or replacement - Effects of hormone therapy on cardiovascular risk","authors":"Julia Kielb ,&nbsp;Süreyya Saffak ,&nbsp;Jessica Weber ,&nbsp;Leonard Baensch ,&nbsp;Khatereh Shahjerdi ,&nbsp;Aylin Celik ,&nbsp;Nora Farahat ,&nbsp;Sally Riek ,&nbsp;Oscar Chavez-Talavera ,&nbsp;Maria Grandoch ,&nbsp;Amin Polzin ,&nbsp;Malte Kelm ,&nbsp;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":"254 ","pages":"Article 108592"},"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}

{"title":"Multi-omics approaches for biomarker discovery in predicting the response of esophageal cancer to neoadjuvant therapy: A multidimensional perspective","authors":"Zhi Yang ,&nbsp;Fada Guan ,&nbsp;Lawrence Bronk ,&nbsp;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":"254 ","pages":"Article 108591"},"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}

{"title":"A novel therapeutic target for kidney diseases: Lessons learned from starvation response","authors":"Kosuke Yamahara,&nbsp;Mako Yasuda-Yamahara,&nbsp;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":"254 ","pages":"Article 108590"},"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}

{"title":"Gene and stem cell therapy for inherited cardiac arrhythmias","authors":"Zhong-He Zhang ,&nbsp;Hector Barajas-Martinez ,&nbsp;Hong Jiang ,&nbsp;Cong-Xin Huang ,&nbsp;Charles Antzelevitch ,&nbsp;Hao Xia ,&nbsp;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":"256 ","pages":"Article 108596"},"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}

{"title":"Non-canonical G protein signaling","authors":"Bernd Nürnberg ,&nbsp;Sandra Beer-Hammer ,&nbsp;Ellen Reisinger ,&nbsp;Veronika Leiss","doi":"10.1016/j.pharmthera.2024.108589","DOIUrl":"10.1016/j.pharmthera.2024.108589","url":null,"abstract":"<div><p>The original paradigm of classical - also referred to as canonical - cellular signal transduction of heterotrimeric G proteins (G protein) is defined by a hierarchical, orthograde interaction of three players: the agonist-activated G protein-coupled receptor (GPCR), which activates the transducing G protein, that in turn regulates its intracellular effectors. This receptor-transducer-effector concept was extended by the identification of regulators and adapters such as the regulators of G protein signaling (RGS), receptor kinases like βARK, or GPCR-interacting arrestin adapters that are integrated into this canonical signaling process at different levels to enable fine-tuning. Finally, the identification of atypical signaling mechanisms of classical regulators, together with the discovery of novel modulators, added a new and fascinating dimension to the cellular G protein signal transduction. This heterogeneous group of accessory G protein modulators was coined “activators of G protein signaling” (AGS) proteins and plays distinct roles in canonical and non-canonical G protein signaling pathways. AGS proteins contribute to the control of essential cellular functions such as cell development and division, intracellular transport processes, secretion, autophagy or cell movements. As such, they are involved in numerous biological processes that are crucial for diseases, like diabetes mellitus, cancer, and stroke, which represent major health burdens. Although the identification of a large number of non-canonical G protein signaling pathways has broadened the spectrum of this cellular communication system, their underlying mechanisms, functions, and biological effects are poorly understood. In this review, we highlight and discuss atypical G protein-dependent signaling mechanisms with a focus on inhibitory G proteins (G_i) involved in canonical and non-canonical signal transduction, review recent developments and open questions, address the potential of new approaches for targeted pharmacological interventions.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"255 ","pages":"Article 108589"},"PeriodicalIF":13.5,"publicationDate":"2024-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0163725824000093/pdfft?md5=bc5565dedabd2dfbc5d23d1729365c86&pid=1-s2.0-S0163725824000093-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139577914","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}