{"title":"Neutrophil extracellular traps: Potential targets for the treatment of rheumatoid arthritis with traditional Chinese medicine and natural products.","authors":"Yuan Liu, Yuan Qu, Chuanguo Liu, Di Zhang, Bing Xu, Yakun Wan, Ping Jiang","doi":"10.1002/ptr.8311","DOIUrl":"10.1002/ptr.8311","url":null,"abstract":"<p><p>Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease. Abnormal formation of neutrophil extracellular traps (NETs) at the synovial membrane leads to the release of many inflammatory cytokines, including IL-1β, IL-6, and TNF-α. Elastase, histone H3, and myeloperoxidase, which are carried by NETs, damage the soft tissues of the joints and aggravate the progression of RA. The balance of NET formation coordinates the pro-inflammatory and anti-inflammatory effects and plays a key role in the development of RA. Therefore, when NETs are used as effector targets, highly targeted drugs with fewer side effects can be developed to treat RA without damaging the host immune system. Currently, an increasing number of studies have shown that traditional Chinese medicines and natural products can regulate the formation of NETs through multiple pathways to counteract RA, which shows great potential for the treatment of RA and has a promising future for clinical application. In this article, we review the latest biological progress in understanding NET formation, the mechanism of NETs in RA, and the potential targets or pathways related to the modulation of NET formation by Chinese medicines and natural products. This review provides a relevant basis for the use of Chinese medicines and natural products as natural adjuvants in the treatment of RA.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":"5067-5087"},"PeriodicalIF":5.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141894097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Phytotherapy ResearchPub Date : 2024-11-01Epub Date: 2024-09-03DOI: 10.1002/ptr.8315
Yifeng Jin, Mingyue Tan, Yunfei Yin, Chen Lin, Yongjian Zhao, Jun Zhang, Tingbo Jiang, Hongxia Li, Mingqing He
{"title":"Oroxylin A alleviates myocardial ischemia-reperfusion injury by quelling ferroptosis via activating the DUSP10/MAPK-Nrf2 pathway.","authors":"Yifeng Jin, Mingyue Tan, Yunfei Yin, Chen Lin, Yongjian Zhao, Jun Zhang, Tingbo Jiang, Hongxia Li, Mingqing He","doi":"10.1002/ptr.8315","DOIUrl":"10.1002/ptr.8315","url":null,"abstract":"<p><p>Reperfusion therapy is the primary treatment strategy for acute myocardial infarction (AMI). Paradoxically, it can lead to myocardial damage, namely myocardial ischemia/reperfusion injury (MIRI). This study explored whether oroxylin A (OA) protects the myocardium after MIRI by inhibiting ferroptosis and the underlying mechanism. In vivo, we established an MIRI model to investigate the protective effect of OA. In vitro, H9C2 cells were used to explore the regulation of ferroptosis by OA through immunofluorescence staining, western blotting, assay kits, etc. Additionally, RNA sequencing analysis (RNA-seq) and network pharmacology analyses were conducted to elucidate the molecular mechanisms. Our results showed that MIRI caused cardiac structural and functional damage in rats. MIRI promoted ferroptosis, which was consistently observed in vitro. However, pretreatment with OA reversed these effects. The mitogen-activated protein kinases (MAPK) signaling pathway participated in the MIRI process, with dual-specificity phosphatase 10 (DUSP10) found to regulate it. Further confirmation was provided by knocking down DUSP10 using small interfering RNA (siRNA), demonstrating the activation of the DUSP10/MAPK-Nrf2 pathway by OA to protect H9C2 cells from ferroptosis. Our research has demonstrated the mitigating effect of OA on MIRI and the improvement of myocardial function for the first time. The inhibition of ferroptosis has been identified as one of the mechanisms through which OA exerts its myocardial protective effects. Moreover, we have first unveiled that DUSP10 serves as an upstream target involved in mediating ferroptosis, and the regulation of the DUSP10/MAPK-Nrf2 pathway by OA is crucial in inhibiting ferroptosis to protect the myocardium.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":"5290-5308"},"PeriodicalIF":6.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Harmine promotes megakaryocyte differentiation and thrombopoiesis by activating the Rac1/Cdc42/JNK pathway through a potential target of 5-HTR2A.","authors":"Xiaoxi Liu, Jia Lai, Xiaoqin Zhang, Anguo Wu, Ling Zhou, Yueyue Li, Qianqian Huang, Xinwu Huang, Hua Li, Cai Lan, Jian Liu, Feihong Huang, Jianming Wu","doi":"10.1002/ptr.8317","DOIUrl":"10.1002/ptr.8317","url":null,"abstract":"<p><p>Harmine (HM), a β-carboline alkaloid extracted from plants, is a crucial component of traditional Chinese medicine (TCM) known for its diverse pharmacological activities. Thrombocytopenia, a common and challenging hematological disorder, often coexists with serious illnesses. Previous research has shown a correlation between HM and thrombocytopenia, but the mechanism needs further elucidation. The aim of this study was to clarify the mechanisms underlying the effects of HM on thrombocytopenia and to develop new therapeutic strategies. Flow cytometry, Giemsa staining, and Phalloidin staining were used to assess HM's impact on Meg-01 and HEL cell differentiation and maturation in vitro. A radiation-induced thrombocytopenic mouse model was employed to evaluate HM's effect on platelet production in vivo. Network pharmacology, molecular docking, and protein blotting were utilized to investigate HM's targets and mechanisms. The results demonstrated that HM dose-dependently promoted Meg-01 and HEL cell differentiation and maturation in vitro and restored platelet levels in irradiated mice in vivo. Subsequently, HM was found to be involved in the biological process of platelet production by upregulating the expressions of Rac1, Cdc42, JNK, and 5-HTR2A. Furthermore, the targeting of HM to 5-HTR2A and its correlation with downstream Rac1/Cdc42/JNK were also confirmed. In conclusion, HM regulates megakaryocyte differentiation and thrombopoiesis through the 5-HTR2A and Rac1/Cdc42/JNK pathways, providing a potential treatment strategy for thrombocytopenia.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":"5134-5149"},"PeriodicalIF":6.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Ginsenoside Re inhibits non-small cell lung cancer progression by suppressing macrophage M2 polarization induced by AMPKα1/STING positive feedback loop.","authors":"Xiaoyu Tang, Man Zhu, Zeren Zhu, Wenjun Tang, Hongmei Zhang, Yanbin Chen, Feng Liu, Yanmin Zhang","doi":"10.1002/ptr.8309","DOIUrl":"10.1002/ptr.8309","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs) in non-small cell lung cancer (NSCLC) promote tumor cell metastasis by interacting with cancer cells. Ginsenoside Re is capable of modulating the host immune system and exerts anticancer effects through multiple pathways. Both AMPK and STING are involved in the regulation of MΦ polarization, thereby affecting tumor progression. However, whether there is a regulatory relationship between them and its effect on MΦ polarization and tumor progression is unclear. The aim of this study was to provide mechanistic evidence that ginsenoside Re modulates MΦ phenotype through inhibition of the AMPKα1/STING positive feedback loop and thus exerts an antimetastatic effect in NSCLC immunotherapy. Cell culture models and conditioned media (CM) systems were constructed, and the treated MΦ were analyzed by database analysis, RT-PCR, Western blotting, flow cytometry, and immunofluorescence to determine the regulatory relationship between AMPK and STING and the effects of ginsenoside Re on MΦ polarization and tumor cells migration. The effects of ginsenoside Re (10, 20 mg/kg/day) on TAMs phenotype as well as tumor progression in mice were assessed by HE staining, immunohistochemical staining, and Western blotting. In this study, AMPKα1/STING positive feedback loop in NSCLC TAMs induced M2 type polarization, which in turn promoted NSCLC cell migration. In addition, ginsenoside Re was discovered to inhibit M2-like MΦ polarization, thereby inhibiting NSCLC cell migration. Mechanistically, Re was able to inhibit the formation of the AMPKα1/STING positive feedback loop, thereby inhibiting its induction of M2-like MΦ and consequently inhibiting the epithelial-mesenchymal transition (EMT) process of NSCLC cells. Furthermore, in mouse models, Re was found to suppress LLC tumor growth and colonization by inhibiting M2-type polarization of TAMs. Our finding indicates that ginsenoside Re can effectively modulate MΦ polarization and thus play an important role in antimetastatic immunotherapy of NSCLC.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":"5088-5106"},"PeriodicalIF":6.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141907371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Quercetin supplementation prevents kidney damage and improves long-term prognosis in hypertensive patients.","authors":"Yawei Zheng, Yuan Fang, Li Li, Huihui Wang, Siqi Zhang, Yuan Zhu, Yating Wang, Xianze Meng, Zhen Fang, Yu Luo, Zhuyuan Fang","doi":"10.1002/ptr.8306","DOIUrl":"10.1002/ptr.8306","url":null,"abstract":"<p><p>Quercetin has shown potential antihypertensive-like activities in several studies. The present study aimed to test the effect of quercetin supplementation on kidney damage and long-term prognosis in hypertensive patients. The data of enrolled hypertensive patients were acquired from the NHANES dataset. The flavanol intake data was extracted from the FNDDS flavonoid database. Information regarding mortality was extracted from the NCHS. A total of 5801 hypertensive patients were included in this study. Preliminary analysis found that the total flavanols intake dosage was the independent influence factor of the kidney damage prevalence in hypertension, and it was found that only the quercetin supplementation was the protective factor for kidney damage after stratification analysis. For every 10 mg/d increase in quercetin intake, the kidney damage prevalence decreased by 8% [OR = 0.92, 95% CI: 0.85-0.99, p = 0.032]. The comprehensive analysis results suggested that hypertensive patients in the quercetin-high group had a lower kidney damage prevalence and a higher survival probability than those in the quercetin-low group. The urine microalbumin of hypertensive patients in the quercetin-high group was significantly lower than that of hypertensive patients in the quercetin-low group. In addition, at a median follow-up time of 122 months, the mortality decreased by 9% [HR = 0.91, 95% CI: 0.84-0.99, p = 0.031] for every 10 mg/d increase in quercetin intake. The findings suggested that high quercetin intake was associated with low kidney damage prevalence and high survival probability. Based on the existing evidence, promoting quercetin supplementation as a supplementary treatment for hypertensive patients was warranted.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":"5376-5388"},"PeriodicalIF":6.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Phytotherapy ResearchPub Date : 2024-11-01Epub Date: 2024-08-04DOI: 10.1002/ptr.8301
Da Hee Lee, Hye Jin Lee, Gabsik Yang, Dae Yong Kim, Jong Uk Kim, Tae Han Yook, Jun Ho Lee, Hong Jun Kim
{"title":"A novel treatment strategy targeting cellular pathways with natural products to alleviate sarcopenia.","authors":"Da Hee Lee, Hye Jin Lee, Gabsik Yang, Dae Yong Kim, Jong Uk Kim, Tae Han Yook, Jun Ho Lee, Hong Jun Kim","doi":"10.1002/ptr.8301","DOIUrl":"10.1002/ptr.8301","url":null,"abstract":"<p><p>Sarcopenia is a condition marked by a significant reduction in muscle mass and strength, primarily due to the aging process, which critically impacts muscle protein dynamics, metabolic functions, and overall physical functionality. This condition leads to increased body fat and reduced daily activity, contributing to severe health issues and a lower quality of life among the elderly. Recognized in the ICD-10-CM only in 2016, sarcopenia lacks definitive treatment options despite its growing prevalence and substantial social and economic implications. Given the aging global population, addressing sarcopenia has become increasingly relevant and necessary. The primary causes include aging, cachexia, diabetes, and nutritional deficiencies, leading to imbalances in protein synthesis and degradation, mitochondrial dysfunction, and hormonal changes. Exercise remains the most effective intervention, but it is often impractical for individuals with limited mobility, and pharmacological options such as anabolic steroids and myostatin inhibitors are not FDA-approved and are still under investigation. This review is crucial as it examines the potential of natural products as a novel treatment strategy for sarcopenia, targeting multiple mechanisms involved in its pathogenesis. By exploring natural products' multi-targeted effects, this study aims to provide innovative and practical solutions for sarcopenia management. Therefore, this review indicates significant improvements in muscle mass and function with the use of specific natural compounds, suggesting promising alternatives for those unable to engage in regular physical activity.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":"5033-5051"},"PeriodicalIF":5.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Phytotherapy ResearchPub Date : 2024-11-01Epub Date: 2024-09-03DOI: 10.1002/ptr.8319
Roua Ben Dassi, Salah Ibidhi, Hedya Jemai, Ameur Cherif, Rim Driouich Chaouachi
{"title":"Resveratrol: Challenges and prospects in extraction and hybridization with nanoparticles, polymers, and bio-ceramics.","authors":"Roua Ben Dassi, Salah Ibidhi, Hedya Jemai, Ameur Cherif, Rim Driouich Chaouachi","doi":"10.1002/ptr.8319","DOIUrl":"10.1002/ptr.8319","url":null,"abstract":"<p><p>Resveratrol (RSV), a bioactive natural phenolic compound found in plants, fruits, and vegetables, has garnered significant attention in pharmaceutical, food, and cosmetic industries due to its remarkable biological and pharmacological activities. Despite its potential in treating various diseases, its poor pharmacokinetic properties, such as low solubility, stability, bioavailability, and susceptibility to rapid oxidation, limit its biomedical applications. Recent advancements focus on incorporating resveratrol into innovative materials like nanoparticles, polymers, and bio-ceramics to enhance its properties and bioavailability. In this review, an exhaustive literature search was conducted from PubMed, Google Scholar, Science Direct, Scopus, and Web of Science databases to explore these advancements, to compares conventional and innovative extraction methods, and to highlights resveratrol's therapeutic potential, including its anti-inflammatory, anti-oxidative, anti-cancerogenic, antidiabetic, neuroprotective, and cardio-protective properties. Additionally, we discuss the challenges and prospects of hybrid materials combining resveratrol with nanoparticles, polymers, and bio-ceramics for therapeutic applications. Rigorous studies are still needed to confirm their clinical efficacy.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":"5309-5322"},"PeriodicalIF":5.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142126297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Phytotherapy ResearchPub Date : 2024-11-01Epub Date: 2024-08-15DOI: 10.1002/ptr.8314
Xirui He, Xufei Chen, Yan Yang, Jingyi Gu, Yulu Xie, Yujie Liu, Man Hao, Michael Heinrich
{"title":"The role of gastrodin in the management of CNS-related diseases: Underlying mechanisms to therapeutic perspectives.","authors":"Xirui He, Xufei Chen, Yan Yang, Jingyi Gu, Yulu Xie, Yujie Liu, Man Hao, Michael Heinrich","doi":"10.1002/ptr.8314","DOIUrl":"10.1002/ptr.8314","url":null,"abstract":"<p><p>Central nervous system (CNS)-related diseases have a high mortality rate, are a serious threat to physical and mental health, and have always been an important area of research. Gastrodin, the main active metabolite of Gastrodia elata Blume, used in Chinese medicine and food, has a wide range of pharmacological effects, mostly related to CNS disorders. This review aims to systematically summarize and discuss the effects and underlying mechanisms of gastrodin in the treatment of CNS diseases, and to assess its potential for further development as a lead drug in both biomedicine and traditional Chinese medicine. Studies on the pharmacological effects of gastrodin on the CNS indicate that it may exert anti-neurodegenerative, cerebrovascular protective, and ameliorative effects on diabetic encephalopathy, perioperative neurocognitive dysfunction, epilepsy, Tourette's syndrome, depression and anxiety, and sleep disorders through various mechanisms. To date, 110 gastrodin products have been approved for clinical use, but further multicenter clinical case-control studies are relatively scarce. Preclinical studies have confirmed that gastrodin can be used to treat CNS-related disorders. However, important concerns need to be addressed in the context of likely non-specific, assay interfering effects when gastrodin is studied using in vitro and in silico approaches, calling for a systematic assessment of the evidence to date. High-quality clinical trials should have priority to evaluate the therapeutic safety and clinical efficacy of gastrodin. Further experimental research using appropriate in vivo models is also needed, focusing on neurodegenerative diseases, cerebral ischemic and hypoxic diseases, brain damage caused by methamphetamine or heavy metals, and epilepsy.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":"5107-5133"},"PeriodicalIF":5.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Phytotherapy ResearchPub Date : 2024-11-01Epub Date: 2024-08-27DOI: 10.1002/ptr.8310
Xiang Zheng, Fang-Chen Ye, Tao Sun, Fei-Jun Liu, Ming-Jian Wu, Wen-Hao Zheng, Ling-Feng Wu
{"title":"Delay the progression of glucocorticoid-induced osteoporosis: Fraxin targets ferroptosis via the Nrf2/GPX4 pathway.","authors":"Xiang Zheng, Fang-Chen Ye, Tao Sun, Fei-Jun Liu, Ming-Jian Wu, Wen-Hao Zheng, Ling-Feng Wu","doi":"10.1002/ptr.8310","DOIUrl":"10.1002/ptr.8310","url":null,"abstract":"<p><p>Glucocorticoid-induced osteoporosis (GIOP) commonly accelerates bone loss, increasing the risk of fractures and osteonecrosis more significantly than traditional menopausal osteoporosis. The extracellular environment influenced by glucocorticoids heightens fracture and osteonecrosis risks. Fraxin (Fra), a key component of the traditional Chinese herbal remedy Cortex Fraxini, is known for its wide-ranging pharmacological effects, but its impact on GIOP remains unexplored. This investigation aims to delineate the effects and underlying mechanisms of Fra in combating dexamethasone (Dex)-induced ferroptosis and GIOP. We established a mouse model of GIOP via intraperitoneal injections of Dex and cultured osteoblasts with Dex treatment for in vitro analysis. We evaluated the impact of Fra on Dex-treated osteoblasts through assays such as C11-BODIPY and FerroOrange staining, mitochondrial functionality tests, and protein expression analyses via Western blot and immunofluorescence. The influence of Fra on bone microarchitecture of GIOP in mice was assessed using microcomputerized tomography, hematoxylin and eosin staining, double-labeling with Calcein-Alizarin Red S, and immunohistochemistry at imaging and histological levels. Based on our data, Fra prevented Dex-induced ferroptosis and bone loss. In vitro, glutathione levels increased and malondialdehyde, lipid peroxidation, and mitochondrial reactive oxygen species decreased. Fra treatment also increases nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4), and COL1A1 expression and promotes bone formation. To delve deeper into the mechanism, the findings revealed that Fra triggered the activation of Nrf2/GPX4 signaling. Moreover, the use of siRNA-Nrf2 blocked the beneficial effect of Fra in osteoblasts cultivated with Dex. Fra effectively combats GIOP by activating the Nrf2/GPX4 signaling pathway to inhibit ferroptosis.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":"5203-5224"},"PeriodicalIF":6.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142081258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}