{"title":"Salidroside improves blood-brain barrier integrity and cognitive function in hypobaric hypoxia mice by inhibiting microglia activation through GSK3β.","authors":"Xianxie Zhang, Huiting Zhang, Zuoxu Liu, Tianke Huang, Ru Yi, Zengchun Ma, Yue Gao","doi":"10.1002/ptr.8264","DOIUrl":"https://doi.org/10.1002/ptr.8264","url":null,"abstract":"<p><p>Salidroside, an active component found in Rhodiola rosea L., has emerged as a potential therapeutic agent for the prevention and treatment of hypoxic brain injury, while the precise target and mechanism of salidroside were remain unclear. The study utilized techniques such as network pharmacology, transcriptome sequencing to investigate the mechanism and target of salidroside in regulating blood-brain barrier (BBB) function to protect hypoxic brain injury in vivo. Utilized macromolecular docking and molecular biology techniques to explore the molecular mechanism of salidroside in alleviating brain injury induced by hypoxia in BV2 cell model. The results show that salidroside alleviated the learning and memory dysfunction and pathological injury in mice exposed to hypobaric hypoxia, reduced brain water content and attenuate the inflammatory response and oxidative stress, effectively reversed S100β in serum and promoted the repair of BBB. GSK3β is an important therapeutic target of salidroside in the treatment of hypoxic cognitive impairment, and salidroside can specifically bind GSK3β in the ATP binding pocket, inducing the phosphorylation of GSK3β, targeting downstream Nrf-2 to regulate microglia activity, promoting the accumulation of β-catenin, thereby inhibiting microglial activation, improving the BBB integrity injury and achieving a neuroprotective effect. This study demonstrates that salidroside can inhibit the activation of microglia by inducing GSK3β phosphorylation, achieve neuroprotective effects and alleviate learning and memory dysfunction in hypobaric hypoxia mice. This study provides a theoretical basis for the development of salidroside and the clinical application of Rhodiola rosea L.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372565","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}
Patrícia C Pires, Mahzad Motallebi, Mário Pedro Marques, Mafalda Correia, Ankur Sharma, Fouad Damiri, Huma Hameed, Sachin Kumar Singh, Kamal Dua, Niraj Kumar Jha, Célia Cabral, Francisco Veiga, Ana Cláudia Paiva-Santos
{"title":"Mentha aquatica (Water Mint) as a Source of Active Pharmaceutical and Cosmetic Ingredients: A Critical Review.","authors":"Patrícia C Pires, Mahzad Motallebi, Mário Pedro Marques, Mafalda Correia, Ankur Sharma, Fouad Damiri, Huma Hameed, Sachin Kumar Singh, Kamal Dua, Niraj Kumar Jha, Célia Cabral, Francisco Veiga, Ana Cláudia Paiva-Santos","doi":"10.1002/ptr.8337","DOIUrl":"https://doi.org/10.1002/ptr.8337","url":null,"abstract":"<p><p>Mentha aquatica L., or water mint, is an important member of the Mentha genus, and has long been used in traditional medicine, mainly to treat respiratory diseases such as the common cold. Nevertheless, although over the years many studies have shown that it's potential grows beyond this use, a review that highlights M. aquatica L.'s true potential is still lacking. Thus, the main purpose of the present article is to provide a thorough and multidisciplinary critical review of M. aquatica L., including its phytochemical characterization, main bioactivities, and current marketed cosmetic products. Many compounds have been identified as part of M. aquatica L. composition, such as terpenes, phenolic acids, phenols, and terpenoids, which have been linked to a vast therapeutic potential, namely anti-inflammatory, antioxidant, antibacterial, antifungal, antiobesity, and hepatoprotection bioactivities, with additional anticancer potential for several types of tumors (breast, lung, and skin), and psycho and neuroactive potential in depression, or Alzheimer's or Parkinson's disease. Additionally, it has been proven to be suitable for cosmetic application since several cleansing, hydrating, protecting, and/or odor masking products containing it are already available, with the main functions attributed to M. aquatica including refreshing/cooling effects, calming/soothing/relaxing effects, and purifying effects, properties closely related to its anti-inflammatory and antioxidant bioactivities. Hence, M. aquatica is an extremely versatile plant, with its extracts and essential oils having great therapeutic and cosmetic potential. With many marketed cosmetic products, future studies should focus on this plant's medicinal aspects, so that 1 day it can be part of therapeutic regimens.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372564","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":"The role of selected nutraceuticals in management of prediabetes and diabetes: An updated review of the literature. Part II.","authors":"Giuseppe Derosa, Angela D'Angelo, Pamela Maffioli","doi":"10.1002/ptr.8312","DOIUrl":"https://doi.org/10.1002/ptr.8312","url":null,"abstract":"<p><p>We have already published a review about the results of clinical trials evaluating the effects of selected nutraceuticals on glycemia in humans. In this second part, we describe the role of other nutraceuticals involved in dysglycemia. The available evidence showed promising hypoglycemic effects of the nutraceuticals reviewed both for their efficacy and safety profile. However, contradictory results as regard the efficacy of some supplements such as Allium sativum, Juglans regia, and Lycium barbarum on glucose homeostasis have emerged from some clinical studies. Other nutraceuticals including Aloe vera, Amorphophallus Konjac, Bauhinia forficata, Coccinia, Ganoderma lucidum, Ipomoea batatas, and Lupinus mutabilis require larger and long-term studies rigorously designed to confirm their hypoglycemic effects due to the scarce data available and the poor quality of clinical trials. Further studies are also required for Cinnamomum, Cynara scolymus, Momordica charantia, Olea europaea, and Opuntia streptacantha. Moreover, well-designed large and long-term clinical trials including the use of standardized nutraceutical preparations are necessary for Phaseolus vulgaris and Vaccinium myrtillus.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372566","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":"Cinnamaldehyde induces apoptosis and enhances anti-colorectal cancer activity via covalent binding to HSPD1.","authors":"Weiyi Zhang, Wei Lei, Fukui Shen, Mukuo Wang, Linlin Li, Junmin Chang","doi":"10.1002/ptr.7840","DOIUrl":"10.1002/ptr.7840","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is a common malignant tumor with high morbidity and mortality rates worldwide. Although surgical resection and adjuvant radiotherapy/chemotherapy are the mainstays of CRC treatment, the efficacy is unsatisfactory due to several limitations, including high drug resistance. Accordingly, there is a dire need for new drugs or a novel combination approach to treat this patient population. Herein, we found that cinnamaldehyde (CA) could exert an antitumor effect in HCT-116 cell lines. Target fishing, molecular imaging, and live-cell tracing using an alkynyl-CA probe revealed that the heat shock 60 kDa protein 1 (HSPD1) protein was the target of CA. The covalent binding of CA with HSPD1 altered its stability. Furthermore, our results demonstrated that CA could induce cell apoptosis by inhibiting the PI3K/Akt signaling pathway and enhanced anti-CRC activity both in vitro and in vivo. Meanwhile, CA combined with different chemotherapeutic agents was beneficial to patients resistant to anti-CRC drug therapy.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9385596","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 : 2024-10-01Epub Date: 2023-02-15DOI: 10.1002/ptr.7773
Mariam Sanjari-Pour, Nassim Faridi, Ping Wang, S Zahra Bathaie
{"title":"Protective effect of saffron carotenoids against amyloid beta-induced neurotoxicity in differentiated PC12 cells via the unfolded protein response and autophagy.","authors":"Mariam Sanjari-Pour, Nassim Faridi, Ping Wang, S Zahra Bathaie","doi":"10.1002/ptr.7773","DOIUrl":"10.1002/ptr.7773","url":null,"abstract":"<p><p>The preventive effect of saffron against Alzheimer's disease (AD) has been reported. Herein, we studied the effect of Cro and Crt, saffron carotenoids, on the cellular model of AD. The MTT assay, flow cytometry, and elevated p-JNK, p-Bcl-2, and c-PARP indicated the AβOs-induced apoptosis in differentiated PC12 cells. Then, the protective effects of Cro/Crt on dPC12 cells against AβOs were investigated in preventive and therapeutic modalities. Starvation was used as a positive control. RT-PCR and Western blot results revealed the reduced eIF2α phosphorylation and increased spliced-XBP1, Beclin1, LC3II, and p62, which indicate the AβOs-induced autophagic flux defect, autophagosome accumulation, and apoptosis. Cro and Crt inhibited the JNK-Bcl-2-Beclin1 pathway. They altered Beclin1 and LC3II and decreased p62 expressions, leading cells to survival. Cro and Crt altered the autophagic flux by different mechanisms. So, Cro increased the rate of autophagosome degradation more than Crt, while Crt increased the rate of autophagosome formation more than Cro. The application of 4μ8C and chloroquine as the inhibitors of XBP1 and autophagy, respectively, confirmed these results. So, augmentation of the survival branches of UPR and autophagy is involved and may serve as an effective strategy to prevent the progression of AβOs toxicity.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10514664","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":"Ginsenosides modulate hypothalamic-pituitary-adrenal function by inhibiting FKBP51 on glucocorticoid receptor to ameliorate depression in mice exposed to chronic unpredictable mild stress.","authors":"Hui Li, Meng Ge, Bofan Lu, Wei Wang, Yujuan Fu, Lili Jiao, Wei Wu","doi":"10.1002/ptr.8075","DOIUrl":"10.1002/ptr.8075","url":null,"abstract":"<p><p>Depression, which affects millions of individuals worldwide, is associated with glucocorticoid (GC) impairment, with the FKBP51 protein playing a pivotal role. Ginsenosides, extracted from the root of Panax ginseng C.A. Mey, have demonstrated the potential to mitigate depression associated with GC dysregulation. This study evaluated the therapeutic efficacy of ethanol extract of P. ginseng (PG) in treating depression and its underlying FKBP51-linked mechanism. Using chronic unpredictable stress, a depression model was developed in Kunming mice to test the efficacy of PG by observing changes in behaviors and protein expression in depressed mice. The mechanism of action was investigated through transfection with HEK293T cells. Depressed mice treated with PG demonstrated notable improvements: the rate of weight loss was reduced, sucrose preference and open-field activity were enhanced, and the rate of apoptosis in hippocampal cells was decreased. Additionally, the HPA axis function appeared to be restored. These physiological adjustments coincided with an increase in GR levels and a decrease in FKBP51 levels. Altogether, these results suggested that PG treatment effectively alleviates depressive symptoms in mice. PG also moderated FKBP51-GR interaction, lessening FKBP51's restraint on GR nuclear entry. This modulation may enhance the sensitivity of the GR response, reinforcing the negative feedback regulation of the HPA axis and thereby reducing depressive symptoms in mice. These findings highlight the potential of PG as a promising curative treatment for depression, providing a basis for the development of innovative treatments targeting the FKBP51-GR pathway.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142293208","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":"Safflower yellow and its main component hydroxysafflor yellow A alleviate hyperleptinemia in diet-induced obesity mice through a dual inhibition of the GIP-GIPR signaling axis.","authors":"Xiaorui Lyu, Kemin Yan, WenJing Hu, Hanyuan Xu, Xiaonan Guo, Zhibo Zhou, Huijuan Zhu, Hui Pan, Linjie Wang, Hongbo Yang, Fengying Gong","doi":"10.1002/ptr.7788","DOIUrl":"10.1002/ptr.7788","url":null,"abstract":"<p><p>Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone secreted by K cells in the small intestine and is considered an obesity-promoting factor. In this study, we systematically investigated the anti-obesity effects of intragastric safflower yellow (SY)/hydroxysafflor yellow A (HSYA) and the underlying mechanism for the first time. Our results showed that intragastric SY/HSYA, rather than an intraperitoneal injection, notably decreased serum GIP levels and GIP staining in the small intestine in diet-induced obese (DIO) mice. Moreover, intragastric SY/HSYA was also first found to significantly suppress GIP receptor (GIPR) signaling in both the hypothalamus and subcutaneous White adipose tissue. Our study is the first to show that intragastric SY/HSYA obviously reduced food intake and body weight gain in leptin sensitivity experiments and decreased serum leptin levels in DIO mice. Further experiments demonstrated that SY treatment also significantly reduced leptin levels, whereas the inhibitory effect of SY on leptin levels was reversed by activating GIPR in 3 T3-L1 adipocytes. In addition, intragastric SY/HSYA had already significantly reduced serum GIP levels and GIPR expression before the serum leptin levels were notably changed in high-fat-diet-fed mice. These findings suggested that intragastric SY/HSYA may alleviate diet-induced obesity in mice by ameliorating hyperleptinemia via dual inhibition of the GIP-GIPR axis.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9500467","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":"Remodeling of white adipose tissue microenvironment against obesity by phytochemicals.","authors":"Shuwei Ke, Qingyuan Hu, Guanyao Zhu, Linghuan Li, Xuechao Sun, Hongbin Cheng, Lingqiao Li, Yuanfa Yao, Hanbing Li","doi":"10.1002/ptr.7758","DOIUrl":"10.1002/ptr.7758","url":null,"abstract":"<p><p>Obesity is a kind of chronic disease due to a long-term imbalance between energy intake and expenditure. In recent years, the number of obese people around the world has soared, and obesity problem should not be underestimated. Obesity is characterized by changes in the adipose microenvironment, mainly manifested as hypertrophy, chronic inflammatory status, hypoxia, and fibrosis, thus contributing to the pathological changes of other tissues. A plethora of phytochemicals have been found to improve adipose microenvironment, thus prevent and resist obesity, providing a new research direction for the treatment of obesity and related diseases. This paper discusses remodeling of the adipose tissue microenvironment as a therapeutic avenue and reviews the progress of phytochemicals in fighting obesity by improving the adipose microenvironment.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10699855","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 : 2024-10-01Epub Date: 2022-10-17DOI: 10.1002/ptr.7623
Ni Ni, Lu-Ping Yang, Xiao Lin, Yan-Long Hong, Lan Shen
{"title":"Studies on the mechanism of energy metabolism via AMPK/PGC-1α signaling pathway induced by compatibility of Ligusticum chuanxiong Hort and Gastrodia.","authors":"Ni Ni, Lu-Ping Yang, Xiao Lin, Yan-Long Hong, Lan Shen","doi":"10.1002/ptr.7623","DOIUrl":"10.1002/ptr.7623","url":null,"abstract":"<p><p>AMP-activated protein kinase (AMPK) regulates overall energy consumption and energy intake through cytokines. Ligusticum striatum DC (CX) combined with Gastrodia elata Blume (TM) has been used for migraine treatment for millennia. When used alone in clinical practice, CX causes symptoms of thirst, irritability, and yellow urine and has influenced the levels of cytokines such as AMP that activate the AMPK pathway of energy metabolism. However, relationships between this compatibility prescription, integral biological energy metabolism, and the AMPK pathway remain unclear. Studies were performed by treating normal rats with physiological saline, CX extract, CX coupled TM extract, and TM extracts separately for 4 weeks. Food intake, water intake, urine output, stool output, and body weight were monitored once a week by the metabolic cage method. Values of FBG, BUN, TP, TC and TG in blood samples were detected approaching the whole blood automatic detector from 1 to 4 weeks. Na<sup>+</sup>-K<sup>+</sup>-ATPase, Ca<sup>2+</sup>-Mg<sup>2+</sup>-ATPase, cAMP, and cGMP activity were determined by the enzyme-linked immunosorbent assay (ELISA); the biological samples that were obtained at 1, 2, 3, and 4 weeks after drug administration were tested by GC-TOF-MS. Then real-time PCR and Western Blot were applied to detect changes in expression of some substances involved in energy metabolism. The results demonstrated that administering CX alone increased energy input, mobility, and respiratory exchange ratio, accelerated energy consumption, and caused inflammatory infiltration in the liver. CX coupled with TM led to lower energy metabolism and liver damage in comparison with CX used alone. Moreover, CX-treated rats harbored higher levels of differential metabolites (including pyrophosphate, oxaloacetic acid, and galactinol). Glycerophospholipid metabolism and the citrate cycle are closely related to the differential metabolites above. In addition, CX-induced unbalanced energy metabolism depends on cAMP activation mediated by the AMPK/PGC-1α pathway in rats. Our findings suggest that CX-induced energy metabolism imbalance was corrected after coupling with TM by mediating the AMPK/PGC-1α pathway.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33519386","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":"Nephrotoxicity assessment of Esculentoside A using human-induced pluripotent stem cell-derived organoids.","authors":"Shuyi Gu, Gaosong Wu, Dong Lu, Guofeng Meng, Yu Wang, Liming Tang, Weidong Zhang","doi":"10.1002/ptr.7721","DOIUrl":"10.1002/ptr.7721","url":null,"abstract":"<p><p>Drug-induced nephrotoxicity is a leading cause of acute kidney injury (AKI). A major obstacle in predicting AKI is the lack of a comprehensive experimental model that mimics stable and physiologically relevant kidney functions and accurately reflects the changes a drug induces. Organoids derived from human-induced pluripotent stem cells (iPSCs) are promising models because of their reproducibility and similarity to the in vivo conditions. In this study, Esculentoside A, the triterpene saponin with the highest concentration isolated from the root of Phytolacca acinose Roxb., was used to induce kidney injury models in vivo and kidney organoids. Esculentoside A induced AKI in mice, together with pathological changes and enhanced apoptosis. Moreover, Esculentoside A damaged podocytes and proximal tubular endothelial cells in kidney organoids in a similar way as in vivo. We also found that treatment with 60 μM Esculentoside A induced the known biomarkers of kidney damage and inflammatory cytokines (such as kidney injury molecule (KIM-1), β2-microglobulin (β2-M), and cystatin C (CysC)) in the organoids, in which activation of Cleaved Caspase-3 was involved, possibly due to lowered mitochondrial membrane potential. In summary, this study strongly suggests using kidney organoids as a reliable platform to assess Chinese medicine-induced nephrotoxicity.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10230773","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}