Pharmaceuticals (Basel, Switzerland)最新文献

{"title":"Identification of Novel Arachidonic Acid 15-Lipoxygenase Inhibitors Based on the Bayesian Classifier Model and Computer-Aided High-Throughput Virtual Screening.","authors":"Yinglin Liao,&nbsp;Peng Cao,&nbsp;Lianxiang Luo","doi":"10.3390/ph15111440","DOIUrl":"https://doi.org/10.3390/ph15111440","url":null,"abstract":"<p><p>Ferroptosis is an iron-dependent lipid peroxidative form of cell death that is distinct from apoptosis and necrosis. ALOX15, also known as arachidonic acid 15-lipoxygenase, promotes ferroptosis by converting intracellular unsaturated lipids into oxidized lipid intermediates and is an important ferroptosis target. In this study, a naive Bayesian machine learning classifier with a structure-based, high-throughput screening approach and a molecular docking program were combined to screen for three compounds with excellent target-binding potential. In the absorption, distribution, metabolism, excretion, and toxicity characterization, three candidate molecules were predicted to exhibit drug-like properties. The subsequent molecular dynamics simulations confirmed their stable binding to the targets. The findings indicated that the compounds exhibited excellent potential ALOX15 inhibitor capacity, thereby providing novel candidates for the treatment of inflammatory ischemia-related diseases caused by ferroptosis.</p>","PeriodicalId":520747,"journal":{"name":"Pharmaceuticals (Basel, Switzerland)","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2022-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9695033/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40704911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fasudil Ameliorates Methotrexate-Induced Hepatotoxicity by Modulation of Redox-Sensitive Signals.","authors":"Esam M Aboubakr,&nbsp;Ahmed R N Ibrahim,&nbsp;Fares E M Ali,&nbsp;Ahmed A E Mourad,&nbsp;Adel M Ahmad,&nbsp;Amal Hofni","doi":"10.3390/ph15111436","DOIUrl":"https://doi.org/10.3390/ph15111436","url":null,"abstract":"<p><p>Methotrexate (MTX) is one of the most widely used cytotoxic chemotherapeutic agents, and it is used in the treatment of different autoimmune disorders. However, the clinical applications of MTX are limited by its hepatic toxicity. Hence, the present study was conducted to evaluate the efficacy of fasudil (Rho-Kinase inhibitor) in the amelioration of MTX hepatotoxicity and the possible underlying mechanisms. Experimentally, 32 male Sprague Dawley rats were used and divided into four groups: control, MTX (20 mg/kg, i.p., single dose), fasudil (10 mg/kg/day i.p.) for one week, and fasudil plus MTX. It was found that MTX significantly induced hepatitis and hepatocellular damage, as shown by abnormal histological findings and liver dysfunction (ALT and AST), with up-regulation of the inflammatory mediators NF-κB-p65 and IL-1β. Moreover, MTX remarkably disrupted oxidant/antioxidant status, as evidenced by malondialdehyde (MDA) up-regulation associated with the depletion of superoxide dismutase (SOD), catalase, and reduced glutathione (GSH) levels. Moreover, MTX reduced the hepatic expression of B-cell lymphoma 2 (Bcl-2). On the contrary, the i.p. administration of fasudil significantly ameliorated MTX hepatotoxicity by histopathological improvement, restoring oxidant/antioxidant balance, preventing hepatic inflammation, and improving the hepatic anti-apoptotic capability. Furthermore, fasudil hepatic concentration was determined for the first time using the validated RP-HPLC method. In conclusion, the present study revealed that fasudil has a reliable hepatoprotective effect against MTX hepatotoxicity with underlying antioxidant, anti-inflammatory, and anti-apoptotic mechanisms. It also introduced a new method for the determination of fasudil hepatic tissue concentration using the RP-HPLC technique.</p>","PeriodicalId":520747,"journal":{"name":"Pharmaceuticals (Basel, Switzerland)","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2022-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9693476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40704908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Naringin's Prooxidant Effect on Tumor Cells: Copper's Role and Therapeutic Implications.","authors":"Mohd Farhan","doi":"10.3390/ph15111431","DOIUrl":"https://doi.org/10.3390/ph15111431","url":null,"abstract":"<p><p>Plant-derived polyphenolic chemicals are important components of human nutrition and have been found to have chemotherapeutic effects against a variety of cancers. Several studies in animal models have proven polyphenols' potential to promote apoptosis and tumor regression. However, the method by which polyphenols show their anticancer effects on malignant cells is not well understood. It is generally known that cellular copper rises within malignant cells and in the serum of cancer patients. In this communication, investigations reveal that naringin (a polyphenol found in citrus fruits) can strongly suppress cell proliferation and trigger apoptosis in various cancer cell lines in the presence of copper ions. The cuprous chelator neocuproine, which confirms copper-mediated DNA damage, prevents such cell death to a large extent. The studies further show that the cellular copper transporters CTR1 and ATP7A have a role in the survival dynamics of malignant cells after naringin exposure. The findings emphasize the crucial function of copper dynamics and mobilization in cancer cells and pave the path for a better understanding of polyphenols as nutraceutical supplements for cancer prevention and treatment.</p>","PeriodicalId":520747,"journal":{"name":"Pharmaceuticals (Basel, Switzerland)","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2022-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9697029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40704413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute and Reproductive Toxicity Evaluation of Ormona^® SI and Ormona^® RC-Two New Nutraceuticals with Geranylgeraniol, Tocotrienols, Anthocyanins, and Isoflavones-In Adult Zebrafish.","authors":"Clarice Flexa da Rocha,&nbsp;Camila de Nazaré Nunes Flexa,&nbsp;Gisele Custodio de Souza,&nbsp;Arlindo César Matias Pereira,&nbsp;Helison de Oliveira Carvalho,&nbsp;Aline Lopes do Nascimento,&nbsp;Natasha Juliana Perdigão de Jesus Vasconcelos,&nbsp;Heitor Ribeiro da Silva,&nbsp;José Carlos Tavares Carvalho","doi":"10.3390/ph15111434","DOIUrl":"https://doi.org/10.3390/ph15111434","url":null,"abstract":"<p><p>The zebrafish is a popular organism to test the toxicity of compounds. Here, we evaluate the acute and reproductive toxicity of Ormona SI^® (OSI) and RC^® (ORC), two herbal products developed for menopausal women with tocotrienols, geranylgeraniol, isoflavones, and anthocyanins. The acute toxicity was evaluated by behavioral alterations, lethality, and tissue changes (intestine, liver, kidney) after oral treatment with high product doses (500, 1000, and 2000 mg/kg). The reproductive toxicity was evaluated after 21 days of oral treatment with OSI and ORC at 200 mg/kg. Our results show that the LD₅₀ could not be assessed due to the low mortality rate even with the highest dose; the behavioral alterations were not different from those of the group treated only with the vehicle (2% DMSO). The tissue changes were minor in OSI and more severe in ORC at the highest (2000 mg/kg) dose, while no tissue abnormality was observed at 500 mg/kg. In the reproductive assessment, continuous treatment could decrease the maturation of the reproductive cells, which also significantly decreases the egg spawning. This effect was attributed to the estrogenic activity of the isoflavones. In conclusion, the acute toxicity analysis shows that the products did not elicit lethal or sublethal effects observed in the model when used up to 500 mg/kg. Regarding the reproductive toxicity, decreased fertility was observed, which was expected due to the presence of isoflavones (phytoestrogens). Considering that the product is intended for menopausal and postmenopausal women, the presence of isoflavones is beneficial. Further studies should be performed to corroborate these results in mammals.</p>","PeriodicalId":520747,"journal":{"name":"Pharmaceuticals (Basel, Switzerland)","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2022-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9692698/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40704909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimization of Formulation Parameters in Preparation of <i>Fructus ligustri lucidi</i> Dropping Pills by Solid Dispersion Using 2³ Full Experimental Design.","authors":"Kai-Rong Wu,&nbsp;Wen-Ho Chuo,&nbsp;Yuh-Tyng Huang","doi":"10.3390/ph15111433","DOIUrl":"https://doi.org/10.3390/ph15111433","url":null,"abstract":"<p><p>Oleanolic acid (OA) is an active ingredient of the traditional Chinese medicine (TCM) <i>Fructus ligustri lucidi</i> (FLL). Its clinical use is restricted because it is water-insoluble and has limited dosage forms of administration at present. Hence, the FFL dropping pills were prepared by the hot-melt method of solid dispersion technology. A 2³ factorial design was used to examine the effects of the materials used to prepare the dropping pills (e.g., different ratios of PEG4000 and PEG6000, FLL extract loading, and percentage of Tween 80) on parameters such as dropping pill roundness, weight variation, and disintegration time. Moreover, 2³ full factorial design was utilized to search for the optimal formulation for dissolution experiments. The results showed that the percentage of Tween 80 demonstrated significant effects on dropping pill roundness, weight variation, and disintegration time; FLL extract loading affected roundness and weight variation; and different ratios of PEG4000 and PEG6000 only affected disintegration time. The optimal formulation of the dropping pills released 70% of the drug after 30 min of dissolution release, which was faster than commercially available FLL Chinese medicines. Furthermore, the amount released was higher than that of commercially available formulations. In this study, a solid dispersion technique was used to successfully produce FLL dropping pills. In addition to improving the water insolubility of FLL and increasing the dissolution release percentage of the drug, we increased the application value of FLL and reduced the issues of traditional administration dosage forms.</p>","PeriodicalId":520747,"journal":{"name":"Pharmaceuticals (Basel, Switzerland)","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2022-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9699142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40704414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated Chemical Characterization, Network Pharmacology and Transcriptomics to Explore the Mechanism of Sesquiterpenoids Isolated from <i>Gynura divaricata</i> (L.) DC. against Chronic Myelogenous Leukemia.","authors":"Xinyuan Ye,&nbsp;Long Wang,&nbsp;Xin Yang,&nbsp;Jie Yang,&nbsp;Jie Zhou,&nbsp;Cai Lan,&nbsp;Fahsai Kantawong,&nbsp;Warunee Kumsaiyai,&nbsp;Jianming Wu,&nbsp;Jing Zeng","doi":"10.3390/ph15111435","DOIUrl":"https://doi.org/10.3390/ph15111435","url":null,"abstract":"<p><p>Chronic myelogenous leukemia (CML) is a serious threat to human health, while drugs for CML are limited. Herbal medicines with structural diversity, low toxicity and low drug resistance are always the most important source for drug discoveries. <i>Gynura divaricata</i> (L.) DC. is a well-known herbal medicine whose non-alkaline ingredients (GD-NAIs) were isolated. The GD-NAIs demonstrated potential anti-CML activity in our preliminary screening tests. However, the chemical components and underlying mechanism are still unknown. In this study, GD-NAIs were tentatively characterized using UHPLC-HRMS combined with molecular networking, which were composed of 75 sesquiterpenoids. Then, the anti-CML activities of GD-NAIs were evaluated and demonstrated significant suppression of proliferation and promotion of apoptosis in K562 cells. Furthermore, the mechanism of GD-NAIs against CML were elucidated using network pharmacology combined with RNA sequencing. Four sesquiterpenoids would be the main active ingredients of GD-NAIs against CML, which could regulate PD-L1 expression and the PD-1 checkpoint pathway in cancer, PI3K/AKT, JAK/STAT, TGF-β, estrogen, Notch and Wnt signaling pathways. In conclusion, our study reveals the composition of GD-NAIs, confirms its anti-CML activity and elucidates their underlying mechanism, which is a potential countermeasure for the treatment of CML.</p>","PeriodicalId":520747,"journal":{"name":"Pharmaceuticals (Basel, Switzerland)","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2022-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9693606/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40704416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Changes in Tryptophan-Kynurenine Metabolism in Patients with Depression Undergoing ECT-A Systematic Review.","authors":"Tore Ivar Malmei Aarsland,&nbsp;Johanne Telnes Instanes,&nbsp;Maj-Britt Rocio Posserud,&nbsp;Arve Ulvik,&nbsp;Ute Kessler,&nbsp;Jan Haavik","doi":"10.3390/ph15111439","DOIUrl":"https://doi.org/10.3390/ph15111439","url":null,"abstract":"<p><p>The kynurenine pathway of tryptophan (Trp) metabolism generates multiple biologically active metabolites (kynurenines) that have been implicated in neuropsychiatric disorders. It has been suggested that modulation of kynurenine metabolism could be involved in the therapeutic effect of electroconvulsive therapy (ECT). We performed a systematic review with aims of summarizing changes in Trp and/or kynurenines after ECT and assessing methodological issues. The inclusion criterium was measures of Trp and/or kynurenines before and after ECT. Animal studies and studies using Trp administration or Trp depletion were excluded. Embase, MEDLINE, PsycInfo and PubMed were searched, most recently in July 2022. Outcomes were levels of Trp, kynurenines and ratios before and after ECT. Data on factors affecting Trp metabolism and ECT were collected for interpretation and discussion of the reported changes. We included 17 studies with repeated measures for a total of 386 patients and 27 controls. Synthesis using vote counting based on the direction of effect found no evidence of effect of ECT on any outcome variable. There were considerable variations in design, patient characteristics and reported items. We suggest that future studies should include larger samples, assess important covariates and determine between- and within-subject variability. PROSPERO (CRD42020187003).</p>","PeriodicalId":520747,"journal":{"name":"Pharmaceuticals (Basel, Switzerland)","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2022-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9694349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40704910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanism and Prospect of Gastrodin in Osteoporosis, Bone Regeneration, and Osseointegration.","authors":"Yi Li,&nbsp;Fenglan Li","doi":"10.3390/ph15111432","DOIUrl":"https://doi.org/10.3390/ph15111432","url":null,"abstract":"<p><p>Gastrodin, a traditional Chinese medicine ingredient, is widely used to treat vascular and neurological diseases. However, recently, an increasing number of studies have shown that gastrodin has anti-osteoporosis effects, and its mechanisms of action include its antioxidant effect, anti-inflammatory effect, and anti-apoptotic effect. In addition, gastrodin has many unique advantages in promoting bone healing in tissue engineering, such as inducing high hydrophilicity in the material surface, its anti-inflammatory effect, and pro-vascular regeneration. Therefore, this paper summarized the effects and mechanisms of gastrodin on osteoporosis and bone regeneration in the current research. Here we propose an assumption that the use of gastrodin in the surface loading of oral implants may greatly promote the osseointegration of implants and increase the success rate of implants. In addition, we speculated on the potential mechanisms of gastrodin against osteoporosis, by affecting actin filament polymerization, renin-angiotensin system (RAS) and ferroptosis, and proposed that the potential combination of gastrodin with Mg²⁺, angiotensin type 2 receptor blockers or artemisinin may greatly inhibit osteoporosis. The purpose of this review is to provide a reference for more in-depth research and application of gastrodin in the treatment of osteoporosis and implant osseointegration in the future.</p>","PeriodicalId":520747,"journal":{"name":"Pharmaceuticals (Basel, Switzerland)","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2022-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9698149/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40704415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating Mechanisms in Thrombotic Peripheral Arterial Disease.","authors":"Magdolna Nagy,&nbsp;Paola E J van der Meijden,&nbsp;Julia Glunz,&nbsp;Leon Schurgers,&nbsp;Esther Lutgens,&nbsp;Hugo Ten Cate,&nbsp;Stefan Heitmeier,&nbsp;Henri M H Spronk","doi":"10.3390/ph15111428","DOIUrl":"https://doi.org/10.3390/ph15111428","url":null,"abstract":"<p><p>Peripheral arterial disease (PAD), a manifestation of systemic atherosclerosis, is underdiagnosed in the general population. Despite the extensive research performed to unravel its pathophysiology, inadequate knowledge exists, thus preventing the development of new treatments. This review aims to highlight the essential elements of atherosclerosis contributing to the pathophysiology of PAD. Furthermore, emphasis will be placed on the role of thrombo-inflammation, with particular focus on platelet and coagulation activation as well as cell-cell interactions. Additional insight will be then discussed to reveal the contribution of hypercoagulability to the development of vascular diseases such as PAD. Lastly, the current antithrombotic treatments will be discussed, and light will be shed on promising new targets aiming to aid the development of new treatments.</p>","PeriodicalId":520747,"journal":{"name":"Pharmaceuticals (Basel, Switzerland)","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2022-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9695058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40704411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protection against Lipopolysaccharide-Induced Endotoxemia by Terrein Is Mediated by Blocking Interleukin-1β and Interleukin-6 Production.","authors":"Yeo Dae Yoon,&nbsp;Myeong Youl Lee,&nbsp;Byeong Jo Choi,&nbsp;Chang Woo Lee,&nbsp;Hyunju Lee,&nbsp;Joo-Hee Kwon,&nbsp;Jeong-Wook Yang,&nbsp;Jong Soon Kang","doi":"10.3390/ph15111429","DOIUrl":"https://doi.org/10.3390/ph15111429","url":null,"abstract":"<p><p>Terrein is a fungal metabolite and has been known to exert anti-melanogenesis, anti-cancer, and anti-bacterial activities. However, its role in endotoxemia has never been investigated until now. In the present study, we examined the effect of terrein on lipopolysaccharide (LPS)-induced endotoxemia in mice and characterized the potential mechanisms of action. Treatment with terrein increased the survival of mice and decreased the production of inflammatory cytokines, including interleukin-1β (IL-1β) and interleukin-6 (IL-6) in an LPS-induced endotoxemia model. In addition, terrein suppressed the LPS-induced production of IL-1β and IL-6 in RAW 264.7 cells, a murine macrophage-like cell line, and the mRNA expression of IL-1β and IL-6 was also inhibited by terrein in LPS-stimulated RAW 264.7 cells. Further study demonstrated that terrein blocked LPS-induced phosphorylation of p65 subunit of nuclear factor (NF)/κB and the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) was also suppressed by terrein treatment. Collectively, these results suggest that terrein exerts a protective effect again LPS-induced endotoxemia in mice by blocking the production of inflammatory cytokines. Our results also suggest that the anti-inflammatory effect of terrein might be mediated, at least in part, by blocking the activation of NF-κB, JNK, and p38 MAPK signaling pathways.</p>","PeriodicalId":520747,"journal":{"name":"Pharmaceuticals (Basel, Switzerland)","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2022-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9693353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40704410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}