Naunyn-Schmiedeberg's archives of pharmacology最新文献

{"title":"Immunocyte phenotypes and childhood disease susceptibility: insights from bidirectional Mendelian randomization and implications for immunomodulatory therapies.","authors":"Yanggang Hong, Yi Wang, Wanyi Shu","doi":"10.1007/s00210-025-04091-1","DOIUrl":"https://doi.org/10.1007/s00210-025-04091-1","url":null,"abstract":"<p><p>Immune cells are essential for maintaining immune homeostasis during childhood and influence both growth and disease susceptibility. However, the causal relationships between immunocyte phenotypes and childhood diseases remain unclear. This study employed a two-sample Mendelian Randomization (MR) analysis to assess causal associations between 731 immunocyte phenotypes and four major childhood diseases: childhood obesity, childhood absence epilepsy, childhood asthma, and childhood allergies. Genome-wide association study (GWAS) data were used, and stringent instrumental variable (IV) selection and multiple sensitivity analyses, including MR-Egger, weighted median, and leave-one-out tests, were applied to validate the robustness of the results. Significant associations were identified between specific T cell, monocyte, and B cell phenotypes and childhood diseases. Notably, CD8bright T cells and CD19 + B cells were positively correlated with childhood obesity, while monocyte subtypes were strongly associated with asthma pathophysiology. Reverse MR analysis indicated no significant causal effects of childhood diseases on immune phenotypes, except for negative associations between childhood asthma and TCRgd AC, and childhood allergy and CD28 + CD45RA + CD4 + cells. These findings highlight the critical role of immune dysregulation in childhood disease etiology and suggest potential targets for immunomodulatory therapies. Understanding these immune-disease interactions may inform novel pharmacological interventions, particularly in immune-mediated disorders such as asthma and obesity. Further research into immune-targeted therapies could enhance treatment strategies for pediatric conditions associated with chronic inflammation and immune dysfunction.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the therapeutic potential of tryptophan and vitamin A in modulating immune responses in celiac disease: an experimental study.","authors":"Fatemeh Asgari, Abdolrahim Nikzamir, Kaveh Baghaei, Andrea Masotti, Mohammad Rostami-Nejad","doi":"10.1007/s00210-025-04089-9","DOIUrl":"https://doi.org/10.1007/s00210-025-04089-9","url":null,"abstract":"<p><p>Dendritic cells (DCs) play a crucial role in gliadin-induced inflammation in celiac disease as they are the first immune cells to encounter gliadin. Tryptophan (Trp) and vitamin A (retinol, Ret) are known to influence the immune response of DCs to gliadin and increase their tolerogenicity. CD4 + CD25 + Foxp3 + regulatory T cells (Tregs), which are important for immune tolerance, can be generated from naive T cells in the presence of retinoic acid (RA) and TGF-β.The aim of this study was to determine the combined effect of Ret and Trp in altering the phenotypic and functional maturation of DCs by gliadin and their contribution to the differentiation of Tregs. Monocyte cells derived from the peripheral blood mononuclear cells (PBMCs) of patients with celiac disease were differentiated into DCs and stimulated with PT-gliadin. These cells were then treated with Trp + Ret. The expression of CD11c, CD14, CD83, CD86, PDL1, CD4, CD25 and FOXP3 was examined using flow cytometry. TGF-β, IL-10, IL-12, and TNF-α levels were measured by ELISA. qRT-PCR was used to quantify the mRNA levels of retinaldehyde dehydrogenase 2 (RALDH2), integrin αE (CD103), and NF-κB. Indoleamine 2,3-dioxygenase (IDO) mRNA and protein levels were assessed using qRT-PCR and Western blot assays, respectively. The maturation of DCs by PT-gliadin was defined through co-stimulatory molecule expression (CD83 and CD86) and promotion of TNF-α and IL-12 secretion. We found that after treatment with Ret + Trp, the production levels of IL-12, TNF-α, and NF-κB were significantly reduced, while the expression of IL-10, TGF-β, and the inhibitory markers PDL1, CD103, IDO, and RALDH2 by PT-gliadin-stimulated DCs was significantly increased. Furthermore, in a DC and T cell co-culture system, treatment of DCs with Ret + Trp increased TGF-β expression in DCS and promoted CD4 + CD25 + FOXP3 Treg induction. These results indicate the potential benefit of vitamin A and tryptophan as therapeutic options for individuals with celiac disease. Further research is required to fully understand the mechanisms of action of these substances in these cells.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of key immune genes of drug-induced liver injury induced by tolvaptan based on bioinformatics.","authors":"Xiyun Yang, Yuxuan Ming, Zhihui Zhou, Xinyi Zhou, Chaolong Rao","doi":"10.1007/s00210-025-04084-0","DOIUrl":"https://doi.org/10.1007/s00210-025-04084-0","url":null,"abstract":"<p><p>Drug-induced liver injury (DILI) poses critical challenges in preclinical drug development and is a primary reason for candidate drug attrition. The incidence of DILI has risen in recent years. While immune-related genes (IRGs) are crucial in immune infiltration, their expression and regulatory mechanisms in tolvaptan-induced DILI remain largely uncharacterized. RNA sequencing data related to DILI and associated clinical data were sourced from the Gene Expression Omnibus (GEO), and IRGs were obtained from the ImmPort database. Differentially expressed genes (DEGs) from DILI and IRGs were intersected to identify differentially expressed immune-related genes (DEIRGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to elucidate the biological functions of DEIRGs. In addition, a protein-protein interaction (PPI) network of DEIRGs was constructed. Immunocytes and immune regulation analyses were conducted using the CIBERSORT tool. Receiver operating characteristic (ROC) curves were constructed to assess the diagnostic accuracy of individual DEIRGs. Networks of transcription factor and microRNA co-regulation were constructed using the NetworkAnalyst database. The expression of DEIRGs in DILI samples was quantified with RT-qPCR. From GSE99878, 204 DEGs were identified, with 23 matching IRGs exhibiting significant expression differences in 17 DEIRGs. The ROC curve analysis suggested satisfactory diagnostic values for six DEIRGs. The potential gene regulatory network comprised 214 microRNAs, 257 transcription factors, and 23 DEIRGs. Finally, RT-qPCR confirmed the expression levels of nine DEIRGs, aligning with public database results. The study revealed numerous immune-related biomarkers, verifying expression in five pivotal genes (ICAM1, CXCL10, IGF1, CX3CL1, and EGFR) and highlighting four genes with notable diagnostic potential (TNFAIP3, BDNF, NR1D2, and PPARA). Additionally, it explored the roles of key biomarkers in inflammatory responses, relevant signaling pathways, and interaction networks, offering new insights into DILI diagnosis, mechanistic understanding, and treatment strategies.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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 irisin in exercise-induced muscle and metabolic health: a narrative review.","authors":"Sumaya Nadhim Mohammed, Mohannad Hamid Jasim, Shahad Hisham Mahmood, Eman Naji Saleh, Alireza Hashemzadeh","doi":"10.1007/s00210-025-04083-1","DOIUrl":"https://doi.org/10.1007/s00210-025-04083-1","url":null,"abstract":"<p><p>Irisin, a myokine released during physical exercise, has emerged as a key mediator of muscle health and metabolic regulation. This review synthesizes current evidence on how aerobic exercise stimulates irisin release and its subsequent effects, including enhanced muscle mass, strength, and recovery. Additionally, irisin promotes the browning of white adipose tissue, improving fat metabolism and glucose regulation. These adaptations position irisin as a promising therapeutic target for preventing metabolic disorders and optimizing exercise protocols. By exploring human studies and mechanistic insights, this review underscores irisin's potential to address global health challenges, such as obesity and type 2 diabetes, while advancing strategies for personalized exercise interventions.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Crocus sativus and its active constituents on cytochrome P450: a review.","authors":"Pooneh Bathaei, Mohsen Imenshahidi, Nasser Vahdati-Mashhadian, Hossein Hosseinzadeh","doi":"10.1007/s00210-024-03525-6","DOIUrl":"https://doi.org/10.1007/s00210-024-03525-6","url":null,"abstract":"<p><p>Cytochrome P450 (CYP) enzymes play an important role in the biotransformation of drugs and endogenous substances. Clinical medications and herbal remedies can either enhance or inhibit the activity of CYP enzymes, leading to potential drug interactions between herbal supplements and prescribed medications. Such interactions can lead to serious consequences, especially for drugs with a narrow therapeutic index, such as digoxin, warfarin, and cyclosporine A. In this review article, we provide an updated review of the impact of saffron, and its active constituents, safranal and crocin, on the 12 major human CYP enzymes and possible drug interactions between saffron and prescription drugs. The available evidence indicates that saffron and its active constituents affect the expression or activity of some CYP isoforms, including the CYP1A1/2, CYP3A4, and CYP2E1 subfamily. Considering the important role of these CYPs in the biotransformation of frequently prescribed medications and the activation of procarcinogen into carcinogenic metabolites, it can be expected that the consumption of saffron and its active constituents may influence the pharmacokinetics and toxicity of several substances. In particular, given the critical role of CYP3A4 in drug metabolism, and saffron's inhibitory impact on this CYP enzyme, it appears that saffron's most significant interaction is linked to its inhibition of CYP3A4. In addition, the inhibitory effect of saffron on CYP1A1/2, and CYP2E1 expression can play a role in the chemopreventive effect of this herbal medicine. Additional research is crucial for evaluating the clinical significance of these interactions in patients who consume saffron along with prescription drugs and determining the dose that can lead to drug interactions.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting therapy of PI3K/AKT signaling pathway via non-coding RNAs in diabetic retinopathy.","authors":"Shuai Lu, Jian Cai","doi":"10.1007/s00210-025-04093-z","DOIUrl":"https://doi.org/10.1007/s00210-025-04093-z","url":null,"abstract":"<p><p>Phosphoinositide 3-kinases (PI3Ks) are essential for maintaining glucose homeostasis. When these molecules malfunction, it can lead to increased blood glucose levels, which is the primary pathophysiological characteristic of diabetes. New data indicates that the PI3K/AKT signaling pathway is interacting reciprocally with non-coding RNAs (ncRNAs) such as miRNAs, long ncRNAs (lnc RNA), and circRNAs. Thus, it is clear that aberrant ncRNA regulation in the PI3K/AKT axis is connected to clinicopathological characteristics and is required for regulating biological processes. Diabetic retinopathy (DR) is a common complication of diabetes resulting from high blood sugar levels damaging the retina. Consequently, there is a greater need than ever for this prevention and treatment of disease. There has been a lot of interest in treating DR by targeting particular ncRNAs. The pathogenic functions of ncRNAs in DR are the main topic of this review. This review aims to explain the relationship between the PI3K/AKT signaling system and different miRNAs/lncRNAs/circRNAs and their significance in the biology of DR.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antitumor activity of functionalized iron oxide nanoparticles in Ehrlich tumor carcinoma-bearing mice enhanced by magnetic field.","authors":"Ebtesam A Mohamad, Ebtehal Mohammad Fikry, Monira M Rageh","doi":"10.1007/s00210-025-04063-5","DOIUrl":"https://doi.org/10.1007/s00210-025-04063-5","url":null,"abstract":"<p><p>Iron oxide nanoparticles show an intrinsic therapeutic effect on cancer growth. In vivo, the combination of iron oxide nanoparticles as magnetic particles and a low-frequency magnetic field significantly decreases the growth of Ehrlich tumor carcinoma in mice. Magnetic fields can vibrate and enhance iron oxide nanoparticles movement inside of cells, affecting their structure. In this study, iron oxide nanoparticles were synthesized and assessed by UV-visible spectrophotometer, dynamic light scattering (DLS), transmission electron microscope (TEM), X-ray diffraction (XRD), and vibrating sample magnetometer (VSM). The damage effects of iron oxide nanoparticles and low-frequency magnetic fields (0.5 T, 50 Hz) on tumor tissues were evaluated by assessment of DNA comet assay, and Fourier transformed infrared (FTIR), oxidative stress, assessment of inflammatory biomarkers, and histopathology studies. Also, the effect on the heart, liver, and kidney organs was studied. Our results suggest that iron oxide nanoparticles and magnetic fields could be applied to help in cancer treatment.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Innovative approaches in breast cancer therapy: repurposing nanocarriers for enhanced outcomes.","authors":"Sana Naaz Siddiqui, Md Faheem Haider, Md Azizur Rahman","doi":"10.1007/s00210-025-04012-2","DOIUrl":"https://doi.org/10.1007/s00210-025-04012-2","url":null,"abstract":"<p><p>Breast cancer is one of the most prevalent cancers globally, affecting over 685,000 women annually. While traditional treatment modalities such as surgery, chemotherapy, and radiation therapy have contributing to improved survival rates; however, they are often plagued by limitations such as systemic toxicity, lack of targeted therapy, development of resistance, and collateral damage to healthy tissues. While targeted therapies and endocrine treatment have provided more personalized approaches, challenges like side effects and limited effectiveness in specific subtypes remain. Nanotechnology offers new avenues for addressing these challenges, particularly through the development of advanced nanocarrier systems. Nanocarrier systems are designed to enhance drug targeting, improve bioavailability, reduce side effects, and combat drug resistance. These advanced delivery systems facilitate controlled release, higher drug concentration at target sites, and the potential for combination therapies, thus improving treatment outcomes. Breast cancer clinical trials assess treatment effectiveness, providing critical insights through their statuses and outcomes. The aim of this study is to explore the potential of nanocarrier systems in overcoming the limitation of traditional therapy, enhancing the effectiveness of drug delivery, and enhancing overall treatment outcomes for breast cancer treatment.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial-based therapies for neurodegenerative diseases: a review of the current literature.","authors":"Al-Hassan Soliman Wadan, Ahmed H Shaaban, Mohamed Z El-Sadek, Salah Abdelfatah Mostafa, Ahmed Sherief Moshref, Ahmed El-Hussein, Doha El-Sayed Ellakwa, Samah S Mehanny","doi":"10.1007/s00210-025-04014-0","DOIUrl":"https://doi.org/10.1007/s00210-025-04014-0","url":null,"abstract":"<p><p>Neurodegenerative disorders present significant challenges to modern medicine because of their complex etiology, pathogenesis, and progressive nature, which complicate practical treatment approaches. Mitochondrial dysfunction is an important contributor to the pathophysiology of various neurodegenerative illnesses, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This review paper examines the current literature highlighting the multifaceted functions of mitochondria, including energy production, calcium signaling, apoptosis regulation, mitochondrial biogenesis, mitochondrial dynamics, axonal transport, endoplasmic reticulum-mitochondrial interactions, mitophagy, mitochondrial proteostasis, and their crucial involvement in neuronal health. The literature emphasizes the increasing recognition of mitochondrial dysfunction as a critical factor in the progression of neurodegenerative disorders, marking a shift from traditional symptom management to innovative mitochondrial-based therapies. By discussing mitochondrial mechanisms, including mitochondrial quality control (MQC) processes and the impact of oxidative stress, this review highlights the need for novel therapeutic strategies to restore mitochondrial function, protect neuronal connections and integrity, and slow disease progression. This comprehensive review aims to provide insights into potential interventions that could transform the treatment landscape for neurodegenerative diseases, addressing symptoms and underlying pathophysiological changes.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143752766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The active ingredients and targets of Kouqiangjie formula on periodontitis: a multi-approach study.","authors":"Yeke Wu, Jiawei Li, Min Liu, Ranran Gao, Yunfei Xie, Huijing Li, Li Li","doi":"10.1007/s00210-025-03942-1","DOIUrl":"https://doi.org/10.1007/s00210-025-03942-1","url":null,"abstract":"<p><p>Periodontitis (PD) is a complex oral inflammatory disease with diverse pathogenic factors, demanding effective multi-target therapeutic approaches. Traditional Chinese Medicine (TCM) formulations, like the Kouqiangjie Formula (KQJF), hold potential as alternative therapies due to their multiple pharmacological effects. This study comprehensively investigated the key active ingredients and molecular targets of KQJF in treating PD through a combination of network pharmacology, machine learning, Mendelian randomization (MR), and experimental validation. The active components and targets of KQJF were identified via the TCMSP and HERB databases, while PD-related genes were sourced from GeneCards, CTD, and DisGeNET. Gene expression data from GEO datasets enabled differential expression analysis. Machine learning models, including Random Forest (RF) and Support Vector Machine (SVM), were employed to evaluate the diagnostic potential of gene sets. Molecular docking was utilized to assess the interactions between active ingredients and targets, and MR analysis was conducted to explore the causal relationships with PD. Experimental validation was carried out using a rat model. The results indicated that KQJF consists of 193 active compounds that target 561 proteins, with a significant overlap of 272 targets related to PD. Key compounds such as luteolin, linolenic acid, and naringenin were identified. The SVM model demonstrated excellent predictive performance, with an AUC of 0.954. MR analysis revealed a significant causal effect of the CASP3 gene on the risk of PD (OR = 1.595, p = 0.015). Experimental findings showed that these compounds could reduce the expression of CASP3 and improve the integrity of periodontal tissues. In conclusion, luteolin, linolenic acid, and naringenin are the core compounds in KQJF, and CASP3 is an important target. This study emphasizes the great potential of KQJF for PD treatment and provides a solid data base for the development of new therapeutic strategies.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}