Archiv der Pharmazie最新文献

{"title":"Design, synthesis and biological evaluation of (E)-kojyl-styryl-sulfones: Novel recilisib hybrids as promising radioprotectors.","authors":"Reza Ahmadi, Seyed Jalal Hosseinimehr, Saeed Emami","doi":"10.1002/ardp.202400657","DOIUrl":"https://doi.org/10.1002/ardp.202400657","url":null,"abstract":"<p><p>Radioprotectors are synthetic compounds, natural products, or biological agents that are administered before irradiation to protect normal cells against ionizing radiation (IR)-induced injuries. We have designed novel hybrid (E)-kojyl-styryl-sulfones 10a-n by applying the pharmacophore hybridization strategy to combine key structural motifs of the natural antioxidant kojic acid and the emerging radioprotector Ex-RAD (recilisib sodium). These hybrids were successfully synthesized and characterized with (E)-geometry. In vitro radioprotective activity along with the corresponding O-benzylated and O-methoxylated derivatives (9a-n, 14, and 15) was evaluated on human foreskin fibroblast 1 (HFF-1) cells irradiated with a 10-Gy dose of X-rays. In particular, hybrids 10b, 10d, 10f, 10g, and 10n exhibited the highest radioprotection effect at the 10 µM concentration, more effective than the parent compounds. It should be noted that the 3,4,5-trimethoxystyryl analog 10n was the most effective compound. Surprisingly, the O-benzylated 3,4,5-trimethoxystyryl analog (9n) also showed an excellent radioprotective effect. Moreover, the antioxidant evaluation of these selected hybrids on the IR-induced reactive oxygen species (ROS) generation and lipid peroxidation in the HFF-1 cells revealed that they could significantly downregulate IR-induced oxidative stress in the HFF-1 cells, while mechanistically recilisib is not a well-established ROS scavenger. The obtained results suggest that these privileged (E)-kojyl-styryl-sulfones can serve as promising radioprotectors for further studies and development.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":" ","pages":"e2400657"},"PeriodicalIF":4.3,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design and synthesis of pyridazin-4-one derivatives as necroptosis inhibitors.","authors":"Yuxiang An, Xia Peng, Tianchen Wang, Kaiyuan Liu, Dazhi Feng, Chen Fang, Xuan Zhou, Meiyu Geng, Wenhu Duan, Jing Ai, Hefeng Zhang","doi":"10.1002/ardp.202400594","DOIUrl":"https://doi.org/10.1002/ardp.202400594","url":null,"abstract":"<p><p>Necroptosis is a regulated inflammatory cell death process that is closely associated with autoimmune diseases, acute ischemic injuries, neurodegenerative disorders, and so on. Due to the crucial role of receptor-interacting protein kinase 1 (RIPK1) in the necroptosis pathway, RIPK1 inhibitors are believed to have great potential in the treatment of necroptosis-related diseases. In this article, we reported a series of pyridazin-4-one derivatives as potent necroptosis inhibitors for both human and mouse cells. The representative compound 13 exhibited favorable RIPK1 selectivity and dose-dependently inhibited RIPK1 phosphorylation. The in vivo pharmacokinetic study indicated that compound 13 was an orally available candidate. Finally, molecular docking and molecular dynamics simulations were performed to elucidate the binding pattern of compound 13 with RIPK1. Collectively, compound 13 represents a promising lead compound for the future development of RIPK1-targeted necroptosis inhibitors.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":" ","pages":"e2400594"},"PeriodicalIF":4.3,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sumac liposomes/mesenchymal stem cells fight methotrexate-induced nephrotoxicity in rats via regulating Nrf-2/Keap-1/HO-1 and apoptotic signaling pathways.","authors":"Eman Maher Zahran, Reham H Mohyeldin, Hesham Refaat, Hesham A Abou-Zied, Mai H ElNaggar, Ghada M Abbas, Sherif A Maher, Entesar Ali Saber, Mohamed A Zarka, Mahmoud A Elrehany, Usama Ramadan Abdelmohsen","doi":"10.1002/ardp.202400684","DOIUrl":"https://doi.org/10.1002/ardp.202400684","url":null,"abstract":"<p><p>Methotrexate (MTX) is commonly employed in cancer treatment, but its clinical use is restricted due to the MTX-associated renal injury. This study investigates the combined potential of Rhus coriaria (sumac) and bone marrow mesenchymal stem cells (BMMSCs) against MTX-induced nephrotoxicity in rats. The high-resolution-liquid chromatography-mass spectrometry (HR-LC-MS) of sumac extract tentatively identified 22 phytochemicals, mostly flavonoids, anthocyanins, and steroids. Preparation of sumac liposomes attained a suitable particle size of 3041.33 ± 339.42 nm, a polydispersity index of 0.208 ± 0.086, and an encapsulation efficiency of 84.92 ± 3.47%. Rat BMMSCs were injected into the tail vein of the experimental rats (0.5 × 10⁶ cells, intravenous [iv]) of seven treated groups. The experimental design relies on either pre- or posttreatment of rats with intraperitoneal (IP) sumac liposomes (SL) (200 mg/kg, daily with a dose of MTX (300 µg/kg/14 days). The histopathological examination and serum analysis of creatinine and urea revealed good results, besides regulating levels of oxidative stress and inflammatory markers. Additionally, a significant decrease in the gene expression levels of B-Cell Lymphoma 2 (Bcl-2) and caspases-3 and -9, a remarkable increase in the Bcl-2 Associated X-Protein (Bax), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme-oxygenase 1 expression, and a downregulation of Kelch-like ECH-associated protein 1 (Keap1). Collectively, the coadministration of SL with BMMSCs might be a potent therapeutic strategy for attenuation of MTX-induced renal damage. The network pharmacology analysis identified the involved key hub genes as KEAP1, Nrf2, HMOX1, mitogen-activated protein kinase (MAPK1), nuclear factor-kappa B (NF-KB), interleukin-1 beta (IL-1B), and caspase-3. The docking results revealed strong binding affinities of 7-O-methyl-cyanidin-3-O-(2″-galloyl)-galactoside with Keap1 and amentoflavone with MAPK. These insights pave the way for future experimental validation and therapeutic development of sumac-based phytoconstituents against MTX-induced nephrotoxicity.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":" ","pages":"e2400684"},"PeriodicalIF":4.3,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis of hydroxytyrosol analogs with enhanced antioxidant and cytostatic properties against MG-63 human osteoblast-like cells and their potential implications for bone health.","authors":"Eleftheria A Georgiou, Ioanna Kalpaktsi, Katerina Gioti, Maria Choleva, Elizabeth Fragopoulou, Alexios-Leandros Skaltsounis, Roxane Tenta, Ioannis K Kostakis","doi":"10.1002/ardp.202400469","DOIUrl":"https://doi.org/10.1002/ardp.202400469","url":null,"abstract":"<p><p>Sixteen novel hydroxytyrosol (HT) analogs with substitutions at the C-1 position of the HT aliphatic side chain were synthesized and evaluated for their cytostatic activity against MG-63 human osteoblast-like cells and for their antioxidant properties. The results revealed that these analogs exhibited significantly higher inhibitory activity compared with HT, which served as the positive control. Among these, the cyclo-substituted compounds stood out as particularly potent, demonstrating strong radical scavenging abilities and notable cytostatic effects against MG-63 cells. These findings suggest that the cyclo-substituted HT analogs hold considerable promise for the development of novel antioxidants with potential applications in bone physiology.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":" ","pages":"e2400469"},"PeriodicalIF":4.3,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Secondary metabolite profiles and anti-SARS-CoV-2 activity of ethanolic extracts from nine genotypes of Cannabis sativa L.","authors":"Ermin Schadich, Dominika Kaczorová, Tibor Béres, Petr Džubák, Marián Hajdúch, Petr Tarkowski, Sanja Ćavar Zeljković","doi":"10.1002/ardp.202400607","DOIUrl":"https://doi.org/10.1002/ardp.202400607","url":null,"abstract":"<p><p>This study deals with the comprehensive phytochemical composition and antiviral activity against SARS-CoV-2 of acidic (non-decarboxylated) and neutral (decarboxylated) ethanolic extracts from seven high-cannabidiol (CBD) and two high-Δ⁹-tetrahydrocannabinol (Δ⁹-THC) Cannabis sativa L. genotypes. Their secondary metabolite profiles, phytocannabinoid, terpenoid, and phenolic, were determined by LC-UV, GC-MS, and LC-MS/MS analyses, respectively. All three secondary metabolite profiles, cannabinoid, terpenoid, and phenolic, varied significantly among cannabinoid extracts of different genotypes. The dose-response analyses of their antiviral activity against SARS-CoV-2 showed that only the single predominant phytocannabinoids (CBD or THC) of the neutral extracts exhibited antiviral activity (all IC₅₀ < 10.0 μM). The correlation matrix between phytoconstituent levels and antiviral activity revealed that the phenolic acids, salicylic acid and its glucoside, chlorogenic acid, and ferulic acid, and two flavonoids, abietin, and luteolin, in different cannabinoid extracts from high-CBD genotypes are implicated in the genotype-distinct antagonistic effects on the predominant phytocannabinoid. On the other hand, these analyses also suggested that the other phytocannabinoids and the flavonoid orientin can enrich the extract's pharmacological profiles. Thus, further preclinical studies on cannabinoid extract formulations with adjusted non-phytocannabinoid compositions are warranted to develop supplementary antiviral treatments.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":" ","pages":"e2400607"},"PeriodicalIF":4.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing the anticancer effect of metformin through nanoencapsulation: Apoptotic induction, inflammatory reduction, and suppression of cell migration in colorectal cancer cells.","authors":"Shaimaa A Gouhar, Maha Nasr, Cinderella A Fahmy, Mona A M AboZeid, Sherien M El-Daly","doi":"10.1002/ardp.202400628","DOIUrl":"https://doi.org/10.1002/ardp.202400628","url":null,"abstract":"<p><p>Colorectal cancer (CRC) continues to be a significant health challenge, necessitating the development of efficient therapeutic strategies. Drug repurposing, which involves the use of existing medications for new purposes, presents a promising opportunity. Metformin, a widely used antidiabetic drug, has demonstrated potential anticancer effects. To enhance its efficacy, we formulated nano-metformin, metformin encapsulated within pectin nanoparticles. Our study aimed to evaluate the superiority of nano-metformin over free metformin in treating CRC. The cytotoxicity of both metformin and nano-metformin on Caco-2 CRC cells was assessed using the MTT assay, revealing a significant dose-dependent inhibition of cell growth using nano-metformin. The anti-inflammatory potential was evaluated by measuring the levels of nitric oxide and the pro-inflammatory cytokines IL-2 and IL-6 following lipopolysaccharide (LPS) induction, and the results revealed that treating LPS-induced cells with nano-metformin significantly reduced the production of these inflammatory mediators. To elucidate the mechanism of cell death, we employed an acridine orange/ethidium bromide staining assay, which revealed the enhancement of apoptotic cell death following treatment with nano-metformin. Additionally, we examined the expression of key apoptotic regulators using real-time qPCR. Nano-metformin, in particular, significantly downregulated the expression of the antiapoptotic markers Bcl-2 and Survivin while upregulating the proapoptotic caspases 3, 7, and 9. The comet assay revealed significant DNA damage induced by treatment with the nano-metformin compared with that in the free form. Moreover, nano-metformin significantly reduced the migration ability of cells. In conclusion, our work revealed the superior efficacy of our formulated nanoform over free metformin, highlighting its potential as a promising therapeutic agent for CRC treatment.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":" ","pages":"e2400628"},"PeriodicalIF":4.3,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Halogen-based quinazolin-4(3H)-one derivatives as MCF-7 breast cancer inhibitors: Current developments and structure-activity relationship.","authors":"Rachana Upadhyay, Pooja Tandel, Amit B Patel","doi":"10.1002/ardp.202400740","DOIUrl":"https://doi.org/10.1002/ardp.202400740","url":null,"abstract":"<p><p>Currently, cancer is a serious health challenge with predominance beyond restrictions. Breast cancer remains one of the major contributors to cancer-related morbidity and mortality in women. Chemotherapy continues to be crucial in the treatment of all variants of cancer. Several antitumor drugs are presently in different phases of clinical trials, whereas many more have been approved for clinical use. However, these drugs have the potential to cause adverse effects, and certain individuals may become resistant to them, which would eventually reduce the drug's efficacy. Therefore, it is essential to discover, develop, and improve newer anticancer drug molecules that could potentially inhibit proliferative pathways. In recent years, quinazolinone derivatives, more specifically halogen-substituted 4(3H)-quinazolinone, have drawn attention as a promising new class of chemotherapeutic agents. In addition, these molecules showed significant inhibition in micromolar ranges when tested in vitro against the MCF-7 cell line. Therefore, this study aims to emphasize the intriguing versatility of halogen atoms, providing an in-depth summary and highlighting recent developments in the anticancer properties of halogenated 4(3H)-quinazolinones. It also features a detailed discussion of the structure-activity relationship (SAR) of various functional groups and their interaction with amino acid residues utilizing molecular docking studies. The intent is to foster novel discoveries that can inspire innovative investigations in this domain. Hence, this study simplifies the drug design and development strategies by prolonging the array of pharmacologically active candidates.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":" ","pages":"e2400740"},"PeriodicalIF":4.3,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights into podophyllotoxin lactone features: New cyclolignans as potential dual tubulin-topoisomerase II inhibitors.","authors":"Ángela-Patricia Hernández, Celia Rosales-Fernández, Carolina Miranda-Vera, Anzhela Veselinova, Pablo G Jambrina, Pilar García-García, Pablo A García, David Díez, María Ángeles Castro, Manuel Fuentes","doi":"10.1002/ardp.202400600","DOIUrl":"https://doi.org/10.1002/ardp.202400600","url":null,"abstract":"<p><p>Chemomodulation of natural cyclolignans as podophyllotoxin has been a successful approach to obtain semisynthetic bioactive derivates. One example of this approach is the FDA-approved drug etoposide for solid and hematological tumors. It differs from the antimitotic activity of the natural product in its mechanism of action, this drug being a topoisomerase II inhibitor instead of a tubulin antimitotic. Within the molecular requirements for the activity of these compounds, the trans-γ-lactone moiety presented in the parent compound has always been a feature to be explored to chemomodulate its bioactivity. In this study, we have obtained different compounds that comply with the molecular characteristics for antitubulin and antitopoisomerase II activity combined in a single molecule. Furthermore, we explored the influence of the trans-lactone moiety on the final activity, finding that the cis-lactone was also interesting in terms of bioactivity. The best values of cytotoxicity and cell cycle inhibition were obtained for a compound lacking the lactone ring, thus mimicking the podophyllic aldehyde functionalization, a selective antimitotic podophyllotoxin derivate. The analogs with cis-lactone also presented interesting cytotoxic activity. The present study illustrates the potential of the chemomodulation of natural products such as natural cyclolignan podophyllotoxin derivates for the discovery of new antitumor agents.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":" ","pages":"e2400600"},"PeriodicalIF":4.3,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pre-ADMET studies of 5-(3',4'-dihydroxyphenyl)-γ-valerolactone, the bioactive intestinal metabolite of proanthocyanidins.","authors":"Larissa Della Vedova, Islam Husain, Yan-Hong Wang, Hari Babu Kothapalli, Francesca Gado, Giovanna Baron, Simone Manzi, Paolo Morazzoni, Giancarlo Aldini, Ikhals A Khan","doi":"10.1002/ardp.202400575","DOIUrl":"https://doi.org/10.1002/ardp.202400575","url":null,"abstract":"<p><p>5-(3',4'-Dihydroxyphenyl)-γ-valerolactone (VL) is a bioactive metabolite resulting from the gut microbial metabolism of proanthocyanidins and flavonoids, known for its health-promoting effects, including antidiabetic and anti-inflammatory activities. Although VL has been observed in different in vivo studies, its pre-absorption, distribution, metabolism, excretion, toxicity (ADMET) properties have rarely been investigated. This study aims to address this gap by evaluating the pre-ADMET properties of VL for the first time. Also, the understanding of these properties is significant for correlating the encountered activities to this metabolite. In vitro absorption studies revealed that VL is rapidly metabolized and absorbed as its sulfate phase II conjugate (valerolactone sulfate), which enters systemic circulation and mildly activates the Breast Cancer Resistance Protein efflux transporter. In human S9 liver fraction, a mixture of liver enzymes used to simulate in vivo liver metabolism, VL is metabolized into glucuronic phase II conjugates (valerolactone glucuronide 1 [VLG1] and 2 [VLG2]) with a half-life of 8.72 min and an 80% conversion rate. In human liver microsomes, VL is metabolized at a slower rate (half-life of 23.08 min), suggesting that oxidative metabolism is secondary. Additionally, VL did not activate the pregnane X receptor or inhibit Cytochrome P3A4 (CYP3A4) and Cytochrome P1A2 (CYP1A2) enzymes, indicating no risk of herb-drug interactions with coadministered prescription drugs.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":" ","pages":"e2400575"},"PeriodicalIF":4.3,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and antitumor evaluation of glycyrrhetinic acid-dithiocarbamate hybrids.","authors":"Jiahong Su, Xingyue Wang, Sha Li, Xu Wu, Mingxing Li, Fukuan Du, Shuai Deng, Jing Shen, Yueshui Zhao, Zhangang Xiao, Yu Chen","doi":"10.1002/ardp.202400421","DOIUrl":"https://doi.org/10.1002/ardp.202400421","url":null,"abstract":"<p><p>Glycyrrhetinic acid (GA) is a naturally occurring triterpene compound. The aim of this study was to employ the pharmacophore hybrid strategy to merge GA with various dithiocarbamates and obtain novel compounds with better antitumor activities. We present a two-step synthetic protocol wherein the GA derivative underwent reaction with carbon disulfide and various secondary amines in a one-pot manner under mild conditions, facilitating the preparation of a series of structurally novel GA-dithiocarbamate derivatives. Bioassay screening revealed that the representative compound 3c demonstrated the capacity to reduce the mitochondrial membrane potential in Hep3B and Huh-7 cells, induce nuclear apoptosis, inhibit invasion and migration, and prompt both early and late apoptosis. Furthermore, our research findings indicated that this apoptotic phenomenon may be associated with the expression of Bcl-2, Bax, Bak, PARP, and cleaved-PARP proteins. Utilizing network pharmacology for predicting core targets and signaling pathways of compound 3c for hepatocellular carcinoma (HCC) treatment involved employing molecular docking models to demonstrate high affinity between compound and target protein. In conjunction with Western blot analysis, compound 3c may impact HCC through the PI3K-AKT-mTOR pathway.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":" ","pages":"e2400421"},"PeriodicalIF":4.3,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}