Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"Brain distribution and muscarinic receptor occupancy of an active metabolite of fesoterodine in rats.","authors":"Mizuki Shiho, Shimako Tanaka, Eriko Nakatani, Toshiki Kurosawa, Yoshiyuki Kubo, Yoshiharu Deguchi, Takashi Okura","doi":"10.1016/j.jpet.2024.100058","DOIUrl":"10.1016/j.jpet.2024.100058","url":null,"abstract":"<p><p>Several large-scale clinical trials have shown that long-term use of antimuscarinic agents for overactive bladder treatment increases the risk of dementia and that this risk varies between agents. Fesoterodine, an overactive bladder antimuscarinic, reportedly has no significant effect on cognitive function. Differences in the brain distribution of antimuscarinic agents and blockade of muscarinic receptors could be the reasons for the differences in central side effects among antimuscarinics. In this study, we assessed the brain distribution of antimuscarinic agents and muscarinic receptor occupancy using brain microdialysis and in vivo receptor-binding analysis in rats. The test drugs were 5-hydroxymethyl tolterodine (5-HMT), an active metabolite of fesoterodine, oxybutynin, and trihexyphenidyl, a central antimuscarinic agent. The brain/plasma unbound concentration ratio at steady state (K_puu) of 5-HMT was much lower than that of oxybutynin and trihexyphenidyl, indicating very low 5-HMT distribution in the brain. The muscarinic receptor occupancy in the rat brain at clinical plasma concentrations of 5-HMT was rarely observed, whereas the occupancy by oxybutynin and trihexyphenidyl was 20% and 67%, respectively. The brain muscarinic receptor occupancy, reconstituted using K_puu values and muscarinic receptor affinity retrieved from literature, revealed a significant correlation between the calculated and measured values. These results indicate that 5-HMT has low brain distribution and muscarinic receptor occupancy, which might be the reasons for the insignificant effect of fesoterodine on cognitive function. SIGNIFICANCE STATEMENT: This study reports that 5-hydroxymethyl tolterodine, the active metabolite of fesoterodine, has much lower brain distribution and muscarinic receptor occupancy compared with oxybutynin and trihexyphenidyl based on brain microdialysis and in vivo receptor-binding analysis with unlabeled muscarinic tracer in rats. The low brain distribution and muscarinic receptor occupancy of 5-hydroxymethyl tolterodine might be the reasons for the insignificant effect of fesoterodine on cognitive function.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"100058"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537287","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":"Unlocking the potential: FKK6 as a microbial mimicry-based therapy for chronic inflammation-associated colorectal cancer in a murine model.","authors":"Lucia Sládeková, Hao Li, Vera M DesMarais, Amanda P Beck, Hillary Guzik, Barbora Vyhlídalová, Haiwei Gu, Sridhar Mani, Zdenek Dvořák","doi":"10.1016/j.jpet.2024.100059","DOIUrl":"10.1016/j.jpet.2024.100059","url":null,"abstract":"<p><p>Chronic intestinal inflammation significantly contributes to the development of colorectal cancer and remains a pertinent clinical challenge, necessitating novel therapeutic approaches. Indole-based microbial metabolite mimics Felix Kopp Kortagere 6 (FKK6), which is a ligand and agonist of the pregnane X receptor (PXR), was recently demonstrated to have PXR-dependent anti-inflammatory and protective effects in a mouse model of dextran sodium sulfate (DSS)-induced acute colitis. Here, we examined the therapeutic potential of FKK6 in a mouse model (C57BL/6 FVB humanized PXR mice) of colitis-associated colon cancer (CAC) induced by azoxymethane and DSS. FKK6 (2 mg/kg) displayed substantial antitumor activity, as revealed by reduced size and number of colon tumors, improved colon histopathology, and decreased expression of tumor markers (c-MYC, β-catenin, Ki-67, and cyclin D) in the colon. In addition, we carried out a chronic toxicity (30 days) assessment of FKK6 (1 mg/kg and 2 mg/kg) in C57BL/6 mice. Histological examination of tissues, biochemical blood analyses, and immunohistochemical staining for Ki-67 and γ-H2AX showed no difference between FKK6-treated and control mice. Comparative metabolomic analyses in mice exposed for 5 days to DSS and administered with FKK6 (0.4 mg/kg) revealed no significant effects on several classes of metabolites in the mouse fecal metabolome. Ames and micronucleus tests showed no genotoxic and mutagenic potential of FKK6 in vitro. In conclusion, anticancer effects of FKK6 in azoxymethane/DSS-induced CAC, together with FKK6 safety data from in vitro tests and in vivo chronic toxicity study, and comparative metabolomic study, are supportive of the potential therapeutic use of FKK6 in the treatment of CAC. SIGNIFICANCE STATEMENT: Microbial metabolite mimicry proposes that chemical mimics of microbial metabolites that serve to protect hosts against aberrant inflammation in the gut could serve as a new paradigm for the development of drugs targeting inflammatory bowel disease if, like the parent metabolite, is devoid of toxicity but more potent against the microbial metabolite receptor. We identified a chemical mimic of Felix Kopp Kortagere 6, and we propose that Felix Kopp Kortagere 6 is devoid of toxicity yet significantly reduces tumor formation in an azoxymethane-dextran sodium sulfate model of murine colitis-induced colon cancer.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"100059"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537289","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":"Baclofen and opioid interactions in mice could inform pain treatment methods.","authors":"Stacie K Totsch, Remy Y Meir, Aaron R Landis, Tammie L Quinn, Robert E Sorge","doi":"10.1016/j.jpet.2024.100531","DOIUrl":"10.1016/j.jpet.2024.100531","url":null,"abstract":"<p><p>With the current pressure to reduce opioid usage in the clinical setting, there is a call for the development of adjunct therapies. Although opioids remain the primary analgesic used in the treatment of moderate to severe pain, these drugs come with negative side effects, such as increased potential for abuse. The overlap in expression of opioid and GABA receptors suggests that the 2 systems may interact. Therefore, to investigate this interaction, our study used the GABA_B receptor agonist, baclofen, because it has previously been used as a treatment for spasticity and addiction and has demonstrated weak analgesic properties. Our study focused on the interaction between baclofen and opioid analgesics regarding analgesic efficacy and abuse potential. Analgesia was assessed through hot plate testing and reward was assessed through conditioned place preference testing in outbred CD1 mice. These interactions were examined with morphine, methadone, oxycodone, and fentanyl using isobolographic analyses. All opioids tested with baclofen demonstrate synergism in analgesia and no consistent significant interactions in place preference conditioning. Together these data support the use of baclofen coupled with opioids to enhance the analgesia, with no concomitant increase in abuse liability and associated common side effects of opioid drugs. SIGNIFICANCE STATEMENT: The combination of the commonly prescribed drug, baclofen, and a variety of opioids exhibits a synergistic analgesic effect allowing for lower doses of opioids to be used for equivalent analgesic effect. Synergistic analgesia was seen without concomitant enhanced tolerance, constipation, or reward, and across species, suggesting a beneficial interaction for pain relief.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"100531"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537285","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":"Editorial on recent trends in the pharmacology of cardiovascular diseases for the Journal of Pharmacology and Experimental Therapeutics.","authors":"Hideyuki Yamawaki, Tetsuo Nakata","doi":"10.1016/j.jpet.2024.103384","DOIUrl":"https://doi.org/10.1016/j.jpet.2024.103384","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"103384"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537340","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":"Exploration of a novel therapeutic option: Use of a β₂ agonist to prevent neuropathic pain development secondary to spinal cord injury in a mouse model.","authors":"Robert C Barnes, Josée Guindon","doi":"10.1016/j.jpet.2024.100038","DOIUrl":"https://doi.org/10.1016/j.jpet.2024.100038","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"100038"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536647","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":"Preventing cisplatin-induced kidney injury through inhibition of fatty acid amide hydrolase.","authors":"Johannes C K van der Mijn","doi":"10.1016/j.jpet.2024.100044","DOIUrl":"https://doi.org/10.1016/j.jpet.2024.100044","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"100044"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536784","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":"TLR4 downregulation protects against cisplatin-induced ototoxicity in adult and pediatric patients with cancer.","authors":"John J W Lee, Asna Latif, Erika N Scott, Abhinav Thakral, Mary B Mahler, Beth Brooks, Katrina Hueniken, Astrid Billfalk-Kelly, Osvaldo Espin-Garcia, Luna Jia Zhan, S Rod Rassekh, Lucie Pecheux, Maria Spavor, Yuling Li, David Goldstein, Andrew Hope, Colin J Ross, Geoffrey Liu, Bruce C Carleton, Amit P Bhavsar","doi":"10.1016/j.jpet.2024.100057","DOIUrl":"10.1016/j.jpet.2024.100057","url":null,"abstract":"<p><p>Cisplatin causes permanent hearing loss or cisplatin-induced ototoxicity in over 50% of treated patients with cancer, leading to significant social and functional limitations. Interindividual variability in developing hearing loss suggests the role of genetic predispositions to cisplatin-induced hearing loss. We investigated genetic associations between cisplatin-induced ototoxicity and toll-like receptor 4 (TLR4), an immune receptor known to mediate inflammatory responses to cisplatin. Using a case-control candidate gene approach, we identified 20 single nucleotide polymorphisms at the TLR4 locus with significant protection against ototoxicity in a cohort of 213 adult patients, followed by an independent pediatric patient cohort (n = 357). Combined cohort analysis demonstrated a significant association between cisplatin-induced ototoxicity protection and a single variant in the TLR4 promoter, rs10759932. We showed that rs10759932 downregulated TLR4 expression that is normally induced by cisplatin. This work provides pharmacogenetic and functional evidence to implicate TLR4 with cisplatin-induced hearing loss in patients. SIGNIFICANCE STATEMENT: Adult and pediatric patients carrying toll-like receptor 4 (TLR4) genetic variants were protected against developing cisplatin-induced hearing loss following cisplatin treatment. Important variants in the TLR4 promoter disrupted a drug-gene interaction between cisplatin and TLR4, mirroring the protective effect conferred by genetic inhibition of TLR4. These variants have the potential to improve the prediction of cisplatin toxicity, allowing for more precise chemotherapy treatment.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"100057"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537199","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":"Mitigation of cisplatin-induced acute kidney injury through oral administration of fatty acid amide hydrolase inhibitor PF-04457845.","authors":"Chaoling Chen, Weili Wang, Justin L Poklis, Pin-Lan Li, Aron H Lichtman, David A Gewirtz, Ningjun Li","doi":"10.1124/jpet.124.002282","DOIUrl":"10.1124/jpet.124.002282","url":null,"abstract":"<p><p>Fatty acid amide hydrolase (FAAH) serves as the primary enzyme responsible for degrading the endocannabinoid anandamide. Inhibition of FAAH, either through pharmacological means or genetic manipulation, can effectively reduce inflammation in various organs, including the brain, colon, heart, and kidneys. Infusion of a FAAH inhibitor into the kidney medulla induces diuretic and natriuretic effects. Moreover, FAAH knockout mice show protection against both post renal ischemia/reperfusion injury and cisplatin-induced acute kidney injury (AKI), although through distinct mechanisms. This study tested the hypothesis that pharmacological inhibition of FAAH activity mitigates cisplatin-induced AKI, thus, exploring potential renoprotective mechanism. Male wild-type C57BL/6J were administered an oral gavage of a FAAH inhibitor (PF-04457845, 5 mg/kg) or vehicle (10% PEG200+5% Tween 80+normal saline) at 72, 48, 24, and 2 hours before and 24 and 48 hours after a single intraperitoneal injection of cisplatin (25 mg/kg). Mice were euthanized 72 hours after cisplatin treatment. Compared with vehicle-treated mice, PF-04457845-treated mice showed a decrease of cisplatin-induced plasma creatinine, blood urea nitrogen levels, kidney injury biomarkers (neutrophil gelatinase-associated lipocalin and kidney injury molecule-1) and renal tubular damage. The renal protection from oral gavage of PF-04457845 against cisplatin-induced nephrotoxicity was associated with an enhanced endocannabinoid anandamide tone and reduced levels of DNA damage response biomarkers p53 and p21. Our work demonstrated that PF-04457845 effectively alleviates cisplatin-induced nephrotoxicity in mice, underscoring the potential of oral administration of a FAAH inhibitor as a novel strategy to prevent cisplatin nephrotoxicity. SIGNIFICANCE STATEMENT: Oral administration of the fatty acid amide hydrolase (FAAH) inhibitor, PF-04457845, reduced cisplatin-induced DNA damage response, tubular damage, and kidney dysfunction. Inhibition of FAAH represents a promising approach to prevent cisplatin-induced nephrotoxicity.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"100032"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536751","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":"CNOT6L deadenylase suppresses cardiac remodeling in heart failure through downregulation of tenascin-C mRNA.","authors":"Teruki Sato, Tomokazu Yamaguchi, Takafumi Minato, Midori Hoshizaki, Ayaha Yamamoto, Masahiro Morita, Toru Suzuki, Yasushi Fujio, Yumiko Imai, Yutaka Suzuki, Tadashi Yamamoto, Hiroyuki Watanabe, Keiji Kuba","doi":"10.1016/j.jpet.2024.100052","DOIUrl":"10.1016/j.jpet.2024.100052","url":null,"abstract":"<p><p>Heart failure is rapidly increasing and is a growing burden on human health and the economy in the world. The functional role of mRNA regulation in the pathogenesis of heart failure remains to be elucidated. Carbon catabolite repression 4-negative on TATA-less complex is a multisubunit protein complex that deadenylates mRNA, a process of exonuclease-mediated degradation of mRNA poly(A) tail. Here we show the cardiac protective roles of deadenylase subunit CNOT6L against cardiac stress. After 2 weeks of transverse aortic constriction (TAC)-induced pressure overload, expression of CNOT6L deadenylase subunit was significantly upregulated in the mouse hearts. When CNOT6L gene was genetically deleted, the mice exhibited marked decline of left ventricular contractility and enhancement of fibrosis at 2 weeks after TAC. Transcriptome analyses elucidated that CNOT6L targets tenascin-C mRNA, which stimulates tissue fibrosis and inflammation. CNOT6L deletion markedly upregulated tenascin-C expression in cardiac fibroblasts. Poly(A) tail length and luciferase reporter analyses revealed that CNOT6L catalyzes deadenylation of tenascin-C mRNA likely through interaction with the cis-element in its 3'-untranslated region. Double knockout of tenascin-C and CNOT6L ameliorated cardiac fibrosis and dysfunction in single CNOT6 knockout mice under TAC or chronic infusion of angiotensin II. Thus, CNOT6L deadenylase prevents the progression of heart failure through downregulation of the expression of tenascin-C in cardiac fibroblasts, implicating a potential therapeutic strategy of targeting mRNA deadenylation. SIGNIFICANCE STATEMENT: To our knowledge, this study provides the first evidence that posttranscriptional regulation of tenascin-C expression in cardiac fibroblasts, including cell-type-specific roles of CNOT6L-mediated mRNA deadenylation, is crucial to maintain heart functions against pressure overload stress or angiotensin II-induced hypertension, implicating a potential therapeutic strategy of targeting mRNA deadenylation.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"100052"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537336","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":"Elesclomol rescues mitochondrial copper deficiency in disease models without triggering cuproptosis.","authors":"Mohammad Zulkifli, Krishna P Maremanda, Adriana U Okonkwo, Ifrah Farid, Vishal M Gohil","doi":"10.1016/j.jpet.2024.100048","DOIUrl":"10.1016/j.jpet.2024.100048","url":null,"abstract":"<p><p>Copper (Cu) is an essential cofactor for metalloenzymes such as cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial electron transport chain. Mutations that directly or indirectly prevent Cu transport to mitochondria result in lethal pediatric diseases, such as Menkes disease. There is no clinically approved treatment for Menkes disease. We recently discovered that an investigational chemotherapy drug, elesclomol (ES), when complexed with Cu (ES-Cu), rescues mitochondrial Cu deficiency, activates CcO, and prevents perinatal lethality in a mouse model of Menkes disease. However, ES-Cu also has the potential to trigger cuproptosis, a type of Cu-dependent cell death. Therefore, to develop ES-Cu as a therapeutic agent for Menkes disease, it is critical to determine the therapeutic index of ES-Cu in Cu-deficient models. To this end, we used a Cu-deficient rat cardiomyocyte cell line and a mottled-brindled mouse model of severe Menkes disease to determine the toxicity and efficacy of ES-Cu. Our cell culture studies demonstrated that the EC₅₀ of ES-Cu is ∼50-fold lower than IC₅₀. Moreover, the biomarkers of Cu toxicity, including lipoylated proteins and a subset of iron-sulfur cluster-containing proteins of mitochondria, are activated only when ES-Cu is used at ∼10-fold to 25-fold higher than its EC₅₀. Importantly, none of these biomarkers are activated in mottled-brindled mice treated with therapeutic doses of ES-Cu. Our study shows that ES-Cu can deliver Cu to CcO both in vitro and in vivo without triggering cuproptosis, a finding that could facilitate its use in Cu deficiency disorders, such as Menkes disease. SIGNIFICANCE STATEMENT: Genetic copper (Cu) deficiency causes lethal pediatric diseases, such as Menkes disease, which lacks approved treatment. Recently, the therapeutic potential of elesclomol (ES), a Cu-transporting chemotherapeutic drug, in a mouse model of Menkes disease has been reported. Because of the potential risk of Cu-induced toxicity from ES-Cu, it is crucial to determine its therapeutic index. Here, the biomarkers of ES-Cu efficacy and toxicity in Cu-deficient disease models were measured to demonstrate that ES-Cu can restore cuproenzymes without triggering toxicity biomarkers.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"100048"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537342","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}