Pub Date : 2025-12-17DOI: 10.1038/s41392-025-02527-x
Minjeong Jang, Hyung Jin Choi, Hae-June Lee, Hong Nam Kim
Hypoglycemia is a frequent and potentially severe complication that can result in significant brain injury in individuals with diabetes treated with insulin or other hypoglycemic agents and in those undergoing prolonged fasting. Despite its clinical importance, the molecular mechanisms through which hypoglycemia induces neurodegeneration remain poorly defined. We therefore investigated the molecular and cellular basis of hypoglycemia-induced brain damage using human neuron and glial cell cultures in vitro and hypoglycemic mouse models in vivo. We found that starvation-induced hypoglycemia triggers hallmark neurodegenerative features, such as astrocyte activation and microglial reactivity, that closely resemble those found in the brains of hypoglycemic mouse models. Neurons notably activate an adaptive survival response mediated by serum response factor (SRF) and myocardin-related transcription factor-A (MRTF-A), which drives a metabolic reprogramming process. This shift enables neurons to use extracellular matrix components as alternative energy sources under glucose deprivation. However, this compensatory mechanism results in the excessive accumulation of urea cycle byproducts, which subsequently exacerbates neuronal damage and promotes glial activation. Glucose refeeding remarkably reversed these neurodegenerative features by deactivating SRF/MRTF-A signaling in both in vitro and in vivo. Collectively, our results revealed a neuron-intrinsic mechanism linking glucose deprivation to reversible neurodegeneration via SRF/MRTF-A, offering potential targets for preventing hypoglycemia-associated brain damage.
低血糖是一种常见的、潜在的严重并发症，在接受胰岛素或其他降糖药治疗的糖尿病患者和长期禁食的糖尿病患者中可导致严重的脑损伤。尽管它的临床重要性，通过低血糖诱导神经变性的分子机制仍然不清楚。因此，我们利用体外培养的人类神经元和神经胶质细胞和体内低血糖小鼠模型来研究低血糖诱导脑损伤的分子和细胞基础。我们发现，饥饿引起的低血糖会触发标志性的神经退行性特征，如星形胶质细胞激活和小胶质细胞反应，这些特征与低血糖小鼠模型中的大脑非常相似。神经元激活由血清反应因子（SRF）和心肌素相关转录因子- a （MRTF-A）介导的适应性生存反应，从而驱动代谢重编程过程。这种转变使神经元能够利用细胞外基质成分作为葡萄糖剥夺下的替代能量来源。然而，这种代偿机制导致尿素循环副产物的过度积累，从而加剧神经元损伤并促进胶质细胞激活。在体外和体内，葡萄糖再喂养通过使SRF/MRTF-A信号失活，显著逆转了这些神经退行性特征。总的来说，我们的研究结果揭示了通过SRF/MRTF-A将葡萄糖剥夺与可逆性神经变性联系起来的神经元内在机制，为预防低血糖相关的脑损伤提供了潜在的靶点。
{"title":"Hypoglycemia induces brain metabolic reprogramming and neurodegeneration via serum response factor and myocardin-related transcription factor-A","authors":"Minjeong Jang, Hyung Jin Choi, Hae-June Lee, Hong Nam Kim","doi":"10.1038/s41392-025-02527-x","DOIUrl":"https://doi.org/10.1038/s41392-025-02527-x","url":null,"abstract":"Hypoglycemia is a frequent and potentially severe complication that can result in significant brain injury in individuals with diabetes treated with insulin or other hypoglycemic agents and in those undergoing prolonged fasting. Despite its clinical importance, the molecular mechanisms through which hypoglycemia induces neurodegeneration remain poorly defined. We therefore investigated the molecular and cellular basis of hypoglycemia-induced brain damage using human neuron and glial cell cultures in vitro and hypoglycemic mouse models in vivo. We found that starvation-induced hypoglycemia triggers hallmark neurodegenerative features, such as astrocyte activation and microglial reactivity, that closely resemble those found in the brains of hypoglycemic mouse models. Neurons notably activate an adaptive survival response mediated by serum response factor (SRF) and myocardin-related transcription factor-A (MRTF-A), which drives a metabolic reprogramming process. This shift enables neurons to use extracellular matrix components as alternative energy sources under glucose deprivation. However, this compensatory mechanism results in the excessive accumulation of urea cycle byproducts, which subsequently exacerbates neuronal damage and promotes glial activation. Glucose refeeding remarkably reversed these neurodegenerative features by deactivating SRF/MRTF-A signaling in both in vitro and in vivo. Collectively, our results revealed a neuron-intrinsic mechanism linking glucose deprivation to reversible neurodegeneration <jats:italic>via</jats:italic> SRF/MRTF-A, offering potential targets for preventing hypoglycemia-associated brain damage.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"1 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145770718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-17DOI: 10.1038/s41392-025-02528-w
Liu-Zheng Wu, Ya-Ying Huang, Hai-Jing Hu, Wen-Bin Hong, Han Yan, Yuan-Li Ai, Xiang-Yu Mi, De-Yi Feng, Jian-Yi Guo, Yang Ding, Zai-Jun Liu, Bo Zhou, Li Xiao, Tianwei Lin, Fu-Nan Li, Xue-Qin Chen, Hang-Zi Chen, Qiao Wu
Pyroptosis plays a crucial role in physiological and pathological processes. As melanoma cells are resistant to apoptosis but express gasdermin proteins, it is appealing to counter melanoma with the induction of gasdermin-executed pyroptosis. GSDMC, initially cloned from metastatic melanoma cells, has been demonstrated as a potential executioner of pyroptosis. However, no lead compounds that trigger GSDMC-mediated pyroptosis have been reported, which limits the in-depth investigation of GSDMC functions. Here, we discovered a chemical compound, dodecyl 1H-benzo[d]imidazole-5-carboxylate (DdBIC), that targeted the nuclear receptor Nur77 to induce pyroptosis through cleaving GSDMC by granzyme B in melanoma cells. Upon DdBIC binding, Nur77 was translocated to the mitochondria to activate the hemoprotein SDHA to overconsume succinyl-CoA, subsequently disrupting the homeostasis of heme in the SDH complex and resulting in electron leakage to induce mito-ROS production. This mito-ROS signal was sensed by the mitochondrial protease OMA1 via oxidation, which led to downstream OPA1 cleavage and subsequent released into the cytoplasm. Cytosolic OPA1 activated PERK to induce the integrated stress response (ISR), which further activated granzyme B to cleave GSDMC, culminating in the induction of pyroptosis. Together, this study elucidates a signal cascade from Nur77-impaired homeostasis of heme metabolism to PERK-mediated ISR activation, and reveals a novel paradigm, by which granzyme B, rather than caspases, cleaves GSDMC for pyroptotic induction and provides a new strategy for the therapeutic treatment of melanoma by lead compound DdBIC.
{"title":"Disruption of heme homeostasis by nuclear receptor Nur77 induces pyroptosis through granzyme B-dependent GSDMC cleavage","authors":"Liu-Zheng Wu, Ya-Ying Huang, Hai-Jing Hu, Wen-Bin Hong, Han Yan, Yuan-Li Ai, Xiang-Yu Mi, De-Yi Feng, Jian-Yi Guo, Yang Ding, Zai-Jun Liu, Bo Zhou, Li Xiao, Tianwei Lin, Fu-Nan Li, Xue-Qin Chen, Hang-Zi Chen, Qiao Wu","doi":"10.1038/s41392-025-02528-w","DOIUrl":"https://doi.org/10.1038/s41392-025-02528-w","url":null,"abstract":"Pyroptosis plays a crucial role in physiological and pathological processes. As melanoma cells are resistant to apoptosis but express gasdermin proteins, it is appealing to counter melanoma with the induction of gasdermin-executed pyroptosis. GSDMC, initially cloned from metastatic melanoma cells, has been demonstrated as a potential executioner of pyroptosis. However, no lead compounds that trigger GSDMC-mediated pyroptosis have been reported, which limits the in-depth investigation of GSDMC functions. Here, we discovered a chemical compound, dodecyl 1H-benzo[d]imidazole-5-carboxylate (DdBIC), that targeted the nuclear receptor Nur77 to induce pyroptosis through cleaving GSDMC by granzyme B in melanoma cells. Upon DdBIC binding, Nur77 was translocated to the mitochondria to activate the hemoprotein SDHA to overconsume succinyl-CoA, subsequently disrupting the homeostasis of heme in the SDH complex and resulting in electron leakage to induce mito-ROS production. This mito-ROS signal was sensed by the mitochondrial protease OMA1 via oxidation, which led to downstream OPA1 cleavage and subsequent released into the cytoplasm. Cytosolic OPA1 activated PERK to induce the integrated stress response (ISR), which further activated granzyme B to cleave GSDMC, culminating in the induction of pyroptosis. Together, this study elucidates a signal cascade from Nur77-impaired homeostasis of heme metabolism to PERK-mediated ISR activation, and reveals a novel paradigm, by which granzyme B, rather than caspases, cleaves GSDMC for pyroptotic induction and provides a new strategy for the therapeutic treatment of melanoma by lead compound DdBIC.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"22 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145770705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wnt and its crosstalk signaling pathways are involved in the modulating ischemia‒reperfusion (I/R) injury. However, whether Wnt2 is a novel therapeutic agent for I/R injury is largely unknown. Here, we show that the downregulation of serum Wnt2 levels in acute myocardial infarction (AMI) patients following reperfusion therapy, and Wnt2 levels are inversely correlated with the levels of myocardial injury markers (cTnT and CK-MB). Therapeutic administration of recombinant Wnt2 protein (rbWnt2) alleviates cardiac I/R injury and improves cardiac function by suppressing ROS levels and cardiomyocyte death in mice. Further analysis revealed that rbWnt2 downregulated Nap1L1 to reactivate the transcription of antioxidant genes (SOD, GPX, and UCP3) to reduce ROS levels and subsequently inhibit cardiomyocyte apoptosis and ferroptosis during the I/R process. Cardiac-specific Nap1L1 knockdown attenuated I/R injury, whereas overexpression of Nap1L1 partly abolished the cardiac protection mediated by rbWnt2 administration in the I/R model. Mechanistically, Wnt2 promoted Nap1L1 ubiquitination and degradation to restore ROS scavenging systems via Lrp6-mediated recruitment of the E3 ligase Trim11 in I/R hearts. Nap1L1 suppression plays a critical role in mediating the cardioprotective effects of rbWnt2. These findings establish Wnt2 as a therapeutic agent that targets compartmentalized oxidative damage, suggesting a novel strategy to mitigate I/R injury through the Lrp6/Trim11/Nap1L1 axis.
{"title":"Nucleosome assembly protein-like 1 degradation-dependent novel cardioprotection mechanism of Wnt2 against ischemia‒reperfusion injury.","authors":"Ying Wang,Liming Chen,Jinyi Lin,Xi Liu,Kejia Jin,Chenxing Huang,Hao Wang,Jianguo Jia,Jian Wu,Zhiwen Ding,Pan Gao,Junbo Ge,Hui Gong,Yunzeng Zou","doi":"10.1038/s41392-025-02503-5","DOIUrl":"https://doi.org/10.1038/s41392-025-02503-5","url":null,"abstract":"Wnt and its crosstalk signaling pathways are involved in the modulating ischemia‒reperfusion (I/R) injury. However, whether Wnt2 is a novel therapeutic agent for I/R injury is largely unknown. Here, we show that the downregulation of serum Wnt2 levels in acute myocardial infarction (AMI) patients following reperfusion therapy, and Wnt2 levels are inversely correlated with the levels of myocardial injury markers (cTnT and CK-MB). Therapeutic administration of recombinant Wnt2 protein (rbWnt2) alleviates cardiac I/R injury and improves cardiac function by suppressing ROS levels and cardiomyocyte death in mice. Further analysis revealed that rbWnt2 downregulated Nap1L1 to reactivate the transcription of antioxidant genes (SOD, GPX, and UCP3) to reduce ROS levels and subsequently inhibit cardiomyocyte apoptosis and ferroptosis during the I/R process. Cardiac-specific Nap1L1 knockdown attenuated I/R injury, whereas overexpression of Nap1L1 partly abolished the cardiac protection mediated by rbWnt2 administration in the I/R model. Mechanistically, Wnt2 promoted Nap1L1 ubiquitination and degradation to restore ROS scavenging systems via Lrp6-mediated recruitment of the E3 ligase Trim11 in I/R hearts. Nap1L1 suppression plays a critical role in mediating the cardioprotective effects of rbWnt2. These findings establish Wnt2 as a therapeutic agent that targets compartmentalized oxidative damage, suggesting a novel strategy to mitigate I/R injury through the Lrp6/Trim11/Nap1L1 axis.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"13 1","pages":"403"},"PeriodicalIF":39.3,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cellular senescence is deeply involved in physiological homeostasis, development, tissue repair, aging, and diseases. Senescent cells (SnCs) accumulate in aged tissues and exert deleterious effects by secreting proinflammatory molecules that contribute to chronic inflammation and aging-related diseases. We revealed that an aberrant interaction between glycolytic PGAM1 and Chk1 kinase is augmented in SnCs associated with increased glycolysis, whose byproduct, lactate, promotes this binding in a noncell autonomous manner. The pseudo-Warburg effect of SnCs with enhanced PPP (pentose phosphate pathway) activity is maintained by HIF-2α phosphorylation by Chk1 and subsequent upregulation of glycolytic enzymes, creating a vicious cycle reprogramming the glycolytic pathway in SnCs. HIF-2α also activates FoxM1 expression, which transcriptionally suppresses proapoptotic profiles, including BIM, and upregulates DNA repair machineries in SnCs. FoxM1 thus supports the genomic integrity and survival capacity of SnCs during their glycolytic changes. Chemical abrogation of PGAM1-Chk1 binding reverts these phenotypes and eliminates SnCs through senolysis. Inhibition of the PGAM1-Chk1 interaction improves physiological parameters during aging and inhibits lung fibrosis in mouse models. Our study highlights a novel pathway contributing to the metabolic reprogramming of SnCs and how the use of a new senolytic molecule that targets the PGAM-Chk1 interaction creates a specific vulnerability of those cells to potentially fight age-related diseases.
{"title":"Abrogation of aberrant glycolytic interactions eliminates senescent cells and alleviates aging-related dysfunctions.","authors":"Takumi Mikawa,Masahiro Kameda,Sumiko Ikari,Eri Shibata,Shuyu Liu,Sawa Miyagawa,Koh Ono,Tomiko Ito,Akihiko Yoshizawa,Masataka Sugimoto,Shuichi Shibuya,Takahiko Shimizu,Julio Almunia,Noboru Ogiso,Gwladys Revêchon,Alberta Palazzo,David Bernard,Hiroaki Kanda,Tomoyoshi Soga,Keiyo Takubo,Shin Morioka,Junko Sasaki,Takehiko Sasaki,Akihiro Itamoto,Takayuki Fujii,Hiroshi Seno,Nobuya Inagaki,Hiroshi Kondoh","doi":"10.1038/s41392-025-02502-6","DOIUrl":"https://doi.org/10.1038/s41392-025-02502-6","url":null,"abstract":"Cellular senescence is deeply involved in physiological homeostasis, development, tissue repair, aging, and diseases. Senescent cells (SnCs) accumulate in aged tissues and exert deleterious effects by secreting proinflammatory molecules that contribute to chronic inflammation and aging-related diseases. We revealed that an aberrant interaction between glycolytic PGAM1 and Chk1 kinase is augmented in SnCs associated with increased glycolysis, whose byproduct, lactate, promotes this binding in a noncell autonomous manner. The pseudo-Warburg effect of SnCs with enhanced PPP (pentose phosphate pathway) activity is maintained by HIF-2α phosphorylation by Chk1 and subsequent upregulation of glycolytic enzymes, creating a vicious cycle reprogramming the glycolytic pathway in SnCs. HIF-2α also activates FoxM1 expression, which transcriptionally suppresses proapoptotic profiles, including BIM, and upregulates DNA repair machineries in SnCs. FoxM1 thus supports the genomic integrity and survival capacity of SnCs during their glycolytic changes. Chemical abrogation of PGAM1-Chk1 binding reverts these phenotypes and eliminates SnCs through senolysis. Inhibition of the PGAM1-Chk1 interaction improves physiological parameters during aging and inhibits lung fibrosis in mouse models. Our study highlights a novel pathway contributing to the metabolic reprogramming of SnCs and how the use of a new senolytic molecule that targets the PGAM-Chk1 interaction creates a specific vulnerability of those cells to potentially fight age-related diseases.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"20 1","pages":"402"},"PeriodicalIF":39.3,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
SAMHD1 is a human deoxyribonucleoside triphosphatase (dNTPase) known for its role as a restriction factor that targets a wide spectrum of viruses, its involvement in autoimmune disease Aicardi-Goutières syndrome (AGS), and its participation in innate immune regulation. The role of SAMHD1 in cancer, particularly its contribution to drug resistance, has gained increasing attention in recent years. One significant scientific challenge is how to inhibit SAMHD1 function in tumor cells while preserving its function in normal primary cells. Herein, we identified that increased SAMHD1 expression levels correlate with poor prognosis across multiple cancer types, and that SAMHD1 is upregulated in a variety of tumors. Through proteomic analysis and drug screening, we identified a promising strategy for selectively depleting tumor-associated SAMHD1 while minimizing its impact on SAMHD1 expression in key normal cell types. Our approach effectively enhanced tumor cytotoxicity when combined with multiple chemotherapeutic agents and suppressed tumor growth in vivo. Moreover, selective depletion of tumor-associated SAMHD1 activated innate immune responses, leading to enhanced tumor cell killing by immune cells. Collectively, these findings suggest that targeting tumor-specific SAMHD1 represents a novel and promising therapeutic strategy for cancers characterized by elevated SAMHD1 expression, offering potential for improved treatment outcomes in cancer patients with high SAMHD1 expression.
{"title":"Selective depletion of tumor-associated SAMHD1 enhances chemotherapeutic efficacy and antitumor immune responses.","authors":"Jing Sun,Wenwen Zheng,Zheng-Guo Zhang,Hongkun Zhou,Songdi Wang,Dingbo Huang,Xiao-Yi Hu,Qing-Feng Yu,Zhao-Xing Wu,Yi-Fei Shi,Runxin Ye,Fengyan Xia,Wangwei Li,Shurui Lyu,Yu Huang,Xu-Zhao Zhang,Fei Xu,Ke Zhao,Jie Yang,Juan Du,Jiaming Su,Yajuan Rui,Rongzhen Xu,Wei-Ming Yang,Cang Li,Jia Ling Xu,Ruiyu Zhu,Xiaoguang Wang,Wei Wei,Xiao-Fang Yu","doi":"10.1038/s41392-025-02523-1","DOIUrl":"https://doi.org/10.1038/s41392-025-02523-1","url":null,"abstract":"SAMHD1 is a human deoxyribonucleoside triphosphatase (dNTPase) known for its role as a restriction factor that targets a wide spectrum of viruses, its involvement in autoimmune disease Aicardi-Goutières syndrome (AGS), and its participation in innate immune regulation. The role of SAMHD1 in cancer, particularly its contribution to drug resistance, has gained increasing attention in recent years. One significant scientific challenge is how to inhibit SAMHD1 function in tumor cells while preserving its function in normal primary cells. Herein, we identified that increased SAMHD1 expression levels correlate with poor prognosis across multiple cancer types, and that SAMHD1 is upregulated in a variety of tumors. Through proteomic analysis and drug screening, we identified a promising strategy for selectively depleting tumor-associated SAMHD1 while minimizing its impact on SAMHD1 expression in key normal cell types. Our approach effectively enhanced tumor cytotoxicity when combined with multiple chemotherapeutic agents and suppressed tumor growth in vivo. Moreover, selective depletion of tumor-associated SAMHD1 activated innate immune responses, leading to enhanced tumor cell killing by immune cells. Collectively, these findings suggest that targeting tumor-specific SAMHD1 represents a novel and promising therapeutic strategy for cancers characterized by elevated SAMHD1 expression, offering potential for improved treatment outcomes in cancer patients with high SAMHD1 expression.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"4 1","pages":"406"},"PeriodicalIF":39.3,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To assess the efficacy and safety of L-oxiracetam, a novel nootropic agent, in improving cognition in patients with TBI, we performed a multicentre, double-blind, randomized controlled trial in China. Participants aged 18 to 75 years with TBI (Glasgow Coma Scale score of 10 to 15) were recruited from 51 hospitals from 2019 to 2024. Patients were randomly assigned to L-oxiracetam, 4 g/day, oxiracetam 6 g/day, or placebo in 2:2:1. The primary outcome was the change in the Loewenstein Occupational Therapy Cognitive Assessment (LOTCA) score from baseline to 90 days post treatment. Secondary outcomes included changes in additional cognitive evaluations, neurological function, activities of daily living (ADL), and adverse events (AEs). The trial was approved by the China National Medical Products Administration (2016L03521), and registered at Clinicaltrials.gov (NCT04205565) and Chinadrugtrials.org.cn (CTR20192539). Five hundred and ninety patients were included (mean age (SD), 50.9 (14.5); 421 males). The least squares (LS) mean of LOTCA change from baseline to 90 days post treatment was 20.45 (95% confidence interval [CI] 17.23, 23.66) in the L-oxiracetam group, 15.90 (95% CI 12.71, 19.10) in the oxiracetam group, and 11.47 (95% CI 7.75, 15.20) in the placebo group (P value < 0.05 for all groups). The LS mean difference of the L-oxiracetam was significantly higher than the placebo group (8.97, 95% CI 5.69,12.26; P < 0.001; Cohen's d = 0.48 [95% CI: 0.26,0.69]) and the oxiracetam group (4.54, 95% CI 1.85,7.23). Secondary efficacy outcomes did not differ between the L-oxiracetam and oxiracetam groups. The proportion of serious AEs did not differ among the three groups. L-oxiracetam could improve cognitive function in patients with mild-to-moderate TBI. L-oxiracetam might be more efficacious than oxiracetam. No significant safety concerns were reported. Despite limitations such as loss to follow-up, the findings of this study provide important evidence for the clinical management of cognitive dysfunction following TBI. Future studies in real-world clinical settings are warranted to further substantiate the efficacy of L-oxiracetam and oxiracetam.
为了评估l -奥拉西坦（一种新型益智药物）改善TBI患者认知能力的有效性和安全性，我们在中国进行了一项多中心、双盲、随机对照试验。2019年至2024年从51家医院招募年龄在18至75岁之间的TBI患者（格拉斯哥昏迷评分为10至15）。患者按2:2:1的比例随机分配到l -奥拉西坦组，4 g/天，6 g/天，或安慰剂组。主要结果是Loewenstein职业治疗认知评估（LOTCA）评分从基线到治疗后90天的变化。次要结局包括额外认知评估、神经功能、日常生活活动（ADL）和不良事件（ae）的变化。该试验已获得中国国家药品监督管理局批准（2016L03521），并在Clinicaltrials.gov （NCT04205565）和chinadrutrials.org.cn （CTR20192539）上注册。纳入590例患者(平均年龄（SD）， 50.9岁（14.5岁）；421男性)。治疗后90天，l -奥拉西坦组LOTCA变化的最小二乘（LS）平均值为20.45(95%可信区间[CI] 17.23, 23.66)，奥拉西坦组为15.90 (95% CI 12.71, 19.10)，安慰剂组为11.47 (95% CI 7.75, 15.20)（各组P值均< 0.05）。l -奥拉西坦的LS平均差异显著高于安慰剂组（8.97,95% CI 5.69,12.26; P < 0.001; Cohen’s d = 0.48 [95% CI: 0.26,0.69]）和奥拉西坦组（4.54,95% CI 1.85,7.23）。l -奥拉西坦组和奥拉西坦组的次要疗效结果没有差异。三组患者发生严重不良反应的比例无显著差异。l -奥拉西坦可改善轻中度TBI患者的认知功能。左旋奥拉西坦可能比奥拉西坦更有效。没有重大的安全隐患报告。尽管缺乏随访等局限性，但本研究结果为TBI后认知功能障碍的临床治疗提供了重要证据。未来的临床研究将进一步证实l-奥拉西坦和奥拉西坦的疗效。
{"title":"Efficacy and safety of L-oxiracetam on cognitive function in patients with traumatic brain injury: a multicentre, randomised, double-blind, phase 3 clinical trial.","authors":"Tao Liu,Jiao Wang,Zhihao Zhao,Weiwei Jiang,Minzhi Zhang,Yunhu Yu,Yang Liu,Mingqi Liu,Linan Chen,Hengzhu Zhang,Yingbiao Hong,Bohe Li,Rutong Yu,Hongming Ji,Liang Mi,Biao Zhao,Chuanxiang Lv,Chenglong Liu,Jianning Zhang,Rongcai Jiang, ","doi":"10.1038/s41392-025-02492-5","DOIUrl":"https://doi.org/10.1038/s41392-025-02492-5","url":null,"abstract":"To assess the efficacy and safety of L-oxiracetam, a novel nootropic agent, in improving cognition in patients with TBI, we performed a multicentre, double-blind, randomized controlled trial in China. Participants aged 18 to 75 years with TBI (Glasgow Coma Scale score of 10 to 15) were recruited from 51 hospitals from 2019 to 2024. Patients were randomly assigned to L-oxiracetam, 4 g/day, oxiracetam 6 g/day, or placebo in 2:2:1. The primary outcome was the change in the Loewenstein Occupational Therapy Cognitive Assessment (LOTCA) score from baseline to 90 days post treatment. Secondary outcomes included changes in additional cognitive evaluations, neurological function, activities of daily living (ADL), and adverse events (AEs). The trial was approved by the China National Medical Products Administration (2016L03521), and registered at Clinicaltrials.gov (NCT04205565) and Chinadrugtrials.org.cn (CTR20192539). Five hundred and ninety patients were included (mean age (SD), 50.9 (14.5); 421 males). The least squares (LS) mean of LOTCA change from baseline to 90 days post treatment was 20.45 (95% confidence interval [CI] 17.23, 23.66) in the L-oxiracetam group, 15.90 (95% CI 12.71, 19.10) in the oxiracetam group, and 11.47 (95% CI 7.75, 15.20) in the placebo group (P value < 0.05 for all groups). The LS mean difference of the L-oxiracetam was significantly higher than the placebo group (8.97, 95% CI 5.69,12.26; P < 0.001; Cohen's d = 0.48 [95% CI: 0.26,0.69]) and the oxiracetam group (4.54, 95% CI 1.85,7.23). Secondary efficacy outcomes did not differ between the L-oxiracetam and oxiracetam groups. The proportion of serious AEs did not differ among the three groups. L-oxiracetam could improve cognitive function in patients with mild-to-moderate TBI. L-oxiracetam might be more efficacious than oxiracetam. No significant safety concerns were reported. Despite limitations such as loss to follow-up, the findings of this study provide important evidence for the clinical management of cognitive dysfunction following TBI. Future studies in real-world clinical settings are warranted to further substantiate the efficacy of L-oxiracetam and oxiracetam.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"20 1","pages":"401"},"PeriodicalIF":39.3,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1038/s41392-025-02491-6
Michael Rassner,Tony Andreas Müller,Kirstyn Anne Crossley,Geoffroy Andrieux,Sabina Schaberg,Cornelia Endres,Lena Jakob,Teresa Poggio,Natalie Köhler,Julia Kolter,Gerhard Müller-Newen,Katharina Schönberger,Nina Cabezas-Wallscheid,Irene Gonzalez-Menendez,Leticia Quintanilla-Martinez,Melissa Zwick,Driti Ashok,Tanja Nicole Hartmann,Olaf Groß,Oliver Gorka,Marie Follo,Anna Lena Illert,Melanie Boerries,Robert Zeiser,Justus Duyster
Understanding the interplay between oncogenic mutations and the tumor microenvironment could help improve therapy for hematological malignancies. We found that the STAT5-activating oncogenes JAK2 p.V617F, FLT3-ITD, and BCR::ABL1 induce oncostatin M (OSM), which triggers disease progression and immunosuppression. The OSM receptor was predominantly expressed on nonhematopoietic bone marrow (BM) stromal cells. OSM reprogrammed these cells via STAT3 and induced the secretion of cytokines connected to T-cell exhaustion, including IL-6 and MCP-1. Compared with control mice, OSM-overexpressing mice presented reduced T-cell numbers, increased levels of inhibitory receptors on T cells, and elevated lactic acid production by BM stromal cells. OSM induced the expansion of myeloid cells which suppressed T cells. Conversely, genetic deletion of Osm in a JAK2 p.V617F-driven polycythemia vera mouse model reduced polycythemia, BM fibrosis, inflammatory cytokine levels and the expression of inhibitory markers on T cells. Transcriptomic analyses of T cells from OSM-overexpressing mice revealed enrichment of IL6-JAK-STAT3 and inflammatory signaling pathways. Additionally, pharmacological inhibition of OSM reduced disease activity and cytokine production. These findings establish OSM as a key mediator linking oncogenic STAT5 activation to remodeling of the microenvironment and immune suppression. Targeting OSM signaling therefore represents a promising therapeutic strategy to alleviate disease progression in myeloproliferative neoplasms and related malignancies.
{"title":"Oncostatin M induced by STAT5-activating oncogenes promotes disease progression in hematologic malignancies.","authors":"Michael Rassner,Tony Andreas Müller,Kirstyn Anne Crossley,Geoffroy Andrieux,Sabina Schaberg,Cornelia Endres,Lena Jakob,Teresa Poggio,Natalie Köhler,Julia Kolter,Gerhard Müller-Newen,Katharina Schönberger,Nina Cabezas-Wallscheid,Irene Gonzalez-Menendez,Leticia Quintanilla-Martinez,Melissa Zwick,Driti Ashok,Tanja Nicole Hartmann,Olaf Groß,Oliver Gorka,Marie Follo,Anna Lena Illert,Melanie Boerries,Robert Zeiser,Justus Duyster","doi":"10.1038/s41392-025-02491-6","DOIUrl":"https://doi.org/10.1038/s41392-025-02491-6","url":null,"abstract":"Understanding the interplay between oncogenic mutations and the tumor microenvironment could help improve therapy for hematological malignancies. We found that the STAT5-activating oncogenes JAK2 p.V617F, FLT3-ITD, and BCR::ABL1 induce oncostatin M (OSM), which triggers disease progression and immunosuppression. The OSM receptor was predominantly expressed on nonhematopoietic bone marrow (BM) stromal cells. OSM reprogrammed these cells via STAT3 and induced the secretion of cytokines connected to T-cell exhaustion, including IL-6 and MCP-1. Compared with control mice, OSM-overexpressing mice presented reduced T-cell numbers, increased levels of inhibitory receptors on T cells, and elevated lactic acid production by BM stromal cells. OSM induced the expansion of myeloid cells which suppressed T cells. Conversely, genetic deletion of Osm in a JAK2 p.V617F-driven polycythemia vera mouse model reduced polycythemia, BM fibrosis, inflammatory cytokine levels and the expression of inhibitory markers on T cells. Transcriptomic analyses of T cells from OSM-overexpressing mice revealed enrichment of IL6-JAK-STAT3 and inflammatory signaling pathways. Additionally, pharmacological inhibition of OSM reduced disease activity and cytokine production. These findings establish OSM as a key mediator linking oncogenic STAT5 activation to remodeling of the microenvironment and immune suppression. Targeting OSM signaling therefore represents a promising therapeutic strategy to alleviate disease progression in myeloproliferative neoplasms and related malignancies.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"29 1","pages":"400"},"PeriodicalIF":39.3,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hyperuricemia is considered a modifiable risk factor for the development and progression of chronic kidney disease (CKD). There remains controversy over the effects of urate-lowering therapy (ULT) on kidney outcomes in patients with CKD and hyperuricemia. We conducted a cohort study using a sequential target trial emulation framework to evaluate the composite kidney outcomes in patients with CKD and hyperuricemia initiating ULT versus supportive care alone (control). A total of 269,831 eligible person trials (56,936 unique persons) with CKD and hyperuricemia who had received supportive care were included from the China Renal Data System database. The primary outcome was a composite kidney outcome defined as a greater than 40% decline in the estimated GFR or end-stage kidney disease (ESKD). The 3-year cumulative incidence rates of the composite kidney outcomes were 19.69% and 23.22% in the ULT group and the control group, respectively, with a risk difference of -3.53% (95% CI, -5.25% to -1.94%). The estimated 3-year risk differences for ESKD, all-cause mortality, and cardiovascular mortality were -1.88% (-3.28% to -0.45%), -2.25% (-3.02% to -1.51%), and -0.69% (-1.33% to -0.05%), respectively, all of which favor the ULT group. The estimates from the subgroup and sensitivity analyses were consistent with those from the primary analysis. Thus, ULT is associated with a significantly lower risk of kidney disease progression and mortality in patients with stage 3 or higher CKD and hyperuricemia. Large randomized clinical trials with refined designs are needed to assess the effect of ULT in these patients.
{"title":"Urate-lowering therapy and kidney outcomes in patients with chronic kidney disease and hyperuricemia.","authors":"Sheng Nie,Shiyu Zhou,Ruixuan Chen,Lantian Li,Yinfang Sun,Jiao Liu,Luhua Jin,Xian Shao,Mingzhen Pang,Licong Su,Fan Luo,Xin Xu,Fan Fan Hou","doi":"10.1038/s41392-025-02497-0","DOIUrl":"https://doi.org/10.1038/s41392-025-02497-0","url":null,"abstract":"Hyperuricemia is considered a modifiable risk factor for the development and progression of chronic kidney disease (CKD). There remains controversy over the effects of urate-lowering therapy (ULT) on kidney outcomes in patients with CKD and hyperuricemia. We conducted a cohort study using a sequential target trial emulation framework to evaluate the composite kidney outcomes in patients with CKD and hyperuricemia initiating ULT versus supportive care alone (control). A total of 269,831 eligible person trials (56,936 unique persons) with CKD and hyperuricemia who had received supportive care were included from the China Renal Data System database. The primary outcome was a composite kidney outcome defined as a greater than 40% decline in the estimated GFR or end-stage kidney disease (ESKD). The 3-year cumulative incidence rates of the composite kidney outcomes were 19.69% and 23.22% in the ULT group and the control group, respectively, with a risk difference of -3.53% (95% CI, -5.25% to -1.94%). The estimated 3-year risk differences for ESKD, all-cause mortality, and cardiovascular mortality were -1.88% (-3.28% to -0.45%), -2.25% (-3.02% to -1.51%), and -0.69% (-1.33% to -0.05%), respectively, all of which favor the ULT group. The estimates from the subgroup and sensitivity analyses were consistent with those from the primary analysis. Thus, ULT is associated with a significantly lower risk of kidney disease progression and mortality in patients with stage 3 or higher CKD and hyperuricemia. Large randomized clinical trials with refined designs are needed to assess the effect of ULT in these patients.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"26 1","pages":"399"},"PeriodicalIF":39.3,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Clear cell renal cell carcinoma (ccRCC) is characterized by profound lipid metabolic dysregulation, yet the mechanisms linking peritumoral adipose tissue (PAT)-derived lipid metabolites to tumor aggressiveness remain poorly defined. Here, we identified lysophosphatidylethanolamine 18:1 (LPE18:1), a lipid metabolite enriched in PAT and the arterial blood of ccRCC patients, as a critical driver of tumor growth and lipid deposition. Through multiomics analyses and functional studies, we demonstrated that LPE18:1 upregulates F-actin-capping protein subunit alpha-1 (CAPZA1), which recruits ubiquitin-specific peptidase 48 (USP48) to stabilize the NAD-dependent protein deacetylase sirtuin-6 (SIRT6) by inhibiting its proteasomal degradation. Increased SIRT6 epigenetically promotes acetyl-CoA acetyltransferase 2 (ACAT2) expression, redirecting lipid metabolism toward free cholesterol accumulation-a hallmark of ccRCC aggressiveness. Clinically, CAPZA1 and SIRT6 levels correlate with advanced tumor stage and poor prognosis in ccRCC cohorts. Genetic or pharmacological inhibition of the CAPZA1/SIRT6 axis can reverse LPE18:1-induced lipid deposition and tumor progression in xenograft models. Notably, targeting this axis with the SIRT6 inhibitor OSS-128167 combined with CAPZA1 depletion significantly suppresses ccRCC cell growth. Our study reveals a PAT-derived lipid metabolite-fuelled signaling cascade that reprograms lipid metabolism in ccRCC, identifying CAPZA1/USP48/SIRT6 as actionable therapeutic targets for metabolic malignancies.
{"title":"Lysophosphatidylethanolamine 18:1 drives clear cell renal cell carcinoma by stabilizing SIRT6 to reprogram lipid metabolism.","authors":"Nanxi Yue,Hongye Zhao,Yong Zhang,Junfei Gu,Jinchun Qi,Jinkun Wen,Wei Wang,Mingming Lv,Hao Sun,Jinsuo Chen,Chenxiao Yang,Changbao Qu,Xiaonan Chen,Zhan Yang","doi":"10.1038/s41392-025-02496-1","DOIUrl":"https://doi.org/10.1038/s41392-025-02496-1","url":null,"abstract":"Clear cell renal cell carcinoma (ccRCC) is characterized by profound lipid metabolic dysregulation, yet the mechanisms linking peritumoral adipose tissue (PAT)-derived lipid metabolites to tumor aggressiveness remain poorly defined. Here, we identified lysophosphatidylethanolamine 18:1 (LPE18:1), a lipid metabolite enriched in PAT and the arterial blood of ccRCC patients, as a critical driver of tumor growth and lipid deposition. Through multiomics analyses and functional studies, we demonstrated that LPE18:1 upregulates F-actin-capping protein subunit alpha-1 (CAPZA1), which recruits ubiquitin-specific peptidase 48 (USP48) to stabilize the NAD-dependent protein deacetylase sirtuin-6 (SIRT6) by inhibiting its proteasomal degradation. Increased SIRT6 epigenetically promotes acetyl-CoA acetyltransferase 2 (ACAT2) expression, redirecting lipid metabolism toward free cholesterol accumulation-a hallmark of ccRCC aggressiveness. Clinically, CAPZA1 and SIRT6 levels correlate with advanced tumor stage and poor prognosis in ccRCC cohorts. Genetic or pharmacological inhibition of the CAPZA1/SIRT6 axis can reverse LPE18:1-induced lipid deposition and tumor progression in xenograft models. Notably, targeting this axis with the SIRT6 inhibitor OSS-128167 combined with CAPZA1 depletion significantly suppresses ccRCC cell growth. Our study reveals a PAT-derived lipid metabolite-fuelled signaling cascade that reprograms lipid metabolism in ccRCC, identifying CAPZA1/USP48/SIRT6 as actionable therapeutic targets for metabolic malignancies.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"1 1","pages":"398"},"PeriodicalIF":39.3,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The nuclear receptor 4A1(NR4A1) plays a crucial role in maintaining cellular homeostasis and is involved in various disease processes; however, its functional role and pharmacological potential in mesangial proliferative glomerulonephritis (MsPGN) remain unexplored. In this study, we found that downregulation of NR4A1 promotes the pathogenesis of MsPGN by regulating inflammatory and proliferative responses in mesangial cells (MCs), whereas overexpression of NR4A1 reverses these processes. Bruceine A (BA) binds to NR4A1 at residues D481/Q568 and exhibits NR4A1-dependent anti-inflammatory and anti-proliferative effects both in vitro and in vivo. Notably, adeno-associated virus serotype 9 (AAV9)-mediated overexpression of NR4A1 alleviates glomerular injury and inflammatory cascades, while knockout of NR4A1 impairs the renoprotective effects of BA. BA binds to the ligand-binding domain (LBD) of NR4A1 and further sterically blocks K48-linked polyubiquitination at K558, thereby stabilizing NR4A1 protein levels. This stabilization enables NR4A1 to auto-activate its own promoter, amplifying the transcriptional repression of nuclear factor kappa-B (NF-κB) signaling phosphorylation, which ultimately attenuates inflammatory cascades and mesangial proliferation to confer renal protection. This study provides a promising therapeutic avenue for the development of next-generation therapies against MsPGN.
核受体4A1（NR4A1）在维持细胞内稳态中起着至关重要的作用，并参与各种疾病过程；然而，其在系膜增生性肾小球肾炎（MsPGN）中的功能作用和药理潜力仍未被探索。在这项研究中，我们发现NR4A1的下调通过调节系膜细胞（MCs）的炎症和增殖反应来促进MsPGN的发病机制，而NR4A1的过表达则逆转这些过程。Bruceine A （BA）在D481/Q568位点与NR4A1结合，在体外和体内均表现出NR4A1依赖的抗炎和抗增殖作用。值得注意的是，腺相关病毒血清型9 （AAV9）介导的NR4A1过表达减轻了肾小球损伤和炎症级联反应，而敲除NR4A1则削弱了BA的肾保护作用。BA结合NR4A1的配体结合域（LBD），进一步在K558位点立体阻断k48连接的多泛素化，从而稳定NR4A1蛋白水平。这种稳定性使NR4A1能够自动激活其自身的启动子，放大对核因子κ b （NF-κB）信号磷酸化的转录抑制，最终减轻炎症级联反应和肾系膜增殖，从而赋予肾脏保护作用。该研究为开发下一代治疗MsPGN的方法提供了一条有希望的治疗途径。
{"title":"Bruceine A protects nuclear receptor 4A1 from ubiquitin-degradation to alleviate mesangial proliferative glomerulonephritis.","authors":"Huating Hu,Runze Li,Kancheng He,Lingling Wu,Rongrong Li,Jiayan Lu,Ruimin Tian,Chuanghai Zhang,Jiayan He,Yulian Chen,Ruogu Lai,Jiaqi Zhang,Jiaqi Wu,Ying Zheng,Jinlian He,Liang Liu,Xiangmei Chen,Hudan Pan","doi":"10.1038/s41392-025-02495-2","DOIUrl":"https://doi.org/10.1038/s41392-025-02495-2","url":null,"abstract":"The nuclear receptor 4A1(NR4A1) plays a crucial role in maintaining cellular homeostasis and is involved in various disease processes; however, its functional role and pharmacological potential in mesangial proliferative glomerulonephritis (MsPGN) remain unexplored. In this study, we found that downregulation of NR4A1 promotes the pathogenesis of MsPGN by regulating inflammatory and proliferative responses in mesangial cells (MCs), whereas overexpression of NR4A1 reverses these processes. Bruceine A (BA) binds to NR4A1 at residues D481/Q568 and exhibits NR4A1-dependent anti-inflammatory and anti-proliferative effects both in vitro and in vivo. Notably, adeno-associated virus serotype 9 (AAV9)-mediated overexpression of NR4A1 alleviates glomerular injury and inflammatory cascades, while knockout of NR4A1 impairs the renoprotective effects of BA. BA binds to the ligand-binding domain (LBD) of NR4A1 and further sterically blocks K48-linked polyubiquitination at K558, thereby stabilizing NR4A1 protein levels. This stabilization enables NR4A1 to auto-activate its own promoter, amplifying the transcriptional repression of nuclear factor kappa-B (NF-κB) signaling phosphorylation, which ultimately attenuates inflammatory cascades and mesangial proliferation to confer renal protection. This study provides a promising therapeutic avenue for the development of next-generation therapies against MsPGN.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"203 1","pages":"397"},"PeriodicalIF":39.3,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145673898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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