Journal of Investigative Medicine最新文献

{"title":"Why non-human primates are needed in stroke preclinical research.","authors":"Xiya Long, Jinsheng Zeng","doi":"10.1136/svn-2024-003504","DOIUrl":"https://doi.org/10.1136/svn-2024-003504","url":null,"abstract":"<p><p>Numerous seemingly promising cerebroprotectants previously validated in rodents almost all have failed in stroke clinical trials. The failure of clinical translation strikes an essential need to employ more ideal animal models in stroke research. Compared with the most commonly used rodent models of stroke, non-human primates (NHPs) are far more comparable to humans regarding brain anatomy, functionality and pathological features. The aim of this perspective was to summarise the advantages of NHPs stroke models over rodents, discuss the current limitations of NHPs models, and cast an outlook on the future development of NHPs in stroke preclinical research.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142113762","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}

{"title":"Surgical timing and long-term outcomes in patients with severe haemorrhagic spinal cord cavernous malformations.","authors":"An Tian, Ziwei Cui, Jian Ren, Yeqing Ren, Ming Ye, Guilin Li, Chuan He, Xiaoyu Li, Gao Zeng, Peng Hu, Yongjie Ma, Jiaxing Yu, Jingwei Li, Lisong Bian, Fan Yang, Qianwen Li, Feng Ling, Tao Hong, Liyong Sun, Hongqi Zhang","doi":"10.1136/svn-2023-002745","DOIUrl":"10.1136/svn-2023-002745","url":null,"abstract":"<p><strong>Background: </strong>Surgical resection of the lesions remains the main treatment method for most symptomatic spinal cord cavernous malformations (SCCMs) to eliminate the occupation and associated subsequent lifelong haemorrhagic risk. However, the timing of surgical intervention remains controversial, especially for patients in the acute stage after severe haemorrhage.</p><p><strong>Methods: </strong>Patients diagnosed with SCCMs who were surgically treated between January 2002 and December 2021 were selected and retrospectively reviewed. The Modified McCormick Scale (MMS) was used to evaluate neurological and disability status. All medical information was reviewed, and all patients were followed up for at least 6 months.</p><p><strong>Results: </strong>A total of 279 patients were ultimately included. With regard to long-term outcomes, 110 (39.4%) patients improved, 159 (57.0%) remained unchanged and 10 (3.6%) worsened. For patients with an MMS score of 2-5 on admission, in univariate and multivariate analyses, a ≤6 weeks period between onset and surgery (adjusted OR 3.211, 95% CI 1.504 to 6.856, p=0.003) was a significant predictor of improved MMS. Among 69 patients who first presented with severe haemorrhage, undergoing surgery within 6 weeks of the onset of severe haemorrhage (adjusted OR 4.901, 95% CI 1.126 to 21.325, p=0.034) was significantly associated with improvement of MMS score.</p><p><strong>Conclusion: </strong>Surgical timing can influence the long-term outcome of SCCMs. For patients with symptomatic SCCMs, especially those with severe haemorrhage, early surgical intervention within 6 weeks can provide more benefit.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":"439-445"},"PeriodicalIF":2.6,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420913/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72211460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reperfusion and cytoprotective agents are a mutually beneficial pair in ischaemic stroke therapy: an overview of pathophysiology, pharmacological targets and candidate drugs focusing on excitotoxicity and free radical.","authors":"Xiumei Xu, Mingyu Chen, Dongya Zhu","doi":"10.1136/svn-2023-002671","DOIUrl":"10.1136/svn-2023-002671","url":null,"abstract":"<p><p>Stroke is the second-leading cause of death and the leading cause of disability in much of the world. In particular, China faces the greatest challenge from stroke, since the population is aged quickly. In decades of clinical trials, no neuroprotectant has had reproducible efficacy on primary clinical end points, because reperfusion is probably a necessity for neuroprotection to be clinically beneficial. Fortunately, the success of thrombolysis and endovascular thrombectomy has taken us into a reperfusion era of acute ischaemic stroke (AIS) therapy. Brain cytoprotective agents can prevent detrimental effects of ischaemia, and therefore 'freeze' ischaemic penumbra before reperfusion, extend the time window for reperfusion therapy. Because reperfusion often leads to reperfusion injury, including haemorrhagic transformation, brain oedema, infarct progression and neurological worsening, cytoprotective agents will enhance the efficacy and safety of reperfusion therapy by preventing or reducing reperfusion injuries. Therefore, reperfusion and cytoprotective agents are a mutually beneficial pair in AIS therapy. In this review, we outline critical pathophysiological events causing cell death within the penumbra after ischaemia or ischaemia/reperfusion in the acute phase of AIS, focusing on excitotoxicity and free radicals. We discuss key pharmacological targets for cytoprotective therapy and evaluate the recent advances of cytoprotective agents going through clinical trials, highlighting multitarget cytoprotective agents that intervene at multiple levels of the ischaemic and reperfusion cascade.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":"351-359"},"PeriodicalIF":2.6,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41216801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cerebral small vessel disease modifies outcomes after minimally invasive surgery for intracerebral haemorrhage.","authors":"Yunke Li, Sung-Min Cho, Radhika Avadhani, Hassan Ali, Yi Hao, Santosh B Murthy, Joshua N Goldstein, Fan Xia, Xin Hu, Natalie L Ullman, Issam Awad, Daniel Hanley, Wendy C Ziai","doi":"10.1136/svn-2023-002463","DOIUrl":"10.1136/svn-2023-002463","url":null,"abstract":"<p><strong>Background: </strong>Minimally invasive surgery (MIS) for spontaneous supratentorial intracerebral haemorrhage (ICH) is controversial but may be beneficial if end-of-treatment (EOT) haematoma volume is reduced to ≤15 mL. We explored whether MRI findings of cerebral small vessel disease (CSVD) modify the effect of MIS on long-term outcomes.</p><p><strong>Methods: </strong>Prespecified blinded subgroup analysis of 288 subjects with qualified imaging sequences from the phase 3 Minimally Invasive Surgery Plus Alteplase for Intracerebral Haemorrhage Evacuation (MISTIE) trial. We tested for heterogeneity in the effects of MIS and MIS+EOT volume ≤15 mL on the trial's primary outcome of good versus poor function at 1 year by the presence of single CSVD features and CSVD scores using multivariable models.</p><p><strong>Results: </strong>Of 499 patients enrolled in MISTIE III, 288 patients had MRI, 149 (51.7%) randomised to MIS and 139 (48.3%) to standard medical care (SMC). Median (IQR) ICH volume was 42 (30-53) mL. In the full MRI cohort, there was no statistically significant heterogeneity in the effects of MIS versus SMC on 1-year outcomes by any specific CSVD feature or by CSVD scores (all P_interaction >0.05). In 94 MIS patients with EOT ICH volume ≤15 mL, significant reduction in odds of poor outcome was found with cerebral amyloid angiopathy score <2 (OR, 0.14 (0.05-0.42); P_interaction=0.006), absence of lacunes (OR, 0.37 (0.18-0.80); P_interaction=0.02) and absence of severe white matter hyperintensities (WMHs) (OR, 0.22 (0.08-0.58); P_interaction=0.03).</p><p><strong>Conclusions: </strong>Following successful haematoma reduction by MIS, we found significantly lower odds of poor functional outcome with lower total burden of CSVD in addition to absence of lacunes and severe WMHs. CSVD features may have utility for prognostication and patient selection in clinical trials of MIS.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":"446-456"},"PeriodicalIF":2.6,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72211457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Src inhibition rescues FUNDC1-mediated neuronal mitophagy in ischaemic stroke.","authors":"Tianchi Tang, Li-Bin Hu, Chao Ding, Zhihua Zhang, Ning Wang, Tingting Wang, Hang Zhou, Siqi Xia, Linfeng Fan, Xiong-Jie Fu, Feng Yan, Xiangnan Zhang, Gao Chen, Jianru Li","doi":"10.1136/svn-2023-002606","DOIUrl":"10.1136/svn-2023-002606","url":null,"abstract":"<p><strong>Background: </strong>Ischaemic stroke triggers neuronal mitophagy, while the involvement of mitophagy receptors in ischaemia/reperfusion (I/R) injury-induced neuronal mitophagy remain not fully elucidated. Here, we aimed to investigate the involvement of mitophagy receptor FUN14 domain-containing 1 (FUNDC1) and its modulation in neuronal mitophagy induced by I/R injury.</p><p><strong>Methods: </strong>Wild-type and FUNDC1 knockout mice were generated to establish models of neuronal I/R injury, including transient middle cerebral artery occlusion (tMCAO) in vivo and oxygen glucose deprivation/reperfusion in vitro. Stroke outcomes of mice with two genotypes were assessed. Neuronal mitophagy was analysed both in vivo and in vitro. Activities of FUNDC1 and its regulator Src were evaluated. The impact of Src on FUNDC1-mediated mitophagy was assessed through administration of Src antagonist PP1.</p><p><strong>Results: </strong>To our surprise, FUNDC1 knockout mice subjected to tMCAO showed stroke outcomes comparable to those of their wild-type littermates. Although neuronal mitophagy could be activated by I/R injury, FUNDC1 deletion did not disrupt neuronal mitophagy. Transient activation of FUNDC1, represented by dephosphorylation of Tyr18, was detected in the early stages (within 3 hours) of neuronal I/R injury; however, phosphorylated Tyr18 reappeared and even surpassed baseline levels in later stages (after 6 hours), accompanied by a decrease in FUNDC1-light chain 3 interactions. Spontaneous inactivation of FUNDC1 was associated with Src activation, represented by phosphorylation of Tyr416, which changed in parallel with the level of phosphorylated FUNDC1 (Tyr18) during neuronal I/R injury. Finally, FUNDC1-mediated mitophagy in neurons under I/R conditions can be rescued by pharmacological inhibition of Src.</p><p><strong>Conclusions: </strong>FUNDC1 is inactivated by Src during the later stage (after 6 hours) of neuronal I/R injury, and rescue of FUNDC1-mediated mitophagy may serve as a potential therapeutic strategy for treating ischaemic stroke.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":"367-379"},"PeriodicalIF":2.6,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41152568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"One-year direct and indirect costs of ischaemic stroke in China.","authors":"Wei Lv, Anxin Wang, Qianyi Wang, Ruimin Wang, Qin Xu, Shuqing Wu, Yi Han, Yong Jiang, Jinxi Lin, Jing Jing, Hao Li, Yongjun Wang, Xia Meng","doi":"10.1136/svn-2023-002296","DOIUrl":"10.1136/svn-2023-002296","url":null,"abstract":"<p><strong>Background: </strong>This is the first real-world study to estimate the direct costs and indirect costs of first-ever ischaemic stroke with 1-year follow-up in China, based on a nationally representative sample.</p><p><strong>Methods: </strong>Patients were chosen from 20 geographically diverse sites from the nationally representative database China National Stroke Registry-III (CNSR-III). The inclusion criteria were surviving patients who were hospitalised with first-ever ischaemic stroke from February 2017 to February 2018 (the index event); aged 18-80 during the index event; no history of other stroke types. The primary endpoints were direct medical costs, direct non-medical costs, indirect costs and total cost (ie, the sum of all cost components). Patient characteristics and clinical data were extracted from CNSR-III. Stroke-related in-hospital direct medical costs were collected from hospital electronic medical records. The patient survey collected data related to out-of-hospital direct medical costs, direct non-medical costs and indirect costs. The secondary objective was to explore clinical factors associated with cost outcomes through univariate analysis and multiple regression.</p><p><strong>Results: </strong>The study enrolled 520 patients. The total cost was 57 567.48 CNY, with 26 612.67 CNY direct medical costs, 2 787.56 CNY direct non-medical costs and 28 167.25 CNY indirect costs. Univariate analysis showed that longer lengths of stay during the index event, higher National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale scores were associated with higher costs in all categories. Conversely, EuroQol 5 Dimension utility scores were associated with decreased costs except direct non-medical costs. Multiple regressions showed that higher admission NIHSS scores were independently associated with higher direct medical costs, indirect costs and total cost. Higher 3-month utilities were associated with lower total cost.</p><p><strong>Conclusion: </strong>This real-world study showed substantial 1-year economic burden following first-ever ischaemic stroke in China, and that indirect costs are a non-negligible driver of costs.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":"380-389"},"PeriodicalIF":2.6,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41153687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal associations of cardiovascular health and vascular events with incident dementia.","authors":"Ya-Nan Ou, Kevin Kuo, Liu Yang, Ya-Ru Zhang, Shu-Yi Huang, Shi-Dong Chen, Yue-Ting Deng, Yu Guo, Rui-Qi Zhang, Bang-Sheng Wu, Lan Tan, Qiang Dong, Jian-Feng Feng, Wei Cheng, Jin-Tai Yu","doi":"10.1136/svn-2023-002665","DOIUrl":"10.1136/svn-2023-002665","url":null,"abstract":"<p><strong>Introduction: </strong>Evidence supporting cardiovascular diseases could increase the risk of dementia remains fragmented. A comprehensive study to illuminate the distinctive associations across different dementia types is still lacking. This study is sought to: (1) determine the clinical validity of Framingham General Cardiovascular Risk Score (FGCRS) for dementia assessment and (2) examine the associations between cardiovascular diseases and the risk of dementia.</p><p><strong>Methods: </strong>A total of 432 079 dementia-free individuals at baseline from UK Biobank were included. Multivariable Cox proportional hazard models were used to investigate the prospective associations for FGCRS and a series of cardiovascular diseases with all-cause dementia (ACD) and its major components, Alzheimer's disease (AD) and vascular dementia (VaD).</p><p><strong>Results: </strong>During a median follow-up of 110.1 months, 4711 individuals were diagnosed with dementia. FGCRS was associated with increased risks across the dementia spectrum. In stratification analysis, high-risk groups have demonstrated the greatest dementia burdens, particularly to VaD. Over 74 traits, 9 adverse associations, such as chronic ischaemic heart disease (ACD: HR=1.354; AD: HR=1.269; VaD: HR=1.768), atrioventricular block (ACD: HR=1.562; AD: HR=1.556; VaD: HR=2.069), heart failure (ACD: HR=1.639; AD: HR=1.543; VaD: HR=2.141) and hypotension (ACD: HR=2.912; AD: HR=2.361; VaD: HR=3.315) were observed. Several distinctions were also found, with atrial fibrillation, cerebral infarction, and haemorrhage only associated with greater risks of ACD and VaD.</p><p><strong>Discussion: </strong>By identifying distinctive associations between cardiovascular diseases and dementia, this study has established a comprehensive 'mapping' that may untangle the long-standing discrepancy. FGCRS has demonstrated its predictivity beyond cardiovascular diseases burdens, suggesting potential opportunities for implantation.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":"418-428"},"PeriodicalIF":2.6,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41216800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combined effect of cortical superficial siderosis and cerebral microbleed on short-term and long-term outcomes after intracerebral haemorrhage.","authors":"Yujia Jin, Yu-Hui Huang, Yu-Ping Chen, Yao-Dan Zhang, Jiawen Li, Kai-Cheng Yang, Xianghua Ye, Lu-Hang Jin, Jian Wu, Chang-Zheng Yuan, Feng Gao, Lu-Sha Tong","doi":"10.1136/svn-2023-002439","DOIUrl":"10.1136/svn-2023-002439","url":null,"abstract":"<p><strong>Background and purpose: </strong>Cortical superficial siderosis (cSS) and cerebral microbleed (CMB) have distinct effects on intracerebral haemorrhage (ICH). We aim to investigate the combined effect of cSS and CMB on outcomes after ICH.</p><p><strong>Methods: </strong>Based on a single-centre stroke registry database, patients with spontaneous ICH who had CT scan within 48 hours after ictus and MRI subsequently were identified. Eligible patients were divided into four groups (cSS-CMB-, cSS-CMB+, cSS+CMB-, cSS+CMB+) according to cSS and CMB on susceptibility-weighted image of MRI. Primary outcomes were haematoma volume on admission and unfavourable outcome defined as modified Rankin Scale scores ≥3 at 3 months. Secondary outcomes were all-cause death, recurrence of stroke and ICH during follow-up (median follow-up 2.0 years, IQR 1.0-3.0 years).</p><p><strong>Results: </strong>A total of 673 patients were identified from 1044 patients with spontaneous ICH. 131 (19.5%) had cSS and 468 (69.5%) had CMB. Patients with cSS+CMB+ had the highest rate of poor outcome at 3 months, as well as all-cause death, recurrent stroke and ICH during follow-up. In cSS- patients, CMB was associated with smaller haematoma (β -0.13; 95% CI -0.22 to -0.03; p=0.009), but it still increased risks of recurrent ICH (OR 4.6; 95% CI 1.3 to 15.6; p=0.015) and stroke (OR 2.0; 95% CI 1.0 to 4.0; p=0.049). These effects of CMB became unremarkable in the context of cSS+.</p><p><strong>Conclusions: </strong>Patients with different combinations of cSS and CMB have distinct patterns of short-term and long-term outcomes. Although CMB is related to restrained haematoma, it does not improve long-term outcomes.</p><p><strong>Trial registration number: </strong>NCT04803292.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":"429-438"},"PeriodicalIF":2.6,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11423268/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72211459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advanced rehabilitation in ischaemic stroke research.","authors":"Jixian Wang, Yongfang Li, Lin Qi, Muyassar Mamtilahun, Chang Liu, Ze Liu, Rubing Shi, Shengju Wu, Guo-Yuan Yang","doi":"10.1136/svn-2022-002285","DOIUrl":"10.1136/svn-2022-002285","url":null,"abstract":"<p><p>At present, due to the rapid progress of treatment technology in the acute phase of ischaemic stroke, the mortality of patients has been greatly reduced but the number of disabled survivors is increasing, and most of them are elderly patients. Physicians and rehabilitation therapists pay attention to develop all kinds of therapist techniques including physical therapy techniques, robot-assisted technology and artificial intelligence technology, and study the molecular, cellular or synergistic mechanisms of rehabilitation therapies to promote the effect of rehabilitation therapy. Here, we discussed different animal and in vitro models of ischaemic stroke for rehabilitation studies; the compound concept and technology of neurological rehabilitation; all kinds of biological mechanisms of physical therapy; the significance, assessment and efficacy of neurological rehabilitation; the application of brain-computer interface, rehabilitation robotic and non-invasive brain stimulation technology in stroke rehabilitation.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":"328-343"},"PeriodicalIF":2.6,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420926/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41152726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PRCP is a promising drug target for intracranial aneurysm rupture supported via multi-omics analysis.","authors":"Jinghao Wu, Yunyun Mei, XinYu Li, Wen-Kai Yu, Zi Han Zhou, Yinghao Yang, Pengpeng Niu, Yunchao Wang, Chang-He Shi, Hanghang Zhu, Wenjun He, Yuan Gao, Yuming Xu, Yusheng Li","doi":"10.1136/svn-2023-003076","DOIUrl":"https://doi.org/10.1136/svn-2023-003076","url":null,"abstract":"<p><strong>Background: </strong>Cerebral aneurysms are life-threatening cerebrovascular disorders. Currently, there are no effective treatments for preventing disease progression. Mendelian randomisation (MR) is widely used to repurify licensed drugs and identify new therapeutic targets. Therefore, this study aims to investigate effective drug targets for preventing the formation and rupture of cerebral aneurysms and analyse their potential mechanisms.</p><p><strong>Methods: </strong>We performed a comprehensive study integrating two-sample MR analysis, colocalisation analysis and summary data-based Mendelian randomisation (SMR) to assess the causal effects of blood and brain druggable cis-expression quantitative trait loci (cis-eQTLs) on intracranial aneurysm (IA), unruptured intracranial aneurysm (UIA) and subarachnoid haemorrhage of IA rupture (SAH). Druggable genes were obtained from the study by Chris Finan <i>et al</i>, cis-eQTLs from the eQTLGen and PsychENCODE consortia. Results were validated using proteomic and transcriptomic data. Single-gene functional analyses probed potential mechanisms, culminating in the construction of a drug-gene regulation network.</p><p><strong>Results: </strong>Through the MR analysis, we identified four potential drug targets in the blood, including prolylcarboxypeptidase (PRCP), proteasome 20S subunit alpha 4 (PSMA4), LTBP4 and GPR160 for SAH. Furthermore, two potential drug targets (PSMA4 and SLC22A4) were identified for IA and one potential drug target (KL) for UIA after accounting for multiple testing (P(inverse-variance weighted)<8.28e-6). Strong evidence of colocalisation and SMR analysis confirmed the relevance of PSMA4 and PRCP in outcomes. Elevated PRCP circulating proteins correlated with a lower SAH risk. PRCP gene expression was significantly downregulated in the disease cohort.</p><p><strong>Conclusions: </strong>This study supports that elevated PRCP gene expression in blood is causally associated with the decreased risk of IA rupture. Conversely, increased PSMA4 expression in the blood is causally related to an increased risk of IA rupture and formation.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056959","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}