Journal of Investigative Medicine最新文献

{"title":"Exosomes-mediated delivery of miR-486-3p alleviates neuroinflammation via SIRT2-mediated inhibition of mitophagy after subarachnoid hemorrhage.","authors":"Bin Sheng, Sen Gao, XiangXin Chen, Yang Liu, Niansheng Lai, Jin Dong, Jiaqing Sun, Yan Zhou, Lingyun Wu, Chun-Hua Hang, Wei Li","doi":"10.1136/svn-2024-003509","DOIUrl":"10.1136/svn-2024-003509","url":null,"abstract":"<p><strong>Background: </strong>Neuroinflammation participates in the pathogenesis of subarachnoid haemorrhage (SAH); however, no effective treatments exist. MicroRNAs regulate several aspects of neuronal dysfunction. In a previous study, we found that exosomal miR-486-3p is involved in the pathophysiology of SAH. Targeted delivery of miR-486-3p without blood-brain barrier (BBB) restriction to alleviate SAH is a promising neuroinflammation approach.</p><p><strong>Methods: </strong>In this study, we modified exosomes (Exo) to form an RVG-miR-486-3p-Exo (Exo/miR) to achieve targeted delivery of miR-486-3p to the brain. Neurological scores, brain water content, BBB damage, flow cytometry and FJC staining were used to determine the effect of miR-486-3p on SAH. Western blot analysis, ELISA and RT-qPCR were used to measure relevant protein and mRNA levels. Immunofluorescence staining and laser confocal detection were used to measure the expression of mitochondria, lysosomes and autophagosomes, and transmission electron microscopy was used to observe the level of mitophagy in the brain tissue of mice after SAH.</p><p><strong>Results: </strong>Tail vein injection of Exo/miR improved targeting of miR-486-3p to the brains of SAH mice. The injection reduced levels of neuroinflammation-related factors by changing the phenotype switching of microglia, inhibiting the expression of sirtuin 2 (SIRT2) and enhancing mitophagy. miR-486-3p treatment alleviated neurobehavioral disorders, brain oedema, BBB damage and neurodegeneration. Further research found that the mechanism was achieved by regulating the acetylation level of peroxisome proliferator-activated receptor γ coactivator l alpha (PGC-1α) after SIRT2 enters the nucleus.</p><p><strong>Conclusion: </strong>Exo/miR treatment attenuates neuroinflammation after SAH by inhibiting SIRT2 expression and stimulating mitophagy, suggesting potential clinical applications.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":"335-346"},"PeriodicalIF":2.6,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12285680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142367095","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":"Bone marrow-derived mesenchymal stem cell ameliorates post-stroke enterobacterial translocation through liver-gut axis.","authors":"Xiaotao Su, Tiemei Li, Yuge Wang, Lei Wei, Banghao Jian, Xinmei Kang, Mengyan Hu, Chunyi Li, Shisi Wang, Danli Lu, Shishi Shen, Huipeng Huang, Yuxin Liu, Xiaohui Deng, Bingjun Zhang, Wei Cai, Zhengqi Lu","doi":"10.1136/svn-2024-003494","DOIUrl":"10.1136/svn-2024-003494","url":null,"abstract":"<p><strong>Background: </strong>Enterobacterial translocation is a leading contributor to fatal infection among patients with acute ischaemic stroke (AIS). Accumulative evidence suggests that mesenchymal stem cell (MSC) effectively ameliorates stroke outcomes. Whether MSC could inhibit post-stroke enterobacterial translocation remains elusive.</p><p><strong>Methods: </strong>Patients with AIS and healthy individuals were enrolled in the study. Mice subjected to transient middle cerebral artery occlusion were treated with bone marrow-derived MSC (BM-MSC) right after reperfusion. Enterobacterial translocation was evaluated with Stroke Dysbiosis Index and circulating endotoxin. Thickness of mucus was assessed with Alcian blue staining. Hepatic glucocorticoid (GC) metabolism was analysed with expression of HSD11B2, HSD11B1 and SRD5A1.</p><p><strong>Results: </strong>We report that the gut mucus layer was attenuated after the stroke leading to pronounced enterobacterial translocation. The attenuation of the gut mucus was attributed to diminished mucin production by goblet cells in response to the elevated systemic GC after cerebral ischaemia. Transferred-BM-MSC restored the mucus thickness, thus preserving gut microbiota homeostasis and preventing enterobacterial invasion. Mechanistically, the transferred-BM-MSC stationed in the liver and enhanced peroxisome proliferator-activated receptor γ signalling in hepatocytes. Consequently, expression of HSD11B2 and SRD5A1 was increased while HSD11B1 expression was downregulated which promoted GC catabolism and subsequently restored mucin production.</p><p><strong>Conclusions: </strong>Our findings reveal that MSC transfer improves post-stroke gut barrier integrity and inhibits enterobacterial translocation by enhancing the hepatic GC metabolism thus representing a protective modulator of the liver-gut-brain axis in AIS.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":"359-370"},"PeriodicalIF":2.6,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12230223/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142376180","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":"Central post-stroke pain: advances in clinical and preclinical research.","authors":"Xiqian Yuan, Siyuan Hu, Xiaochong Fan, Chao Jiang, Yan Xu, Ruochen Hao, Zili Xu, Yiyang Yu, Yousef Rastegar-Kashkooli, Leo Huang, Tom J Wang, Qiao Wang, Songxue Su, Limin Wang, Junyang Wang, Menglu Wang, Yun Tai Kim, Ujjal K Bhawal, Fushun Wang, Ting Zhao, Junmin Wang, Xuemei Chen, Jian Wang","doi":"10.1136/svn-2024-003418","DOIUrl":"10.1136/svn-2024-003418","url":null,"abstract":"<p><p>Central poststroke pain (CPSP) is a medical complication that arises poststroke and significantly impacts the quality of life and social functioning of affected individuals. Despite ongoing research, the exact pathomechanisms of CPSP remain unclear, and practical treatments are still unavailable. Our review aims to systematically analyse current clinical and preclinical studies on CPSP, which is critical for identifying gaps in knowledge and guiding the development of effective therapies. The review will clarify the clinical characteristics, evaluation scales and contemporary therapeutic approaches for CPSP based on clinical investigations. It will particularly emphasise the CPSP model initiated by stroke, shedding light on its underlying mechanisms and evaluating treatments validated in preclinical studies. Furthermore, the review will not only highlight methodological limitations in animal trials but also offer specific recommendations to researchers to improve the quality of future investigations and guide the development of effective therapies. This review is expected to provide valuable insights into the current knowledge regarding CPSP and can serve as a guide for future research and clinical practice. The review will contribute to the scientific understanding of CPSP and help develop effective clinical interventions.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":"391-406"},"PeriodicalIF":2.6,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12230222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142356520","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":"Extracellular vesicles bearing serum amyloid A1 exacerbate neuroinflammation after intracerebral haemorrhage.","authors":"Huimin Zhu, Ningning Wang, Yingying Chang, Ying Zhang, Shihe Jiang, Xiaoping Ren, Meng Yuan, Haoxiao Chang, Wei-Na Jin","doi":"10.1136/svn-2024-003525","DOIUrl":"10.1136/svn-2024-003525","url":null,"abstract":"<p><strong>Introduction: </strong>Intracerebral haemorrhage (ICH) elicits a robust inflammatory response, which significantly contributes to secondary brain damage. Extracellular vesicles (EVs) play a pivotal role in intercellular communication by transporting immune-regulatory proteins. However, the precise contribution of these EV-carried proteins to neuroinflammation following ICH remains elusive. Here, we identified proteins dysregulated in EVs and further studied the EVs-enriched Serum amyloid A 1 (SAA1) to understand its role in neuroinflammation and ICH injury.</p><p><strong>Methods: </strong>We used mass spectrometry to analyse the EV protein cargo isolated from plasma samples of 30 ICH patients and 30 healthy controls. To validate the function of the dysregulated protein SAA1, an ICH mouse model was conducted to assess the effects of SAA1 neutralisation on brain oedema, neurological function and infiltration of peripheral leucocytes.</p><p><strong>Results: </strong>49 upregulated proteins and 12 downregulated proteins were observed in EVs from ICH patients compared with controls. Notably, SAA1 demonstrated a significant increase in EVs associated with ICH. We observed that exogenous SAA1 stimulation led to an augmentation in the population of microglia and astrocytes, exacerbating neuroinflammation. Neutralising SAA1 with an anti-SAA1 monoclonal antibody (mAb) diminished the prevalence of proinflammatory microglia and the infiltration of peripheral leucocytes, which ameliorates brain oedema and neurological function in ICH mice.</p><p><strong>Conclusion: </strong>Our findings provide compelling evidence implicating EVs and their cargo proteins in ICH pathogenesis. SAA1 emerges as a potential therapeutic target for mitigating neuroinjury and neuroinflammation following ICH.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":"347-358"},"PeriodicalIF":2.6,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12230225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142367096","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":"Understanding external carotid artery collateralisation after cerebral revascularisation in moyamoya disease: insights from quantitative analysis.","authors":"Wenjie Li, Meng Zhao, Xingju Liu, Peijiong Wang, Huan Zhu, Qihang Zhang, Chenyu Zhu, Qian Zhang, Xun Ye, Jizong Zhao, Yan Zhang","doi":"10.1136/svn-2024-003336","DOIUrl":"10.1136/svn-2024-003336","url":null,"abstract":"<p><strong>Background: </strong>This study aims to quantitatively evaluate collateralisation angiogenesis ratio (CAR) of external carotid artery and intracranial arterial residual volumes (ARV) postcerebral revascularisation in moyamoya disease (MMD) and elucidate the factors influencing external carotid artery collateralisation.</p><p><strong>Methods: </strong>The study retrospectively analysed 297 patients diagnosed with MMD who underwent cerebral revascularisation at our University's Hospital, between January 2015 and May 2023. The clinical data, imaging results and surgical specifics for the patients were collected. Using a newly proposed digital subtraction angiography-based evaluation system, the CAR of external carotid artery and the intracranial ARV were evaluated quantitatively following standardised protocols.</p><p><strong>Results: </strong>The study included 136 male and 161 female patients. The severity of ischaemic (r=-0.297) and haemorrhagic (r=-0.270) MMD, as assessed by the Suzuki stage, demonstrated a significant negative correlation with intracranial ARV (p<0.001). However, no significant correlation was observed between the intracranial ARV and the modified Rankin Scale scores. Patients with fetal-type posterior cerebral arteries exhibited greater intracranial ARV compared with those without (p=0.003). Additionally, a positive correlation was observed between external carotid artery collateralisation and intracranial ARV post-revascularisation (r=0.340, p<0.001). The CAR of external carotid artery following cerebral revascularisation in patients with MMD remained independent correlation of the intracranial ARV (β=0.385, 95% CI (0.921 to 1.669), p<0.001) and Suzuki stage (β=0.211, 95% CI (0.009 to 0.030), p<0.001).</p><p><strong>Conclusions: </strong>This study showed a complex association between ARV, the Suzuki stage and the collateralisation of the external carotid artery in patients with MMD who are undergoing revascularisation. These findings provide insights into MMD progression and revascularisation outcomes and may guide clinical decision-making to improve patient care.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":"371-378"},"PeriodicalIF":2.6,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12230219/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478297","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":"Genetically predicted white matter microstructure mediates the relationship between risk factors and lacunar stroke.","authors":"Jie Zhang, Min Wu, Douglas Neville, Yue Zou, Kaisi Ren, Qing Ye, Shuchang Zhong, Haiying Xiang, Wenshi Wang, Xiangming Ye, Benyan Luo, Li Zhang","doi":"10.1136/svn-2025-004208","DOIUrl":"https://doi.org/10.1136/svn-2025-004208","url":null,"abstract":"<p><strong>Background and purpose: </strong>Lacunar stroke is a complex, multifactorial disease with significant genetic underpinnings. However, the mechanisms through which genetic predispositions and risk factors contribute to its pathogenesis remain poorly understood. We investigated whether genetically predicted white matter (WM) microstructure mediates causal relationships between risk factors and lacunar stroke.</p><p><strong>Methods: </strong>Data from genome-wide association studies were used to perform two-sample Mendelian randomisation (MR) analyses. Genetic variants associated with risk factors (n=34 461-898 130), lacunar stroke (n=232 596) and eight MRI-derived WM microstructural metrics across 48 tracts (n=20 859-20 860) were analysed. Univariable MR assessed causal effects of risk factors on lacunar stroke. Two-step MR analysis evaluated mediation roles of WM microstructure, whereas multivariable MR accounted for confounders.</p><p><strong>Results: </strong>Hypertension was identified as the strongest risk factor for lacunar stroke (OR=1.38; 95% CI: 1.28 to 1.50, p=4.43×10^-15). Only hypertension showed a significant causal association with genetically predicted WM microstructure. Elevated mean diffusivity (MD), isotropic volume fraction (ISOVF) and the tertiary eigenvalue in the anterior limb of the internal capsule (ALIC) were independently linked to increased lacunar stroke risk, beyond the influence of WM hyperintensities, dilated perivascular spaces and brain volume. Mediation analysis suggested that hypertension-induced lacunar stroke was partially mediated through bilateral MD and left ISOVF in the ALIC, with mediation proportions of 23.70%-33.44%.</p><p><strong>Conclusions: </strong>Hypertension may contribute to lacunar stroke pathogenesis in part through WM microstructure alterations, particularly in the ALIC. MD and ISOVF in the ALIC may serve as structural brain reserves and early biomarkers of hypertension-induced pathophysiology associated with lacunar stroke.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144508942","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":"Efficacy and safety of Y-3 intracalvariosseous injection versus intravenous injection in the treatment of acute large hemispheric infarction (SOLUTION-2): rationale and design of a multicentre, prospective, randomised, open-label, blind endpoint (PROBE) trial.","authors":"Nanxing Wang, Meiyang Zhang, Mo Yang, Wenqian Liu, Weiming Liu, Yunwei Ou, Mengyuan Zhou, Xuan Wang, Zhiwei Sun, Yuesong Pan, Yongjun Wang, Yilong Wang","doi":"10.1136/svn-2024-004011","DOIUrl":"https://doi.org/10.1136/svn-2024-004011","url":null,"abstract":"<p><strong>Rationale: </strong>The blood-brain barrier (BBB) largely restricts the efficacy of neuroprotectants, which is an important approach in treating large hemispheric infarction (LHI). In this study, we harnessed intracalvariosseous (ICO) injection to bypass the BBB and facilitate drug delivery.</p><p><strong>Aim: </strong>To compare the efficacy and safety of ICO injection versus intravenous injection in the treatment of acute LHI within 24 hours of disease onset.</p><p><strong>Methods and design: </strong>The efficacy and safety of Y-3 ICO injection versus intravenous injection in the treatment of acute LHI (SOLUTION-2) is a multicentre, prospective, randomised, open-label, blind endpoint trial. 134 patients with acute LHI from more than six centres will be enrolled and randomised in the trial to receive ICO or intravenous injection of Y-3 in a 1:1 ratio.</p><p><strong>Study outcomes: </strong>The primary efficacy outcome is the proportion of patients with a modified Rankin Scale score of 0-3 at 90 days after symptom onset. Primary safety outcomes include infection events related to ICO injection procedures.</p><p><strong>Discussion: </strong>Results from the SOLUTION-2 trial will contribute to the understanding of the efficacy and safety of the Y-3 ICO injection in patients with LHI.</p><p><strong>Trial registry: </strong>The efficacy and safety of Y-3 ICO injection versus intravenous injection in the treatment of acute LHI (SOLUTION-2). URL: https://clinicaltrials.gov/study/NCT06374667?cond=SOLUTION-2&intr=y-3&rank=1.</p><p><strong>Trial registration number: </strong>NCT06374667.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144217310","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":"Associations of accelerated biological ageing with incident dementia, cognitive functions and brain structure: a prospective cohort study based on UK Biobank.","authors":"Xiaowei Zheng, Wenyang Han, Yiqun Li, Minglan Jiang, Xiao Ren, Pinni Yang, Yiming Jia, Lulu Sun, Ruirui Wang, Mengyao Shi, Zhengbao Zhu, Yonghong Zhang","doi":"10.1136/svn-2024-003690","DOIUrl":"https://doi.org/10.1136/svn-2024-003690","url":null,"abstract":"<p><strong>Background: </strong>Several small-sample studies have suggested that biological processes of ageing are implicated with dementia and cognitive function. We aimed to prospectively investigate the associations of biological age with incident dementia, cognitive functions and brain structure based on the UK Biobank.</p><p><strong>Methods: </strong>A total of 287 846 participants without dementia at baseline (followed until November 2022) were analysed. We measured biological age from clinical traits using the Klemera-Doubal method Biological Age (KDM-BA) and PhenoAge algorithms. Cox models were applied to evaluate the risk of dementia. Logistic regression models and linear regression models were used to assess the association between cognitive functions and brain structural measures.</p><p><strong>Results: </strong>During a median follow-up of 13.68 years, 4744 incident all-cause dementia (ACD) events (including 3013 Alzheimer's disease (AD) and 853 vascular dementia (VaD)) were recorded. Participants with older biological age were at increased risk of incident dementia (HR=1.35, 95% CI 1.23 to 1.48 for KDM-BA acceleration, 1.71 (1.52 to 1.91) for PhenoAge acceleration). Those with the highest level of KDM-BA and PhenoAge acceleration had the highest risk of ACD risk, with the corresponding HR of 1.80 (95% CI 1.60 to 2.03) and 1.19 (1.09 to 1.29), respectively. The associations between biological ageing with AD and VaD were also significant. Furthermore, a higher level of biological age was associated with worse performance in multiple cognitive domains and brain structural measures.</p><p><strong>Conclusion: </strong>A higher level of biological age may represent a potential risk factor for incident dementia and is associated with worse performance in multiple cognitive domains and brain structural measures.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144217347","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":"Electroacupuncture reduces neuroinflammation and neuronal pyroptosis via downregulating Neat1 in rats after stroke.","authors":"Wanqing Lin, Zhaolian Cai, Xiaoyong Zhong, Xiaofang You, Renyu Yu, Bin Chen","doi":"10.1136/svn-2024-003964","DOIUrl":"https://doi.org/10.1136/svn-2024-003964","url":null,"abstract":"<p><strong>Background: </strong>We investigated the potential contribution of the lncRNA Neat1 to the therapeutic efficacy of electroacupuncture (EA) after ischaemic stroke.</p><p><strong>Methods: </strong>EA stimulation was used to treat cerebral ischaemia/reperfusion injury (CIRI) in the rat model. Post-therapeutic intervention, infarct volume (IV), brain water content and neurological impairments were assessed. Furthermore, TUNEL and immunofluorescence staining were performed to examine cellular apoptosis, neuronal loss and neuroglial activation. Additionally, Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR), western blotting, ELISA and electron microscopy were employed to assess the NLRC4 inflammasome pathway and neuronal pyroptosis in rats subjected to CIRI.</p><p><strong>Results: </strong>Present findings confirmed that EA successfully downregulated Neat1 and IV in response to CIRI. Moreover, the positive impacts of EA on neurobehavioural recovery, suppression of brain damage and reduction in MAP2 degradation were reversed by Neat1 overexpression. Neat1 overexpression also blocked the reduction in NLRC4 activation, including that of components such as NLRC4, Caspase-1 and gasdermin D, as well as the decrease in cellular apoptosis and neuronal pyroptosis induced by EA. Furthermore, Neat1 overexpression counteracted the suppressive effects of EA on proinflammatory microglial polarisation (Iba1⁺/CD11b⁺) and increased neurogenesis (Nestin⁺/Sox2⁺) in EA-treated rats. Finally, Neat1 overexpression inhibited the ability of EA to lower proinflammatory factors and elevated anti-inflammatory cytokines in the ischaemic striatum.</p><p><strong>Conclusions: </strong>These results highlight a novel anti-inflammatory mechanism of EA that involves the lncRNA Neat1/NLRC4 pathway, which regulates the inhibition of neuronal pyroptosis and neuroinflammation. This mechanism may work as an attainable therapeutic objective for EA-induced neuroprotection against ischaemic stroke.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144175392","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":"Role of histone deacetylases and sirtuins in the ischaemic stroke: a systematic review and meta-analysis of animal studies.","authors":"Ali Majdi, Shahin Yaraghi, Ali Moharrami, Amirreza Ghaffari Tabrizi, Morteza Dojahani, Erfan Alirezapour, Kamyar Mansori, Mehdi Eskandari, Hossein Mostafavi","doi":"10.1136/svn-2025-004159","DOIUrl":"https://doi.org/10.1136/svn-2025-004159","url":null,"abstract":"<p><strong>Background: </strong>Treatment of ischaemic stroke requires exploration of novel neuroprotective strategies owing to the constraints of thrombolytic therapy. Recent research implies that modulation of histone deacetylases (HDAC) or sirtuins (SIRT) could be beneficial in achieving this goal.</p><p><strong>Methods: </strong>This systematic review and meta-analysis evaluates the effectiveness of HDAC/SIRT enzyme modulation in treating acute ischaemic stroke. It includes relevant studies but excludes human and in vitro research and non-primary studies. An electronic search was conducted across databases PubMed, Web of Science and Scopus until 20 March 2025. The methodological quality was assessed using a modified SYRCLE risk of bias tool. Infarct volume and neurological responses were extracted as key outcomes, and a random-effects meta-analysis of infarct volume was conducted for studies directly targeting HDAC/SIRT enzymes.</p><p><strong>Results: </strong>A review of 71 studies involving over 1600 animals focused on ischaemic stroke treatments, predominantly using male rodents in a transient middle cerebral artery occlusion model. Most treatments were administered intraperitoneally, starting from the inception of ischaemia until 5 days afterwards. Non-selective HDAC inhibitors and SIRT1 modulators were targeted most frequently. The meta-analysis on infarct volume with 95% CI showed an overall effect estimate of -1.529 and suggested that non-selective HDAC inhibitors exhibit the most promise in reducing infarct size. Additionally, agonists of SIRT3/7, SIRT6, SIRT1 and HDAC1, along with inhibitors of SIRT5, HDAC6 and HDAC3, may play a significant role in the treatment of ischaemic stroke. Importantly, neuroprotective treatments have been found to be most effective in reducing infarct volume when administered within 24 hours following ischaemia.</p><p><strong>Discussion: </strong>This study highlights the most promising neuroprotective trials for ischaemic stroke by focusing on infarct volume as a key outcome. However, relying exclusively on infarct volume may not fully capture the effectiveness of these treatments.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144017844","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}