Integrated analysis of the proteome and transcriptome in a MCAO mouse model revealed the molecular landscape during stroke progression

Li, Litao; Dong, Lipeng; Xiao, Zhen; He, Weiliang; Zhao, Jingru; Pan, Henan; Bao, Chunde; Cheng, Ju Chien; Wang, Hebo

doi:10.1016/j.jare.2020.01.005

Cited by 33 publications

(31 citation statements)

References 63 publications

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“…In plasma, it is a relatively stable and easily measurable protein and has been proposed as a potential biomarker of inflammatory processes. Calprotectin was previously shown as a useful biomarker of cardiovascular disease risk [ 23 ] and cardiovascular event and recurrence [ 24 ]. A very recent study of 4785 patients with AIS from 2 independent cohorts has reported that high plasma calprotectin concentrations at baseline were independently associated with poor prognosis and death within 3 months after ischemic stroke [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Association of calprotectin with other inflammatory parameters in the prediction of mortality for ischemic stroke

Marta-Enguita

Navarro-Oviedo

Rubio-Baines

et al. 2021

J Neuroinflammation

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Background Inflammatory response plays an important role in many processes related to acute ischemic stroke (AIS). Calprotectin (S100A8/S100A9), released by monocytes and neutrophils, is a key protein in the regulation of inflammation and thrombosis. The purpose of this study is to evaluate the association of circulating calprotectin with other inflammatory biomarkers and AIS prognosis, as well as the calprotectin content in stroke thrombi. Methods Among the 748 patients treated at a comprehensive stroke center between 2015 and 2017, 413 patients with confirmed acute ischemic injury were prospectively evaluated. Patients with systemic inflammation or infection at onset were excluded. Plasma calprotectin was measured by ELISA in blood samples of AIS patients within the first 24 h. Univariate and multivariate logistic regression models were performed to evaluate its association with mortality and functional independence (FI) at 3 months (defined as modified Rankin Scale < 3) and hemorrhagic transformation (HT) after ischemic stroke. Further, S100A9 was localized by immunostaining in stroke thrombi (n = 44). Results Higher calprotectin levels were associated with 3-month mortality, HT, and lower 3-month FI. After adjusting for potential confounders, plasma calprotectin remained associated with 3-month mortality [OR (95% CI) 2.31 (1.13–4.73)]. Patients with calprotectin ≥ 2.26 μg/mL were 4 times more likely to die [OR 4.34 (1.95–9.67)]. Addition of calprotectin to clinical variables led to significant improvement in the discrimination capacity of the model [0.91 (0.87–0.95) vs 0.89 (0.85–0.93); p < 0.05]. A multimarker approach demonstrated that patients with increased calprotectin, CRP, and NLR had the poorest outcome with a mortality rate of 42.3% during follow-up. S100A9 protein, as part of the heterodimer calprotectin, was present in all thrombi retrieved from AIS patients. Mean S100A9 content was 3.5% and tended to be higher in patients who died (p = 0.09). Moreover, it positively correlated with platelets (Pearson r 0.46, p < 0.002), leukocytes (0.45, p < 0.01), and neutrophil elastase (0.70, p < 0.001) thrombus content. Conclusions Plasma calprotectin is an independent predictor of 3-month mortality and provides complementary prognostic information to identify patients with poor outcome after AIS. The presence of S100A9 in stroke thrombi suggests a possible inflammatory mechanism in clot formation, and further studies are needed to determine its influence in resistance to reperfusion.

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Section: Discussionmentioning

confidence: 99%

Association of calprotectin with other inflammatory parameters in the prediction of mortality for ischemic stroke

Marta-Enguita

Navarro-Oviedo

Rubio-Baines

et al. 2021

J Neuroinflammation

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“…Recently, in an experimental model of transient focal ischemia, inhibition of S100A9 reduced infarct volume and brain swelling [20] and a therapeutic vaccine against MRP14 (S100A9) resulted in thrombosis inhibition in a murine model of ischemic stroke [12]. In addition, calprotectin overexpression has been localized in ischemic hemisphere CD11b-positive cells [20] and brain proteomic analysis has shown that calprotectin was up-regulated in experimental models of brain ischemia [21]. Upon cell activation, calprotectin is released and can be detected in serum or body uids as a clinical in ammatory marker.…”

Section: Discussionmentioning

confidence: 99%

Calprotectin predicts mortality after ischemic stroke and is present in the thrombus

Marta-Enguita¹,

Navarro-Oviedo²,

Rubio-Baines³

et al. 2020

Preprint

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Background- Inflammatory response plays an important role in many processes related to acute ischemic stroke (AIS). Calprotectin (S100A8/S100A9), released by monocytes and neutrophils, is a key protein in the regulation of inflammation and thrombosis. The purpose of this study is to evaluate the association of circulating calprotectin with other inflammatory biomarkers and AIS prognosis, as well as the calprotectin content in stroke thrombi.Methods- Among the 748 patients treated at a comprehensive stroke centre between 2015-2017, 413 patients with confirmed acute ischemic injury were evaluated. Patients with systemic inflammation or infection at onset were excluded. Plasma calprotectin was measured by ELISA in blood samples of AIS patients within the first 24h. Univariate and multivariate logistic regression models were performed to evaluate its association with mortality and functional independence (FI) at 3-months (defined as modified Rankin Scale<2), and intracranial haemorrhage (ICH) after stroke. Further, S100A9 was localized by immunostaining in stroke thrombi (n=44). Results- Higher calprotectin levels were associated with 3-month mortality and ICH, while lower calprotectin levels were documented in patients with 3-month FI. After adjusting for potential confounders, plasma calprotectin levels remained associated with 3-month mortality [OR (95%CI); 3.06, (1.67-5.61)]. Patients with calprotectin≥2.26 µg/mL were 4-times more likely to die [OR 3.98, (1.88-8.41)]. Likewise, Neutrophil-Lymphocyte Ratio (NLR) and C-Reactive Protein (CRP) were also associated with 3-month mortality [OR 1.98, (1.17-3.35); and 1.39, (1.02-1.89) respectively]. A multimarker approach demonstrated that patients with increased calprotectin, CRP and NLR had the poorest outcome with a mortality rate of 42.3% during follow-up. S100A9 protein, as part of the heterodimer calprotectin, was present in all thrombi retrieved from AIS patients. Mean S100A9 content was 3.5% and tended to be higher in patients who died (p=0.09). Moreover, it positively correlated with platelets (Pearson r 0.46, p<0.002); leukocytes (0.45, p<0.01) and neutrophil elastase (0.70, p<0.001) thrombi content. Conclusions- Plasma calprotectin is an independent predictor of 3-month mortality and provides complementary prognostic information to identify patients with poor outcome after AIS. Presence of S100A9 in stroke thrombi suggests a possible inflammatory mechanism in clot formation and further studies are needed to determine its influence in resistance to reperfusion.

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“…The C18 ZipTip was used to desalt the digested peptides. Then, the Pierce TM Quantitative Colorimetric Peptide Assay (23275) and the SpeedVac were used in quantification and lyophilization, respectively (22).…”

Section: Sample Pretreatment For Mass Spectrometric Analysismentioning

confidence: 99%

Brain Proteomic Profiling in Intractable Epilepsy Caused by TSC1 Truncating Mutations: A Small Sample Study

Liu

et al. 2020

Front. Neurol.

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Tuberous sclerosis complex (TSC) is a genetic disease characterized by seizures, mental deficiency, and abnormalities of the skin, brain, kidney, heart, and lungs. TSC is inherited in an autosomal dominant manner and is caused by variations in either the TSC1 or TSC2 gene. TSC-related epilepsy (TRE) is the most prevalent and challenging clinical feature of TSC, and more than half of the patients have refractory epilepsy. In clinical practice, we found several patients of intractable epilepsy caused by TSC1 truncating mutations. To study the changes of protein expression in the brain, three cases of diseased brain tissue with TSC1 truncating mutation resected in intractable epilepsy operations and three cases of control brain tissue resected in craniocerebral trauma operations were collected to perform protein spectrum detection, and then the data-independent acquisition (DIA) workflow was used to analyze differentially expressed proteins. As a result, there were 55 up-and 55 down-regulated proteins found in the damaged brain tissue with TSC1 mutation compared to the control. Further bioinformatics analysis revealed that the differentially expressed proteins were mainly concentrated in the synaptic membrane between the patients with TSC and the control. Additionally, TSC1 truncating mutations may affect the pathway of amino acid metabolism. Our study provides a new idea to explore the brain damage mechanism caused by TSC1 mutations.

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Integrated analysis of the proteome and transcriptome in a MCAO mouse model revealed the molecular landscape during stroke progression

Cited by 33 publications

References 63 publications

Association of calprotectin with other inflammatory parameters in the prediction of mortality for ischemic stroke

Association of calprotectin with other inflammatory parameters in the prediction of mortality for ischemic stroke

Calprotectin predicts mortality after ischemic stroke and is present in the thrombus

Brain Proteomic Profiling in Intractable Epilepsy Caused by TSC1 Truncating Mutations: A Small Sample Study

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