Home Life Sciences Plasma levels of CD36 and glutathione as biomarkers for ruptured intracranial aneurysm
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Plasma levels of CD36 and glutathione as biomarkers for ruptured intracranial aneurysm

  • Hanbin Wang , Luxuan Wang , Yunmei Liu , Weidong Men , Wanjiao Hao , Chuan Fang EMAIL logo , Chunhui Li EMAIL logo and Lijian Zhang EMAIL logo
Published/Copyright: December 31, 2023

Abstract

Evidence has proved that intracranial aneurysm (IA) formation and rupture might be closely related to inflammatory response and oxidative stress. Our objective was to evaluate the potential of CD36 and glutathione (GSH) as biomarkers for IA. In this study, the enzyme-linked immunosorbent assay was used to measure the plasma levels of CD36 and GSH in 30 IA patients and 30 healthy controls. Then, correlation analysis, receiver operating characteristic (ROC) curve, and logistic regression analysis were performed. The results showed that the plasma level of CD36 in IA patients was significantly higher than that in the control group (P < 0.0001), and plasma GSH was significantly lower compared with that in the control group (P < 0.0001). ROC analysis showed that CD36 and GSH had high sensitivity (90.0 and 96.6%) and specificity (96.6 and 86.6%) for IA diagnosis. The combined sensitivity and specificity achieved were 100 and 100%, respectively. The plasma levels of CD36 and GSH did not show a significant correlation with age, the Glasgow Coma Scale, Hunter–Hess score, aneurysm size, aneurysm height, aneurysm neck, and aspect ratio. The AUC of the logistic regression model based on CD36 and GSH was 0.505. Our results suggested that the combination of plasma CD36 and GSH could serve as potential biomarkers for IA rupture.

1 Introduction

An intracranial aneurysm (IA) is an abnormal bulge of blood vessels caused by damage to the intracranial artery wall [1]. IA has an incidence of 3% in the general population. With the advances in medical imaging, an increasing number of patients are diagnosed with IA [2]. Patients with IA are usually accompanied by neurological dysfunction, and the mortality rate resulting from ruptured IA is as high as 50% [3,4]. Until now, the pathological mechanisms of IA formation and rupture remain unclear, which deserves deeper exploration for biomarker identification and therapeutic target discovery [5].

Previous studies have demonstrated that the formation and rupture of IA were closely related to several factors, including hemodynamics, inflammation, oxidative stress, endothelial dysfunction, and vascular remodeling [6,7]. Among them, inflammatory response and oxidative stress might be crucial pathophysiological processes for its occurrence, development, and rupture [8]. In order to identify new therapeutic targets and determine their prognostic roles to assist IA management, we selected a panel of inflammatory and oxidative stress-related markers, involved in vascular dysfunction. In this study, we focused on CD36 and glutathione (GSH), which are reported to participate in vascular remodeling under different pathological conditions of cardiovascular disease [9,10]. As a membrane glycoprotein, CD36 has been evidenced to play an essential role in physiological processes and cellular events such as inflammation, lipid metabolism, endothelial dysfunction, smooth muscle cell dysfunction, and foam cell formation [11]. GSH, a non-protein thiol, is involved in various redox reactions in the body and plays a vital role in protecting cells from oxidative damage and maintaining redox homeostasis [12,13].

Previous studies have documented that CD36 and GSH play crucial roles in processes such as inflammation and oxidative stress responses of arterial walls in cardiovascular diseases such as atherosclerosis [14,15]. CD36 expressed by macrophages promotes the inflammatory response and the formation of foam cells leading to the development of atherosclerosis [16]. The activation of inflammatory response and the upregulated expression of CD36 could also increase the production of reactive oxygen species (ROS), which would deplete GSH and trigger oxidative stress. Decreased GSH levels could further increase CD36 expression [17]. Recent studies have shown that IA is also a macrophage-mediated chronic inflammatory disease and that it may have atherosclerotic wall properties [18,19]. Here, we proposed that CD36 and GSH might play significant roles in IA rupture. To the best of our knowledge, however, there are no studies that have evaluated their expression profile in IA.

In this study, we measured the expression levels of plasma CD36 and GSH in IA patients and healthy controls (HCs) by using enzyme-linked immunosorbent assay (ELISA). We further investigated the correlation between clinical parameters of IA patients as well as CD36 and GSH expression levels. Further, we evaluated their potential utility as biomarkers for IA rupture.

2 Materials and methods

2.1 Study population

In this study, we recruited 30 IA patients from the Department of Neurosurgery, Affiliated Hospital of Hebei University. Inclusion criteria for the IA group were as follows: at least one ruptured IA found by digital subtraction angiography (DSA) or cerebral CT angiography (CTA) in patients with subarachnoid hemorrhage, no relevant symptoms, received non-operative and conservative observation treatment, and signing the informed consent. The exclusion criteria were as follows: the presence of intracranial tumors in patients with other cerebrovascular diseases (such as intracranial arteriovenous malformations, arteriovenous fistula, and Moyamoya syndrome/disease)and patients with myocardial infarction, pulmonary infarction, diabetes, metabolic syndrome, hepatitis, kidney diseases or progressive muscular atrophy, malignant tumor, leukemia, hemolytic anemia, etc. In parallel, another 30 age- and gender-matched healthy volunteers with no history of IA were included. Healthy volunteers underwent CTA before joining the control group, which recruited healthy volunteers with negative examination results. All protocols in this study were approved by the Institutional Review Board for human studies at the Affiliated Hospital of Hebei University, Hebei, China (HDFYLL-KY-2022-014). All participants signed informed consent of this study.

  1. Informed consent: Informed consent has been obtained from all individuals included in this study.

  2. Ethical approval: The research related to human use has complied with all the relevant national regulations, and institutional policies and in accordance with the tenets of the Helsinki Declaration, and has been approved by the Affiliated Hospital of Hebei University, Hebei, China (HDFYLL-KY-2022-014).

2.2 Standardized clinical assessment

Standard clinical scores were employed in this study: neurological status was assessed using the Glasgow Coma Scale (GCS) and the Hunt–Hess scale. The lower the GCS score and the higher the Hunt–Hess scale grading, the worse the patient’s state of consciousness. Meanwhile, the demographics of all participants were collected. Aneurysm parameters include aneurysm location, aneurysm size, aneurysm height, aneurysm width, and aspect ratio (aneurysm height/aneurysm width) [20]. Aneurysm parameters were determined by analyzing the original and three-dimensional reconstruction images of the imaging examinations of CTA or DSA (Figure 1). The aneurysm height was measured as the maximum perpendicular distance between the dome and the neck plane [21]. The aneurysm width was measured as the maximal horizontal length of the aneurysm [22]. The aneurysm parameters were collected by two experienced neurosurgeons. All differences were resolved by consensus.

Figure 1 
                  Definition of aneurysm parameters with representative image of DSA.
Figure 1

Definition of aneurysm parameters with representative image of DSA.

2.3 Blood sample collection

Blood samples were collected from patients within 12 h of admission. About 10 mL of venous blood from patients and healthy volunteers were collected, placed in EDTA tubes, stored at 4℃, and processed within 4 h. The venous blood was put into a centrifuge and centrifuged at 1,600g for 10 min at 4℃. The plasma obtained after centrifugation of the venous blood was then stored in a −80℃ freezer until further analysis [23].

2.4 Measurement of CD36 and GSH

The GSH and CD36 expression levels in the plasma of IA and HC were measured using ELISA as described previously [24,25]. We measured the concentration of sCD36 in plasma using ELISA kits (Nordic BioSite, Täby, Sweden). In the measurement of CD36, a pool of EDTA plasma was aliquoted, analyzed at seven different dilutions, and used as a standard concentration curve. Two dilutions of another EDTA pool served as internal controls, each of which was reproduced four times on each ELISA plate. According to the manufacturer’s instructions for the ELISA kit (A006-2-1, Nanjing Jian Cheng Bioengineering Institute, Nanjing, China), GSH levels were measured. Standards and samples were added to the wells precoated with GSH antigen. After incubation, the biotin-labeled anti-GSH antibody was added. The colorimetric reaction was initiated by the addition of yellow para-nitrophenylphosphatase (pNPP; Sigma) to each well, and absorbance values at 405 and 603 nm were measured on an ELISA microplate reader (Bio-Tek, Winooski, VT, USA).

2.5 Construction of the logistic regression model

Logistic regression is a classifier that uses a set of weighted measurements to predict the class (e.g., healthy, diseased) to which a sample belongs based on the probability. Moreover, the logistic regression is used to fit models for the probability of disease, given the marker values [26]. To investigate the reliability of GSH and CD36 as biomarkers for IA, the logistic regression models were constructed by using the glm function in R language. Logistic analysis can be used to predict the probability of an event. A model for predicting the occurrence of IA was established by logistic analysis combining clinical characteristics, aneurysm parameters, CD36, and GSH. In this logistic regression model, the expression values of GSH and CD36 were considered as predictive variables, and the clinical characteristics and aneurysm parameters, were considered as a binary responsive variable. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the performance of the model.

2.6 Statistical analysis

All data were statistically analyzed and graphically displayed using GraphPad Prism 7.0 (GraphPad Software Inc., San Diego, CA, USA) and SPSS v.21.0 statistical packages (IBM, Armonk, NY, USA). The normal distribution of all data in this study was evaluated using the Shapiro–Wilk method (Table S1). Independent sample t-tests and Chi-square tests were used to compare the difference between baselines and stimuli tests. The values of CD36 and GSH expression levels did not conform to the normal distribution. Thus, the Mann–Whitney U test was used to analyze the difference in the CD36 and GSH expression between IA and control groups. Spearman correlation was applied to evaluate the relationship between the concentrations of GSH and CD36 expression, clinical data, and aneurysm parameters. The area under the ROC curve was employed to evaluate the potential diagnostic capability. The investigator who performed the statistical analysis was blind to the experimental groups. We repeated the analysis of the sample data. All values are expressed as mean ± SD. A P-value <0.05 was considered statistically significant.

3 Results

3.1 Demographic characteristics of the participants

There were 22 females and 8 males enrolled in the IA group, and the mean age of the IA patients was 56.2 ± 10.1 years (range 36–75). There were 20 females and 10 males in the HC group, and the mean age of the HC volunteers was 52.7 ± 11.6 years (range: 32–72). There was no age- and gender-related difference in the CD36 and GSH expression. The clinical data and aneurysm parameters of IA patients are presented in Table 1.

Table 1

Clinical data and aneurysm parameters of the study population

HCs (n = 30) IA patients (n = 30)
Gender (female/male) 20/10 22/8
Age, years 52.7 ± 11.6 56.2 ± 10.1
Smoking 7 6
Alcohol 8 6
Hypertension 15 19
GCS
Mild (13–15 points) 22
Moderate (9–12 points) 8
Severe (3–8 points) 0
HuntHess grade
4
23
Ⅲ–Ⅴ 3
Size of the aneurysm
<5 mm 15
5–10 mm 12
>10 mm 3
Location of the aneurysm
Middle cerebral artery 10
Internal carotid artery 10
Anterior cerebral artery 2
Posterior cerebral artery 1
Anterior communicating artery 5
Posterior communicating artery 1
Basilar artery 1
Height of the aneurysm (mm) 5.1 ± 2.5 (range, 1.9–12.4)
Aneurysm neck (mm) 3.1 ± 1.5 (range, 1.2–7.3)

Bold value represents there was no difference in smoking between the healthy and IA groups (P = 0.754); alcohol between the healthy and IA groups (P = 0.542); hypertension between the healthy and IA groups (P = 0.297).

3.2 Plasma concentrations of CD36 and GSH

ELISA analysis was used to measure the CD36 and GSH expression levels in plasma. CD36 and GSH were detected in the plasma of both IA and control groups. The expression level of plasma CD36 in the IA group was significantly higher than that in the HC group, and the difference reached statistical significance (P < 0.0001) (Figure 2a). The expression level of plasma GSH in the IA group was significantly lower than that in the HC group (P < 0.0001) (Figure 2b). Moreover, no significant difference was reached among patients with different IA locations (Figure S1).

Figure 2 
                  The expression levels of CD36 and GSH in the plasma of IA patients and HCs. (a) Expression levels of CD36 in the plasma of IA patients and HCs. (b) Expression levels of GSH in the plasma of IA patients and HCs. Data are presented as mean ± SD. ****P < 0.0001, n = 30 per group.
Figure 2

The expression levels of CD36 and GSH in the plasma of IA patients and HCs. (a) Expression levels of CD36 in the plasma of IA patients and HCs. (b) Expression levels of GSH in the plasma of IA patients and HCs. Data are presented as mean ± SD. ****P < 0.0001, n = 30 per group.

3.3 Correlation and ROC curve analysis

To evaluate the relationship between CD36, GSH, and clinical parameters of IA patients, we analyzed the correlation among the expression levels of CD36, GSH, IA clinical data, and aneurysm parameters. Our results showed no significant correlation between the CD36 expression level and clinical data such as the patient’s age (P = 0.420, r = −0.153), GCS (P = 0.130, r = −0.164), and Hunt–Hess (P = 0.086, r = 0.319) (Figure 3). Also, there was no significant correlation between the CD36 expression level and aneurysm parameters such as the aneurysm size (P = 0.928, r = −0.017), aneurysm height (P = 0.971, r = −0.007), aneurysm width (P = 0.675, r = 0.080), and aspect ratio (P = 0.814, r = 0.045) (Figure 4). For GSH, there were no significant correlations between the patient’s age (P = 0.532, r = 0.119), GCS (P = 0.173, r = −0.255), Hunt–Hess (P = 0.598, r = −0.100), aneurysm size (P = 0.500, r = 0.128), aneurysm height (P = 0.817, r = −0.044), aneurysm width (P = 0.773, r = 0.055), and aspect ratio (P = 0.110, r = −0.298) (Figures 3 and 4). Moreover, there is also no significant correlation between aneurysm characteristics, GCS score, and H&H score (Figure S2). The correlation analysis also showed that the expression of GSH significantly correlated with the height of the aneurysm in the middle cerebral artery IA patients (P = 0.0415, r = 0.6266). Also, the expression of CD36 significantly correlated with the height of the aneurysm in the internal carotid artery IA patients (P = 0.0490, r = −0.6485) (Figure S3). We further analyzed the sensitivity and specificity of CD36 and GSH for IA prediction using ROC curves. The optimal cutoff point was determined by the ROC curve based on the Youden index. The CD36’s Youden index was 0.867, and the GSH’s Youden index was 0.834. The sensitivity and specificity of CD36 were 90.0 and 96.6%, respectively, and that of GSH was 96.6 and 86.6%, respectively. Moreover, the sensitivity and specificity of CD36 combined with GSH achieved were 100 and 100% (Figure 5).

Figure 3 
                  Correlation analysis between the clinical data (patient’s age, GCS, and Hunt–Hess) of IA patients and the expression levels of GSH and CD36.
Figure 3

Correlation analysis between the clinical data (patient’s age, GCS, and Hunt–Hess) of IA patients and the expression levels of GSH and CD36.

Figure 4 
                  Correlation analysis between the aneurysm parameters (aneurysm size, aneurysm height, aneurysm width, and aspect ratio) of IA patients and the expression levels of GSH and CD36.
Figure 4

Correlation analysis between the aneurysm parameters (aneurysm size, aneurysm height, aneurysm width, and aspect ratio) of IA patients and the expression levels of GSH and CD36.

Figure 5 
                  ROC analysis of expression levels of CD36 and GSH in the plasma.
Figure 5

ROC analysis of expression levels of CD36 and GSH in the plasma.

3.4 Evaluation of the logistic regression model

The expressions of GSH and CD36 were used as predictive variables. The logistic regression model showed a normal distribution (Figure 6) (Table 2), and the GSH and CD36 values had a good linear relationship with the response variables (clinical data and aneurysm parameters). There are no extreme points that significantly affect the accuracy of the model. The AUC of the logistic model was 0.505, suggesting that the logistic regression model based on GSH and CD36 could reliably distinguish the patients with IA and HCs, and GSH and CD36 could be used as potential biomarkers for the diagnosis of patients with IA (Figure 7).

Figure 6 
                  Construction of the logistic regression model. The black dotted line represents the COOK distance, and the points with COOK distance >0.5 were considered as influential points, which would affect the reliability of the model. There were no influential points in the model.
Figure 6

Construction of the logistic regression model. The black dotted line represents the COOK distance, and the points with COOK distance >0.5 were considered as influential points, which would affect the reliability of the model. There were no influential points in the model.

Table 2

Coefficients (standard error) and P-values for the multivariate logistic regression

Estimate Std. error P value
Intercept −4.846 8.307 0.56
CD36 5.284 2.128 0.013
GSH −3.074 1.332 0.021
Figure 7 
                  The ROC analysis and cross-validation plot with logistic LASSO regression. For the logistic LASSO regression, self-reported IA was included as the dependent variable, Y, and coded as 0 for no IA and 1 for the presence of IA.
Figure 7

The ROC analysis and cross-validation plot with logistic LASSO regression. For the logistic LASSO regression, self-reported IA was included as the dependent variable, Y, and coded as 0 for no IA and 1 for the presence of IA.

4 Discussion

Although the underlying pathophysiological mechanisms of IA formation and rupture remain unclear, previous studies suggested that vascular endothelial cell inflammation is one of the initiating factors for IA [27]. Oxidative stress, as a significant component in the pathophysiological mechanism of inflammation, also plays a role in the progress of IA formation and rupture [28]. Previous studies have documented that CD36 and GSH were involved in various pathological conditions related to inflammation and oxidative stress [29]. Whether CD36 and GSH could serve as potential biomarkers for IA rupture needs further investigation.

In this study, we aimed to compare the expression levels of plasma CD36 and GSH between patients with ruptured IA and HCs. Further, we evaluated their potential roles as biomarkers for IA rupture. The results showed that plasma CD36 expression was increased in IA patients, while plasma GSH was significantly decreased compared with HCs, confirming our conjecture. The evidence indicated that the pro-inflammatory signaling in vascular endothelial cells could be initially activated by high wall shear stress of blood flow, resulting in abundant macrophages infiltrating the vascular endothelium [30]. Subsequently, macrophages release various cytokines, which further recruit other inflammatory cells, such as neutrophils, T cells, and mast cells [31,27]. CD36 is a scavenger receptor expressed in monocytes, endothelial cells, and platelets, which plays significant roles in mediating lipid uptake, immune recognition, inflammation, molecular adhesion, and apoptosis [32]. CD36 mediates the production of ROS and promotes the occurrence of inflammatory responses by activating the NLRP3 inflammasome [33]. By contrast, CD36 could also upregulate the expression and phosphorylation of focal adhesion kinase, thereby promoting the expression of matrix metalloproteinases (MMPs) [34]. MMPs are proteases most closely related to the formation and rupture of IA. It was reported that MMPs could degrade elastin on the arterial wall, resulting in the loss of the inner elastic layer and weakening of the vessel wall, eventually leading to the rupture of IA [35,36]. Studies have showed that despite the normal lipid levels in IA patients, lipid accumulation, foam cells, and oxidized lipids could be found in both unruptured and ruptured IA walls [37]. Moreover, macrophages infiltrating the vascular endothelium could internalize oxidized low-density lipoprotein (ox-LDL) via CD36 and confine it to the vascular intima, which ultimately leads to the accumulation of vascular wall lipids and the conversion of macrophages to foam cells [38]. The reduction of smooth muscle cells is characteristic of arterial remodeling, which is one of the primary causes of IA formation and rupture [39]. It was also demonstrated that the binding of CD36 on macrophages to ox-LDL could activate the nuclear factor-κB (NF-κB) signaling pathway to trigger an inflammatory response [40]. The NF-κB pathway is a pivotal link in the inflammatory response, and NF-κB-mediated inflammation has been demonstrated to be involved in the pathogenesis of IA [41,42]. Studies have found that the inhibition of NF-κB activity can inhibit the formation and expansion of IA [43]. The above findings indicated that therapeutic targeting CD36-mediated inflammatory responses could be potential candidates for the treatment of IAs.

In addition, inflammation could increase the production of ROS and lead to oxidative stress. ROS could directly increase the expression of inflammatory and adhesion factors, aggravate the inflammatory response, and promote ox-LDL formation [44,45]. Large amounts of ROS deplete antioxidant compounds (GSH, polyphenols, and vitamins) and enzymes in the body, further unbalancing oxidative and antioxidant effects in the body toward oxidation [46]. Among them, GSH is a significant antioxidant that plays a crucial role in maintaining redox homeostasis. GSH-related metabolism is the principal mechanism by which cells protect themselves against oxidative stress [47]. Decreased GSH makes cells more susceptible to oxidative stress, thereby accelerating apoptosis [48]. Studies have shown that oxidative stress can stimulate cells to initiate programmed cell death through an endogenous pathway, resulting in a reduction in the number of cells on the IA wall and a weakening of the vessel wall, which accelerates aneurysm development and rupture [49]. Moreover, oxidative stress can increase CD36 expression, which may be closely related to GSH levels [50]. Studies have found that decreased GSH levels also induced CD36 expression in macrophages and enhanced ox-LDL uptake, thereby promoting lipid accumulation in the vascular wall and foam cell formation [51,52]. Studies have shown that lipid accumulation and foam cell formation are important factors promoting aneurysm wall degeneration, and lipid accumulation in aneurysm walls has been confirmed to be related to aneurysm rupture [53]. The principal sources of macrophages in the walls of IA are monocyte-differentiated macrophages and reduced GSH levels induce monocyte differentiation into macrophages and promote inflammation response [54]. Some studies have found that certain antioxidants restore intracellular GSH levels, which could prevent the transformation of monocytes to macrophages and reduce the expression of CD36, thus playing a protective role [51,54,55]. These findings may provide new therapeutic ideas for antioxidant therapy to inhibit the formation and rupture of IA. Based on our observation, we suggest that CD36 and GSH are involved in the pathological process of inflammation and oxidative stress, which may predispose to rupture and formation of IA. Based on our observation and previous studies, we suggested that the upregulated CD34 and decreased GSH result in an inflammatory and oxidative microenvironment in the blood vessels, and eventually lead to endothelial dysfunction. The altered structure of the vessel wall finally promotes the formation and rupture of IA. This hypothesis needs to be validated by in vitro experiments such as using vascular smooth muscle cells.

In order to evaluate the diagnostic values of plasma CD36 and GSH for IA, the ROC curve analysis was performed. The results showed their excellent predictive performance. Previous studies have shown that combining multiple biomarkers could improve diagnostic accuracy than using a single marker [56]. The combination of biomarkers has great potential in identifying diseases, and the improved diagnostic accuracy could even achieve 100% sensitivity and 100% specificity [57]. In this study, the ROC analysis of the combination of two biomarkers showed excellent sensitivity and specificity (each 100.0%), which suggested their potential for serving as biomarkers for IA diagnosis. Furthermore, correlation analysis between the levels of CD36, GSH, and the clinical parameters was conducted to determine their roles in the diagnosis of IA. To our surprise, the results showed that CD36 and GSH had no significant correlation with the GCS score, Hunt–Hess score, age, aneurysm width, aneurysm height, aneurysm neck, and aspect ratio in IA patients. Moreover, logistic regression was used to examine their performance of IA prediction. Our results showed that GSH and CD36 have poor discrimination between IA patients and HCs when clinical characteristics were combined with aneurysm parameters. We speculated that there might be several explanations for these results. First, the study population is too small to represent the predictive values with the logistic regression model [58]. Second, it might be caused by the disease spectrum bias. Clinical studies with a population that lacks diagnostic uncertainty may produce a biased estimate of a test’s performance [59]. Third, our correlation analysis indicated that the expression levels of CD36 and GSH did not correlate with the aneurysm parameters, which implies that they might not participate in the changes in the aneurysm morphology. Evidence also demonstrated a pathogenetic link between hemodynamics and inflammatory response in the development and rupture of IA [60]. As suggested by a previous study, the hemodynamics factor might play a crucial role in the morphologic changes of IA [61]. Here, we suspected that CD36 and GSH might participate in the process of IA formation and rupture but do not affect its morphology. Further, the logistic regression model was established by combining clinical characteristics and aneurysm parameters. Although we evaluated the utility of plasma CD36 and GSH as biomarkers for IA, their diagnostic power deserves further validation in a larger cohort. In addition, IA is a complex disease with both ruptured and unruptured forms. In the future, exploring the expression levels of CD36 and GSH in different subtypes of IA could unravel how these biomarkers change over the course of disease development, providing more valuable insights into their diagnostic and prognostic implications. Investigating the potential roles of CD36 and GSH in IA could offer valuable insights for the development of novel therapeutic strategies and drug targets, providing a stronger foundation for personalized therapy. In conclusion, further study of the role of CD36 and GSH in IA is crucial for the occurrence, development, and treatment of IA, which will provide new insights and directions for the diagnosis, prognosis, and treatment of IA.

This study has some limitations. First, the sample size of this study is small, which may cause biased results to a certain extent. Due to the limited sample size, the enormous difference in the proportion of male and female subjects is also a significant limitation of this study. Evidence has shown that the aneurysm characteristics have a huge difference compared with male and female subjects. In previous studies, women had a higher risk of rupture of IAs than men [62]. Moreover, one previous study has demonstrated that female patients have a greater risk of multiple aneurysms and left internal carotid artery aneurysms, but a lower risk of anterior communicating artery aneurysms [63]. In this study, our results showed no age- and gender-related differences in CD36 and GSH expression. The small sample sizes used in the present study may not provide adequate precision. Moreover, the absence of an unruptured IA group may be another limitation of this study. Previous studies have also demonstrated that aneurysmal subarachnoid hemorrhage might alter the metabolic conditions compared with unruptured IA [64,65]. The unruptured IA group was not included in this study, which may affect the assessment of their diagnostic values as biomarkers. Further sub-group studies (unruptured aneurysm and ruptured aneurysm) with large cohorts are needed in our future work. Second, further investigation of the potential variations within subtypes of IA could provide valuable insights into the heterogeneity of the disease and guide personalized treatment approaches. A previous study reported that cerebral aneurysmal formation depends on their location [66]. In our future work, we hope to carry out another study focusing on the location-dependent difference with a larger sample size. Third, this is an observational study without further animal or in vitro cell experiments to understand their underlying mechanisms in the IA pathology process. Furthermore, CD36 knock out (KO) or the GSH metabolism-related gene KO IA mice model could also help in evaluating the role of CD36 and GSH in IA formation. Moreover, we did not measure the expression levels of CD36 and GSH in the aneurysm wall. These limitations are subjects of future work.

In summary, this study revealed a significant increase of plasma CD36 and a decrease of plasma GSH in the patients with ruptured IA compared with HCs. We proposed that CD36 and GSH might be involved in the progress of IA rupture but did not affect the aneurysm morphology. Here, we emphasize the potential of plasma CD36 and GSH as therapeutic targets for the treatment of IA. Subsequent in vivo study using a rat model of IA should be carried out to confirm our hypothesis in future work. Moreover, plasma CD36 and GSH could serve as potential biomarkers for IA rupture. Our findings suggest a future role for plasma CD36 and GSH assays in attempting to identify cerebral aneurysms before rupture.


# These authors contributed equally to this work.

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  1. Funding information: This work was supported by China Postdoctoral Science Foundation (No. 2022M710997), Provincial Medical Talents Project funded by Hebei Province (No. 361007), the Hebei Natural Science Foundation Precision Medicine Joint Project (grant number H2020201206), and The Central Government Guided Local Science and Technology Development Fund Project of Hebei Province (grant number 216Z7711G).

  2. Author contributions: L.Z. designed the study. L.W., Y.L., W.M., and W.H. were involved in the acquisition and processing of samples. H.W. and L.W. performed the statistical analyses for all of the studies. H.W. and L.Z. wrote the first draft of the manuscript. H.W., L.W., C.F., C.L., and L.Z. participated in the evaluation of the data and editing of the manuscript.

  3. Conflict of interest: Authors state no conflict of interest.

  4. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2023-06-16
Revised: 2023-08-18
Accepted: 2023-09-24
Published Online: 2023-12-31

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  163. Favorable response to surufatinib in a patient with necrolytic migratory erythema: A case report
  164. Case report of atypical undernutrition of hypoproteinemia type
  165. Down-regulation of COL1A1 inhibits tumor-associated fibroblast activation and mediates matrix remodeling in the tumor microenvironment of breast cancer
  166. Sarcoma protein kinase inhibition alleviates liver fibrosis by promoting hepatic stellate cells ferroptosis
  167. Research progress of serum eosinophil in chronic obstructive pulmonary disease and asthma
  168. Clinicopathological characteristics of co-existing or mixed colorectal cancer and neuroendocrine tumor: Report of five cases
  169. Role of menopausal hormone therapy in the prevention of postmenopausal osteoporosis
  170. Precisional detection of lymph node metastasis using tFCM in colorectal cancer
  171. Advances in diagnosis and treatment of perimenopausal syndrome
  172. A study of forensic genetics: ITO index distribution and kinship judgment between two individuals
  173. Acute lupus pneumonitis resembling miliary tuberculosis: A case-based review
  174. Plasma levels of CD36 and glutathione as biomarkers for ruptured intracranial aneurysm
  175. Fractalkine modulates pulmonary angiogenesis and tube formation by modulating CX3CR1 and growth factors in PVECs
  176. Novel risk prediction models for deep vein thrombosis after thoracotomy and thoracoscopic lung cancer resections, involving coagulation and immune function
  177. Exploring the diagnostic markers of essential tremor: A study based on machine learning algorithms
  178. Evaluation of effects of small-incision approach treatment on proximal tibia fracture by deep learning algorithm-based magnetic resonance imaging
  179. An online diagnosis method for cancer lesions based on intelligent imaging analysis
  180. Medical imaging in rheumatoid arthritis: A review on deep learning approach
  181. Predictive analytics in smart healthcare for child mortality prediction using a machine learning approach
  182. Utility of neutrophil–lymphocyte ratio and platelet–lymphocyte ratio in predicting acute-on-chronic liver failure survival
  183. A biomedical decision support system for meta-analysis of bilateral upper-limb training in stroke patients with hemiplegia
  184. TNF-α and IL-8 levels are positively correlated with hypobaric hypoxic pulmonary hypertension and pulmonary vascular remodeling in rats
  185. Stochastic gradient descent optimisation for convolutional neural network for medical image segmentation
  186. Comparison of the prognostic value of four different critical illness scores in patients with sepsis-induced coagulopathy
  187. Application and teaching of computer molecular simulation embedded technology and artificial intelligence in drug research and development
  188. Hepatobiliary surgery based on intelligent image segmentation technology
  189. Value of brain injury-related indicators based on neural network in the diagnosis of neonatal hypoxic-ischemic encephalopathy
  190. Analysis of early diagnosis methods for asymmetric dementia in brain MR images based on genetic medical technology
  191. Early diagnosis for the onset of peri-implantitis based on artificial neural network
  192. Clinical significance of the detection of serum IgG4 and IgG4/IgG ratio in patients with thyroid-associated ophthalmopathy
  193. Forecast of pain degree of lumbar disc herniation based on back propagation neural network
  194. SPA-UNet: A liver tumor segmentation network based on fused multi-scale features
  195. Systematic evaluation of clinical efficacy of CYP1B1 gene polymorphism in EGFR mutant non-small cell lung cancer observed by medical image
  196. Rehabilitation effect of intelligent rehabilitation training system on hemiplegic limb spasms after stroke
  197. A novel approach for minimising anti-aliasing effects in EEG data acquisition
  198. ErbB4 promotes M2 activation of macrophages in idiopathic pulmonary fibrosis
  199. Clinical role of CYP1B1 gene polymorphism in prediction of postoperative chemotherapy efficacy in NSCLC based on individualized health model
  200. Lung nodule segmentation via semi-residual multi-resolution neural networks
  201. Evaluation of brain nerve function in ICU patients with Delirium by deep learning algorithm-based resting state MRI
  202. A data mining technique for detecting malignant mesothelioma cancer using multiple regression analysis
  203. Markov model combined with MR diffusion tensor imaging for predicting the onset of Alzheimer’s disease
  204. Effectiveness of the treatment of depression associated with cancer and neuroimaging changes in depression-related brain regions in patients treated with the mediator-deuterium acupuncture method
  205. Molecular mechanism of colorectal cancer and screening of molecular markers based on bioinformatics analysis
  206. Monitoring and evaluation of anesthesia depth status data based on neuroscience
  207. Exploring the conformational dynamics and thermodynamics of EGFR S768I and G719X + S768I mutations in non-small cell lung cancer: An in silico approaches
  208. Optimised feature selection-driven convolutional neural network using gray level co-occurrence matrix for detection of cervical cancer
  209. Incidence of different pressure patterns of spinal cerebellar ataxia and analysis of imaging and genetic diagnosis
  210. Pathogenic bacteria and treatment resistance in older cardiovascular disease patients with lung infection and risk prediction model
  211. Adoption value of support vector machine algorithm-based computed tomography imaging in the diagnosis of secondary pulmonary fungal infections in patients with malignant hematological disorders
  212. From slides to insights: Harnessing deep learning for prognostic survival prediction in human colorectal cancer histology
  213. Ecology and Environmental Science
  214. Monitoring of hourly carbon dioxide concentration under different land use types in arid ecosystem
  215. Comparing the differences of prokaryotic microbial community between pit walls and bottom from Chinese liquor revealed by 16S rRNA gene sequencing
  216. Effects of cadmium stress on fruits germination and growth of two herbage species
  217. Bamboo charcoal affects soil properties and bacterial community in tea plantations
  218. Optimization of biogas potential using kinetic models, response surface methodology, and instrumental evidence for biodegradation of tannery fleshings during anaerobic digestion
  219. Understory vegetation diversity patterns of Platycladus orientalis and Pinus elliottii communities in Central and Southern China
  220. Studies on macrofungi diversity and discovery of new species of Abortiporus from Baotianman World Biosphere Reserve
  221. Food Science
  222. Effect of berrycactus fruit (Myrtillocactus geometrizans) on glutamate, glutamine, and GABA levels in the frontal cortex of rats fed with a high-fat diet
  223. Guesstimate of thymoquinone diversity in Nigella sativa L. genotypes and elite varieties collected from Indian states using HPTLC technique
  224. Analysis of bacterial community structure of Fuzhuan tea with different processing techniques
  225. Untargeted metabolomics reveals sour jujube kernel benefiting the nutritional value and flavor of Morchella esculenta
  226. Mycobiota in Slovak wine grapes: A case study from the small Carpathians wine region
  227. Elemental analysis of Fadogia ancylantha leaves used as a nutraceutical in Mashonaland West Province, Zimbabwe
  228. Microbiological transglutaminase: Biotechnological application in the food industry
  229. Influence of solvent-free extraction of fish oil from catfish (Clarias magur) heads using a Taguchi orthogonal array design: A qualitative and quantitative approach
  230. Chromatographic analysis of the chemical composition and anticancer activities of Curcuma longa extract cultivated in Palestine
  231. The potential for the use of leghemoglobin and plant ferritin as sources of iron
  232. Investigating the association between dietary patterns and glycemic control among children and adolescents with T1DM
  233. Bioengineering and Biotechnology
  234. Biocompatibility and osteointegration capability of β-TCP manufactured by stereolithography 3D printing: In vitro study
  235. Clinical characteristics and the prognosis of diabetic foot in Tibet: A single center, retrospective study
  236. Agriculture
  237. Biofertilizer and NPSB fertilizer application effects on nodulation and productivity of common bean (Phaseolus vulgaris L.) at Sodo Zuria, Southern Ethiopia
  238. On correlation between canopy vegetation and growth indexes of maize varieties with different nitrogen efficiencies
  239. Exopolysaccharides from Pseudomonas tolaasii inhibit the growth of Pleurotus ostreatus mycelia
  240. A transcriptomic evaluation of the mechanism of programmed cell death of the replaceable bud in Chinese chestnut
  241. Melatonin enhances salt tolerance in sorghum by modulating photosynthetic performance, osmoregulation, antioxidant defense, and ion homeostasis
  242. Effects of plant density on alfalfa (Medicago sativa L.) seed yield in western Heilongjiang areas
  243. Identification of rice leaf diseases and deficiency disorders using a novel DeepBatch technique
  244. Artificial intelligence and internet of things oriented sustainable precision farming: Towards modern agriculture
  245. Animal Sciences
  246. Effect of ketogenic diet on exercise tolerance and transcriptome of gastrocnemius in mice
  247. Combined analysis of mRNA–miRNA from testis tissue in Tibetan sheep with different FecB genotypes
  248. Isolation, identification, and drug resistance of a partially isolated bacterium from the gill of Siniperca chuatsi
  249. Tracking behavioral changes of confined sows from the first mating to the third parity
  250. The sequencing of the key genes and end products in the TLR4 signaling pathway from the kidney of Rana dybowskii exposed to Aeromonas hydrophila
  251. Development of a new candidate vaccine against piglet diarrhea caused by Escherichia coli
  252. Plant Sciences
  253. Crown and diameter structure of pure Pinus massoniana Lamb. forest in Hunan province, China
  254. Genetic evaluation and germplasm identification analysis on ITS2, trnL-F, and psbA-trnH of alfalfa varieties germplasm resources
  255. Tissue culture and rapid propagation technology for Gentiana rhodantha
  256. Effects of cadmium on the synthesis of active ingredients in Salvia miltiorrhiza
  257. Cloning and expression analysis of VrNAC13 gene in mung bean
  258. Chlorate-induced molecular floral transition revealed by transcriptomes
  259. Effects of warming and drought on growth and development of soybean in Hailun region
  260. Effects of different light conditions on transient expression and biomass in Nicotiana benthamiana leaves
  261. Comparative analysis of the rhizosphere microbiome and medicinally active ingredients of Atractylodes lancea from different geographical origins
  262. Distinguish Dianthus species or varieties based on chloroplast genomes
  263. Comparative transcriptomes reveal molecular mechanisms of apple blossoms of different tolerance genotypes to chilling injury
  264. Study on fresh processing key technology and quality influence of Cut Ophiopogonis Radix based on multi-index evaluation
  265. An advanced approach for fig leaf disease detection and classification: Leveraging image processing and enhanced support vector machine methodology
  266. Erratum
  267. Erratum to “Protein Z modulates the metastasis of lung adenocarcinoma cells”
  268. Erratum to “BRCA1 subcellular localization regulated by PI3K signaling pathway in triple-negative breast cancer MDA-MB-231 cells and hormone-sensitive T47D cells”
  269. Retraction
  270. Retraction to “Protocatechuic acid attenuates cerebral aneurysm formation and progression by inhibiting TNF-alpha/Nrf-2/NF-kB-mediated inflammatory mechanisms in experimental rats”
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