Home lncRNA WT1-AS attenuates hypoxia/ischemia-induced neuronal injury during cerebral ischemic stroke via miR-186-5p/XIAP axis
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lncRNA WT1-AS attenuates hypoxia/ischemia-induced neuronal injury during cerebral ischemic stroke via miR-186-5p/XIAP axis

  • Jianquan You , Fei Qian , Yu Huang , Yingxuan Guo , Yaqian Lv , Yuqi Yang , Xiupan Lu , Ting Guo , Jun Wang EMAIL logo and Bin Gu EMAIL logo
Published/Copyright: July 25, 2022
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Open Medicine
From the journal Open Medicine Volume 17 Issue 1

Abstract

This study aimed to investigate the role and mechanism of long non-coding RNA (lncRNA) WT1 antisense RNA (WT1-AS) in cerebral ischemic stroke. The Starbase database and dual-luciferase reporter gene assay were used to analyze the interaction between lncRNA WT1 antisense RNA (lncRNA WT1-AS) and microRNA-186-5p (miR-186-5p). Reverse transcription-quantitative PCR analysis was performed to determine lncRNA WT1-AS and miR-186-5p levels. An oxygen glucose deprivation (OGD)-induced SH-SY5Y cell injury model was established. Cell viability and apoptosis were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and flow cytometric assays, respectively. Caspase 3 activity was evaluated using a caspase 3 activity detection kit. The results showed that miR-186-5p is a direct target of the lncRNA WT1-AS. In addition, lncRNA WT1-AS levels were downregulated and miR-186-5p levels were upregulated in the blood samples of patients with ischemic stroke and OGD-induced SH-SY5Y cells. WT1-AS overexpression promoted OGD-induced cell viability and reduced the cell apoptosis and caspase 3 activity. However, these effects were reversed by miR-186-5p overexpression. Furthermore, the results demonstrated that the X-linked inhibitor of apoptosis (XIAP) was directly targeted by miR-186-5p. Similarly, transfection with the miR-186-5p inhibitor reduced OGD-induced neuronal damage by upregulating XIAP expression. In conclusion, lncRNA WT1-AS attenuates hypoxia/ischemia-induced neuronal injury in cerebral ischemic stroke through the miR-186-5p/XIAP axis.

Keywords: wilms tumor 1 antisense RNA; cerebral ischemic stroke; microRNA-186-5p; X-linked inhibitor of apoptosis; oxygen glucose deprivation

1 Introduction

Stroke is the leading cause of cerebral dysfunction and mortality worldwide [1]. Approximately 795,000 new cases of stroke are recorded in the United States annually, while more than 140,000 individuals die from stroke [2]. Eighty percent of stroke cases are attributed to ischemic stroke [3]. The main features of ischemic stroke include interruption of blood flow and lack of oxygen and glucose supply in the brain cells, eventually leading to impaired neuronal cell function. Current treatment approaches for stroke mainly focus on stimulating nerve replacement and timely resolving the infarction to limit continuous hypoxic stress-mediated damage, which eventually results in neuronal injury [4]. To date, the mechanisms and treatment strategies for ischemia/hypoxia-induced neuronal damage remain elusive. Recently, numerous studies have shown that long non-coding RNAs (lncRNAs) and miRNAs are involved in mechanisms underlying ischemia/hypoxia-induced neuronal damage.

lncRNAs are approximately 200 nucleotides in length. Among lncRNAs, genomic DNA can be transcribed into RNA, but it cannot be translated into proteins [5]. lncRNAs play crucial roles in several biological processes, including the regulation of the cell cycle and differentiation and epigenetic regulation [6,7]. The roles of various lncRNAs in different diseases have been extensively reported. Several studies have shown that lncRNA expression is upregulated or downregulated in several diseases, including cancer, neurological diseases, and diabetes [8,9]. WT1 antisense RNA (WT1-AS) encodes a zinc finger transcription domain [10]. Emerging evidence has shown that WT1-AS is involved in the onset of numerous types of cancers, including breast cancer, non-small-cell lung cancer, cervical cancer, and glioma [11,12,13,14]. This study aimed to investigate the role of WT1-AS in cerebral ischemic stroke.

miRNA is a general term for a class of small non-coding RNAs, ∼20–22 nucleotides in length, that are not translated into proteins and inhibit the expression of their target genes [15]. microRNA-186-5p (miR-186-5p), a cancer-related miRNA, is involved in the occurrence and development of several types of cancers [16,17]. Zhu et al. [16] showed that miR-186-5p acts as a tumor suppressor gene that is downregulated in neuroblastoma. In addition, Jones et al. [17] demonstrated that miR-186-5p silencing inhibits the proliferation, growth, and invasion of metastatic cancer cells. Tao et al. [18] indicated that miR-186-5p may be involved in the development of atherosclerosis. However, the role of miR-186-5p in cerebral ischemic stroke has not yet been investigated. Therefore, the current study aimed to investigate whether lncRNA WT1 antisense RNA (lncRNA WT1-AS), miR-186-5p, and X-linked inhibitor of apoptosis (XIAP) could interact with each other and to uncover the underlying mechanism of action of these molecules in cerebral ischemic stroke.

2 Methods

2.1 Clinical samples

Blood samples were obtained from 30 patients with ischemic stroke within 3 h of stroke onset. In addition, 30 blood samples collected from healthy volunteers served as the control group. The characteristics of patients are shown in Table 1. The levels of lncRNA WT1-AS and miR-186-5p in the plasma of patients with ischemic stroke and healthy volunteers were determined using reverse transcription-quantitative PCR (RT-qPCR). Inclusion criteria were as follows: patients who demonstrated new-onset cerebral infarction on magnetic resonance imaging within 3 h from the time of admission were included in the study. The exclusion criteria were evidence of prior cerebral infarcts, diabetes mellitus, coronary artery disease, hypertension, kidney diseases, circulatory disorders, or autoimmune diseases. The study protocol was approved by the Ethics Committee of Taizhou People’s Hospital. All the patients in the current study approved the use of their specimens.

Table 1

Characteristics of patients

Characteristic Healthy control Stroke P value
Age (year) 63–72 64–75 >0.05
Gender (male), n (%) 15 (50.0) 15 (50.0) >0.05
BMI (kg/m2) 23.3 ± 0.34 25.1 ± 0.48 >0.05
Smoking, n (%) 6 (20.0) 5 (16.7) >0.05
Drinking, n (%) 3 (10.0) 4 (13.3) >0.05
Hypertension, n (%) 4 (13.4) 17 (56.7) <0.05
Diabetes mellitus, n (%) 3 (10.0) 4 (13.3) >0.05
Total cholesterol (mm) 4.25 ± 0.13 4.35 ± 0.26 >0.05
Triglycerides (mm) 1.53 ± 0.13 1.41 ± 0.12 >0.05
LDL (mm) 2.63 ± 0.15 2.70 ± 0.17 >0.05
HDL (mm) 1.14 ± 0.05 1.31 ± 0.07 >0.05
NIHSS score
 1–4 9 (30.0%)
 5–15 14 (46.7%)
 15–20 6 (20%)
 21–42 1 (3.3%)

BMI, body mass index; HDL, high-density lipoprotein; LDL, low-density lipoprotein; NIHSS, National Institute of Health Stroke Scale.

2.2 Dual luciferase reporter assay

The wild-type (WT) or mutant (MUT) 3′-untranslated region (3′-UTR) of WT1-AS were subcloned into the pmiRGLO vector (cat. no. E1330; Promega Corporation) to assess the association between WT1-AS and miR-186-5p. Subsequently, 293T cells were co-transfected with miR-186-5p, control mimics, or the above plasmids. Following transfection for 48 h, luciferase activity was measured using a dual-luciferase assay kit (cat. no. E1910; Promega Corporation). To evaluate the association between miR-186-5p and XIAP, XIAP-WT and XIAP-MUT 3′-UTR luciferase reporter plasmids were constructed. Then, 293T cells were co-transfected with Renilla luciferase, luciferase reporter plasmids, and miR-186-5p or control mimics for 48 h. Luciferase activity was determined using a dual luciferase assay kit (Promega Corporation), according to the manufacturer’s instructions.

2.3 Cell culture and transfection

The neuroblastoma cell line, SH-SY5Y, was obtained from the American Tissue Culture Collection (cat. no. CRL-2266). Cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum (both from Gibco; Thermo Fisher Scientific, Inc.) in a cell culture incubator with 5% CO2 at 37°C. SH-SY5Y cells were then transfected with WT1-AS plasmid, control plasmid, mimic control (5′-UUCUCCGAACGUGUCACGUTT-3′; Shanghai GenePharma Co., Ltd., China), miR-186-5p mimics (5′-CAAAGAAUUCUCCUUUUGGGCU-3′; Shanghai GenePharma Co., Ltd., China), WT1-AS plasmid + mimic control, WT1-AS plasmid + miR-186-5p mimics, inhibitor control (5′-GCCUCCGGCUUCGCACCUCU-3′; Shanghai GenePharma Co., Ltd., China), miR-186-5p inhibitor (5′-AGCCCAAAAGGAGAAUUCUUUG-3′; Shanghai GenePharma Co., Ltd., China), control small interfering (si)-RNA, XIAP small-interfering RNA (siRNA), miR-186-5p inhibitor + control siRNA, or miR-186-5p inhibitor + XIAP siRNA for 48 h using Lipofectamine™ 2000 transfection reagent (cat. no. 11668019; Invitrogen; Thermo Fisher Scientific, Inc.), according to the manufacturer’s instructions. The cells were incubated for 48 h prior to subsequent experiments.

2.4 RT-qPCR assay

Total RNA was extracted from SH-SY5Y cells using TRIzol reagent (cat. no. 9108; Takara Bio, Inc.), following standard operating procedures. Total RNA was reverse transcribed into cDNA using a reverse transcriptase kit (cat no. R211-01; Vazyme Biotech Co., Ltd.). Subsequently, qPCR was performed using the SYBR Green PCR kit (cat. no. Q311-02; Vazyme Biotech Co., Ltd.), according to the manufacturer’s instructions. Glyceraldehyde-3-phosphate dehydrogenase (for mRNA) and uracil 6 (for miRNA) were used as endogenous controls. The relative gene expression was quantified using the 2−ΔΔCq method. Primer sequences are listed in Table 2.

Table 2

Primer sequences for PCR

Gene name Sequences: 5′–3′
lncRNA WT1-AS Forward, 5′-GCCTCTCTGTCCTCTTCTTTG-3′
Reverse, 5′-GCTGTGAGTCCTGGTGCTTA-3′
miR-186-5p Forward, 5′-TCAAAGAATTCTCCTTTTGGGCT-3′
Reverse, 5′-CGCTTCACGAATTTGCGTGTCAT-3′
GAPDH Forward, 5′-ATCACTGCCACCCAGAAGAC-3′
Reverse, 5′-TTTCTAGACGGCAGGTCAGG-3′
U6 Forward, 5′-CTCGCTTCGGCAGCACA-3′
Reverse, 5′-AACGCTTCACGAATTTGCGT-3′
XIAP Forward, 5′-ACCGTGCGGTGCTTTAGTT-3′
Reverse, 5′-TGCGTGGCACTATTTTCAAGATA-3′

2.5 Establishment of the oxygen glucose deprivation/reoxygenation (OGD/R) cell model

To establish an in vitro OGD/R model, the cells were cultured in glucose-free DMEM at 37°C in an atmosphere of 1% O2, 94% N2, and 5% CO2 for 4 h. Subsequently, the cells were cultured under normoxic conditions of 95% air and 5% CO2 for an additional 24 h.

2.6 Western blotting analysis

The cells were lysed with the radioimmunoprecipitation assay buffer (cat. no. R0010; Beijing Solarbio Science & Technology Co., Ltd.), and the protein concentration was measured using a bicinchoninic acid kit (cat no. 23225; Pierce; Thermo Fisher Scientific, Inc.). Equal amounts of proteins were separated via 12% sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred onto polyvinylidene fluoride membranes. Following blocking with 5% nonfat milk to prevent nonspecific binding, the membranes were incubated with primary antibodies against XIAP (cat. no. ab21278; dilution, 1:1,000) and GAPDH (cat. no. ab9485; dilution, 1:1,000; both from Abcam) at 4°C overnight. The next day, membranes were incubated with the corresponding secondary antibodies for 2 h. Protein bands were visualized using the ECL method (cat. no. 34579; Applygen Technologies, Inc.).

2.7 Flow cytometric assay

Cell apoptosis was evaluated using the Annexin-V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) Apoptosis Detection Kit (cat. no. 556570; BD Bioscience). Briefly, after treatment, the cells were collected and centrifuged at a high speed and low temperature. Following centrifugation, the supernatant was discarded and the cells were resuspended in 100 μL FITC-binding buffer. Subsequently, the cell suspension was supplemented with 5 μL ready-to-use annexin V-FITC and 5 μL PI. The cells were incubated for 30 min at room temperature in the dark. Cell apoptosis rate was assessed using a BD FACSCalibur flow cytometer (BD Technologies).

2.8 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay

Following treatment, cells were seeded into a 96-well plate and incubated for 24 h. Subsequently, each well was supplemented with 20 μL MTT reagent (5 mg/mL; cat. no. CT02; Sigma-Aldrich), and the cells were cultured for an additional 4 h. The supernatant was discarded and each well was supplemented with 200 µL dimethyl sulfoxide. The absorbance of each well was measured at 570 nm wavelength.

2.9 Caspase 3 activity detection

Caspase 3 activity was assessed using the corresponding detection kit (cat. no. C1116; Beyotime Institute of Biotechnology). Briefly, transfected cells were collected into tubes and centrifuged at 600×g for 5 min at 4°C. The cells were resuspended in an appropriate volume of lysis buffer and lysed for 15 min in an ice bath. Following centrifugation for 10 min, the supernatant was transferred to a pre-cooled centrifuge tube and incubated on ice. The enzymatic activity of caspase 3 was measured immediately at a wavelength of 405 nm.

2.10 Statistical analysis

All experiments were repeated at least three times. All data were analyzed using GraphPad Prism software (version 6.0; GraphPad Software, Inc.). Statistically significant differences between two groups were evaluated using unpaired Student’s t-test, while those among multiple groups were evaluated using one-way analysis of variance followed by Tukey’s post hoc test. Data are expressed as the mean ± standard deviation from three independent experiments. P < 0.05 was considered to be statistically significant.

3 Results

3.1 lncRNA WT1-AS directly interacts with miR-186-5p

First, the association between WT1-AS and miR-186-5p was predicted using the StarBase bioinformatics tool. Bioinformatics analysis revealed that miR-186-5p and lncRNA WT1-AS shared mutual binding sites (Figure 1a), suggesting that miR-186-5p could bind to the WT1-AS 3′-UTR. Subsequently, 293T cells were cotransfected with WT1-AS-WT, WT1-AS-MUT, miR-186-5p, or mimic control for 48 h. A dual-luciferase reporter assay was then performed to evaluate the luciferase activity. The results revealed that miR-186-5p mimics inhibited the activity of WT1-AS-WT but not that of WT1-AS-MUT (Figure 1b). These findings indicate that miR-186-5p is directly targeted by the lncRNA WT1-AS. Subsequently, blood samples from 30 patients with ischemic stroke were collected within 3 h of stroke onset. RT-qPCR assay results demonstrated that, compared with the healthy control group, lncRNA WT1-AS was substantially downregulated (Figure 1c) and miR-186-5p was upregulated (Figure 1d) in the blood samples of patients with ischemic stroke.

Figure 1 Expression levels of lncRNA WT1-AS and miR-186-5p in patients with ischemic stroke. (a) Interaction between miR-186-5p and WT1-AS 3′-UTR was predicted using the Starbase prediction software. (b) Dual luciferase reporter gene assay was used to verify the interaction between WT1-AS and miR-186-5p in 293T cells co-transfected with miR-186-5p mimics and WT or MUT WT1-AS 3′-UTR reporter plasmids. (c and d) Expression levels of WT1-AS and miR-186-5p in blood samples of patients with ischemic stroke and healthy individuals. ** P < 0.01 vs control mimics group; ## P < 0.01 vs healthy control group. GraphPad Prism 6.0 software (GraphPad Software, Inc.) was used for creation of the figure.
Figure 1

Expression levels of lncRNA WT1-AS and miR-186-5p in patients with ischemic stroke. (a) Interaction between miR-186-5p and WT1-AS 3′-UTR was predicted using the Starbase prediction software. (b) Dual luciferase reporter gene assay was used to verify the interaction between WT1-AS and miR-186-5p in 293T cells co-transfected with miR-186-5p mimics and WT or MUT WT1-AS 3′-UTR reporter plasmids. (c and d) Expression levels of WT1-AS and miR-186-5p in blood samples of patients with ischemic stroke and healthy individuals. ** P < 0.01 vs control mimics group; ## P < 0.01 vs healthy control group. GraphPad Prism 6.0 software (GraphPad Software, Inc.) was used for creation of the figure.

3.2 lncRNA WT1-AS levels are downregulated and miR-186-5p levels are upregulated in OGD-induced SH-SY5Y cells

The results showed that, compared with the control group, the expression of lncRNA WT1-AS was significantly reduced in OGD-induced SH-SY5Y cells (Figure 2a), while miR-186-5p expression was significantly upregulated (Figure 2b).

Figure 2 Expression levels of lncRNA WT1-AS/miR-186-5p in OGD-induced SH-SY5Y cells. (a) RT-qPCR analysis results showing lncRNA WT1-AS expression levels. (b) RT-qPCR analysis results showing miR-186-5p expression levels. ** P < 0.01 vs control group. GraphPad Prism 6.0 software (GraphPad Software, Inc.) was used for creation of the figure.
Figure 2

Expression levels of lncRNA WT1-AS/miR-186-5p in OGD-induced SH-SY5Y cells. (a) RT-qPCR analysis results showing lncRNA WT1-AS expression levels. (b) RT-qPCR analysis results showing miR-186-5p expression levels. ** P < 0.01 vs control group. GraphPad Prism 6.0 software (GraphPad Software, Inc.) was used for creation of the figure.

3.3 WT1-AS negatively regulates miR-186-5p levels in SH-SY5Y cells

Compared with the control plasmid group, cell transfection with the WT1-AS plasmid successfully overexpressed WT1-AS in SH-SY5Y cells (Figure 3a). In addition, compared to the mimic control group, transfection with miR-186-5p mimics notably increased miR-186-5p expression in SH-SY5Y cells (Figure 3b). There were no significant changes in the expression of WT1-AS in WT1-AS plasmid + mimic control and WT1-AS plasmid + miR-186-5p mimics groups (Figure 3c). Finally, WT1-AS overexpression inhibited miR-186-5p expression compared to the control plasmid group, while this effect was notably reversed by miR-186-5p overexpression (Figure 3d). The data indicated that WT1-AS negatively regulates miR-186-5p levels in SH-SY5Y cells.

Figure 3 lncRNA WT1-AS negatively regulates miR-186-5p expression levels in SH-SY5Y cells. (a) RT-qPCR analysis results showing WT1-AS expression levels in SH-SY5Y cells transfected with the control or WT1-AS-plasmids. (b) RT-qPCR analysis results showing miR-186-5p expression levels in SH-SY5Y cells transfected with the control or miR-186-5p mimics. (c) RT-qPCR analysis showing the expression levels of WT1-AS in SH-SY5Y cells transfected with the control plasmid, miR-186-5p mimics, WT1-AS plasmid + control mimics, or WT1-AS plasmid + miR-186-5p mimics. (d) RT-qPCR analysis showing the expression levels of miR-186-5p in SH-SY5Y cells transfected with the control plasmid, miR-186-5p mimics, WT1-AS plasmid + control mimics, or WT1-AS plasmid + miR-186-5p mimics. ** P < 0.01 vs control plasmid group; ## P < 0.01 vs control mimics group; && P < 0.01 vs WT1-AS plasmid + control mimics group. GraphPad Prism 6.0 software (GraphPad Software, Inc.) was used for creation of the figure.
Figure 3

lncRNA WT1-AS negatively regulates miR-186-5p expression levels in SH-SY5Y cells. (a) RT-qPCR analysis results showing WT1-AS expression levels in SH-SY5Y cells transfected with the control or WT1-AS-plasmids. (b) RT-qPCR analysis results showing miR-186-5p expression levels in SH-SY5Y cells transfected with the control or miR-186-5p mimics. (c) RT-qPCR analysis showing the expression levels of WT1-AS in SH-SY5Y cells transfected with the control plasmid, miR-186-5p mimics, WT1-AS plasmid + control mimics, or WT1-AS plasmid + miR-186-5p mimics. (d) RT-qPCR analysis showing the expression levels of miR-186-5p in SH-SY5Y cells transfected with the control plasmid, miR-186-5p mimics, WT1-AS plasmid + control mimics, or WT1-AS plasmid + miR-186-5p mimics. ** P < 0.01 vs control plasmid group; ## P < 0.01 vs control mimics group; && P < 0.01 vs WT1-AS plasmid + control mimics group. GraphPad Prism 6.0 software (GraphPad Software, Inc.) was used for creation of the figure.

3.4 lncRNA WT1-AS attenuates OGD-induced neuronal injury by downregulating miR-186-5p levels

Compared to the control group, miR-186-5p expression was significantly enhanced in the OGD group. In addition, the expression of miR-186-5p was significantly reduced in the OGD + WT1-AS plasmid group compared to that in the OGD + control plasmid group. However, this effect was reversed by miR-186-5p overexpression (Figure 4a). Furthermore, RT-qPCR analysis showed that compared to the control group, the expression of lncRNA WT1-AS decreased in the OGD group. In addition, compared to the OGD + control plasmid group, lncRNA WT1-AS was upregulated in the OGD + WT1-AS plasmid group (Figure 4b). MTT assay and flow cytometric analysis revealed that compared to the control group, cell viability decreased (Figure 4c) and cell apoptosis increased (Figure 4d and e), respectively, in the OGD group. Compared to the control group, the activity of caspase 3 was enhanced in the OGD group (Figure 4f). Compared to the OGD + control plasmid group, cell viability was significantly increased (Figure 4c), apoptosis (Figure 4d and e) was reduced, and caspase 3 activity was attenuated (Figure 4f) in the OGD + WT1-AS plasmid group. Furthermore, all the aforementioned effects caused by WT1-AS plasmid were reversed following miR-186-5p overexpression. These findings suggested that lncRNA WT1-AS attenuates OGD-induced neuronal injury by downregulating miR-186-5p levels.

Figure 4 Effect of lncRNA WT1-AS on OGD-induced nerve cell injury. (a) RT-qPCR analysis results showing microRNA-186-5p expression levels. (b) RT-qPCR analysis results showing lncRNA WT1-AS expression levels. (c) A MTT assay was used to assess the cell viability. (d) A flow cytometric assay was used to evaluate cell apoptosis. (e) The apoptosis ratio is presented. (f) Caspase 3 activity was detected using the corresponding kit. ** P < 0.01 vs control group; ## P < 0.01 vs OGD + control mimics group; && P < 0.01 vs OGD + WT1-AS plasmid + control mimics group. GraphPad Prism 6.0 software (GraphPad Software, Inc.) was used for creation of the figure.
Figure 4

Effect of lncRNA WT1-AS on OGD-induced nerve cell injury. (a) RT-qPCR analysis results showing microRNA-186-5p expression levels. (b) RT-qPCR analysis results showing lncRNA WT1-AS expression levels. (c) A MTT assay was used to assess the cell viability. (d) A flow cytometric assay was used to evaluate cell apoptosis. (e) The apoptosis ratio is presented. (f) Caspase 3 activity was detected using the corresponding kit. ** P < 0.01 vs control group; ## P < 0.01 vs OGD + control mimics group; && P < 0.01 vs OGD + WT1-AS plasmid + control mimics group. GraphPad Prism 6.0 software (GraphPad Software, Inc.) was used for creation of the figure.

3.5 miR-186-5p directly interacts with XIAP

A literature review [19] and bioinformatic analysis using the TargetScan database identified a mutual binding site between miR-186-5p and XIAP (Figure 5a). Furthermore, a dual-luciferase reporter assay verified the association between miR-186-5p and XIAP. As shown in Figure 5b, miR-186-5p mimics inhibited the activity of XIAP-WT but not that of XIAP-MUT. Then, we determined the level of XIAP in the blood samples of patients with ischemic stroke. The results indicated that compared with the healthy control group, XIAP was significantly downregulated (Figure 5c) in the blood samples of patients with ischemic stroke. Taken together, these findings suggest that XIAP is directly targeted by miR-186-5p, and it is downregulated in the blood samples of patients with ischemic stroke.

Figure 5 XIAP is directly targeted by miR-186-5p. (a) The interaction between miR-186-5p and XIAP 3′-UTR was predicted by TargetScan. (b) A dual luciferase reporter gene assay was performed to verify the interaction between miR-186-5p and XIAP in 293T cells co-transfected with miR-186-5p mimics and WT or MUT XIAP 3′-UTR reporter plasmids. (c) Expression levels of XIAP in blood samples of patients with ischemic stroke and healthy individuals.** P < 0.01 vs control mimics group; ## P < 0.01 vs Healthy control group. GraphPad Prism 6.0 software (GraphPad Software, Inc.) was used for creation of the figure.
Figure 5

XIAP is directly targeted by miR-186-5p. (a) The interaction between miR-186-5p and XIAP 3′-UTR was predicted by TargetScan. (b) A dual luciferase reporter gene assay was performed to verify the interaction between miR-186-5p and XIAP in 293T cells co-transfected with miR-186-5p mimics and WT or MUT XIAP 3′-UTR reporter plasmids. (c) Expression levels of XIAP in blood samples of patients with ischemic stroke and healthy individuals.** P < 0.01 vs control mimics group; ## P < 0.01 vs Healthy control group. GraphPad Prism 6.0 software (GraphPad Software, Inc.) was used for creation of the figure.

3.6 miR-186-5p negatively regulated XIAP expression in SH-SY5Y cells

SH-SY5Y cells were transfected with inhibitor control, miR-186-5p inhibitor, control siRNA, XIAP siRNA, miR-186-5p inhibitor + control siRNA, or miR-186-5p inhibitor + XIAP siRNA for 24 h. RT-qPCR was performed to assess the transfection efficiency. Compared to the inhibitor control group, transfection with the miR-186-5p inhibitor significantly reduced miR-186-5p expression in SH-SY5Y cells (Figure 6a). Consistently, compared to the control siRNA group, transfection with XIAP siRNA notably attenuated XIAP expression (Figure 6b). However, miR-186-5p silencing significantly increased the mRNA and protein expression levels of XIAP compared to those in the control inhibitor group, and this effect was reversed by XIAP knockdown (Figure 6c–e). These findings suggest that XIAP is negatively regulated by miR-186-5p in SH-SY5Y cells.

Figure 6 miR-186-5p negatively regulates XIAP expression levels in SH-SY5Y cells. (a) RT-qPCR assay results showing miR-186-5p expression levels in SH-SY5Y cells transfected with the inhibitor control or miR-186-5p inhibitors. (b) RT-qPCR assay results showing XIAP expression levels in SH-SY5Y cells transfected with the control or XIAP siRNAs. (c) RT-qPCR assay results showing XIAP expression levels in SH-SY5Y cells transfected with the miR-186-5p inhibitor + control siRNA or miR-186-5p inhibitor + XIAP siRNA. (d) Western blotting analysis results showing the protein expression levels of XIAP. (e) XIAP/GAPDH. ** P < 0.01 vs control inhibitor group; ## P < 0.01 vs control siRNA group; && P < 0.01 vs miR-186-5p inhibitor + control siRNA group. GraphPad Prism 6.0 software (GraphPad Software, Inc.) was used for creation of the figure.
Figure 6

miR-186-5p negatively regulates XIAP expression levels in SH-SY5Y cells. (a) RT-qPCR assay results showing miR-186-5p expression levels in SH-SY5Y cells transfected with the inhibitor control or miR-186-5p inhibitors. (b) RT-qPCR assay results showing XIAP expression levels in SH-SY5Y cells transfected with the control or XIAP siRNAs. (c) RT-qPCR assay results showing XIAP expression levels in SH-SY5Y cells transfected with the miR-186-5p inhibitor + control siRNA or miR-186-5p inhibitor + XIAP siRNA. (d) Western blotting analysis results showing the protein expression levels of XIAP. (e) XIAP/GAPDH. ** P < 0.01 vs control inhibitor group; ## P < 0.01 vs control siRNA group; && P < 0.01 vs miR-186-5p inhibitor + control siRNA group. GraphPad Prism 6.0 software (GraphPad Software, Inc.) was used for creation of the figure.

3.7 Effect of miR-186-5p silencing on OGD-induced nerve cell injury

Following cell transfection with inhibitor control, miR-186-5p inhibitor, miR-186-5p inhibitor + control-siRNA, or miR-186-5p inhibitor + XIAP-siRNA for 24 h, an OGD-induced cell injury model was established in SH-SY5Y cells. The results demonstrated that miR-186-5p levels were upregulated (Figure 7a) and XIAP levels were downregulated (Figure 7b) in the OGD group compared to those in the control group. In addition, compared with the OGD + inhibitor control group, the expression of miR-186-5p and XIAP decreased and increased, respectively, in the OGD + miR-186-5p inhibitor group. Finally, compared with the OGD + inhibitor control group, cell viability was improved (Figure 7c) and cell apoptosis (Figure 7d and e) and caspase 3 activity (Figure 7f) were reduced in the OGD + miR-186-5p inhibitor group, and all these effects were reversed by the knockdown of XIAP. In general, miR-186-5p silencing relieves OGD-induced nerve cell injury via up-regulating XIAP expression.

Figure 7 miR-186-5p inhibitor attenuates OGD-induced neuronal injury by upregulating XIAP expression. (a) RT-qPCR analysis results showing miR-186-5p expression levels. (b) RT-qPCR analysis results showing XIAP expression levels. (c) MTT assay was used to assess the cell viability. (d) Flow cytometric assay was carried out to evaluate cell apoptosis. (e) The cell apoptosis ratio is presented. (f) Caspase 3 activity was detected using the corresponding kit. ** P < 0.01 vs control group; ## P < 0.01 vs OGD + inhibitor control group; && P < 0.01 vs OGD + miR-186-5p inhibitor + control siRNA group. GraphPad Prism 6.0 software (GraphPad Software, Inc.) was used for creation of the figure.
Figure 7

miR-186-5p inhibitor attenuates OGD-induced neuronal injury by upregulating XIAP expression. (a) RT-qPCR analysis results showing miR-186-5p expression levels. (b) RT-qPCR analysis results showing XIAP expression levels. (c) MTT assay was used to assess the cell viability. (d) Flow cytometric assay was carried out to evaluate cell apoptosis. (e) The cell apoptosis ratio is presented. (f) Caspase 3 activity was detected using the corresponding kit. ** P < 0.01 vs control group; ## P < 0.01 vs OGD + inhibitor control group; && P < 0.01 vs OGD + miR-186-5p inhibitor + control siRNA group. GraphPad Prism 6.0 software (GraphPad Software, Inc.) was used for creation of the figure.

4 Discussion

Acute cerebral ischemic stroke is characterized by an increased mortality rate in humans and is commonly accompanied by several complications, such as behavioral, social, attention, cognitive, and functional motor dysfunctions [20,21]. The pathological process of ischemic stroke is complicated and the factors contributing to the disease are diverse. Neuroinflammation and oxidative stress have been reported to play significant roles in ischemic brain injury [22,23]. Although several treatment strategies have been previously applied to treat ischemic stroke, the therapeutic potential of currently available treatment approaches remains unsatisfactory [24,25,26]. Therefore, novel treatment methods for ischemic stroke are urgently required.

The current study aimed to investigate the role of the lncRNA WT1-AS in cerebral ischemic stroke. The roles of lncRNAs in several diseases, including cerebral ischemic stroke, have attracted increasing attention. Shan et al. [27] showed that the lncRNA taurine-upregulated gene 1 (TUG1) is involved in the development of cerebral ischemic stroke, and TUG1 silencing can diminish OGD/R-induced injury. Another study by Wen et al. [28] indicated that lncRNA Gm4419 overexpression upregulates TNF-α, IL-1β, and IL-6 levels, thereby enhancing OGD/R damage. Hu et al. [29] showed that knockdown of lncRNA small nucleolar RNA host gene 15 could improve ischemia/hypoxia-induced neuronal injury and microglial inflammation by targeting the miR-302a-3p/signal transducer and activator of transcription 1 axis. Furthermore, Xiao et al. [30] demonstrated that lncRNA H19 was significantly upregulated in patients with ischemic stroke, whereas its silencing could attenuate neuronal apoptosis in OGD-induced neuronal cells by targeting miR-19a. In this study, bioinformatics analysis and dual-luciferase reporter assays were performed to verify the interaction between lncRNA WT1-AS and miR-186-5p.

lncRNA WT1-AS is involved in cancer development [31,32,33]. To the best of our knowledge, the effects of lncRNA WT1-AS on ischemic stroke have not yet been reported. Consistent with previous studies, the results of the present study demonstrated that WT1-AS levels were downregulated and miR-186-5p levels were upregulated in the blood samples of patients with ischemic stroke. Similarly, the expression levels of WT1-AS and miR-186-5p were enhanced and reduced, respectively, in OGD-treated SH-SY5Y cells in vitro.

Subsequently, the mechanisms underlying the effects of WT1-AS and miR-186-5p on OGD-induced SH-SY5Y cell injury were investigated. Du et al. [34] showed that LINC01705 was directly targeted by miR-186-5p and was involved in breast cancer development. In addition, Zhu et al. [35] demonstrated that HLA complex P5 could promote neuroblastoma cell proliferation by downregulating miR-186-5p expression. In osteosarcoma, miR-186-5p attenuates cell proliferation, invasion, and metastasis by targeting Forkhead Box K1 [36]. In this study, WT1-AS overexpression attenuated OGD-induced neuronal injury by downregulating the expression of miR-186-5p. Furthermore, the results of the current study revealed that XIAP was a direct target of miR-186-5p.

XIAP, a member of the inhibitor of apoptosis protein family, is a cytoplasmic inhibitor of caspases 3, 7, and 9 [37]. As a target for cancer treatment, XIAP is abnormally expressed in cancer, thus playing a significant role in regulating patient mortality [38]. Huang et al. [39] revealed that miR-377-3p can suppress colorectal cancer by regulating XIAP expression. Deng et al. [40] demonstrated that XIAP is involved in the development of ischemic stroke, and its expression is reduced in middle cerebral artery occlusion (MCAO) model rats. Therefore, XIAP silencing can reverse the effects of miR-130a downregulation on neurological function and angiogenesis in MCAO model rats. In this study, miR-186-5p silencing alleviated the OGD-induced SH-SY5Y cell injury. Besides, activation of caspase3 was found to be mechanism of XIAP silencing-induced apoptosis. Since caspase3 is activated by proteolytic cleavage, total caspase3 and cleaved caspase3 levels could be determined. This study did not analyze the total caspase3 and cleaved caspase3 level, which was a limitation of this study. Overall, the results of the present study indicate that WT1-AS plays a crucial role in cerebral ischemic stroke by regulating the miR-186-5p/XIAP axis. lncRNA WT1-AS attenuates hypoxia/ischemia-induced neuronal injury in cerebral ischemic stroke via the miR-186-5p/XIAP axis.

However, to further elucidate the role of lncRNA WT1-AS in ischemic stroke, future in-depth studies are needed. For example, more cell lines may be required to confirm that the effect of IncRNA WT1-AS on neuronal damage is general activity and not SH-SY5Y specific. The effects of XIAP over-expression on OGD induced neuronal injury should be further clarified. Besides, the role of lncRNA WT1-AS in ischemic stroke should be explored using animal models. In addition, the correlation between lncRNA WT1-AS expression and clinicopathological parameters of ischemic stroke patients should be investigated. These issues will be addressed in the future.

5 Conclusion

In this study, we found that lncRNA WT1-AS reduced OGD-induced SH-SY5Y cell injury via the miR-186-5p/XIAP axis, indicating the protective role of lncRNA WT1-AS in hypoxia/ischemia-induced neuronal injury in cerebral ischemic stroke.

Abbreviations

FITC

fluorescein isothiocyanate

lncRNA

long non-coding RNA

MTT

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide

OGD

oxygen glucose deprivation

PI

propidium iodide

RT-qPCR

reverse transcription-quantitative PCR

WT1-AS

WT1 antisense RNA

XIAP

X-linked inhibitor of apoptosis

# Equal contributors.

Acknowledgments

Not applicable.

  1. Funding information: This study was supported by the Taizhou Science and Technology Support Plan (Social Development, grant no. SSF20210117), the Scientific Research Foundation of Taizhou People’s Hospital (Grant No. ZL202015) and the Project of Taizhou City Personnel Bureau (Grant No. RCPY201937).

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

  3. Data availability statement: The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.

References

[1] Meschia JF, Bushnell C, Boden-Albala B, Braun LT, Bravata DM, Chaturvedi S, et al. Guidelines for the primary prevention of stroke. Stroke. 2014;45:3754–832.10.1161/STR.0000000000000046Search in Google Scholar PubMed PubMed Central

[2] Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, et al. Heart disease and stroke statistics-2020 update: a report from the american heart association. Circulation. 2020;141:e139–596.10.1161/CIR.0000000000000757Search in Google Scholar PubMed

[3] Thrift AG, Dewey HM, Macdonell RA, McNeil JJ, Donnan GA. Incidence of the major stroke subtypes: initial findings from the North East Melbourne stroke incidence study (NEMESIS). Stroke. 2001;32:1732–8.10.1161/01.STR.32.8.1732Search in Google Scholar PubMed

[4] Kuriakose D, Xiao Z. Pathophysiology and treatment of stroke: Present status and future perspectives. Int J Mol Sci. 2020;21:7609.10.3390/ijms21207609Search in Google Scholar PubMed PubMed Central

[5] Rinn JL, Chang HY. Long noncoding RNAs: molecular modalities to organismal functions. Annu Rev Biochem. 2020;89:283–308.10.1146/annurev-biochem-062917-012708Search in Google Scholar PubMed

[6] Lekka E, Hall J. Noncoding RNAs in disease. FEBS Lett. 2018;592:2884–900.10.1002/1873-3468.13182Search in Google Scholar PubMed PubMed Central

[7] Kopp F, Mendell JT. Functional classification and experimental dissection of long noncoding RNAs. Cell. 2018;172:393–407.10.1016/j.cell.2018.01.011Search in Google Scholar PubMed PubMed Central

[8] Carter G, Miladinovic B, Patel AA, Deland L, Mastorides S, Patel NA. Circulating long noncoding RNA GAS5 levels are correlated to prevalence of type 2 diabetes mellitus. BBA Clin. 2015;4:102–7.10.1016/j.bbacli.2015.09.001Search in Google Scholar PubMed PubMed Central

[9] Zheng Y, Song D, Xiao K, Yang C, Ding Y, Deng W, et al. LncRNA GAS5 contributes to lymphatic metastasis in colorectal cancer. Oncotarget. 2016;7:83727–34.10.18632/oncotarget.13384Search in Google Scholar PubMed PubMed Central

[10] Le F, Luo P, Ouyang Q, Zhong X. LncRNA WT1-AS downregulates survivin by upregulating miR-203 in papillary thyroid carcinoma. Cancer Manag Res. 2020 Jan 20;12:443–9.10.2147/CMAR.S232294Search in Google Scholar PubMed PubMed Central

[11] Wang J, Xi C, Yang X, Lu X, Yu K, Zhang Y, et al. LncRNA WT1-AS inhibits triple-negative breast cancer cell migration and invasion by downregulating transforming growth factor beta1. Cancer Biother Radiopharm. 2019;34:671–5.10.1089/cbr.2019.2925Search in Google Scholar PubMed

[12] Wu C, Yang J, Li R, Lin X, Wu J, Wu J. LncRNA WT1-AS/miR-494-3p regulates cell proliferation, apoptosis, migration and invasion via PTEN/PI3K/AKT signaling pathway in non-small cell lung cancer. Onco Targets Ther. 2021;14:891–904.10.2147/OTT.S278233Search in Google Scholar PubMed PubMed Central

[13] Qiu G, Tong W, Jiang C, Xie Q, Zou J, Luo C, et al. Long noncoding RNA WT1-AS inhibit cell malignancy via miR-494-3p in glioma. Technol Cancer Res Treat. 2020;19:1533033820919759.10.1177/1533033820919759Search in Google Scholar PubMed PubMed Central

[14] Luo H, Zhang J, He Z, Wu S. Long noncoding RNA WT1-AS inhibits the progression of cervical cancer by sponging miR-205. Cancer Biother Radiopharm. 2021;36:491–500.10.1089/cbr.2019.3279Search in Google Scholar PubMed

[15] Saliminejad K, Khorram Khorshid HR, Soleymani Fard S, Ghaffari SH. An overview of microRNAs: Biology, functions, therapeutics, and analysis methods. J Cell Physiol. 2019;234:5451–65.10.1002/jcp.27486Search in Google Scholar PubMed

[16] Zhu K, Su Y, Xu B, Wang Z, Sun H, Wang L, et al. MicroRNA-186-5p represses neuroblastoma cell growth via downregulation of Eg5. Am J Transl Res. 2019;11:2245–56.Search in Google Scholar

[17] Jones DZ, Schmidt ML, Suman S, Hobbing KR, Barve SS, Gobejishvili L, et al. Micro-RNA-186-5p inhibition attenuates proliferation, anchorage independent growth and invasion in metastatic prostate cancer cells. BMC Cancer. 2018;18:421.10.1186/s12885-018-4258-0Search in Google Scholar PubMed PubMed Central

[18] Tao Z, Cao Z, Wang X, Pan D, Jia Q. Long noncoding RNA SNHG14 regulates ox-LDL-induced atherosclerosis cell proliferation and apoptosis by targeting miR-186-5p/WIPF2 axis. Hum Exp Toxicol. 2021;40(1):47–59.10.1177/0960327120940363Search in Google Scholar PubMed

[19] Zhou Y, Li T, Chen Z, Huang J, Qin Z, Li L. Overexpression of lncRNA TUG1 alleviates NLRP3 inflammasome-mediated cardiomyocyte pyroptosis through targeting the miR-186-5p/XIAP axis in coronary microembolization-induced myocardial damage. Front Immunol. 2021;12:637598.10.3389/fimmu.2021.637598Search in Google Scholar PubMed PubMed Central

[20] Ren C, Li N, Gao C, Zhang W, Yang Y, Li S, et al. Ligustilide provides neuroprotection by promoting angiogenesis after cerebral ischemia. Neurol Res. 2020;42:683–92.10.1080/01616412.2020.1782122Search in Google Scholar PubMed

[21] Li B, Concepcion K, Meng X, Zhang L. Brain-immune interactions in perinatal hypoxic-ischemic brain injury. Prog Neurobiol. 2017;159:50–68.10.1016/j.pneurobio.2017.10.006Search in Google Scholar PubMed PubMed Central

[22] Tobin MK, Bonds JA, Minshall RD, Pelligrino DA, Testai FD, Lazarov O. Neurogenesis and inflammation after ischemic stroke: what is known and where we go from here. J Cereb Blood Flow Metab. 2014;34:1573–84.10.1038/jcbfm.2014.130Search in Google Scholar PubMed PubMed Central

[23] Yu W, Gao D, Jin W, Liu S, Qi S. Propofol prevents oxidative stress by decreasing the ischemic accumulation of succinate in focalcerebral ischemia-reperfusion injury. Neurochem Res. 2018;43:420–9.10.1007/s11064-017-2437-zSearch in Google Scholar PubMed

[24] Rabinstein AA. Update on treatment of acute ischemic stroke. Contin (Minneap Minn). 2020;26:268–86.10.1212/CON.0000000000000840Search in Google Scholar PubMed

[25] Warach SJ, Dula AN, Milling TJ Jr. Tenecteplase thrombolysis for acute ischemic stroke. Stroke. 2020;51:3440–51.10.1161/STROKEAHA.120.029749Search in Google Scholar PubMed PubMed Central

[26] Paul S, Candelario-Jalil E. Emerging neuroprotective strategies for the treatment of ischemic stroke: An overview of clinical and preclinical studies. Exp Neurol. 2021;335:113518.10.1016/j.expneurol.2020.113518Search in Google Scholar PubMed PubMed Central

[27] Shan W, Chen W, Zhao X, Pei A, Chen M, Yu Y, et al. Long noncoding RNA TUG1 contributes to cerebral ischaemia/reperfusion injury by sponging mir-145 to up-regulate AQP4 expression. J Cell Mol Med. 2020;24:250–9.10.1111/jcmm.14712Search in Google Scholar PubMed PubMed Central

[28] Wen Y, Yu Y, Fu X. LncRNA Gm4419 contributes to OGD/R injury of cerebral microglial cells via IκB phosphorylation and NF-κB activation. Biochem Biophys Res Commun. 2017;487:923–9.10.1016/j.bbrc.2017.05.005Search in Google Scholar PubMed

[29] Hu C, Li C, Ma Q, Wang R, He Y, Wang H, et al. Inhibition of long noncoding RNA SNHG15 ameliorates hypoxia/ischemia-induced neuronal damage by regulating miR-302a-3p/STAT1/NF-κB axis. Yonsei Med J. 2021;62:325–37.10.3349/ymj.2021.62.4.325Search in Google Scholar PubMed PubMed Central

[30] Xiao Z, Qiu Y, Lin Y, Medina R, Zhuang S, Rosenblum JS, et al. Blocking lncRNA H19-miR-19a-Id2 axis attenuates hypoxia/ischemia induced neuronal injury. Aging (Albany NY). 2019;11(11):3600.10.18632/aging.101999Search in Google Scholar PubMed PubMed Central

[31] Cui L, Nai M, Zhang K, Li L, Li R. LncRNA WT1-AS inhibits the aggressiveness of cervical cancer cell via regulating p53 expression via sponging miR-330-5p. Cancer Manag Res. 2019;11:651–67.10.2147/CMAR.S176525Search in Google Scholar PubMed PubMed Central

[32] Li F, Luo P, Ouyang Q, Zhong XM. LncRNA WT1-AS downregulates survivin by upregulating miR-203 in papillary thyroid carcinoma. Cancer Manag Res. 2020;12:443–9.10.2147/CMAR.S232294Search in Google Scholar PubMed PubMed Central

[33] Zhang Y, Na R, Wang X. LncRNA WT1-AS up-regulates p53 to inhibit the proliferation of cervical squamous carcinoma cells. BMC Cancer. 2019;19:1052.10.1186/s12885-019-6264-2Search in Google Scholar PubMed PubMed Central

[34] Du C, Zhang J, Wang Y, Zhang Y, Zhang J, Zhang L, Li J. The long non-coding RNA LINC01705 regulates the development of breast cancer by sponging miR-186-5p to mediate TPR expression as a competitive endogenous RNA. Front Genet. 2020;11:799.10.3389/fgene.2020.00779Search in Google Scholar PubMed PubMed Central

[35] Zhu K, Wang L, Zhang X, Sun H, Chen T, Sun C, et al. LncRNA HCP5 promotes neuroblastoma proliferation by regulating miR-186-5p/MAP3K2 signal axis. J Pediatr Surg. 2021;56:778–87.10.1016/j.jpedsurg.2020.10.011Search in Google Scholar PubMed

[36] Zhang Z, Zhang W, Mao J, Xu Z, Fan M. miR-186-5p functions as a tumor suppressor in human osteosarcoma by targeting FOXK1. Cell Physiol Biochem. 2019;52:553–64.10.33594/000000039Search in Google Scholar PubMed

[37] Jost PJ, Vucic D. Regulation of cell death and immunity by XIAP. Cold Spring Harb Perspect Biol. 2020;12:a036426.10.1101/cshperspect.a036426Search in Google Scholar PubMed PubMed Central

[38] Tu H, Costa M. XIAP’s profile in human cancer. Biomolecules. 2020;10:1493.10.3390/biom10111493Search in Google Scholar PubMed PubMed Central

[39] Huang L, Liu Z, Hu J, Luo Z, Zhang C, Wang L, et al. MiR-377-3p suppresses colorectal cancer through negative regulation on Wnt/beta-catenin signaling by targeting XIAP and ZEB2. Pharmacol Res. 2020;156:104774.10.1016/j.phrs.2020.104774Search in Google Scholar PubMed

[40] Deng W, Fan C, Zhao Y, Mao Y, Li J, Zhang Y, et al. MicroRNA-130a regulates neurological deficit and angiogenesis in rats with ischaemic stroke by targeting XIAP. J Cell Mol Med. 2020;24:10987–1000.10.1111/jcmm.15732Search in Google Scholar PubMed PubMed Central

Received: 2022-03-29
Revised: 2022-06-27
Accepted: 2022-06-30
Published Online: 2022-07-25

© 2022 Jianquan You et al., published by De Gruyter

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

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  139. Ultrasound-guided lumbar plexus block versus transversus abdominis plane block for analgesia in children with hip dislocation: A double-blind, randomized trial
  140. Relationship of plasma MBP and 8-oxo-dG with brain damage in preterm
  141. Identification of a novel necroptosis-associated miRNA signature for predicting the prognosis in head and neck squamous cell carcinoma
  142. Delayed femoral vein ligation reduces operative time and blood loss during hip disarticulation in patients with extremity tumors
  143. The expression of ASAP3 and NOTCH3 and the clinicopathological characteristics of adult glioma patients
  144. Longitudinal analysis of factors related to Helicobacter pylori infection in Chinese adults
  145. HOXA10 enhances cell proliferation and suppresses apoptosis in esophageal cancer via activating p38/ERK signaling pathway
  146. Meta-analysis of early-life antibiotic use and allergic rhinitis
  147. Marital status and its correlation with age, race, and gender in prognosis of tonsil squamous cell carcinomas
  148. HPV16 E6E7 up-regulates KIF2A expression by activating JNK/c-Jun signal, is beneficial to migration and invasion of cervical cancer cells
  149. Amino acid profiles in the tissue and serum of patients with liver cancer
  150. Pain in critically ill COVID-19 patients: An Italian retrospective study
  151. Immunohistochemical distribution of Bcl-2 and p53 apoptotic markers in acetamiprid-induced nephrotoxicity
  152. Estradiol pretreatment in GnRH antagonist protocol for IVF/ICSI treatment
  153. Long non-coding RNAs LINC00689 inhibits the apoptosis of human nucleus pulposus cells via miR-3127-5p/ATG7 axis-mediated autophagy
  154. The relationship between oxygen therapy, drug therapy, and COVID-19 mortality
  155. Monitoring hypertensive disorders in pregnancy to prevent preeclampsia in pregnant women of advanced maternal age: Trial mimicking with retrospective data
  156. SETD1A promotes the proliferation and glycolysis of nasopharyngeal carcinoma cells by activating the PI3K/Akt pathway
  157. The role of Shunaoxin pills in the treatment of chronic cerebral hypoperfusion and its main pharmacodynamic components
  158. TET3 governs malignant behaviors and unfavorable prognosis of esophageal squamous cell carcinoma by activating the PI3K/AKT/GSK3β/β-catenin pathway
  159. Associations between morphokinetic parameters of temporary-arrest embryos and the clinical prognosis in FET cycles
  160. Long noncoding RNA WT1-AS regulates trophoblast proliferation, migration, and invasion via the microRNA-186-5p/CADM2 axis
  161. The incidence of bronchiectasis in chronic obstructive pulmonary disease
  162. Integrated bioinformatics analysis shows integrin alpha 3 is a prognostic biomarker for pancreatic cancer
  163. Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway
  164. Comparison of hospitalized patients with severe pneumonia caused by COVID-19 and influenza A (H7N9 and H1N1): A retrospective study from a designated hospital
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  166. Pathological characteristics of liver injury induced by N,N-dimethylformamide: From humans to animal models
  167. lncRNA ELFN1-AS1 enhances the progression of colon cancer by targeting miR-4270 to upregulate AURKB
  168. DARS-AS1 modulates cell proliferation and migration of gastric cancer cells by regulating miR-330-3p/NAT10 axis
  169. Dezocine inhibits cell proliferation, migration, and invasion by targeting CRABP2 in ovarian cancer
  170. MGST1 alleviates the oxidative stress of trophoblast cells induced by hypoxia/reoxygenation and promotes cell proliferation, migration, and invasion by activating the PI3K/AKT/mTOR pathway
  171. Bifidobacterium lactis Probio-M8 ameliorated the symptoms of type 2 diabetes mellitus mice by changing ileum FXR-CYP7A1
  172. circRNA DENND1B inhibits tumorigenicity of clear cell renal cell carcinoma via miR-122-5p/TIMP2 axis
  173. EphA3 targeted by miR-3666 contributes to melanoma malignancy via activating ERK1/2 and p38 MAPK pathways
  174. Pacemakers and methylprednisolone pulse therapy in immune-related myocarditis concomitant with complete heart block
  175. miRNA-130a-3p targets sphingosine-1-phosphate receptor 1 to activate the microglial and astrocytes and to promote neural injury under the high glucose condition
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  178. Hearing loss and brain disorders: A review of multiple pathologies
  179. The rationale for using low-molecular weight heparin in the therapy of symptomatic COVID-19 patients
  180. Amyotrophic lateral sclerosis and delayed onset muscle soreness in light of the impaired blink and stretch reflexes – watch out for Piezo2
  181. Interleukin-35 in autoimmune dermatoses: Current concepts
  182. Recent discoveries in microbiota dysbiosis, cholangiocytic factors, and models for studying the pathogenesis of primary sclerosing cholangitis
  183. Advantages of ketamine in pediatric anesthesia
  184. Congenital adrenal hyperplasia. Role of dentist in early diagnosis
  185. Migraine management: Non-pharmacological points for patients and health care professionals
  186. Atherogenic index of plasma and coronary artery disease: A systematic review
  187. Physiological and modulatory role of thioredoxins in the cellular function
  188. Case Reports
  189. Intrauterine Bakri balloon tamponade plus cervical cerclage for the prevention and treatment of postpartum haemorrhage in late pregnancy complicated with acute aortic dissection: Case series
  190. A case of successful pembrolizumab monotherapy in a patient with advanced lung adenocarcinoma: Use of multiple biomarkers in combination for clinical practice
  191. Unusual neurological manifestations of bilateral medial medullary infarction: A case report
  192. Atypical symptoms of malignant hyperthermia: A rare causative mutation in the RYR1 gene
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  194. A rare case of endometrial polyp complicated with uterine inversion: A case report and clinical management
  195. Spontaneous rupturing of splenic artery aneurysm: Another reason for fatal syncope and shock (Case report and literature review)
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  197. Concurrent aspergillosis and cystic pulmonary metastases in a patient with tongue squamous cell carcinoma
  198. Paraganglioma-induced inverted takotsubo-like cardiomyopathy leading to cardiogenic shock successfully treated with extracorporeal membrane oxygenation
  199. Lineage switch from lymphoma to myeloid neoplasms: First case series from a single institution
  200. Trismus during tracheal extubation as a complication of general anaesthesia – A case report
  201. Simultaneous treatment of a pubovesical fistula and lymph node metastasis secondary to multimodal treatment for prostate cancer: Case report and review of the literature
  202. Two case reports of skin vasculitis following the COVID-19 immunization
  203. Ureteroiliac fistula after oncological surgery: Case report and review of the literature
  204. Synchronous triple primary malignant tumours in the bladder, prostate, and lung harbouring TP53 and MEK1 mutations accompanied with severe cardiovascular diseases: A case report
  205. Huge mucinous cystic neoplasms with adhesion to the left colon: A case report and literature review
  206. Commentary
  207. Commentary on “Clinicopathological features of programmed cell death-ligand 1 expression in patients with oral squamous cell carcinoma”
  208. Rapid Communication
  209. COVID-19 fear, post-traumatic stress, growth, and the role of resilience
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  211. Erratum to “Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway”
  212. Erratum to “Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study”
  213. Erratum to “lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2”
  214. Retraction
  215. Expression and role of ABIN1 in sepsis: In vitro and in vivo studies
  216. Retraction to “miR-519d downregulates LEP expression to inhibit preeclampsia development”
  217. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part II
  218. Usefulness of close surveillance for rectal cancer patients after neoadjuvant chemoradiotherapy
https://doi.org/10.1515/med-2022-0528
Keywords for this article
wilms tumor 1 antisense RNA; cerebral ischemic stroke; microRNA-186-5p; X-linked inhibitor of apoptosis; oxygen glucose deprivation
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BY 4.0

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  151. Immunohistochemical distribution of Bcl-2 and p53 apoptotic markers in acetamiprid-induced nephrotoxicity
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  153. Long non-coding RNAs LINC00689 inhibits the apoptosis of human nucleus pulposus cells via miR-3127-5p/ATG7 axis-mediated autophagy
  154. The relationship between oxygen therapy, drug therapy, and COVID-19 mortality
  155. Monitoring hypertensive disorders in pregnancy to prevent preeclampsia in pregnant women of advanced maternal age: Trial mimicking with retrospective data
  156. SETD1A promotes the proliferation and glycolysis of nasopharyngeal carcinoma cells by activating the PI3K/Akt pathway
  157. The role of Shunaoxin pills in the treatment of chronic cerebral hypoperfusion and its main pharmacodynamic components
  158. TET3 governs malignant behaviors and unfavorable prognosis of esophageal squamous cell carcinoma by activating the PI3K/AKT/GSK3β/β-catenin pathway
  159. Associations between morphokinetic parameters of temporary-arrest embryos and the clinical prognosis in FET cycles
  160. Long noncoding RNA WT1-AS regulates trophoblast proliferation, migration, and invasion via the microRNA-186-5p/CADM2 axis
  161. The incidence of bronchiectasis in chronic obstructive pulmonary disease
  162. Integrated bioinformatics analysis shows integrin alpha 3 is a prognostic biomarker for pancreatic cancer
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  164. Comparison of hospitalized patients with severe pneumonia caused by COVID-19 and influenza A (H7N9 and H1N1): A retrospective study from a designated hospital
  165. lncRNA ZFAS1 promotes intervertebral disc degeneration by upregulating AAK1
  166. Pathological characteristics of liver injury induced by N,N-dimethylformamide: From humans to animal models
  167. lncRNA ELFN1-AS1 enhances the progression of colon cancer by targeting miR-4270 to upregulate AURKB
  168. DARS-AS1 modulates cell proliferation and migration of gastric cancer cells by regulating miR-330-3p/NAT10 axis
  169. Dezocine inhibits cell proliferation, migration, and invasion by targeting CRABP2 in ovarian cancer
  170. MGST1 alleviates the oxidative stress of trophoblast cells induced by hypoxia/reoxygenation and promotes cell proliferation, migration, and invasion by activating the PI3K/AKT/mTOR pathway
  171. Bifidobacterium lactis Probio-M8 ameliorated the symptoms of type 2 diabetes mellitus mice by changing ileum FXR-CYP7A1
  172. circRNA DENND1B inhibits tumorigenicity of clear cell renal cell carcinoma via miR-122-5p/TIMP2 axis
  173. EphA3 targeted by miR-3666 contributes to melanoma malignancy via activating ERK1/2 and p38 MAPK pathways
  174. Pacemakers and methylprednisolone pulse therapy in immune-related myocarditis concomitant with complete heart block
  175. miRNA-130a-3p targets sphingosine-1-phosphate receptor 1 to activate the microglial and astrocytes and to promote neural injury under the high glucose condition
  176. Review Articles
  177. Current management of cancer pain in Italy: Expert opinion paper
  178. Hearing loss and brain disorders: A review of multiple pathologies
  179. The rationale for using low-molecular weight heparin in the therapy of symptomatic COVID-19 patients
  180. Amyotrophic lateral sclerosis and delayed onset muscle soreness in light of the impaired blink and stretch reflexes – watch out for Piezo2
  181. Interleukin-35 in autoimmune dermatoses: Current concepts
  182. Recent discoveries in microbiota dysbiosis, cholangiocytic factors, and models for studying the pathogenesis of primary sclerosing cholangitis
  183. Advantages of ketamine in pediatric anesthesia
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  186. Atherogenic index of plasma and coronary artery disease: A systematic review
  187. Physiological and modulatory role of thioredoxins in the cellular function
  188. Case Reports
  189. Intrauterine Bakri balloon tamponade plus cervical cerclage for the prevention and treatment of postpartum haemorrhage in late pregnancy complicated with acute aortic dissection: Case series
  190. A case of successful pembrolizumab monotherapy in a patient with advanced lung adenocarcinoma: Use of multiple biomarkers in combination for clinical practice
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  192. Atypical symptoms of malignant hyperthermia: A rare causative mutation in the RYR1 gene
  193. A case report of dermatomyositis with the missed diagnosis of non-small cell lung cancer and concurrence of pulmonary tuberculosis
  194. A rare case of endometrial polyp complicated with uterine inversion: A case report and clinical management
  195. Spontaneous rupturing of splenic artery aneurysm: Another reason for fatal syncope and shock (Case report and literature review)
  196. Fungal infection mimicking COVID-19 infection – A case report
  197. Concurrent aspergillosis and cystic pulmonary metastases in a patient with tongue squamous cell carcinoma
  198. Paraganglioma-induced inverted takotsubo-like cardiomyopathy leading to cardiogenic shock successfully treated with extracorporeal membrane oxygenation
  199. Lineage switch from lymphoma to myeloid neoplasms: First case series from a single institution
  200. Trismus during tracheal extubation as a complication of general anaesthesia – A case report
  201. Simultaneous treatment of a pubovesical fistula and lymph node metastasis secondary to multimodal treatment for prostate cancer: Case report and review of the literature
  202. Two case reports of skin vasculitis following the COVID-19 immunization
  203. Ureteroiliac fistula after oncological surgery: Case report and review of the literature
  204. Synchronous triple primary malignant tumours in the bladder, prostate, and lung harbouring TP53 and MEK1 mutations accompanied with severe cardiovascular diseases: A case report
  205. Huge mucinous cystic neoplasms with adhesion to the left colon: A case report and literature review
  206. Commentary
  207. Commentary on “Clinicopathological features of programmed cell death-ligand 1 expression in patients with oral squamous cell carcinoma”
  208. Rapid Communication
  209. COVID-19 fear, post-traumatic stress, growth, and the role of resilience
  210. Erratum
  211. Erratum to “Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway”
  212. Erratum to “Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study”
  213. Erratum to “lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2”
  214. Retraction
  215. Expression and role of ABIN1 in sepsis: In vitro and in vivo studies
  216. Retraction to “miR-519d downregulates LEP expression to inhibit preeclampsia development”
  217. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part II
  218. Usefulness of close surveillance for rectal cancer patients after neoadjuvant chemoradiotherapy
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