Startseite Artemisinin protects against cerebral ischemia and reperfusion injury via inhibiting the NF-κB pathway
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Artemisinin protects against cerebral ischemia and reperfusion injury via inhibiting the NF-κB pathway

  • Hui Ji , Haifeng Jin , Guangwei Li , Li Jin , Xiaoxu Ren , Ying Lv und Yuchun Wang EMAIL logo
Veröffentlicht/Copyright: 11. Mai 2022
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Open Medicine
Aus der Zeitschrift Open Medicine Band 17 Heft 1

Abstract

This study investigated whether artemisinin (ART) exerts a neuroprotective effect against cerebral ischemia/reperfusion (I/R) injury. Hypoxia-glucose deprivation and reoxygenation (OGD/R) of SH-SY5Y cells were used as the I/R injury model in vitro. Cell viability was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and lactate dehydrogenase (LDH) release was measured. Cell apoptosis and apoptosis-associated protein expression were determined via flow cytometry and western blotting, respectively. The levels of glutathione peroxidase, superoxide dismutase, catalase, and malondialdehyde were determined. The secretion of tumor necrosis factor-α and interleukin-1β was measured using ELISA. The activation of the nuclear factor kappa B (NF-κB) pathway was also determined. The indicated ART concentrations (0, 25, 50, 75, and 100 μM) had no significant effect on SH-SY5Y cell viability and LDH activity. ART promoted cell viability, reduced cell apoptosis, repressed cellular inflammation, and inhibited cellular oxidative stress and NF-κB signaling pathway in OGD/R-induced SH-SY5Y cells. In addition, all the protective effects of ART on OGD/R-induced SH-SY5Y cell injury were significantly reversed by an NF-κB agonist. In conclusion, ART protects neurons from OGD/R-induced damage in vitro by inhibiting the NF-κB signaling pathway. These results suggest that ART may be a potential agent for the treatment of cerebral I/R injury.

Keywords: cerebral infaction; artemisinin; NF-κB; inflammation; apoptosis; oxidative stress

1 Introduction

Artemisia annua L. has been used as a medicinal plant in the treatment of numerous diseases for centuries [1]. Artemisinin (ART) is a sesquiterpene trioxane lactone compound extracted from Artemisia annua L., which contains a peroxide group. ART can kill malaria parasites by interfering with mitochondrial function, particularly in the treatment of drug-resistant and recurrent malaria, and has been used worldwide [2,3]. In addition to anti-malarial effect, ART has immunosuppressive [4], anti-schistosomiasis [5], anti-virus [6], and anti-tumor effects [7,8,9,10]. In multiple cancers, combined treatment with ART drugs has achieved improved therapeutic effects [11], and no evident cytotoxicity of ART to normal cells was observed in more than 4,000 cases, which makes it a potential drug for treating numerous diseases [12]. ART has been reported to be a potential drug for treating Alzheimer’s disease by protecting against amyloid beta damage [13]. Studies have revealed that ART is involved in regulating the expression of various nuclear factor kappa B (NF-κB) reporter genes [14,15]. ART inhibits endometrial cancer cell proliferation by disrupting the interaction between NF-κB and the CDK4 promoter and transcriptionally downregulates CDK4 expression [9]. Gu et al. indicated that ART could inhibit the NF-κB pathway by blocking IKBα phosphorylation, which results in reduced myocardial remodeling [16]. Wang et al. found that ART pretreatment effectively protected against myocardial ischemia/reperfusion (I/R) injury by inhibiting the activation of the NLRP3 inflammasome [17]. Besides, ART attenuated the oxidative damage of SH-SY5Y cells and hippocampal neurons induced by hydrogen peroxide (H2O2) by activating the AMPK signaling pathway, suggesting a neuroprotective effect of ART [18]. However, whether ART has a neuroprotective effect on cerebral I/R injury remains unclear.

Ischemic stroke remains the primary cause of disability and death worldwide [19]. The pathogenesis of cerebral ischemia is insufficient oxygen and glucose transport caused by tissue ischemia, which leads to irreversible neuronal damage or death [20]. Recanalization therapy, which supplements nutrients and oxygen and removes toxic metabolites, is currently the main treatment method of ischemic stroke [21,22]. However, the recovery of blood flow leads to occasional side effects [23]. In the process of cerebral I/R, various procedures related to nerve cell death are activated, such as necrosis, apoptosis, or autophagy [24,25], and apoptosis has been reported as a key event in cerebral ischemic brain injury [26]. Astragaloside IV protects against cerebral I/R injury by suppressing apoptosis [27]. The inhibition of oxidative stress and inflammation has been widely reported to alleviate cerebral I/R injury [28,29].

In this study, we hypothesized that ART plays a protective role in cerebral ischemia and reperfusion injury by inhibiting NF-κB pathway. Therefore, this study employed the SH-SY5Y cell OGD/R model to explore the effect of ART on cerebral I/R injury and analyze its potential molecular mechanism.

2 Material and methods

2.1 Cell culture and reagent

The human neuroblastoma cell line SH-SY5Y was obtained from the American Type Culture Collection (Rockville, MD, USA) and was cultured in Dulbecco’s Modified Eagle Medium (DMEM; Sigma-Aldrich, St. Louis, MO, USA) containing 10% (v/v) fetal bovine serum (Thermo Fisher Scientific, Waltham, MA, USA), 2% l-glutamine (v/v), 100 μg/mL streptomycin, and 100 U/mL penicillin (Gibco, Amarillo, TX, USA). The cells were cultured in a moist environment at 37°C and 5% CO2. ART was purchased from Merck (Darmstadt, Germany; cat. no. 361593).

2.2 Cell treatment

OGD/R-exposed model [30]: SH-SY5Y cells were seeded into 96-well plates, and then OGD experiments were performed when cell density reached approximately 80% confluence. SH-SY5Y cell culture medium was replaced with oxygen-glucose-free DMEM and incubated in an anaerobic gas mixture (1% O2, 5% CO2, and 94% N2) at 37°C. After 3 h, the cell medium and culture conditions were restored to normal, and the culture was continued for 24 h.

ART interferes with the OGD/R-exposed model: SH-SY5Y cells were pre-treated with the indicated concentration of ART (0, 25, 50, and 100 μM) [31] for 2 h and then exposed to OGD/R.

2.3 Cell proliferation ability

The proliferation ability of SH-SY5Y cells was determined using the MTT assay. The processed cells were seeded into 96-well plates at a density of 6 × 103 cells per well and cultured in 5% CO2 at 37°C for 48 h. Subsequently, 20 μL of MTT solution (5 mg/mL) was added to each well and cultured for 4 h. Then, the supernatant was carefully removed, and 150 μL of dimethyl sulfoxide was added to each well at room temperature to completely dissolve the formazan crystals. The absorbance of each well was measured at 570 nm using an enzyme-linked immunosorbent analyzer (Victor X3, PerkinElmer, Shelton, CT, USA).

2.4 LDH release cell death assay

An LDH assay kit (Promega, Madison, WI, USA) was used to detect the release of LDH from cells. Briefly, 2 × 106 processed cells were collected, washed with pre-cold phosphate-buffered saline (PBS), resuspended in 200 μL of cold assay buffer, and centrifuged at 4°C at 8,000 rpm for 15 min, and the supernatant was preserved. Next 10 μL of supernatant and 100 μL of reaction reagent were mixed and incubated for 30 min at room temperature. The absorbance of each well was determined using an enzyme-linked immunosorbent analyzer (Victor X3, PerkinElmer) at 490 nm.

2.5 Flow cytometry analysis of cell apoptosis

SH-SY5Y cell apoptosis was detected using the Annexin V-FITC Assay Kit (BioVision, Palo Alto, CA, USA) according to the manufacturer’s instructions. Briefly, the processed SH-SY5Y cells were collected and washed with pre-cold PBS. SH-SY5Y cells were resuspended in 195 μL of binding buffer, and then stained with 5 μL of Annexin V-FITC (10 μg/mL) and 10 μL of propidium iodide for 15 min in the dark at 25°C. Finally, the cells were analyzed via flow cytometry (FCM; Beckman, Brea, CA, USA). Data were analyzed using FlowJo version 7.6.1 (FlowJo LLC).

2.6 Caspase-3 activity detection

Caspase-3 activity was detected using a Caspase-3 Activity Assay Kit (Abcam, Cambridge, UK; cat no. ab252897). The detection principle is that the synthetic substrate DEVD-AFC will emit a strong and stable fluorescence signal (Ex/Em = 400/505 nm) after being cleaved by caspase-3, and caspase-3 enzyme activity can be reflected according to the fluorescence intensity. The processed cells were collected and lysed with RIPA lysis buffer (Merck; cat no. R0278), and the supernatant was collected. The supernatant was then incubated with the final reaction solution, which comprised 40 μL of assay buffer, 50 μL of supernatant, and 10 μL of caspase-3 substrate DEVD-AFC (2 mM) at 37°C for 2 h. Finally, the absorbance of each sample was measured at 400 nm using an enzyme-linked immunosorbent analyzer (Victor X3, PerkinElmer,).

2.7 Western blot analysis

SH-SY5Y cells were washed with PBS and lysed with RIPA lysis buffer (Merck; cat. no. R0278). The supernatant with 20 μg total protein content was separated via polyacrylamide gel electrophoresis and electro-transferred to a nitrocellulose membrane (Millipore, Burlington, MA, USA). The membranes were incubated with specific primary antibodies (1:200 for anti-cleaved caspase-3, cat. no. ab2302; 1:1,000 for anti-p65, cat. no. ab32536; 1:500 for anti-p-p65, cat. no. ab31624; 1:1,000 for anti-GAPDH, cat. no. ab22555; all from Abcam), and secondary antibodies (1:5,000, cat. no. ab97080; Abcam). The enhanced chemiluminescence method (Cytiva, Marlborough, MA, USA) was used to detect immune-response bands. The band intensity was quantified by ImageJ version 1.8.0 (National Institutes of Health).

2.8 Determination of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities

Superoxide dismutase activity assay kit (Solarbio, Beijing, China; cat. no. BC0170) was used to determine the activity of SOD, catalase detection kit (Solarbio; cat. no. BC0200) was used to determine the activity of CAT, and glutathione peroxidase activity assay kit (Solarbio; cat. no. BC1190) was used to determine GSH-Px activity. In the SOD determination system, xanthine and xanthine oxidase reaction can produce O2−, which reduces nitroblue tetrazolium to formazan, and SOD reduces formazan formation by reacting with O2−. Formazan can be dissolved in organic solvents, and absorbance at 560 nm indicates the SOD activity. CAT can decompose H2O2, which has a characteristic absorption peak at 240 nm. The absorbance of the reaction solution at 240 nm decreased with the reaction time, and the CAT activity was calculated according to the change rate of the absorbance. GSH-Px catalyzes the oxidation of GSH by H2O2 to produce oxidized glutathione. GSH reacts with 5,5’-dithiobis-(2-nitrobenzoic acid) to generate a compound with a characteristic absorption at 412 nm. Therefore, the absorbance of the reaction solution at 412 nm was used to measure the activity of GSH-Px.

2.9 Malondialdehyde (MDA) detection

A Malondialdehyde Assay Kit (Abcam; cat. no. ab118970) was used to detect MDA. MDA in the sample reacts with thiobarbituric acid (TBA) to form an MDA–TBA complex. The MDA–TBA complex had a specific absorption at 532 nm. Therefore, MDA was quantified according to the absorbance of the reaction solution at 532 nm.

2.10 Enzyme-linked immunosorbent assay (ELISA)

The secretion of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 in SH-SY5Y cells was detected using an ELISA kit (cat. no. ab181421 for TNF-α; cat. no. ab214025 for IL-1β; cat. no. ab178013 for IL-6; all from Abcam). The cell culture supernatant was collected by centrifugation at 2,000 rpm for 15 min. Afterward, 50 μL of cell culture supernatant and 50 μL of antibody cocktail were added to the 96-well plate included in the kit, incubated in a shaker at 400 rpm for 90 min at room temperature, and then washed three times with 350 μL of wash buffer. Subsequently, 100 μL TMB buffer was added to the system and incubated in a shaker at 400 rpm for 10 min. After incubation, the reaction was stopped with 100 μL of stopping solution. Absorbance was measured at 450 nm wavelength.

2.11 Reverse transcription quantitative-PCR (RT-qPCR)

The p65 transcription level was determined via RT-qPCR. Total RNA was extracted using the MiniBEST Universal RNA Extraction Kit (TaKaRa, cat. no. 9767), according to the manufacturer’s instructions. A One Step PrimeScript III RT-qPCR kit (TaKaRa, cat. no. RR600A) was used for the RT-qPCR analysis. The reaction solution was prepared according to the manufacturer’s instructions and applied in a Thermal Cycler Dice Real Time System. GAPDH was used as an internal control. The PCR primer sequence of p65 and GAPDH was as follows: p65 forward, 5′-CGCGGATCCGCCACCATGGACGAACTG-3′ and reverse, 5′-CCGCTCGAGTTAGGAGCTGATCTG-3′; GAPDH forward, 5′-CTTTGGTATCGTGGAAGGACTC-3′ and reverse, 5′-GTAGAGGCAGGGATGATGTTCT-3′. The relative expression of p65 was calculated using the 2−ΔΔCq method.

2.12 Statistical analysis

All experiments were performed at least three times, and the data are presented as mean value ± SD. GraphPad Prism software (GraphPad Software, Inc., San Diego, CA, USA) was used for the statistical analysis. The statistical significance of the differences between the two groups was tested using Student’s t-test. Multiple comparisons were performed using the one-way analysis of variance (ANOVA) followed by Tukey’s post hoc test. Differences were considered statistically significant at p < 0.05.

3 Results

3.1 Cytotoxicity of ART to SH-SY5Y cells

SH-SY5Y cells were treated with ART at different concentrations (25, 50, 75, and 100 μM) for 24 h. Different ART concentrations had no significant effect on SH-SY5Y cell viability and LDH viability (Figure 1a and b), suggesting that ART has no significant cytotoxic effect on SH-SY5Y cells. Therefore, 0, 25, 50, and 100 μM ART were used for subsequent experiments.

Figure 1 Cytotoxic effect of ART on SH-SY5Y cells. SH-SY5Y cells were treated with ART at different concentrations (0, 25, 50,75, and 100 μM) for 24 h. Different ART concentrations had no significant effect on SH-SY5Y: (a) cell viability and (b) lactate dehydrogenase activity.
Figure 1

Cytotoxic effect of ART on SH-SY5Y cells. SH-SY5Y cells were treated with ART at different concentrations (0, 25, 50,75, and 100 μM) for 24 h. Different ART concentrations had no significant effect on SH-SY5Y: (a) cell viability and (b) lactate dehydrogenase activity.

3.1.1 ART protects SH-SY5Y cells from OGD/R-induced injuries

SH-SY5Y cells were pre-treated with the indicated concentrations of ART (25, 50, and 100 μM) for 2 h and then exposed to OGD/R. The results of the MTT and LDH release cell death assays indicated that OGD/R-exposure significantly repressed the viability of SH-SY5Y cells (Figure 2a) and enhanced LDH activity (Figure 2b). FCM results showed that OGD/R treatment markedly increased SH-SY5Y cell apoptosis (Figure 2c and d), and caspase-3 activity in OGD/R-injured SH-SY5Y cells was significantly increased (Figure 2e). Western blot analysis revealed that the cleaved caspase-3 protein expression and ratio of cleaved caspase-3/GAPDH were apparently increased in OGD/R-injured SH-SY5Y cells (Figure 2f and g). All the effects could be reversed by ART treatment. This reversal was dependent on ART concentration, and the reversal effect was positively correlated with ART concentration. These results indicated that ART increased the viability and reduced the apoptosis of OGD/R-exposed SH-SY5Y cells in a dose-dependent manner.

Figure 2 ART increases the viability and reduces apoptosis of hypoxia-glucose deprivation and reoxygenation (OGD/R)-exposed SH-SY5Y cells in a dose-dependent manner. SH-SY5Y cells were pre-treated with the indicated concentrations of ART (0, 25, 50, and 100 μM) for 2 h and then exposed to OGD/R. (a) Viability of SH-SY5Y cells was determined using an MTT assay. (b) LDH activity was measured using an LDH assay kit. (c and d) Cell apoptosis was detected via flow cytometry. (e) Caspase-3 activity was measured using a caspase-3 activity detection kit. (f) Cleaved caspase-3 protein detection was detected using western blotting. (g) Cleaved caspase-3/GAPDH ratio. **p < 0.01 vs Control; #,## p < 0.05, 0.01 vs OGD/R.
Figure 2

ART increases the viability and reduces apoptosis of hypoxia-glucose deprivation and reoxygenation (OGD/R)-exposed SH-SY5Y cells in a dose-dependent manner. SH-SY5Y cells were pre-treated with the indicated concentrations of ART (0, 25, 50, and 100 μM) for 2 h and then exposed to OGD/R. (a) Viability of SH-SY5Y cells was determined using an MTT assay. (b) LDH activity was measured using an LDH assay kit. (c and d) Cell apoptosis was detected via flow cytometry. (e) Caspase-3 activity was measured using a caspase-3 activity detection kit. (f) Cleaved caspase-3 protein detection was detected using western blotting. (g) Cleaved caspase-3/GAPDH ratio. **p < 0.01 vs Control; #,## p < 0.05, 0.01 vs OGD/R.

The secretion of TNF-α, IL-1β, and IL-6 in SH-SY5Y cells was detected using ELISA. The results indicated that the secretion of TNF-α, IL-1β, and IL-6 was increased in OGD/R-exposed SH-SY5Y cells (Figure 3a–c), and ART decreased the secretion of TNF-α, IL-1β, and IL-6 in a dose-dependent manner in OGD/R-exposed SH-SY5Y cells (Figure 3a–c).

Figure 3 Effects of ART on cell inflammation in hypoxia-glucose deprivation and reoxygenation (OGD/R)-induced SH-SY5Y cells. SH-SY5Y cells were pre-treated with the indicated concentrations of ART (0, 25, 50, and 100 μM) for 2 h and then exposed to OGD/R. (a–c) ELISA was used to determine the secretion of TNF-α, IL-1β, and IL-6 in the supernatant of SH-SY5Y cells. **p < 0.01 vs Control; #,## p < 0.05, 0.01 vs OGD/R.
Figure 3

Effects of ART on cell inflammation in hypoxia-glucose deprivation and reoxygenation (OGD/R)-induced SH-SY5Y cells. SH-SY5Y cells were pre-treated with the indicated concentrations of ART (0, 25, 50, and 100 μM) for 2 h and then exposed to OGD/R. (a–c) ELISA was used to determine the secretion of TNF-α, IL-1β, and IL-6 in the supernatant of SH-SY5Y cells. **p < 0.01 vs Control; #,## p < 0.05, 0.01 vs OGD/R.

The activities of SOD, CAT, and GSH-Px in SH-SY5Y cells were significantly inhibited, and the level of malondialdehyde (MAD) was significantly increased by OGD/R exposure (Figure 4a–d). In OGD/R-exposed SH-SY5Y cells, ART treatment alleviated the inhibition of SOD, CAT, and GSH-Px activities and increased MAD levels in a dose-dependent manner (Figure 4a–d).

Figure 4 Effects of ART on the oxidative stress in OGD/R-induced SH-SY5Y cells. SH-SY5Y cells were pre-treated with the indicated concentrations of ART (0, 25, 50, and 100 μM) for 2 h and then exposed to OGD/R. Next the activities of SOD (a), CAT (b), and GSH-Px (c) and the level of MAD (d) were determined. **p < 0.01 vs Control; #,## p < 0.05, 0.01 vs OGD/R.
Figure 4

Effects of ART on the oxidative stress in OGD/R-induced SH-SY5Y cells. SH-SY5Y cells were pre-treated with the indicated concentrations of ART (0, 25, 50, and 100 μM) for 2 h and then exposed to OGD/R. Next the activities of SOD (a), CAT (b), and GSH-Px (c) and the level of MAD (d) were determined. **p < 0.01 vs Control; #,## p < 0.05, 0.01 vs OGD/R.

Western blotting was used to assess the expression of p65 and p-p65, and RT-qPCR was performed to analyze the transcription level of p65. The results indicated that p-p65 expression and the ratio of p-p65/p65 were notably increased, and ART treatment reduced p-p65 expression and the ratio of p-p65/p65 in OGD/R-exposed SH-SY5Y cells in a dose-dependent manner (Figure 5a and b). There was no significant change in p65 transcription levels among the groups (Figure 5c).

Figure 5 ART inhibits the activation of NF-κB signaling pathway in OGD/R-induced SH-SY5Y cells. SH-SY5Y cells were pre-treated with the indicated concentrations of ART (0, 25, 50, and 100 μM) for 2 h and then exposed to OGD/R. (a) Protein expressions of p-p65 and p65 were measured using western blotting. (b) p-p65/p65 ratio. (c) mRNA expression of p65 was determined via RT-qPCR. **p < 0.01 vs Control; #,## p < 0.05, 0.01 vs OGD/R.
Figure 5

ART inhibits the activation of NF-κB signaling pathway in OGD/R-induced SH-SY5Y cells. SH-SY5Y cells were pre-treated with the indicated concentrations of ART (0, 25, 50, and 100 μM) for 2 h and then exposed to OGD/R. (a) Protein expressions of p-p65 and p65 were measured using western blotting. (b) p-p65/p65 ratio. (c) mRNA expression of p65 was determined via RT-qPCR. **p < 0.01 vs Control; #,## p < 0.05, 0.01 vs OGD/R.

3.1.2 ART protects SH-SY5Y cells from OGD/R-induced injury by inhibiting the NF-κB signaling pathway

Findings indicated that OGD/R-exposed SH-SY5Y cell viability was significantly improved and LDH activity was reduced by treatment with ART or an NF-κB agonist (Figure 6a and b). The NF-κB agonist reversed the ART-induced increase in cell viability in OGD/R-exposed SH-SY5Y cells (Figure 6a and b). Apoptosis was distinctly decreased by treatment with ART or an NF-κB agonist, whereas apoptosis was distinctly increased by co-treatment with ART and an NF-κB agonist in OGD/R-exposed SH-SY5Y cells compared with that of ART treatment alone (Figure 6c and d). Caspase-3 activity in OGD/R-exposed SH-SY5Y cells was markedly inhibited by treatment with ART or an NF-κB agonist; however, co-treatment with ART and the NF-κB agonist markedly improved caspase-3 activity in OGD/R-exposed SH-SY5Y cells compared with that of ART treatment alone (Figure 6e). Cleaved caspase-3 protein expression and the ratio of cleaved caspase-3/GAPDH were significantly decreased by treatment with ART or an NF-κB agonist. Compared with that of the ART treatment group, cleaved caspase-3 expression and the ratio of cleaved caspase-3/GAPDH were significantly increased by co-treatment with ART and NF-κB agonist in OGD/R-exposed SH-SY5Y cells (Figure 6f and g).

Figure 6 NF-κB agonist reverses the effects of ART on the viability and apoptosis of SH-SY5Y cells triggered by OGD/R exposure. SH-SY5Y cells were pre-treated with 100 μM ART, an NF-κB antagonist, or 100 μM ART + NF-κB agonist for 2 h and then exposed to OGD/R. (a) SH-SY5Y cell viability was determined using an MTT assay. (b) LDH activity was measured using an LDH assay kit. (c and d) Cell apoptosis was detected via flow cytometry (e) Caspase-3 activity was measured using a caspase-3 activity detection kit. (f) Protein expression of cleaved caspase-3 was detected using western blotting. (g) Cleaved caspase-3/GAPDH ratio. **p < 0.01 vs OGD/R; ## p < 0.05, 0.01 vs OGD/R + ART.
Figure 6

NF-κB agonist reverses the effects of ART on the viability and apoptosis of SH-SY5Y cells triggered by OGD/R exposure. SH-SY5Y cells were pre-treated with 100 μM ART, an NF-κB antagonist, or 100 μM ART + NF-κB agonist for 2 h and then exposed to OGD/R. (a) SH-SY5Y cell viability was determined using an MTT assay. (b) LDH activity was measured using an LDH assay kit. (c and d) Cell apoptosis was detected via flow cytometry (e) Caspase-3 activity was measured using a caspase-3 activity detection kit. (f) Protein expression of cleaved caspase-3 was detected using western blotting. (g) Cleaved caspase-3/GAPDH ratio. **p < 0.01 vs OGD/R; ## p < 0.05, 0.01 vs OGD/R + ART.

The secretion of TNF-α, IL-1β, and IL-6 was evidently decreased in OGD/R-exposed SH-SY5Y cells by treatment with ART or an NF-κB agonist, and co-treatment with ART and the NF-κB agonist evidently increased the secretion of TNF-α, IL-1β, and IL-6 compared with that of ART treatment alone (Figure 7a–c). In OGD/R-exposed SH-SY5Y cells, the activities of SOD, CAT, and GSH-Px were markedly inhibited by treatment with ART or an NF-κB agonist, whereas the inhibitory effect was attenuated by co-treatment with ART and the NF-κB agonist (Figure 7d–f). ART or NF-κB agonist treatment significantly decreased the level of MAD in OGD/R-exposed SH-SY5Y cells; however, the level of MAD was significantly increased by co-treatment with ART or an NF-κB agonist (Figure 7g).

Figure 7 NF-κB agonist reverses the effects of ART on inflammation and oxidative stress of SH-SY5Y cells triggered by OGD/R exposure. SH-SY5Y cells were pre-treated with 100 μM ART, an NF-κB antagonist, or 100 μM ART + NF-κB agonist for 2 h and then exposed to OGD/R. (a–c) ELISA was used to determine the secretion of TNF-α, IL-1β, and IL-6 in the supernatant of SH-SY5Y cells. (d–g) Activities of SOD, CAT, and GSH-Px and the level of MAD were determined. **p < 0.01 vs OGD/R; ## p < 0.05, 0.01 vs OGD/R + ART.
Figure 7

NF-κB agonist reverses the effects of ART on inflammation and oxidative stress of SH-SY5Y cells triggered by OGD/R exposure. SH-SY5Y cells were pre-treated with 100 μM ART, an NF-κB antagonist, or 100 μM ART + NF-κB agonist for 2 h and then exposed to OGD/R. (a–c) ELISA was used to determine the secretion of TNF-α, IL-1β, and IL-6 in the supernatant of SH-SY5Y cells. (d–g) Activities of SOD, CAT, and GSH-Px and the level of MAD were determined. **p < 0.01 vs OGD/R; ## p < 0.05, 0.01 vs OGD/R + ART.

The findings suggested that p-p65 expression and the ratio of p-p65/p65 were significantly inhibited in OGD/R-injured SH-SY5Y cells after treatment with ART or the NF-κB agonist; however, the inhibitory effect of ART on OGD/R-injured SH-SY5Y cells was reversed by co-treatment with ART and the NF-κB agonist (Figure 8a and b). The transcription level of p65 did not differ among the groups (Figure 8c). ART attenuates OGD/R injury by inhibiting the NF-κB signaling pathway.

Figure 8 NF-κB agonist reverses the inhibitory effect of ART on the NF-κB signaling pathway in OGD/R-exposed SH-SY5Y cells. SH-SY5Y cells were pre-treated with 100 μM ART, an NF-κB antagonist, or 100 μM ART + NF-κB agonist for 2 h and then exposed to OGD/R. (a) Protein expressions of p-p65 and p65 were measured using western blotting. (b) p-p65/p65 ratio. (c) mRNA expression of p65 was determined via RT-qPCR. **p < 0.01 vs OGD/R; ## p < 0.05, 0.01 vs OGD/R + ART.
Figure 8

NF-κB agonist reverses the inhibitory effect of ART on the NF-κB signaling pathway in OGD/R-exposed SH-SY5Y cells. SH-SY5Y cells were pre-treated with 100 μM ART, an NF-κB antagonist, or 100 μM ART + NF-κB agonist for 2 h and then exposed to OGD/R. (a) Protein expressions of p-p65 and p65 were measured using western blotting. (b) p-p65/p65 ratio. (c) mRNA expression of p65 was determined via RT-qPCR. **p < 0.01 vs OGD/R; ## p < 0.05, 0.01 vs OGD/R + ART.

4 Discussion

Ischemic strokes cause severe disability and death, accounting for approximately 87% of all stroke cases [19,32]. Extensive studies have revealed that strokes cause complex cellular biochemical events that ultimately result in necrosis, apoptosis, or autophagy in ischemic areas [24,25,26]. A comprehensive understanding of neuronal death during ischemic brain injury facilitates the development of new therapies. The pathogenesis of ischemic stroke includes excitatory toxicity, oxidative stress, inflammatory responses, and apoptosis [33]. There is increasing evidence that ART derivatives participate in I/R injury. In this study, we investigated the effects of ART on OGD/R-exposed SH-SY5Y cells. The results indicated that ART increased the viability and decreased the apoptosis of SH-SY5Y cells exposed to OGD/R in a dose-dependent manner.

The inflammatory response caused by leukocyte infiltration after cerebral ischemia plays an important role in the occurrence and development of cerebral I/R injury [34]. The inflammatory cascade after cerebral ischemia is a dynamic process involving the interaction of various cells in the ischemic area, which can cause a second injury after cerebral ischemia. The damaged brain cells produce a large number of platelet activating factors, TNF, IL-6, and other inflammatory mediators after cerebral ischemia [35,36]. The regulatory effect of ART on pro-inflammatory cytokine expression has been widely reported. In LL37-induced rosacea-like mice, ART and its derivatives significantly inhibited the expression of pro-inflammatory factors (IL-1β, IL-6, and TNFα) and TLR2 [37]. In OGD/R-exposed SH-SY5Y cells, our results indicated that the secretion of inflammatory cytokines TNF-α, IL-1β, and IL-6 was significantly increased, and ART treatment inhibited the OGD/R-induced SH-SY5Y cell inflammatory response. The secretion of TNF-α, IL-1β, and IL-6 was inhibited by ART treatment in a dose-dependent manner.

Oxidative stress mediated by ROS is another important factor associated with cerebral I/R injury dysfunction. Antioxidant therapy helps to reduce neuronal variability and improve neurological prognosis [38,39]. Thus, we examined oxidative stress in SH-SY5Y cells following exposure to OGD/R. The levels of free radicals are difficult to measure because of their relatively short half-lives. Therefore, the activities of antioxidant enzymes, such as SOD, CAT, and GSH-Px, and lipid peroxidation by-products, such as MDA, can be used to indirectly evaluate the level of free radicals [40]. In OGD/R-induced SH-SY5Y cells, the antioxidant enzyme (SOD, CAT, and GSH-Px) activities were significantly decreased, and the MAD level was significantly increased. ART contains an endoperoxide bridge, which makes it an antioxidant. The mechanism of killing malaria parasites is related to the production of destructive ROS induced by ART [41]. Our results revealed that ART treatment could alleviate the inhibition of SOD, CAT, and GSH-Px activities and decrease MAD levels induced by OGD/R exposure in a dose-dependent manner.

NF-κB activation is involved in various cellular processes, including the regulation of cell survival, apoptosis, inflammation, and oxidative stress [42,43]. Moreover, NF-κB plays an important role in I/R injury [9,14,16,44]. NF-κB pathway is activated in cerebral I/R [45,46]. After cerebral I/R, NF-κB downregulation can alleviate cerebral edema and neurological dysfunction, and the NF-κB signaling pathway plays an important role in ventricular remodeling after myocardial infarction [16,47,48]. Matsui et al. found that an NF-κB inhibitor could reduce I/R injury in animal experiments [49]. In our study, p-p65 expression and the p-p65/p65 ratio in OGD/R-exposed SH SY5Y cells were significantly increased, and ART treatment could reduce p-p65 expression and the p-p65/p65 ratio in a dose-dependent manner. NF-κB agonist treatment could significantly increase the cell viability, decrease the apoptosis, and inhibit the inflammatory response and oxidative stress of OGD/R-exposed SH-SY5Y cells, suggesting that NF-κB is involved in the regulation of OGD/R-induced cell proliferation, apoptosis, inflammation, and oxidative stress. The NF-κB agonist and ART have similar effects on OGD/R-exposed SH-SY5Y cells. We then investigated whether the regulation of ART in OGD/R-exposed SH SY5Y cells is related to NF-κB pathway. As expected, all the effects of ART on OGD/R-exposed SH SY5Y cells could be reversed by co-treatment with an NF-κB agonist and ART.

Overall, ART protects neurons from OGD/R-induced damage in vitro by inhibiting the NF-κB signaling pathway. However, to make the effect of ART in cerebral ischemia and reperfusion injury more convincing, in vivo investigations should be performed. This study did not study the effect of ART in cerebral ischemia and reperfusion injury in animal models, and this was a limitation of the present study. We will delve into this in our next study.

5 Conclusion

We found that ART can significantly promote cell viability and inhibit cell apoptosis, inflammatory response, and oxidative stress in OGD/R induced SH SY5Y cells. The effect of ART on OGD/R-exposed SH SY5Y cells is achieved by inhibiting the NF-κB signaling pathway. These results indicate that ART may be a potential agent for the treatment of cerebral I/R injury.

  1. Funding information: The present study was supported by the Joint Guidance Project of Science and Technology Plan of Qiqihar (No. LHYD-2021016), and the Science Research Foundation of Education department of Heilongjiang Province (No. 2021-KYYWF-0377).

  2. Conflict of Interest: The authors declare that they have no competing interests.

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

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Received: 2021-11-07
Revised: 2022-01-10
Accepted: 2022-01-10
Published Online: 2022-05-11

© 2022 Hui Ji et al., published by De Gruyter

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

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  118. Neonatal stroke surveillance study protocol in the United Kingdom and Republic of Ireland
  119. Oncogenic role of TWF2 in human tumors: A pan-cancer analysis
  120. Mean corpuscular hemoglobin predicts the length of hospital stay independent of severity classification in patients with acute pancreatitis
  121. Association of gallstone and polymorphisms of UGT1A1*27 and UGT1A1*28 in patients with hepatitis B virus-related liver failure
  122. TGF-β1 upregulates Sar1a expression and induces procollagen-I secretion in hypertrophic scarring fibroblasts
  123. Antisense lncRNA PCNA-AS1 promotes esophageal squamous cell carcinoma progression through the miR-2467-3p/PCNA axis
  124. NK-cell dysfunction of acute myeloid leukemia in relation to the renin–angiotensin system and neurotransmitter genes
  125. The effect of dilution with glucose and prolonged injection time on dexamethasone-induced perineal irritation – A randomized controlled trial
  126. miR-146-5p restrains calcification of vascular smooth muscle cells by suppressing TRAF6
  127. Role of lncRNA MIAT/miR-361-3p/CCAR2 in prostate cancer cells
  128. lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2
  129. Noninvasive diagnosis of AIH/PBC overlap syndrome based on prediction models
  130. lncRNA FAM230B is highly expressed in colorectal cancer and suppresses the maturation of miR-1182 to increase cell proliferation
  131. circ-LIMK1 regulates cisplatin resistance in lung adenocarcinoma by targeting miR-512-5p/HMGA1 axis
  132. LncRNA SNHG3 promoted cell proliferation, migration, and metastasis of esophageal squamous cell carcinoma via regulating miR-151a-3p/PFN2 axis
  133. Risk perception and affective state on work exhaustion in obstetrics during the COVID-19 pandemic
  134. lncRNA-AC130710/miR-129-5p/mGluR1 axis promote migration and invasion by activating PKCα-MAPK signal pathway in melanoma
  135. SNRPB promotes cell cycle progression in thyroid carcinoma via inhibiting p53
  136. Xylooligosaccharides and aerobic training regulate metabolism and behavior in rats with streptozotocin-induced type 1 diabetes
  137. Serpin family A member 1 is an oncogene in glioma and its translation is enhanced by NAD(P)H quinone dehydrogenase 1 through RNA-binding activity
  138. Silencing of CPSF7 inhibits the proliferation, migration, and invasion of lung adenocarcinoma cells by blocking the AKT/mTOR signaling pathway
  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
  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
  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
  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
https://doi.org/10.1515/med-2022-0435
Schlagwörter für diesen Artikel
cerebral infaction; artemisinin; NF-κB; inflammation; apoptosis; oxidative stress
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Research Articles
  2. AMBRA1 attenuates the proliferation of uveal melanoma cells
  3. A ceRNA network mediated by LINC00475 in papillary thyroid carcinoma
  4. Differences in complications between hepatitis B-related cirrhosis and alcohol-related cirrhosis
  5. Effect of gestational diabetes mellitus on lipid profile: A systematic review and meta-analysis
  6. Long noncoding RNA NR2F1-AS1 stimulates the tumorigenic behavior of non-small cell lung cancer cells by sponging miR-363-3p to increase SOX4
  7. Promising novel biomarkers and candidate small-molecule drugs for lung adenocarcinoma: Evidence from bioinformatics analysis of high-throughput data
  8. Plasmapheresis: Is it a potential alternative treatment for chronic urticaria?
  9. The biomarkers of key miRNAs and gene targets associated with extranodal NK/T-cell lymphoma
  10. Gene signature to predict prognostic survival of hepatocellular carcinoma
  11. Effects of miRNA-199a-5p on cell proliferation and apoptosis of uterine leiomyoma by targeting MED12
  12. Does diabetes affect paraneoplastic thrombocytosis in colorectal cancer?
  13. Is there any effect on imprinted genes H19, PEG3, and SNRPN during AOA?
  14. Leptin and PCSK9 concentrations are associated with vascular endothelial cytokines in patients with stable coronary heart disease
  15. Pericentric inversion of chromosome 6 and male fertility problems
  16. Staple line reinforcement with nebulized cyanoacrylate glue in laparoscopic sleeve gastrectomy: A propensity score-matched study
  17. Retrospective analysis of crescent score in clinical prognosis of IgA nephropathy
  18. Expression of DNM3 is associated with good outcome in colorectal cancer
  19. Activation of SphK2 contributes to adipocyte-induced EOC cell proliferation
  20. CRRT influences PICCO measurements in febrile critically ill patients
  21. SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis
  22. lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells
  23. circ_AKT3 knockdown suppresses cisplatin resistance in gastric cancer
  24. Prognostic value of nicotinamide N-methyltransferase in human cancers: Evidence from a meta-analysis and database validation
  25. GPC2 deficiency inhibits cell growth and metastasis in colon adenocarcinoma
  26. A pan-cancer analysis of the oncogenic role of Holliday junction recognition protein in human tumors
  27. Radiation increases COL1A1, COL3A1, and COL1A2 expression in breast cancer
  28. Association between preventable risk factors and metabolic syndrome
  29. miR-29c-5p knockdown reduces inflammation and blood–brain barrier disruption by upregulating LRP6
  30. Cardiac contractility modulation ameliorates myocardial metabolic remodeling in a rabbit model of chronic heart failure through activation of AMPK and PPAR-α pathway
  31. Quercitrin protects human bronchial epithelial cells from oxidative damage
  32. Smurf2 suppresses the metastasis of hepatocellular carcinoma via ubiquitin degradation of Smad2
  33. circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury
  34. Sonoclot’s usefulness in prediction of cardiopulmonary arrest prognosis: A proof of concept study
  35. Four drug metabolism-related subgroups of pancreatic adenocarcinoma in prognosis, immune infiltration, and gene mutation
  36. Decreased expression of miR-195 mediated by hypermethylation promotes osteosarcoma
  37. LMO3 promotes proliferation and metastasis of papillary thyroid carcinoma cells by regulating LIMK1-mediated cofilin and the β-catenin pathway
  38. Cx43 upregulation in HUVECs under stretch via TGF-β1 and cytoskeletal network
  39. Evaluation of menstrual irregularities after COVID-19 vaccination: Results of the MECOVAC survey
  40. Histopathologic findings on removed stomach after sleeve gastrectomy. Do they influence the outcome?
  41. Analysis of the expression and prognostic value of MT1-MMP, β1-integrin and YAP1 in glioma
  42. Optimal diagnosis of the skin cancer using a hybrid deep neural network and grasshopper optimization algorithm
  43. miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells
  44. Clinical value of SIRT1 as a prognostic biomarker in esophageal squamous cell carcinoma, a systematic meta-analysis
  45. circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8
  46. miR-22-5p regulates the self-renewal of spermatogonial stem cells by targeting EZH2
  47. hsa-miR-340-5p inhibits epithelial–mesenchymal transition in endometriosis by targeting MAP3K2 and inactivating MAPK/ERK signaling
  48. circ_0085296 inhibits the biological functions of trophoblast cells to promote the progression of preeclampsia via the miR-942-5p/THBS2 network
  49. TCD hemodynamics findings in the subacute phase of anterior circulation stroke patients treated with mechanical thrombectomy
  50. Development of a risk-stratification scoring system for predicting risk of breast cancer based on non-alcoholic fatty liver disease, non-alcoholic fatty pancreas disease, and uric acid
  51. Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway
  52. circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis
  53. Human amniotic fluid as a source of stem cells
  54. lncRNA NONRATT013819.2 promotes transforming growth factor-β1-induced myofibroblastic transition of hepatic stellate cells by miR24-3p/lox
  55. NORAD modulates miR-30c-5p-LDHA to protect lung endothelial cells damage
  56. Idiopathic pulmonary fibrosis telemedicine management during COVID-19 outbreak
  57. Risk factors for adverse drug reactions associated with clopidogrel therapy
  58. Serum zinc associated with immunity and inflammatory markers in Covid-19
  59. The relationship between night shift work and breast cancer incidence: A systematic review and meta-analysis of observational studies
  60. LncRNA expression in idiopathic achalasia: New insight and preliminary exploration into pathogenesis
  61. Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway
  62. Moscatilin suppresses the inflammation from macrophages and T cells
  63. Zoledronate promotes ECM degradation and apoptosis via Wnt/β-catenin
  64. Epithelial-mesenchymal transition-related genes in coronary artery disease
  65. The effect evaluation of traditional vaginal surgery and transvaginal mesh surgery for severe pelvic organ prolapse: 5 years follow-up
  66. Repeated partial splenic artery embolization for hypersplenism improves platelet count
  67. Low expression of miR-27b in serum exosomes of non-small cell lung cancer facilitates its progression by affecting EGFR
  68. Exosomal hsa_circ_0000519 modulates the NSCLC cell growth and metastasis via miR-1258/RHOV axis
  69. miR-455-5p enhances 5-fluorouracil sensitivity in colorectal cancer cells by targeting PIK3R1 and DEPDC1
  70. The effect of tranexamic acid on the reduction of intraoperative and postoperative blood loss and thromboembolic risk in patients with hip fracture
  71. Isocitrate dehydrogenase 1 mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to ferroptosis
  72. Artemisinin protects against cerebral ischemia and reperfusion injury via inhibiting the NF-κB pathway
  73. A 16-gene signature associated with homologous recombination deficiency for prognosis prediction in patients with triple-negative breast cancer
  74. Lidocaine ameliorates chronic constriction injury-induced neuropathic pain through regulating M1/M2 microglia polarization
  75. MicroRNA 322-5p reduced neuronal inflammation via the TLR4/TRAF6/NF-κB axis in a rat epilepsy model
  76. miR-1273h-5p suppresses CXCL12 expression and inhibits gastric cancer cell invasion and metastasis
  77. Clinical characteristics of pneumonia patients of long course of illness infected with SARS-CoV-2
  78. circRNF20 aggravates the malignancy of retinoblastoma depending on the regulation of miR-132-3p/PAX6 axis
  79. Linezolid for resistant Gram-positive bacterial infections in children under 12 years: A meta-analysis
  80. Rack1 regulates pro-inflammatory cytokines by NF-κB in diabetic nephropathy
  81. Comprehensive analysis of molecular mechanism and a novel prognostic signature based on small nuclear RNA biomarkers in gastric cancer patients
  82. Smog and risk of maternal and fetal birth outcomes: A retrospective study in Baoding, China
  83. Let-7i-3p inhibits the cell cycle, proliferation, invasion, and migration of colorectal cancer cells via downregulating CCND1
  84. β2-Adrenergic receptor expression in subchondral bone of patients with varus knee osteoarthritis
  85. Possible impact of COVID-19 pandemic and lockdown on suicide behavior among patients in Southeast Serbia
  86. In vitro antimicrobial activity of ozonated oil in liposome eyedrop against multidrug-resistant bacteria
  87. Potential biomarkers for inflammatory response in acute lung injury
  88. A low serum uric acid concentration predicts a poor prognosis in adult patients with candidemia
  89. Antitumor activity of recombinant oncolytic vaccinia virus with human IL2
  90. ALKBH5 inhibits TNF-α-induced apoptosis of HUVECs through Bcl-2 pathway
  91. Risk prediction of cardiovascular disease using machine learning classifiers
  92. Value of ultrasonography parameters in diagnosing polycystic ovary syndrome
  93. Bioinformatics analysis reveals three key genes and four survival genes associated with youth-onset NSCLC
  94. Identification of autophagy-related biomarkers in patients with pulmonary arterial hypertension based on bioinformatics analysis
  95. Protective effects of glaucocalyxin A on the airway of asthmatic mice
  96. Overexpression of miR-100-5p inhibits papillary thyroid cancer progression via targeting FZD8
  97. Bioinformatics-based analysis of SUMOylation-related genes in hepatocellular carcinoma reveals a role of upregulated SAE1 in promoting cell proliferation
  98. Effectiveness and clinical benefits of new anti-diabetic drugs: A real life experience
  99. Identification of osteoporosis based on gene biomarkers using support vector machine
  100. Tanshinone IIA reverses oxaliplatin resistance in colorectal cancer through microRNA-30b-5p/AVEN axis
  101. miR-212-5p inhibits nasopharyngeal carcinoma progression by targeting METTL3
  102. Association of ST-T changes with all-cause mortality among patients with peripheral T-cell lymphomas
  103. LINC00665/miRNAs axis-mediated collagen type XI alpha 1 correlates with immune infiltration and malignant phenotypes in lung adenocarcinoma
  104. The perinatal factors that influence the excretion of fecal calprotectin in premature-born children
  105. Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study
  106. Does the use of 3D-printed cones give a chance to postpone the use of megaprostheses in patients with large bone defects in the knee joint?
  107. lncRNA HAGLR modulates myocardial ischemia–reperfusion injury in mice through regulating miR-133a-3p/MAPK1 axis
  108. Protective effect of ghrelin on intestinal I/R injury in rats
  109. In vivo knee kinematics of an innovative prosthesis design
  110. Relationship between the height of fibular head and the incidence and severity of knee osteoarthritis
  111. lncRNA WT1-AS attenuates hypoxia/ischemia-induced neuronal injury during cerebral ischemic stroke via miR-186-5p/XIAP axis
  112. Correlation of cardiac troponin T and APACHE III score with all-cause in-hospital mortality in critically ill patients with acute pulmonary embolism
  113. LncRNA LINC01857 reduces metastasis and angiogenesis in breast cancer cells via regulating miR-2052/CENPQ axis
  114. Endothelial cell-specific molecule 1 (ESM1) promoted by transcription factor SPI1 acts as an oncogene to modulate the malignant phenotype of endometrial cancer
  115. SELENBP1 inhibits progression of colorectal cancer by suppressing epithelial–mesenchymal transition
  116. Visfatin is negatively associated with coronary artery lesions in subjects with impaired fasting glucose
  117. Treatment and outcomes of mechanical complications of acute myocardial infarction during the Covid-19 era: A comparison with the pre-Covid-19 period. A systematic review and meta-analysis
  118. Neonatal stroke surveillance study protocol in the United Kingdom and Republic of Ireland
  119. Oncogenic role of TWF2 in human tumors: A pan-cancer analysis
  120. Mean corpuscular hemoglobin predicts the length of hospital stay independent of severity classification in patients with acute pancreatitis
  121. Association of gallstone and polymorphisms of UGT1A1*27 and UGT1A1*28 in patients with hepatitis B virus-related liver failure
  122. TGF-β1 upregulates Sar1a expression and induces procollagen-I secretion in hypertrophic scarring fibroblasts
  123. Antisense lncRNA PCNA-AS1 promotes esophageal squamous cell carcinoma progression through the miR-2467-3p/PCNA axis
  124. NK-cell dysfunction of acute myeloid leukemia in relation to the renin–angiotensin system and neurotransmitter genes
  125. The effect of dilution with glucose and prolonged injection time on dexamethasone-induced perineal irritation – A randomized controlled trial
  126. miR-146-5p restrains calcification of vascular smooth muscle cells by suppressing TRAF6
  127. Role of lncRNA MIAT/miR-361-3p/CCAR2 in prostate cancer cells
  128. lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2
  129. Noninvasive diagnosis of AIH/PBC overlap syndrome based on prediction models
  130. lncRNA FAM230B is highly expressed in colorectal cancer and suppresses the maturation of miR-1182 to increase cell proliferation
  131. circ-LIMK1 regulates cisplatin resistance in lung adenocarcinoma by targeting miR-512-5p/HMGA1 axis
  132. LncRNA SNHG3 promoted cell proliferation, migration, and metastasis of esophageal squamous cell carcinoma via regulating miR-151a-3p/PFN2 axis
  133. Risk perception and affective state on work exhaustion in obstetrics during the COVID-19 pandemic
  134. lncRNA-AC130710/miR-129-5p/mGluR1 axis promote migration and invasion by activating PKCα-MAPK signal pathway in melanoma
  135. SNRPB promotes cell cycle progression in thyroid carcinoma via inhibiting p53
  136. Xylooligosaccharides and aerobic training regulate metabolism and behavior in rats with streptozotocin-induced type 1 diabetes
  137. Serpin family A member 1 is an oncogene in glioma and its translation is enhanced by NAD(P)H quinone dehydrogenase 1 through RNA-binding activity
  138. Silencing of CPSF7 inhibits the proliferation, migration, and invasion of lung adenocarcinoma cells by blocking the AKT/mTOR signaling pathway
  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
  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
  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
  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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Heruntergeladen am 18.9.2025 von https://www.degruyterbrill.com/document/doi/10.1515/med-2022-0435/html
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