Home Dihydroartemisinin ameliorates cerebral I/R injury in rats via regulating VWF and autophagy-mediated SIRT1/FOXO1 pathway
Article Open Access

Dihydroartemisinin ameliorates cerebral I/R injury in rats via regulating VWF and autophagy-mediated SIRT1/FOXO1 pathway

  • Qi Duan and Junxia Wu EMAIL logo
Published/Copyright: July 3, 2023
Download Article (PDF)
Open Medicine
From the journal Open Medicine Volume 18 Issue 1

Abstract

Dihydroartemisinin (DHA) has been found to inhibit the expression of von Willebrand factor (VWF), a marker of endothelial cell injury, but its mechanism in cerebral ischemia/reperfusion (I/R) injury remains obscure. In this study, I/R model was constructed through middle cerebral artery occlusion (MCAO) in rats, followed by DHA administration. The effect of DHA on rat cerebral I/R injury was investigated by 2,3,5-triphenyltetrazolium chloride staining, hematoxylin and eosin staining, TUNEL staining, and Western blot. Brain microvascular endothelial cells (BMVECs) isolated from newborn rats were exposed to oxygen–glucose deprivation/reoxygenation (OGD/R), and then treated with DHA. The results showed that MCAO treatment induced infarction, nerve cell apoptosis, and brain tissue impairment in rats, which was mitigated by DHA. OGD/R inhibited viability and accelerated apoptosis of BMVECs, which was alleviated by DHA. I/R procedures or OGD/R up-regulated expressions of VWF, ATG7, Beclin1, and LC3-II/LC3-I ratio, while down-regulating Occludin, Claudin-5, ZO-1, P62, SIRT1, and FOXO1 expressions in vivo and in vitro; however, these effects of I/R procedures or OGD/R were offset by DHA. VWF overexpression reversed the above effects of DHA on OGD/R-induced BMVECs. In summary, DHA ameliorates cerebral I/R injury in rats by reducing VWF level and activating autophagy-mediated SIRT1/FOXO1 signaling pathway.

Keywords: cerebral ischemia/reperfusion injury; brain microvascular endothelial cells; dihydroartemisinin; von Willebrand factor; SIRT1/FOXO1 pathway; autophagy

1 Introduction

The annually rising incidence of cerebral ischemic stroke (CIS) is consequent on population aging worldwide [1]. As a common neurological disorder, CIS is characterized by high rates of recurrence, disability, and mortality [2]. Revascularization therapy is now widely recognized as an effective treatment for cerebral infarction caused by the occlusion of main arteries in China and abroad. However, extensive data showed that patients with CIS are predisposed to cerebral ischemia/reperfusion (I/R) injury after revascularization, including increased vascular permeability, disruption of the blood–brain barrier (BBB), and cerebral edema, posing a threat to the life of patients [3,4]. Brain microvascular endothelial cells (BMVECs), connected by tight junction proteins, are the main cells that contribute to the formation of BBB [5]. A study has demonstrated that I/R-induced BMVEC impairment is the initial stage of BBB disruption, leading to poor prognosis of patients with CIS [6]. Hence, studying how to maintain normal function of BMVECs is an essential part of protecting the BBB, thus alleviating cerebral I/R injury.

Von Willebrand factor (VWF), a glycoprotein synthesized and secreted by vascular endothelial cells and megakaryocytes, has been early identified to be associated with vascular hemophilia, and is perceived as a marker of endothelial cell damage [7]. In recent years, numerous studies have confirmed that elevated VWF expression is a risk factor for vascular diseases [8–10]. Besides, VWF was found to be highly expressed in mice with liver I/R injury, and to exacerbate the disease progression [11]. Presently, the role of VWF in cerebral I/R injury has not been fully elucidated.

The main pathological mechanism of ischemic cerebrovascular disease is irreversible damage and death of brain neurons [12]. It is generally believed that necrosis and apoptosis are the primary processes of cell death. Notably, autophagy has been identified to be critical in a range of pathophysiological changes following cerebral I/R [13–15]. Autophagy is a cellular self-stabilization program that is highly conserved in eukaryotic evolution. In this process, autophagic vesicles encapsulate damaged organelles and proteins, and deliver them to lysosomes for degradation which in turn provides substrates for cellular metabolism [16]. Sirtuin1 (SIRT1)/forkhead box O1 (FOXO1) signaling pathway-mediated autophagy has been proved to be implicated in a variety of organ damages, including cerebral I/R injury [17–19]. Therefore, probing into the mechanisms that activate the SIRT1/FOXO1 signaling pathway to inhibit autophagy has become a topical issue in cerebral I/R injury research.

Dihydroartemisinin (DHA) is a semi-synthetic derivative of the natural compound artemisinin, which exerts assorted pharmacological effects such as anti-malaria, anti-oxidation, anti-inflammation, and anti-apoptosis [20–22]. An existing study has identified that DHA is capable of regulating multiple biological properties of endothelial cells and suppressing VWF expression [23]. Also, DHA has been proven to protect against myocardial I/R injury [24], but its role in cerebral I/R injury needs further study.

Here, the current study investigated the role of DHA in rat cerebral I/R injury, and whether its potential mechanisms are related to VWF expression and SIRT1/FOXO1 signaling pathway through in vivo and in vitro experiments.

2 Methods

2.1 Animals and ethics statement

This study was carried out on newborn Sprague Dawley (SD) rats (10 days old) and adult male SD rats weighing 240–310 g (Charles River Laboratories, Beijing, China). The rats were housed in a specific pathogen-free environment and given a standard diet and drinking water ad libitum. Animal surgical procedures were approved by the Committee of Laboratory Animals of Nantong Rich Hospital (CIR20201006), and performed in accordance with the Guideline for the Care and Use of Laboratory Animals.

2.2 Cerebral I/R procedures and drug administration

All rats were randomly divided into three groups: Control group, I/R group, and I/R + DHA group. The cerebral I/R model was constructed using middle cerebral artery occlusion (MCAO), as previously reported [25]. Briefly, the rats in the I/R group and I/R + DHA group were anesthetized with pentobarbital sodium (45 mg/kg, P-010; Whitehouse Station, New Jersey, Merck, USA). Then, a midline incision was created to expose the right common carotid artery, internal carotid artery, and external carotid artery (ECA). After the ECA was separated, a nylon suture (0.26 mm in diameter) was inserted into the lumen of the ECA for 18–20 mm until blunted distal end met resistance. Two hours later, the incision was sutured when the suture was withdrawn. The rats in the Control group received identical surgical procedures aside from the occlusion. Subsequently, 15 min later, 0.5 mL dimethyl sulfoxide (DMSO, 10% v/v, D8418, Merck, USA) and DMSO-dissolved DHA (0.1 mg/kg, C15H24O5, D140839, Aladdin, China) were used to treat rats in I/R group and I/R + DHA group, respectively, by tail vein injection [24]. Following 14 days of reperfusion, all animals were euthanized by anesthesia and cervical dislocation for histological analysis of brain tissues.

2.3 Histological analysis

To evaluate the neuroprotective effect of DHA on I/R rat brain, 2,3,5-triphenyltetrazolium chloride (TTC) staining was applied to calculate cerebral infarct volumes, as previously described [26]. The frozen brain tissues were cut into sections (5 μm) and stained with TTC solution (17779, Merck, USA) at 37°C in the dark for 30 min. Then, the TTC-stained sections were fixed with 4% paraformaldehyde (abs9179, Absin, China). Infarction areas, which are manifested by a lack of red staining on the sections, were quantified using Image J software (vision 1.8.0, National Institutes of Health, Bethesda, MD, USA).

For morphological evaluation, hematoxylin and eosin (HE) staining was carried out using HE Staining Kit (G1121, Solarbio, China). According to the protocols, the frozen sections were stained with hematoxylin at room temperature for 10 min followed by differentiation. Afterward, the sections were subjected to bluing treatment, then were stained with eosin for 2 min and washed with water. A microscope (CX23, Olympus, Japan) was finally used for observation under ×100 magnification.

Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining was conducted using a TUNEL kit (MK1015, Wuhan Boster Biological Technology, Ltd). A microscope was applied to observe five randomly selected fields in the injury site of brain tissues in a blinded manner and determine the TUNEL-positive neurons.

2.4 Cell culture

BMVECs were isolated from newborn SD rats as previously described [6]. In brief, the sacrificed rats were scrubbed with 75% ethanol (E111991, Aladdin, China) and the cranial cavity was exposed. Next, the cerebral cortex was separated after removal of the meninges and blood vessels. The cortex was minced, and collagenase and dispase two-step combined dissociation (10269638001, Roche, Basel, Switzerland) was used to digest the tissues. By centrifugation at 1,000×g for 5 min at 4℃, BMVECs were aspirated and suspended with Dulbecco’s Modified Eagle Medium/Nutrient Mixture F-12 (DMEM/F-12, 11320033, Thermo Fisher, Waltham, MA, USA) supplemented with 20% fetal bovine serum (FBS, 10091155, Thermo Fisher, USA) and basic fibroblast growth factor (70 ng/mL, TL-401, Wolcavi, China). Lastly, BMVECs were seeded (1 × 105/cm2) in a gelatin-coated plastic dish at 37°C with 5% CO2 for 2 days of subculture.

2.5 Oxygen–glucose deprivation/reoxygenation (OGD/R) treatment

The cultured BMVECs were treated with glucose-free medium (E600010-0500, Sangon Biotech, China) with 2% FBS in an incubator (37°C, 5% CO2 and 95% N2) as per guidance. Six hours later, the cells were transferred to the standard medium and incubated in a normoxic condition (25% O2, 5% CO2, and 70% N2) for 4 h. BMVECs cultured in the normoxic condition were used as the control.

2.6 Cell transfection and DHA treatment

VWF-overexpressing plasmids (Bes-mR-053889) and control plasmids (NC) were purchased from BersinBio (Guangzhou, China). BMVECs were transfected with VWF-overexpressing plasmids or control plasmids by Lipofectamine 3000 (L3000008, Thermo Fisher, USA) according to the specification. After OGD/R treatment, the cells were incubated with 25 μM DHA for 24 h [23]. In the end, five groups were constructed: Control group, OGD/R group, OGD/R + DHA group, OGD/R + DHA + NC group, and OGD/R + DHA + VWF group. The cells from above groups were subsequently subjected to quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), cell function experiments, and Western blot.

2.7 RNA extraction and qRT-PCR

Total RNA from BMVECs with different treatments was isolated with Trizol (9108, Takara, Japan) according to the manufacturer’s instructions, and then was reverse-transcribed using cDNA Synthesis Kit (6130, Takara, Japan). After that, qRT-PCR was conducted on a Real-Time System (CFX96, Bio-Rad, Hercules, CA, USA) with Fast SYBR Green Master Mix (4385612, Thermo Fisher, USA). The gene-specific primer sequences were VWF (forward: 5′-ATGGCCCTTTCCTGACCTAC-3′; reverse: 5′-GGATTAGGGTTGGCCCTGAG-3′) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH, forward: 5′-TAATGCCGCCCCTTACCATC-3′; reverse: 5′-GGTGCAGCGATGCTTTACTT-3′). The conditions of PCR reaction were as follows: predenaturation at 95°C for 20 s and 40 cycles of amplification at 95°C for 10 s, annealing at 60°C for 20 s and extension at 60°C for 30 s. The relative expression of VWF was normalized based on the 2−ΔΔCt method [27], with GAPDH serving as the endogenous control.

2.8 Cell counting kit 8 (CCK-8) assay

After OGD/R, BMVECs transfected with VWF-overexpressing plasmids or not were adjusted to the density of 2 × 103 cells/well and seeded in a 96-well plate (100 μL/well). Following 24 h of incubation, the cells were subjected to DHA treatment and incubation with 10 μL CCK-8 solution (M4839, Abmole Bioscience, Houston, TX, USA) for 1 h. Thereafter, the optical density value was detected by a microplate reader (Synergy HTX, BioTek, Winooski, VT, USA).

2.9 Flow cytometry

Annexin V-FITC/propidium iodide (PI) Apoptosis Detection Kit (CA1020, Solarbio, China) was employed to detect cell apoptosis. In short, BMVECs treated with DHA for 24 h were collected at a concentration of 1  ×  105 cells/mL, washed with cold phosphate buffered solution (PBS, abs9459, Absin, China), suspended with Binding Buffer, and centrifuged. Then, 100 μL cell suspension was incubated with 5 μL Annexin V-FITC at room temperature for 10 min away from light, and 5 μL PI for 5 min. The cells were mixed with 500 μL PBS, and apoptotic cells were analyzed using a flow cytometer (CytoFlex LX, Beckman Coulter, Miami, FL, USA).

2.10 Western blot

Total protein from rat cerebral cortex and BMVECs was extracted with a lysis buffer (BC-R327, Elabscience, China), and protein concentration was determined using BCA Protein Assay Kit (ab102536; Abcam, Cambridge, UK) according to the protocols. Equal numbers of protein samples (30 μg) were separated by 10% SDS-PAGE (P0670, Beyotime, China). After electrophoresis, the protein samples were transferred onto polyvinylidene fluoride membranes (P2438, Merck, USA), which were then treated with Tris buffered saline with Tween 20 (TBST)-dissolved in 5% skim milk (E-BC-R337, Elabscience, China) at room temperature for 1 h. Then, the membranes were cultured with diluted primary antibodies overnight (4℃). The next day, the membranes were washed with TBST and probed with secondary antibodies at room temperature for 1 h. Immunoblots were visualized by ECL Western Blotting Substrate (PE0010, Solarbio, China), and immunoreactivity was analyzed using a Tanon 5200 Imaging System (Shanghai, China). GAPDH served as the loading control. All antibodies used were as follows: VWF (1/1,000, 309 kDa, ab174290; Abcam, UK), Occludin (1/1,000, 59 kDa, ab167161; Abcam, UK), Claudin-5 (1 mg/mL, 23 kDa, AF5216; Affinity Biosciences, China), ZO-1 (1/500, 195 kDa, ab190085; Abcam, UK), LC3-I/LC3-II (1/2,000, 14, 16 kDa, ab192890; Abcam, UK), P62 (1/10,000, 62 kDa, ab109012; Abcam, UK), GAPDH (1/10,000, 36 kDa, ab181602; Abcam, UK), SIRT1 (0.125 µg/mL, 81 kDa, ab110304; Abcam, UK), FOXO1 (1/2,000, 70 kDa, ab70382; Abcam, UK), transcription factor 5 (ATF5) (1/2,000, 31 kDa, ab184923; Abcam, UK), autophagy-related gene 7 (ATG7) (1/10,000, 77 kDa, ab133528; Abcam, UK), Beclin1 (2 µg/mL, 52 kDa, ab217179; Abcam, UK), goat anti-rabbit IgG H&L (HRP) (1/2,000, ab205718; Abcam, UK), and goat anti-mouse IgG H&L (HRP) (1/2,000, ab205719; Abcam, UK).

2.11 Statistical analysis

Data were analyzed by Graphpad Prism 8.0 (GraphPad Software Inc., San Diego, CA, USA) and expressed as mean ± standard deviation. Differences of CCK-8 assay results among multiple groups were compared using two-way analysis of variance (ANOVA). Differences of other experiment results were analyzed using one-way ANOVA. Values of p < 0.05 indicated significant difference.

3 Results

3.1 DHA attenuated cerebral I/R injury and apoptosis in rats

As illustrated in Figure 1a, no infarction was observed in TTC-stained brain sections in the Control group. By contrast, cerebral I/R procedures induced a high infarction rate in the I/R group, but treatment with DHA in I/R-induced rats significantly reduced the infarction rate in IR + DHA group (Figure 1a, p < 0.001). The degree of rat brain injury after I/R was assessed by HE staining. The results revealed an intact tissue structure and normal neuron cells with clear membranes and nuclei in the Control group, but different degrees of interstitial edema, neuronal cell swelling, and nucleus disintegration in the I/R group. These conditions were mitigated by DHA administration in IR + DHA group (Figure 1b). In addition, TUNEL results indicated that DHA administration evidently reduced the number of TUNEL-positive cells in I/R-induced rats on day 14 following recovery (Figure 1c, p < 0.001). These results demonstrated that DHA administration exerted a protective effect by relieving the injury and apoptosis of nerve cells following IR.

Figure 1 Effects of DHA on cerebral I/R injury in vivo. SD rats were subjected to MCAO to mimic I/R injury and then administrated with DHA (0.1 mg/kg), with unprocessed rats serving as the control. (a) Brain tissues were collected from sacrificed rats to calculate infarction area by TTC staining. (b) HE staining was applied to evaluate histopathological conditions in rat brain (magnification ×100, scale bar: 100 μm). (c) TUNEL staining indicated neuron nuclei (brown). Red arrows indicated TUNEL-positive neurons after I/R injury (magnification ×100, scale bar: 100 μm). (d–j) Western blot was employed to detect relative protein levels of VWF, Occludin, Claudin-5, ZO-1, LC3I, LC3II, and P62 in rat brain tissues. GAPDH was used as the loading control. (k–n) Western blot was applied to detect relative protein levels of ATF5, ATG7, and Beclin1 in rat brain tissues. GAPDH was used as the loading control. ** p < 0.01, *** p < 0.001 vs Control; ++ p < 0.01, +++ p < 0.001 vs I/R, ischemia/reperfusion; DHA, dihydroartemisinin; VWF, von Willebrand factor; ATF5, transcription factor 5; ATG7, autophagy-related gene 7; ZO-1, zonula occludens 1; LC3, microtubule associated protein 1 light chain 3 alpha; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; TTC, triphenyltetrazolium chloride; HE, hematoxylin and eosin.
Figure 1

Effects of DHA on cerebral I/R injury in vivo. SD rats were subjected to MCAO to mimic I/R injury and then administrated with DHA (0.1 mg/kg), with unprocessed rats serving as the control. (a) Brain tissues were collected from sacrificed rats to calculate infarction area by TTC staining. (b) HE staining was applied to evaluate histopathological conditions in rat brain (magnification ×100, scale bar: 100 μm). (c) TUNEL staining indicated neuron nuclei (brown). Red arrows indicated TUNEL-positive neurons after I/R injury (magnification ×100, scale bar: 100 μm). (d–j) Western blot was employed to detect relative protein levels of VWF, Occludin, Claudin-5, ZO-1, LC3I, LC3II, and P62 in rat brain tissues. GAPDH was used as the loading control. (k–n) Western blot was applied to detect relative protein levels of ATF5, ATG7, and Beclin1 in rat brain tissues. GAPDH was used as the loading control. ** p < 0.01, *** p < 0.001 vs Control; ++ p < 0.01, +++ p < 0.001 vs I/R, ischemia/reperfusion; DHA, dihydroartemisinin; VWF, von Willebrand factor; ATF5, transcription factor 5; ATG7, autophagy-related gene 7; ZO-1, zonula occludens 1; LC3, microtubule associated protein 1 light chain 3 alpha; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; TTC, triphenyltetrazolium chloride; HE, hematoxylin and eosin.

3.2 DHA down-regulated VWF expression, protected BBB from breakdown, and inhibited autophagy in rat brain with I/R injury

Previous evidence indicated that VWF contributes to endothelial cell injury, which could be associated with autophagy-related SIRT1/FOXO1 pathway. Hence, we measured protein expressions of VWF, BBB-related proteins, and autophagy-related genes in rat brain tissues by Western blot. In the I/R group compared with the Control group, VWF, ATG7, and Beclin1 protein expressions and LC3-II/LC3-I rate were obviously elevated, yet Occludin, Claudun-5, ZO-1, P62, and ATF5 protein expressions were markedly lessened (Figure 1d–n, p < 0.01). In contrast, these trends were reversed by DHA treatment in the I/R + DHA group (Figure 1d–n, p < 0.01).

3.3 DHA promoted viability and suppressed apoptosis of BMVECs by down-regulating VWF expression

To figure out whether the effect of DHA on cerebral I/R injury is mediated by VWF, we carried out in vitro experiments using BMVECs exposed to OGD/R. The results of qRT-PCR unveiled that VWF plasmid remarkably elevated the mRNA level of VWF in BMVECs, indicating successful transfection (Figure 2a, p < 0.001). Furthermore, the results showed that OGD/R led to VWF overexpression, the effect of which was notably reversed after DHA treatment (Figure 2b, p < 0.001). In the OGD/R + DHA + VWF group compared with the OGD/R + DHA + NC group, the expression of VWF was significantly augmented (Figure 2b, p < 0.001). CCK-8 assay results unraveled that DHA treatment remarkably enhanced OGD/R-suppressed cell viability, which, however, was reversed by VWF overexpression (Figure 2c, p < 0.001). Moreover, the analysis of flow cytometry demonstrated that cell apoptosis was boosted by OGD/R, but was then inhibited after DHA treatment (Figure 2d, p < 0.001). However, VWF overexpression offset the protecting effect of DHA on cell apoptosis (Figure 2d, p < 0.001).

Figure 2 DHA promoted viability and repressed apoptosis of OGD/R-treated BMVECs by down-regulating VWF level. BMVECs isolated from newborn SD rats were transfected with VWF-overexpressing plasmids or control plasmids. OGD/R exposure was conducted on the cells with or without transfection, followed by 24 h 25 μM DHA treatment. (a and b) mRNA expression of VWF in BMVECs was determined by qRT-PCR. GAPDH served as the internal control. (c) Cell viability was assessed using CCK-8 assay. (d) Apoptotic cells were stained with Annexin V-FITC/PI and apoptosis rate was analyzed by flow cytometry. *** p < 0.001 vs Control; +++ p < 0.001 vs OGD/R; ^^^ p < 0.001 vs OGD/R + DHA + NC. BMVECs, brain microvascular endothelial cells; DHA, dihydroartemisinin; VWF, von Willebrand factor; OGD/R, oxygen–glucose deprivation/reoxygenation; qRT-PCR, quantitative real-time reverse transcription polymerase chain reaction; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; CCK-8, cell counting kit 8; NC, negative control.
Figure 2

DHA promoted viability and repressed apoptosis of OGD/R-treated BMVECs by down-regulating VWF level. BMVECs isolated from newborn SD rats were transfected with VWF-overexpressing plasmids or control plasmids. OGD/R exposure was conducted on the cells with or without transfection, followed by 24 h 25 μM DHA treatment. (a and b) mRNA expression of VWF in BMVECs was determined by qRT-PCR. GAPDH served as the internal control. (c) Cell viability was assessed using CCK-8 assay. (d) Apoptotic cells were stained with Annexin V-FITC/PI and apoptosis rate was analyzed by flow cytometry. *** p < 0.001 vs Control; +++ p < 0.001 vs OGD/R; ^^^ p < 0.001 vs OGD/R + DHA + NC. BMVECs, brain microvascular endothelial cells; DHA, dihydroartemisinin; VWF, von Willebrand factor; OGD/R, oxygen–glucose deprivation/reoxygenation; qRT-PCR, quantitative real-time reverse transcription polymerase chain reaction; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; CCK-8, cell counting kit 8; NC, negative control.

3.4 DHA inhibited SIRT1/FOXO1 pathway-mediated autophagy and improved tight junction of BMVECs by down-regulating VWF expression

To explore the mechanism of DHA in tight junction of BMVECs exposed to OGD/R, we quantified protein expressions of Occludin, Claudin-5, and ZO-1 by Western blot. The results proved that prominent decreases of Occludin, Claudin-5, and ZO-1 expressions were observed in OGD/R-treated BMVECs, which was counteracted after DHA treatment (Figure 3a–d, p < 0.01). The protein levels of these three genes were down-regulated by VWF overexpression in the OGD/R- and DHA-treated BMVECs, which reversed the effect of DHA (Figure 3a–d, p < 0.01). Furthermore, to elucidate the mechanism by which DHA treatment may suppress autophagy via VWF/SIRT1/FOXO1 axis in OGD/R-treated BMVECs, we measured protein expressions of ATF5, ATG7, Beclin1, LC3-I, LC3-II, P62, SIRT1, and FOXO1 through Western blot. The results demonstrated that the protein expressions of ATF5, SIRT1, FOXO1, and P62 were decreased, and those of ATG7 and Beclin1 as well as LC3-II/LC3-I ratio were increased in the cells exposed to OGD/R, which was reversed by DHA treatment (Figure 3e–m, p < 0.01). Notably, VWF overexpression offset the effects of DHA treatment, and strikingly reduced ATF5, SIRT1, FOXO1, and P62 expressions, yet increased the protein expressions of ATG7 and Beclin1 as well as the LC3-II/LC3-I ratio in DHA- and OGD/R-treated BMVECs (Figure 3e–m, p < 0.01).

Figure 3 DHA increased tight junction proteins and inhibited autophagy in OGD/R-treated BMVECs via VWF/SIRT1/FOXO1 axis. BMVECs isolated from newborn SD rats were transfected with VWF-overexpressing plasmids or control plasmids. OGD/R exposure was conducted on the cells with or without transfection, followed by 24 h 25 μM DHA treatment. (a–d) Relative protein levels of Occludin, Claudin-5, and ZO-1 in BMVECs were measured by Western blot. GAPDH was used as the loading control. (e–i) Relative protein levels of SIRT1, FOXO1, LC3I, LC3II, and P62 in BMVECs were detected via Western blot. GAPDH was used as the loading control. (j–m) Relative protein levels of ATF5, ATG7, and Beclin1 in BMVECs were measured by Western blot. GAPDH was used as the loading control. ** p < 0.01, *** p < 0.001 vs Control; ++ p < 0.01, +++ p < 0.001 vs OGD/R; ^^ p < 0.01, ^^^ p < 0.001 vs OGD/R + DHA + NC. ATF5, transcription factor 5; ATG7, autophagy-related gene 7; BMVECs, brain microvascular endothelial cells; DHA, dihydroartemisinin; VWF, von Willebrand factor; OGD/R, oxygen–glucose deprivation/reoxygenation; ZO-1, zonula occludens 1; LC3, microtubule associated protein 1 light chain 3 alpha; SIRT1, sirtuin1; FOXO1, forkhead box O1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; NC, negative control.
Figure 3

DHA increased tight junction proteins and inhibited autophagy in OGD/R-treated BMVECs via VWF/SIRT1/FOXO1 axis. BMVECs isolated from newborn SD rats were transfected with VWF-overexpressing plasmids or control plasmids. OGD/R exposure was conducted on the cells with or without transfection, followed by 24 h 25 μM DHA treatment. (a–d) Relative protein levels of Occludin, Claudin-5, and ZO-1 in BMVECs were measured by Western blot. GAPDH was used as the loading control. (e–i) Relative protein levels of SIRT1, FOXO1, LC3I, LC3II, and P62 in BMVECs were detected via Western blot. GAPDH was used as the loading control. (j–m) Relative protein levels of ATF5, ATG7, and Beclin1 in BMVECs were measured by Western blot. GAPDH was used as the loading control. ** p < 0.01, *** p < 0.001 vs Control; ++ p < 0.01, +++ p < 0.001 vs OGD/R; ^^ p < 0.01, ^^^ p < 0.001 vs OGD/R + DHA + NC. ATF5, transcription factor 5; ATG7, autophagy-related gene 7; BMVECs, brain microvascular endothelial cells; DHA, dihydroartemisinin; VWF, von Willebrand factor; OGD/R, oxygen–glucose deprivation/reoxygenation; ZO-1, zonula occludens 1; LC3, microtubule associated protein 1 light chain 3 alpha; SIRT1, sirtuin1; FOXO1, forkhead box O1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; NC, negative control.

4 Discussion

It is documented that reperfusion after cerebral ischemia triggers more intense neurological damage, including excitotoxicity, oxidative stress, and inflammatory responses, in which oxidative stress is the most severe and longest-lasting risk factor [28]. An increasing number of natural compounds have been found to have anti-inflammatory and anti-oxidant biological activities with low toxicity and stable efficacy, which have a wide application prospect in the treatment of cerebrovascular diseases [29–31]. Khan et al. verified that DHA markedly reduces myocardial infarct size and attenuates reperfusion injury in a rat model of myocardial I/R [24]. In a study of lung injury, DHA is able to inhibit tissue fibrosis by reducing oxidative stress [22]. Furthermore, Xiong et al. [32] recently identified that DHA attenuates the damage and improves the function of brains in neonatal SD rats with hypoxic-ischemic brain damage by inhibiting oxidative stress. Similarly, by observing the staining results of brain tissue from rats with cerebral I/R, we found that DHA signally decreased infarct rate, neuronal deficits, and apoptosis, implying that DHA may play a protective role in cerebral I/R injury.

Studies have suggested that high expression of VWF is closely associated with the development and progression of ischemic cerebrovascular diseases through thrombus formation and endothelial dysfunction [9,33,34]. Evidence from Martinez de Lizarrondo et al. confirmed that N-acetylcysteine can exert a potent thrombolytic effect in stroke by inhibiting the production of VWF [35]. Moreover, Dong et al. revealed that VWF transcription is decreased by DHA, which is beneficial to vascular homeostasis [23]. In this study, we determined high expression of VWF in rat cerebral cortex after MCAO, and DHA treatment dwindled VWF expression, indicating that VWF may be the molecular target of DHA in cerebral I/R injury.

Research has shown that the development and progression of vasogenic cerebral edema is closely dependent on BBB integrity [36]. In the formation of BBB, tight junction formed between BMVECs is an important factor in maintaining the stability of BBB. Occludin and Claudin-5, as major transmembrane proteins, contribute to the tight junction of endothelial cells, and can interact with cytoplasmic adhesion protein ZO-1 to regulate the structural alterations of tight junction and thus maintain the normal function of BBB [37,38]. The present findings indicated that DHA may stabilize BBB in cerebral I/R injury by enhancing the tight junction. During cerebral I/R, the generation of substantial reactive oxygen species in the ischemic region induces the accumulation of endoplasmic reticulum stress and oxidative stress, so as to prompt excessive autophagy and cause cell death. Shao et al. uncovered that apelin-13 inhibits excessive autophagy through upregulation of P62 and downregulation of LC3B, thereby exerting neuroprotective effects in rats with cerebral I/R injury [39]. P62, as an autophagic substrate, can bind to LC3-II on the internal membrane of autophagic vesicles to form a complex and trigger the autophagic program [40]. In this study, we observed that P62 and ATF5 expressions were reduced, while ATG7 and Beclin1 expressions as well as LC3-II/LC3-I ratio were elevated in the cortex of I/R rats and OGD/R-exposed BMVECs, manifesting that reperfusion-induced excessive autophagy may be the pathological mechanism of BBB dysfunction; however, DHA treatment reversed the above effects of OGD/R. In addition, the following cell function assays identified that DHA improved viability and suppressed apoptosis of OGD/R-induced BMVECs. Based on the above findings, it is suggested that DHA may mitigate the damage of BMVECs and maintain the integrity of BBB through inhibiting autophagy. Nevertheless, whether the molecular mechanism of DHA in these processes is related to VWF has not been anatomized in any study.

SIRT1, as a NAD+-dependent deacetylase, is generated through FOXO3 deacetylation, and plays an important role in inhibiting apoptosis, resisting oxidative stress, and delaying cellular senescence [41]. The study by Wang et al. found that piceatannol diminishes oxidative stress in cerebral I/R mice by activating the SIRT1/FOXO1 signaling pathway, thereby alleviating brain damage [42]. Moreover, SIRT1/FOXO1 signaling pathway has been identified as a promising target to prevent VWF-mediated arterial thrombosis [43]. Therefore, we presumed that DHA plays a protective role in cerebral I/R injury by regulating VWF/SIRT1/FOXO1 axis. In order to validate our speculation, we transfected VWF-overexpressing plasmid into BMVECs to carried out recue assays. Interestingly, VWF overexpression neutralized the effect of DHA on the viability, apoptosis, and autophagy of BMVECs as well as on the expressions of tight junction proteins. More importantly, we found that SIRT1 and FOXO1 expressions were enhanced in OGD/R-induced BMVECs after DHA treatment, which was counteracted by VWF overexpression. Although the present findings evidenced that significant effects of DHA treatment can be attenuated by VWF overexpression, whether DHA directly interacts with VWF has not been fully testified. According to a recent study, DHA modulates the E26 transformation-specific (ETS) related gene (ERG) binding with the −56 ETS-binding motif on the human VWF promoter, signifying that DHA decreases VWF expression by the transcription factor ERG [23].

However, on one hand, the singularity of subjects in the in vitro experiments is a shortcoming of this study, which will be improved in the next phase of the study. On the other hand, the metabolism of DHA occurs by conjugation with the UDP-glucuronosyltransferase system [44], with an average half-life of 1–2 h [45]. As the degradation of DHA in vivo is dependent on its half-life period [24], and animals in this study were subjected to 24 h of reperfusion and 14 days of recovery, it might be necessary to increase the administration times during the treatment.

5 Conclusion

To conclude, we provide the first evidence that DHA may reduce BBB damage by inhibiting VWF and activating SIRT1/FOXO1 signaling pathway, thereby ameliorating cerebral I/R injury in rats.

tel: +86-0513-80886205

Acknowledgements

Not applicable.

  1. Funding information: None.

  2. Author contributions: Substantial contributions to conception and design: QD. Data acquisition, data analysis and interpretation: JXW. Drafting the article or critically revising it for important intellectual content: QD. Final approval of the version to be published: QD and JXW. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of the work are appropriately investigated and resolved: QD and JXW.

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

  4. Data availability statement: The data generated during the current study are available from the corresponding author on a reasonable request.

References

[1] Roy-O’Reilly M, McCullough LD. Age and sex are critical factors in ischemic stroke pathology. Endocrinology. 2018;159(8):3120–31.10.1210/en.2018-00465Search in Google Scholar PubMed PubMed Central

[2] Wang L, Kong L, Wu F, Bai Y, Burton R. Preventing chronic diseases in China. Lancet (London, England). 2005;366(9499):1821–4.10.1016/S0140-6736(05)67344-8Search in Google Scholar PubMed

[3] Sun MS, Jin H, Sun X, Huang S, Zhang FL, Guo ZN, et al. Free radical damage in ischemia–reperfusion injury: an obstacle in acute ischemic stroke after revascularization therapy. Oxid Med Cell Longev. 2018;2018:3804979.10.1155/2018/3804979Search in Google Scholar PubMed PubMed Central

[4] Kirchoff-Torres KF, Bakradze E. Cerebral hyperperfusion syndrome after carotid revascularization and acute ischemic stroke. Curr Pain Headache Rep. 2018;22(4):24.10.1007/s11916-018-0678-4Search in Google Scholar PubMed

[5] Zuo G, Zhang D, Mu R, Shen H, Li X, Wang Z, et al. Resolvin D2 protects against cerebral ischemia/reperfusion injury in rats. Mol Brain. 2018;11(1):9.10.1186/s13041-018-0351-1Search in Google Scholar PubMed PubMed Central

[6] Li H, Gao A, Feng D, Wang Y, Zhang L, Cui Y, et al. Evaluation of the protective potential of brain microvascular endothelial cell autophagy on blood–brain barrier integrity during experimental cerebral ischemia–reperfusion injury. Transl Stroke Res. 2014;5(5):618–26.10.1007/s12975-014-0354-xSearch in Google Scholar PubMed

[7] Du R, Wang Y, Teng JF, Lu H, Lu R, Shi Z. Effect of integrin combined laminin on peripheral blood vessel of cerebral infarction and endogenous nerve regeneration. J Biol Regul Homeost Agents. 2015;29(1):167–74.Search in Google Scholar

[8] Pozzi N, Lancellotti S, De Cristofaro R, De Filippis V. Modeling ADAMTS13-von Willebrand factor interaction: implications for oxidative stress-related cardiovascular diseases and type 2A von Willebrand disease. Biophys Chem. 2012;160(1):1–11.10.1016/j.bpc.2011.07.007Search in Google Scholar PubMed

[9] Lip GY, Blann AD. von Willebrand factor and its relevance to cardiovascular disorders. Br Heart J. 1995;74(6):580–3.10.1136/hrt.74.6.580Search in Google Scholar PubMed PubMed Central

[10] Horvath B, Hegedus D, Szapary L, Marton Z, Alexy T, Koltai K, et al. Measurement of von willebrand factor as the marker of endothelial dysfunction in vascular diseases. Exp Clin Cardiol. 2004;9(1):31–4.Search in Google Scholar

[11] Urisono Y, Sakata A, Matsui H, Kasuda S, Ono S, Yoshimoto K, et al. Von willebrand factor aggravates hepatic ischemia–reperfusion injury by promoting neutrophil recruitment in mice. Thromb Haemost. 2018;118(4):700–8.10.1055/s-0038-1636529Search in Google Scholar PubMed

[12] Hu X, De Silva TM, Chen J, Faraci FM. Cerebral vascular disease and neurovascular injury in ischemic stroke. Circ Res. 2017;120(3):449–71.10.1161/CIRCRESAHA.116.308427Search in Google Scholar PubMed PubMed Central

[13] Huang L, Chen C, Zhang X, Li X, Chen Z, Yang C, et al. Neuroprotective effect of curcumin against cerebral ischemia–reperfusion via mediating autophagy and inflammation. J Mol Neurosci. 2018;64(1):129–39.10.1007/s12031-017-1006-xSearch in Google Scholar PubMed

[14] Mu Q, Zhou H, Xu Y, He Q, Luo X, Zhang W, et al. NPD1 inhibits excessive autophagy by targeting RNF146 and wnt/β-catenin pathway in cerebral ischemia–reperfusion injury. J Recept Signal Transduct Res. 2020;40(5):456–63.10.1080/10799893.2020.1756325Search in Google Scholar PubMed

[15] Adhami F, Schloemer A, Kuan CY. The roles of autophagy in cerebral ischemia. Autophagy. 2007;3(1):42–4.10.4161/auto.3412Search in Google Scholar PubMed

[16] Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell. 2010;140(3):313–26.10.1016/j.cell.2010.01.028Search in Google Scholar PubMed PubMed Central

[17] Cheng Y, Di S, Fan C, Cai L, Gao C, Jiang P, et al. SIRT1 activation by pterostilbene attenuates the skeletal muscle oxidative stress injury and mitochondrial dysfunction induced by ischemia reperfusion injury. Apoptosis. 2016;21(8):905–16.10.1007/s10495-016-1258-xSearch in Google Scholar PubMed

[18] Wang B, Yang Q, Sun YY, Xing YF, Wang YB, Lu XT, et al. Resveratrol-enhanced autophagic flux ameliorates myocardial oxidative stress injury in diabetic mice. J Cell Mol Med. 2014;18(8):1599–611.10.1111/jcmm.12312Search in Google Scholar PubMed PubMed Central

[19] Mei ZG, Huang YG, Feng ZT, Luo YN, Yang SB, Du LP, et al. Electroacupuncture ameliorates cerebral ischemia/reperfusion injury by suppressing autophagy via the SIRT1-FOXO1 signaling pathway. Aging. 2020;12(13):13187–205.10.18632/aging.103420Search in Google Scholar PubMed PubMed Central

[20] Liu J, Ren Y, Hou Y, Zhang C, Wang B, Li X, et al. Dihydroartemisinin induces endothelial cell autophagy through suppression of the Akt/mTOR pathway. J Cancer. 2019;10(24):6057–64.10.7150/jca.33704Search in Google Scholar PubMed PubMed Central

[21] Yang D, Yuan W, Lv C, Li N, Liu T, Wang L, et al. Dihydroartemisinin supresses inflammation and fibrosis in bleomycine-induced pulmonary fibrosis in rats. Int J Clin Exp Pathol. 2015;8(2):1270–81.Search in Google Scholar

[22] Yang DX, Qiu J, Zhou HH, Yu Y, Zhou DL, Xu Y, et al. Dihydroartemisinin alleviates oxidative stress in bleomycin-induced pulmonary fibrosis. Life Sci. 2018;205:176–83.10.1016/j.lfs.2018.05.022Search in Google Scholar PubMed

[23] Dong F, Zhao X, Wang J, Huang X, Li X, Zhang L, et al. Dihydroartemisinin inhibits the expression of von Willebrand factor by downregulation of transcription factor ERG in endothelial cells. Fundam Clin Pharmacol. 2021;35(2):321–30.10.1111/fcp.12622Search in Google Scholar PubMed PubMed Central

[24] Khan AI, Kapoor A, Chen J, Martin L, Rogazzo M, Mercier T, et al. The antimalarial drug artesunate attenuates cardiac injury in a rodent model of myocardial infarction. Shock (Augusta, GA). 2018;49(6):675–81.10.1097/SHK.0000000000000963Search in Google Scholar PubMed

[25] Shi CX, Jin J, Wang XQ, Song T, Li GH, Li KZ, et al. Sevoflurane attenuates brain damage through inhibiting autophagy and apoptosis in cerebral ischemia‑reperfusion rats. Mol Med Rep. 2020;21(1):123–30.10.3892/mmr.2019.10832Search in Google Scholar PubMed PubMed Central

[26] Luo SY, Li R, Le ZY, Li QL, Chen ZW. Anfibatide protects against rat cerebral ischemia/reperfusion injury via TLR4/JNK/caspase-3 pathway. Eur J Pharmacol. 2017;807:127–37.10.1016/j.ejphar.2017.04.002Search in Google Scholar PubMed

[27] Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods (San Diego, CA). 2001;25(4):402–8.10.1006/meth.2001.1262Search in Google Scholar PubMed

[28] Rodrigo R, Fernández-Gajardo R, Gutiérrez R, Matamala JM, Carrasco R, Miranda-Merchak A, et al. Oxidative stress and pathophysiology of ischemic stroke: novel therapeutic opportunities. CNS Neurol Disord Drug Targets. 2013;12(5):698–714.10.2174/1871527311312050015Search in Google Scholar PubMed

[29] Yan RY, Wang SJ, Yao GT, Liu ZG, Xiao N. The protective effect and its mechanism of 3-n-butylphthalide pretreatment on cerebral ischemia reperfusion injury in rats. Eur Rev Med Pharmacol Sci. 2017;21(22):5275–82.Search in Google Scholar

[30] Fan Y, Luo Q, Wei J, Lin R, Lin L, Li Y, et al. Mechanism of salvianolic acid B neuroprotection against ischemia/reperfusion induced cerebral injury. Brain Res. 2018;1679:125–33.10.1016/j.brainres.2017.11.027Search in Google Scholar PubMed

[31] Zhou F, Wang L, Liu P, Hu W, Zhu X, Shen H, et al. Puerarin protects brain tissue against cerebral ischemia/reperfusion injury by inhibiting the inflammatory response. Neural Regener Res. 2014;9(23):2074–80.10.4103/1673-5374.147934Search in Google Scholar PubMed PubMed Central

[32] Xiong Q, Li X, Xia L, Yao Z, Shi X, Dong Z. Dihydroartemisinin attenuates hypoxic-ischemic brain damage in neonatal rats by inhibiting oxidative stress. Mol Brain. 2022;15(1):36.10.1186/s13041-022-00921-ySearch in Google Scholar PubMed PubMed Central

[33] Haybar H, Khodadi E, Kavianpour M, Saki N. Mutations and common polymorphisms in ADAMTS13 and vWF genes responsible for increasing risk of thrombosis. Cardiovasc Hematol Disord Drug Targets. 2018;18(3):176–81.10.2174/1871529X18666180419102214Search in Google Scholar PubMed

[34] Arslan Y, Yoldaş TK, Zorlu Y. Interaction between vWF levels and aspirin resistance in ischemic stroke patients. Transl Stroke Res. 2013;4(5):484–7.10.1007/s12975-013-0259-0Search in Google Scholar PubMed

[35] Martinez de Lizarrondo S, Gakuba C, Herbig BA, Repessé Y, Ali C, Denis CV, et al. Potent thrombolytic effect of N-acetylcysteine on arterial thrombi. Circulation. 2017;136(7):646–60.10.1161/CIRCULATIONAHA.117.027290Search in Google Scholar PubMed PubMed Central

[36] Keep RF, Andjelkovic AV, Xiang J, Stamatovic SM, Antonetti DA, Hua Y, et al. Brain endothelial cell junctions after cerebral hemorrhage: changes, mechanisms and therapeutic targets. J Cereb Blood Flow Metab. 2018;38(8):1255–75.10.1177/0271678X18774666Search in Google Scholar PubMed PubMed Central

[37] Feng S, Zou L, Wang H, He R, Liu K, Zhu H. RhoA/ROCK-2 pathway inhibition and tight junction protein upregulation by catalpol suppresses lipopolysaccaride-induced disruption of blood–brain barrier permeability. Molecules (Basel, Switz). 2018;23(9):2371.10.3390/molecules23092371Search in Google Scholar PubMed PubMed Central

[38] Abdullahi W, Tripathi D, Ronaldson PT. Blood–brain barrier dysfunction in ischemic stroke: targeting tight junctions and transporters for vascular protection. Am J Physiol Cell Physiol. 2018;315(3):C343–56.10.1152/ajpcell.00095.2018Search in Google Scholar PubMed PubMed Central

[39] Shao ZQ, Dou SS, Zhu JG, Wang HQ, Wang CM, Cheng BH, et al. Apelin-13 inhibits apoptosis and excessive autophagy in cerebral ischemia/reperfusion injury. Neural Regener Res. 2021;16(6):1044–51.10.4103/1673-5374.300725Search in Google Scholar PubMed PubMed Central

[40] Ma K, Wu H, Li P, Li B. LC3-II may mediate ATR-induced mitophagy in dopaminergic neurons through SQSTM1/p62 pathway. Acta Biochim Biophys Sin. 2018;50(10):1047–61.10.1093/abbs/gmy091Search in Google Scholar PubMed

[41] Zhang F, Li ZL, Xu XM, Hu Y, Yao JH, Xu W, et al. Protective effects of icariin-mediated SIRT1/FOXO3 signaling pathway on intestinal ischemia/reperfusion-induced acute lung injury. Mol Med Rep. 2015;11(1):269–76.10.3892/mmr.2014.2679Search in Google Scholar PubMed

[42] Wang KJ, Zhang WQ, Liu JJ, Cui Y, Cui JZ. Piceatannol protects against cerebral ischemia/reperfusion‑induced apoptosis and oxidative stress via the Sirt1/FoxO1 signaling pathway. Mol Med Rep. 2020;22(6):5399–411.10.3892/mmr.2020.11618Search in Google Scholar PubMed PubMed Central

[43] Wu Q, Hu Y, Jiang M, Wang F, Gong G. Effect of autophagy regulated by sirt1/Foxo1 pathway on the release of factors promoting thrombosis from vascular endothelial cells. Int J Mol Sci. 2019;20(17):4132.10.3390/ijms20174132Search in Google Scholar PubMed PubMed Central

[44] Ilett KF, Ethell BT, Maggs JL, Davis TM, Batty KT, Burchell B, et al. Glucuronidation of dihydroartemisinin in vivo and by human liver microsomes and expressed UDP-glucuronosyltransferases. Drug Metab Dispos. 2002;30(9):1005–12.10.1124/dmd.30.9.1005Search in Google Scholar PubMed

[45] Morris CA, Duparc S, Borghini-Fuhrer I, Jung D, Shin CS, Fleckenstein L. Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous, intramuscular, oral or rectal administration. Malar J. 2011;10:263.10.1186/1475-2875-10-263Search in Google Scholar PubMed PubMed Central

Received: 2022-08-17
Revised: 2023-03-06
Accepted: 2023-03-22
Published Online: 2023-07-03

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

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

Articles in the same Issue

  1. Research Articles
  2. Exosomes derived from mesenchymal stem cells overexpressing miR-210 inhibits neuronal inflammation and contribute to neurite outgrowth through modulating microglia polarization
  3. Current situation of acute ST-segment elevation myocardial infarction in a county hospital chest pain center during an epidemic of novel coronavirus pneumonia
  4. circ-IARS depletion inhibits the progression of non-small-cell lung cancer by circ-IARS/miR-1252-5p/HDGF ceRNA pathway
  5. circRNA ITGA7 restrains growth and enhances radiosensitivity by up-regulating SMAD4 in colorectal carcinoma
  6. WDR79 promotes aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) by the suppression of SIRT4
  7. Up-regulation of collagen type V alpha 2 (COL5A2) promotes malignant phenotypes in gastric cancer cell via inducing epithelial–mesenchymal transition (EMT)
  8. Inhibition of TERC inhibits neural apoptosis and inflammation in spinal cord injury through Akt activation and p-38 inhibition via the miR-34a-5p/XBP-1 axis
  9. 3D-printed polyether-ether-ketone/n-TiO2 composite enhances the cytocompatibility and osteogenic differentiation of MC3T3-E1 cells by downregulating miR-154-5p
  10. Propofol-mediated circ_0000735 downregulation restrains tumor growth by decreasing integrin-β1 expression in non-small cell lung cancer
  11. PVT1/miR-16/CCND1 axis regulates gastric cancer progression
  12. Silencing of circ_002136 sensitizes gastric cancer to paclitaxel by targeting the miR-16-5p/HMGA1 axis
  13. Short-term outcomes after simultaneous gastrectomy plus cholecystectomy in gastric cancer: A pooling up analysis
  14. SCARA5 inhibits oral squamous cell carcinoma via inactivating the STAT3 and PI3K/AKT signaling pathways
  15. Molecular mechanism by which the Notch signaling pathway regulates autophagy in a rat model of pulmonary fibrosis in pigeon breeder’s lung
  16. lncRNA TPT1-AS1 promotes cell migration and invasion in esophageal squamous-cell carcinomas by regulating the miR-26a/HMGA1 axis
  17. SIRT1/APE1 promotes the viability of gastric cancer cells by inhibiting p53 to suppress ferroptosis
  18. Glycoprotein non-metastatic melanoma B interacts with epidermal growth factor receptor to regulate neural stem cell survival and differentiation
  19. Treatments for brain metastases from EGFR/ALK-negative/unselected NSCLC: A network meta-analysis
  20. Association of osteoporosis and skeletal muscle loss with serum type I collagen carboxyl-terminal peptide β glypeptide: A cross-sectional study in elder Chinese population
  21. circ_0000376 knockdown suppresses non-small cell lung cancer cell tumor properties by the miR-545-3p/PDPK1 pathway
  22. Delivery in a vertical birth chair supported by freedom of movement during labor: A randomized control trial
  23. UBE2J1 knockdown promotes cell apoptosis in endometrial cancer via regulating PI3K/AKT and MDM2/p53 signaling
  24. Metabolic resuscitation therapy in critically ill patients with sepsis and septic shock: A pilot prospective randomized controlled trial
  25. Lycopene ameliorates locomotor activity and urinary frequency induced by pelvic venous congestion in rats
  26. UHRF1-induced connexin26 methylation is involved in hearing damage triggered by intermittent hypoxia in neonatal rats
  27. LINC00511 promotes melanoma progression by targeting miR-610/NUCB2
  28. Ultra-high-performance liquid chromatography-tandem mass spectrometry analysis of serum metabolomic characteristics in people with different vitamin D levels
  29. Role of Jumonji domain-containing protein D3 and its inhibitor GSK-J4 in Hashimoto’s thyroiditis
  30. circ_0014736 induces GPR4 to regulate the biological behaviors of human placental trophoblast cells through miR-942-5p in preeclampsia
  31. Monitoring of sirolimus in the whole blood samples from pediatric patients with lymphatic anomalies
  32. Effects of osteogenic growth peptide C-terminal pentapeptide and its analogue on bone remodeling in an osteoporosis rat model
  33. A novel autophagy-related long non-coding RNAs signature predicting progression-free interval and I-131 therapy benefits in papillary thyroid carcinoma
  34. WGCNA-based identification of potential targets and pathways in response to treatment in locally advanced breast cancer patients
  35. Radiomics model using preoperative computed tomography angiography images to differentiate new from old emboli of acute lower limb arterial embolism
  36. Dysregulated lncRNAs are involved in the progress of myocardial infarction by constructing regulatory networks
  37. Single-arm trial to evaluate the efficacy and safety of baclofen in treatment of intractable hiccup caused by malignant tumor chemotherapy
  38. Genetic polymorphisms of MRPS30-DT and NINJ2 may influence lung cancer risk
  39. Efficacy of immune checkpoint inhibitors in patients with KRAS-mutant advanced non-small cell lung cancer: A retrospective analysis
  40. Pyroptosis-based risk score predicts prognosis and drug sensitivity in lung adenocarcinoma
  41. Upregulation of lncRNA LANCL1-AS1 inhibits the progression of non-small-cell lung cancer via the miR-3680-3p/GMFG axis
  42. CircRANBP17 modulated KDM1A to regulate neuroblastoma progression by sponging miR-27b-3p
  43. Exosomal miR-93-5p regulated the progression of osteoarthritis by targeting ADAMTS9
  44. Downregulation of RBM17 enhances cisplatin sensitivity and inhibits cell invasion in human hypopharyngeal cancer cells
  45. HDAC5-mediated PRAME regulates the proliferation, migration, invasion, and EMT of laryngeal squamous cell carcinoma via the PI3K/AKT/mTOR signaling pathway
  46. The association between sleep duration, quality, and nonalcoholic fatty liver disease: A cross-sectional study
  47. Myostatin silencing inhibits podocyte apoptosis in membranous nephropathy through Smad3/PKA/NOX4 signaling pathway
  48. A novel long noncoding RNA AC125257.1 facilitates colorectal cancer progression by targeting miR-133a-3p/CASC5 axis
  49. Impact of omicron wave and associated control measures in Shanghai on health management and psychosocial well-being of patients with chronic conditions
  50. Clinicopathological characteristics and prognosis of young patients aged ≤45 years old with non-small cell lung cancer
  51. TMT-based comprehensive proteomic profiling identifies serum prognostic signatures of acute myeloid leukemia
  52. The dose limits of teeth protection for patients with nasopharyngeal carcinoma undergoing radiotherapy based on the early oral health-related quality of life
  53. miR-30b-5p targeting GRIN2A inhibits hippocampal damage in epilepsy
  54. Long non-coding RNA AL137789.1 promoted malignant biological behaviors and immune escape of pancreatic carcinoma cells
  55. IRF6 and FGF1 polymorphisms in non-syndromic cleft lip with or without cleft palate in the Polish population
  56. Comprehensive analysis of the role of SFXN family in breast cancer
  57. Efficacy of bronchoscopic intratumoral injection of endostar and cisplatin in lung squamous cell carcinoma patients underwent conventional chemoradiotherapy
  58. Silencing of long noncoding RNA MIAT inhibits the viability and proliferation of breast cancer cells by promoting miR-378a-5p expression
  59. AG1024, an IGF-1 receptor inhibitor, ameliorates renal injury in rats with diabetic nephropathy via the SOCS/JAK2/STAT pathway
  60. Downregulation of KIAA1199 alleviated the activation, proliferation, and migration of hepatic stellate cells by the inhibition of epithelial–mesenchymal transition
  61. Exendin-4 regulates the MAPK and WNT signaling pathways to alleviate the osteogenic inhibition of periodontal ligament stem cells in a high glucose environment
  62. Inhibition of glycolysis represses the growth and alleviates the endoplasmic reticulum stress of breast cancer cells by regulating TMTC3
  63. The function of lncRNA EMX2OS/miR-653-5p and its regulatory mechanism in lung adenocarcinoma
  64. Tectorigenin alleviates the apoptosis and inflammation in spinal cord injury cell model through inhibiting insulin-like growth factor-binding protein 6
  65. Ultrasound examination supporting CT or MRI in the evaluation of cervical lymphadenopathy in patients with irradiation-treated head and neck cancer
  66. F-box and WD repeat domain containing 7 inhibits the activation of hepatic stellate cells by degrading delta-like ligand 1 to block Notch signaling pathway
  67. Knockdown of circ_0005615 enhances the radiosensitivity of colorectal cancer by regulating the miR-665/NOTCH1 axis
  68. Long noncoding RNA Mhrt alleviates angiotensin II-induced cardiac hypertrophy phenotypes by mediating the miR-765/Wnt family member 7B pathway
  69. Effect of miR-499-5p/SOX6 axis on atrial fibrosis in rats with atrial fibrillation
  70. Cholesterol induces inflammation and reduces glucose utilization
  71. circ_0004904 regulates the trophoblast cell in preeclampsia via miR-19b-3p/ARRDC3 axis
  72. NECAB3 promotes the migration and invasion of liver cancer cells through HIF-1α/RIT1 signaling pathway
  73. The poor performance of cardiovascular risk scores in identifying patients with idiopathic inflammatory myopathies at high cardiovascular risk
  74. miR-2053 inhibits the growth of ovarian cancer cells by downregulating SOX4
  75. Nucleophosmin 1 associating with engulfment and cell motility protein 1 regulates hepatocellular carcinoma cell chemotaxis and metastasis
  76. α-Hederin regulates macrophage polarization to relieve sepsis-induced lung and liver injuries in mice
  77. Changes of microbiota level in urinary tract infections: A meta-analysis
  78. Identification of key enzalutamide-resistance-related genes in castration-resistant prostate cancer and verification of RAD51 functions
  79. Falls during oxaliplatin-based chemotherapy for gastrointestinal malignancies – (lessons learned from) a prospective study
  80. Outcomes of low-risk birth care during the Covid-19 pandemic: A cohort study from a tertiary care center in Lithuania
  81. Vitamin D protects intestines from liver cirrhosis-induced inflammation and oxidative stress by inhibiting the TLR4/MyD88/NF-κB signaling pathway
  82. Integrated transcriptome analysis identifies APPL1/RPS6KB2/GALK1 as immune-related metastasis factors in breast cancer
  83. Genomic analysis of immunogenic cell death-related subtypes for predicting prognosis and immunotherapy outcomes in glioblastoma multiforme
  84. Circular RNA Circ_0038467 promotes the maturation of miRNA-203 to increase lipopolysaccharide-induced apoptosis of chondrocytes
  85. An economic evaluation of fine-needle cytology as the primary diagnostic tool in the diagnosis of lymphadenopathy
  86. Midazolam impedes lung carcinoma cell proliferation and migration via EGFR/MEK/ERK signaling pathway
  87. Network pharmacology combined with molecular docking and experimental validation to reveal the pharmacological mechanism of naringin against renal fibrosis
  88. PTPN12 down-regulated by miR-146b-3p gene affects the malignant progression of laryngeal squamous cell carcinoma
  89. miR-141-3p accelerates ovarian cancer progression and promotes M2-like macrophage polarization by targeting the Keap1-Nrf2 pathway
  90. lncRNA OIP5-AS1 attenuates the osteoarthritis progression in IL-1β-stimulated chondrocytes
  91. Overexpression of LINC00607 inhibits cell growth and aggressiveness by regulating the miR-1289/EFNA5 axis in non-small-cell lung cancer
  92. Subjective well-being in informal caregivers during the COVID-19 pandemic
  93. Nrf2 protects against myocardial ischemia-reperfusion injury in diabetic rats by inhibiting Drp1-mediated mitochondrial fission
  94. Unfolded protein response inhibits KAT2B/MLKL-mediated necroptosis of hepatocytes by promoting BMI1 level to ubiquitinate KAT2B
  95. Bladder cancer screening: The new selection and prediction model
  96. circNFATC3 facilitated the progression of oral squamous cell carcinoma via the miR-520h/LDHA axis
  97. Prone position effect in intensive care patients with SARS-COV-2 pneumonia
  98. Clinical observation on the efficacy of Tongdu Tuina manipulation in the treatment of primary enuresis in children
  99. Dihydroartemisinin ameliorates cerebral I/R injury in rats via regulating VWF and autophagy-mediated SIRT1/FOXO1 pathway
  100. Knockdown of circ_0113656 assuages oxidized low-density lipoprotein-induced vascular smooth muscle cell injury through the miR-188-3p/IGF2 pathway
  101. Low Ang-(1–7) and high des-Arg9 bradykinin serum levels are correlated with cardiovascular risk factors in patients with COVID-19
  102. Effect of maternal age and body mass index on induction of labor with oral misoprostol for premature rupture of membrane at term: A retrospective cross-sectional study
  103. Potential protective effects of Huanglian Jiedu Decoction against COVID-19-associated acute kidney injury: A network-based pharmacological and molecular docking study
  104. Clinical significance of serum MBD3 detection in girls with central precocious puberty
  105. Clinical features of varicella-zoster virus caused neurological diseases detected by metagenomic next-generation sequencing
  106. Collagen treatment of complex anorectal fistula: 3 years follow-up
  107. LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through down-regulating SP-A by sponging to miR-424
  108. Efficacy analysis of empirical bismuth quadruple therapy, high-dose dual therapy, and resistance gene-based triple therapy as a first-line Helicobacter pylori eradication regimen – An open-label, randomized trial
  109. SMOC2 plays a role in heart failure via regulating TGF-β1/Smad3 pathway-mediated autophagy
  110. A prospective cohort study of the impact of chronic disease on fall injuries in middle-aged and older adults
  111. circRNA THBS1 silencing inhibits the malignant biological behavior of cervical cancer cells via the regulation of miR-543/HMGB2 axis
  112. hsa_circ_0000285 sponging miR-582-3p promotes neuroblastoma progression by regulating the Wnt/β-catenin signaling pathway
  113. Long non-coding RNA GNAS-AS1 knockdown inhibits proliferation and epithelial–mesenchymal transition of lung adenocarcinoma cells via the microRNA-433-3p/Rab3A axis
  114. lncRNA UCA1 regulates miR-132/Lrrfip1 axis to promote vascular smooth muscle cell proliferation
  115. Twenty-four-color full spectrum flow cytometry panel for minimal residual disease detection in acute myeloid leukemia
  116. Hsa-miR-223-3p participates in the process of anthracycline-induced cardiomyocyte damage by regulating NFIA gene
  117. Anti-inflammatory effect of ApoE23 on Salmonella typhimurium-induced sepsis in mice
  118. Analysis of somatic mutations and key driving factors of cervical cancer progression
  119. Hsa_circ_0028007 regulates the progression of nasopharyngeal carcinoma through the miR-1179/SQLE axis
  120. Variations in sexual function after laparoendoscopic single-site hysterectomy in women with benign gynecologic diseases
  121. Effects of pharmacological delay with roxadustat on multi-territory perforator flap survival in rats
  122. Analysis of heroin effects on calcium channels in rat cardiomyocytes based on transcriptomics and metabolomics
  123. Risk factors of recurrent bacterial vaginosis among women of reproductive age: A cross-sectional study
  124. Alkbh5 plays indispensable roles in maintaining self-renewal of hematopoietic stem cells
  125. Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients
  126. Correlation between microvessel maturity and ISUP grades assessed using contrast-enhanced transrectal ultrasonography in prostate cancer
  127. The protective effect of caffeic acid phenethyl ester in the nephrotoxicity induced by α-cypermethrin
  128. Norepinephrine alleviates cyclosporin A-induced nephrotoxicity by enhancing the expression of SFRP1
  129. Effect of RUNX1/FOXP3 axis on apoptosis of T and B lymphocytes and immunosuppression in sepsis
  130. The function of Foxp1 represses β-adrenergic receptor transcription in the occurrence and development of bladder cancer through STAT3 activity
  131. Risk model and validation of carbapenem-resistant Klebsiella pneumoniae infection in patients with cerebrovascular disease in the ICU
  132. Calycosin protects against chronic prostatitis in rats via inhibition of the p38MAPK/NF-κB pathway
  133. Pan-cancer analysis of the PDE4DIP gene with potential prognostic and immunotherapeutic values in multiple cancers including acute myeloid leukemia
  134. The safety and immunogenicity to inactivated COVID-19 vaccine in patients with hyperlipemia
  135. Circ-UBR4 regulates the proliferation, migration, inflammation, and apoptosis in ox-LDL-induced vascular smooth muscle cells via miR-515-5p/IGF2 axis
  136. Clinical characteristics of current COVID-19 rehabilitation outpatients in China
  137. Luteolin alleviates ulcerative colitis in rats via regulating immune response, oxidative stress, and metabolic profiling
  138. miR-199a-5p inhibits aortic valve calcification by targeting ATF6 and GRP78 in valve interstitial cells
  139. The application of iliac fascia space block combined with esketamine intravenous general anesthesia in PFNA surgery of the elderly: A prospective, single-center, controlled trial
  140. Elevated blood acetoacetate levels reduce major adverse cardiac and cerebrovascular events risk in acute myocardial infarction
  141. The effects of progesterone on the healing of obstetric anal sphincter damage in female rats
  142. Identification of cuproptosis-related genes for predicting the development of prostate cancer
  143. Lumican silencing ameliorates β-glycerophosphate-mediated vascular smooth muscle cell calcification by attenuating the inhibition of APOB on KIF2C activity
  144. Targeting PTBP1 blocks glutamine metabolism to improve the cisplatin sensitivity of hepatocarcinoma cells through modulating the mRNA stability of glutaminase
  145. A single center prospective study: Influences of different hip flexion angles on the measurement of lumbar spine bone mineral density by dual energy X-ray absorptiometry
  146. Clinical analysis of AN69ST membrane continuous venous hemofiltration in the treatment of severe sepsis
  147. Antibiotics therapy combined with probiotics administered intravaginally for the treatment of bacterial vaginosis: A systematic review and meta-analysis
  148. Construction of a ceRNA network to reveal a vascular invasion associated prognostic model in hepatocellular carcinoma
  149. A pan-cancer analysis of STAT3 expression and genetic alterations in human tumors
  150. A prognostic signature based on seven T-cell-related cell clustering genes in bladder urothelial carcinoma
  151. Pepsin concentration in oral lavage fluid of rabbit reflux model constructed by dilating the lower esophageal sphincter
  152. The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC
  153. Tanshinone IIA attenuates valvular interstitial cells’ calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress
  154. AS-IV enhances the antitumor effects of propofol in NSCLC cells by inhibiting autophagy
  155. Establishment of two oxaliplatin-resistant gallbladder cancer cell lines and comprehensive analysis of dysregulated genes
  156. Trial protocol: Feasibility of neuromodulation with connectivity-guided intermittent theta-burst stimulation for improving cognition in multiple sclerosis
  157. LncRNA LINC00592 mediates the promoter methylation of WIF1 to promote the development of bladder cancer
  158. Factors associated with gastrointestinal dysmotility in critically ill patients
  159. Mechanisms by which spinal cord stimulation intervenes in atrial fibrillation: The involvement of the endothelin-1 and nerve growth factor/p75NTR pathways
  160. Analysis of two-gene signatures and related drugs in small-cell lung cancer by bioinformatics
  161. Silencing USP19 alleviates cigarette smoke extract-induced mitochondrial dysfunction in BEAS-2B cells by targeting FUNDC1
  162. Menstrual irregularities associated with COVID-19 vaccines among women in Saudi Arabia: A survey during 2022
  163. Ferroptosis involves in Schwann cell death in diabetic peripheral neuropathy
  164. The effect of AQP4 on tau protein aggregation in neurodegeneration and persistent neuroinflammation after cerebral microinfarcts
  165. Activation of UBEC2 by transcription factor MYBL2 affects DNA damage and promotes gastric cancer progression and cisplatin resistance
  166. Analysis of clinical characteristics in proximal and distal reflux monitoring among patients with gastroesophageal reflux disease
  167. Exosomal circ-0020887 and circ-0009590 as novel biomarkers for the diagnosis and prediction of short-term adverse cardiovascular outcomes in STEMI patients
  168. Upregulated microRNA-429 confers endometrial stromal cell dysfunction by targeting HIF1AN and regulating the HIF1A/VEGF pathway
  169. Bibliometrics and knowledge map analysis of ultrasound-guided regional anesthesia
  170. Knockdown of NUPR1 inhibits angiogenesis in lung cancer through IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways
  171. D-dimer trends predict COVID-19 patient’s prognosis: A retrospective chart review study
  172. WTAP affects intracranial aneurysm progression by regulating m6A methylation modification
  173. Using of endoscopic polypectomy in patients with diagnosed malignant colorectal polyp – The cross-sectional clinical study
  174. Anti-S100A4 antibody administration alleviates bronchial epithelial–mesenchymal transition in asthmatic mice
  175. Prognostic evaluation of system immune-inflammatory index and prognostic nutritional index in double expressor diffuse large B-cell lymphoma
  176. Prevalence and antibiogram of bacteria causing urinary tract infection among patients with chronic kidney disease
  177. Reactive oxygen species within the vaginal space: An additional promoter of cervical intraepithelial neoplasia and uterine cervical cancer development?
  178. Identification of disulfidptosis-related genes and immune infiltration in lower-grade glioma
  179. A new technique for uterine-preserving pelvic organ prolapse surgery: Laparoscopic rectus abdominis hysteropexy for uterine prolapse by comparing with traditional techniques
  180. Self-isolation of an Italian long-term care facility during COVID-19 pandemic: A comparison study on care-related infectious episodes
  181. A comparative study on the overlapping effects of clinically applicable therapeutic interventions in patients with central nervous system damage
  182. Low intensity extracorporeal shockwave therapy for chronic pelvic pain syndrome: Long-term follow-up
  183. The diagnostic accuracy of touch imprint cytology for sentinel lymph node metastases of breast cancer: An up-to-date meta-analysis of 4,073 patients
  184. Mortality associated with Sjögren’s syndrome in the United States in the 1999–2020 period: A multiple cause-of-death study
  185. CircMMP11 as a prognostic biomarker mediates miR-361-3p/HMGB1 axis to accelerate malignant progression of hepatocellular carcinoma
  186. Analysis of the clinical characteristics and prognosis of adult de novo acute myeloid leukemia (none APL) with PTPN11 mutations
  187. KMT2A maintains stemness of gastric cancer cells through regulating Wnt/β-catenin signaling-activated transcriptional factor KLF11
  188. Evaluation of placental oxygenation by near-infrared spectroscopy in relation to ultrasound maturation grade in physiological term pregnancies
  189. The role of ultrasonographic findings for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer
  190. Construction of immunogenic cell death-related molecular subtypes and prognostic signature in colorectal cancer
  191. Long-term prognostic value of high-sensitivity cardiac troponin-I in patients with idiopathic dilated cardiomyopathy
  192. Establishing a novel Fanconi anemia signaling pathway-associated prognostic model and tumor clustering for pediatric acute myeloid leukemia patients
  193. Integrative bioinformatics analysis reveals STAT2 as a novel biomarker of inflammation-related cardiac dysfunction in atrial fibrillation
  194. Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway
  195. Real-world practice of idiopathic pulmonary fibrosis: Results from a 2000–2016 cohort
  196. lncRNA LENGA sponges miR-378 to promote myocardial fibrosis in atrial fibrillation
  197. Diagnostic value of urinary Tamm-Horsfall protein and 24 h urine osmolality for recurrent calcium oxalate stones of the upper urinary tract: Cross-sectional study
  198. The value of color Doppler ultrasonography combined with serum tumor markers in differential diagnosis of gastric stromal tumor and gastric cancer
  199. The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A
  200. Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis
  201. MiR-1278 targets CALD1 and suppresses the progression of gastric cancer via the MAPK pathway
  202. Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson’s disease after dietary supplementation with branched-chain amino acids
  203. Cimifugin inhibits adipogenesis and TNF-α-induced insulin resistance in 3T3-L1 cells
  204. Predictors of gastrointestinal complaints in patients on metformin therapy
  205. Prescribing patterns in patients with chronic obstructive pulmonary disease and atrial fibrillation
  206. A retrospective analysis of the effect of latent tuberculosis infection on clinical pregnancy outcomes of in vitro fertilization–fresh embryo transferred in infertile women
  207. Appropriateness and clinical outcomes of short sustained low-efficiency dialysis: A national experience
  208. miR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD
  209. Clinical features and management of lymphoepithelial cyst
  210. Serum VEGF, high-sensitivity CRP, and cystatin-C assist in the diagnosis of type 2 diabetic retinopathy complicated with hyperuricemia
  211. ENPP1 ameliorates vascular calcification via inhibiting the osteogenic transformation of VSMCs and generating PPi
  212. Significance of monitoring the levels of thyroid hormone antibodies and glucose and lipid metabolism antibodies in patients suffer from type 2 diabetes
  213. The causal relationship between immune cells and different kidney diseases: A Mendelian randomization study
  214. Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units
  215. Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction
  216. Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway
  217. miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor
  218. Diagnostic and prognostic value of MR-pro ADM, procalcitonin, and copeptin in sepsis
  219. Review Articles
  220. Prenatal diagnosis of fetal defects and its implications on the delivery mode
  221. Electromagnetic fields exposure on fetal and childhood abnormalities: Systematic review and meta-analysis
  222. Characteristics of antibiotic resistance mechanisms and genes of Klebsiella pneumoniae
  223. Saddle pulmonary embolism in the setting of COVID-19 infection: A systematic review of case reports and case series
  224. Vitamin C and epigenetics: A short physiological overview
  225. Ebselen: A promising therapy protecting cardiomyocytes from excess iron in iron-overloaded thalassemia patients
  226. Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery
  227. Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review
  228. Surgical management and outcomes of traumatic global brachial plexus injury: A concise review and our center approach
  229. The progress of autoimmune hepatitis research and future challenges
  230. METTL16 in human diseases: What should we do next?
  231. New insights into the prevention of ureteral stents encrustation
  232. VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature
  233. Case Reports
  234. Mycobacterium xenopi infection of the kidney and lymph nodes: A case report
  235. Genetic mutation of SLC6A20 (c.1072T > C) in a family with nephrolithiasis: A case report
  236. Chronic hepatitis B complicated with secondary hemochromatosis was cured clinically: A case report
  237. Liver abscess complicated with multiple organ invasive infection caused by hematogenous disseminated hypervirulent Klebsiella pneumoniae: A case report
  238. Urokinase-based lock solutions for catheter salvage: A case of an upcoming kidney transplant recipient
  239. Two case reports of maturity-onset diabetes of the young type 3 caused by the hepatocyte nuclear factor 1α gene mutation
  240. Immune checkpoint inhibitor-related pancreatitis: What is known and what is not
  241. Does total hip arthroplasty result in intercostal nerve injury? A case report and literature review
  242. Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review
  243. Synchronous triple primary gastrointestinal malignant tumors treated with laparoscopic surgery: A case report
  244. CT-guided percutaneous microwave ablation combined with bone cement injection for the treatment of transverse metastases: A case report
  245. Malignant hyperthermia: Report on a successful rescue of a case with the highest temperature of 44.2°C
  246. Anesthetic management of fetal pulmonary valvuloplasty: A case report
  247. Rapid Communication
  248. Impact of COVID-19 lockdown on glycemic levels during pregnancy: A retrospective analysis
  249. Erratum
  250. Erratum to “Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway”
  251. Erratum to: “Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p”
  252. Retraction
  253. Retraction of “Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients”
  254. Retraction of “circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis”
  255. Retraction of “miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells”
  256. Retraction of “SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis”
  257. Retraction of “circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury”
  258. Retraction of “lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells”
  259. Special issue Linking Pathobiological Mechanisms to Clinical Application for cardiovascular diseases
  260. Effect of cardiac rehabilitation therapy on depressed patients with cardiac insufficiency after cardiac surgery
  261. Special issue The evolving saga of RNAs from bench to bedside - Part I
  262. FBLIM1 mRNA is a novel prognostic biomarker and is associated with immune infiltrates in glioma
  263. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part III
  264. Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer
https://doi.org/10.1515/med-2023-0698
Keywords for this article
cerebral ischemia/reperfusion injury; brain microvascular endothelial cells; dihydroartemisinin; von Willebrand factor; SIRT1/FOXO1 pathway; autophagy
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Articles
  2. Exosomes derived from mesenchymal stem cells overexpressing miR-210 inhibits neuronal inflammation and contribute to neurite outgrowth through modulating microglia polarization
  3. Current situation of acute ST-segment elevation myocardial infarction in a county hospital chest pain center during an epidemic of novel coronavirus pneumonia
  4. circ-IARS depletion inhibits the progression of non-small-cell lung cancer by circ-IARS/miR-1252-5p/HDGF ceRNA pathway
  5. circRNA ITGA7 restrains growth and enhances radiosensitivity by up-regulating SMAD4 in colorectal carcinoma
  6. WDR79 promotes aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) by the suppression of SIRT4
  7. Up-regulation of collagen type V alpha 2 (COL5A2) promotes malignant phenotypes in gastric cancer cell via inducing epithelial–mesenchymal transition (EMT)
  8. Inhibition of TERC inhibits neural apoptosis and inflammation in spinal cord injury through Akt activation and p-38 inhibition via the miR-34a-5p/XBP-1 axis
  9. 3D-printed polyether-ether-ketone/n-TiO2 composite enhances the cytocompatibility and osteogenic differentiation of MC3T3-E1 cells by downregulating miR-154-5p
  10. Propofol-mediated circ_0000735 downregulation restrains tumor growth by decreasing integrin-β1 expression in non-small cell lung cancer
  11. PVT1/miR-16/CCND1 axis regulates gastric cancer progression
  12. Silencing of circ_002136 sensitizes gastric cancer to paclitaxel by targeting the miR-16-5p/HMGA1 axis
  13. Short-term outcomes after simultaneous gastrectomy plus cholecystectomy in gastric cancer: A pooling up analysis
  14. SCARA5 inhibits oral squamous cell carcinoma via inactivating the STAT3 and PI3K/AKT signaling pathways
  15. Molecular mechanism by which the Notch signaling pathway regulates autophagy in a rat model of pulmonary fibrosis in pigeon breeder’s lung
  16. lncRNA TPT1-AS1 promotes cell migration and invasion in esophageal squamous-cell carcinomas by regulating the miR-26a/HMGA1 axis
  17. SIRT1/APE1 promotes the viability of gastric cancer cells by inhibiting p53 to suppress ferroptosis
  18. Glycoprotein non-metastatic melanoma B interacts with epidermal growth factor receptor to regulate neural stem cell survival and differentiation
  19. Treatments for brain metastases from EGFR/ALK-negative/unselected NSCLC: A network meta-analysis
  20. Association of osteoporosis and skeletal muscle loss with serum type I collagen carboxyl-terminal peptide β glypeptide: A cross-sectional study in elder Chinese population
  21. circ_0000376 knockdown suppresses non-small cell lung cancer cell tumor properties by the miR-545-3p/PDPK1 pathway
  22. Delivery in a vertical birth chair supported by freedom of movement during labor: A randomized control trial
  23. UBE2J1 knockdown promotes cell apoptosis in endometrial cancer via regulating PI3K/AKT and MDM2/p53 signaling
  24. Metabolic resuscitation therapy in critically ill patients with sepsis and septic shock: A pilot prospective randomized controlled trial
  25. Lycopene ameliorates locomotor activity and urinary frequency induced by pelvic venous congestion in rats
  26. UHRF1-induced connexin26 methylation is involved in hearing damage triggered by intermittent hypoxia in neonatal rats
  27. LINC00511 promotes melanoma progression by targeting miR-610/NUCB2
  28. Ultra-high-performance liquid chromatography-tandem mass spectrometry analysis of serum metabolomic characteristics in people with different vitamin D levels
  29. Role of Jumonji domain-containing protein D3 and its inhibitor GSK-J4 in Hashimoto’s thyroiditis
  30. circ_0014736 induces GPR4 to regulate the biological behaviors of human placental trophoblast cells through miR-942-5p in preeclampsia
  31. Monitoring of sirolimus in the whole blood samples from pediatric patients with lymphatic anomalies
  32. Effects of osteogenic growth peptide C-terminal pentapeptide and its analogue on bone remodeling in an osteoporosis rat model
  33. A novel autophagy-related long non-coding RNAs signature predicting progression-free interval and I-131 therapy benefits in papillary thyroid carcinoma
  34. WGCNA-based identification of potential targets and pathways in response to treatment in locally advanced breast cancer patients
  35. Radiomics model using preoperative computed tomography angiography images to differentiate new from old emboli of acute lower limb arterial embolism
  36. Dysregulated lncRNAs are involved in the progress of myocardial infarction by constructing regulatory networks
  37. Single-arm trial to evaluate the efficacy and safety of baclofen in treatment of intractable hiccup caused by malignant tumor chemotherapy
  38. Genetic polymorphisms of MRPS30-DT and NINJ2 may influence lung cancer risk
  39. Efficacy of immune checkpoint inhibitors in patients with KRAS-mutant advanced non-small cell lung cancer: A retrospective analysis
  40. Pyroptosis-based risk score predicts prognosis and drug sensitivity in lung adenocarcinoma
  41. Upregulation of lncRNA LANCL1-AS1 inhibits the progression of non-small-cell lung cancer via the miR-3680-3p/GMFG axis
  42. CircRANBP17 modulated KDM1A to regulate neuroblastoma progression by sponging miR-27b-3p
  43. Exosomal miR-93-5p regulated the progression of osteoarthritis by targeting ADAMTS9
  44. Downregulation of RBM17 enhances cisplatin sensitivity and inhibits cell invasion in human hypopharyngeal cancer cells
  45. HDAC5-mediated PRAME regulates the proliferation, migration, invasion, and EMT of laryngeal squamous cell carcinoma via the PI3K/AKT/mTOR signaling pathway
  46. The association between sleep duration, quality, and nonalcoholic fatty liver disease: A cross-sectional study
  47. Myostatin silencing inhibits podocyte apoptosis in membranous nephropathy through Smad3/PKA/NOX4 signaling pathway
  48. A novel long noncoding RNA AC125257.1 facilitates colorectal cancer progression by targeting miR-133a-3p/CASC5 axis
  49. Impact of omicron wave and associated control measures in Shanghai on health management and psychosocial well-being of patients with chronic conditions
  50. Clinicopathological characteristics and prognosis of young patients aged ≤45 years old with non-small cell lung cancer
  51. TMT-based comprehensive proteomic profiling identifies serum prognostic signatures of acute myeloid leukemia
  52. The dose limits of teeth protection for patients with nasopharyngeal carcinoma undergoing radiotherapy based on the early oral health-related quality of life
  53. miR-30b-5p targeting GRIN2A inhibits hippocampal damage in epilepsy
  54. Long non-coding RNA AL137789.1 promoted malignant biological behaviors and immune escape of pancreatic carcinoma cells
  55. IRF6 and FGF1 polymorphisms in non-syndromic cleft lip with or without cleft palate in the Polish population
  56. Comprehensive analysis of the role of SFXN family in breast cancer
  57. Efficacy of bronchoscopic intratumoral injection of endostar and cisplatin in lung squamous cell carcinoma patients underwent conventional chemoradiotherapy
  58. Silencing of long noncoding RNA MIAT inhibits the viability and proliferation of breast cancer cells by promoting miR-378a-5p expression
  59. AG1024, an IGF-1 receptor inhibitor, ameliorates renal injury in rats with diabetic nephropathy via the SOCS/JAK2/STAT pathway
  60. Downregulation of KIAA1199 alleviated the activation, proliferation, and migration of hepatic stellate cells by the inhibition of epithelial–mesenchymal transition
  61. Exendin-4 regulates the MAPK and WNT signaling pathways to alleviate the osteogenic inhibition of periodontal ligament stem cells in a high glucose environment
  62. Inhibition of glycolysis represses the growth and alleviates the endoplasmic reticulum stress of breast cancer cells by regulating TMTC3
  63. The function of lncRNA EMX2OS/miR-653-5p and its regulatory mechanism in lung adenocarcinoma
  64. Tectorigenin alleviates the apoptosis and inflammation in spinal cord injury cell model through inhibiting insulin-like growth factor-binding protein 6
  65. Ultrasound examination supporting CT or MRI in the evaluation of cervical lymphadenopathy in patients with irradiation-treated head and neck cancer
  66. F-box and WD repeat domain containing 7 inhibits the activation of hepatic stellate cells by degrading delta-like ligand 1 to block Notch signaling pathway
  67. Knockdown of circ_0005615 enhances the radiosensitivity of colorectal cancer by regulating the miR-665/NOTCH1 axis
  68. Long noncoding RNA Mhrt alleviates angiotensin II-induced cardiac hypertrophy phenotypes by mediating the miR-765/Wnt family member 7B pathway
  69. Effect of miR-499-5p/SOX6 axis on atrial fibrosis in rats with atrial fibrillation
  70. Cholesterol induces inflammation and reduces glucose utilization
  71. circ_0004904 regulates the trophoblast cell in preeclampsia via miR-19b-3p/ARRDC3 axis
  72. NECAB3 promotes the migration and invasion of liver cancer cells through HIF-1α/RIT1 signaling pathway
  73. The poor performance of cardiovascular risk scores in identifying patients with idiopathic inflammatory myopathies at high cardiovascular risk
  74. miR-2053 inhibits the growth of ovarian cancer cells by downregulating SOX4
  75. Nucleophosmin 1 associating with engulfment and cell motility protein 1 regulates hepatocellular carcinoma cell chemotaxis and metastasis
  76. α-Hederin regulates macrophage polarization to relieve sepsis-induced lung and liver injuries in mice
  77. Changes of microbiota level in urinary tract infections: A meta-analysis
  78. Identification of key enzalutamide-resistance-related genes in castration-resistant prostate cancer and verification of RAD51 functions
  79. Falls during oxaliplatin-based chemotherapy for gastrointestinal malignancies – (lessons learned from) a prospective study
  80. Outcomes of low-risk birth care during the Covid-19 pandemic: A cohort study from a tertiary care center in Lithuania
  81. Vitamin D protects intestines from liver cirrhosis-induced inflammation and oxidative stress by inhibiting the TLR4/MyD88/NF-κB signaling pathway
  82. Integrated transcriptome analysis identifies APPL1/RPS6KB2/GALK1 as immune-related metastasis factors in breast cancer
  83. Genomic analysis of immunogenic cell death-related subtypes for predicting prognosis and immunotherapy outcomes in glioblastoma multiforme
  84. Circular RNA Circ_0038467 promotes the maturation of miRNA-203 to increase lipopolysaccharide-induced apoptosis of chondrocytes
  85. An economic evaluation of fine-needle cytology as the primary diagnostic tool in the diagnosis of lymphadenopathy
  86. Midazolam impedes lung carcinoma cell proliferation and migration via EGFR/MEK/ERK signaling pathway
  87. Network pharmacology combined with molecular docking and experimental validation to reveal the pharmacological mechanism of naringin against renal fibrosis
  88. PTPN12 down-regulated by miR-146b-3p gene affects the malignant progression of laryngeal squamous cell carcinoma
  89. miR-141-3p accelerates ovarian cancer progression and promotes M2-like macrophage polarization by targeting the Keap1-Nrf2 pathway
  90. lncRNA OIP5-AS1 attenuates the osteoarthritis progression in IL-1β-stimulated chondrocytes
  91. Overexpression of LINC00607 inhibits cell growth and aggressiveness by regulating the miR-1289/EFNA5 axis in non-small-cell lung cancer
  92. Subjective well-being in informal caregivers during the COVID-19 pandemic
  93. Nrf2 protects against myocardial ischemia-reperfusion injury in diabetic rats by inhibiting Drp1-mediated mitochondrial fission
  94. Unfolded protein response inhibits KAT2B/MLKL-mediated necroptosis of hepatocytes by promoting BMI1 level to ubiquitinate KAT2B
  95. Bladder cancer screening: The new selection and prediction model
  96. circNFATC3 facilitated the progression of oral squamous cell carcinoma via the miR-520h/LDHA axis
  97. Prone position effect in intensive care patients with SARS-COV-2 pneumonia
  98. Clinical observation on the efficacy of Tongdu Tuina manipulation in the treatment of primary enuresis in children
  99. Dihydroartemisinin ameliorates cerebral I/R injury in rats via regulating VWF and autophagy-mediated SIRT1/FOXO1 pathway
  100. Knockdown of circ_0113656 assuages oxidized low-density lipoprotein-induced vascular smooth muscle cell injury through the miR-188-3p/IGF2 pathway
  101. Low Ang-(1–7) and high des-Arg9 bradykinin serum levels are correlated with cardiovascular risk factors in patients with COVID-19
  102. Effect of maternal age and body mass index on induction of labor with oral misoprostol for premature rupture of membrane at term: A retrospective cross-sectional study
  103. Potential protective effects of Huanglian Jiedu Decoction against COVID-19-associated acute kidney injury: A network-based pharmacological and molecular docking study
  104. Clinical significance of serum MBD3 detection in girls with central precocious puberty
  105. Clinical features of varicella-zoster virus caused neurological diseases detected by metagenomic next-generation sequencing
  106. Collagen treatment of complex anorectal fistula: 3 years follow-up
  107. LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through down-regulating SP-A by sponging to miR-424
  108. Efficacy analysis of empirical bismuth quadruple therapy, high-dose dual therapy, and resistance gene-based triple therapy as a first-line Helicobacter pylori eradication regimen – An open-label, randomized trial
  109. SMOC2 plays a role in heart failure via regulating TGF-β1/Smad3 pathway-mediated autophagy
  110. A prospective cohort study of the impact of chronic disease on fall injuries in middle-aged and older adults
  111. circRNA THBS1 silencing inhibits the malignant biological behavior of cervical cancer cells via the regulation of miR-543/HMGB2 axis
  112. hsa_circ_0000285 sponging miR-582-3p promotes neuroblastoma progression by regulating the Wnt/β-catenin signaling pathway
  113. Long non-coding RNA GNAS-AS1 knockdown inhibits proliferation and epithelial–mesenchymal transition of lung adenocarcinoma cells via the microRNA-433-3p/Rab3A axis
  114. lncRNA UCA1 regulates miR-132/Lrrfip1 axis to promote vascular smooth muscle cell proliferation
  115. Twenty-four-color full spectrum flow cytometry panel for minimal residual disease detection in acute myeloid leukemia
  116. Hsa-miR-223-3p participates in the process of anthracycline-induced cardiomyocyte damage by regulating NFIA gene
  117. Anti-inflammatory effect of ApoE23 on Salmonella typhimurium-induced sepsis in mice
  118. Analysis of somatic mutations and key driving factors of cervical cancer progression
  119. Hsa_circ_0028007 regulates the progression of nasopharyngeal carcinoma through the miR-1179/SQLE axis
  120. Variations in sexual function after laparoendoscopic single-site hysterectomy in women with benign gynecologic diseases
  121. Effects of pharmacological delay with roxadustat on multi-territory perforator flap survival in rats
  122. Analysis of heroin effects on calcium channels in rat cardiomyocytes based on transcriptomics and metabolomics
  123. Risk factors of recurrent bacterial vaginosis among women of reproductive age: A cross-sectional study
  124. Alkbh5 plays indispensable roles in maintaining self-renewal of hematopoietic stem cells
  125. Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients
  126. Correlation between microvessel maturity and ISUP grades assessed using contrast-enhanced transrectal ultrasonography in prostate cancer
  127. The protective effect of caffeic acid phenethyl ester in the nephrotoxicity induced by α-cypermethrin
  128. Norepinephrine alleviates cyclosporin A-induced nephrotoxicity by enhancing the expression of SFRP1
  129. Effect of RUNX1/FOXP3 axis on apoptosis of T and B lymphocytes and immunosuppression in sepsis
  130. The function of Foxp1 represses β-adrenergic receptor transcription in the occurrence and development of bladder cancer through STAT3 activity
  131. Risk model and validation of carbapenem-resistant Klebsiella pneumoniae infection in patients with cerebrovascular disease in the ICU
  132. Calycosin protects against chronic prostatitis in rats via inhibition of the p38MAPK/NF-κB pathway
  133. Pan-cancer analysis of the PDE4DIP gene with potential prognostic and immunotherapeutic values in multiple cancers including acute myeloid leukemia
  134. The safety and immunogenicity to inactivated COVID-19 vaccine in patients with hyperlipemia
  135. Circ-UBR4 regulates the proliferation, migration, inflammation, and apoptosis in ox-LDL-induced vascular smooth muscle cells via miR-515-5p/IGF2 axis
  136. Clinical characteristics of current COVID-19 rehabilitation outpatients in China
  137. Luteolin alleviates ulcerative colitis in rats via regulating immune response, oxidative stress, and metabolic profiling
  138. miR-199a-5p inhibits aortic valve calcification by targeting ATF6 and GRP78 in valve interstitial cells
  139. The application of iliac fascia space block combined with esketamine intravenous general anesthesia in PFNA surgery of the elderly: A prospective, single-center, controlled trial
  140. Elevated blood acetoacetate levels reduce major adverse cardiac and cerebrovascular events risk in acute myocardial infarction
  141. The effects of progesterone on the healing of obstetric anal sphincter damage in female rats
  142. Identification of cuproptosis-related genes for predicting the development of prostate cancer
  143. Lumican silencing ameliorates β-glycerophosphate-mediated vascular smooth muscle cell calcification by attenuating the inhibition of APOB on KIF2C activity
  144. Targeting PTBP1 blocks glutamine metabolism to improve the cisplatin sensitivity of hepatocarcinoma cells through modulating the mRNA stability of glutaminase
  145. A single center prospective study: Influences of different hip flexion angles on the measurement of lumbar spine bone mineral density by dual energy X-ray absorptiometry
  146. Clinical analysis of AN69ST membrane continuous venous hemofiltration in the treatment of severe sepsis
  147. Antibiotics therapy combined with probiotics administered intravaginally for the treatment of bacterial vaginosis: A systematic review and meta-analysis
  148. Construction of a ceRNA network to reveal a vascular invasion associated prognostic model in hepatocellular carcinoma
  149. A pan-cancer analysis of STAT3 expression and genetic alterations in human tumors
  150. A prognostic signature based on seven T-cell-related cell clustering genes in bladder urothelial carcinoma
  151. Pepsin concentration in oral lavage fluid of rabbit reflux model constructed by dilating the lower esophageal sphincter
  152. The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC
  153. Tanshinone IIA attenuates valvular interstitial cells’ calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress
  154. AS-IV enhances the antitumor effects of propofol in NSCLC cells by inhibiting autophagy
  155. Establishment of two oxaliplatin-resistant gallbladder cancer cell lines and comprehensive analysis of dysregulated genes
  156. Trial protocol: Feasibility of neuromodulation with connectivity-guided intermittent theta-burst stimulation for improving cognition in multiple sclerosis
  157. LncRNA LINC00592 mediates the promoter methylation of WIF1 to promote the development of bladder cancer
  158. Factors associated with gastrointestinal dysmotility in critically ill patients
  159. Mechanisms by which spinal cord stimulation intervenes in atrial fibrillation: The involvement of the endothelin-1 and nerve growth factor/p75NTR pathways
  160. Analysis of two-gene signatures and related drugs in small-cell lung cancer by bioinformatics
  161. Silencing USP19 alleviates cigarette smoke extract-induced mitochondrial dysfunction in BEAS-2B cells by targeting FUNDC1
  162. Menstrual irregularities associated with COVID-19 vaccines among women in Saudi Arabia: A survey during 2022
  163. Ferroptosis involves in Schwann cell death in diabetic peripheral neuropathy
  164. The effect of AQP4 on tau protein aggregation in neurodegeneration and persistent neuroinflammation after cerebral microinfarcts
  165. Activation of UBEC2 by transcription factor MYBL2 affects DNA damage and promotes gastric cancer progression and cisplatin resistance
  166. Analysis of clinical characteristics in proximal and distal reflux monitoring among patients with gastroesophageal reflux disease
  167. Exosomal circ-0020887 and circ-0009590 as novel biomarkers for the diagnosis and prediction of short-term adverse cardiovascular outcomes in STEMI patients
  168. Upregulated microRNA-429 confers endometrial stromal cell dysfunction by targeting HIF1AN and regulating the HIF1A/VEGF pathway
  169. Bibliometrics and knowledge map analysis of ultrasound-guided regional anesthesia
  170. Knockdown of NUPR1 inhibits angiogenesis in lung cancer through IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways
  171. D-dimer trends predict COVID-19 patient’s prognosis: A retrospective chart review study
  172. WTAP affects intracranial aneurysm progression by regulating m6A methylation modification
  173. Using of endoscopic polypectomy in patients with diagnosed malignant colorectal polyp – The cross-sectional clinical study
  174. Anti-S100A4 antibody administration alleviates bronchial epithelial–mesenchymal transition in asthmatic mice
  175. Prognostic evaluation of system immune-inflammatory index and prognostic nutritional index in double expressor diffuse large B-cell lymphoma
  176. Prevalence and antibiogram of bacteria causing urinary tract infection among patients with chronic kidney disease
  177. Reactive oxygen species within the vaginal space: An additional promoter of cervical intraepithelial neoplasia and uterine cervical cancer development?
  178. Identification of disulfidptosis-related genes and immune infiltration in lower-grade glioma
  179. A new technique for uterine-preserving pelvic organ prolapse surgery: Laparoscopic rectus abdominis hysteropexy for uterine prolapse by comparing with traditional techniques
  180. Self-isolation of an Italian long-term care facility during COVID-19 pandemic: A comparison study on care-related infectious episodes
  181. A comparative study on the overlapping effects of clinically applicable therapeutic interventions in patients with central nervous system damage
  182. Low intensity extracorporeal shockwave therapy for chronic pelvic pain syndrome: Long-term follow-up
  183. The diagnostic accuracy of touch imprint cytology for sentinel lymph node metastases of breast cancer: An up-to-date meta-analysis of 4,073 patients
  184. Mortality associated with Sjögren’s syndrome in the United States in the 1999–2020 period: A multiple cause-of-death study
  185. CircMMP11 as a prognostic biomarker mediates miR-361-3p/HMGB1 axis to accelerate malignant progression of hepatocellular carcinoma
  186. Analysis of the clinical characteristics and prognosis of adult de novo acute myeloid leukemia (none APL) with PTPN11 mutations
  187. KMT2A maintains stemness of gastric cancer cells through regulating Wnt/β-catenin signaling-activated transcriptional factor KLF11
  188. Evaluation of placental oxygenation by near-infrared spectroscopy in relation to ultrasound maturation grade in physiological term pregnancies
  189. The role of ultrasonographic findings for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer
  190. Construction of immunogenic cell death-related molecular subtypes and prognostic signature in colorectal cancer
  191. Long-term prognostic value of high-sensitivity cardiac troponin-I in patients with idiopathic dilated cardiomyopathy
  192. Establishing a novel Fanconi anemia signaling pathway-associated prognostic model and tumor clustering for pediatric acute myeloid leukemia patients
  193. Integrative bioinformatics analysis reveals STAT2 as a novel biomarker of inflammation-related cardiac dysfunction in atrial fibrillation
  194. Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway
  195. Real-world practice of idiopathic pulmonary fibrosis: Results from a 2000–2016 cohort
  196. lncRNA LENGA sponges miR-378 to promote myocardial fibrosis in atrial fibrillation
  197. Diagnostic value of urinary Tamm-Horsfall protein and 24 h urine osmolality for recurrent calcium oxalate stones of the upper urinary tract: Cross-sectional study
  198. The value of color Doppler ultrasonography combined with serum tumor markers in differential diagnosis of gastric stromal tumor and gastric cancer
  199. The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A
  200. Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis
  201. MiR-1278 targets CALD1 and suppresses the progression of gastric cancer via the MAPK pathway
  202. Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson’s disease after dietary supplementation with branched-chain amino acids
  203. Cimifugin inhibits adipogenesis and TNF-α-induced insulin resistance in 3T3-L1 cells
  204. Predictors of gastrointestinal complaints in patients on metformin therapy
  205. Prescribing patterns in patients with chronic obstructive pulmonary disease and atrial fibrillation
  206. A retrospective analysis of the effect of latent tuberculosis infection on clinical pregnancy outcomes of in vitro fertilization–fresh embryo transferred in infertile women
  207. Appropriateness and clinical outcomes of short sustained low-efficiency dialysis: A national experience
  208. miR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD
  209. Clinical features and management of lymphoepithelial cyst
  210. Serum VEGF, high-sensitivity CRP, and cystatin-C assist in the diagnosis of type 2 diabetic retinopathy complicated with hyperuricemia
  211. ENPP1 ameliorates vascular calcification via inhibiting the osteogenic transformation of VSMCs and generating PPi
  212. Significance of monitoring the levels of thyroid hormone antibodies and glucose and lipid metabolism antibodies in patients suffer from type 2 diabetes
  213. The causal relationship between immune cells and different kidney diseases: A Mendelian randomization study
  214. Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units
  215. Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction
  216. Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway
  217. miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor
  218. Diagnostic and prognostic value of MR-pro ADM, procalcitonin, and copeptin in sepsis
  219. Review Articles
  220. Prenatal diagnosis of fetal defects and its implications on the delivery mode
  221. Electromagnetic fields exposure on fetal and childhood abnormalities: Systematic review and meta-analysis
  222. Characteristics of antibiotic resistance mechanisms and genes of Klebsiella pneumoniae
  223. Saddle pulmonary embolism in the setting of COVID-19 infection: A systematic review of case reports and case series
  224. Vitamin C and epigenetics: A short physiological overview
  225. Ebselen: A promising therapy protecting cardiomyocytes from excess iron in iron-overloaded thalassemia patients
  226. Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery
  227. Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review
  228. Surgical management and outcomes of traumatic global brachial plexus injury: A concise review and our center approach
  229. The progress of autoimmune hepatitis research and future challenges
  230. METTL16 in human diseases: What should we do next?
  231. New insights into the prevention of ureteral stents encrustation
  232. VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature
  233. Case Reports
  234. Mycobacterium xenopi infection of the kidney and lymph nodes: A case report
  235. Genetic mutation of SLC6A20 (c.1072T > C) in a family with nephrolithiasis: A case report
  236. Chronic hepatitis B complicated with secondary hemochromatosis was cured clinically: A case report
  237. Liver abscess complicated with multiple organ invasive infection caused by hematogenous disseminated hypervirulent Klebsiella pneumoniae: A case report
  238. Urokinase-based lock solutions for catheter salvage: A case of an upcoming kidney transplant recipient
  239. Two case reports of maturity-onset diabetes of the young type 3 caused by the hepatocyte nuclear factor 1α gene mutation
  240. Immune checkpoint inhibitor-related pancreatitis: What is known and what is not
  241. Does total hip arthroplasty result in intercostal nerve injury? A case report and literature review
  242. Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review
  243. Synchronous triple primary gastrointestinal malignant tumors treated with laparoscopic surgery: A case report
  244. CT-guided percutaneous microwave ablation combined with bone cement injection for the treatment of transverse metastases: A case report
  245. Malignant hyperthermia: Report on a successful rescue of a case with the highest temperature of 44.2°C
  246. Anesthetic management of fetal pulmonary valvuloplasty: A case report
  247. Rapid Communication
  248. Impact of COVID-19 lockdown on glycemic levels during pregnancy: A retrospective analysis
  249. Erratum
  250. Erratum to “Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway”
  251. Erratum to: “Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p”
  252. Retraction
  253. Retraction of “Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients”
  254. Retraction of “circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis”
  255. Retraction of “miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells”
  256. Retraction of “SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis”
  257. Retraction of “circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury”
  258. Retraction of “lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells”
  259. Special issue Linking Pathobiological Mechanisms to Clinical Application for cardiovascular diseases
  260. Effect of cardiac rehabilitation therapy on depressed patients with cardiac insufficiency after cardiac surgery
  261. Special issue The evolving saga of RNAs from bench to bedside - Part I
  262. FBLIM1 mRNA is a novel prognostic biomarker and is associated with immune infiltrates in glioma
  263. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part III
  264. Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 11.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/med-2023-0698/html
Scroll to top button