Home Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway
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Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway

  • Zhi Tang , Chunhua Yang , Zhengwen He , Zhiyong Deng and Xiaoming Li EMAIL logo
Published/Copyright: April 13, 2022
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Open Medicine
From the journal Open Medicine Volume 17 Issue 1

Abstract

Spinal cord injury (SCI) is a devastating incident that induces neuronal loss and dysfunction. Notoginsenoside R1 (NGR1) has been reported to exhibit a neuroprotective role after SCI. In this study, the effect and molecular mechanisms of NGR1 in models of SCI were further investigated. Rat adrenal pheochromocytoma cell line (PC-12) were stimulated with lipopolysaccharide (LPS) to establish a cell model of SCI-like condition. The changes of proinflammatory cytokines and associated proteins were analyzed using enzyme linked immunosorbent assay (ELISA) and western blotting. A rat model of SCI was established. Nissl staining were used to observe the morphological characteristics of spinal cord tissues. reverse transcription-quantitative PCR (RT-qPCR) was used to measure the expression of miR-301a andKrüppel-like factor 7 (KLF7). Our results showed that NGR1 alleviated LPS-triggered apoptosis and inflammation in PC-12 cells. MiR-301a was upregulated in LPS-stimulated PC-12 cells and was downregulated by NGR1 treatment. MiR-301a overexpression reversed the effect of NGR1 in LPS-treated PC-12 cells. KLF7 was verified to be targeted by miR-301a. NGR1 activated Wnt/β-catenin signaling in LPS-treated PC-12 cells by inhibiting miR-301a and upregulating KLF7. Moreover, blocking wingless/integrated (Wnt)/β-catenin signaling eliminated the protective effect of NGR1 against SCI in vitro and in vivo. Overall, NGR1 could reduce inflammation and apoptosis and promote functional recovery of SCI rats by activating Wnt/β-catenin pathway.

Keywords: notoginsenoside R1; miR-301a; KLF7; spinal cord injury

1 Introduction

Spinal cord injury (SCI) is a serious neurological injury in the central nervous system caused by fracture or dislocation of the spine [1]. The pathological process of SCI is typically divided into two phases: primary and secondary injury. Secondary SCI is mainly promoted by inflammatory response caused by the excretion of proinflammatory cytokines, which promotes nerve injury and apoptosis (Tator, 1991 #3231). Studies have shown that interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 levels are increased in the early stage of SCI [2,3]. The inflammation and apoptosis of the spinal cord are important parts of the mechanism of secondary SCI and affect the recovery and outcome of nerve function after SCI [4,5]. Therefore, the regulatory mechanism of inflammation and apoptosis should be studied. Neuronlike rat adrenal pheochromocytoma cell line (PC-12) originate from neuroblastic cells, which can differentiate into sympathetic-neuron-like cells and thus have been regarded as a tool for the study of molecular processes associated with neuronal differentiation and morphogenesis [6,7]. This cell line is a widely used cell model for studying SCI [8–10]. Lipopolysaccharide (LPS), an endotoxin in the outer membranes of gram-negative bacteria, can trigger the release of a large number of inflammatory cytokines such as TNF-α and IL-6 [11]. Therefore, in this study, we constructed an inflammatory injury model of PC-12 cells using LPS to mimic the second injury of SCI, and cell viability, apoptosis, and release of inflammatory cytokines were measured to evaluate cell injury.

Notoginsenoside R1 (NGR1) is a herbal medicine extracted from panax notoginsenoside, which is well known in the prescription for mediating the micro-circulatory hemostasis in humans [12]. It has been found that the pharmacological properties of panax notoginsenoside are mainly attributed to the effect of NGR1 [13]. NGR1 exhibits potent characteristics of neuroprotective, anti-inflammatory, anti-apoptosis, anti-ischemia-reperfusion injury properties, etc. [14]. NGR1 substantially eliminates oxidative stress, consequently maintains mitochondrial homeostasis, and finally impedes excessive inflammatory responses [15]. Notably, it was demonstrated that panax notoginsenoside produces neuroprotective effects in the rat models of acute spinal cord ischemia-reperfusion injury [16]. NGR1 has an anti-inflammatory effect on SCI injury by controlling miR-132 [17]. However, the exact regulatory mechanisms related to NGR1 in SCI need further investigation.

MicroRNAs (miRNAs) are a subtype of non-coding RNA that is involved in the regulation of a variety of biological processes [18]. In previous studies, miRNAs have been demonstrated to play significant roles in numerous diseases. For instance, miR-182-5p restrains the lymphangiogenesis and tumorigenesis in colon cancer by targeting vascular endothelial growth factor-C (VEGF-C) [19]. MiR-155 silencing attenuates inflammation in chronic obstructive pulmonary disease [20]. MiR-370-3p promotes endothelial cell proliferation and tube formation via regulating phosph-small mothers against decapentaplegic 3 (SMAD3) [21]. In addition, numerous miRNAs have been found to be associated with the pathological response after SCI [22]. The dysregulation of miRNAs has shown to cause uncontrolled generation of inflammatory cytokines resulting in various diseases [23]. MiR-301a is located in the first intron of the host gene spindle and kinetochore-associated protein-2 [24]. MiR-301a is described to be implicated in the pathogenesis of inflammation. As widely suggested, miR-301a overexpression exacerbates inflammation [25,26]. Mechanically, studies have found that miR-301a directly regulates cytokines expression or indirectly mediates the transcriptional progress by activating or blunting relevant signaling pathways [25,27]. Moreover, a study indicated that NGR1 mitigates LPS-elicited inflammatory injury in mouse clonal chondrogenic cell line (ATDC5) cells by inhibiting miR-301a [28]. This suggests that NGR1 may interfere with miR-301a under inflammatory conditions. More studies are needed to test whether miR-301a joins in the influence of NGR1 on LPS-stimulated PC-12 cells.

In this study, we further consolidated the protective effect of NGR1 against LPS-triggered inflammatory injury. The molecular mechanisms involved in miR-301a were investigated. We aimed to uncover the association between NGR1 and miR-301a in the pathological response of SCI.

2 Materials and methods

2.1 Cell culture and treatment

PC-12 (CRL-1721™) and human embryonic kidney (HEK)293T (ACS-4500™) cells were obtained from American Type Culture Collection (ATCC) (Manassas, VA, USA), and cultured in Dulbecco’s Modified Eagle’s medium (DMEM) (cat. no. 10569010; Gibco, Grand Island, NY, USA) containing 10% fetal bovine serum (FBS) (cat. no. SH30070.03; HyClone, Logan, UT, USA) in a humidified 5% CO2 condition at 37°C. Inflammatory conditions of PC-12 cells were induced by treatment with doses of LPS (0, 1, 5, and 10 µg/mL; cat. no. L2880; Sigma-Aldrich, MO, USA) for 12 h. NGR1 (0, 10, 20, 30, 40, and 50 µM; cat. no. 80418-24-2; Shanghai Zheyan Biotech Co., Ltd, China) was prepared for 24 h before cells were stimulated by LPS.

2.2 Cell transfection

The miR-301a mimics and NC mimics were synthesized by GenePharma (Shanghai, China). The Krüppel-like factor 7 (KLF7) knockdown plasmid vector (sh-KLF7) and sh-NC were constructed by Genearray Biotechnology (Shanghai, China). PC-12 cells (1 × 105 cells/well) were seeded in 6-well plates. Transient transfection with 50 nM oligonucleotides or 2 µg/mL vectors was done utilizing Lipofectamine 3000 (cat. no. L3000-015; Invitrogen, CA, USA). Subsequent analysis was performed after 48 h.

2.3 Reverse transcription-quantitative PCR (RT-qPCR)

Total RNA was isolated from the LPS-treated PC-12 cells or spinal cord tissue using TRIzol (cat. no. 15596026; Invitrogen). PrimeScript RT reagent kit (cat. no. HRR037A; Takara, Dalian, China) was used to transcribe RNAs into cDNAs. PCR was performed by using synergy brands (SYBR) Green PCR kit (cat. no. RR086A; TaKaRa) on applied biosystems (ABI) PRISM 7900 Sequence Detector System (Applied Biosystems, Foster City, CA, USA). For the evaluation of the expression of miR-301a, Mir-X™ miRNA First-Strand Synthesis Kit (cat. no. 638313; TaKaRa) was used for reverse transcription. U6 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were used as internal controls for miRNA and mRNA expression, respectively. The data calculation was subjected to the 2−ΔΔCT method. The primers were designed by GenePharma and are shown as follows:

miR-301a: 5′-GCCGAGCAGTGCAATAGTATTG-3′ (forward)

5′-CTCAACTGGTGTCGTGGA-3′ (reverse)

KLF7: 5′-ACAAAACAAAAGGGCCACTG-3′ (forward)

5′-GCTGAGAAGTAGCCGGTGTC-3′ (reverse)

GAPDH: 5′-GCAAGTTCAACGGCACAG-3′ (forward)

5′-GCCAGTAGACTCCACGACAT-3′ (reverse)

U6: 5′-CTCGCTTCGGCAGCACA-3′ (forward)

5′-AACGCTTCACGAATTTGCGT-3′ (reverse).

2.4 Western blotting

Total protein from the LPS-treated PC-12 cells and spinal cord tissue was extracted using radio-immunoprecipitation assay (RIPA) buffer (cat. no. 9800; Cell Signaling Technology, Inc., USA). Then, the concentration of protein was determined using bicinchoninic acid protein quantitative kit (cat. no. P0010S; Beyotime, Shanghai, China). The protein extractions were separated by 12% sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred on polyvinylidene difluoride (PVDF) membranes (cat. no. IPVH00010; Millipore, Billerica, MA, USA). After blocking with 5% nonfat milk for 1 h, the membranes were incubated with the primary antibodies against Bax (ab32503; 1:1,000, abcam, Cambridge, UK), B-cell lymphoma-2 (Bcl-2) (ab194583; 1:1,000), cleaved-caspase-3 (#9661; 1:1,000, Cell signaling Technology), total-caspase-3 (#14220 S; 1:1,000), IL-6 (ab259341; 1:1,000), TNF-α (ab205587; 1:1,000), IL-1β (ab254360; 1:1,000), KLF7 (ab197690; 1:1,000), β-catenin (ab32572; 1:1,000), cyclin D1 (ab16663; 1:200), c-Myc (ab32072; 1:1,000), and GAPDH (ab181602; 1:10,000) at 4°C overnight. Subsequently, the membranes were incubated with a horseradish peroxidase-conjugated anti-rabbit IgG secondary antibody (cat. no. 7074; Cell Signaling Technology) at room temperature for 2 h. Eventually, an enhanced electrochemiluminescence detection system (Millipore) was applied to visualize the bands.

2.5 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay

A total of 3 × 103 PC-12 cells transfected with indicated plasmids were seeded in a 96-well plate for 24 h of incubation, and 0.5% MTT solution (20 µL; cat. no. M1025; Solarbio, Beijing, China) was added. Then, the incubation continued for 4 h at 37°C. Subsequently, dimethyl sulfoxide (cat. no. D2650; Sigma-Aldrich) was added to dissolve the formazan. A microtiter plate reader (Molecular devices, Shanghai, China) was used to record the absorbance at 490 nm.

2.6 Flow cytometry analysis

The apoptosis of PC-12 cells was examined using Annexin V fluorescein isothiocyanate (FITC)/propidium iodide (PI) (Annexin V-FITC/PI) apoptosis detection kit (cat. no. A211-01; Nanjing Novizan Biotechnology Co., China). PC-12 cells in 6-well plates at 1 × 105 cells/well were cultured overnight at 37°C. Cells were cultured at 80% confluence and suspended in binding buffer at 1 × 106 cells/mL. Thereafter, 10 µL Annexin V-FITC and PI were added into cells and maintained in the dark for 25 min. Finally, the apoptosis was detected using FACScan (Beckman Coulter, Fullerton, CA) and measured with FlowJo software (Tree Star, CA, USA).

2.7 Enzyme linked immunosorbent assay (ELISA)

Spinal cord tissues were mixed with a volume of normal saline 10 times the tissue mass. Then, tissues were placed in a glass homogenizer and were homogenized on ice for 8 min. After centrifugation at 4°C and 5,000 rpm for 5 min, the supernatant was obtained. The supernatants of tissues and PC-12 cells were collected for evaluating the levels of IL-6 (ab234570), TNF-α (ab236712), IL-1β (ab255730) using ELISA kits (Abcam). The absorbance at 450 nm was measured by the use of a microplate reader (Molecular Devices).

2.8 Luciferase reporter assay

The online tool (http://www.targetscan.org/vert_70/) was applied to predict putative binding sites between rno-miR-301a and its targets. To test the binding affinity between rno-miR-301a and 3′UTR of KLF7, the wild-type (Wt) or mutated (Mut) 3′UTR of KLF7 was cloned into the pmirGLO reporter vector (cat. no. E1330; Promega, Madison WI, USA) and named as KLF7-Wt and KLF7-Mut. KLF7-Wt/Mut plasmids were co-transfected with miR-301a mimics or NC mimics into HEK293T cells with Lipofectamine 3000. Luciferase activity was detected using the Dual-Luciferase Reporter assay system (Promega) after 48 h.

2.9 Animals and NGR1 treatment

Sixty healthy SD rats (30 males and 30 females, weighing 150–180 g) were purchased from Vital River Co. Ltd (Beijing, China). Animals were kept at 24 ± 0.5°C in a comfortable environment with a 12-h light/dark cycle. Each cage had five rats. The rats were divided into four groups: sham, SCI, SCI + NGR1, SCI + NGR1 + XAV939. N = 15 each group. All experimental procedures were approved by the Animal Ethics Committee of the First Hospital of Changsha.

In the SCI + NGR1 group, 20 mg/kg NGR1 was intraperitoneally injected daily for the first 2 weeks after SCI. In the SCI + NGR1 + XAV939 group, 0.4 mg/kg XAV939 (cat. no. M1796; Abmole, USA) was intraperitoneally injected daily, and then NGR1 was intraperitoneally injected daily for 2 weeks after SCI.

2.10 SCI rat model

The SCI model was established using the modified Allen method [29]. In brief, anesthesia was performed using 10% chloral hydrate (0.33 mg/kg; cat. no. 23100; Sigma-Aldrich) through intraperitoneal injection. The rats were placed in a stereotactic frame. After spinous T 9/10 was removed, the spinal cords were aseptically exposed. Next, a 2 mm diameter striker weighing 10 g was dropped from a height of 25 mm. Neurogenic bladder and hind limb paralysis were induced. The sham rats underwent laminectomy only after anesthesia. After the surgery, the spinal cords were cleaned with saline solution, and the incisions were disinfected with antibiotics for 3 consecutive days to avoid infection. Manual bladder massage was done twice a day to recover bladder function.

2.11 Nissl staining

The 20 µm sections were reheated and soaked overnight in a mixed solution of anhydrous ethanol (cat. no. KL809056; KALANG, Shanghai, China) and chloroform (cat. no. 613312-1EA; Sigma-Aldrich) at a 1:1 ratio. The next day, sections were dehydrated in 100% alcohol, 95% alcohol, and distilled water, followed by staining with 0.05% cresyl violet solution (cat. no. GMS80052; GENMED Scientifics Inc., USA) at 40°C for 10 min. The sections were then immediately washed with distilled water, differentiated in 95% ethanol for 10 min, and immersed in xylene (cat. no. 2-10023463; JiangShun Chemical Technology co., China) for 6 min. The sections were observed with an optical microscope after being sealed with neutral gum. The spinal cord tissue lesion and the number of neurons in the anterior horn were assessed from five randomly selected staining sections.

2.12 Statistical analysis

Data analyses were processed using GraphPad Prism 7 (GraphPad Inc., USA). The data were shown as the mean ± SD derived from at least three separate experiments. The significant differences between the two groups were analyzed by Student’s t test and differences among more than two groups were assessed using a one-way analysis of variance. p < 0.05 was considered statistically significant.

3 Results

3.1 LPS triggers PC-12 cell apoptosis and inflammation

PC-12 cells were exposed to different concentrations of LPS for 12 h. The viability was detected by MTT. The results showed that the viability of PC-12 cells was significantly decreased after the addition of LPS from 2 µg/mL to 10 µg/mL (p < 0.01) (Figure S1a). Flow cytometry analysis was used for investigating the apoptosis of PC-12 cells. As shown, the apoptosis was increased in the presence of 5 and 10 µg/mL LPS (p < 0.01) (Figure S1b and c). In addition, the protein levels of Bax and cleaved caspase-3 were elevated while those of Bcl-2 reduced after LPS treatment, as demonstrated by western blotting (Figure S1d). The ELISA results showed that IL-6 (p < 0.05; p < 0.01), TNF-α (p < 0.05; p < 0.01) and IL-1β (p < 0.05; p < 0.01) levels in the culture supernatant of PC-12 cells were increased after LPS was added (Figure S1e–g). Similarly, LPS also upregulated the protein expression of these pro-inflammatory cytokines in PC-12 cells (Figure S1h). Overall, these results indicated that LPS triggered inflammatory damage of PC-12 cells. LPS at the concentration of 5 µg/mL was used for further experiments.

3.2 NGR1 reduces the effect of LPS in PC-12 cells

Next, NGR1 was introduced to determine its role in PC-12 cell damage induced by LPS. The MTT results showed that the treatment with varying doses of NGR1 had no significant influence on the viability of PC-12 cells (Figure S2a), indicating that NGR1 had no significant cytotoxicity on PC-12 cells. However, in the presence of LPS (5 µg/mL), NGR1 (10–50 µM) markedly increased PC-12 cell viability and had the best effect at a concentration of 50 µM (p < 0.01) (Figure S2b). Therefore, NGR1 at a concentration of 50 µM was selected for further use. As the flow cytometry results presented, NGR1 reversed the LPS-stimulated increase of PC-12 cell apoptosis (p < 0.001) (Figure S2c and d). The elevated protein levels of Bax, cleaved caspase-3, and reduced protein levels of Bcl-2 mediated by LPS were also reversed after NGR1 was introduced (Figure S2e). In addition, in LPS-stimulated PC-12 cells, the levels of IL-6 (p < 0.001), TNF-α (p < 0.001), and IL-1β (p < 0.001) were all reduced in the presence of NGR1, in comparison to the absence of NGR1 (Figure S2f–h). Similar results were observed in the Western blotting analysis, showing that NGR1 decreased the protein levels of these pro-inflammatory cytokines in LPS-treated PC-12 cells (Figure S2i). These data confirmed that NGR1 protected PC-12 cells from LPS-triggered injury.

3.3 MiR-301a reverses the effect of NGR1

Subsequently, the molecular mechanisms addressed by NGR1 were investigated. NGR1 was reported to relieve LPS-elicited inflammatory injury in a miR-301a-silenced manner in ATDC5 cells [28]. Therefore, we investigated whether NGR1 could regulate miR-301a in LPS-stimulated PC-12 cells. As indicated by RT-qPCR, upregulated miR-301a expression was detected in PC-12 cells with LPS treatment (p < 0.001), and the miR-301a level was decreased after NGR1 addition (p < 0.001) (Figure 1a), implying a relationship between miR-301a and NGR1 in LPS-stimulated PC-12 cells. MiR-301a was effectively upregulated in PC-12 cells after miR-301a mimics were transfected (p < 0.01) (Figure 1b). The data from MTT showed that the increased viability of LPS-treated PC-12 cells by NGR1 was reduced after miR-301a overexpression (p < 0.01) (Figure 1c). The apoptosis of LPS-treated PC-12 cells was decreased by NGR1 (p < 0.01), which was then promoted by miR-301a mimics (p < 0.01) (Figure 1d and e). Furthermore, miR-301a overexpression eliminated the effect of NGR1 on Bax, cleaved-caspase-3, and Bcl-2 levels in LPS-treated PC-12 cells (Figure 1f). Furthermore, the levels of IL-6 (p < 0.01), TNF-α (p < 0.01) and IL-1β (p < 0.01) were decreased by NGR1 treatment but restored as a result of miR-301a overexpression (Figure 1g–j). Overall, we concluded that NGR1 might attenuate LPS-triggered PC-12 cell injury by downregulating miR-301a.

Figure 1 MiR-301a reverses the effect of NGR1. (a) MiR-301a expression in PC-12 cells with LPS treatment or co-treatment of LPS and NGR1 was measured by RT-qPCR. (b) RT-qPCR was used to detect miR-301a overexpression efficiency in PC-12 cells. PC-12 cells were divided into five groups: control, LPS, LPS + NGR1, LPS + NGR1 + NC mimics, and LPS + NGR1 + miR-301a mimics. (c) MTT assay was applied to detect the viability of PC-12 cells in each group. (d and e) Flow cytometry analysis was used to assess the apoptosis of PC-12 cells in each group. (f) The protein levels of Bax, Bcl-2, and cleaved caspase-3 in PC-12 cells were assessed by western blotting. (g–i) The concentrations of IL-6, TNF-α, IL-1β in PC-12 cells were assessed by ELISA. (j) The cytokine protein levels in PC-12 cells were measured by western blotting. **p < 0.01, ***p < 0.001.
Figure 1

MiR-301a reverses the effect of NGR1. (a) MiR-301a expression in PC-12 cells with LPS treatment or co-treatment of LPS and NGR1 was measured by RT-qPCR. (b) RT-qPCR was used to detect miR-301a overexpression efficiency in PC-12 cells. PC-12 cells were divided into five groups: control, LPS, LPS + NGR1, LPS + NGR1 + NC mimics, and LPS + NGR1 + miR-301a mimics. (c) MTT assay was applied to detect the viability of PC-12 cells in each group. (d and e) Flow cytometry analysis was used to assess the apoptosis of PC-12 cells in each group. (f) The protein levels of Bax, Bcl-2, and cleaved caspase-3 in PC-12 cells were assessed by western blotting. (g–i) The concentrations of IL-6, TNF-α, IL-1β in PC-12 cells were assessed by ELISA. (j) The cytokine protein levels in PC-12 cells were measured by western blotting. **p < 0.01, ***p < 0.001.

3.4 NGR1 activates wingless/integrated (Wnt)/β-catenin signaling by upregulating KLF7

We examined the online tools to identify the targets of rno-miR-301a. Seven genes ranking ahead in the TargetScan database were found to have a binding site for miR-301a (Figure 2a), in which KLF7 mRNA expression was significantly downregulated in miR-301a-overexpressed PC-12 cells (p < 0.01) (Figure 2b). The other targets had no significant change. Western blotting showed reduced protein expression of KLF7 after miR-301a overexpression (Figure 2c). In addition, downregulated KLF7 expression was detected in PC-12 cells with LPS treatment (p < 0.001), and the KLF7 level was elevated by NGR1 (p < 0.001) (Figure 2d). The rno-miR-301a binding site at position 847-853 of KLF7 3′UTR was shown in Figure 2e. Wt or Mut KLF7 sequence was synthesized, and the luciferase activity in HEK293T cells transfected with KLF7-Wt reporters was notably reduced (p < 0.001); however, cells transfected with KLF7-Mut reporters had no change in the luciferase activity (Figure 2f). This demonstrated that KLF7 was targeted by miR-301a. Wnt/β-catenin signaling participates in the regulation of apoptosis and inflammatory response after SCI. We then investigated the status of Wnt/β-catenin signaling in LPS-treated PC-12 cells. KLF7 was effectively silenced in PC-12 cells after sh-KLF7 was transfected (p < 0.001) (Figure 2g). The results in Figure 2h showed that, in the presence of LPS, KLF7, and Wnt/β-catenin signaling-associated genes (β-catenin, cyclin D1, and c-Myc), protein levels were reduced compared to those in control cells. NGR1 significantly reversed these changes. Strikingly, miR-301a overexpression and KLF7 knockdown then decreased these protein levels restored by NGR1. These findings suggested that NGR1 activated Wnt/β-catenin signaling in LPS-treated PC-12 cells by inhibiting miR-301a and upregulating KLF7.

Figure 2 NGR1 activates Wnt/β-catenin by upregulating KLF7. (a) Seven genes ranking ahead in the TargetScan database were found to have a binding site for miR-301a. (b) RT-qPCR analysis was used to measure gene expression after miR-301a overexpression. (c) Western blotting was used to measure KLF7 protein expression after miR-301a overexpression. (d) RT-qPCR was used to measure KLF7 expression in PC-12 cells with LPS treatment or co-treatment of LPS and NGR1. (e) The rno-miR-301a binding site at position 847-853 of KLF7 3′UTR. (f) Luciferase reporter assay was performed in HEK293T cells transfected with KLF7-Wt/Mut reporters and miR-301a mimics or control. (g) RT-qPCR analysis was used to examine KLF7 silencing efficiency. (h) Western blotting was used to measure KLF7 and Wnt/β-catenin-associated gene protein levels in PC-12 cells in the control, LPS, LPS + NGR1, LPS + NGR1 + NC mimics + sh-NC, LPS + NGR1 + miR-301a mimics + sh-NC, and LPS + NGR1 + NC mimics + sh-KLF7 groups. **p < 0.01, ***p < 0.001.
Figure 2

NGR1 activates Wnt/β-catenin by upregulating KLF7. (a) Seven genes ranking ahead in the TargetScan database were found to have a binding site for miR-301a. (b) RT-qPCR analysis was used to measure gene expression after miR-301a overexpression. (c) Western blotting was used to measure KLF7 protein expression after miR-301a overexpression. (d) RT-qPCR was used to measure KLF7 expression in PC-12 cells with LPS treatment or co-treatment of LPS and NGR1. (e) The rno-miR-301a binding site at position 847-853 of KLF7 3′UTR. (f) Luciferase reporter assay was performed in HEK293T cells transfected with KLF7-Wt/Mut reporters and miR-301a mimics or control. (g) RT-qPCR analysis was used to examine KLF7 silencing efficiency. (h) Western blotting was used to measure KLF7 and Wnt/β-catenin-associated gene protein levels in PC-12 cells in the control, LPS, LPS + NGR1, LPS + NGR1 + NC mimics + sh-NC, LPS + NGR1 + miR-301a mimics + sh-NC, and LPS + NGR1 + NC mimics + sh-KLF7 groups. **p < 0.01, ***p < 0.001.

3.5 XAV939 reverses the effect of NGR1 in PC-12 cells

We next addressed whether the interfering Wnt/β-catenin pathway could reverse the protective effect of NGR1 against LPS-induced injury in PC-12 cells. We treated PC-12 cells with 50 µM NGR1 either alone or in combination with 10 µM Wnt/β‑catenin inhibitor XAV939 for 24 h. The MTT results showed that the increased viability of LPS-treated PC-12 cells by NGR1 was reduced after the addition of XAV939 (p < 0.01) (Figure 3a). The apoptosis of LPS-treated PC-12 cells was decreased by NGR1 (p < 0.001), which was elevated by XAV939 (p < 0.01) (Figure 3b and c). XAV939 also eliminated the effect of NGR1 on Bax, cleaved-caspase-3, and Bcl-2 levels in LPS-treated PC-12 cells (Figure 3d). Furthermore, XAV939 increased the levels of IL-6 (p < 0.01), TNF-α (p < 0.01) and IL-1β (p < 0.01) in the presence of NGR1 (Figure 3e–h). These data verified that NGR1 inhibited LPS-triggered PC-12 cell injury by activating the Wnt/β-catenin pathway.

Figure 3 XAV939 reverses the effect of NGR1 in PC-12 cells. PC-12 cells were divided into four groups: control, LPS, LPS + NGR1, and LPS + NGR1 + XAV939. (a) MTT assay was applied to detect the viability of PC-12 cells in each group. (b and c) Flow cytometry analysis was used to assess the apoptosis of PC-12 cells in each group. (d) The protein levels of Bax, Bcl-2, and cleaved caspase-3 in PC-12 cells were assessed by western blotting. (e–g) The concentrations of IL-6, TNF-α, IL-1β in PC-12 cells were assessed by ELISA (Jh). The cytokine protein levels in PC-12 cells were measured by western blotting. **p < 0.01, ***p < 0.001.
Figure 3

XAV939 reverses the effect of NGR1 in PC-12 cells. PC-12 cells were divided into four groups: control, LPS, LPS + NGR1, and LPS + NGR1 + XAV939. (a) MTT assay was applied to detect the viability of PC-12 cells in each group. (b and c) Flow cytometry analysis was used to assess the apoptosis of PC-12 cells in each group. (d) The protein levels of Bax, Bcl-2, and cleaved caspase-3 in PC-12 cells were assessed by western blotting. (e–g) The concentrations of IL-6, TNF-α, IL-1β in PC-12 cells were assessed by ELISA (Jh). The cytokine protein levels in PC-12 cells were measured by western blotting. **p < 0.01, ***p < 0.001.

3.6 NGR1 improves neuronal survival and alleviates inflammation after SCI by activating Wnt/β-catenin signaling

Nissl staining was performed to assess the spinal cord tissue lesion and determine the number of neurons in the anterior horn 14 days after SCI (Figure 4a). The staining results exhibited more neurons in the anterior horn in the NGR1 group than the SCI group (p < 0.001), however; pretreatment with XAV939 reduced the number of neurons in the NGR1 group (p < 0.001) (Figure 4b). In addition, NGR1 attenuated the proportion of lesion size in the spinal cord of rats after SCI (p < 0.001), while XAV939 reversed this effect (p < 0.001) (Figure 4c). We further examined the cytokines in the spinal cord of rats in each group. The NGR1 group showed lower levels of IL-6 (p < 0.01), TNF-α (p < 0.01), and IL-1β (p < 0.01) than in the SCI group, which were restored in the NGR1 + XAV939 group (Figure 4d–g). Moreover, NGR1 downregulated Bax and cleaved-caspase-3 protein levels and upregulated Bcl-2 protein levels in SCI rats, while this effect was reversed by XAV939 (Figure 4h). The NGR1 group showed upregulated levels of β-catenin, cyclin D1, and c-Myc compared to the SCI group, which were reduced in the NGR1 + XAV939 group (Figure 4i). In addition, elevated miR-301a expression (p < 0.001) and reduced KLF7 expression (p < 0.001) were found in rats after SCI (Figure 4j–l). These data indicated that NGR1 promoted the recovery of SCI rats by regulating the miR-301a/KLF7-Wnt/β-catenin pathway.

Figure 4 NGR1 improves neuronal survival and alleviates inflammation after SCI by activating Wnt/β-catenin. (a) Nissl staining showing (b) the number of surviving neurons and (c) proportion of lesion size in the spinal cord in the sham, SCI, SCI + NGR1, and SCI + NGR1 + XAV939 groups. (d) Western blotting was used to measure IL-6, TNF-α, IL-1β protein levels in the spinal cord in the sham, SCI, SCI + NGR1, and SCI + NGR1 + XAV939 groups. (e–g) ELISA was used to measure IL-6, TNF-α, IL-1β levels in the spinal cord in the sham, SCI, SCI + NGR1, and SCI + NGR1 + XAV939 groups. (h and i) The protein levels of Bax, Bcl-2, cleaved-caspase-3, β-catenin, cyclin D1, and c-Myc in the spinal cord in the sham, SCI, SCI + NGR1, and SCI + NGR1 + XAV939 groups. RT-qPCR was used to measure (j) miR-301a and (k) KLF7 expression in the spinal cord in the sham, SCI, and SCI + NGR1 groups. (l) KLF7 protein expression in each group. **p < 0.01, ***p < 0.001.
Figure 4

NGR1 improves neuronal survival and alleviates inflammation after SCI by activating Wnt/β-catenin. (a) Nissl staining showing (b) the number of surviving neurons and (c) proportion of lesion size in the spinal cord in the sham, SCI, SCI + NGR1, and SCI + NGR1 + XAV939 groups. (d) Western blotting was used to measure IL-6, TNF-α, IL-1β protein levels in the spinal cord in the sham, SCI, SCI + NGR1, and SCI + NGR1 + XAV939 groups. (e–g) ELISA was used to measure IL-6, TNF-α, IL-1β levels in the spinal cord in the sham, SCI, SCI + NGR1, and SCI + NGR1 + XAV939 groups. (h and i) The protein levels of Bax, Bcl-2, cleaved-caspase-3, β-catenin, cyclin D1, and c-Myc in the spinal cord in the sham, SCI, SCI + NGR1, and SCI + NGR1 + XAV939 groups. RT-qPCR was used to measure (j) miR-301a and (k) KLF7 expression in the spinal cord in the sham, SCI, and SCI + NGR1 groups. (l) KLF7 protein expression in each group. **p < 0.01, ***p < 0.001.

3.7 Schematic diagram of the protective function of NGR1 through the miR-301a/KLF7-Wnt/β-catenin pathway

NGR1-inhibited miR-301a in LPS-stimulated PC-12 cells, subsequently upregulating KLF7 expression and activating the Wnt/β-catenin pathway, leading to the alleviation of apoptosis and inflammation, eventually alleviating the development of SCI (Figure 5).

Figure 5 Schematic of the protective function of NGR1 through the miR-301a/KLF7-Wnt/β-catenin pathway.
Figure 5

Schematic of the protective function of NGR1 through the miR-301a/KLF7-Wnt/β-catenin pathway.

4 Discussion

Increasing studies have demonstrated that SCI is associated with inflammatory response [30], and increased reactive oxygen species activity in SCI leads to an increase in the concentrations of inflammatory cytokines. It has been reported that NGR1 has extensive pharmacological activities, including anti-cancer, anti-inflammatory, cardioprotective, and neuroprotective effects [31]. Previous studies indicated that NGR1 protects different types of cell lines against LPS-induced injury [32,33]. Moreover, NGR1 alleviates LPS-triggered inflammatory damage in PC-12 cells via elevating miR-132 [28]. Consistent with previous findings, our study revealed that NGR1 alleviated LPS-triggered apoptosis and inflammation of PC-12 cells. More importantly, our study was the first to use animal experiments demonstrating that NGR1 promoted functional and pathological recovery in rats after SCI by improving the number of neurons and attenuating lesion size in the spinal cord of rats after SCI. These findings provide stronger evidence that NGR1 may be effective in promoting the recovery of SCI rats. Although the biological and pharmacological effects of NGR1 from in vitro and in vivo studies have been reported, clinical trials with NGR1 are also rare, more controlled trials should be conducted in the future. Meanwhile, NGR1 has been approved by the Food and Drug Administration of China to start clinical arthritis prevention and treatment trials [34]. It provides more possibilities for the application of NGR1 in clinical trials of various diseases, including SCI.

Studies about the associations of apoptosis and inflammation with SCI were frequently reported. For instance, miR-124 attenuates the apoptosis of spinal neurons by targeting guanosine 5'-triphosphate cyclohydrolase I (GCH1) [35]. MiR-223-5p downregulation inhibits the inflammation in microglia of rats with SCI [36]. However, whether miR-301a is responsible for apoptosis and inflammation following SCI is still unclear. MiR-301a is frequently highly expressed in response to chronic inflammation and stimulates the production of cytokines [37,38]. Specific inhibition of miR-301a displays a protective effect against inflammatory injury [27]. However, direct inhibition of miR-301a is inadvisable because miR-301a downregulation is related to elevated chronic inflammation and circulation [39]. Instead of silencing miR-301a, NGR1 functionally interferes with miR-301a, which may be significantly advisable compared to an absolute inhibition of miR-301a. As reported, NGR1 mitigates LPS-elicited inflammatory injury in ATDC5 cells by inhibiting miR-301a [28]. In this study, NGR1 relieved LPS-induced PC-12 cell injury by decreasing the expression of miR-301a. In addition, miR-301a was downregulated in the spinal cord or NGR1-treated SCI rats. Our study was the first to reveal the association between NGR1 and miR-301a in the pathological response of SCI, and clarified a new molecular mechanism of the neuroprotective effect of NGR1 on SCI. The biological effect of NGR1 by controlling miR-301a may be investigated and verified in different pathological conditions.

In our work, bioinformatics analysis showed that KLF7, belonging to the KLFs family, has a potential binding site for miR-301a. KLF7 is considered a key modulator of axon outgrowth. It was shown that KLF7 depletion mainly affects gene activities involving axonal growth, olfactory sensory neuron differentiation, cell adhesion, synaptogenesis, and cytoskeletal dynamics [40]. Moreover, KLF7 exerts a positive role in the central nervous system and peripheral nerve injury by contributing to survival and axonal regeneration in injured nerves [41]. These reports suggest that KLF7 could be beneficial to neuronal regeneration. In the present study, the KLF7 level was downregulated by LPS and increased by NGR1 co-treatment. We demonstrated that miR-301a negatively regulated KLF7 expression. Therefore, the miR-301a/KLF7 axis may be a new molecular mechanism in LPS-induced inflammatory injury. In addition, KLF7 was reported to activate the β-catenin pathway by interacting with coiled-coil domain containing 85c (Ccdc85c) [42]. Studies showed that Wnt pathway activation is beneficial to axonal regeneration and functional recovery [43]. In particular, activation of Wnt after SCI promotes neuronal growth and mitigates neuropathic pain [44]. As previously reported, NGR1 enhances human alveolar osteoblast differentiation in an inflammatory microenvironment as well as facilitates the growth of cultured cortical neurons by activating the Wnt/β‑catenin pathway [45]. Here, the NGR1 activated Wnt/β-catenin signaling in LPS-treated PC-12 cells by inhibiting miR-301a and upregulating KLF7. Furthermore, the protective function of NGR1 was prevented by an inhibitor of the Wnt/β‑catenin pathway. These findings showed that the protective role of NGR1 in SCI may be mediated by the Wnt/β‑catenin pathway.

In conclusion, this study demonstrated that NGR1 decreased neural cell apoptosis and inflammation and contributed to functional recovery in rats after SCI by the miR-301a/KLF7 axis to activate Wnt/β‑catenin signaling. This finding provides a new molecular mechanism for how NGR1 promotes neuroprotection, which might provide a potential treatment for SCI. Further investigations should be conducted to elucidate the role of NGR1 in other neural cell types after SCI and possible molecular mechanisms addressed by NGR1. The therapeutic mechanism of NGR1 in patients with SCI will be studied in a clinic in the future.

Abbreviations

SCI

spinal cord injury

NGR1

notoginsenoside R1

LPS

lipopolysaccharide

miRNAs

microRNAs

Acknowledgments

Not applicable.

  1. Funding information: No funds.

  2. Author contributions: Zhi Tang and Xiaoming Li conceived and designed research; Zhi Tang, Chunhua Yang, Zhengwen He, and Zhiyong Deng performed the research; Zhi Tang and Xiaoming Li analyzed the data; Zhi Tang wrote the paper. All authors approved final version of manuscript.

  3. Conflict of interest: The authors declare that there is no conflict of interest regarding the publication of this study.

  4. Data availability statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.

Appendix

Figure S1 LPS triggers PC-12 cell apoptosis and inflammation. (a) PC-12 cell viability after treatment with LPS for 12 h was detected by MTT. (b and c) PC-12 cell apoptosis after LPS treatment was assessed by flow cytometry. (d) The protein levels of apoptotic genes in PC-12 cells after LPS treatment were measured by western blotting. (e–g) The concentrations of IL-6, TNF-α, IL-1β in PC-12 cells after LPS treatment were assessed by ELISA. (h) The cytokine protein levels in PC-12 cells after LPS treatment were measured by western blotting. *p < 0.05, **p < 0.01.
Figure S1

LPS triggers PC-12 cell apoptosis and inflammation. (a) PC-12 cell viability after treatment with LPS for 12 h was detected by MTT. (b and c) PC-12 cell apoptosis after LPS treatment was assessed by flow cytometry. (d) The protein levels of apoptotic genes in PC-12 cells after LPS treatment were measured by western blotting. (e–g) The concentrations of IL-6, TNF-α, IL-1β in PC-12 cells after LPS treatment were assessed by ELISA. (h) The cytokine protein levels in PC-12 cells after LPS treatment were measured by western blotting. *p < 0.05, **p < 0.01.

Figure S2 NGR1 reduces the effect of LPS in PC-12 cells. (a) PC-12 cell viability after treatment with NGR1 (10, 20, 30, 40, 50 µM) for 24 h was detected by MTT. (b) The viability of LPS-stimulated PC-12 cells after treatment with different concentrations of NGR1 was detected by MTT. (c and d) The apoptosis of LPS-stimulated PC-12 cells after NGR1 treatment was assessed by flow cytometry. (e) The protein levels of apoptotic genes in LPS-stimulated PC-12 cells after NGR1 treatment were assessed by western blotting. (f–h) The concentrations of IL-6, TNF-α, IL-1β in LPS-treated PC-12 cells after NGR1 treatment were assessed by ELISA. (i) The cytokine protein levels in LPS-treated PC-12 cells after NGR1 treatment were measured by western blotting. *p < 0.05, **p < 0.01, ***p < 0.001.
Figure S2

NGR1 reduces the effect of LPS in PC-12 cells. (a) PC-12 cell viability after treatment with NGR1 (10, 20, 30, 40, 50 µM) for 24 h was detected by MTT. (b) The viability of LPS-stimulated PC-12 cells after treatment with different concentrations of NGR1 was detected by MTT. (c and d) The apoptosis of LPS-stimulated PC-12 cells after NGR1 treatment was assessed by flow cytometry. (e) The protein levels of apoptotic genes in LPS-stimulated PC-12 cells after NGR1 treatment were assessed by western blotting. (f–h) The concentrations of IL-6, TNF-α, IL-1β in LPS-treated PC-12 cells after NGR1 treatment were assessed by ELISA. (i) The cytokine protein levels in LPS-treated PC-12 cells after NGR1 treatment were measured by western blotting. *p < 0.05, **p < 0.01, ***p < 0.001.

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Received: 2021-11-30
Revised: 2022-02-12
Accepted: 2022-02-22
Published Online: 2022-04-13

© 2022 Zhi Tang et al., published by De Gruyter

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

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  51. Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway
  52. circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis
  53. Human amniotic fluid as a source of stem cells
  54. lncRNA NONRATT013819.2 promotes transforming growth factor-β1-induced myofibroblastic transition of hepatic stellate cells by miR24-3p/lox
  55. NORAD modulates miR-30c-5p-LDHA to protect lung endothelial cells damage
  56. Idiopathic pulmonary fibrosis telemedicine management during COVID-19 outbreak
  57. Risk factors for adverse drug reactions associated with clopidogrel therapy
  58. Serum zinc associated with immunity and inflammatory markers in Covid-19
  59. The relationship between night shift work and breast cancer incidence: A systematic review and meta-analysis of observational studies
  60. LncRNA expression in idiopathic achalasia: New insight and preliminary exploration into pathogenesis
  61. Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway
  62. Moscatilin suppresses the inflammation from macrophages and T cells
  63. Zoledronate promotes ECM degradation and apoptosis via Wnt/β-catenin
  64. Epithelial-mesenchymal transition-related genes in coronary artery disease
  65. The effect evaluation of traditional vaginal surgery and transvaginal mesh surgery for severe pelvic organ prolapse: 5 years follow-up
  66. Repeated partial splenic artery embolization for hypersplenism improves platelet count
  67. Low expression of miR-27b in serum exosomes of non-small cell lung cancer facilitates its progression by affecting EGFR
  68. Exosomal hsa_circ_0000519 modulates the NSCLC cell growth and metastasis via miR-1258/RHOV axis
  69. miR-455-5p enhances 5-fluorouracil sensitivity in colorectal cancer cells by targeting PIK3R1 and DEPDC1
  70. The effect of tranexamic acid on the reduction of intraoperative and postoperative blood loss and thromboembolic risk in patients with hip fracture
  71. Isocitrate dehydrogenase 1 mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to ferroptosis
  72. Artemisinin protects against cerebral ischemia and reperfusion injury via inhibiting the NF-κB pathway
  73. A 16-gene signature associated with homologous recombination deficiency for prognosis prediction in patients with triple-negative breast cancer
  74. Lidocaine ameliorates chronic constriction injury-induced neuropathic pain through regulating M1/M2 microglia polarization
  75. MicroRNA 322-5p reduced neuronal inflammation via the TLR4/TRAF6/NF-κB axis in a rat epilepsy model
  76. miR-1273h-5p suppresses CXCL12 expression and inhibits gastric cancer cell invasion and metastasis
  77. Clinical characteristics of pneumonia patients of long course of illness infected with SARS-CoV-2
  78. circRNF20 aggravates the malignancy of retinoblastoma depending on the regulation of miR-132-3p/PAX6 axis
  79. Linezolid for resistant Gram-positive bacterial infections in children under 12 years: A meta-analysis
  80. Rack1 regulates pro-inflammatory cytokines by NF-κB in diabetic nephropathy
  81. Comprehensive analysis of molecular mechanism and a novel prognostic signature based on small nuclear RNA biomarkers in gastric cancer patients
  82. Smog and risk of maternal and fetal birth outcomes: A retrospective study in Baoding, China
  83. Let-7i-3p inhibits the cell cycle, proliferation, invasion, and migration of colorectal cancer cells via downregulating CCND1
  84. β2-Adrenergic receptor expression in subchondral bone of patients with varus knee osteoarthritis
  85. Possible impact of COVID-19 pandemic and lockdown on suicide behavior among patients in Southeast Serbia
  86. In vitro antimicrobial activity of ozonated oil in liposome eyedrop against multidrug-resistant bacteria
  87. Potential biomarkers for inflammatory response in acute lung injury
  88. A low serum uric acid concentration predicts a poor prognosis in adult patients with candidemia
  89. Antitumor activity of recombinant oncolytic vaccinia virus with human IL2
  90. ALKBH5 inhibits TNF-α-induced apoptosis of HUVECs through Bcl-2 pathway
  91. Risk prediction of cardiovascular disease using machine learning classifiers
  92. Value of ultrasonography parameters in diagnosing polycystic ovary syndrome
  93. Bioinformatics analysis reveals three key genes and four survival genes associated with youth-onset NSCLC
  94. Identification of autophagy-related biomarkers in patients with pulmonary arterial hypertension based on bioinformatics analysis
  95. Protective effects of glaucocalyxin A on the airway of asthmatic mice
  96. Overexpression of miR-100-5p inhibits papillary thyroid cancer progression via targeting FZD8
  97. Bioinformatics-based analysis of SUMOylation-related genes in hepatocellular carcinoma reveals a role of upregulated SAE1 in promoting cell proliferation
  98. Effectiveness and clinical benefits of new anti-diabetic drugs: A real life experience
  99. Identification of osteoporosis based on gene biomarkers using support vector machine
  100. Tanshinone IIA reverses oxaliplatin resistance in colorectal cancer through microRNA-30b-5p/AVEN axis
  101. miR-212-5p inhibits nasopharyngeal carcinoma progression by targeting METTL3
  102. Association of ST-T changes with all-cause mortality among patients with peripheral T-cell lymphomas
  103. LINC00665/miRNAs axis-mediated collagen type XI alpha 1 correlates with immune infiltration and malignant phenotypes in lung adenocarcinoma
  104. The perinatal factors that influence the excretion of fecal calprotectin in premature-born children
  105. Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study
  106. Does the use of 3D-printed cones give a chance to postpone the use of megaprostheses in patients with large bone defects in the knee joint?
  107. lncRNA HAGLR modulates myocardial ischemia–reperfusion injury in mice through regulating miR-133a-3p/MAPK1 axis
  108. Protective effect of ghrelin on intestinal I/R injury in rats
  109. In vivo knee kinematics of an innovative prosthesis design
  110. Relationship between the height of fibular head and the incidence and severity of knee osteoarthritis
  111. lncRNA WT1-AS attenuates hypoxia/ischemia-induced neuronal injury during cerebral ischemic stroke via miR-186-5p/XIAP axis
  112. Correlation of cardiac troponin T and APACHE III score with all-cause in-hospital mortality in critically ill patients with acute pulmonary embolism
  113. LncRNA LINC01857 reduces metastasis and angiogenesis in breast cancer cells via regulating miR-2052/CENPQ axis
  114. Endothelial cell-specific molecule 1 (ESM1) promoted by transcription factor SPI1 acts as an oncogene to modulate the malignant phenotype of endometrial cancer
  115. SELENBP1 inhibits progression of colorectal cancer by suppressing epithelial–mesenchymal transition
  116. Visfatin is negatively associated with coronary artery lesions in subjects with impaired fasting glucose
  117. Treatment and outcomes of mechanical complications of acute myocardial infarction during the Covid-19 era: A comparison with the pre-Covid-19 period. A systematic review and meta-analysis
  118. Neonatal stroke surveillance study protocol in the United Kingdom and Republic of Ireland
  119. Oncogenic role of TWF2 in human tumors: A pan-cancer analysis
  120. Mean corpuscular hemoglobin predicts the length of hospital stay independent of severity classification in patients with acute pancreatitis
  121. Association of gallstone and polymorphisms of UGT1A1*27 and UGT1A1*28 in patients with hepatitis B virus-related liver failure
  122. TGF-β1 upregulates Sar1a expression and induces procollagen-I secretion in hypertrophic scarring fibroblasts
  123. Antisense lncRNA PCNA-AS1 promotes esophageal squamous cell carcinoma progression through the miR-2467-3p/PCNA axis
  124. NK-cell dysfunction of acute myeloid leukemia in relation to the renin–angiotensin system and neurotransmitter genes
  125. The effect of dilution with glucose and prolonged injection time on dexamethasone-induced perineal irritation – A randomized controlled trial
  126. miR-146-5p restrains calcification of vascular smooth muscle cells by suppressing TRAF6
  127. Role of lncRNA MIAT/miR-361-3p/CCAR2 in prostate cancer cells
  128. lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2
  129. Noninvasive diagnosis of AIH/PBC overlap syndrome based on prediction models
  130. lncRNA FAM230B is highly expressed in colorectal cancer and suppresses the maturation of miR-1182 to increase cell proliferation
  131. circ-LIMK1 regulates cisplatin resistance in lung adenocarcinoma by targeting miR-512-5p/HMGA1 axis
  132. LncRNA SNHG3 promoted cell proliferation, migration, and metastasis of esophageal squamous cell carcinoma via regulating miR-151a-3p/PFN2 axis
  133. Risk perception and affective state on work exhaustion in obstetrics during the COVID-19 pandemic
  134. lncRNA-AC130710/miR-129-5p/mGluR1 axis promote migration and invasion by activating PKCα-MAPK signal pathway in melanoma
  135. SNRPB promotes cell cycle progression in thyroid carcinoma via inhibiting p53
  136. Xylooligosaccharides and aerobic training regulate metabolism and behavior in rats with streptozotocin-induced type 1 diabetes
  137. Serpin family A member 1 is an oncogene in glioma and its translation is enhanced by NAD(P)H quinone dehydrogenase 1 through RNA-binding activity
  138. Silencing of CPSF7 inhibits the proliferation, migration, and invasion of lung adenocarcinoma cells by blocking the AKT/mTOR signaling pathway
  139. Ultrasound-guided lumbar plexus block versus transversus abdominis plane block for analgesia in children with hip dislocation: A double-blind, randomized trial
  140. Relationship of plasma MBP and 8-oxo-dG with brain damage in preterm
  141. Identification of a novel necroptosis-associated miRNA signature for predicting the prognosis in head and neck squamous cell carcinoma
  142. Delayed femoral vein ligation reduces operative time and blood loss during hip disarticulation in patients with extremity tumors
  143. The expression of ASAP3 and NOTCH3 and the clinicopathological characteristics of adult glioma patients
  144. Longitudinal analysis of factors related to Helicobacter pylori infection in Chinese adults
  145. HOXA10 enhances cell proliferation and suppresses apoptosis in esophageal cancer via activating p38/ERK signaling pathway
  146. Meta-analysis of early-life antibiotic use and allergic rhinitis
  147. Marital status and its correlation with age, race, and gender in prognosis of tonsil squamous cell carcinomas
  148. HPV16 E6E7 up-regulates KIF2A expression by activating JNK/c-Jun signal, is beneficial to migration and invasion of cervical cancer cells
  149. Amino acid profiles in the tissue and serum of patients with liver cancer
  150. Pain in critically ill COVID-19 patients: An Italian retrospective study
  151. Immunohistochemical distribution of Bcl-2 and p53 apoptotic markers in acetamiprid-induced nephrotoxicity
  152. Estradiol pretreatment in GnRH antagonist protocol for IVF/ICSI treatment
  153. Long non-coding RNAs LINC00689 inhibits the apoptosis of human nucleus pulposus cells via miR-3127-5p/ATG7 axis-mediated autophagy
  154. The relationship between oxygen therapy, drug therapy, and COVID-19 mortality
  155. Monitoring hypertensive disorders in pregnancy to prevent preeclampsia in pregnant women of advanced maternal age: Trial mimicking with retrospective data
  156. SETD1A promotes the proliferation and glycolysis of nasopharyngeal carcinoma cells by activating the PI3K/Akt pathway
  157. The role of Shunaoxin pills in the treatment of chronic cerebral hypoperfusion and its main pharmacodynamic components
  158. TET3 governs malignant behaviors and unfavorable prognosis of esophageal squamous cell carcinoma by activating the PI3K/AKT/GSK3β/β-catenin pathway
  159. Associations between morphokinetic parameters of temporary-arrest embryos and the clinical prognosis in FET cycles
  160. Long noncoding RNA WT1-AS regulates trophoblast proliferation, migration, and invasion via the microRNA-186-5p/CADM2 axis
  161. The incidence of bronchiectasis in chronic obstructive pulmonary disease
  162. Integrated bioinformatics analysis shows integrin alpha 3 is a prognostic biomarker for pancreatic cancer
  163. Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway
  164. Comparison of hospitalized patients with severe pneumonia caused by COVID-19 and influenza A (H7N9 and H1N1): A retrospective study from a designated hospital
  165. lncRNA ZFAS1 promotes intervertebral disc degeneration by upregulating AAK1
  166. Pathological characteristics of liver injury induced by N,N-dimethylformamide: From humans to animal models
  167. lncRNA ELFN1-AS1 enhances the progression of colon cancer by targeting miR-4270 to upregulate AURKB
  168. DARS-AS1 modulates cell proliferation and migration of gastric cancer cells by regulating miR-330-3p/NAT10 axis
  169. Dezocine inhibits cell proliferation, migration, and invasion by targeting CRABP2 in ovarian cancer
  170. MGST1 alleviates the oxidative stress of trophoblast cells induced by hypoxia/reoxygenation and promotes cell proliferation, migration, and invasion by activating the PI3K/AKT/mTOR pathway
  171. Bifidobacterium lactis Probio-M8 ameliorated the symptoms of type 2 diabetes mellitus mice by changing ileum FXR-CYP7A1
  172. circRNA DENND1B inhibits tumorigenicity of clear cell renal cell carcinoma via miR-122-5p/TIMP2 axis
  173. EphA3 targeted by miR-3666 contributes to melanoma malignancy via activating ERK1/2 and p38 MAPK pathways
  174. Pacemakers and methylprednisolone pulse therapy in immune-related myocarditis concomitant with complete heart block
  175. miRNA-130a-3p targets sphingosine-1-phosphate receptor 1 to activate the microglial and astrocytes and to promote neural injury under the high glucose condition
  176. Review Articles
  177. Current management of cancer pain in Italy: Expert opinion paper
  178. Hearing loss and brain disorders: A review of multiple pathologies
  179. The rationale for using low-molecular weight heparin in the therapy of symptomatic COVID-19 patients
  180. Amyotrophic lateral sclerosis and delayed onset muscle soreness in light of the impaired blink and stretch reflexes – watch out for Piezo2
  181. Interleukin-35 in autoimmune dermatoses: Current concepts
  182. Recent discoveries in microbiota dysbiosis, cholangiocytic factors, and models for studying the pathogenesis of primary sclerosing cholangitis
  183. Advantages of ketamine in pediatric anesthesia
  184. Congenital adrenal hyperplasia. Role of dentist in early diagnosis
  185. Migraine management: Non-pharmacological points for patients and health care professionals
  186. Atherogenic index of plasma and coronary artery disease: A systematic review
  187. Physiological and modulatory role of thioredoxins in the cellular function
  188. Case Reports
  189. Intrauterine Bakri balloon tamponade plus cervical cerclage for the prevention and treatment of postpartum haemorrhage in late pregnancy complicated with acute aortic dissection: Case series
  190. A case of successful pembrolizumab monotherapy in a patient with advanced lung adenocarcinoma: Use of multiple biomarkers in combination for clinical practice
  191. Unusual neurological manifestations of bilateral medial medullary infarction: A case report
  192. Atypical symptoms of malignant hyperthermia: A rare causative mutation in the RYR1 gene
  193. A case report of dermatomyositis with the missed diagnosis of non-small cell lung cancer and concurrence of pulmonary tuberculosis
  194. A rare case of endometrial polyp complicated with uterine inversion: A case report and clinical management
  195. Spontaneous rupturing of splenic artery aneurysm: Another reason for fatal syncope and shock (Case report and literature review)
  196. Fungal infection mimicking COVID-19 infection – A case report
  197. Concurrent aspergillosis and cystic pulmonary metastases in a patient with tongue squamous cell carcinoma
  198. Paraganglioma-induced inverted takotsubo-like cardiomyopathy leading to cardiogenic shock successfully treated with extracorporeal membrane oxygenation
  199. Lineage switch from lymphoma to myeloid neoplasms: First case series from a single institution
  200. Trismus during tracheal extubation as a complication of general anaesthesia – A case report
  201. Simultaneous treatment of a pubovesical fistula and lymph node metastasis secondary to multimodal treatment for prostate cancer: Case report and review of the literature
  202. Two case reports of skin vasculitis following the COVID-19 immunization
  203. Ureteroiliac fistula after oncological surgery: Case report and review of the literature
  204. Synchronous triple primary malignant tumours in the bladder, prostate, and lung harbouring TP53 and MEK1 mutations accompanied with severe cardiovascular diseases: A case report
  205. Huge mucinous cystic neoplasms with adhesion to the left colon: A case report and literature review
  206. Commentary
  207. Commentary on “Clinicopathological features of programmed cell death-ligand 1 expression in patients with oral squamous cell carcinoma”
  208. Rapid Communication
  209. COVID-19 fear, post-traumatic stress, growth, and the role of resilience
  210. Erratum
  211. Erratum to “Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway”
  212. Erratum to “Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study”
  213. Erratum to “lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2”
  214. Retraction
  215. Expression and role of ABIN1 in sepsis: In vitro and in vivo studies
  216. Retraction to “miR-519d downregulates LEP expression to inhibit preeclampsia development”
  217. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part II
  218. Usefulness of close surveillance for rectal cancer patients after neoadjuvant chemoradiotherapy
https://doi.org/10.1515/med-2022-0461
Keywords for this article
notoginsenoside R1; miR-301a; KLF7; spinal cord injury
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Articles
  2. AMBRA1 attenuates the proliferation of uveal melanoma cells
  3. A ceRNA network mediated by LINC00475 in papillary thyroid carcinoma
  4. Differences in complications between hepatitis B-related cirrhosis and alcohol-related cirrhosis
  5. Effect of gestational diabetes mellitus on lipid profile: A systematic review and meta-analysis
  6. Long noncoding RNA NR2F1-AS1 stimulates the tumorigenic behavior of non-small cell lung cancer cells by sponging miR-363-3p to increase SOX4
  7. Promising novel biomarkers and candidate small-molecule drugs for lung adenocarcinoma: Evidence from bioinformatics analysis of high-throughput data
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  9. The biomarkers of key miRNAs and gene targets associated with extranodal NK/T-cell lymphoma
  10. Gene signature to predict prognostic survival of hepatocellular carcinoma
  11. Effects of miRNA-199a-5p on cell proliferation and apoptosis of uterine leiomyoma by targeting MED12
  12. Does diabetes affect paraneoplastic thrombocytosis in colorectal cancer?
  13. Is there any effect on imprinted genes H19, PEG3, and SNRPN during AOA?
  14. Leptin and PCSK9 concentrations are associated with vascular endothelial cytokines in patients with stable coronary heart disease
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  17. Retrospective analysis of crescent score in clinical prognosis of IgA nephropathy
  18. Expression of DNM3 is associated with good outcome in colorectal cancer
  19. Activation of SphK2 contributes to adipocyte-induced EOC cell proliferation
  20. CRRT influences PICCO measurements in febrile critically ill patients
  21. SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis
  22. lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells
  23. circ_AKT3 knockdown suppresses cisplatin resistance in gastric cancer
  24. Prognostic value of nicotinamide N-methyltransferase in human cancers: Evidence from a meta-analysis and database validation
  25. GPC2 deficiency inhibits cell growth and metastasis in colon adenocarcinoma
  26. A pan-cancer analysis of the oncogenic role of Holliday junction recognition protein in human tumors
  27. Radiation increases COL1A1, COL3A1, and COL1A2 expression in breast cancer
  28. Association between preventable risk factors and metabolic syndrome
  29. miR-29c-5p knockdown reduces inflammation and blood–brain barrier disruption by upregulating LRP6
  30. Cardiac contractility modulation ameliorates myocardial metabolic remodeling in a rabbit model of chronic heart failure through activation of AMPK and PPAR-α pathway
  31. Quercitrin protects human bronchial epithelial cells from oxidative damage
  32. Smurf2 suppresses the metastasis of hepatocellular carcinoma via ubiquitin degradation of Smad2
  33. circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury
  34. Sonoclot’s usefulness in prediction of cardiopulmonary arrest prognosis: A proof of concept study
  35. Four drug metabolism-related subgroups of pancreatic adenocarcinoma in prognosis, immune infiltration, and gene mutation
  36. Decreased expression of miR-195 mediated by hypermethylation promotes osteosarcoma
  37. LMO3 promotes proliferation and metastasis of papillary thyroid carcinoma cells by regulating LIMK1-mediated cofilin and the β-catenin pathway
  38. Cx43 upregulation in HUVECs under stretch via TGF-β1 and cytoskeletal network
  39. Evaluation of menstrual irregularities after COVID-19 vaccination: Results of the MECOVAC survey
  40. Histopathologic findings on removed stomach after sleeve gastrectomy. Do they influence the outcome?
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  42. Optimal diagnosis of the skin cancer using a hybrid deep neural network and grasshopper optimization algorithm
  43. miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells
  44. Clinical value of SIRT1 as a prognostic biomarker in esophageal squamous cell carcinoma, a systematic meta-analysis
  45. circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8
  46. miR-22-5p regulates the self-renewal of spermatogonial stem cells by targeting EZH2
  47. hsa-miR-340-5p inhibits epithelial–mesenchymal transition in endometriosis by targeting MAP3K2 and inactivating MAPK/ERK signaling
  48. circ_0085296 inhibits the biological functions of trophoblast cells to promote the progression of preeclampsia via the miR-942-5p/THBS2 network
  49. TCD hemodynamics findings in the subacute phase of anterior circulation stroke patients treated with mechanical thrombectomy
  50. Development of a risk-stratification scoring system for predicting risk of breast cancer based on non-alcoholic fatty liver disease, non-alcoholic fatty pancreas disease, and uric acid
  51. Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway
  52. circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis
  53. Human amniotic fluid as a source of stem cells
  54. lncRNA NONRATT013819.2 promotes transforming growth factor-β1-induced myofibroblastic transition of hepatic stellate cells by miR24-3p/lox
  55. NORAD modulates miR-30c-5p-LDHA to protect lung endothelial cells damage
  56. Idiopathic pulmonary fibrosis telemedicine management during COVID-19 outbreak
  57. Risk factors for adverse drug reactions associated with clopidogrel therapy
  58. Serum zinc associated with immunity and inflammatory markers in Covid-19
  59. The relationship between night shift work and breast cancer incidence: A systematic review and meta-analysis of observational studies
  60. LncRNA expression in idiopathic achalasia: New insight and preliminary exploration into pathogenesis
  61. Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway
  62. Moscatilin suppresses the inflammation from macrophages and T cells
  63. Zoledronate promotes ECM degradation and apoptosis via Wnt/β-catenin
  64. Epithelial-mesenchymal transition-related genes in coronary artery disease
  65. The effect evaluation of traditional vaginal surgery and transvaginal mesh surgery for severe pelvic organ prolapse: 5 years follow-up
  66. Repeated partial splenic artery embolization for hypersplenism improves platelet count
  67. Low expression of miR-27b in serum exosomes of non-small cell lung cancer facilitates its progression by affecting EGFR
  68. Exosomal hsa_circ_0000519 modulates the NSCLC cell growth and metastasis via miR-1258/RHOV axis
  69. miR-455-5p enhances 5-fluorouracil sensitivity in colorectal cancer cells by targeting PIK3R1 and DEPDC1
  70. The effect of tranexamic acid on the reduction of intraoperative and postoperative blood loss and thromboembolic risk in patients with hip fracture
  71. Isocitrate dehydrogenase 1 mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to ferroptosis
  72. Artemisinin protects against cerebral ischemia and reperfusion injury via inhibiting the NF-κB pathway
  73. A 16-gene signature associated with homologous recombination deficiency for prognosis prediction in patients with triple-negative breast cancer
  74. Lidocaine ameliorates chronic constriction injury-induced neuropathic pain through regulating M1/M2 microglia polarization
  75. MicroRNA 322-5p reduced neuronal inflammation via the TLR4/TRAF6/NF-κB axis in a rat epilepsy model
  76. miR-1273h-5p suppresses CXCL12 expression and inhibits gastric cancer cell invasion and metastasis
  77. Clinical characteristics of pneumonia patients of long course of illness infected with SARS-CoV-2
  78. circRNF20 aggravates the malignancy of retinoblastoma depending on the regulation of miR-132-3p/PAX6 axis
  79. Linezolid for resistant Gram-positive bacterial infections in children under 12 years: A meta-analysis
  80. Rack1 regulates pro-inflammatory cytokines by NF-κB in diabetic nephropathy
  81. Comprehensive analysis of molecular mechanism and a novel prognostic signature based on small nuclear RNA biomarkers in gastric cancer patients
  82. Smog and risk of maternal and fetal birth outcomes: A retrospective study in Baoding, China
  83. Let-7i-3p inhibits the cell cycle, proliferation, invasion, and migration of colorectal cancer cells via downregulating CCND1
  84. β2-Adrenergic receptor expression in subchondral bone of patients with varus knee osteoarthritis
  85. Possible impact of COVID-19 pandemic and lockdown on suicide behavior among patients in Southeast Serbia
  86. In vitro antimicrobial activity of ozonated oil in liposome eyedrop against multidrug-resistant bacteria
  87. Potential biomarkers for inflammatory response in acute lung injury
  88. A low serum uric acid concentration predicts a poor prognosis in adult patients with candidemia
  89. Antitumor activity of recombinant oncolytic vaccinia virus with human IL2
  90. ALKBH5 inhibits TNF-α-induced apoptosis of HUVECs through Bcl-2 pathway
  91. Risk prediction of cardiovascular disease using machine learning classifiers
  92. Value of ultrasonography parameters in diagnosing polycystic ovary syndrome
  93. Bioinformatics analysis reveals three key genes and four survival genes associated with youth-onset NSCLC
  94. Identification of autophagy-related biomarkers in patients with pulmonary arterial hypertension based on bioinformatics analysis
  95. Protective effects of glaucocalyxin A on the airway of asthmatic mice
  96. Overexpression of miR-100-5p inhibits papillary thyroid cancer progression via targeting FZD8
  97. Bioinformatics-based analysis of SUMOylation-related genes in hepatocellular carcinoma reveals a role of upregulated SAE1 in promoting cell proliferation
  98. Effectiveness and clinical benefits of new anti-diabetic drugs: A real life experience
  99. Identification of osteoporosis based on gene biomarkers using support vector machine
  100. Tanshinone IIA reverses oxaliplatin resistance in colorectal cancer through microRNA-30b-5p/AVEN axis
  101. miR-212-5p inhibits nasopharyngeal carcinoma progression by targeting METTL3
  102. Association of ST-T changes with all-cause mortality among patients with peripheral T-cell lymphomas
  103. LINC00665/miRNAs axis-mediated collagen type XI alpha 1 correlates with immune infiltration and malignant phenotypes in lung adenocarcinoma
  104. The perinatal factors that influence the excretion of fecal calprotectin in premature-born children
  105. Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study
  106. Does the use of 3D-printed cones give a chance to postpone the use of megaprostheses in patients with large bone defects in the knee joint?
  107. lncRNA HAGLR modulates myocardial ischemia–reperfusion injury in mice through regulating miR-133a-3p/MAPK1 axis
  108. Protective effect of ghrelin on intestinal I/R injury in rats
  109. In vivo knee kinematics of an innovative prosthesis design
  110. Relationship between the height of fibular head and the incidence and severity of knee osteoarthritis
  111. lncRNA WT1-AS attenuates hypoxia/ischemia-induced neuronal injury during cerebral ischemic stroke via miR-186-5p/XIAP axis
  112. Correlation of cardiac troponin T and APACHE III score with all-cause in-hospital mortality in critically ill patients with acute pulmonary embolism
  113. LncRNA LINC01857 reduces metastasis and angiogenesis in breast cancer cells via regulating miR-2052/CENPQ axis
  114. Endothelial cell-specific molecule 1 (ESM1) promoted by transcription factor SPI1 acts as an oncogene to modulate the malignant phenotype of endometrial cancer
  115. SELENBP1 inhibits progression of colorectal cancer by suppressing epithelial–mesenchymal transition
  116. Visfatin is negatively associated with coronary artery lesions in subjects with impaired fasting glucose
  117. Treatment and outcomes of mechanical complications of acute myocardial infarction during the Covid-19 era: A comparison with the pre-Covid-19 period. A systematic review and meta-analysis
  118. Neonatal stroke surveillance study protocol in the United Kingdom and Republic of Ireland
  119. Oncogenic role of TWF2 in human tumors: A pan-cancer analysis
  120. Mean corpuscular hemoglobin predicts the length of hospital stay independent of severity classification in patients with acute pancreatitis
  121. Association of gallstone and polymorphisms of UGT1A1*27 and UGT1A1*28 in patients with hepatitis B virus-related liver failure
  122. TGF-β1 upregulates Sar1a expression and induces procollagen-I secretion in hypertrophic scarring fibroblasts
  123. Antisense lncRNA PCNA-AS1 promotes esophageal squamous cell carcinoma progression through the miR-2467-3p/PCNA axis
  124. NK-cell dysfunction of acute myeloid leukemia in relation to the renin–angiotensin system and neurotransmitter genes
  125. The effect of dilution with glucose and prolonged injection time on dexamethasone-induced perineal irritation – A randomized controlled trial
  126. miR-146-5p restrains calcification of vascular smooth muscle cells by suppressing TRAF6
  127. Role of lncRNA MIAT/miR-361-3p/CCAR2 in prostate cancer cells
  128. lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2
  129. Noninvasive diagnosis of AIH/PBC overlap syndrome based on prediction models
  130. lncRNA FAM230B is highly expressed in colorectal cancer and suppresses the maturation of miR-1182 to increase cell proliferation
  131. circ-LIMK1 regulates cisplatin resistance in lung adenocarcinoma by targeting miR-512-5p/HMGA1 axis
  132. LncRNA SNHG3 promoted cell proliferation, migration, and metastasis of esophageal squamous cell carcinoma via regulating miR-151a-3p/PFN2 axis
  133. Risk perception and affective state on work exhaustion in obstetrics during the COVID-19 pandemic
  134. lncRNA-AC130710/miR-129-5p/mGluR1 axis promote migration and invasion by activating PKCα-MAPK signal pathway in melanoma
  135. SNRPB promotes cell cycle progression in thyroid carcinoma via inhibiting p53
  136. Xylooligosaccharides and aerobic training regulate metabolism and behavior in rats with streptozotocin-induced type 1 diabetes
  137. Serpin family A member 1 is an oncogene in glioma and its translation is enhanced by NAD(P)H quinone dehydrogenase 1 through RNA-binding activity
  138. Silencing of CPSF7 inhibits the proliferation, migration, and invasion of lung adenocarcinoma cells by blocking the AKT/mTOR signaling pathway
  139. Ultrasound-guided lumbar plexus block versus transversus abdominis plane block for analgesia in children with hip dislocation: A double-blind, randomized trial
  140. Relationship of plasma MBP and 8-oxo-dG with brain damage in preterm
  141. Identification of a novel necroptosis-associated miRNA signature for predicting the prognosis in head and neck squamous cell carcinoma
  142. Delayed femoral vein ligation reduces operative time and blood loss during hip disarticulation in patients with extremity tumors
  143. The expression of ASAP3 and NOTCH3 and the clinicopathological characteristics of adult glioma patients
  144. Longitudinal analysis of factors related to Helicobacter pylori infection in Chinese adults
  145. HOXA10 enhances cell proliferation and suppresses apoptosis in esophageal cancer via activating p38/ERK signaling pathway
  146. Meta-analysis of early-life antibiotic use and allergic rhinitis
  147. Marital status and its correlation with age, race, and gender in prognosis of tonsil squamous cell carcinomas
  148. HPV16 E6E7 up-regulates KIF2A expression by activating JNK/c-Jun signal, is beneficial to migration and invasion of cervical cancer cells
  149. Amino acid profiles in the tissue and serum of patients with liver cancer
  150. Pain in critically ill COVID-19 patients: An Italian retrospective study
  151. Immunohistochemical distribution of Bcl-2 and p53 apoptotic markers in acetamiprid-induced nephrotoxicity
  152. Estradiol pretreatment in GnRH antagonist protocol for IVF/ICSI treatment
  153. Long non-coding RNAs LINC00689 inhibits the apoptosis of human nucleus pulposus cells via miR-3127-5p/ATG7 axis-mediated autophagy
  154. The relationship between oxygen therapy, drug therapy, and COVID-19 mortality
  155. Monitoring hypertensive disorders in pregnancy to prevent preeclampsia in pregnant women of advanced maternal age: Trial mimicking with retrospective data
  156. SETD1A promotes the proliferation and glycolysis of nasopharyngeal carcinoma cells by activating the PI3K/Akt pathway
  157. The role of Shunaoxin pills in the treatment of chronic cerebral hypoperfusion and its main pharmacodynamic components
  158. TET3 governs malignant behaviors and unfavorable prognosis of esophageal squamous cell carcinoma by activating the PI3K/AKT/GSK3β/β-catenin pathway
  159. Associations between morphokinetic parameters of temporary-arrest embryos and the clinical prognosis in FET cycles
  160. Long noncoding RNA WT1-AS regulates trophoblast proliferation, migration, and invasion via the microRNA-186-5p/CADM2 axis
  161. The incidence of bronchiectasis in chronic obstructive pulmonary disease
  162. Integrated bioinformatics analysis shows integrin alpha 3 is a prognostic biomarker for pancreatic cancer
  163. Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway
  164. Comparison of hospitalized patients with severe pneumonia caused by COVID-19 and influenza A (H7N9 and H1N1): A retrospective study from a designated hospital
  165. lncRNA ZFAS1 promotes intervertebral disc degeneration by upregulating AAK1
  166. Pathological characteristics of liver injury induced by N,N-dimethylformamide: From humans to animal models
  167. lncRNA ELFN1-AS1 enhances the progression of colon cancer by targeting miR-4270 to upregulate AURKB
  168. DARS-AS1 modulates cell proliferation and migration of gastric cancer cells by regulating miR-330-3p/NAT10 axis
  169. Dezocine inhibits cell proliferation, migration, and invasion by targeting CRABP2 in ovarian cancer
  170. MGST1 alleviates the oxidative stress of trophoblast cells induced by hypoxia/reoxygenation and promotes cell proliferation, migration, and invasion by activating the PI3K/AKT/mTOR pathway
  171. Bifidobacterium lactis Probio-M8 ameliorated the symptoms of type 2 diabetes mellitus mice by changing ileum FXR-CYP7A1
  172. circRNA DENND1B inhibits tumorigenicity of clear cell renal cell carcinoma via miR-122-5p/TIMP2 axis
  173. EphA3 targeted by miR-3666 contributes to melanoma malignancy via activating ERK1/2 and p38 MAPK pathways
  174. Pacemakers and methylprednisolone pulse therapy in immune-related myocarditis concomitant with complete heart block
  175. miRNA-130a-3p targets sphingosine-1-phosphate receptor 1 to activate the microglial and astrocytes and to promote neural injury under the high glucose condition
  176. Review Articles
  177. Current management of cancer pain in Italy: Expert opinion paper
  178. Hearing loss and brain disorders: A review of multiple pathologies
  179. The rationale for using low-molecular weight heparin in the therapy of symptomatic COVID-19 patients
  180. Amyotrophic lateral sclerosis and delayed onset muscle soreness in light of the impaired blink and stretch reflexes – watch out for Piezo2
  181. Interleukin-35 in autoimmune dermatoses: Current concepts
  182. Recent discoveries in microbiota dysbiosis, cholangiocytic factors, and models for studying the pathogenesis of primary sclerosing cholangitis
  183. Advantages of ketamine in pediatric anesthesia
  184. Congenital adrenal hyperplasia. Role of dentist in early diagnosis
  185. Migraine management: Non-pharmacological points for patients and health care professionals
  186. Atherogenic index of plasma and coronary artery disease: A systematic review
  187. Physiological and modulatory role of thioredoxins in the cellular function
  188. Case Reports
  189. Intrauterine Bakri balloon tamponade plus cervical cerclage for the prevention and treatment of postpartum haemorrhage in late pregnancy complicated with acute aortic dissection: Case series
  190. A case of successful pembrolizumab monotherapy in a patient with advanced lung adenocarcinoma: Use of multiple biomarkers in combination for clinical practice
  191. Unusual neurological manifestations of bilateral medial medullary infarction: A case report
  192. Atypical symptoms of malignant hyperthermia: A rare causative mutation in the RYR1 gene
  193. A case report of dermatomyositis with the missed diagnosis of non-small cell lung cancer and concurrence of pulmonary tuberculosis
  194. A rare case of endometrial polyp complicated with uterine inversion: A case report and clinical management
  195. Spontaneous rupturing of splenic artery aneurysm: Another reason for fatal syncope and shock (Case report and literature review)
  196. Fungal infection mimicking COVID-19 infection – A case report
  197. Concurrent aspergillosis and cystic pulmonary metastases in a patient with tongue squamous cell carcinoma
  198. Paraganglioma-induced inverted takotsubo-like cardiomyopathy leading to cardiogenic shock successfully treated with extracorporeal membrane oxygenation
  199. Lineage switch from lymphoma to myeloid neoplasms: First case series from a single institution
  200. Trismus during tracheal extubation as a complication of general anaesthesia – A case report
  201. Simultaneous treatment of a pubovesical fistula and lymph node metastasis secondary to multimodal treatment for prostate cancer: Case report and review of the literature
  202. Two case reports of skin vasculitis following the COVID-19 immunization
  203. Ureteroiliac fistula after oncological surgery: Case report and review of the literature
  204. Synchronous triple primary malignant tumours in the bladder, prostate, and lung harbouring TP53 and MEK1 mutations accompanied with severe cardiovascular diseases: A case report
  205. Huge mucinous cystic neoplasms with adhesion to the left colon: A case report and literature review
  206. Commentary
  207. Commentary on “Clinicopathological features of programmed cell death-ligand 1 expression in patients with oral squamous cell carcinoma”
  208. Rapid Communication
  209. COVID-19 fear, post-traumatic stress, growth, and the role of resilience
  210. Erratum
  211. Erratum to “Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway”
  212. Erratum to “Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study”
  213. Erratum to “lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2”
  214. Retraction
  215. Expression and role of ABIN1 in sepsis: In vitro and in vivo studies
  216. Retraction to “miR-519d downregulates LEP expression to inhibit preeclampsia development”
  217. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part II
  218. Usefulness of close surveillance for rectal cancer patients after neoadjuvant chemoradiotherapy
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