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Glycoprotein non-metastatic melanoma B interacts with epidermal growth factor receptor to regulate neural stem cell survival and differentiation

  • Hua Yang , Gang Jin , Shihong Chen , Jing Luo and Wei Xu EMAIL logo
Published/Copyright: February 14, 2023
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Open Medicine
From the journal Open Medicine Volume 18 Issue 1

Abstract

The functional recovery following spinal cord injury (SCI) remains a challenge clinically. Among the proteins interacted with the glycoprotein non-metastatic melanoma B (GPNMB), epidermal growth factor receptor (EGFR) during activation is able to promote the proliferation of neural stem cells (NSCs) in the spinal cord. We investigated the roles of GPNMB and EGFR in regulating the survival and differentiation of the NSCs. By overexpression and short-hairpin RNA-mediated knockdown of GPNMB in the NSCs, GPNMB promoted cell viability and differentiation by increasing the expressions of βIII tubulin and CNPase (2′,3′-cyclic nucleotide 3-phosphodiesterase). Using co-immunoprecipitation, we found that EGFR interacted with GPNMB. Furthermore, EGFR had a similar effect as GPNMB on promoting cell viability and differentiation. Overexpression of EGFR reversed the decrease in viability and differentiation caused by the knockdown of GPNMB, and vice versa. Last but not least, we tested the effect of GPNMB and EGFR on several intracellular pathways and found that GPNMB/EGFR modulated the phosphorylated (p)-c-Jun N-terminal kinase (JNK)1/2/JNK1/2 ratio and the p-nuclear factor κB (NF-κB p65)/NF-κB p65 ratio. In sum, our findings demonstrate the interaction between GPNMB and EGFR that regulates cell bioprocesses, with the hope to provide a new strategy of SCI therapy.

Keywords: glycoprotein non-metastatic melanoma B; epidermal growth factor receptor; spinal cord injury; functional recovery; cell differentiation

1 Introduction

Spinal cord injury (SCI) has been emerged as a serious and irreversible disease in the central nervous system (CNS) [1], bringing about permanent or temporary loss of function in the motor or sensory capability and leading to destructive neurological and functional deficiency inclusive of paraplegia or quadriplegia [2]. Due to the lack of regeneration capacity, the recovery of the body function as impaired by SCI remains a significant challenge clinically [3]. In this case, the efforts devoted into exploring the functions of endogenous spinal cord neural stem cells (NSCs) shed a light on the treatment of SCI [4,5].

NSCs, primarily indwelling in the CNS including the spinal cord and the brain, are competent to self-renew for the maintenance of the stem cell bank size and to differentiate into neurons for the repairmen of the tissues [4,6], which is likely to be distinguished in the functional recovery of SCI. Given the inclination of NSCs to differentiate into microenvironment-dependent glia lineages, many researchers have committed to facilitating the differentiation into functional neurons from the spinal cord neural progenitor cells (NPCs) [7,8].

The differentiation inducement attempts involve the regulation of the proteins in the spinal cord to trigger the endogenous repair [9]. We started our study by analyzing transcriptome changes via the aberrant gene expressions either in the young or aged patients perplexed by SCI based on the data set GSE93561 and captured 90 genes expressing aberrantly after crossover analysis. Glycoprotein non-metastatic melanoma B (GPNMB) has aroused our interest by dint of its multiple functions, encompassing tissue repairment facilitation, kinase signaling stimulation, cell–cell adhesion and migration acceleration, tumorigenesis promotion, modulation of the cell growth and differentiation, etc. [10]. GPNMB is a type I transmembrane glycoprotein [11], whose expression level is found upregulated in SCI according to the analyses of the above-mentioned data set. Apart from that, GPNMB also exhibits dysregulated expression in the spinal cord transcriptome after peripheral nerve injury [12] and in a high-fat diet-fed male rat model of thoracic spinal contusion [13]. However, the regulatory mechanism of GPNMB in SCI remains uncharacterized.

To figure out the regulatory mechanism of GPNMB in SCI, we adopted bioinformatics analysis to predict the proteins interacting with GPNMB. Notably, epidermal growth factor receptor (EGFR), a transmembrane glycoprotein of ErbB family, was finalized, given that the activation of EGFR contributed to the proliferation of NSCs in SCI [14]. EGFR signaling cascade features in the proliferation, division, differentiation, and survival of the cells [15]. It has been elucidated that EGFR can regulate a variety of downstream pathways, including Janus kinase/signal transducer and activator of transcription, extracellular signal-regulated kinase/mitogen-activated protein kinase, phosphatidylinositol 3-kinase (PI3K)/Akt, and Notch pathways, and promote the NSC proliferation [16,17,18]. EGF (epidermal growth factor), a ligand of EGFR, activates EGFR and enhances the proliferation of local NSCs, playing an active role in SCI [19]. In line with the above findings, we are dedicating to validating whether GPNMB interacts with EGFR to regulate cell survival and differentiation in SCI, so as to provide a novel insight for the further prognosis for SCI patients.

2 Methods

2.1 Ethics statement

All the research studies related to animal use were complied with the relevant national regulations and institutional policies for the care and use of animals. This study was conducted on the premise of authorization from the Ethic Committee of Experimental Animals of Taizhou Central Hospital (Taizhou University Hospital) with approval number SJWK202001010. Every effort was exploited to minimize the pain and discomfort to the animals.

2.2 Bioinformatics analysis

SCI microarray data were downloaded from the gene expression omnibus database (http://www.ncbi.nlm.nih.gov/geo/) using the accession number, GSE93561 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE93561) [20]. Search tool, the Retrieval of Interacting Genes Database (STRING) (https://www.string-db.org/), was adopted to comprehensively analyze the data for protein–protein interaction (PPI) network [21].

2.3 Neurosphere culture

Before the operation, the C57BL/6 mice neonates (<12 h after birth) from five pregnant C57BL/6 mice (C57BL/6JNifdc; Charles River Laboratories, Wilmington, MA, USA) in this study were anesthetized with ketamine (80 mg/kg; K-002; Sigma-Aldrich) and intraperitoneally injected with xylazine (10 mg/kg, X1126; Sigma-Aldrich). Next, T10 spinal cord was exposed after the removal of the vertebral lamina and then completely cut by the scissors. NPCs were obtained as previously described [3]. The cut-off spinal cords were then dissociated by TrypLE Express (12604013; Gibco, USA) at 37°C for 25 min. Subsequently, the single-cell suspension of the NPCs was placed in Dulbecco’s modified Eagle’s medium (DMEM)/F-12 (31331093; Gibco) supplemented with 1% penicillin–streptomycin antibiotics (15240096; Gibco), 2% B27 (A3582801; Gibco), 20 ng/mL EGF (AF-100-15; PeproTech, New Jersey, USA), and 20 ng/mL fibroblast growth factor-basic (bFGF; AF-100-18B; PeproTech). Afterward, the neurospheres were digested by Trypsin (R001100; Gibco) digestion buffer in the subsequent experiments and cultured in DMEM with high glucose (DMEM-H; 11995040; Gibco) supplemented with 10% fetal bovine serum (FBS; 12664025; Gibco).

2.4 NPC differentiation

NPC differentiation inducement was implemented as previously described [22]. Briefly, cells were digested and resuspended into single-cell suspension, followed by the seeding in culture dishes coated with poly-l-lysine (P4707; Sigma-Aldrich). Thereafter, cells were cultured in DMEM/F-12 medium supplemented with 2% B27 and 1% FBS to induce differentiation. The culture medium was replaced every 2 days. NPCs cultured in DMEM/F-12 medium without any treatment served as the control group.

2.5 Cell transfection

Cells were initially transfected with overexpressed plasmid of GPNMB, short-hairpin RNA (shRNA) targeting GPNMB (shGPNMB) and their negative controls (shNC) [21], and subsequently continued for transfection with EGFR overexpression plasmid and shRNA targeting EGFR (shEGFR). Overexpressed plasmids for GPNMB or EGFR were constructed by inserting the whole sequences of GPNMB or EGFR into pcDNA 3.1 empty vector (V79020; Thermo Fisher Scientific, Waltham, MA, USA). Empty vector was used as NC (negative control). ShNC, shGPNMB (5′-TGAGGGAGCACAATCAATTAA-3′), shGPNMB (shRNA#2; 5′-GTGTACATATTCTACTCATTA-3′), shGPNMB (shRNA#3; 5′-GGAGCTTTGTCTACGTCTTTC-3′), shEGFR (5′-GAATAGGTATTGGTGAATTTA-3′), shEGFR (shRNA#2; 5′-GCATAGGCATTGGTGAATTTA-3′), and shEGFR (shRNA#3; 5′-CCAAGCCAAATGGCATATTTA-3′) were all synthesized by GenePharma (Shanghai, China). Before transfection, cells were cultured in six-well plates (CLS3335, Corning, NY, USA) till 90% confluence was reached. Prior to transfection, the culture medium was removed and cells were washed with phosphate-buffered saline (PBS) (806552; Sigma-Aldrich) and then transfected with commercially available GenePharma substances via Lipofectamine 2000 transfection reagent (11668027; Invitrogen, CA, USA). Briefly, 50 nanogram/mol (nM) shGPNMB, shEGFR or NC and 10 μL Lipofectamine reagent were diluted in 250 μL serum-free DMEM, and then cultured in the Opti-MEM™ medium (11058021; Thermo Fisher Scientific) at room temperature for 5 min. After the addition of DNA–lipid complex, cells were incubated at 37°C for 24 h before analysis.

2.6 Western blot assay

Protein expression levels of βIII tubulin, 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase), GPNMB, EGFR, c‑Jun NH2‑terminal kinase (JNK)1/2, phosphorylated (p)-JNK1/2 (p-JNK1/2), and nuclear factor κB (NF-κB) p65 were measured by Western blot assay, with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as the internal reference. Simply put, cells were harvested and extracted by 300 μL RIPA lysis buffer (20-188; Sigma-Aldrich) containing protease and phosphatase inhibitor (P1045; Beyotime, Shanghai, China), followed by the centrifugation for collection of supernatant. Thereafter, concentrations of proteins in the supernatant were measured by a bicinchoninic acid kit (P0011; Beyotime) based on manufacturer’s directions. Subsequently, the proteins with equal weight of 30 µg were electrophoresed on 10% sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and then transferred onto the polyvinylidene fluoride (PVDF) membrane (FFP28; Beyotime). The membrane was blocked with 5% skimmed milk at room temperature for 1 h and then incubated with the primary antibodies at 4℃ overnight. Herein, the varied primary antibodies included anti-βIII tubulin (rabbit, 1:1,000, 50 kDa, ab18207; Abcam, Cambridge, UK), anti-CNPase (rabbit, 1:1,000, 48 kDa, ab250658; Abcam), anti-GPNMB (rabbit, 1:5,000, 120 kDa, ab188222; Abcam), anti-EGFR (rabbit, 1:2,000, 175 kDa, ab52894; Abcam), anti-JNK1/2 (mouse, 1:500, 54 kDa, sc-137019; Santa Cruz, Texas, USA), anti-p-JNK1/2 (rabbit, 1:1,000, 46–54 kDa, ab124956; Abcam), anti-NF-κB p65 (rabbit, 1:1,000, 65 kDa, ab32536; Abcam), anti-p-NF-κB p65 (rabbit, 1:1,000, 65 kDa, ab239882; Abcam), and anti-GAPDH (mouse, 1:500, 36 kDa, ab9484; Abcam). Afterward, the membranes were thereupon incubated with horseradish peroxidase-conjugated secondary antibodies goat anti-rabbit IgG (1:3,000, ab205718; Abcam) and goat anti-mouse IgG (1:3,000, ab6789; Abcam) at room temperature for 2 h. Protein signals were tested and collected via the enhanced chemiluminescence Kit (P0018S; Beyotime) and quantified through ImageJ software (ImageJ 1.8.0; Bethesda, MD, USA).

2.7 Quantitative reverse-transcription polymerase chain reaction (qRT-PCR)

Relative GPNMB and EGFR mRNA expression levels were measured by qRT-PCR. Briefly, total RNAs were extracted via TRIzol reagent (15596026; Invitrogen), whose quantities and purities were determined by a spectrophotometer (ND-LITE-PR; Thermo Fisher Scientific) and transcribed reversely by an RNA transcriptase kit (K1621; Thermo Fisher Scientific) based on the manufacturer’s instructions. qRT-PCR experiment was carried out with the SYBR PremixEx Taq II Kit (RR820L; TaKaRa, Japan) in LightCycler 480-II System (Roche Diagnostics, Penzberg, Germany). The qRT-PCR amplification conditions were listed as follows: 95℃ for 5 min; 40 cycles at 95℃ for 5 s, 60℃ for 20 s, and 72°C for 40 s. Primer sequences for GPNMB were 5′-ACTTGGGCCTCAACTCATGG-3′ (Forward) and 5′-GCAGGTGGGGTCAGAAATGA-3′ (Reverse). Primer sequences for EGFR were 5′-TCTCCAAAATGGCCCGAGAC-3′ (Forward) and 5′-CAGGATTCTGCACAGAGCCA-3′ (Reverse). Primer sequences for GAPDH were 5′-TTCACCACCATGGAGAAGGC-3′ (Forward) and 5′-GATGGCATGGACTGTGGTCA-3′ (Reverse). For results calculations, 2−ΔΔCt method was adopted [23] with GAPDH as the internal reference.

2.8 Cell counting kit-8 (CCK-8) assay

Cell viability was measured by CCK-8 assay kit (C0037; Beyotime) following the manufacturer’s instructions. Cells were first seeded into 96-well plates (CLS3922; Corning) at a density of 4 × 104 cells per well for 24, 48, and 72 h. Subsequently, 10 µL of CCK-8 solution was added into every well for further 2-h incubation. Afterward, the optical density (OD) was assessed at a wavelength of 450 nm via a microplate reader (Varioskan LUX; Thermo Fisher).

2.9 Immunofluorescence

Cells were immobilized with 4% precooling paraformaldehyde (P1110; Solarbio, Beijing, China) for 30 min and permeabilized with 0.3% Triton X-100 (T8200; Solarbio) at room temperature for 10 min. After being blocked in 1% bovine serum albumin (BSA; A8020; Solarbio) for 30 min, cells were incubated with primary antibodies including anti-βIII tubulin (1 μg/mL) and anti-CNPase (5 µg/mL) at 4℃ overnight. Post three times of washing in PBS (806552; Sigma-Aldrich), the primary antibodies were identified with Alexa Fluor 594 goat-anti rabbit antibodies (B40925; Invitrogen) for 60-min incubation at room temperature. Subsequently, the nuclei were counter-stained with DAPI (C1002; Beyotime) at 37℃ for 10 min. Ultimately, the slides were mounted and observed under a fluorescence microscope (Leica, TCS SP5II, Germany).

2.10 Co-immunoprecipitation (Co-IP) assay

Co-IP assay was implemented utilizing the Pierce Co-IP Kit (26149; Thermo Fisher Scientific) following the manufacturer’s instructions. In a nutshell, the harvested cells were homogenized by ice-cold non-denaturing lysis buffer (25 mM Tris, 150 mM NaCl, 1 mM EDTA [ethylenediamine tetra acetic acid], 1% Nonidet P-40 [NP-40] and 5% glycerol; pH 7.4) with the addition of 2× complete protease inhibitor cocktails (11206893001; Roche, Mannheim, Germany) and then centrifuged for 20 min. The supernatant was collected and the protein concentration was quantified. A 50 μL aliquot of cell lysate was saved as the input, and the resulting supernatant was pre-cleaned for 1-h incubation with Pierce Control Agarose Resin at 4℃. Subsequently, the antibody against GPNMB (1:30) or EGFR (1:20) was incubated with AminoLink Plus coupling Resin for 2 h and washed three times with the Coupling Buffer (10 mM sodium phosphate, 150 mM NaCl; pH 7.2). Meanwhile, the antibody against IgG was set as the NC. The pre-cleaned lysates (1 mg of proteins) were incubated with antibody-coated Resin at 4℃ for 2 h. After being washed three times with the lysis buffer, the precipitates were separated on SDS-PAGE for Western blot analysis and probed with anti-GPNMB or anti-EGFR antibody, respectively.

2.11 Statistical analysis

All values were presented as mean ± standard deviation (SD). Independent samples t test was applied for the analysis between two variables. One-way analysis of variance was adopted to analyze one categorical independent variable in multiple groups, followed by Bonferroni post hoc analysis. GraphPad Prism 8 software (GraphPad, CA, USA) was utilized for data analysis. For measurements, P < 0.05 was perceived as statistical significance.

3 Results

3.1 GPNMB promoted neuronal viability and differentiation while shGPNMB performed differently

Post bone marrow NSC extraction and differentiation inducement, we utilized Western blot assay to detect the differentiation degree of the cells. Upregulated protein expression of the neural differentiation marker, βIII tubulin, indicated the successful differentiation of NSCs into neurons (Figure 1a, P < 0.001). Then, we measured GPNMB expression changes after cell differentiation via qRT-PCR and Western blot assay. Results from both assays demonstrated that GPNMB expression level was upregulated in the differentiated cells relative to that in control cells (Figure 1b and c, P < 0.001). Next, we transfected the cells with the overexpressed or silenced GPNMB plasmid to figure out the impact of GPNMB upon cell viability and neural differentiations. shGPNMB was used for further experiment due to its more efficiency of GPNMB knock down (Figure A1a, P < 0.01). Moreover, qRT-PCR and Western blot assays demonstrated that overexpressed GPNMB promoted while shGPNMB reduced GPNMB expression, indicating the success of transfection (Figure 1d–e, P < 0.001). Besides, CCK-8 assay manifested that GPNMB overexpression boosted cell viability; yet, shGPNMB restrained cell viability in the endured test time (Figure 1f, P < 0.05). Finally, neural differentiation was assessed by the immunolabeling profiles of the neuronal marker βIII tubulin and oligodendrocyte marker CNPase [24], followed by the measurement of Western blot assay, the results of which displayed that overexpressed GPNMB upregulated βIII tubulin and CNPase expression levels (Figure 1g–h, P < 0.05), whilst shGPNMB downregulated the expressions of the neural differentiation markers (Figure 1g–h, P < 0.001).

Figure 1 GPNMB promoted cell viability and neuronal differentiation while shGPNMB performed differently. (a) Relative βIII tubulin expression was measured by qRT-PCR and Western blot assay. Upregulation of βIII tubulin expression suggested the successful differentiation of the neural stem cells into neurons. (b and c) Relative GPNMB expression was measured by qRT-PCR and Western blot assay. (d and e) Transfection efficiency was validated by qRT-PCR and Western blot assay. (f) Cell viability was measured via CCK-8. GPNMB promoted while shGPNMB inhibited cell viability. (g) Immunofluorescence assay was adopted to assess the status of neuronal differentiation (magnification 200×, scale bar 100 µm). Red part referred to the targeted proteins, and blue meant the nuclei as stained by DAPI. (h) Relative neural differentiation markers’ (βIII tubulin and CNPase) expressions were measured by Western blot assay. GAPDH was set as the internal reference. ** P < 0.01 or *** P < 0.001 vs Control; + P < 0.05 or +++ P < 0.001 vs NC; ## P < 0.01, ### P < 0.001 vs shNC. All results represent means ± SD of triplicate determinations. qRT-PCR: quantitative reverse-transcription polymerase chain reaction; GPNMB: glycoprotein non-metastatic melanoma B; shNC: short-hairpin-negative control; CCK-8: cell counting kit-8; CNPase: 2′,3′-cyclic nucleotide 3′ phosphodiesterase.
Figure 1

GPNMB promoted cell viability and neuronal differentiation while shGPNMB performed differently. (a) Relative βIII tubulin expression was measured by qRT-PCR and Western blot assay. Upregulation of βIII tubulin expression suggested the successful differentiation of the neural stem cells into neurons. (b and c) Relative GPNMB expression was measured by qRT-PCR and Western blot assay. (d and e) Transfection efficiency was validated by qRT-PCR and Western blot assay. (f) Cell viability was measured via CCK-8. GPNMB promoted while shGPNMB inhibited cell viability. (g) Immunofluorescence assay was adopted to assess the status of neuronal differentiation (magnification 200×, scale bar 100 µm). Red part referred to the targeted proteins, and blue meant the nuclei as stained by DAPI. (h) Relative neural differentiation markers’ (βIII tubulin and CNPase) expressions were measured by Western blot assay. GAPDH was set as the internal reference. ** P < 0.01 or *** P < 0.001 vs Control; + P < 0.05 or +++ P < 0.001 vs NC; ## P < 0.01, ### P < 0.001 vs shNC. All results represent means ± SD of triplicate determinations. qRT-PCR: quantitative reverse-transcription polymerase chain reaction; GPNMB: glycoprotein non-metastatic melanoma B; shNC: short-hairpin-negative control; CCK-8: cell counting kit-8; CNPase: 2′,3′-cyclic nucleotide 3′ phosphodiesterase.

3.2 EGFR interacted with GPNMB and its expression level was upregulated in the differentiated cells

To figure out the regulatory mechanism of GPNMB, we adopted STRING to analyze the proteins interacting with GPNMB (Figure 2a). Ultimately, EGFR was selected as the candidate on the basis of literature study. To validate the interaction between GPNMB and EGFR, we performed Co-IP assay with identification that GPNMB coprecipitated with EGFR (Figure 2b and c). Then, we conducted qRT-PCR and Western blot assay again to measure the expression level of EGFR and discovered that EGFR was upregulated in the differentiated cells relative to that in control cells (Figure 2d–e, P < 0.001).

Figure 2 EGFR interacted with GPNMB and its expression level was downregulated after cell differentiation. (a) STRING (https://www.string-db.org/) was adopted to comprehensively analyze the data for PPI network. GPNMB interacted with EGFR. (b and c) A Co-IP assay was performed to identify if GPNMB coprecipitated with EGFR. (d and e) Relative EGFR expression was measured by qRT-PCR and Western blot assay. GAPDH was set as the internal reference. ** P < 0.01 *** P < 0.001 vs control. All results represent means ± SD of triplicate determinations. STRING: Retrieval of Interacting Genes Database; PPI: protein–protein interaction; EGFR: epidermal growth factor receptor; Co-IP: co-immunoprecipitation.
Figure 2

EGFR interacted with GPNMB and its expression level was downregulated after cell differentiation. (a) STRING (https://www.string-db.org/) was adopted to comprehensively analyze the data for PPI network. GPNMB interacted with EGFR. (b and c) A Co-IP assay was performed to identify if GPNMB coprecipitated with EGFR. (d and e) Relative EGFR expression was measured by qRT-PCR and Western blot assay. GAPDH was set as the internal reference. ** P < 0.01 *** P < 0.001 vs control. All results represent means ± SD of triplicate determinations. STRING: Retrieval of Interacting Genes Database; PPI: protein–protein interaction; EGFR: epidermal growth factor receptor; Co-IP: co-immunoprecipitation.

3.3 EGFR boosted cell viability and partly reversed the effect of shGPNMB

Subsequently, we further explored the mechanism with the participation of aberrant EGFR expression through transfection. ShEGFR was used for next experiment because of its more efficiency of EGFR knock down (Figure A1b, P < 0.001). As supported by the measurements from qRT-PCR and Western blot assays, overexpressed EGFR upregulated EGFR expression, whereas shEGFR downregulated EGFR expression, which indicated the success of transfection (Figure 3a and b, P < 0.001). Then, we implemented CCK-8 assay to reveal the effect of EGFR on cell viability, finding that shEGFR suppressed cell viability; yet, GPNMB boosted cell viability and could partly reverse the inhibiting effect of shEGFR (Figure 3c, P < 0.05). Besides, shGPNMB restrained cell viability, while EGFR stimulated cell viability and partly counteracted the suppressive effect of shGPNMB (Figure 3d, P < 0.05).

Figure 3 EGFR facilitated cell viability and partly reversed the effect of shGPNMB. (a and b) Transfection efficiency was verified by qRT-PCR and Western blot assay. Overexpressed EGFR promoted EGFR expression but shEGFR reduced EGFR expression. (c and d) Cell viability was measured through CCK-8. GAPDH was used as the internal reference. *** P < 0.001 vs NC; +++ P < 0.001 vs shNC; ^ P < 0.05，^^^ P < 0.001 vs NC + shNC; ## P < 0.01 vs GPNMB + shNC; &&& P < 0.001 vs NC + shEGFR; ε P < 0.05, εε P < 0.01, εεε P < 0.001 vs shNC + NC; ΩΩΩ P < 0.001 vs shGPNMB + NC; Δ P < 0.05, ΔΔ P < 0.01 vs shNC + EGFR. All results represent means ± SD of triplicate determinations. shEGFR: short-hairpin RNA-targeting EGFR.
Figure 3

EGFR facilitated cell viability and partly reversed the effect of shGPNMB. (a and b) Transfection efficiency was verified by qRT-PCR and Western blot assay. Overexpressed EGFR promoted EGFR expression but shEGFR reduced EGFR expression. (c and d) Cell viability was measured through CCK-8. GAPDH was used as the internal reference. *** P < 0.001 vs NC; +++ P < 0.001 vs shNC; ^ P < 0.05，^^^ P < 0.001 vs NC + shNC; ## P < 0.01 vs GPNMB + shNC; &&& P < 0.001 vs NC + shEGFR; ε P < 0.05, εε P < 0.01, εεε P < 0.001 vs shNC + NC; ΩΩΩ P < 0.001 vs shGPNMB + NC; Δ P < 0.05, ΔΔ P < 0.01 vs shNC + EGFR. All results represent means ± SD of triplicate determinations. shEGFR: short-hairpin RNA-targeting EGFR.

3.4 EGFR facilitated p-JNK1/2/JNK1/2 ratio and NF-κB p65 expression and partly counteracted the inhibitory effects of shGPNMB on the JNK/NF-κB signaling pathway while shEGFR displayed oppositely

Then, we adopted the immunofluorescence assay to explore the status of neuronal differentiation after the second-phase transfection, followed by Western blot assay. The results uncovered that overexpressed GPNMB increased βIII tubulin and CNPase protein expressions, while shEGFR decreased βIII tubulin and CNPase expressions and could partly neutralize the promotive effects of GPNMB on the expressions of these two proteins (Figure 4a, P < 0.001). Moreover, shGPNMB lessened βIII tubulin and CNPase protein expressions, whereas EGFR enhanced βIII tubulin and CNPase expressions and partly offset the restraining function of shGPNMB in the above aspects (Figure 4b, P < 0.001). Finally, we validated our conjecture through detecting JNK/NF-κB signaling pathway-related indicators via Western blot assay. GPNMB boosted the p-JNK1/2/JNK1/2 ratio and the p-NF-κB p65/NF-κB p65 ratio, but shEGFR worked inversely and partly reversed the enhancing effects of GPNMB on JNK/NF-κB signaling pathway-related markers (Figure 4c, P < 0.05). On the contrary, shGPNMB reduced the p-JNK1/2/JNK1/2 ratio and the p-NF-κB p65/NF-κB p65 ratio; yet, EGFR facilitated these ratios and partly counteracted the inhibitory effect of shGPNMB on the JNK/NF-κB signaling pathway-associated markers (Figure 4d, P < 0.001).

Figure 4 EGFR up-regulated p-JNK1/2/JNK1/2 ratio and NF-κB p65 expression and partly offset the suppressive effect of shGPNMB on the JNK/NF-κB signaling pathway while shEGFR worked inversely. (a and b) Relative βIII tubulin and CNPase expressions were measured by Western blot assay. (c and d) Expressions of JNK/NF-κB signaling pathway-related indicators were measured by Western blot assay. GAPDH was employed as the internal reference. ^ P < 0.05 or ^^^ P < 0.001 vs NC + shNC; ### P < 0.001 vs GPNMB + shNC; && P < 0.01, &&& P < 0.001 vs NC + shEGFR; ε P < 0.05 or εεε P < 0.001 vs shNC + NC; Ω P < 0.05 or ΩΩΩ P < 0.001 vs shGPNMB + NC; ΔΔΔ P < 0.001 vs shNC + EGFR. All results represent means ± SD of triplicate determinations. JNK 1/2: c‑Jun NH2‑terminal kinase 1/2; p-JNK 1/2: phosphorylated JNK1/2; NF-κB p65: nuclear factor κB p65.
Figure 4

EGFR up-regulated p-JNK1/2/JNK1/2 ratio and NF-κB p65 expression and partly offset the suppressive effect of shGPNMB on the JNK/NF-κB signaling pathway while shEGFR worked inversely. (a and b) Relative βIII tubulin and CNPase expressions were measured by Western blot assay. (c and d) Expressions of JNK/NF-κB signaling pathway-related indicators were measured by Western blot assay. GAPDH was employed as the internal reference. ^ P < 0.05 or ^^^ P < 0.001 vs NC + shNC; ### P < 0.001 vs GPNMB + shNC; && P < 0.01, &&& P < 0.001 vs NC + shEGFR; ε P < 0.05 or εεε P < 0.001 vs shNC + NC; Ω P < 0.05 or ΩΩΩ P < 0.001 vs shGPNMB + NC; ΔΔΔ P < 0.001 vs shNC + EGFR. All results represent means ± SD of triplicate determinations. JNK 1/2: c‑Jun NH2‑terminal kinase 1/2; p-JNK 1/2: phosphorylated JNK1/2; NF-κB p65: nuclear factor κB p65.

4 Discussion

In the present study, we found that GPNMB and EGFR formed PPIs and both proteins were downregulated in differentiated neuronal cells. In addition, GPNMB and EGFR have at least partial complementary functions, with one protein overexpression reversing the effects of the other protein silencing, including cell viability, differentiation, and JNK/NF-κB signaling activation.

GPNMB has aroused overriding interest from researchers by virtue of its aberrant expression in cancers and the correlation with multiple biological processes composing of tissues’ regeneration and cell differentiation [25]. As put forward by Spann et al., GPNMB is a promising objective for chronic SCI treatment, whose expression is upregulated in SCI [13]. Weng et al. further validated the upregulation of GPNMB in the spinal cord after sciatic nerve injury and its participation in the cellular events of growth and development [12]. Both of these findings verify the correlation of GPNMB with SCI, but the underlying mechanism remains elusive.

On the basis of a previous research, we further conducted our study on the perspective of functional recovery of SCI, which was impacted by the neuron loss in most occasions [3]. Generally, the main obstacle for SCI treatment would be the effective usage of the stimulated endogenous NPCs. A previous study stated GPNMB as a novel neuroprotective factor in cerebral ischemia–reperfusion injury [26]. Also, a recent study demonstrated that GPNMB could be a novel strategy for peripheral nerve regeneration after transection by promoting the proliferation of Schwann cells as well as expression and secretion of neurotrophic factors and neural adhesion molecules in vitro [27]. In our study, we uncovered that overexpression of GPNMB was beneficial to cell viability and neuronal differentiations as supported by the expression changes of the neural differentiation-associated markers (βIII tubulin and CNPase) in vitro which might avail the restricted recovery after SCI. We took over the studies against GPNMB from Spann et al. and Weng et al. and ulteriorly proved the possible role of GPNMB in SCI from the perspective of probing into the underlying regulation of cell differentiation rather than lingering on the surface.

As for the detailed mechanism, the interaction between GPNMB and EGFR in SCI, on the basis of a research reported by Han et al. who had already demonstrated GPNMB as an activator in cell migration, and its upregulation might be related to the oncogenic property of EGFR in lung cancer [28]. Despite the different study field and research direction, we substantiated the synergistic effect between GPNMB and EGFR in the non-cancer field and raised that the interaction between the two functioned in the biological processes and cell differentiation in NSCs. Liu et al. conducted a study on the individual role of RGFR in SCI and validated the promotive role of EGFR in NSC activation after SCI [14]. Similar to Liu et al., we also highlighted the significance of EGFR in NSC activation for functional recovery after SCI, although two of us focused on a different signaling pathway.

Fang et al. had confirmed the participation of JNK/NF-κB pathway in SCI through the inhibitory regulation of miR-132-3p on attenuating the injury [29]. It has been evidenced that NF-κB signaling pathway functions prominently in immune response and neuroinflammation; with a great detail, the neuroinflammation could be triggered by the NF-κB signaling pathway after SCI [30]. In addition, inactivation of this pathway can ameliorate the SCI via modulating the inflammatory reaction [31,32]. As for the JNK pathway, its significance has been validated in the contribution to the neuronal apoptosis after neuron injury [33,34]. In our study, we further confirmed the involvement of JNK/NF-κB signaling pathway in SCI and uncovered that GPNMB interacted with EGFR to modulate JNK phosphorylation and NF-κB p65 phosphorylation, thereby making an impact upon neuronal differentiation. This finding is a further extension of Fang et al. in SCI treatment and provides a novel cue in the regulatory mechanism of stimulating endogenous NPCs for SCI therapy. Typically, PI3K/protein kinase B (Akt) and RAS/RAF pathways are the main downstream pathways that EGFR regulates survival and differentiation. These two pathways are not detected in this study, which is the shortcoming of this study. Moreover, whether GPNMB regulates EGFR protein abundance and PI3K/Akt and whether RAS/RAF pathway affects the survival and differentiation of NSCs need further investigation. At present, the study of GPNMB is still in its infancy and the role of GPNMB in the multiple tumors or non-tumor cases requires to be further elucidated. Further studies toward GPNMB in SCI are welcomed and recommended to validate the performances and properties in the actual practice. Besides, the interaction between GPNMB and EGFR or other proteins is worth pursuing due to the extensive scope captured from the bioinformatics analysis. Furthermore, ulterior studies are expected to exploit the actual value of this interaction as therapeutic entity to induce NPCs in terms of feasibility and practicability.

In conclusion, we prove that the interaction between GPNMB and EGFR regulates neuronal survival and differentiation through the modulation of JNK/NF-κB signaling pathway.

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Acknowledgments

Not applicable.

  1. Funding information: This work was supported by the Zhejiang Provincial Medical and Health Science and Technology Plan Project, which is named as Regulation of Nrf2/HO-1 by sinomenine promotes the repair of blood-spinal barrier after spinal cord injury and its mechanism [2021KY1225].

  2. Author contributions: Hua Yang designed the experiments and Gang Jin carried them out. Shihong Chen, Jing Luo, and Wei Xu made data acquisition, data analysis, and interpretation. Hua Yang prepared the article with contributions from all co-authors. Hua Yang drafted the article or critically revised it for important intellectual content. All authors have made 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.

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

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

Appendix

Figure A1 The efficiency of knock down for GPNMB and EGFR. (a) The knock down efficiency of shGPNMB, shGPNMB (shRNA#2) and shGPNMB (shRNA#3) for GPNMB. (b) The knock down efficiency of shEGFR, shEGFR (shRNA#2) and shEGFR (shRNA#3) for EGFR. GAPDH was set as the internal reference. ++P < 0.01 or +++P < 0.001 vs. shNC. All results represent means of ±standard deviation (SD) of triplicate determinations. (qRT-PCR: quantitative reverse-transcription polymerase chain reaction; GPNMB: glycoprotein non-metastatic melanoma B; EGFR: epidermal growth factor receptor; shNC: short hairpin negative control).
Figure A1

The efficiency of knock down for GPNMB and EGFR. (a) The knock down efficiency of shGPNMB, shGPNMB (shRNA#2) and shGPNMB (shRNA#3) for GPNMB. (b) The knock down efficiency of shEGFR, shEGFR (shRNA#2) and shEGFR (shRNA#3) for EGFR. GAPDH was set as the internal reference. ++P < 0.01 or +++P < 0.001 vs. shNC. All results represent means of ±standard deviation (SD) of triplicate determinations. (qRT-PCR: quantitative reverse-transcription polymerase chain reaction; GPNMB: glycoprotein non-metastatic melanoma B; EGFR: epidermal growth factor receptor; shNC: short hairpin negative control).

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Received: 2022-05-10
Revised: 2022-11-09
Accepted: 2022-12-19
Published Online: 2023-02-14

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

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

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  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-2023-0639
Keywords for this article
glycoprotein non-metastatic melanoma B; epidermal growth factor receptor; spinal cord injury; functional recovery; cell differentiation
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
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