Startseite Significant role and the underly mechanism of cullin-1 in chronic obstructive pulmonary disease
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Significant role and the underly mechanism of cullin-1 in chronic obstructive pulmonary disease

  • Wenbo Hao , Fei Lin , Weili Kong , Hanbing Shi , Haiying Dong , Zhanjiang Guan , Guohua Liu , Xiao Wang , Li Wang , Moran Liu und Yunfei Jiang EMAIL logo
Veröffentlicht/Copyright: 18. November 2024
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Open Medicine
Aus der Zeitschrift Open Medicine Band 19 Heft 1

Abstract

Background

This study investigated the role and mechanisms of cullin-1 (CUL1) in chronic obstructive pulmonary disease (COPD).

Methods

Cigarette smoke extract (CSE)-treated mouse pulmonary microvascular endothelial cells (mPMECs) and cigarette smoke inhalation (CSI)-stimulated mice were used to construct in vitro and in vivo COPD models, respectively. CUL1 expression was assessed using reverse transcriptase-quantitative polymerase chain reaction, Western blotting, and immunohistochemistry. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and flow cytometry were used to detect cell viability and apoptosis, respectively. We conducted an enzyme-linked immunosorbent assay on mPMECs and bronchoalveolar lavage fluid (BALF) to detect inflammatory factors. Reactive oxygen species, malondialdehyde, and superoxide dismutase were detected using the corresponding kits. The histological characteristics of the lung tissues were determined by hematoxylin and eosin staining.

Results

CUL1 expression was downregulated in COPD. CUL1 overexpression significantly promoted cell viability, reduced cell apoptosis, and inhibited inflammatory responses and oxidative stress in CSE-treated mPMECs. These changes were reversed by the p53 agonist nutlin-3. In addition, CUL1 overexpression significantly relieved COPD in mice, as confirmed by the reduced secretion of inflammatory factors in BALF, inhibited oxidative stress response, and improved lung function.

Conclusion

CUL1 plays a protective role in CSE-treated mPMECs and CSI-stimulated mice by inhibiting the p53 signaling pathway.

Keywords: chronic obstructive pulmonary disease; cigarette smoke extract; cigarette smoke inhalation; cullin-1; p53 pathway

1 Introduction

Chronic obstructive pulmonary disease (COPD) is a common chronic respiratory disease characterized by irreversible obstructive ventilation dysfunction. It is currently the third leading cause of death owing to respiratory failure and severe complications worldwide, placing an enormous burden on the global economy and health [1,2]. In 2019, 3.23 million people died of COPD worldwide. As the population ages, the number of deaths from COPD and its complications will continue to increase, showing a more severe trend over time [3]. In recent years, a preference for early prevention and disease stabilization of COPD has emerged. Studies have shown that smoking cessation, avoiding exposure to polluted environments, and exercising regularly can help alleviate symptoms [4,5,6]. In addition, medication has remained the primary treatment option, with options including long-acting β2 agonists (LABAs), inhaled corticosteroids (ICS), and long-acting muscarinic antagonists (LAMAs) depending on patient response and preference [4]; in particular, the combination of LABA and LAMA is more effective [7]. Furthermore, a series of molecular-targeted therapeutic drugs have been developed to prevent and control COPD by targeting molecules involved in signal transduction. Studies have shown that resveratrol, a sirtuin 1 agonist, can reduce lung inflammation in rats with COPD, making it a potential drug candidate for the treatment of COPD [8]. Reports have stated that troxerutin can inhibit the occurrence and development of COPD and may become an important drug for the treatment of COPD in the future [9,10].

Cullin-1 (CUL1), a member of the cullin ubiquitin ligase family, is involved in the process of ubiquitination. CUL1, together with the adaptor proteins S-phase kinase-associated protein 1 (Skp1) and RING-box protein 1 (RBX1), forms the Skp1–Cullin–F-box (SCF) complex [11]. It regulates various biological processes such as cell development, differentiation, and death by binding to F-box proteins [12]. CUL1 has been suggested to play a role in embryonic development [13]. Zhang et al. reported that abnormal expression of CUL1 may be associated with preeclampsia [14]. Sun et al. reported that aberrant CUL1 ubiquitin modification was involved in the pathogenesis of recurrent spontaneous abortion [15]. In addition, CUL1 was shown to promote fibroblast proliferation in patients with COPD by mediating functional signals of organelle fission, thereby participating in disease progression [16]. However, the potential relationship between the function, pathways, and physiological processes of CUL1 in COPD has not been clearly elucidated. Therefore, this study explores the specific role and potential molecular regulatory mechanisms of CUL1 in COPD.

The aim of this study was to investigate the role of CUL1 in cigarette smoke extract (CSE)-induced human pulmonary microvascular endothelial cell injury and in cigarette smoke inhalation (CSI)-stimulated mice as well as to analyze the underlying regulatory molecular mechanisms, thereby providing a potential treatment strategy for COPD.

2 Methods and materials

2.1 Reagent

CSE purchased from PythonBio (AAPR551, Guangzhou, China) was used for the construction of the COPD model.

2.2 Clinical sample collection

Serum samples were collected from 20 patients with COPD and 20 healthy volunteers. Patients who had received treatment were excluded from the study. This study was approved by the Ethics Committee of Qiqihar Medical University (Approval no. [2021]51), and all patients who participated in the study provided written informed consent.

2.3 Mouse pulmonary microvascular endothelial cells (mPMECs) culture

mPMECs were obtained from Procell (cat. no. CP-M001; Wuhan, China). The mPMECs were cultured in a mouse pulmonary vascular endothelial cell culture medium (cat. no. CM-M001; Wuhan, China).

2.4 Animals

Twenty-six-week-old male C57BL/6J mice were purchased from the Experimental Animal Department, Harbin Medical University (Harbin, China). The mice were randomly divided into four groups: control, model, model + control-plasmid, and model + CUL-plasmid. All mice were kept at standard conditions (20–25°C, 30–50% relative humidity, and a light/dark cycle of 12 h) and had access to food and water ad libitum.

2.5 Mice model of COPD induced by cigarette smoke

The COPD mouse model was established as previously described [17]. Briefly, the mice were placed in an airtight box and received eight cigarettes twice daily for 30 min each time, with a smoke-free interval of 3 h for the first 2 weeks. Fifteen cigarettes were subsequently administered twice daily for 30 min each time, with a smoke-free interval of 3 h for the next 10 weeks.

2.6 Reverse transcriptase quantitative polymerase chain reaction assay

After treatment, according to the instructions, the RNA was first extracted from the cells and tissues using TRIpure Total RNA Extraction Reagent (EP013, ELK Biotechnology, Wuhan, China) and then reverse transcribed into cDNA using EntiLink™ 1st Strand cDNA Synthesis Super Mix (EQ031, ELK Biotechnology, Wuhan, China). The quantitative real-time reverse transcription PCR (qRT-PCR) experiments were performed using the EnTurbo™ SYBR Green PCR SuperMix (EQ001, ELK Biotechnology, Wuhan, China). The 2−ΔΔCt method [18] was used to detect the expression levels of CUL1 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The primer sequences were as follows:

GAPDH:

5′-TGAAGGGTGGAGCCAAAAG-3′ (forward (F)).

5′-AGTCTTCTGGGTGGCAGTGAT-3′ (reverse (R)).

CUL1:

5′-CAATGTTGATGAGGTGGAATTG-3′ (F).

5′-CCTTCCTCATTTTCATGATTCTC-3′ (R).

2.7 Western blot assay

The transfected mPMECs were lysed in radioimmunoprecipitation assay buffer (AS1004, ASPEN) for 30 min on ice. The proteins were separated using 10% sodium dodecyl-sulfate polyacrylamide gel electrophoresis, transferred to a polyvinylidene fluoride (PVDF) membrane (IPVH00010, Millipore), and blocked using phosphate-buffered saline with Tween 20 (PBST) (Univ, Shanghai, China) and 5% skim milk powder (AS1033;s ASPEN) for 2 h to avoid nonspecific binding. The PVDF membrane was subsequently incubated with primary antibodies against CUL1 (ab75817, 1:1,000; Abcam), p53 (10442-1-AP, 1:2,000; Wuhan Sanying Biotechnology), p21 (ab109199, 1:1,000; Abcam), caspase-3 (DF6020, 1:500; Affbiotech), caspase-9 (AF6348, 1:500; Affbiotech), and Bcl-2-associated X protein (Bax) (50599-2-Ig, 1:2,000; Wuhan Sanying Biotechnology). After incubating at 4°C for 12 h, the PVDF membrane was washed with PBST and incubated with a secondary antibody (AS1107, 1:10,000; ASPEN) for 2 h, and protein signals were detected using the enhanced chemiluminescence method according to the instructions.

2.8 Cell transfection

Control-plasmid and CUL1-plasmid were transfected into mPMECs using jetPRIME reagent (Polyplus, France) according to the instructions of the manufacturer. After treatment with CSE, mPMECs were cultured at 37°C and 5% carbon dioxide (CO2) for 48 h. The mRNA level of CUL1 was detected using qRT-PCR. In addition, the protein level of CUL1 was detected using a Western blot assay.

2.9 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay

After cell transfection and treatment with CSE, mPMECs were seeded into 96-well plates, and 10 μL of MTT (Beyotime, Shanghai, China) solution was added to the plate. The mPMECs were cultured at 37°C and 5% CO2 for 4 h. The supernatant was subsequently discarded and 100 μL of dimethyl sulfoxide solution was added to each well. The cells were allowed to decompose in the dark, and the optical density value was determined at a wavelength of 570 nm using a UV spectrophotometer (Implen nanophoto-330-31) after lysis in the dark.

2.10 Flow cytometry assay

The mPMECs were collected after transfection and treatment with CSE, and apoptotic cells were detected using an annexin V and propidium iodide (PI) apoptosis detection kit (Beyotime, Shanghai, China). Cells were pooled and incubated in the dark at room temperature for 20 min, followed by the detection of apoptotic cells using flow cytometry (Beckman Coulter) and analysis of apoptotic cells using the Kaluza analysis software.

2.11 Caspase-3 activity assay

To detect the activity of caspase-3 in cells, the transfected cells were digested with trypsin (Gibco, NY, USA), the lysate was added to the sample for 20 min, and the sample was centrifuged at 10,000 rpm for 10 min. The results were analyzed using a microplate reader (Tecan/Infinite F50).

2.12 Reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) activity assays

The levels of ROS in the treated cells and lung tissues were detected using a ROS assay kit (E004-1, Nanjing Jiancheng Bioengineering Institute, Nanjing, China) according to the instructions of the manufacturer, and the absorbance was measured at a wavelength of 525 nm using a spectrophotometer (Thermo, USA).

A lipid peroxidation MDA assay kit (A003-1, Nanjing Jiancheng Bioengineering Institute, Nanjing, China) was used to detect the levels of MDA in the treated cells and lung tissues. The assay was performed according to the instructions of the manufacturer, and the absorbance was measured at a wavelength of 532 nm using a microplate reader (Tecan, Switzerland).

A SOD activity assay kit (A001-3, Nanjing Jiancheng Bioengineering Institute, Nanjing, China) was used to detect the levels of SOD in the treated cells and lung tissues. The assay was performed according to the instructions of the manufacturer, and the absorbance was measured at a wavelength of 450 nm using a microplate reader (Tecan, Switzerland).

2.13 Enzyme-linked immunosorbent assay (ELISA)

The secretion of interleukin-6 (IL-6), interleukin-1β (IL-1β), interleukin-13 (IL-13), matrix metallopeptidase-12 (MMP-12), and tumor necrosis factor-α (TNF-α) in the treated cell supernatant and bronchoalveolar lavage fluid (BALF) was detected using ELISA kits (ELK Biotechnology, Wuhan, China) according to the instructions of the manufacturer.

2.14 Histological examinations

After 24 h of fixation in 4% paraformaldehyde solution, lung tissues were embedded in paraffin and cut into 4 µm slices. The sections were then stained with hematoxylin and eosin (H&E, H9627-25G, Sigma) to observe morphological changes in the lung tissue and photographed using a light microscope (Olympus Corporation, Tokyo, Japan). Mean alveolar septation (mean linear intercept) and number of alveoli per unit area (mean alveolar number) were determined using the counting tool of the Adobe Photoshop CC software.

2.15 Measurement of pulmonary function

The Buxco non-invasive animal airway detection system (NAM, Wilmington, DE, USA) was used to measure the lung function of rats. The rats were placed in the non-invasive animal airway detection chamber. Changes in the volume of the plesiogram chamber as the animal breathes were recorded by a screen-type respiratory sensor inside the chamber, amplified by an amplifier, and processed by a computer. Finally, peak inspiratory flow (PIF), peak expiratory flow (PEF), and expiratory flow at 50% ventilation (EF50) were determined.

2.16 Immunohistochemistry staining

Lung tissues were formalin-fixed, embedded in paraffin, and deparaffinized before incubation in hydrogen peroxide (H2O2) solution for 15 min to block endogenous peroxidases. The sections were then incubated with rabbit anti-rat CUL1 antibody (1:400, ab202555; Abcam) overnight at 4°C and with goat anti-rabbit secondary antibody (1:200, AS1107; ASPEN) for 1 h at room temperature. Subsequently, the nuclei were identified using 3,3′-diaminobenzidine staining and hematoxylin counterstaining. The sections were then imaged using an Olympus microscope (Olympus Optical Co., Ltd., Japan).

2.17 Statistical analysis

The average ± standard deviation measures data from triple repeat. The Student’s t-test was used to compare two cohorts. Tukey’s multiple comparison test was used to compare multiple groups. Statistical significance was set at P < 0.05.

  1. Informed consent: All patients who participated in this study have signed the informed consent.

  2. Ethical approval: This study was completed by the Ethics Committee of the Qiqihar Medical University (Approval no. [2021]51).

3 Results

3.1 CUL1 expression was low in patients with COPD

qRT-PCR was performed to investigate the relationship between CUL1 expression and COPD. The expression of CUL1 in the serum of patients with COPD was significantly lower than that in the serum of healthy volunteers (Figure 1), indicating that CUL1 showed low expression in COPD.

Figure 1 The expression level of CUL1 in the serum of patients with COPD. The expression of CUL1 was detected using qRT-PCR. **P < 0.01. COPD, chronic obstructive pulmonary disease; CUL1, cullin-1; qRT-PCR, quantitative real-time reverse-transcription PCR.
Figure 1

The expression level of CUL1 in the serum of patients with COPD. The expression of CUL1 was detected using qRT-PCR. **P < 0.01. COPD, chronic obstructive pulmonary disease; CUL1, cullin-1; qRT-PCR, quantitative real-time reverse-transcription PCR.

3.2 CUL1 expression was low in CSE-induced mPMECs

To investigate the role of CUL1 in COPD further, mPMECs were treated with 1% CSE for 24 h to generate a CSE-induced COPD cell model. The results of qRT-PCR and Western blot assays showed that, compared with the control, 1% CSE significantly reduced the expression of CUL1 in mPMECs (Figure 2a–c), and the cell model was successfully constructed for subsequent experiments.

Figure 2 The expression level of CUL1 in a CSE-induced cell model. (a) mRNA expression level of CUL1 detected by qRT-PCR. (b) Protein expression level of CUL1 detected by Western blot assay. (c) CUL1/GAPDH ratio. **P < 0.01. CSE, cigarette smoke extract; CUL1, cullin-1; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; qRT-PCR, quantitative real-time reverse-transcription PCR.
Figure 2

The expression level of CUL1 in a CSE-induced cell model. (a) mRNA expression level of CUL1 detected by qRT-PCR. (b) Protein expression level of CUL1 detected by Western blot assay. (c) CUL1/GAPDH ratio. **P < 0.01. CSE, cigarette smoke extract; CUL1, cullin-1; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; qRT-PCR, quantitative real-time reverse-transcription PCR.

3.3 CUL1 reduced CSE-induced apoptosis and inflammatory response in mPMECs

To detect transfection efficiency, mPMECs were transfected with the control-plasmid and CUL1-plasmid, respectively, and qRT-PCR and Western blot assays were performed 48 h later. The results showed that the CUL1-plasmid significantly increased the expression of CUL1 in mPMECs compared with the control-plasmid group (Figure 3a–c).

Figure 3 The effect of CUL1 on the apoptosis of CSE-induced mPMECs. (a–c) mRNA and protein expression levels of CUL1 in mPMECs transfected with control-plasmid and CUL1-plasmid. (d–f) CUL1 expression level detected by qRT-PCR and Western blot after CSE treatment. (g) Viability of mPMECs detected by MTT assay. (h and i) Apoptosis of mPMECs detected by flow cytometry assay. (j) Caspase-3 activity in mPMECs. **P < 0.01. CSE, cigarette smoke extract; CUL1, cullin-1; mPMECs, mouse pulmonary microvascular endothelial cells; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; qRT-PCR, quantitative real-time reverse-transcription PCR.
Figure 3

The effect of CUL1 on the apoptosis of CSE-induced mPMECs. (a–c) mRNA and protein expression levels of CUL1 in mPMECs transfected with control-plasmid and CUL1-plasmid. (d–f) CUL1 expression level detected by qRT-PCR and Western blot after CSE treatment. (g) Viability of mPMECs detected by MTT assay. (h and i) Apoptosis of mPMECs detected by flow cytometry assay. (j) Caspase-3 activity in mPMECs. **P < 0.01. CSE, cigarette smoke extract; CUL1, cullin-1; mPMECs, mouse pulmonary microvascular endothelial cells; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; qRT-PCR, quantitative real-time reverse-transcription PCR.

Subsequently, mPMECs were transfected with the control-plasmid or CUL1-plasmid for 24 h and then treated with 1% CSE for 24 h to explore the effect of CUL1 on CSE-induced mPMECs. The CSE group had a low expression level of CUL1, but CUL1 in the CSE + CUL1-plasmid group was obviously increased (Figure 3d–f). Cell viability significantly decreased in the CSE group and notably increased in the CSE + CUL1-plasmid group (Figure 3g). Cell apoptosis and caspase-3 activity were significantly increased in the CSE group, whereas the opposite trend was observed in the CSE + CUL1-plasmid group (Figure 3h–j).

ELISA was used to detect the secretion of inflammatory cytokines. The results showed that the secretion of TNF-α, IL-1β, IL-6, IL-13, and matrix metalloproteinase-12 (MMP-12) was increased in the CSE group but showed a significant decreasing trend in the CSE + control-plasmid group (Figure 4a–e). In the CSE group, the levels of ROS and MDA were observably increased, and SOD activity was decreased, which was the opposite of the pattern observed in the CSE + CUL1-plasmid group (Figure 4f–h). These results revealed that CUL1 can reduce the CSE-induced apoptosis of mPMECs and attenuate the CSE-induced inflammatory response in mPMECs.

Figure 4 The effects of CUL1 on inflammatory responses and oxidative stress in CSE-induced mPMECs. (a–e) Secretion of TNF-α, IL-1β, IL-6, IL-13, and MMP-12 in mPMECs. (f–h) ROS, MDA, and SOD levels detected by the corresponding kit. **P < 0.01. CSE, cigarette smoke extract; CUL1, cullin-1; IL-1β, interleukin-1β; IL-6, interleukin-6; IL-13, interleukin-13; MDA, malondialdehyde; MMP-12, matrix metalloproteinase-12; mPMECs, mouse pulmonary microvascular endothelial cells; ROS, reactive oxygen species; SOD, superoxide dismutase; TNF-α, tumor necrosis factor-α.
Figure 4

The effects of CUL1 on inflammatory responses and oxidative stress in CSE-induced mPMECs. (a–e) Secretion of TNF-α, IL-1β, IL-6, IL-13, and MMP-12 in mPMECs. (f–h) ROS, MDA, and SOD levels detected by the corresponding kit. **P < 0.01. CSE, cigarette smoke extract; CUL1, cullin-1; IL-1β, interleukin-1β; IL-6, interleukin-6; IL-13, interleukin-13; MDA, malondialdehyde; MMP-12, matrix metalloproteinase-12; mPMECs, mouse pulmonary microvascular endothelial cells; ROS, reactive oxygen species; SOD, superoxide dismutase; TNF-α, tumor necrosis factor-α.

3.4 CUL1 inhibited the p53 signaling pathway in CSE-induced mPMECs

To study the molecular mechanisms of CUL1 in CSE-induced mPMECs, we transfected the control-plasmid and CUL1-plasmid into mPMECs for 24 h and then cultured mPMECs with 1% CSE for 24 h. Western blotting showed that the expression of p53, p21, caspase-3, caspase-9, and Bax was significantly increased in the CSE group, and the increased effect was significantly inhibited in the CUL1-plasmid group (Figure 5a and b). Taken together, these results indicate that CUL1 inhibits the p53 signaling pathway in CSE-induced mPMECs.

Figure 5 The effect of CUL1 on p53 signaling in CSE-induced mPMECs. (a and b) Protein expression levels of p53, p21, caspase-3, caspase-9, and Bax were detected by Western blot assay with quantitative patterns shown. **P < 0.01. Bax, Bcl-2-associated X protein; CSE, cigarette smoke extract; CUL1, cullin-1; mPMECs, mouse pulmonary microvascular endothelial cells.
Figure 5

The effect of CUL1 on p53 signaling in CSE-induced mPMECs. (a and b) Protein expression levels of p53, p21, caspase-3, caspase-9, and Bax were detected by Western blot assay with quantitative patterns shown. **P < 0.01. Bax, Bcl-2-associated X protein; CSE, cigarette smoke extract; CUL1, cullin-1; mPMECs, mouse pulmonary microvascular endothelial cells.

3.5 Nutlin-3 significantly reversed the effect of CUL1 on CSE-induced mPMECs

To further confirm the role of CUL1 in the p53 signaling pathway in CSE-induced mPMECs, we treated mPMECs with 20 μM of the p53 agonist nutlin-3, and then the control-plasmid and CUL1-plasmid were transfected into the cells for 24 h. After treating the cells with 1% CSE for another 24 h, we performed a Western blot assay. The results showed that the p53, p21, caspase-3, caspase-9, and Bax proteins were expressed at low levels in the CSE + CUL1-plasmid group compared with the CSE + control-plasmid group, but the effect was reversed by nutlin-3 (Figure 6a and b).

Figure 6 The effects of CUL1 and nutlin-3 on p53 signaling in CSE-induced mPMECs after nutlin-3 treatment. (a and b) Protein expression levels of p53, p21, caspase-3, caspase-9, and Bax detected by Western blot assay with quantitative patterns shown. **P < 0.01. Bax, Bcl-2-associated X protein; CSE, cigarette smoke extract; CUL1, cullin-1; mPMECs, mouse pulmonary microvascular endothelial cells.
Figure 6

The effects of CUL1 and nutlin-3 on p53 signaling in CSE-induced mPMECs after nutlin-3 treatment. (a and b) Protein expression levels of p53, p21, caspase-3, caspase-9, and Bax detected by Western blot assay with quantitative patterns shown. **P < 0.01. Bax, Bcl-2-associated X protein; CSE, cigarette smoke extract; CUL1, cullin-1; mPMECs, mouse pulmonary microvascular endothelial cells.

In addition, the MTT assay was used to measure cell viability. The results showed that the cell viability of the CSE + CUL1-plasmid group was significantly improved (Figure 7a), and cell apoptosis was reduced by the CUL1-plasmid (Figure 7b and c). At the same time, caspase-3 activity was significantly decreased in the CSE + CUL1-plasmid group (Figure 7d). However, these effects were reversed upon treatment with nutlin-3.

Figure 7 The effects of CUL1 and nutlin-3 on CSE-induced mPMECs. (a) Viability of mPMECs detected by MTT assay. (b and c) Apoptosis of mPMECs detected by flow cytometry assay. (d) Caspase-3 activity in mPMECs. (e) Secretion of TNF-α, IL-1β, IL-6, IL-13, and MMP-12 in mPMECs. (f–h) ROS, MDA, and SOD levels detected by the corresponding kit. **P < 0.01. CSE, cigarette smoke extract; CUL1, cullin-1; IL-1β, interleukin-1β; IL-6, interleukin-6; IL-13, interleukin-13; MDA, malondialdehyde; MMP-12, matrix metalloproteinase-12; mPMECs, mouse pulmonary microvascular endothelial cells; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; ROS, reactive oxygen species; SOD, superoxide dismutase; TNF-α, tumor necrosis factor-α.
Figure 7

The effects of CUL1 and nutlin-3 on CSE-induced mPMECs. (a) Viability of mPMECs detected by MTT assay. (b and c) Apoptosis of mPMECs detected by flow cytometry assay. (d) Caspase-3 activity in mPMECs. (e) Secretion of TNF-α, IL-1β, IL-6, IL-13, and MMP-12 in mPMECs. (f–h) ROS, MDA, and SOD levels detected by the corresponding kit. **P < 0.01. CSE, cigarette smoke extract; CUL1, cullin-1; IL-1β, interleukin-1β; IL-6, interleukin-6; IL-13, interleukin-13; MDA, malondialdehyde; MMP-12, matrix metalloproteinase-12; mPMECs, mouse pulmonary microvascular endothelial cells; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; ROS, reactive oxygen species; SOD, superoxide dismutase; TNF-α, tumor necrosis factor-α.

Upon analyzing the secretion of inflammatory factors after nutlin-3 treatment, we found that the secretion of TNF-α, IL-1β, IL-6, IL-13, and MMP-12 was notably decreased in the CSE + CUL1-plasmid group (Figure 7e), and the same pattern was observed for the levels of ROS and MDA (Figure 7f and g). In addition, SOD activity significantly increased (Figure 7h). However, these effects were reversed upon treatment with nutlin-3. These results show that nutlin-3 reversed the effect of CUL1 on CSE-induced mPMECs, further clarifying the protective effect of CUL1 by inhibiting the p53 signaling pathway.

3.6 CUL1 was downregulated in the lung tissues of mice with COPD

To explore the role of CUL1 in the progression of COPD, we generated the COPD mouse model in vivo using cigarette smoke. As presented in Figure 8a–c, the expression of CUL1 was reduced in the model group mice, but this inhibition was reversed by treatment with the CUL1-plasmid compared with the control-plasmid group. Our findings strongly suggest that CUL1 is associated with the development of COPD.

Figure 8 The expression level of CUL1 in lung tissues of mice with COPD. (a and b) IHC staining was conducted to evaluate the distribution of CUL1. (c) mRNA expression level of CUL1 detected by qRT-PCR. **P < 0.01. COPD, chronic obstructive pulmonary disease; CUL1, cullin-1; IHC, immunohistochemistry; qRT-PCR, quantitative real-time reverse-transcription PCR.
Figure 8

The expression level of CUL1 in lung tissues of mice with COPD. (a and b) IHC staining was conducted to evaluate the distribution of CUL1. (c) mRNA expression level of CUL1 detected by qRT-PCR. **P < 0.01. COPD, chronic obstructive pulmonary disease; CUL1, cullin-1; IHC, immunohistochemistry; qRT-PCR, quantitative real-time reverse-transcription PCR.

3.7 Upregulation of CUL1 improved the lung function of mice with COPD

We also evaluated the effects of CUL1 on lung function in mice with COPD. According to the results of H&E staining, the lung tissue structure of the mice in the control group was intact, the alveolar size was normal, and the alveolar septum structure was clear. Compared with the control group, the mice in the model group showed severe rupture of the alveolar septum, obvious expansion of the alveolar cavity, and partial alveolar fusion to form pulmonary bullae (Figure 9a–c). However, the lung tissue damage was significantly reduced by CUL1-plasmid intervention, indicating that CUL1 plays a protective role in the pulmonary function of mice with COPD. Compared with the control group, PIF, PEF, and EF50 were remarkably reduced in the model group, whereas these parameters were obviously elevated after CUL1-plasmid treatment (Figure 9d–f).

Figure 9 The effects of the CUL1-plasmid on lung function. (a) Pathological changes in the lung tissues of mice detected by H&E staining. (b and c) Changes in MAN and MLI in different groups. (d–f) Calculation of PIF, PEF, and EF50 to evaluate the pulmonary function. *P < 0.05, **P < 0.01. CUL1, cullin-1; EF50, expiratory flow at 50% ventilation; H&E, hematoxylin and eosin; MAN, mean alveolar number; MLI, mean linear intercept; PEF, peak expiratory flow; PIF, peak inspiratory flow.
Figure 9

The effects of the CUL1-plasmid on lung function. (a) Pathological changes in the lung tissues of mice detected by H&E staining. (b and c) Changes in MAN and MLI in different groups. (d–f) Calculation of PIF, PEF, and EF50 to evaluate the pulmonary function. *P < 0.05, **P < 0.01. CUL1, cullin-1; EF50, expiratory flow at 50% ventilation; H&E, hematoxylin and eosin; MAN, mean alveolar number; MLI, mean linear intercept; PEF, peak expiratory flow; PIF, peak inspiratory flow.

3.8 Upregulation of CUL1 suppressed the secretion of pro-inflammatory cytokines and oxidative stress response in the COPD mouse model

We also focused on the underlying mechanisms of CUL1 in regard to the secretion of inflammatory cytokines and oxidative stress response in mice with COPD. As shown in Figure 10a–e, the contents of TNF-α, IL-1β, IL-6, IL-13, and MMP-12 in the BALF of mice were elevated in cigarette smoke-induced mice compared with the control group. Moreover, the production of ROS and MDA increased, and SOD activity was repressed in the lung tissues of mice with COPD (Figure 10f–h). However, these findings were reversed by the upregulation of CUL1, which demonstrated that CUL1 exerts a protective role in COPD by inhibiting the secretion of inflammatory cytokines and the oxidative stress response.

Figure 10 The effects of the CUL1-plasmid on lung tissue inflammation and oxidative stress response. (a–e) Levels of inflammatory factors, such as TNF-α, IL-1β, IL-6, IL-13, and MMP-12, detected in BALF samples using ELISA. (f–h) ROS, MDA, and SOD levels in lung tissues. **P < 0.01. BALF, bronchoalveolar lavage fluid; CUL1, cullin-1; ELISA, enzyme-linked immunosorbent assay; IL-1β, interleukin-1β; IL-6, interleukin-6; IL-13, interleukin-13; MDA, malondialdehyde; MMP-12, matrix metalloproteinase-12; ROS, reactive oxygen species; SOD, superoxide dismutase; TNF-α, tumor necrosis factor-α.
Figure 10

The effects of the CUL1-plasmid on lung tissue inflammation and oxidative stress response. (a–e) Levels of inflammatory factors, such as TNF-α, IL-1β, IL-6, IL-13, and MMP-12, detected in BALF samples using ELISA. (f–h) ROS, MDA, and SOD levels in lung tissues. **P < 0.01. BALF, bronchoalveolar lavage fluid; CUL1, cullin-1; ELISA, enzyme-linked immunosorbent assay; IL-1β, interleukin-1β; IL-6, interleukin-6; IL-13, interleukin-13; MDA, malondialdehyde; MMP-12, matrix metalloproteinase-12; ROS, reactive oxygen species; SOD, superoxide dismutase; TNF-α, tumor necrosis factor-α.

4 Discussion

COPD is a common chronic disease characterized by persistent airflow restriction. This condition is often characterized by coughing, expectoration, and dyspnea, accompanied by a series of complications that lead to chronic systemic inflammation [19]. Currently, in addition to conventional prevention methods (smoking cessation, avoiding exposure to pollution, and adequate exercise) and drug treatment methods (LABAs, LAMAs, and ICS), a series of molecularly targeted therapies have also been studied. Studies have shown that the signal transducer and activator of transcription (STAT) signaling pathway are involved in the pathogenesis of COPD [20]. A pan-Janus kinase (JAK) inhibitor suppressed the increase in phosphorylated STAT 3 (pSTAT3) in the lungs of mice induced by IL-6 in vivo after tracheal administration [21]. In addition, several p38α mitogen-activated protein kinase (MAPK) inhibitors can be used to treat COPD, and these drugs significantly reduce the in vivo expression of MAPK-driven inflammatory mediators (such as TNF-α and IL-1β) in mouse models of acute inflammation [22]. As smoking is an important risk factor for COPD, many researchers have chosen CSE or CSI to construct cell and animal models for studies on COPD [23,24]. In this study, CSE and CSI were similarly used to treat mPMECs or mice to construct damage models for subsequent studies.

CUL1, together with the F-box protein, adaptor protein Skp1, and RING-box proteins 1 and 2 (RBX1 and RBX2), forms the SCF E3 ubiquitin ligase complex, which affects a variety of biological processes. These include cell growth and development, cell signaling pathways, transcriptional regulation of gene expression, and tumor suppression [25]. CUL1 activity can perform tumor-suppressive functions in cells [26]. In addition, CUL1 overexpression improves the proliferative ability of melanoma cells by regulating the level of p27 [27] and promotes the migration of human trophoblast cells [28]. CUL1 overexpression has also been associated with poor prognosis in gastric cancer, non-small-cell lung cancer, and breast cancer [29,30,31]. Studies have shown that CUL1 is involved in the development of COPD; however, its mechanism of action remains unclear. Therefore, in our study, we investigated this association and found low expression levels of CUL1 in patients with COPD, CSE-induced mPMECs, and CSI-treated mice.

The MTT assay detects the number of viable cells by detecting succinate dehydrogenase in the mitochondria, whereas flow cytometry detects the occurrence of apoptosis by labeling apoptotic cells with annexin V and PI [32]. Similarly, caspase-3 is also used to detect cell apoptosis in view of its role as a key enzyme in the process of apoptosis [33]. ROS, MDA, and SOD activity assays can be used to detect apoptosis by measuring oxidative stress levels [33,34]. Through the above assays, we found that CUL1 suppressed the apoptosis of CSE-induced mPMECs and alleviated the inflammatory response of cells as detected by ELISA.

The p53 signaling pathway is an important regulatory pathway for cell survival and death that can promote DNA repair, prevent mutations caused by DNA damage, maintain genomic stability, induce apoptosis, and protect whole tissues from damaged cells, thereby maintaining normal tissue and organ function [35]. This pathway is involved in the development of cancers such as gastric, pancreatic, and lung cancer [36,37,38]. In addition, CUL1 can inhibit atherosclerosis through the p53 pathway [39]. In our study, CUL1 protected mPMECs from CSE-induced apoptosis and inflammatory responses by inhibiting the p53 signaling pathway. Nutlin-3 is a low-molecular-weight cis-imidazoline analog that can induce the regulation and activation of the p53 pathway [40]. Several studies have shown that nutlin-3 can activate the p53 pathway to promote apoptosis without genotoxicity [41,42]. Therefore, in this study, we used nutlin-3 to reverse the effects of CUL1 on CSE-induced mPMECs by activating the p53 signaling pathway, further demonstrating that CUL1 has a protective effect on CSE-damaged cells by inhibiting the p53 signaling pathway.

The primary pathological changes associated with COPD are chronic bronchitis and emphysema [43]. In the present study, we found that rats with cigarette smoke-induced COPD exhibited a significant decline in lung function. In addition, the lung tissues revealed significant histopathological changes, including a reduction in the number of alveoli, narrowing of the alveolar space, partial rupture, and fusion to form bullae, thereby leading to emphysema. A major finding of this study was that CUL1 treatment caused changes in lung function, including a reduction in PIF, PEF, and EF50, as well as a significant improvement in lung histopathology, similar to the results of previous studies [44]. Furthermore, the analysis of inflammatory factors in the BALF of mice in each group showed that CUL1 treatment improved the inflammatory response and reduced oxidative damage in mice with COPD. Our findings are consistent with those of a report by Li et al. showing that CUL1 is a vital regulator of the progression of COPD [45].

There were also some limitations of this study. This study did not analyze the correlation between CUL1 expression and clinicopathological parameters in patients with COPD. In addition, whether there are other signaling pathways involved in the effect of CUL1 on COPD remains to be further explored. We will perform these issues in the future.

In summary, our study is the first to report that the upregulation of CUL1 inhibits the development of COPD by reducing the secretion of inflammatory cytokines and inhibiting the oxidative stress response through the p53 signaling pathway, demonstrating that CUL1 may be a potential therapeutic target in COPD. However, the pathogenesis of COPD is complex, and the exact mechanism by which CUL1 suppresses the development of COPD needs further elucidation.

  1. Funding information: This study was supported by the Basic Research Business Fee Basic Research Project of Provincial Universities in Heilongjiang Province (grant no. 2019-KYYWF-1237).

  2. Author contributions: Wenbo Hao contributed to the study design, data collection, statistical analysis, data interpretation, and manuscript preparation. Fei Lin and Weili Kong contributed to the data collection and statistical analysis. Hanbing Shi, Haiying Dong, Zhanjiang Guan, Guohua Liu, Xiao Wang, Li Wang, and Moran Liu contributed to the data collection. Yunfei Jiang contributed to data collection, statistical analysis, and manuscript preparation. All authors read and approved the final manuscript.

  3. Conflict of interest: The authors declare that they have no competing interests.

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

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Received: 2024-05-15
Revised: 2024-09-14
Accepted: 2024-09-28
Published Online: 2024-11-18

© 2024 the author(s), published by De Gruyter

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

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  111. Postural stability after operative reconstruction of the AFTL in chronic ankle instability comparing three different surgical techniques
  112. Research trends related to emergence agitation in the post-anaesthesia care unit from 2001 to 2023: A bibliometric analysis
  113. Frequency and clinicopathological correlation of gastrointestinal polyps: A six-year single center experience
  114. ACSL4 mediates inflammatory bowel disease and contributes to LPS-induced intestinal epithelial cell dysfunction by activating ferroptosis and inflammation
  115. Affibody-based molecular probe 99mTc-(HE)3ZHER2:V2 for non-invasive HER2 detection in ovarian and breast cancer xenografts
  116. Effectiveness of nutritional support for clinical outcomes in gastric cancer patients: A meta-analysis of randomized controlled trials
  117. The relationship between IFN-γ, IL-10, IL-6 cytokines, and severity of the condition with serum zinc and Fe in children infected with Mycoplasma pneumoniae
  118. Paraquat disrupts the blood–brain barrier by increasing IL-6 expression and oxidative stress through the activation of PI3K/AKT signaling pathway
  119. Sleep quality associate with the increased prevalence of cognitive impairment in coronary artery disease patients: A retrospective case–control study
  120. Dioscin protects against chronic prostatitis through the TLR4/NF-κB pathway
  121. Association of polymorphisms in FBN1, MYH11, and TGF-β signaling-related genes with susceptibility of sporadic thoracic aortic aneurysm and dissection in the Zhejiang Han population
  122. Application value of multi-parameter magnetic resonance image-transrectal ultrasound cognitive fusion in prostate biopsy
  123. Laboratory variables‐based artificial neural network models for predicting fatty liver disease: A retrospective study
  124. Decreased BIRC5-206 promotes epithelial–mesenchymal transition in nasopharyngeal carcinoma through sponging miR-145-5p
  125. Sepsis induces the cardiomyocyte apoptosis and cardiac dysfunction through activation of YAP1/Serpine1/caspase-3 pathway
  126. Assessment of iron metabolism and iron deficiency in incident patients on incident continuous ambulatory peritoneal dialysis
  127. Tibial periosteum flap combined with autologous bone grafting in the treatment of Gustilo-IIIB/IIIC open tibial fractures
  128. The application of intravenous general anesthesia under nasopharyngeal airway assisted ventilation undergoing ureteroscopic holmium laser lithotripsy: A prospective, single-center, controlled trial
  129. Long intergenic noncoding RNA for IGF2BP2 stability suppresses gastric cancer cell apoptosis by inhibiting the maturation of microRNA-34a
  130. Role of FOXM1 and AURKB in regulating keratinocyte function in psoriasis
  131. Parental control attitudes over their pre-school children’s diet
  132. The role of auto-HSCT in extranodal natural killer/T cell lymphoma
  133. Significance of negative cervical cytology and positive HPV in the diagnosis of cervical lesions by colposcopy
  134. Echinacoside inhibits PASMCs calcium overload to prevent hypoxic pulmonary artery remodeling by regulating TRPC1/4/6 and calmodulin
  135. ADAR1 plays a protective role in proximal tubular cells under high glucose conditions by attenuating the PI3K/AKT/mTOR signaling pathway
  136. The risk of cancer among insulin glargine users in Lithuania: A retrospective population-based study
  137. The unusual location of primary hydatid cyst: A case series study
  138. Intraoperative changes in electrophysiological monitoring can be used to predict clinical outcomes in patients with spinal cavernous malformation
  139. Obesity and risk of placenta accreta spectrum: A meta-analysis
  140. Shikonin alleviates asthma phenotypes in mice via an airway epithelial STAT3-dependent mechanism
  141. NSUN6 and HTR7 disturbed the stability of carotid atherosclerotic plaques by regulating the immune responses of macrophages
  142. The effect of COVID-19 lockdown on admission rates in Maternity Hospital
  143. Temporal muscle thickness is not a prognostic predictor in patients with high-grade glioma, an experience at two centers in China
  144. Luteolin alleviates cerebral ischemia/reperfusion injury by regulating cell pyroptosis
  145. Therapeutic role of respiratory exercise in patients with tuberculous pleurisy
  146. Effects of CFTR-ENaC on spinal cord edema after spinal cord injury
  147. Irisin-regulated lncRNAs and their potential regulatory functions in chondrogenic differentiation of human mesenchymal stem cells
  148. DMD mutations in pediatric patients with phenotypes of Duchenne/Becker muscular dystrophy
  149. Combination of C-reactive protein and fibrinogen-to-albumin ratio as a novel predictor of all-cause mortality in heart failure patients
  150. Significant role and the underly mechanism of cullin-1 in chronic obstructive pulmonary disease
  151. Ferroptosis-related prognostic model of mantle cell lymphoma
  152. Observation of choking reaction and other related indexes in elderly painless fiberoptic bronchoscopy with transnasal high-flow humidification oxygen therapy
  153. A bibliometric analysis of Prader-Willi syndrome from 2002 to 2022
  154. The causal effects of childhood sunburn occasions on melanoma: A univariable and multivariable Mendelian randomization study
  155. Oxidative stress regulates glycogen synthase kinase-3 in lymphocytes of diabetes mellitus patients complicated with cerebral infarction
  156. Role of COX6C and NDUFB3 in septic shock and stroke
  157. Trends in disease burden of type 2 diabetes, stroke, and hypertensive heart disease attributable to high BMI in China: 1990–2019
  158. Purinergic P2X7 receptor mediates hyperoxia-induced injury in pulmonary microvascular endothelial cells via NLRP3-mediated pyroptotic pathway
  159. Investigating the role of oviductal mucosa–endometrial co-culture in modulating factors relevant to embryo implantation
  160. Analgesic effect of external oblique intercostal block in laparoscopic cholecystectomy: A retrospective study
  161. Elevated serum miR-142-5p correlates with ischemic lesions and both NSE and S100β in ischemic stroke patients
  162. Correlation between the mechanism of arteriopathy in IgA nephropathy and blood stasis syndrome: A cohort study
  163. Risk factors for progressive kyphosis after percutaneous kyphoplasty in osteoporotic vertebral compression fracture
  164. Predictive role of neuron-specific enolase and S100-β in early neurological deterioration and unfavorable prognosis in patients with ischemic stroke
  165. The potential risk factors of postoperative cognitive dysfunction for endovascular therapy in acute ischemic stroke with general anesthesia
  166. Fluoxetine inhibited RANKL-induced osteoclastic differentiation in vitro
  167. Detection of serum FOXM1 and IGF2 in patients with ARDS and their correlation with disease and prognosis
  168. Rhein promotes skin wound healing by activating the PI3K/AKT signaling pathway
  169. Differences in mortality risk by levels of physical activity among persons with disabilities in South Korea
  170. Review Articles
  171. Cutaneous signs of selected cardiovascular disorders: A narrative review
  172. XRCC1 and hOGG1 polymorphisms and endometrial carcinoma: A meta-analysis
  173. A narrative review on adverse drug reactions of COVID-19 treatments on the kidney
  174. Emerging role and function of SPDL1 in human health and diseases
  175. Adverse reactions of piperacillin: A literature review of case reports
  176. Molecular mechanism and intervention measures of microvascular complications in diabetes
  177. Regulation of mesenchymal stem cell differentiation by autophagy
  178. Molecular landscape of borderline ovarian tumours: A systematic review
  179. Advances in synthetic lethality modalities for glioblastoma multiforme
  180. Investigating hormesis, aging, and neurodegeneration: From bench to clinics
  181. Frankincense: A neuronutrient to approach Parkinson’s disease treatment
  182. Sox9: A potential regulator of cancer stem cells in osteosarcoma
  183. Early detection of cardiovascular risk markers through non-invasive ultrasound methodologies in periodontitis patients
  184. Advanced neuroimaging and criminal interrogation in lie detection
  185. Maternal factors for neural tube defects in offspring: An umbrella review
  186. The chemoprotective hormetic effects of rosmarinic acid
  187. CBD’s potential impact on Parkinson’s disease: An updated overview
  188. Progress in cytokine research for ARDS: A comprehensive review
  189. Utilizing reactive oxygen species-scavenging nanoparticles for targeting oxidative stress in the treatment of ischemic stroke: A review
  190. NRXN1-related disorders, attempt to better define clinical assessment
  191. Lidocaine infusion for the treatment of complex regional pain syndrome: Case series and literature review
  192. Trends and future directions of autophagy in osteosarcoma: A bibliometric analysis
  193. Iron in ventricular remodeling and aneurysms post-myocardial infarction
  194. Case Reports
  195. Sirolimus potentiated angioedema: A case report and review of the literature
  196. Identification of mixed anaerobic infections after inguinal hernia repair based on metagenomic next-generation sequencing: A case report
  197. Successful treatment with bortezomib in combination with dexamethasone in a middle-aged male with idiopathic multicentric Castleman’s disease: A case report
  198. Complete heart block associated with hepatitis A infection in a female child with fatal outcome
  199. Elevation of D-dimer in eosinophilic gastrointestinal diseases in the absence of venous thrombosis: A case series and literature review
  200. Four years of natural progressive course: A rare case report of juvenile Xp11.2 translocations renal cell carcinoma with TFE3 gene fusion
  201. Advancing prenatal diagnosis: Echocardiographic detection of Scimitar syndrome in China – A case series
  202. Outcomes and complications of hemodialysis in patients with renal cancer following bilateral nephrectomy
  203. Anti-HMGCR myopathy mimicking facioscapulohumeral muscular dystrophy
  204. Recurrent opportunistic infections in a HIV-negative patient with combined C6 and NFKB1 mutations: A case report, pedigree analysis, and literature review
  205. Letter to the Editor
  206. Letter to the Editor: Total parenteral nutrition-induced Wernicke’s encephalopathy after oncologic gastrointestinal surgery
  207. Erratum
  208. Erratum to “Bladder-embedded ectopic intrauterine device with calculus”
  209. Retraction
  210. Retraction of “XRCC1 and hOGG1 polymorphisms and endometrial carcinoma: A meta-analysis”
  211. Corrigendum
  212. Corrigendum to “Investigating hormesis, aging, and neurodegeneration: From bench to clinics”
  213. Corrigendum to “Frankincense: A neuronutrient to approach Parkinson’s disease treatment”
  214. Special Issue The evolving saga of RNAs from bench to bedside - Part II
  215. Machine-learning-based prediction of a diagnostic model using autophagy-related genes based on RNA sequencing for patients with papillary thyroid carcinoma
  216. Unlocking the future of hepatocellular carcinoma treatment: A comprehensive analysis of disulfidptosis-related lncRNAs for prognosis and drug screening
  217. Elevated mRNA level indicates FSIP1 promotes EMT and gastric cancer progression by regulating fibroblasts in tumor microenvironment
  218. Special Issue Advancements in oncology: bridging clinical and experimental research - Part I
  219. Ultrasound-guided transperineal vs transrectal prostate biopsy: A meta-analysis of diagnostic accuracy and complication rates
  220. Assessment of diagnostic value of unilateral systematic biopsy combined with targeted biopsy in detecting clinically significant prostate cancer
  221. SENP7 inhibits glioblastoma metastasis and invasion by dissociating SUMO2/3 binding to specific target proteins
  222. MARK1 suppress malignant progression of hepatocellular carcinoma and improves sorafenib resistance through negatively regulating POTEE
  223. Analysis of postoperative complications in bladder cancer patients
  224. Carboplatin combined with arsenic trioxide versus carboplatin combined with docetaxel treatment for LACC: A randomized, open-label, phase II clinical study
  225. Special Issue Exploring the biological mechanism of human diseases based on MultiOmics Technology - Part I
  226. Comprehensive pan-cancer investigation of carnosine dipeptidase 1 and its prospective prognostic significance in hepatocellular carcinoma
  227. Identification of signatures associated with microsatellite instability and immune characteristics to predict the prognostic risk of colon cancer
  228. Single-cell analysis identified key macrophage subpopulations associated with atherosclerosis
https://doi.org/10.1515/med-2024-1070
Schlagwörter für diesen Artikel
chronic obstructive pulmonary disease; cigarette smoke extract; cigarette smoke inhalation; cullin-1; p53 pathway
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Research Articles
  2. EDNRB inhibits the growth and migration of prostate cancer cells by activating the cGMP-PKG pathway
  3. STK11 (LKB1) mutation suppresses ferroptosis in lung adenocarcinoma by facilitating monounsaturated fatty acid synthesis
  4. Association of SOX6 gene polymorphisms with Kashin-Beck disease risk in the Chinese Han population
  5. The pyroptosis-related signature predicts prognosis and influences the tumor immune microenvironment in dedifferentiated liposarcoma
  6. METTL3 attenuates ferroptosis sensitivity in lung cancer via modulating TFRC
  7. Identification and validation of molecular subtypes and prognostic signature for stage I and stage II gastric cancer based on neutrophil extracellular traps
  8. Novel lumbar plexus block versus femoral nerve block for analgesia and motor recovery after total knee arthroplasty
  9. Correlation between ABCB1 and OLIG2 polymorphisms and the severity and prognosis of patients with cerebral infarction
  10. Study on the radiotherapy effect and serum neutral granulocyte lymphocyte ratio and inflammatory factor expression of nasopharyngeal carcinoma
  11. Transcriptome analysis of effects of Tecrl deficiency on cardiometabolic and calcium regulation in cardiac tissue
  12. Aflatoxin B1 induces infertility, fetal deformities, and potential therapies
  13. Serum levels of HMW adiponectin and its receptors are associated with cytokine levels and clinical characteristics in chronic obstructive pulmonary disease
  14. METTL3-mediated methylation of CYP2C19 mRNA may aggravate clopidogrel resistance in ischemic stroke patients
  15. Understand how machine learning impact lung cancer research from 2010 to 2021: A bibliometric analysis
  16. Pressure ulcers in German hospitals: Analysis of reimbursement and length of stay
  17. Metformin plus L-carnitine enhances brown/beige adipose tissue activity via Nrf2/HO-1 signaling to reduce lipid accumulation and inflammation in murine obesity
  18. Downregulation of carbonic anhydrase IX expression in mouse xenograft nasopharyngeal carcinoma model via doxorubicin nanobubble combined with ultrasound
  19. Feasibility of 3-dimensional printed models in simulated training and teaching of transcatheter aortic valve replacement
  20. miR-335-3p improves type II diabetes mellitus by IGF-1 regulating macrophage polarization
  21. The analyses of human MCPH1 DNA repair machinery and genetic variations
  22. Activation of Piezo1 increases the sensitivity of breast cancer to hyperthermia therapy
  23. Comprehensive analysis based on the disulfidptosis-related genes identifies hub genes and immune infiltration for pancreatic adenocarcinoma
  24. Changes of serum CA125 and PGE2 before and after high-intensity focused ultrasound combined with GnRH-a in treatment of patients with adenomyosis
  25. The clinical value of the hepatic venous pressure gradient in patients undergoing hepatic resection for hepatocellular carcinoma with or without liver cirrhosis
  26. Development and validation of a novel model to predict pulmonary embolism in cardiology suspected patients: A 10-year retrospective analysis
  27. Downregulation of lncRNA XLOC_032768 in diabetic patients predicts the occurrence of diabetic nephropathy
  28. Circ_0051428 targeting miR-885-3p/MMP2 axis enhances the malignancy of cervical cancer
  29. Effectiveness of ginkgo diterpene lactone meglumine on cognitive function in patients with acute ischemic stroke
  30. The construction of a novel prognostic prediction model for glioma based on GWAS-identified prognostic-related risk loci
  31. Evaluating the impact of childhood BMI on the risk of coronavirus disease 2019: A Mendelian randomization study
  32. Lactate dehydrogenase to albumin ratio is associated with in-hospital mortality in patients with acute heart failure: Data from the MIMIC-III database
  33. CD36-mediated podocyte lipotoxicity promotes foot process effacement
  34. Efficacy of etonogestrel subcutaneous implants versus the levonorgestrel-releasing intrauterine system in the conservative treatment of adenomyosis
  35. FLRT2 mediates chondrogenesis of nasal septal cartilage and mandibular condyle cartilage
  36. Challenges in treating primary immune thrombocytopenia patients undergoing COVID-19 vaccination: A retrospective study
  37. Let-7 family regulates HaCaT cell proliferation and apoptosis via the ΔNp63/PI3K/AKT pathway
  38. Phospholipid transfer protein ameliorates sepsis-induced cardiac dysfunction through NLRP3 inflammasome inhibition
  39. Postoperative cognitive dysfunction in elderly patients with colorectal cancer: A randomized controlled study comparing goal-directed and conventional fluid therapy
  40. Long-pulsed ultrasound-mediated microbubble thrombolysis in a rat model of microvascular obstruction
  41. High SEC61A1 expression predicts poor outcome of acute myeloid leukemia
  42. Comparison of polymerase chain reaction and next-generation sequencing with conventional urine culture for the diagnosis of urinary tract infections: A meta-analysis
  43. Secreted frizzled-related protein 5 protects against renal fibrosis by inhibiting Wnt/β-catenin pathway
  44. Pan-cancer and single-cell analysis of actin cytoskeleton genes related to disulfidptosis
  45. Overexpression of miR-532-5p restrains oxidative stress response of chondrocytes in nontraumatic osteonecrosis of the femoral head by inhibiting ABL1
  46. Autologous liver transplantation for unresectable hepatobiliary malignancies in enhanced recovery after surgery model
  47. Clinical analysis of incomplete rupture of the uterus secondary to previous cesarean section
  48. Abnormal sleep duration is associated with sarcopenia in older Chinese people: A large retrospective cross-sectional study
  49. No genetic causality between obesity and benign paroxysmal vertigo: A two-sample Mendelian randomization study
  50. Identification and validation of autophagy-related genes in SSc
  51. Long non-coding RNA SRA1 suppresses radiotherapy resistance in esophageal squamous cell carcinoma by modulating glycolytic reprogramming
  52. Evaluation of quality of life in patients with schizophrenia: An inpatient social welfare institution-based cross-sectional study
  53. The possible role of oxidative stress marker glutathione in the assessment of cognitive impairment in multiple sclerosis
  54. Compilation of a self-management assessment scale for postoperative patients with aortic dissection
  55. Left atrial appendage closure in conjunction with radiofrequency ablation: Effects on left atrial functioning in patients with paroxysmal atrial fibrillation
  56. Effect of anterior femoral cortical notch grade on postoperative function and complications during TKA surgery: A multicenter, retrospective study
  57. Clinical characteristics and assessment of risk factors in patients with influenza A-induced severe pneumonia after the prevalence of SARS-CoV-2
  58. Analgesia nociception index is an indicator of laparoscopic trocar insertion-induced transient nociceptive stimuli
  59. High STAT4 expression correlates with poor prognosis in acute myeloid leukemia and facilitates disease progression by upregulating VEGFA expression
  60. Factors influencing cardiovascular system-related post-COVID-19 sequelae: A single-center cohort study
  61. HOXD10 regulates intestinal permeability and inhibits inflammation of dextran sulfate sodium-induced ulcerative colitis through the inactivation of the Rho/ROCK/MMPs axis
  62. Mesenchymal stem cell-derived exosomal miR-26a induces ferroptosis, suppresses hepatic stellate cell activation, and ameliorates liver fibrosis by modulating SLC7A11
  63. Endovascular thrombectomy versus intravenous thrombolysis for primary distal, medium vessel occlusion in acute ischemic stroke
  64. ANO6 (TMEM16F) inhibits gastrointestinal stromal tumor growth and induces ferroptosis
  65. Prognostic value of EIF5A2 in solid tumors: A meta-analysis and bioinformatics analysis
  66. The role of enhanced expression of Cx43 in patients with ulcerative colitis
  67. Choosing a COVID-19 vaccination site might be driven by anxiety and body vigilance
  68. Role of ICAM-1 in triple-negative breast cancer
  69. Cost-effectiveness of ambroxol in the treatment of Gaucher disease type 2
  70. HLA-DRB5 promotes immune thrombocytopenia via activating CD8+ T cells
  71. Efficacy and factors of myofascial release therapy combined with electrical and magnetic stimulation in the treatment of chronic pelvic pain syndrome
  72. Efficacy of tacrolimus monotherapy in primary membranous nephropathy
  73. Mechanisms of Tripterygium wilfordii Hook F on treating rheumatoid arthritis explored by network pharmacology analysis and molecular docking
  74. FBXO45 levels regulated ferroptosis renal tubular epithelial cells in a model of diabetic nephropathy by PLK1
  75. Optimizing anesthesia strategies to NSCLC patients in VATS procedures: Insights from drug requirements and patient recovery patterns
  76. Alpha-lipoic acid upregulates the PPARγ/NRF2/GPX4 signal pathway to inhibit ferroptosis in the pathogenesis of unexplained recurrent pregnancy loss
  77. Correlation between fat-soluble vitamin levels and inflammatory factors in paediatric community-acquired pneumonia: A prospective study
  78. CD1d affects the proliferation, migration, and apoptosis of human papillary thyroid carcinoma TPC-1 cells via regulating MAPK/NF-κB signaling pathway
  79. miR-let-7a inhibits sympathetic nerve remodeling after myocardial infarction by downregulating the expression of nerve growth factor
  80. Immune response analysis of solid organ transplantation recipients inoculated with inactivated COVID-19 vaccine: A retrospective analysis
  81. The H2Valdien derivatives regulate the epithelial–mesenchymal transition of hepatoma carcinoma cells through the Hedgehog signaling pathway
  82. Clinical efficacy of dexamethasone combined with isoniazid in the treatment of tuberculous meningitis and its effect on peripheral blood T cell subsets
  83. Comparison of short-segment and long-segment fixation in treatment of degenerative scoliosis and analysis of factors associated with adjacent spondylolisthesis
  84. Lycopene inhibits pyroptosis of endothelial progenitor cells induced by ox-LDL through the AMPK/mTOR/NLRP3 pathway
  85. Methylation regulation for FUNDC1 stability in childhood leukemia was up-regulated and facilitates metastasis and reduces ferroptosis of leukemia through mitochondrial damage by FBXL2
  86. Correlation of single-fiber electromyography studies and functional status in patients with amyotrophic lateral sclerosis
  87. Risk factors of postoperative airway obstruction complications in children with oral floor mass
  88. Expression levels and clinical significance of serum miR-19a/CCL20 in patients with acute cerebral infarction
  89. Physical activity and mental health trends in Korean adolescents: Analyzing the impact of the COVID-19 pandemic from 2018 to 2022
  90. Evaluating anemia in HIV-infected patients using chest CT
  91. Ponticulus posticus and skeletal malocclusion: A pilot study in a Southern Italian pre-orthodontic court
  92. Causal association of circulating immune cells and lymphoma: A Mendelian randomization study
  93. Assessment of the renal function and fibrosis indexes of conventional western medicine with Chinese medicine for dredging collaterals on treating renal fibrosis: A systematic review and meta-analysis
  94. Comprehensive landscape of integrator complex subunits and their association with prognosis and tumor microenvironment in gastric cancer
  95. New target-HMGCR inhibitors for the treatment of primary sclerosing cholangitis: A drug Mendelian randomization study
  96. Population pharmacokinetics of meropenem in critically ill patients
  97. Comparison of the ability of newly inflammatory markers to predict complicated appendicitis
  98. Comparative morphology of the cruciate ligaments: A radiological study
  99. Immune landscape of hepatocellular carcinoma: The central role of TP53-inducible glycolysis and apoptosis regulator
  100. Serum SIRT3 levels in epilepsy patients and its association with clinical outcomes and severity: A prospective observational study
  101. SHP-1 mediates cigarette smoke extract-induced epithelial–mesenchymal transformation and inflammation in 16HBE cells
  102. Acute hyper-hypoxia accelerates the development of depression in mice via the IL-6/PGC1α/MFN2 signaling pathway
  103. The GJB3 correlates with the prognosis, immune cell infiltration, and therapeutic responses in lung adenocarcinoma
  104. Physical fitness and blood parameters outcomes of breast cancer survivor in a low-intensity circuit resistance exercise program
  105. Exploring anesthetic-induced gene expression changes and immune cell dynamics in atrial tissue post-coronary artery bypass graft surgery
  106. Empagliflozin improves aortic injury in obese mice by regulating fatty acid metabolism
  107. Analysis of the risk factors of the radiation-induced encephalopathy in nasopharyngeal carcinoma: A retrospective cohort study
  108. Reproductive outcomes in women with BRCA 1/2 germline mutations: A retrospective observational study and literature review
  109. Evaluation of upper airway ultrasonographic measurements in predicting difficult intubation: A cross-section of the Turkish population
  110. Prognostic and diagnostic value of circulating IGFBP2 in pancreatic cancer
  111. Postural stability after operative reconstruction of the AFTL in chronic ankle instability comparing three different surgical techniques
  112. Research trends related to emergence agitation in the post-anaesthesia care unit from 2001 to 2023: A bibliometric analysis
  113. Frequency and clinicopathological correlation of gastrointestinal polyps: A six-year single center experience
  114. ACSL4 mediates inflammatory bowel disease and contributes to LPS-induced intestinal epithelial cell dysfunction by activating ferroptosis and inflammation
  115. Affibody-based molecular probe 99mTc-(HE)3ZHER2:V2 for non-invasive HER2 detection in ovarian and breast cancer xenografts
  116. Effectiveness of nutritional support for clinical outcomes in gastric cancer patients: A meta-analysis of randomized controlled trials
  117. The relationship between IFN-γ, IL-10, IL-6 cytokines, and severity of the condition with serum zinc and Fe in children infected with Mycoplasma pneumoniae
  118. Paraquat disrupts the blood–brain barrier by increasing IL-6 expression and oxidative stress through the activation of PI3K/AKT signaling pathway
  119. Sleep quality associate with the increased prevalence of cognitive impairment in coronary artery disease patients: A retrospective case–control study
  120. Dioscin protects against chronic prostatitis through the TLR4/NF-κB pathway
  121. Association of polymorphisms in FBN1, MYH11, and TGF-β signaling-related genes with susceptibility of sporadic thoracic aortic aneurysm and dissection in the Zhejiang Han population
  122. Application value of multi-parameter magnetic resonance image-transrectal ultrasound cognitive fusion in prostate biopsy
  123. Laboratory variables‐based artificial neural network models for predicting fatty liver disease: A retrospective study
  124. Decreased BIRC5-206 promotes epithelial–mesenchymal transition in nasopharyngeal carcinoma through sponging miR-145-5p
  125. Sepsis induces the cardiomyocyte apoptosis and cardiac dysfunction through activation of YAP1/Serpine1/caspase-3 pathway
  126. Assessment of iron metabolism and iron deficiency in incident patients on incident continuous ambulatory peritoneal dialysis
  127. Tibial periosteum flap combined with autologous bone grafting in the treatment of Gustilo-IIIB/IIIC open tibial fractures
  128. The application of intravenous general anesthesia under nasopharyngeal airway assisted ventilation undergoing ureteroscopic holmium laser lithotripsy: A prospective, single-center, controlled trial
  129. Long intergenic noncoding RNA for IGF2BP2 stability suppresses gastric cancer cell apoptosis by inhibiting the maturation of microRNA-34a
  130. Role of FOXM1 and AURKB in regulating keratinocyte function in psoriasis
  131. Parental control attitudes over their pre-school children’s diet
  132. The role of auto-HSCT in extranodal natural killer/T cell lymphoma
  133. Significance of negative cervical cytology and positive HPV in the diagnosis of cervical lesions by colposcopy
  134. Echinacoside inhibits PASMCs calcium overload to prevent hypoxic pulmonary artery remodeling by regulating TRPC1/4/6 and calmodulin
  135. ADAR1 plays a protective role in proximal tubular cells under high glucose conditions by attenuating the PI3K/AKT/mTOR signaling pathway
  136. The risk of cancer among insulin glargine users in Lithuania: A retrospective population-based study
  137. The unusual location of primary hydatid cyst: A case series study
  138. Intraoperative changes in electrophysiological monitoring can be used to predict clinical outcomes in patients with spinal cavernous malformation
  139. Obesity and risk of placenta accreta spectrum: A meta-analysis
  140. Shikonin alleviates asthma phenotypes in mice via an airway epithelial STAT3-dependent mechanism
  141. NSUN6 and HTR7 disturbed the stability of carotid atherosclerotic plaques by regulating the immune responses of macrophages
  142. The effect of COVID-19 lockdown on admission rates in Maternity Hospital
  143. Temporal muscle thickness is not a prognostic predictor in patients with high-grade glioma, an experience at two centers in China
  144. Luteolin alleviates cerebral ischemia/reperfusion injury by regulating cell pyroptosis
  145. Therapeutic role of respiratory exercise in patients with tuberculous pleurisy
  146. Effects of CFTR-ENaC on spinal cord edema after spinal cord injury
  147. Irisin-regulated lncRNAs and their potential regulatory functions in chondrogenic differentiation of human mesenchymal stem cells
  148. DMD mutations in pediatric patients with phenotypes of Duchenne/Becker muscular dystrophy
  149. Combination of C-reactive protein and fibrinogen-to-albumin ratio as a novel predictor of all-cause mortality in heart failure patients
  150. Significant role and the underly mechanism of cullin-1 in chronic obstructive pulmonary disease
  151. Ferroptosis-related prognostic model of mantle cell lymphoma
  152. Observation of choking reaction and other related indexes in elderly painless fiberoptic bronchoscopy with transnasal high-flow humidification oxygen therapy
  153. A bibliometric analysis of Prader-Willi syndrome from 2002 to 2022
  154. The causal effects of childhood sunburn occasions on melanoma: A univariable and multivariable Mendelian randomization study
  155. Oxidative stress regulates glycogen synthase kinase-3 in lymphocytes of diabetes mellitus patients complicated with cerebral infarction
  156. Role of COX6C and NDUFB3 in septic shock and stroke
  157. Trends in disease burden of type 2 diabetes, stroke, and hypertensive heart disease attributable to high BMI in China: 1990–2019
  158. Purinergic P2X7 receptor mediates hyperoxia-induced injury in pulmonary microvascular endothelial cells via NLRP3-mediated pyroptotic pathway
  159. Investigating the role of oviductal mucosa–endometrial co-culture in modulating factors relevant to embryo implantation
  160. Analgesic effect of external oblique intercostal block in laparoscopic cholecystectomy: A retrospective study
  161. Elevated serum miR-142-5p correlates with ischemic lesions and both NSE and S100β in ischemic stroke patients
  162. Correlation between the mechanism of arteriopathy in IgA nephropathy and blood stasis syndrome: A cohort study
  163. Risk factors for progressive kyphosis after percutaneous kyphoplasty in osteoporotic vertebral compression fracture
  164. Predictive role of neuron-specific enolase and S100-β in early neurological deterioration and unfavorable prognosis in patients with ischemic stroke
  165. The potential risk factors of postoperative cognitive dysfunction for endovascular therapy in acute ischemic stroke with general anesthesia
  166. Fluoxetine inhibited RANKL-induced osteoclastic differentiation in vitro
  167. Detection of serum FOXM1 and IGF2 in patients with ARDS and their correlation with disease and prognosis
  168. Rhein promotes skin wound healing by activating the PI3K/AKT signaling pathway
  169. Differences in mortality risk by levels of physical activity among persons with disabilities in South Korea
  170. Review Articles
  171. Cutaneous signs of selected cardiovascular disorders: A narrative review
  172. XRCC1 and hOGG1 polymorphisms and endometrial carcinoma: A meta-analysis
  173. A narrative review on adverse drug reactions of COVID-19 treatments on the kidney
  174. Emerging role and function of SPDL1 in human health and diseases
  175. Adverse reactions of piperacillin: A literature review of case reports
  176. Molecular mechanism and intervention measures of microvascular complications in diabetes
  177. Regulation of mesenchymal stem cell differentiation by autophagy
  178. Molecular landscape of borderline ovarian tumours: A systematic review
  179. Advances in synthetic lethality modalities for glioblastoma multiforme
  180. Investigating hormesis, aging, and neurodegeneration: From bench to clinics
  181. Frankincense: A neuronutrient to approach Parkinson’s disease treatment
  182. Sox9: A potential regulator of cancer stem cells in osteosarcoma
  183. Early detection of cardiovascular risk markers through non-invasive ultrasound methodologies in periodontitis patients
  184. Advanced neuroimaging and criminal interrogation in lie detection
  185. Maternal factors for neural tube defects in offspring: An umbrella review
  186. The chemoprotective hormetic effects of rosmarinic acid
  187. CBD’s potential impact on Parkinson’s disease: An updated overview
  188. Progress in cytokine research for ARDS: A comprehensive review
  189. Utilizing reactive oxygen species-scavenging nanoparticles for targeting oxidative stress in the treatment of ischemic stroke: A review
  190. NRXN1-related disorders, attempt to better define clinical assessment
  191. Lidocaine infusion for the treatment of complex regional pain syndrome: Case series and literature review
  192. Trends and future directions of autophagy in osteosarcoma: A bibliometric analysis
  193. Iron in ventricular remodeling and aneurysms post-myocardial infarction
  194. Case Reports
  195. Sirolimus potentiated angioedema: A case report and review of the literature
  196. Identification of mixed anaerobic infections after inguinal hernia repair based on metagenomic next-generation sequencing: A case report
  197. Successful treatment with bortezomib in combination with dexamethasone in a middle-aged male with idiopathic multicentric Castleman’s disease: A case report
  198. Complete heart block associated with hepatitis A infection in a female child with fatal outcome
  199. Elevation of D-dimer in eosinophilic gastrointestinal diseases in the absence of venous thrombosis: A case series and literature review
  200. Four years of natural progressive course: A rare case report of juvenile Xp11.2 translocations renal cell carcinoma with TFE3 gene fusion
  201. Advancing prenatal diagnosis: Echocardiographic detection of Scimitar syndrome in China – A case series
  202. Outcomes and complications of hemodialysis in patients with renal cancer following bilateral nephrectomy
  203. Anti-HMGCR myopathy mimicking facioscapulohumeral muscular dystrophy
  204. Recurrent opportunistic infections in a HIV-negative patient with combined C6 and NFKB1 mutations: A case report, pedigree analysis, and literature review
  205. Letter to the Editor
  206. Letter to the Editor: Total parenteral nutrition-induced Wernicke’s encephalopathy after oncologic gastrointestinal surgery
  207. Erratum
  208. Erratum to “Bladder-embedded ectopic intrauterine device with calculus”
  209. Retraction
  210. Retraction of “XRCC1 and hOGG1 polymorphisms and endometrial carcinoma: A meta-analysis”
  211. Corrigendum
  212. Corrigendum to “Investigating hormesis, aging, and neurodegeneration: From bench to clinics”
  213. Corrigendum to “Frankincense: A neuronutrient to approach Parkinson’s disease treatment”
  214. Special Issue The evolving saga of RNAs from bench to bedside - Part II
  215. Machine-learning-based prediction of a diagnostic model using autophagy-related genes based on RNA sequencing for patients with papillary thyroid carcinoma
  216. Unlocking the future of hepatocellular carcinoma treatment: A comprehensive analysis of disulfidptosis-related lncRNAs for prognosis and drug screening
  217. Elevated mRNA level indicates FSIP1 promotes EMT and gastric cancer progression by regulating fibroblasts in tumor microenvironment
  218. Special Issue Advancements in oncology: bridging clinical and experimental research - Part I
  219. Ultrasound-guided transperineal vs transrectal prostate biopsy: A meta-analysis of diagnostic accuracy and complication rates
  220. Assessment of diagnostic value of unilateral systematic biopsy combined with targeted biopsy in detecting clinically significant prostate cancer
  221. SENP7 inhibits glioblastoma metastasis and invasion by dissociating SUMO2/3 binding to specific target proteins
  222. MARK1 suppress malignant progression of hepatocellular carcinoma and improves sorafenib resistance through negatively regulating POTEE
  223. Analysis of postoperative complications in bladder cancer patients
  224. Carboplatin combined with arsenic trioxide versus carboplatin combined with docetaxel treatment for LACC: A randomized, open-label, phase II clinical study
  225. Special Issue Exploring the biological mechanism of human diseases based on MultiOmics Technology - Part I
  226. Comprehensive pan-cancer investigation of carnosine dipeptidase 1 and its prospective prognostic significance in hepatocellular carcinoma
  227. Identification of signatures associated with microsatellite instability and immune characteristics to predict the prognostic risk of colon cancer
  228. Single-cell analysis identified key macrophage subpopulations associated with atherosclerosis
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Heruntergeladen am 15.10.2025 von https://www.degruyterbrill.com/document/doi/10.1515/med-2024-1070/html?lang=de
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