Home Medicine Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway
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Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway

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Published/Copyright: November 9, 2023
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Open Medicine
From the journal Open Medicine Volume 18 Issue 1

Abstract

To investigate the effect of adipose-derived stem cells (ASCs) transplantation on radiation-induced lung injury (RILI), Sprague-Dawley rats were divided into phosphate-buffered saline (PBS) group, ASCs group, Radiation + PBS group, and Radiation + ASCs group. Radiation + PBS and Radiation + ASCs groups received single dose of 30 Gy X-ray radiation to the right chest. The Radiation + PBS group received 1 mL PBS suspension and Radiation + ASCs group received 1 mL PBS suspension containing 1 × 107 CM-Dil-labeled ASCs. The right lung tissue was collected on Days 30, 90, and 180 after radiation. Hematoxylin–eosin and Masson staining were performed to observe the pathological changes and collagen fiber content in the lung tissue. Immunohistochemistry (IHC) and western blot (WB) were used to detect levels of fibrotic markers collagen I (Collal), fibronectin (FN), as well as transforming growth factor-β1 (TGF-β1), p-Smad 3, and Smad 3. Compared with the non-radiation groups, the radiation groups showed lymphocyte infiltration on Day 30 after irradiation and thickened incomplete alveolar walls, collagen deposition, and fibroplasia on Days 90 and 180. ASCs relieved these changes on Day 180 (Masson staining, P = 0.0022). Compared with Radiation + PBS group, on Day 180 after irradiation, the Radiation + ASCs group showed that ASCs could significantly decrease the expressions of fibrosis markers Collal (IHC: P = 0.0022; WB: P = 0.0087) and FN (IHC: P = 0.0152; WB: P = 0.026) and inhibit the expressions of TGF-β1 (IHC: P = 0.026; WB: P = 0.0152) and p-Smad 3 (IHC: P = 0.0043; WB: P = 0.0087) in radiation-induced injured lung tissue. These indicated that ASCs could relieve RILI by inhibiting TGF-β1/Smad 3 signaling pathway.

Keywords: adipose-derived stem cells; radiation-induced lung injury; fibroplasia; TGF-β1/Smad 3 signaling pathway

1 Introduction

Radiotherapy plays a fundamental role in the treatment and management of thoracic cancers. Nevertheless, radiotherapy-related toxicities, such as radiation-induced lung injury (RILI), are pivotal dose-limiting factors that directly affect the prognosis and life quality of patients [1]. Pneumonia and fibrosis are common in lung tissues exposed to irradiation [2]. A high-dose radiotherapy for thoracic cancer resulted in RILI in more than 40% of patients and even death in a minority [3]. Unfortunately, there are few safe and effective strategies for treating RILI.

RILI is usually divided into an early-stage radiation-induced pneumonitis and late-stage radiation-induced pulmonary fibrosis (RIPF) [4]. RIPF is an incurable heterogeneous disease characterized by scar formation leading to progressive and irreversible destruction of pulmonary structures, which ultimately resulted in pulmonary dysfunction, disruption of air exchange, and even death from respiratory failure [4–6]. To date, the underlying mechanism of RILI is still not well defined. Transforming growth factor-β1 (TGF-β1), as a pleiotropic cytokine generated by activated immune cells and alveolar type I or II epithelial cells, has been reported to be crucial in the pulmonary fibrosis as it can promote the activation of myofibroblasts, proliferation of fibroblasts, and deposition of extracellular matrix (ECM) [7–9]. Furthermore, TGF-β1/Smad 3 signaling pathway has been reported to undertake a pivotal role in the differentiation of fibroblast to myofibroblast, sustained myofibroblast activation, and aberrant ECM deposition [10,11]. On this basis, it is reasonable to speculate that the inhibition of TGF-β1/Smad 3 signaling pathway may hinder the progression of RILI.

Mesenchymal stem cells (MSCs) have been used to repair tissue damage including lung injury [12]. Among MSCs, adipose tissue-derived MSCs (ASCs) have been used in tissue injury repairment as its convenient acquisition, rapid proliferation in vitro, multi-directional differentiation even after long-term culture, and low immunogenicity [13]. At present, there are many studies of ASCs on TGFβ1/Smad 3 signaling pathway in some tissues such as skin [14], muscle [15], and liver [16]. However, in radiation-induced injured lung tissue, the intervention of ASCs on TGFβ1/Smad 3 signaling pathway has not been reported. Here, we aimed to investigate the roles of ASCs in RILI of Sprague-Dawley (SD) rats. Furthermore, we tried to reveal the underlying mechanism by which ASCs exert their roles.

2 Materials and methods

2.1 Animals

One hundred and thirty adult female SD rats (200 ± 20 g) of specific pathogen free grade were purchased from Shanghai Institute of Family Planning Sciences (certificate No.: 20180006030261; License No.: SCXK 2018-0006; Shanghai, China). Animals were fed with a standard diet and kept in a clean animal room.

  1. Ethical statement: The animal experimental protocol was approved by the Ethical Committee of Nanjing Medical University (approval number: IACUC-2107055).

2.2 Isolation and culture of ASCs

Thirty rats were used for the isolation of ASCs. Briefly, rats were anesthetized by intraperitoneal injection of 1% pentobarbital (40 mg/kg). Then the subcutaneous adipose tissue was excised from the groin. Upon removal of blood vessels, the tissues were cut into pieces and placed in a centrifuge tube. Afterward, the mixture was digested with 40 mL I-type collagenase solution (0.075%) for 60 min in shaking water bath at 37°C. The mixture was transferred to a 50 mL centrifuge tube and centrifuged at 1,500 rpm for 10 min. The pellet was suspended with Dulbecco’s Modified Eagle’s Medium and fetal bovine serum (10%), followed by incubation in a 100 mL culture dish at 37°C for 24 h in an incubator with atmosphere of 5% CO2 and a saturated humidity. Finally, the primary (P0) ASCs were obtained after removing floating impurity cells rinsed with phosphate-buffered saline (PBS). The culture medium was changed twice a week. Cells were passaged at a ratio of 1:3 upon reaching 80% confluence.

2.3 Identification and labeling of ASCs

The identification of ASCs was performed based on flow cytometry for the labeling of the surface markers of passage3 (P3) ASCs. The surface was labeled with rhodamine B isothiocyanate (RBITC)-conjugated anti-CD45 rabbit monoclonal antibody, fluorescein isothiocyanate (FITC)-conjugated anti-CD31 rabbit monoclonal antibody, and FITC-conjugated anti-CD90 mouse monoclonal antibody (Abcam Inc., Cambridge, MA). A nonspecific RBITC/FITC-conjugated IgG (Abcam Inc., Cambridge, MA) was used as an isotype control to assess the background fluorescence. Analysis was done by flow cytometer using the CellQuest Pro software. ASCs (P2) were digested, centrifuged, resuspended in PBS, and labeled with chlormethylbenzamido-1,1′-dioctadecyl-3,3,3′,3′-tetramethyl indocarbocyanine (CM-DiI) (Invitrogen, USA) according to the manufacturer’s instructions. The labeled ASCs were placed in a dark environment for subsequent culture.

2.4 Experimental design

Seventy-two SD rats were randomly divided into (i) PBS group (n = 18), injected with 1 mL PBS via tail vein; (ii) ASCs group (n = 18), injected with 1 mL PBS containing 1 × 107 allogeneic CM-Dil-labeled ASCs via tail vein; (iii) Radiation + PBS group (n = 18), injected with 1 mL PBS via tail vein at 2 h after a single radiation dose of 30 Gy to right chest; and (iv) Radiation + ASCs group (n = 18), injected with 1 mL PBS containing 1 × 107 allogeneic CM-Dil-labeled ASCs via tail vein at 2 h after a single radiation dose of 30 Gy to right chest. Animals were anesthetized by intraperitoneal injection of 1% pentobarbital (40 mg/kg) before radiation. Source-skin distance radiation was carried out using 6 MeV electrons generated by an Elekta infinity linear accelerator (Elekta, Sweden) at 3 cm depth in supine position using a constant dose rate of 600 cGy/min. General behaviors and conditions of the rats were observed daily. Then six rats randomly selected from each group were sacrificed on Days 30, 90, and 180, respectively. Subsequently, the right lung was obtained, and the tissues were stored for subsequent analysis.

2.5 Homing analysis

Twenty-eight rats were divided into the following groups, including (i) ASCs group, injected 1 × 107 allogeneic CM-Dil-labeled ASCs via tail vein and (ii) Radiation + ASCs group, injected 1 × 107 allogeneic CM-Dil-labeled ASCs via tail vein at 2 h after a single radiation dose of 30 Gy to right chest. One rat was sacrificed in each group per day until 14 days after the ASCs injection to obtain the right lung. The homing of ASCs was observed under a fluorescence microscope based on the prepared frozen sections.

2.6 Histological analysis

The freshly harvested tissues were fixed with 10% formaldehyde for 24 h, dehydrated with alcohol, and then embedded in paraffin wax. To reflect the general structure and alveolitis status of lung tissue, the slides were performed hematoxylin–eosin (HE) staining as previously published [17]. Masson staining was performed to mainly reflect the fibrosis in lung tissue, and five fields were randomly selected as previously described [18]. Fibrosis degree was quantified by the percentage of positive collagen fiber area to total area using Image J. Immunohistochemistry (IHC) was performed as described elsewhere [19]. Briefly, the tissue sections were deparaffinized and rehydrated. Endogenous peroxidase activity was blocked with 3% H2O2 for 10 min. Then slides were placed in a citrate buffer solution and heated in a microwave for 10 min for antigen retrieval, followed by blocking in normal serum to reduce the background. Afterward, the tissue sections were washed three times in PBS solution for 10 min and incubated overnight at 4°C with primary rabbit monoclonal antibodies against collagen I (Collal), fibronectin (FN), TGF-β1, Smad 3, and p-Smad 3 (1: 50; Abcam Inc., Cambridge, MA). Slides were then washed with PBS solution, followed by incubation with horseradish peroxidase-conjugated secondary antibody for 1 h at room temperature. Slides were washed again in PBS solution and developed using 3,3′-diaminobenzidine working solution, and the termination of the reaction was determined using microscope. The positive alveolar epithelial cells were observed under a microscope. Integral optical density (IOD) analysis was performed based on images of each section captured from five random fields by semi-quantitative scoring system using Image Pro Plus 6.0.

2.7 Western blot (WB) analysis

Protein extraction was performed according to the instructions of the kit (Keygen Bio Tech, Nanjing, China) after the homogenization of snap-frozen lung tissues. Protein samples were separated using sodium dodecyl sulfate polyacrylamide gel electrophoresis (Keygen Bio Tech, Nanjing, China) and transferred onto a polyvinylidene fluoride membrane. Then the membranes were blocked with 5% skimmed milk for 90 min and incubated overnight at 4°C with primary rabbit monoclonal antibodies against Colla1, FN, TGF-β1, p-Smad 3, and Smad 3 (Abcam Inc., Cambridge, MA). Then the membrane was washed in Tris-buffered saline and Tween (TBST) and incubated with the corresponding secondary antibody for 90 min at room temperature. After washing three times in TBST, images were acquired with an electro-chemiluminescence kit (Keygen Bio Tech, Nanjing, China). Signal intensities of bands were quantified using Image J as described in the previous study [20]. Membranes probed with GAPDH were used as internal reference.

2.8 Statistical analysis

Statistical analysis was performed using SPSS 16.0 software. All measurement data were expressed as mean ± standard deviation (SD). The comparison between groups was performed by Wilcoxon Mann–Whitney U test. Hypothesis testing was two-tailed. A P-value of less than 0.05 was considered to be statistically significant.

3 Results

3.1 Morphology and specific antigen expression of ASCs

ASCs were spindle-shaped fibroblast-like adherent cells, with plump and centered nuclei (Figure 1a). The cell membrane and cytoplasm of ASCs labeled with CM-Dil showed uniform red fluorescence roughly consistent with the cell shape under a fluorescence microscope at 553 nm wavelength. The nuclei were not stained (Figure 1b). Compared with IgG isotype control (Figure 1c), both hematopoietic stem cell-specific antigen CD45 and endothelial cell-specific antigen CD31 showed extremely low or even no expression in ASCs (CD45: 0.07%; CD31: 0%; Figure 1d and e). ASCs-specific antigen CD90 was highly expressed with a positive rate of 97.4% (Figure 1f).

Figure 1 Morphology of ASCs and specific antigen expression in ASCs surface. (a) Microscopic images of ASCs in passage three (P3). (b) Fluorescence microscopic images of CM-Dil-labeled ASCs. (c) IgG isotype control group. (d) There was no expression of hematopoietic stem cell-specific antigen CD45 in ASCs. (e) No expression of endothelial cell-specific antigen CD31 was found in ASCs. (f) There was ASC-specific antigen CD90 in ASCs.
Figure 1

Morphology of ASCs and specific antigen expression in ASCs surface. (a) Microscopic images of ASCs in passage three (P3). (b) Fluorescence microscopic images of CM-Dil-labeled ASCs. (c) IgG isotype control group. (d) There was no expression of hematopoietic stem cell-specific antigen CD45 in ASCs. (e) No expression of endothelial cell-specific antigen CD31 was found in ASCs. (f) There was ASC-specific antigen CD90 in ASCs.

3.2 Tracking of ASCs based on CM-Dil labeling

For the tracking of ASCs in rats, no CM-Dil-labeled ASCs were observed on Days 1 and 3 after ASCs transplantation in ASCs group (Figure 2a and b). There was an extremely small number of CM-Dil-labeled ASCs in ASCs group 7 days after cellular transplantation (Figure 2c). No CM-Dil-labeled ASCs were observed on Day 14 (Figure 2d). In the irradiation group, the CM-Dil-labeled ASCs were sporadically distributed in lung tissues since the day of transplantation (Figure 2e). On Days 3 and 7, there were adequate CM-Dil-labeled ASCs in the lung tissues in Radiation + ASCs group (Figure 2f and g), and only a spot of CM-Dil-labeled ASCs were observed on Day 14 (Figure 2h). On Days 30, 90, and 180, no CM-Dil-labeled ASCs were observed in both the groups. This showed that ASCs can home to injured lung tissues. However, with the decay of fluorescence ASCs could not be seen in injured lung tissue on Days 30, 90, and 180.

Figure 2 Fluorescence microscope pictures of frozen lung tissue sections after tail vein injection of CM-Dil-labeled ASCs in SD rats. Bar = 200 μm. In the ASCs group, there were no CM-Dil-labeled ASCs on Day 1 (a) and Day 3 (b) after ASCs transplantation. (c) An extremely small number of CM-Dil-labeled ASCs were observed on Day 7. (d) No CM-Dil-labeled ASCs were observed on Day 14. (e) In the Radiation + ASCs group, ASCs were sporadically distributed on Day 1. There were adequate CM-Dil-labeled ASCs on Day 3 (f) and Day 7 (g). (h) Only a spot of CM-Dil-labeled ASCs were observed on Day 14.
Figure 2

Fluorescence microscope pictures of frozen lung tissue sections after tail vein injection of CM-Dil-labeled ASCs in SD rats. Bar = 200 μm. In the ASCs group, there were no CM-Dil-labeled ASCs on Day 1 (a) and Day 3 (b) after ASCs transplantation. (c) An extremely small number of CM-Dil-labeled ASCs were observed on Day 7. (d) No CM-Dil-labeled ASCs were observed on Day 14. (e) In the Radiation + ASCs group, ASCs were sporadically distributed on Day 1. There were adequate CM-Dil-labeled ASCs on Day 3 (f) and Day 7 (g). (h) Only a spot of CM-Dil-labeled ASCs were observed on Day 14.

3.3 Histopathological changes of lung tissues

HE staining indicated that the alveolar structure of lung tissues in PBS group and ASCs group was intact, with no obvious exudation and fibroplasia on Days 30, 90, and 180, respectively (Figure 3a–f). Masson staining also showed no obvious formation of collagen fibers in PBS group and ASCs group (Figure 4a–f). In Radiation + PBS group, acute inflammation including congestion, edema, and inflammatory cell infiltration was seen in lung tissues on Day 30 after irradiation (Figure 3g). No significant differences of these changes were observed in Radiation + ASCs group (Figure 3j). Slight Masson staining was seen on Day 30 after irradiation in two groups (Figure 4g and j). In addition, chronic inflammatory changes featured by lymphocyte infiltration in lung tissues were seen on Day 90, along with fibroplasia in pulmonary tissues in Radiation + PBS group (Figure 3h). No significant difference of the change was observed in Radiation + ASCs group (Figure 3k). Consistently, Masson staining of Radiation + PBS and Radiation + ASCs groups showed scattered collagen fibers, with no significant difference in the percentage of collagen fiber-positive area to total area (Figure 4h, k, and m). On Day 180, the alveolar wall was incomplete and obviously thickened after irradiation together with the presence of massive lymphocytes and obvious fibroplasia in Radiation + PBS group (Figure 3i); however, these conditions were significantly attenuated in Radiation + ASCs group (Figure 3l). Masson staining also showed that on Day 180, compared with that in Radiation + PBS group, there was significant decrease in collagen fiber area in the Radiation + ASCs group (Figure 4i, l, and m, P = 0.0022). This showed that ASCs can inhibit fibroplasia and attenuate chronic lung injury induced by irradiation.

Figure 3 HE-staining images (Bar = 50 μm) of lung tissues in PBS, ASCs, Radiation + PBS, and Radiation + ASCs groups on Days 30, 90, and 180 of ASCs injection. (a–f) No obvious exudation and fibroplasia were found in lung tissues in PBS and ASCs groups. (g and j) Acute inflammation including congestion, edema, and inflammatory cell infiltration were seen on Day 30 after irradiation in Radiation + PBS and Radiation + ASCs groups. (h and k) Chronic inflammatory changes featured by lymphocyte infiltration and fibroplasia were seen on Day 90 after irradiation in Radiation + PBS and Radiation + ASCs groups. (i) In Radiation + PBS group, alveolar wall was incomplete and obviously thickened, together with the presence of massive lymphocytes and obvious fibroplasia. (l) These changes were significantly attenuated in Radiation + ASCs group.
Figure 3

HE-staining images (Bar = 50 μm) of lung tissues in PBS, ASCs, Radiation + PBS, and Radiation + ASCs groups on Days 30, 90, and 180 of ASCs injection. (a–f) No obvious exudation and fibroplasia were found in lung tissues in PBS and ASCs groups. (g and j) Acute inflammation including congestion, edema, and inflammatory cell infiltration were seen on Day 30 after irradiation in Radiation + PBS and Radiation + ASCs groups. (h and k) Chronic inflammatory changes featured by lymphocyte infiltration and fibroplasia were seen on Day 90 after irradiation in Radiation + PBS and Radiation + ASCs groups. (i) In Radiation + PBS group, alveolar wall was incomplete and obviously thickened, together with the presence of massive lymphocytes and obvious fibroplasia. (l) These changes were significantly attenuated in Radiation + ASCs group.

Figure 4 Masson staining images (Bar = 50 μm) of lung tissues in PBS, ASCs, Radiation + PBS, and Radiation + ASCs groups on Days 30, 90 and 180 of ASCs injection. (a–f) There were no obvious collagen fibers in lung tissues in PBS and ASCs groups. (g, h, j, and k) On Days 30 and 90, there was no significant difference in collagen fiber area in the Radiation + ASCs group compared with that in Radiation + PBS group. (i and l) On Day 180, the collagen fiber area was significantly decreased in the Radiation + ASCs group compared with that in Radiation + PBS group. (m) On Day 180, ASCs relieved fibrosis degree in chronic lung injury induced by irradiation (P = 0.0022, Wilcoxon Mann–Whitney U test). For each group, n = 6. *P < 0.05, ns means no statistical difference.
Figure 4

Masson staining images (Bar = 50 μm) of lung tissues in PBS, ASCs, Radiation + PBS, and Radiation + ASCs groups on Days 30, 90 and 180 of ASCs injection. (a–f) There were no obvious collagen fibers in lung tissues in PBS and ASCs groups. (g, h, j, and k) On Days 30 and 90, there was no significant difference in collagen fiber area in the Radiation + ASCs group compared with that in Radiation + PBS group. (i and l) On Day 180, the collagen fiber area was significantly decreased in the Radiation + ASCs group compared with that in Radiation + PBS group. (m) On Day 180, ASCs relieved fibrosis degree in chronic lung injury induced by irradiation (P = 0.0022, Wilcoxon Mann–Whitney U test). For each group, n = 6. *P < 0.05, ns means no statistical difference.

3.4 ASCs inhibited fibroplasia

IHC and WB analysis results together indicated that no statistical differences in the expressions of Collal and FN were found in PBS and ASCs groups on Days 30, 90, and 180. The expressions of Collal and FN between Radiation + PBS and Radiation + ASCs groups showed no statistically significant differences on Days 30 and 90. On Day 180, the expressions of Collal (IHC: P = 0.0022; WB: P = 0.0087) and FN (IHC: P = 0.0152; WB: P = 0.026) were significantly down-regulated in Radiation + ASCs group compared with that in Radiation + PBS group (Figures 5 and 6). This showed that ASCs could inhibit fibroplasia in chronic lung injury induced by irradiation.

Figure 5 IHC images (bar = 50 μm) and IOD analysis of Collal and FN in PBS, ASCs, Radiation + PBS, and Radiation + ASCs groups on Days 30, 90, and 180 after irradiation. (a–f) No expressions of Collal and FN were found in lung tissues in PBS and ASCs groups. (g, h, j, and k) On Days 30 and 90, there were no significant differences in expressions of Collal and FN between the Radiation + ASCs group and Radiation + PBS group. (i and l) On Day 180, the expressions of Collal and FN were significantly decreased in the Radiation + ASCs group compared with that in Radiation + PBS group. (m) On Day 180, ASCs decreased fibrosis degree in chronic lung injury induced by irradiation (Collal: P = 0.0022, FN: P = 0.0152, Wilcoxon Mann–Whitney U test). For each group, n = 6. *P < 0.05, ns means no statistical difference.
Figure 5

IHC images (bar = 50 μm) and IOD analysis of Collal and FN in PBS, ASCs, Radiation + PBS, and Radiation + ASCs groups on Days 30, 90, and 180 after irradiation. (a–f) No expressions of Collal and FN were found in lung tissues in PBS and ASCs groups. (g, h, j, and k) On Days 30 and 90, there were no significant differences in expressions of Collal and FN between the Radiation + ASCs group and Radiation + PBS group. (i and l) On Day 180, the expressions of Collal and FN were significantly decreased in the Radiation + ASCs group compared with that in Radiation + PBS group. (m) On Day 180, ASCs decreased fibrosis degree in chronic lung injury induced by irradiation (Collal: P = 0.0022, FN: P = 0.0152, Wilcoxon Mann–Whitney U test). For each group, n = 6. *P < 0.05, ns means no statistical difference.

Figure 6 WB and quantitative analysis of Collal and FN in PBS, ASCs, Radiation + PBS, and Radiation + ASCs groups on Days 30, 90, and 180 after irradiation. (a) Representative bands of western blotting. (b and c) On Day 180, the protein expressions of Collal (P = 0.0087, Wilcoxon Mann–Whitney U test) and FN (P = 0.026, Wilcoxon Mann–Whitney U test) were significantly decreased in the Radiation + ASCs group compared with that in Radiation + PBS group. The density values of blots were normalized to the internal control GAPDH1. Data were expressed as mean ± standard deviation. For each group, n = 6. *P < 0.05, ns means no statistical difference.
Figure 6

WB and quantitative analysis of Collal and FN in PBS, ASCs, Radiation + PBS, and Radiation + ASCs groups on Days 30, 90, and 180 after irradiation. (a) Representative bands of western blotting. (b and c) On Day 180, the protein expressions of Collal (P = 0.0087, Wilcoxon Mann–Whitney U test) and FN (P = 0.026, Wilcoxon Mann–Whitney U test) were significantly decreased in the Radiation + ASCs group compared with that in Radiation + PBS group. The density values of blots were normalized to the internal control GAPDH1. Data were expressed as mean ± standard deviation. For each group, n = 6. *P < 0.05, ns means no statistical difference.

3.5 ASCs repaired RILI via inhibiting TGF-β1/Smad 3 signaling pathway

Expressions of TGF-β1, p-Smad 3, and Smad 3 in PBS and ASCs groups showed no statistically significant differences at all timepoints. Compared with Radiation + PBS group, the levels of TGF-β1 and p-Smad 3 showed no statistical difference in Radiation + ASCs group on Days 30 and 90 after irradiation. On Day 180 after irradiation, the levels of TGF-β1 (IHC: P = 0.026; WB: P = 0.0152) and p-Smad 3 (IHC: P = 0.0043; WB: P = 0.0087) were significantly down-regulated in Radiation + ASCs group than that in Radiation + PBS group. This implied that ASCs can inhibit TGF-β1/Smad 3 signaling pathway in chronic lung injury induced by irradiation. No difference of Smad 3 expression was observed between Radiation + PBS and Radiation + ASCs groups at all timepoints (Figures 7 and 8).

Figure 7 IHC images (bar = 50 μm) and IOD analysis of TGF-β1, p-Smad 3, and Smad 3 in PBS, ASCs, Radiation + PBS, and Radiation + ASCs groups on Days 30, 90, and 180 after irradiation. (a–f) There were no expressions of TGF-β1, p-Smad 3, and Smad 3 in lung tissues in PBS and ASCs groups. (g, h, j, and k) On Days 30 and 90, no significant differences in the expressions of TGF-β1, p-Smad 3, and Smad 3 were found between the Radiation + ASCs group and Radiation + PBS group. (i and l) On Day 180, the expressions of TGF-β1and p-Smad 3 were significantly decreased in the Radiation + ASCs group than that in the Radiation + PBS group. (m) On Day 180, ASCs decreased the levels of TGF-β1 (P = 0.026, Wilcoxon Mann–Whitney U test) and p-Smad 3 (P = 0.0043, Wilcoxon Mann–Whitney U test) in chronic lung injury induced by irradiation. For each group, n = 6. *P < 0.05, ns means no statistical difference.
Figure 7

IHC images (bar = 50 μm) and IOD analysis of TGF-β1, p-Smad 3, and Smad 3 in PBS, ASCs, Radiation + PBS, and Radiation + ASCs groups on Days 30, 90, and 180 after irradiation. (a–f) There were no expressions of TGF-β1, p-Smad 3, and Smad 3 in lung tissues in PBS and ASCs groups. (g, h, j, and k) On Days 30 and 90, no significant differences in the expressions of TGF-β1, p-Smad 3, and Smad 3 were found between the Radiation + ASCs group and Radiation + PBS group. (i and l) On Day 180, the expressions of TGF-β1and p-Smad 3 were significantly decreased in the Radiation + ASCs group than that in the Radiation + PBS group. (m) On Day 180, ASCs decreased the levels of TGF-β1 (P = 0.026, Wilcoxon Mann–Whitney U test) and p-Smad 3 (P = 0.0043, Wilcoxon Mann–Whitney U test) in chronic lung injury induced by irradiation. For each group, n = 6. *P < 0.05, ns means no statistical difference.

Figure 8 WB and quantitative analysis of TGF-β1, p-Smad 3, and Smad 3 in PBS, ASCs, Radiation + PBS, and Radiation + ASCs groups on Days 30, 90, and 180 after irradiation. (a) Representative bands of western blotting. (b–d) On Day 180, compared with Radiation + PBS group, ASCs decreased the protein expressions of TGF-β1 (P = 0.0152, Wilcoxon Mann–Whitney U test) and p-Smad 3 (P = 0.0087, Wilcoxon Mann–Whitney U test). The density values of blots were normalized to the internal control GAPDH2. Data were expressed as mean ± standard deviation. For each group, n = 6. *P < 0.05, ns means no statistical difference.
Figure 8

WB and quantitative analysis of TGF-β1, p-Smad 3, and Smad 3 in PBS, ASCs, Radiation + PBS, and Radiation + ASCs groups on Days 30, 90, and 180 after irradiation. (a) Representative bands of western blotting. (b–d) On Day 180, compared with Radiation + PBS group, ASCs decreased the protein expressions of TGF-β1 (P = 0.0152, Wilcoxon Mann–Whitney U test) and p-Smad 3 (P = 0.0087, Wilcoxon Mann–Whitney U test). The density values of blots were normalized to the internal control GAPDH2. Data were expressed as mean ± standard deviation. For each group, n = 6. *P < 0.05, ns means no statistical difference.

4 Discussion

The results in this study revealed that ASCs could inhibit fibroplasia, attenuate RILI, and inhibit the expressions of TGF-β1 and p-Smad 3 proteins. To our knowledge, this is the first study revealing that ASC could repair RILI by inhibiting the TGF-β1/Smad 3 signaling pathway. Recently, numerous studies have focused on the treatment of RILI, a common post-radiotherapy complication in patients with thoracic cancers [21–23]. In a clinical study on the characteristics and dosimetry of RIPF, 48 enrolled patients received 44–65 Gy irradiation, among whom 39 cases finally developed RIPF, with a dose-dependent manner [24]. RILI animal models have usually been successfully established using a dose of 15–20 Gy irradiation on whole chest or right chest [25–28]. For those studies involving higher-dose irradiation, Vujaskovic et al. utilized 28 Gy irradiation on right hemithorax, and diffuse interstitial fibrosis was observed in the irradiated lung tissue after 6 months of irradiation [29]. Kwock et al. adopted an acute (30 Gy) or fractionated (5 × 6 Gy) dose to one hemithorax of rats, and pulmonary vascular injury was observed after 4–6 weeks of irradiation [30]. In this study, a higher-dose (30 Gy) irradiation was given to the right chest of SD rats to induce RILI. The results showed that the RILI rat model could be successfully established using a higher-dose irradiation. Given that patients often receive higher-dose irradiation, the RILI rat model established by higher-dose irradiation in our study is of great clinical significance.

Homing of ASCs to the injured lung tissues is crucial for RILI repairment. Based on real-time PCR, Ortiz et al. reported that ASCs injected via tail vein could home to the injured lung tissue through the circulation [31]. Through bioluminescence imaging and real-time PCR, Baer et al. found that Atm-deficient mice still showed a strong bioluminescence signal on Day 9 after injection, and the bioluminescence signal was decreased to undetectable level on Day 14. Interestingly, based on real-time PCR, a positive Luc signal in the lung parenchyma still could be detected on Day 50 after injection of ASCs isolated from luciferase transgenic mice (mASCs), which indicated that ASCs could reside in the injured lung tissue for a long time and participate in injury repairment [32]. Jiang et al. reported that the level of ASCs in the RILI lung tissues reached a peak after 72 h of injection by in vivo optical imaging technology and observation of frozen sections. However, ASCs could not be detected on Day 14 after injection [25]. In this study, we explored the homing of ASCs by tail vein injection of CM-Dil-labeled ASCs. The results showed that CM-Dil-labeled ASCs were densely distributed in lung tissues on Days 3–7 after injection in Radiation + ASCs group. Only a spot of CM-DiL-labeled ASCs were observed on Day 14. On Days 30, 90, and 180, no CM-DiL-labeled ASCs were observed. Consistently, our findings suggested that ASCs could home to injured lung tissues, which indicated that CM-Dil tracking was a pivotal tool for observing homing of ASCs in injured lung tissues.

The pathogenesis of RILI is complex, involving multiple factors and cells. Cytokines are highly related to the onset of RILI. Various cytokines regulate the pathogenesis and progression of RILI by forming a cytokine network through autocrine, paracrine, and mutual interaction [33,34]. Among them, TGF-β1 was a representative of pro-inflammatory cytokine and chemokine for radiation-induced injury [35,36]. In the presence of irradiation exposure, TGF-β1 generated by immune cells, alveolar cells, and fibroblasts could regulate fibroblast proliferation in lung tissue via the activation of multiple signaling cascades mediated by the Smad protein family [37–39]. It has been reported that fibroblasts could express Collal and FN, with the capacity to differentiate into myofibrillar cells, while the extra-cellular expression of Collal and FN could lead to alveolar sclerosis and decrease of pulmonary function [40]. TGF-β1/Smad 3 signaling pathway could participate in pulmonary fibrosis of RILI by the expression of Collal and FN [41,42]. In a previous study on stem cell therapy for RILI, irradiation to the whole chest led to pulmonary fibrosis in mice, manifested as up-regulation of TGF-β1, which were effectively reversed by ASCs transplantation [43]. In addition, Hao et al. [44] transplanted human umbilical cord mesenchymal stem cells (UC-MSCs) to beagle dogs with localized irradiation to the right lower lung, which showed that UC-MSCs could alleviate RILI in the chronic phase about 180 days after transplantation. Moreover, Jiang et al. reported that ASCs could reduce the significant up-regulation of TGF-β1 and Collal, and alleviate RILI in rats received 15 Gy irradiation to the right lung on Day 28 [25]. Our results showed that on Day 180, the alveolar wall was incomplete and obviously thickened after irradiation with the presence of obvious fibroplasia in Radiation + PBS group; however, these conditions were significantly attenuated in Radiation + ASCs group. In our study, the levels of fibrosis markers FN and Collal protein in Radiation + ASCs group were significantly lower than those in Radiation + PBS group on Day 180 after the ASCs transplantation, indicating that ASCs could inhibit fibroplasia and alleviate RILI. Furthermore, the levels of TGF-β1 and p-Smad 3 protein in Radiation + ASCs group were significantly lower than that in Radiation + PBS group on Day 180 after the transplantation of ASCs. Therefore, the mechanism by which ASCs attenuated RILI may be inhibition of the activation of the TGF-β1/Smad 3 signaling pathway.

This study has some limitations. First, the sample size is small; therefore, the conclusion still needs to be confirmed by studies with large sample size. Besides, RILI is a complex process involving different signaling pathways at different stages [45]. Except for TGF-β1/Smad 3 signaling pathway, whether ASCS can act on other signaling pathways to repair RILI was not revealed in this study. In our next work, we will explore other possible signaling pathways and molecular mechanism of ASCs in the process of repairing RILI through in vivo and in vitro experiments based on a large sample size. We look forward to providing more theoretical basis for the clinical treatment of RILI.

5 Conclusion

In summary, ASCs could inhibit fibroplasia and attenuate chronic lung injury induced by irradiation. Inhibiting TGF-β1/Smad 3 signaling pathway was considered to involve in the attenuation of RILI by ASCs. In the future, ASCs transplantation may be a clinical effective strategy for the treatment of chronic lung injury induced by irradiation.

# These authors contributed equally to this work and should be considered co-first authors.

tel: +86-519-81086239

  1. Funding information: This study was supported by Major Scientific Research Project of Changzhou Health Commission (No. ZD202022; granted to Xin-chu Ni), Young Talent Development Plan of Changzhou Health Commission (No. CZQM2020066; granted to Wei Sun), Changzhou Sci & Tech Program (No. CJ20200102; granted to Wei Sun), and Jiangsu Provincial Medical Key Discipline Cultivation Unit of Oncology Therapeutics (Radiotherapy) (No. JSDW202237; granted to Xin-ye Ni).

  2. Author contributions: Xin-chu Ni and Xin-ye Ni made conception and design. Xin Huang and Wei Sun did the experiment and paper writing. Fei Jing and Xiao-li Zhou collected the data. Bin Nie and Juan-juan Li performed data analysis and interpretation. Xin-chu Ni performed revision of the paper.

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

  4. Data availability statement: The data are available from the corresponding author upon appropriate request.

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Received: 2023-06-29
Revised: 2023-10-17
Accepted: 2023-10-23
Published Online: 2023-11-09

© 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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  94. Unfolded protein response inhibits KAT2B/MLKL-mediated necroptosis of hepatocytes by promoting BMI1 level to ubiquitinate KAT2B
  95. Bladder cancer screening: The new selection and prediction model
  96. circNFATC3 facilitated the progression of oral squamous cell carcinoma via the miR-520h/LDHA axis
  97. Prone position effect in intensive care patients with SARS-COV-2 pneumonia
  98. Clinical observation on the efficacy of Tongdu Tuina manipulation in the treatment of primary enuresis in children
  99. Dihydroartemisinin ameliorates cerebral I/R injury in rats via regulating VWF and autophagy-mediated SIRT1/FOXO1 pathway
  100. Knockdown of circ_0113656 assuages oxidized low-density lipoprotein-induced vascular smooth muscle cell injury through the miR-188-3p/IGF2 pathway
  101. Low Ang-(1–7) and high des-Arg9 bradykinin serum levels are correlated with cardiovascular risk factors in patients with COVID-19
  102. Effect of maternal age and body mass index on induction of labor with oral misoprostol for premature rupture of membrane at term: A retrospective cross-sectional study
  103. Potential protective effects of Huanglian Jiedu Decoction against COVID-19-associated acute kidney injury: A network-based pharmacological and molecular docking study
  104. Clinical significance of serum MBD3 detection in girls with central precocious puberty
  105. Clinical features of varicella-zoster virus caused neurological diseases detected by metagenomic next-generation sequencing
  106. Collagen treatment of complex anorectal fistula: 3 years follow-up
  107. LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through down-regulating SP-A by sponging to miR-424
  108. Efficacy analysis of empirical bismuth quadruple therapy, high-dose dual therapy, and resistance gene-based triple therapy as a first-line Helicobacter pylori eradication regimen – An open-label, randomized trial
  109. SMOC2 plays a role in heart failure via regulating TGF-β1/Smad3 pathway-mediated autophagy
  110. A prospective cohort study of the impact of chronic disease on fall injuries in middle-aged and older adults
  111. circRNA THBS1 silencing inhibits the malignant biological behavior of cervical cancer cells via the regulation of miR-543/HMGB2 axis
  112. hsa_circ_0000285 sponging miR-582-3p promotes neuroblastoma progression by regulating the Wnt/β-catenin signaling pathway
  113. Long non-coding RNA GNAS-AS1 knockdown inhibits proliferation and epithelial–mesenchymal transition of lung adenocarcinoma cells via the microRNA-433-3p/Rab3A axis
  114. lncRNA UCA1 regulates miR-132/Lrrfip1 axis to promote vascular smooth muscle cell proliferation
  115. Twenty-four-color full spectrum flow cytometry panel for minimal residual disease detection in acute myeloid leukemia
  116. Hsa-miR-223-3p participates in the process of anthracycline-induced cardiomyocyte damage by regulating NFIA gene
  117. Anti-inflammatory effect of ApoE23 on Salmonella typhimurium-induced sepsis in mice
  118. Analysis of somatic mutations and key driving factors of cervical cancer progression
  119. Hsa_circ_0028007 regulates the progression of nasopharyngeal carcinoma through the miR-1179/SQLE axis
  120. Variations in sexual function after laparoendoscopic single-site hysterectomy in women with benign gynecologic diseases
  121. Effects of pharmacological delay with roxadustat on multi-territory perforator flap survival in rats
  122. Analysis of heroin effects on calcium channels in rat cardiomyocytes based on transcriptomics and metabolomics
  123. Risk factors of recurrent bacterial vaginosis among women of reproductive age: A cross-sectional study
  124. Alkbh5 plays indispensable roles in maintaining self-renewal of hematopoietic stem cells
  125. Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients
  126. Correlation between microvessel maturity and ISUP grades assessed using contrast-enhanced transrectal ultrasonography in prostate cancer
  127. The protective effect of caffeic acid phenethyl ester in the nephrotoxicity induced by α-cypermethrin
  128. Norepinephrine alleviates cyclosporin A-induced nephrotoxicity by enhancing the expression of SFRP1
  129. Effect of RUNX1/FOXP3 axis on apoptosis of T and B lymphocytes and immunosuppression in sepsis
  130. The function of Foxp1 represses β-adrenergic receptor transcription in the occurrence and development of bladder cancer through STAT3 activity
  131. Risk model and validation of carbapenem-resistant Klebsiella pneumoniae infection in patients with cerebrovascular disease in the ICU
  132. Calycosin protects against chronic prostatitis in rats via inhibition of the p38MAPK/NF-κB pathway
  133. Pan-cancer analysis of the PDE4DIP gene with potential prognostic and immunotherapeutic values in multiple cancers including acute myeloid leukemia
  134. The safety and immunogenicity to inactivated COVID-19 vaccine in patients with hyperlipemia
  135. Circ-UBR4 regulates the proliferation, migration, inflammation, and apoptosis in ox-LDL-induced vascular smooth muscle cells via miR-515-5p/IGF2 axis
  136. Clinical characteristics of current COVID-19 rehabilitation outpatients in China
  137. Luteolin alleviates ulcerative colitis in rats via regulating immune response, oxidative stress, and metabolic profiling
  138. miR-199a-5p inhibits aortic valve calcification by targeting ATF6 and GRP78 in valve interstitial cells
  139. The application of iliac fascia space block combined with esketamine intravenous general anesthesia in PFNA surgery of the elderly: A prospective, single-center, controlled trial
  140. Elevated blood acetoacetate levels reduce major adverse cardiac and cerebrovascular events risk in acute myocardial infarction
  141. The effects of progesterone on the healing of obstetric anal sphincter damage in female rats
  142. Identification of cuproptosis-related genes for predicting the development of prostate cancer
  143. Lumican silencing ameliorates β-glycerophosphate-mediated vascular smooth muscle cell calcification by attenuating the inhibition of APOB on KIF2C activity
  144. Targeting PTBP1 blocks glutamine metabolism to improve the cisplatin sensitivity of hepatocarcinoma cells through modulating the mRNA stability of glutaminase
  145. A single center prospective study: Influences of different hip flexion angles on the measurement of lumbar spine bone mineral density by dual energy X-ray absorptiometry
  146. Clinical analysis of AN69ST membrane continuous venous hemofiltration in the treatment of severe sepsis
  147. Antibiotics therapy combined with probiotics administered intravaginally for the treatment of bacterial vaginosis: A systematic review and meta-analysis
  148. Construction of a ceRNA network to reveal a vascular invasion associated prognostic model in hepatocellular carcinoma
  149. A pan-cancer analysis of STAT3 expression and genetic alterations in human tumors
  150. A prognostic signature based on seven T-cell-related cell clustering genes in bladder urothelial carcinoma
  151. Pepsin concentration in oral lavage fluid of rabbit reflux model constructed by dilating the lower esophageal sphincter
  152. The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC
  153. Tanshinone IIA attenuates valvular interstitial cells’ calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress
  154. AS-IV enhances the antitumor effects of propofol in NSCLC cells by inhibiting autophagy
  155. Establishment of two oxaliplatin-resistant gallbladder cancer cell lines and comprehensive analysis of dysregulated genes
  156. Trial protocol: Feasibility of neuromodulation with connectivity-guided intermittent theta-burst stimulation for improving cognition in multiple sclerosis
  157. LncRNA LINC00592 mediates the promoter methylation of WIF1 to promote the development of bladder cancer
  158. Factors associated with gastrointestinal dysmotility in critically ill patients
  159. Mechanisms by which spinal cord stimulation intervenes in atrial fibrillation: The involvement of the endothelin-1 and nerve growth factor/p75NTR pathways
  160. Analysis of two-gene signatures and related drugs in small-cell lung cancer by bioinformatics
  161. Silencing USP19 alleviates cigarette smoke extract-induced mitochondrial dysfunction in BEAS-2B cells by targeting FUNDC1
  162. Menstrual irregularities associated with COVID-19 vaccines among women in Saudi Arabia: A survey during 2022
  163. Ferroptosis involves in Schwann cell death in diabetic peripheral neuropathy
  164. The effect of AQP4 on tau protein aggregation in neurodegeneration and persistent neuroinflammation after cerebral microinfarcts
  165. Activation of UBEC2 by transcription factor MYBL2 affects DNA damage and promotes gastric cancer progression and cisplatin resistance
  166. Analysis of clinical characteristics in proximal and distal reflux monitoring among patients with gastroesophageal reflux disease
  167. Exosomal circ-0020887 and circ-0009590 as novel biomarkers for the diagnosis and prediction of short-term adverse cardiovascular outcomes in STEMI patients
  168. Upregulated microRNA-429 confers endometrial stromal cell dysfunction by targeting HIF1AN and regulating the HIF1A/VEGF pathway
  169. Bibliometrics and knowledge map analysis of ultrasound-guided regional anesthesia
  170. Knockdown of NUPR1 inhibits angiogenesis in lung cancer through IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways
  171. D-dimer trends predict COVID-19 patient’s prognosis: A retrospective chart review study
  172. WTAP affects intracranial aneurysm progression by regulating m6A methylation modification
  173. Using of endoscopic polypectomy in patients with diagnosed malignant colorectal polyp – The cross-sectional clinical study
  174. Anti-S100A4 antibody administration alleviates bronchial epithelial–mesenchymal transition in asthmatic mice
  175. Prognostic evaluation of system immune-inflammatory index and prognostic nutritional index in double expressor diffuse large B-cell lymphoma
  176. Prevalence and antibiogram of bacteria causing urinary tract infection among patients with chronic kidney disease
  177. Reactive oxygen species within the vaginal space: An additional promoter of cervical intraepithelial neoplasia and uterine cervical cancer development?
  178. Identification of disulfidptosis-related genes and immune infiltration in lower-grade glioma
  179. A new technique for uterine-preserving pelvic organ prolapse surgery: Laparoscopic rectus abdominis hysteropexy for uterine prolapse by comparing with traditional techniques
  180. Self-isolation of an Italian long-term care facility during COVID-19 pandemic: A comparison study on care-related infectious episodes
  181. A comparative study on the overlapping effects of clinically applicable therapeutic interventions in patients with central nervous system damage
  182. Low intensity extracorporeal shockwave therapy for chronic pelvic pain syndrome: Long-term follow-up
  183. The diagnostic accuracy of touch imprint cytology for sentinel lymph node metastases of breast cancer: An up-to-date meta-analysis of 4,073 patients
  184. Mortality associated with Sjögren’s syndrome in the United States in the 1999–2020 period: A multiple cause-of-death study
  185. CircMMP11 as a prognostic biomarker mediates miR-361-3p/HMGB1 axis to accelerate malignant progression of hepatocellular carcinoma
  186. Analysis of the clinical characteristics and prognosis of adult de novo acute myeloid leukemia (none APL) with PTPN11 mutations
  187. KMT2A maintains stemness of gastric cancer cells through regulating Wnt/β-catenin signaling-activated transcriptional factor KLF11
  188. Evaluation of placental oxygenation by near-infrared spectroscopy in relation to ultrasound maturation grade in physiological term pregnancies
  189. The role of ultrasonographic findings for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer
  190. Construction of immunogenic cell death-related molecular subtypes and prognostic signature in colorectal cancer
  191. Long-term prognostic value of high-sensitivity cardiac troponin-I in patients with idiopathic dilated cardiomyopathy
  192. Establishing a novel Fanconi anemia signaling pathway-associated prognostic model and tumor clustering for pediatric acute myeloid leukemia patients
  193. Integrative bioinformatics analysis reveals STAT2 as a novel biomarker of inflammation-related cardiac dysfunction in atrial fibrillation
  194. Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway
  195. Real-world practice of idiopathic pulmonary fibrosis: Results from a 2000–2016 cohort
  196. lncRNA LENGA sponges miR-378 to promote myocardial fibrosis in atrial fibrillation
  197. Diagnostic value of urinary Tamm-Horsfall protein and 24 h urine osmolality for recurrent calcium oxalate stones of the upper urinary tract: Cross-sectional study
  198. The value of color Doppler ultrasonography combined with serum tumor markers in differential diagnosis of gastric stromal tumor and gastric cancer
  199. The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A
  200. Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis
  201. MiR-1278 targets CALD1 and suppresses the progression of gastric cancer via the MAPK pathway
  202. Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson’s disease after dietary supplementation with branched-chain amino acids
  203. Cimifugin inhibits adipogenesis and TNF-α-induced insulin resistance in 3T3-L1 cells
  204. Predictors of gastrointestinal complaints in patients on metformin therapy
  205. Prescribing patterns in patients with chronic obstructive pulmonary disease and atrial fibrillation
  206. A retrospective analysis of the effect of latent tuberculosis infection on clinical pregnancy outcomes of in vitro fertilization–fresh embryo transferred in infertile women
  207. Appropriateness and clinical outcomes of short sustained low-efficiency dialysis: A national experience
  208. miR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD
  209. Clinical features and management of lymphoepithelial cyst
  210. Serum VEGF, high-sensitivity CRP, and cystatin-C assist in the diagnosis of type 2 diabetic retinopathy complicated with hyperuricemia
  211. ENPP1 ameliorates vascular calcification via inhibiting the osteogenic transformation of VSMCs and generating PPi
  212. Significance of monitoring the levels of thyroid hormone antibodies and glucose and lipid metabolism antibodies in patients suffer from type 2 diabetes
  213. The causal relationship between immune cells and different kidney diseases: A Mendelian randomization study
  214. Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units
  215. Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction
  216. Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway
  217. miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor
  218. Diagnostic and prognostic value of MR-pro ADM, procalcitonin, and copeptin in sepsis
  219. Review Articles
  220. Prenatal diagnosis of fetal defects and its implications on the delivery mode
  221. Electromagnetic fields exposure on fetal and childhood abnormalities: Systematic review and meta-analysis
  222. Characteristics of antibiotic resistance mechanisms and genes of Klebsiella pneumoniae
  223. Saddle pulmonary embolism in the setting of COVID-19 infection: A systematic review of case reports and case series
  224. Vitamin C and epigenetics: A short physiological overview
  225. Ebselen: A promising therapy protecting cardiomyocytes from excess iron in iron-overloaded thalassemia patients
  226. Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery
  227. Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review
  228. Surgical management and outcomes of traumatic global brachial plexus injury: A concise review and our center approach
  229. The progress of autoimmune hepatitis research and future challenges
  230. METTL16 in human diseases: What should we do next?
  231. New insights into the prevention of ureteral stents encrustation
  232. VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature
  233. Case Reports
  234. Mycobacterium xenopi infection of the kidney and lymph nodes: A case report
  235. Genetic mutation of SLC6A20 (c.1072T > C) in a family with nephrolithiasis: A case report
  236. Chronic hepatitis B complicated with secondary hemochromatosis was cured clinically: A case report
  237. Liver abscess complicated with multiple organ invasive infection caused by hematogenous disseminated hypervirulent Klebsiella pneumoniae: A case report
  238. Urokinase-based lock solutions for catheter salvage: A case of an upcoming kidney transplant recipient
  239. Two case reports of maturity-onset diabetes of the young type 3 caused by the hepatocyte nuclear factor 1α gene mutation
  240. Immune checkpoint inhibitor-related pancreatitis: What is known and what is not
  241. Does total hip arthroplasty result in intercostal nerve injury? A case report and literature review
  242. Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review
  243. Synchronous triple primary gastrointestinal malignant tumors treated with laparoscopic surgery: A case report
  244. CT-guided percutaneous microwave ablation combined with bone cement injection for the treatment of transverse metastases: A case report
  245. Malignant hyperthermia: Report on a successful rescue of a case with the highest temperature of 44.2°C
  246. Anesthetic management of fetal pulmonary valvuloplasty: A case report
  247. Rapid Communication
  248. Impact of COVID-19 lockdown on glycemic levels during pregnancy: A retrospective analysis
  249. Erratum
  250. Erratum to “Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway”
  251. Erratum to: “Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p”
  252. Retraction
  253. Retraction of “Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients”
  254. Retraction of “circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis”
  255. Retraction of “miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells”
  256. Retraction of “SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis”
  257. Retraction of “circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury”
  258. Retraction of “lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells”
  259. Special issue Linking Pathobiological Mechanisms to Clinical Application for cardiovascular diseases
  260. Effect of cardiac rehabilitation therapy on depressed patients with cardiac insufficiency after cardiac surgery
  261. Special issue The evolving saga of RNAs from bench to bedside - Part I
  262. FBLIM1 mRNA is a novel prognostic biomarker and is associated with immune infiltrates in glioma
  263. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part III
  264. Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer
https://doi.org/10.1515/med-2023-0850
Keywords for this article
adipose-derived stem cells; radiation-induced lung injury; fibroplasia; TGF-β1/Smad 3 signaling pathway
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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