Startseite Sarcoma protein kinase inhibition alleviates liver fibrosis by promoting hepatic stellate cells ferroptosis
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Sarcoma protein kinase inhibition alleviates liver fibrosis by promoting hepatic stellate cells ferroptosis

  • Zhengyuan Cheng EMAIL logo , Xiaojuan Zhang , Pingsheng Chen , Haitao Wang , Kuangjing Wang und Yingzhou Shen EMAIL logo
Veröffentlicht/Copyright: 6. Dezember 2023
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Aus der Zeitschrift Open Life Sciences Band 18 Heft 1

Abstract

Liver fibrosis is a type of chronic pathological liver damage involving liver tissue hypoxia and abnormal extracellular matrix deposits. Hepatic stellate cells (HSCs) activation is critical for liver fibrosis. Currently, inhibiting HSCs activation or inducing HSCs ferroptosis is considered an effective strategy for the treatment of liver fibrosis. Sarcoma protein kinase (Src) is an important member of the tyrosine protein kinase family. Hypoxia causes Src phosphorylation at tyrosine 416 (Tyr 416), and inhibiting Src activation can alleviate liver fibrosis. There is currently little research on the relationship between Src activation and ferroptosis in liver fibrosis. 1-(1,1-Dimethylethyl)-1-(4-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (PP1) is an inhibitor of Src activation at Tyr 416. Therefore, in this study we treated HSC-T6 cells with PP1 under normoxic and hypoxic culture conditions; moreover, PP1 was also used to treat a carbon tetrachloride-induced mouse liver fibrosis model. We explored whether inhibiting Src activation could alleviate liver fibrosis by promoting HSCs ferroptosis in vitro and in vivo. In vitro experiments showed that inhibiting Src activation in HSC-T6 cells significantly reduced hypoxia-inducible factor-1α (HIF-1α) expression and HSC-T6 cells activation, and ferroptosis was significantly increased. In vivo experiments revealed that inhibiting Src activation in fibrotic livers reduced HIF-1α expression; meanwhile, ferroptosis was promoted, and liver fibrosis was alleviated. Therefore, inhibiting Src activation, which increases HSCs ferroptosis, can alleviate liver fibrosis.

Keywords: liver fibrosis; hypoxia; hepatic stellate cells; sarcoma protein kinase; ferroptosis

1 Introduction

Liver fibrosis is the common developmental stage of many chronic liver diseases. If the liver tissue continues to be damaged, fibrosis will develop into cirrhosis, which leads to liver failure [1]. Numerous studies have confirmed that hepatic stellate cells (HSCs) activation is critical for the development of liver fibrosis. Normally, HSCs are in a quiescent state, and when the liver is continuously damaged, HSCs can be activated to form myofibroblasts (MFs), which is accompanied by high expression of α-smooth muscle actin (α-SMA), Vimentin, and connective tissue growth factor (CTGF) [2–4]. Activated HSCs can synthesize excessive levels of extracellular matrix (ECM), which is critical to the occurrence of liver fibrosis [5]. Ferroptosis is a newly identified iron-dependent form of programmed cell death that results from the accumulation of lipid peroxides. Kong et al. found that artesunate could inhibit the development of liver fibrosis by inducing ferroptosis in activated HSCs [6]. Another study has shown that the upregulation of heme-oxygenase-1 can induce ferroptosis in activated HSCs, thereby inhibiting liver fibrosis [7]. Thus, inducing ferroptosis in activated HSCs is an important strategy to treat liver fibrosis.

During liver fibrosis, hypoxic damage occurs in liver tissue, and hypoxia-inducible factor-1α (HIF-1α) is critical in hypoxic damage, which has been confirmed by many studies [8,9]. Furthermore, HIF-1α is an important factor in activating HSCs and promoting ECM production [10]. Sarcoma protein kinase (Src) is an important member of the tyrosine protein kinase family. Hypoxia can cause the phosphorylation of Src at tyrosine 416 (Tyr 416) [phospho-Src (Tyr 416)]. Phospho-Src (Tyr 416) can regulate a variety of signaling pathways, such as [11–13] HIF-1α, transforming growth factor (TGF-β)/Smad, and signal transducer and activator of transcription 3, and the activation of these pathways can promote the occurrence of fibrosis. Cheng et al. found that in the fibrotic renal tissues of rats, HIF-1α expression was significantly increased, and Src was activated at Tyr 416, which promoted the progression of renal fibrosis [13]. 1-(1,1-Dimethylethyl)-1-(4-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (PP1) is a small molecular compound that can inhibit the phosphorylation of Src at Tyr 416 and thus can play a therapeutic role in a variety of diseases, such as renal fibrosis, ischemic stroke, and pulmonary arterial hypertension [11,14,15]. In renal fibrosis, when PP1 is used to inhibit Src activation, it can reduce HIF-1α expression, which is one of the important mechanisms to alleviate renal fibrosis [13]. HIF-1α can promote HSCs activation; therefore, reducing HIF-1α expression in liver fibrosis plays an important role in alleviating liver fibrosis [16]. Unfortunately, there has been little research on whether inhibiting Src activation can also reduce HIF-1α expression in liver fibrosis. More importantly, it has been confirmed that promoting activated HSCs ferroptosis can alleviate liver fibrosis, but it is still unclear whether inhibiting Src activation at Tyr416 can regulate activated HSCs ferroptosis.

Therefore, in this study, the HSC-T6 cell line and a carbon tetrachloride (CCl4)-induced mouse liver fibrosis model was used to examine whether inhibiting Src activation could promote ferroptosis in HSCs, and whether liver fibrosis could be alleviated through this process. The results showed that inhibiting Src activation, which increased HSCs ferroptosis, could alleviate liver fibrosis. And these findings will provide new ideas for the treatment of liver fibrosis.

2 Materials and methods

2.1 Cell culture and cell counting kit-8 (CCK-8) cytotoxicity analysis

HSC-T6 cells were purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences and cultured in high-glucose DMEM (Servicebio, Wuhan, China) with 10% fetal bovine serum (Tianhang, Zhejiang, China) at 37°C in a 5% CO2 incubator (Thermo, Waltham, USA). The CCK-8 cytotoxicity assay (Apexbio, Houston, USA) was used to determine the treatment time and dose of PP1 (Apexbio). PP1 was dissolved in dimethyl-sulfoxide (DMSO, Beyotime, Shanghai, China). Under hypoxic conditions, different concentrations of PP1 (0, 5, 10, 15, 20, and 25 μM) were administered to HSC-T6 cells, which were divided into six groups of 5 × 103 cells/well in 96-well plates (NEST Biotechnology, Wuxi, China) with 100 µL of culture medium in each well. A hypoxic incubator (Thermo) was used to achieve a hypoxic environment (94% N2/5% CO2/1% O2).

After 24, 48, and 72 h, the optical density at 450 nm was measured by a microplate reader (Biotek, Winooski, USA). After the treatment dose (10 μM) and time (24 h) were determined, the cells were divided into four groups and cultured under different conditions. In the normoxia group, the cells were cultured in normoxic conditions without any treatment; in the hypoxia group, the cells were cultured in hypoxic conditions without any treatment; in the hypoxia + DMSO group, the cells were cultured in hypoxic conditions with DMSO; and in the hypoxia + PP1 group, the cells were cultured in hypoxic conditions with PP1.

2.2 Immunofluorescence analysis

The four groups of cells were cultured in 24-well plates, fixed with 4% paraformaldehyde and then washed with PBS. Then, the cells were incubated with primary antibodies against α-SMA (1:200, Proteintech, Rosemont, USA), Vimentin (1:200, Proteintech), and Collagen-I (1:200, Affinity Biosciences, Cincinnati, USA) overnight at 4°C. The next day, the cells were incubated with a Coralite-594-conjugated secondary antibody (1:400, Proteintech) at 37°C for 1 h. 4′,6-Diamidino-2-phenylindole (Servicebio) was used to stain the nuclei. Fluorescence microscopy (Olympus, Tokyo, Japan) was used to observe the results. The results were analyzed by ImageJ.

2.3 Animal model

Male institute of cancer research mice (ICR mice, 8 weeks old) were purchased from Qinglongshan Biotechnology Company (Nanjing, China) and housed in an air-, temperature-, and light-controlled facility. The mice were divided into two groups. One group was untreated and served as a blank control (control group, n = 15). The other group was the model group (n = 45), and a liver fibrosis model was constructed by intraperitoneal injections of CCl4 (Titan, Shanghai, China) as follows: a 20% CCl4 olive oil solution was administered at a dose of 5 mg/kg twice per week for 8 weeks. There were a total of nine deaths in the model group during the experimental period.

The control group did not change after 8 weeks. The model group was divided into three new groups (n = 12/group): one group was untreated (CCl4 group), one group was intraperitoneally injected with DMSO for 1 week (CCl4 + DMSO group, DMSO 1.6 ml/kg), and one group was intraperitoneally injected with DMSO containing PP1 for 1 week (CCl4 + PP1 group, PP1 5 mg/kg). No mice died during the experimental period. The mice were sacrificed after 1 week, body weight was recorded before sacrifice, and the livers were collected and weighed. The liver weight/body weight ratio was calculated, and the liver tissues were retained for further analysis.

  1. Ethical approval: The research related to animal use has been complied with all the relevant national regulations and institutional policies for the care and use of animals, and was approved by animal ethics committee of Jinling Hospital affiliated to Nanjing university (No. 2019JLHGKJDWLS-161).

2.4 Histopathology

Mouse liver tissue was fixed with 10% formalin for 24 h, embedded in low-temperature paraffin, and cut into 3 μm-thick slices. Then, hematoxylin–eosin (HE) staining and Masson staining were used to examine the pathological changes in liver tissues. The fibrosis score of each group was calculated by the Scheuer scoring system [17].

2.5 Immunohistochemistry

First, the specimens were incubated with anti-α-SMA (1:200, Abcam, Cambridge, UK) and anti-Vimentin (1:2,500, Proteintech) primary antibodies at 4°C overnight, and each slide contained a negative control. Next, a one-step polymer detection kit (Maixin, Fuzhou, China) was used to visualize the results. Finally, the results were observed and evaluated.

2.6 Western blotting

HSC-T6 cells and fresh mouse liver tissues were collected and lysed to extract the proteins. The protein concentration was measured by a bicinchoninic acid protein assay kit (Beyotime). The protein levels of HIF-1α, Src, p-Src (Tyr416), CTGF, Collagen-I, SLC7A11, GPX4, P-53, β-actin, GAPDH, and HSP90 were measured by western blotting. Rabbit anti-HIF-1α (1:1,000, Abcam), rabbit anti-Collagen-I, CTGF (1:1,000, Affinity Biosciences), rabbit anti-Src, SLC7A11 (1:1,000, Proteintech), rabbit anti-P-53, HSP90 (1:5,000, Proteintech), rabbit anti-p-Src (Tyr416) (1:1,000, CST, Danvers, USA), rabbit anti-β-actin, GAPDH (1:2,000, Servicebio), and mouse anti-GPX4 (1:1,000, Proteintech) primary antibodies were used. Horseradish peroxidase-linked goat anti-rabbit (1:3,000, Servicebio) and goat anti-mouse (1:3,000, Servicebio) secondary antibodies were used. An enhanced chemiluminescence (ACE Biotechnology, Nanjing, China) imaging method was used to visualize the protein bands, and the results were analyzed by ImageJ software (Version 1.53, NIH, Bethesda, USA).

2.7 Ferroptosis detection in vitro and in vivo

2.7.1 Reactive oxygen species (ROS) detection

The levels of ROS in cells were measured with a ROS detection kit (Beyotime). HSC-T6 cells were inoculated and treated in 24-well plates according to the conditions described in Section 2.1, washed with PBS, and then cultured in medium containing 10 μM 2,7-dichlorodi-hydrofluorescein diacetate for 30 min. The cells were observed with a fluorescence microscope (Olympus), and the results were analyzed with ImageJ.

2.7.2 Reduced glutathione (GSH), malondialdehyde (MDA), and Fe2+ analysis

A GSH test kit (Boxbio, Beijing, China), MDA test kit (Beyotime), cell Fe2+ test kit (Elabscience, Wuhan, China), and animal tissue Fe2+ test kit (Elabscience) were used to determine the levels of corresponding substances in the four groups of cells and four groups of liver tissues. The specific steps were performed according to the instructions.

2.7.3 Mitochondrial observations

HSC-T6 cells were cultured as described in Section 2.1 and then fixed, dehydrated, soaked, embedded, and stained with lead citrate. Mouse liver tissues were sliced, fixed, dehydrated, soaked, embedded, and stained with lead citrate. Finally, images were obtained using transmission electron microscopy (TEM, Hitachi TEM system, Tokyo, Japan).

2.7.4 Western blotting

The protein levels of SLC7A11, P-53, and GPX4 were measured by western blotting as described in Section 2.6.

2.8 Statistical analysis

The data are expressed as the mean ± standard deviation for each group. Intergroup comparisons were made using one-way analysis of variance, and the differences between two groups were determined by Student’s t test (Graphpad prism v8.0, San Diego, USA). Statistically significant differences between different groups are marked in each graph. A value of P < 0.05 was considered significant. All experiments were repeated three times.

3 Results

3.1 Effect of inhibiting Src activation on HIF-1α expression and HSC-T6 cells activation

3.1.1 CCK-8 cytotoxicity assay

After 24 h of hypoxic culture, cytotoxicity was observed in HSC-T6 cells that were treated with 10, 15, 20, and 25 μM PP1. After 48 and 72 h, cytotoxicity was observed in HSC-T6 cells that were treated with 5, 10, 15, 20, and 25 μM PP1 (Figure 1a).

Figure 1 CCK-8 assay results and protein levels of HIF-1α, p-Src, and Src in the different groups. (a) CCK-8 OD450 results. *P < 0.05 compared with 0 μM. (b and c) Protein levels of HIF-1α, p-Src (Tyr 416), and Src. (d–f) Relative expression of HIF-1α, p-Src (Tyr 416), and Src. *P < 0.05 compared with the other groups.
Figure 1

CCK-8 assay results and protein levels of HIF-1α, p-Src, and Src in the different groups. (a) CCK-8 OD450 results. *P < 0.05 compared with 0 μM. (b and c) Protein levels of HIF-1α, p-Src (Tyr 416), and Src. (d–f) Relative expression of HIF-1α, p-Src (Tyr 416), and Src. *P < 0.05 compared with the other groups.

3.1.2 Protein levels of HIF-1α, p-Src (Tyr 416), and Src in HSC-T6 cells

Western blotting showed that the protein levels of HIF-1α and p-Src (Tyr416) were significantly lower in the normoxia group and hypoxia + PP1 group than in the hypoxia group and hypoxia + DMSO group (Figure 1b–e). No obvious change was observed in the protein level of Src among the four groups (Figure 1c and f).

3.1.3 Inhibiting Src activation can reduce HSC-T6 cells activation

The immunofluorescence results showed that the expression levels of the activation indicators α-SMA, Vimentin, and Collagen-I in HSC-T6 cells were significantly lower in the normoxia group and hypoxia + PP1 group than in the hypoxia group and hypoxia + DMSO group (Figure 2a–f). Western blotting suggested that the protein level of CTGF was significantly lower in the normoxia group and hypoxia + PP1 group than in the hypoxia group and hypoxia + DMSO group (Figure 2g and h).

Figure 2 Expression of activation-related markers in HSC-T6 cells under different culture conditions. (a) α-SMA expression. (b) Vimentin expression. (c) Collagen-I expression. (d–f) Relative expression of α-SMA, Vimentin, and Collagen-I in each group, *P < 0.05. (g) Protein levels of CTGF. (h) Relative expression of CTGF in each group, *P < 0.05.
Figure 2

Expression of activation-related markers in HSC-T6 cells under different culture conditions. (a) α-SMA expression. (b) Vimentin expression. (c) Collagen-I expression. (d–f) Relative expression of α-SMA, Vimentin, and Collagen-I in each group, *P < 0.05. (g) Protein levels of CTGF. (h) Relative expression of CTGF in each group, *P < 0.05.

3.2 Inhibiting Src activation can promote ferroptosis in HSC-T6 cells

Western blotting showed that the protein levels of the ferroptosis genes SLC7A11 and GPX4 in HSC-T6 cells were significantly decreased in the hypoxia, hypoxia + DMSO, and hypoxia + PP1 groups compared with the normoxia group, and the expression levels of these two proteins were lowest in the hypoxia + PP1 group (Figure 3a, c, d, and f). However, the protein levels of the ferroptosis gene P-53 in HSC-T6 cells were significantly increased in the hypoxia, hypoxia + DMSO, and hypoxia + PP1 groups compared with the normoxia group, and the expression levels of this protein was highest in the hypoxia + PP1 group (Figure 3b and e). ROS analysis suggested significant ROS production in HSC-T6 cells in the hypoxia, hypoxia + DMSO, and hypoxia + PP1 groups compared to the normoxia group, and ROS levels in the hypoxia + PP1 group were the highest (Figure 3g and l). TEM indicated shrunken mitochondria in the hypoxia, hypoxia + DMSO, and hypoxia + PP1 groups, but in the normoxia group, mitochondrial morphology was normal (Figure 3h). GSH analysis suggested that GSH levels in the hypoxia, hypoxia + DMSO, and hypoxia + PP1 groups were lower than those in the normoxia group, and GSH levels in the hypoxia + PP1 group were the lowest (Figure 3i). However, compared with those in the normoxia group, the levels of MDA and Fe2+ in the hypoxia group, the hypoxia + DMSO group, and the hypoxia + PP1 group were increased and were highest in the hypoxia + PP1 group (Figure 3j and k).

Figure 3 Protein levels of SLC7A11, P-53, and GPX4; ROS levels; mitochondrial morphology; and the levels of GSH, MDA, and Fe2+ in the different groups. (a–c) Protein levels of SLC7A11, P-53, and GPX4. (d–f) Relative expression levels of SLC7A11, P-53, and GPX4, *P < 0.05. (g) ROS levels in the different groups. (h) Mitochondrial morphology in the different groups; arrows denote normal mitochondria (control group) and shrunken mitochondria (other groups). (i–k) GSH, MDA, and Fe2+ levels in the different groups, *P < 0.05. (l) Relative levels of ROS in each group, *P < 0.05.
Figure 3

Protein levels of SLC7A11, P-53, and GPX4; ROS levels; mitochondrial morphology; and the levels of GSH, MDA, and Fe2+ in the different groups. (a–c) Protein levels of SLC7A11, P-53, and GPX4. (d–f) Relative expression levels of SLC7A11, P-53, and GPX4, *P < 0.05. (g) ROS levels in the different groups. (h) Mitochondrial morphology in the different groups; arrows denote normal mitochondria (control group) and shrunken mitochondria (other groups). (i–k) GSH, MDA, and Fe2+ levels in the different groups, *P < 0.05. (l) Relative levels of ROS in each group, *P < 0.05.

The in vitro experiments showed that inhibiting Src activation not only inhibited the activation of HSC-T6 cells by reducing HIF-1α expression, but also promoted ferroptosis in HSC-T6 cells. Next, we performed in vivo experiments.

3.3 Therapeutic effects of inhibiting Src activation on liver fibrosis

The results showed that the liver surface in the control group was smooth and soft, and the liver weight/body weight ratio in this group was the lowest. In the CCl4 and CCl4 + DMSO groups, the liver surface was very rough, with obvious graininess, and the liver weight/body weight ratio was significantly increased (Figure 4a and c). In the CCl4 + PP1 group, the liver surface was slightly rough, graininess was significantly reduced, and the liver weight/body weight ratio was significantly lower than that in the CCl4 and CCl4 + DMSO groups (Figure 4a and c). HE and Masson staining showed that compared with the control group, the CCl4 and CCl4 + DMSO groups had severe cell edema, inflammatory cell infiltration, fibrous scarring, and collagen deposition, but these changes were significantly alleviated by PP1 treatment (Figure 4b and d). Subsequently, we measured the expression of the liver fibrosis markers Vimentin and α-SMA (Figure 4b). The results showed that Vimentin and α-SMA were not obviously expressed in the control group but were significantly expressed in the CCl4 and CCl4 + DMSO groups (Figure 4e and f). After PP1 treatment, these two markers were significantly reduced (Figure 4e and f). Therefore, PP1 can significantly reduce CCl4-induced liver fibrosis in mice.

Figure 4 Liver gross morphology, HE and Masson staining, immunostaining of Vimentin and α-SMA, the liver weight/body weight ratio, and fibrosis score in the different groups. (a) Liver gross morphology. (b) HE, Masson staining, and immunostaining of Vimentin and α-SMA. HE, arrows denote inflammatory cell infiltration and triangle symbol denotes hepatocyte edema; Masson, arrows denote collagen deposition; Vimentin, arrows denote Vimentin positivity; α-SMA, arrows denote α-SMA positivity. (c) Liver weight/body weight ratio, * P < 0.05. (d) Fibrosis score, * P < 0.05. (e) Vimentin-positive area, * P < 0.05. (f) α-SMA-positive area, * P < 0.05.
Figure 4

Liver gross morphology, HE and Masson staining, immunostaining of Vimentin and α-SMA, the liver weight/body weight ratio, and fibrosis score in the different groups. (a) Liver gross morphology. (b) HE, Masson staining, and immunostaining of Vimentin and α-SMA. HE, arrows denote inflammatory cell infiltration and triangle symbol denotes hepatocyte edema; Masson, arrows denote collagen deposition; Vimentin, arrows denote Vimentin positivity; α-SMA, arrows denote α-SMA positivity. (c) Liver weight/body weight ratio, * P < 0.05. (d) Fibrosis score, * P < 0.05. (e) Vimentin-positive area, * P < 0.05. (f) α-SMA-positive area, * P < 0.05.

3.4 Effects on Collagen-I, CTGF, and HIF-1α expression after inhibiting Src activation in fibrotic liver tissue

Western blotting showed that the protein expression levels of Collagen-I, CTGF, HIF-1α, and p-Src (Tyr416) were significantly lower in the control and CCl4 + PP1 groups than in the CCl4 and CCl4 + DMSO groups after inhibiting Src activation (Figure 5a–h). No obvious change was observed in the protein level of Src among the four groups (Figure 5d and i).

Figure 5 Protein levels of Collagen-I, CTGF, HIF-1α, p-Src, and Src in the different groups. (a–d) Protein levels of Collagen-I, CTGF, HIF-1α, p-Src, and Src. (e–i) Relative expression levels of Collagen-I, CTGF, HIF-1α, p-Src, and Src. *P < 0.05 compared with the other groups.
Figure 5

Protein levels of Collagen-I, CTGF, HIF-1α, p-Src, and Src in the different groups. (a–d) Protein levels of Collagen-I, CTGF, HIF-1α, p-Src, and Src. (e–i) Relative expression levels of Collagen-I, CTGF, HIF-1α, p-Src, and Src. *P < 0.05 compared with the other groups.

3.5 Inhibiting Src activation can induce ferroptosis in fibrotic livers

Western blotting showed that the protein levels of the ferroptosis-related genes SLC7A11 and GPX4 were significantly decreased in the CCl4, CCl4 + DMSO, and CCl4 + PP1 groups compared with the control group, and the expression levels of these two proteins were lowest in the CCl4 + PP1 group (Figure 6a, c, d, and f). However, the protein levels of the ferroptosis-related gene P-53 in HSC-T6 cells were significantly increased in the CCl4, CCl4 + DMSO, and CCl4 + PP1 groups compared with the control group, and the expression levels of this protein was highest in the CCl4 + PP1 group (Figure 6b and e). GSH levels in the CCl4, CCl4 + DMSO, and CCl4 + PP1 groups were lower than those in the control group, and GSH levels in the CCl4 + PP1 group were the lowest (Figure 6g); however, compared with those in the control group, the levels of MDA and Fe2+ in the CCl4, CCl4 + DMSO, and CCl4 + PP1 groups were increased and were highest in the CCl4 + PP1 group (Figure 6h and i). TEM indicated shrunken mitochondria in the CCl4, CCl4 + DMSO, and CCl4 + PP1 groups, but in the normoxia group, mitochondrial morphology was normal (Figure 6j).

Figure 6 Protein levels of SLC7A11, P-53, and GPX4; the levels of GSH, MDA, and Fe2+; and mitochondrial morphology in the different groups. (a–c) Protein levels of SLC7A11, P-53, and GPX4. (d–f) Relative expression levels of SLC7A11, P-53, and GPX4, *P < 0.05. (g–i) GSH, MDA, and Fe2+ levels in the different groups, *P < 0.05. (j) Mitochondrial morphology in the different groups. Arrows denote normal mitochondria (control group) and mitochondrial solidification (other groups).
Figure 6

Protein levels of SLC7A11, P-53, and GPX4; the levels of GSH, MDA, and Fe2+; and mitochondrial morphology in the different groups. (a–c) Protein levels of SLC7A11, P-53, and GPX4. (d–f) Relative expression levels of SLC7A11, P-53, and GPX4, *P < 0.05. (g–i) GSH, MDA, and Fe2+ levels in the different groups, *P < 0.05. (j) Mitochondrial morphology in the different groups. Arrows denote normal mitochondria (control group) and mitochondrial solidification (other groups).

The in vivo experiments showed that the inhibiting Src activation could promote ferroptosis and alleviate liver fibrosis.

4 Discussion

HSCs play an important role in liver fibrosis. After continuous liver injury, HSCs can differentiate into activated MFs, leading to massive, abnormal deposition of ECM components in the liver, resulting in the development of liver fibrosis. Current research suggests that inhibiting HSCs activation or inducing HSCs death are effective ways to prevent liver fibrosis [18]. Ferroptosis is a novel form of programmed cell death that can alleviate liver fibrosis [19].

Src is a member of the tyrosine protein kinase family that plays an important role in the development of renal fibrosis, pulmonary fibrosis, and liver fibrosis [11,20,21]. Hypoxia is an important factor that promotes the development of liver fibrosis and the key to hypoxic damage is HIF-1α. Furthermore, HIF-1α is also important for promoting HSCs activation. In this study, we found that inhibiting Src activation reduced HSCs activation by decreasing HIF-1α expression, and inhibiting HSCs activation is an important way to alleviate liver fibrosis [3,4]. Zou et al. showed that hypoxia promoted ferroptosis in clear cell carcinoma [22], and we found that hypoxia could promote HSCs ferroptosis; furthermore, we observed that ferroptosis in hypoxic liver fibrosis tissues was increased compared with that in normal liver tissues. It is thought that this phenomenon may be associated with increased ROS production by mitochondria under hypoxic condition, which directly promotes lipid peroxidation and thus exacerbates ferroptosis [23,24], but further research is still needed.

Another question is that since hypoxia can promote the occurrence of ferroptosis, and ferroptosis can alleviate liver fibrosis; so does it mean that hypoxia can alleviate liver fibrosis. The answer is no. Although hypoxia can induce ferroptosis in HSCs, the disadvantages of hypoxic damage to liver fibrosis are far greater than the benefits. In addition to promoting the HSCs activation, hypoxia can promote the death of normal liver cells and promote the activation of many pathways related to fibrosis [25,26]. These effects exacerbate liver fibrosis, which has been confirmed by many studies.

Bioinformatics analysis showed that Src and ferroptosis might be associated [27]; however, specific experimental studies are still rare. Huang et al. found that Src homology region 2 domain-containing phosphatase-1 (SHP-1) has a regulatory effect on ferroptosis in hepatocellular carcinoma [28]. In addition, Brown et al. found that in integrin α6β4-depleted human normal mammary epithelial cells (MCF-10A) and breast cancer cells (SUM-159), Src activation is significantly reduced, which promotes ferroptosis in these two types of cells [29]. Our study showed that in liver fibrosis, after Src activation was inhibited, the degree of ferroptosis in both HSCs and fibrotic liver tissue was significantly increased, which could promote the remission of liver fibrosis. This finding suggests that there is a close relationship between Src and ferroptosis, which supports the findings of the bioinformatics analysis [27]. In HSCs, inhibiting Src activation can promote ferroptosis, based on our experimental results, which is considered to be related to the HIF-1α/SLC7A11 pathway [5]. After inhibiting Src activation, HIF-1α expression is inhibited, and GSH synthesis and GPX4 expression can be reduced through the HIF-1α/SLC7A11 pathway, thus promoting ferroptosis in activated HSCs. When HSCs ferroptosis, inflammation in liver tissue is reduced, and the expression of fibrosis indicators, such as α-SMA, Vimentin, Collagen I, and CTGF are decreased; meanwhile, the production of ECM is also reduced. Thus promoting the alleviation of liver fibrosis. However, the specific way in which Src regulates ferroptosis remains unclear, and whether the regulatory effect of Src on ferroptosis in HSCs requires the participation of integrin α6β4 and SHP-1 still needs further study.

In summary, our findings indicate that inhibiting Src activation, which increases HSCs ferroptosis, is an important mechanism to alleviate liver fibrosis. These findings will provide new ideas for the therapy of liver fibrosis (Figure 7).

Figure 7 Inhibiting Src activation can induce HSCs ferroptosis and reduce HSCs activation. Ultimately, liver fibrosis can be alleviated.
Figure 7

Inhibiting Src activation can induce HSCs ferroptosis and reduce HSCs activation. Ultimately, liver fibrosis can be alleviated.

5 Conclusion

Liver cirrhosis is a global public health problem. Once liver cirrhosis develops, it is difficult to reverse, and liver fibrosis is considered a reversible pathological process in chronic liver disease that progresses to liver cirrhosis. Therefore, if appropriate therapeutic targets can be found, liver fibrosis may be reversed, which is critical for restoring liver function and improving the quality of life of patients. Src may be such a target, but further research is needed.

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  1. Funding information: This study was supported by the Natural Science Foundation of Jiangsu Province (BK20200272), Research Foundation of Anhui Medical University (2022xkj129), and Maanshan Medical and Health Science and Technology Plan Project (YL-2022-1).

  2. Author contributions: Zhengyuan Cheng, Xiaojuan Zhang, and Yingzhou Shen conceived the study, Pingsheng Chen and Haitao Wang drew the figures, Zhengyuan Cheng and Kuangjing Wang wrote the manuscript, Zhengyuan Cheng and Yingzhou Shen revised the manuscript. All authors have read and agreed to the published version of the manuscript.

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

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

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Received: 2023-07-31
Revised: 2023-10-21
Accepted: 2023-10-29
Published Online: 2023-12-06

© 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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  235. Clinical characteristics and the prognosis of diabetic foot in Tibet: A single center, retrospective study
  236. Agriculture
  237. Biofertilizer and NPSB fertilizer application effects on nodulation and productivity of common bean (Phaseolus vulgaris L.) at Sodo Zuria, Southern Ethiopia
  238. On correlation between canopy vegetation and growth indexes of maize varieties with different nitrogen efficiencies
  239. Exopolysaccharides from Pseudomonas tolaasii inhibit the growth of Pleurotus ostreatus mycelia
  240. A transcriptomic evaluation of the mechanism of programmed cell death of the replaceable bud in Chinese chestnut
  241. Melatonin enhances salt tolerance in sorghum by modulating photosynthetic performance, osmoregulation, antioxidant defense, and ion homeostasis
  242. Effects of plant density on alfalfa (Medicago sativa L.) seed yield in western Heilongjiang areas
  243. Identification of rice leaf diseases and deficiency disorders using a novel DeepBatch technique
  244. Artificial intelligence and internet of things oriented sustainable precision farming: Towards modern agriculture
  245. Animal Sciences
  246. Effect of ketogenic diet on exercise tolerance and transcriptome of gastrocnemius in mice
  247. Combined analysis of mRNA–miRNA from testis tissue in Tibetan sheep with different FecB genotypes
  248. Isolation, identification, and drug resistance of a partially isolated bacterium from the gill of Siniperca chuatsi
  249. Tracking behavioral changes of confined sows from the first mating to the third parity
  250. The sequencing of the key genes and end products in the TLR4 signaling pathway from the kidney of Rana dybowskii exposed to Aeromonas hydrophila
  251. Development of a new candidate vaccine against piglet diarrhea caused by Escherichia coli
  252. Plant Sciences
  253. Crown and diameter structure of pure Pinus massoniana Lamb. forest in Hunan province, China
  254. Genetic evaluation and germplasm identification analysis on ITS2, trnL-F, and psbA-trnH of alfalfa varieties germplasm resources
  255. Tissue culture and rapid propagation technology for Gentiana rhodantha
  256. Effects of cadmium on the synthesis of active ingredients in Salvia miltiorrhiza
  257. Cloning and expression analysis of VrNAC13 gene in mung bean
  258. Chlorate-induced molecular floral transition revealed by transcriptomes
  259. Effects of warming and drought on growth and development of soybean in Hailun region
  260. Effects of different light conditions on transient expression and biomass in Nicotiana benthamiana leaves
  261. Comparative analysis of the rhizosphere microbiome and medicinally active ingredients of Atractylodes lancea from different geographical origins
  262. Distinguish Dianthus species or varieties based on chloroplast genomes
  263. Comparative transcriptomes reveal molecular mechanisms of apple blossoms of different tolerance genotypes to chilling injury
  264. Study on fresh processing key technology and quality influence of Cut Ophiopogonis Radix based on multi-index evaluation
  265. An advanced approach for fig leaf disease detection and classification: Leveraging image processing and enhanced support vector machine methodology
  266. Erratum
  267. Erratum to “Protein Z modulates the metastasis of lung adenocarcinoma cells”
  268. Erratum to “BRCA1 subcellular localization regulated by PI3K signaling pathway in triple-negative breast cancer MDA-MB-231 cells and hormone-sensitive T47D cells”
  269. Retraction
  270. Retraction to “Protocatechuic acid attenuates cerebral aneurysm formation and progression by inhibiting TNF-alpha/Nrf-2/NF-kB-mediated inflammatory mechanisms in experimental rats”
https://doi.org/10.1515/biol-2022-0781
Schlagwörter für diesen Artikel
liver fibrosis; hypoxia; hepatic stellate cells; sarcoma protein kinase; ferroptosis
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Biomedical Sciences
  2. Systemic investigation of inetetamab in combination with small molecules to treat HER2-overexpressing breast and gastric cancers
  3. Immunosuppressive treatment for idiopathic membranous nephropathy: An updated network meta-analysis
  4. Identifying two pathogenic variants in a patient with pigmented paravenous retinochoroidal atrophy
  5. Effects of phytoestrogens combined with cold stress on sperm parameters and testicular proteomics in rats
  6. A case of pulmonary embolism with bad warfarin anticoagulant effects caused by E. coli infection
  7. Neutrophilia with subclinical Cushing’s disease: A case report and literature review
  8. Isoimperatorin alleviates lipopolysaccharide-induced periodontitis by downregulating ERK1/2 and NF-κB pathways
  9. Immunoregulation of synovial macrophages for the treatment of osteoarthritis
  10. Novel CPLANE1 c.8948dupT (p.P2984Tfs*7) variant in a child patient with Joubert syndrome
  11. Antiphospholipid antibodies and the risk of thrombosis in myeloproliferative neoplasms
  12. Immunological responses of septic rats to combination therapy with thymosin α1 and vitamin C
  13. High glucose and high lipid induced mitochondrial dysfunction in JEG-3 cells through oxidative stress
  14. Pharmacological inhibition of the ubiquitin-specific protease 8 effectively suppresses glioblastoma cell growth
  15. Levocarnitine regulates the growth of angiotensin II-induced myocardial fibrosis cells via TIMP-1
  16. Age-related changes in peripheral T-cell subpopulations in elderly individuals: An observational study
  17. Single-cell transcription analysis reveals the tumor origin and heterogeneity of human bilateral renal clear cell carcinoma
  18. Identification of iron metabolism-related genes as diagnostic signatures in sepsis by blood transcriptomic analysis
  19. Long noncoding RNA ACART knockdown decreases 3T3-L1 preadipocyte proliferation and differentiation
  20. Surgery, adjuvant immunotherapy plus chemotherapy and radiotherapy for primary malignant melanoma of the parotid gland (PGMM): A case report
  21. Dosimetry comparison with helical tomotherapy, volumetric modulated arc therapy, and intensity-modulated radiotherapy for grade II gliomas: A single‑institution case series
  22. Soy isoflavone reduces LPS-induced acute lung injury via increasing aquaporin 1 and aquaporin 5 in rats
  23. Refractory hypokalemia with sexual dysplasia and infertility caused by 17α-hydroxylase deficiency and triple X syndrome: A case report
  24. Meta-analysis of cancer risk among end stage renal disease undergoing maintenance dialysis
  25. 6-Phosphogluconate dehydrogenase inhibition arrests growth and induces apoptosis in gastric cancer via AMPK activation and oxidative stress
  26. Experimental study on the optimization of ANM33 release in foam cells
  27. Primary retroperitoneal angiosarcoma: A case report
  28. Metabolomic analysis-identified 2-hydroxybutyric acid might be a key metabolite of severe preeclampsia
  29. Malignant pleural effusion diagnosis and therapy
  30. Effect of spaceflight on the phenotype and proteome of Escherichia coli
  31. Comparison of immunotherapy combined with stereotactic radiotherapy and targeted therapy for patients with brain metastases: A systemic review and meta-analysis
  32. Activation of hypermethylated P2RY1 mitigates gastric cancer by promoting apoptosis and inhibiting proliferation
  33. Association between the VEGFR-2 -604T/C polymorphism (rs2071559) and type 2 diabetic retinopathy
  34. The role of IL-31 and IL-34 in the diagnosis and treatment of chronic periodontitis
  35. Triple-negative mouse breast cancer initiating cells show high expression of beta1 integrin and increased malignant features
  36. mNGS facilitates the accurate diagnosis and antibiotic treatment of suspicious critical CNS infection in real practice: A retrospective study
  37. The apatinib and pemetrexed combination has antitumor and antiangiogenic effects against NSCLC
  38. Radiotherapy for primary thyroid adenoid cystic carcinoma
  39. Design and functional preliminary investigation of recombinant antigen EgG1Y162–EgG1Y162 against Echinococcus granulosus
  40. Effects of losartan in patients with NAFLD: A meta-analysis of randomized controlled trial
  41. Bibliometric analysis of METTL3: Current perspectives, highlights, and trending topics
  42. Performance comparison of three scaling algorithms in NMR-based metabolomics analysis
  43. PI3K/AKT/mTOR pathway and its related molecules participate in PROK1 silence-induced anti-tumor effects on pancreatic cancer
  44. The altered expression of cytoskeletal and synaptic remodeling proteins during epilepsy
  45. Effects of pegylated recombinant human granulocyte colony-stimulating factor on lymphocytes and white blood cells of patients with malignant tumor
  46. Prostatitis as initial manifestation of Chlamydia psittaci pneumonia diagnosed by metagenome next-generation sequencing: A case report
  47. NUDT21 relieves sevoflurane-induced neurological damage in rats by down-regulating LIMK2
  48. Association of interleukin-10 rs1800896, rs1800872, and interleukin-6 rs1800795 polymorphisms with squamous cell carcinoma risk: A meta-analysis
  49. Exosomal HBV-DNA for diagnosis and treatment monitoring of chronic hepatitis B
  50. Shear stress leads to the dysfunction of endothelial cells through the Cav-1-mediated KLF2/eNOS/ERK signaling pathway under physiological conditions
  51. Interaction between the PI3K/AKT pathway and mitochondrial autophagy in macrophages and the leukocyte count in rats with LPS-induced pulmonary infection
  52. Meta-analysis of the rs231775 locus polymorphism in the CTLA-4 gene and the susceptibility to Graves’ disease in children
  53. Cloning, subcellular localization and expression of phosphate transporter gene HvPT6 of hulless barley
  54. Coptisine mitigates diabetic nephropathy via repressing the NRLP3 inflammasome
  55. Significant elevated CXCL14 and decreased IL-39 levels in patients with tuberculosis
  56. Whole-exome sequencing applications in prenatal diagnosis of fetal bowel dilatation
  57. Gemella morbillorum infective endocarditis: A case report and literature review
  58. An unusual ectopic thymoma clonal evolution analysis: A case report
  59. Severe cumulative skin toxicity during toripalimab combined with vemurafenib following toripalimab alone
  60. Detection of V. vulnificus septic shock with ARDS using mNGS
  61. Novel rare genetic variants of familial and sporadic pulmonary atresia identified by whole-exome sequencing
  62. The influence and mechanistic action of sperm DNA fragmentation index on the outcomes of assisted reproduction technology
  63. Novel compound heterozygous mutations in TELO2 in an infant with You-Hoover-Fong syndrome: A case report and literature review
  64. ctDNA as a prognostic biomarker in resectable CLM: Systematic review and meta-analysis
  65. Diagnosis of primary amoebic meningoencephalitis by metagenomic next-generation sequencing: A case report
  66. Phylogenetic analysis of promoter regions of human Dolichol kinase (DOLK) and orthologous genes using bioinformatics tools
  67. Collagen changes in rabbit conjunctiva after conjunctival crosslinking
  68. Effects of NM23 transfection of human gastric carcinoma cells in mice
  69. Oral nifedipine and phytosterol, intravenous nicardipine, and oral nifedipine only: Three-arm, retrospective, cohort study for management of severe preeclampsia
  70. Case report of hepatic retiform hemangioendothelioma: A rare tumor treated with ultrasound-guided microwave ablation
  71. Curcumin induces apoptosis in human hepatocellular carcinoma cells by decreasing the expression of STAT3/VEGF/HIF-1α signaling
  72. Rare presentation of double-clonal Waldenström macroglobulinemia with pulmonary embolism: A case report
  73. Giant duplication of the transverse colon in an adult: A case report and literature review
  74. Ectopic thyroid tissue in the breast: A case report
  75. SDR16C5 promotes proliferation and migration and inhibits apoptosis in pancreatic cancer
  76. Vaginal metastasis from breast cancer: A case report
  77. Screening of the best time window for MSC transplantation to treat acute myocardial infarction with SDF-1α antibody-loaded targeted ultrasonic microbubbles: An in vivo study in miniswine
  78. Inhibition of TAZ impairs the migration ability of melanoma cells
  79. Molecular complexity analysis of the diagnosis of Gitelman syndrome in China
  80. Effects of maternal calcium and protein intake on the development and bone metabolism of offspring mice
  81. Identification of winter wheat pests and diseases based on improved convolutional neural network
  82. Ultra-multiplex PCR technique to guide treatment of Aspergillus-infected aortic valve prostheses
  83. Virtual high-throughput screening: Potential inhibitors targeting aminopeptidase N (CD13) and PIKfyve for SARS-CoV-2
  84. Immune checkpoint inhibitors in cancer patients with COVID-19
  85. Utility of methylene blue mixed with autologous blood in preoperative localization of pulmonary nodules and masses
  86. Integrated analysis of the microbiome and transcriptome in stomach adenocarcinoma
  87. Berberine suppressed sarcopenia insulin resistance through SIRT1-mediated mitophagy
  88. DUSP2 inhibits the progression of lupus nephritis in mice by regulating the STAT3 pathway
  89. Lung abscess by Fusobacterium nucleatum and Streptococcus spp. co-infection by mNGS: A case series
  90. Genetic alterations of KRAS and TP53 in intrahepatic cholangiocarcinoma associated with poor prognosis
  91. Granulomatous polyangiitis involving the fourth ventricle: Report of a rare case and a literature review
  92. Studying infant mortality: A demographic analysis based on data mining models
  93. Metaplastic breast carcinoma with osseous differentiation: A report of a rare case and literature review
  94. Protein Z modulates the metastasis of lung adenocarcinoma cells
  95. Inhibition of pyroptosis and apoptosis by capsaicin protects against LPS-induced acute kidney injury through TRPV1/UCP2 axis in vitro
  96. TAK-242, a toll-like receptor 4 antagonist, against brain injury by alleviates autophagy and inflammation in rats
  97. Primary mediastinum Ewing’s sarcoma with pleural effusion: A case report and literature review
  98. Association of ADRB2 gene polymorphisms and intestinal microbiota in Chinese Han adolescents
  99. Tanshinone IIA alleviates chondrocyte apoptosis and extracellular matrix degeneration by inhibiting ferroptosis
  100. Study on the cytokines related to SARS-Cov-2 in testicular cells and the interaction network between cells based on scRNA-seq data
  101. Effect of periostin on bone metabolic and autophagy factors during tooth eruption in mice
  102. HP1 induces ferroptosis of renal tubular epithelial cells through NRF2 pathway in diabetic nephropathy
  103. Intravaginal estrogen management in postmenopausal patients with vaginal squamous intraepithelial lesions along with CO2 laser ablation: A retrospective study
  104. Hepatocellular carcinoma cell differentiation trajectory predicts immunotherapy, potential therapeutic drugs, and prognosis of patients
  105. Effects of physical exercise on biomarkers of oxidative stress in healthy subjects: A meta-analysis of randomized controlled trials
  106. Identification of lysosome-related genes in connection with prognosis and immune cell infiltration for drug candidates in head and neck cancer
  107. Development of an instrument-free and low-cost ELISA dot-blot test to detect antibodies against SARS-CoV-2
  108. Research progress on gas signal molecular therapy for Parkinson’s disease
  109. Adiponectin inhibits TGF-β1-induced skin fibroblast proliferation and phenotype transformation via the p38 MAPK signaling pathway
  110. The G protein-coupled receptor-related gene signatures for predicting prognosis and immunotherapy response in bladder urothelial carcinoma
  111. α-Fetoprotein contributes to the malignant biological properties of AFP-producing gastric cancer
  112. CXCL12/CXCR4/CXCR7 axis in placenta tissues of patients with placenta previa
  113. Association between thyroid stimulating hormone levels and papillary thyroid cancer risk: A meta-analysis
  114. Significance of sTREM-1 and sST2 combined diagnosis for sepsis detection and prognosis prediction
  115. Diagnostic value of serum neuroactive substances in the acute exacerbation of chronic obstructive pulmonary disease complicated with depression
  116. Research progress of AMP-activated protein kinase and cardiac aging
  117. TRIM29 knockdown prevented the colon cancer progression through decreasing the ubiquitination levels of KRT5
  118. Cross-talk between gut microbiota and liver steatosis: Complications and therapeutic target
  119. Metastasis from small cell lung cancer to ovary: A case report
  120. The early diagnosis and pathogenic mechanisms of sepsis-related acute kidney injury
  121. The effect of NK cell therapy on sepsis secondary to lung cancer: A case report
  122. Erianin alleviates collagen-induced arthritis in mice by inhibiting Th17 cell differentiation
  123. Loss of ACOX1 in clear cell renal cell carcinoma and its correlation with clinical features
  124. Signalling pathways in the osteogenic differentiation of periodontal ligament stem cells
  125. Crosstalk between lactic acid and immune regulation and its value in the diagnosis and treatment of liver failure
  126. Clinicopathological features and differential diagnosis of gastric pleomorphic giant cell carcinoma
  127. Traumatic brain injury and rTMS-ERPs: Case report and literature review
  128. Extracellular fibrin promotes non-small cell lung cancer progression through integrin β1/PTEN/AKT signaling
  129. Knockdown of DLK4 inhibits non-small cell lung cancer tumor growth by downregulating CKS2
  130. The co-expression pattern of VEGFR-2 with indicators related to proliferation, apoptosis, and differentiation of anagen hair follicles
  131. Inflammation-related signaling pathways in tendinopathy
  132. CD4+ T cell count in HIV/TB co-infection and co-occurrence with HL: Case report and literature review
  133. Clinical analysis of severe Chlamydia psittaci pneumonia: Case series study
  134. Bioinformatics analysis to identify potential biomarkers for the pulmonary artery hypertension associated with the basement membrane
  135. Influence of MTHFR polymorphism, alone or in combination with smoking and alcohol consumption, on cancer susceptibility
  136. Catharanthus roseus (L.) G. Don counteracts the ampicillin resistance in multiple antibiotic-resistant Staphylococcus aureus by downregulation of PBP2a synthesis
  137. Combination of a bronchogenic cyst in the thoracic spinal canal with chronic myelocytic leukemia
  138. Bacterial lipoprotein plays an important role in the macrophage autophagy and apoptosis induced by Salmonella typhimurium and Staphylococcus aureus
  139. TCL1A+ B cells predict prognosis in triple-negative breast cancer through integrative analysis of single-cell and bulk transcriptomic data
  140. Ezrin promotes esophageal squamous cell carcinoma progression via the Hippo signaling pathway
  141. Ferroptosis: A potential target of macrophages in plaque vulnerability
  142. Predicting pediatric Crohn's disease based on six mRNA-constructed risk signature using comprehensive bioinformatic approaches
  143. Applications of genetic code expansion and photosensitive UAAs in studying membrane proteins
  144. HK2 contributes to the proliferation, migration, and invasion of diffuse large B-cell lymphoma cells by enhancing the ERK1/2 signaling pathway
  145. IL-17 in osteoarthritis: A narrative review
  146. Circadian cycle and neuroinflammation
  147. Probiotic management and inflammatory factors as a novel treatment in cirrhosis: A systematic review and meta-analysis
  148. Hemorrhagic meningioma with pulmonary metastasis: Case report and literature review
  149. SPOP regulates the expression profiles and alternative splicing events in human hepatocytes
  150. Knockdown of SETD5 inhibited glycolysis and tumor growth in gastric cancer cells by down-regulating Akt signaling pathway
  151. PTX3 promotes IVIG resistance-induced endothelial injury in Kawasaki disease by regulating the NF-κB pathway
  152. Pancreatic ectopic thyroid tissue: A case report and analysis of literature
  153. The prognostic impact of body mass index on female breast cancer patients in underdeveloped regions of northern China differs by menopause status and tumor molecular subtype
  154. Report on a case of liver-originating malignant melanoma of unknown primary
  155. Case report: Herbal treatment of neutropenic enterocolitis after chemotherapy for breast cancer
  156. The fibroblast growth factor–Klotho axis at molecular level
  157. Characterization of amiodarone action on currents in hERG-T618 gain-of-function mutations
  158. A case report of diagnosis and dynamic monitoring of Listeria monocytogenes meningitis with NGS
  159. Effect of autologous platelet-rich plasma on new bone formation and viability of a Marburg bone graft
  160. Small breast epithelial mucin as a useful prognostic marker for breast cancer patients
  161. Continuous non-adherent culture promotes transdifferentiation of human adipose-derived stem cells into retinal lineage
  162. Nrf3 alleviates oxidative stress and promotes the survival of colon cancer cells by activating AKT/BCL-2 signal pathway
  163. Favorable response to surufatinib in a patient with necrolytic migratory erythema: A case report
  164. Case report of atypical undernutrition of hypoproteinemia type
  165. Down-regulation of COL1A1 inhibits tumor-associated fibroblast activation and mediates matrix remodeling in the tumor microenvironment of breast cancer
  166. Sarcoma protein kinase inhibition alleviates liver fibrosis by promoting hepatic stellate cells ferroptosis
  167. Research progress of serum eosinophil in chronic obstructive pulmonary disease and asthma
  168. Clinicopathological characteristics of co-existing or mixed colorectal cancer and neuroendocrine tumor: Report of five cases
  169. Role of menopausal hormone therapy in the prevention of postmenopausal osteoporosis
  170. Precisional detection of lymph node metastasis using tFCM in colorectal cancer
  171. Advances in diagnosis and treatment of perimenopausal syndrome
  172. A study of forensic genetics: ITO index distribution and kinship judgment between two individuals
  173. Acute lupus pneumonitis resembling miliary tuberculosis: A case-based review
  174. Plasma levels of CD36 and glutathione as biomarkers for ruptured intracranial aneurysm
  175. Fractalkine modulates pulmonary angiogenesis and tube formation by modulating CX3CR1 and growth factors in PVECs
  176. Novel risk prediction models for deep vein thrombosis after thoracotomy and thoracoscopic lung cancer resections, involving coagulation and immune function
  177. Exploring the diagnostic markers of essential tremor: A study based on machine learning algorithms
  178. Evaluation of effects of small-incision approach treatment on proximal tibia fracture by deep learning algorithm-based magnetic resonance imaging
  179. An online diagnosis method for cancer lesions based on intelligent imaging analysis
  180. Medical imaging in rheumatoid arthritis: A review on deep learning approach
  181. Predictive analytics in smart healthcare for child mortality prediction using a machine learning approach
  182. Utility of neutrophil–lymphocyte ratio and platelet–lymphocyte ratio in predicting acute-on-chronic liver failure survival
  183. A biomedical decision support system for meta-analysis of bilateral upper-limb training in stroke patients with hemiplegia
  184. TNF-α and IL-8 levels are positively correlated with hypobaric hypoxic pulmonary hypertension and pulmonary vascular remodeling in rats
  185. Stochastic gradient descent optimisation for convolutional neural network for medical image segmentation
  186. Comparison of the prognostic value of four different critical illness scores in patients with sepsis-induced coagulopathy
  187. Application and teaching of computer molecular simulation embedded technology and artificial intelligence in drug research and development
  188. Hepatobiliary surgery based on intelligent image segmentation technology
  189. Value of brain injury-related indicators based on neural network in the diagnosis of neonatal hypoxic-ischemic encephalopathy
  190. Analysis of early diagnosis methods for asymmetric dementia in brain MR images based on genetic medical technology
  191. Early diagnosis for the onset of peri-implantitis based on artificial neural network
  192. Clinical significance of the detection of serum IgG4 and IgG4/IgG ratio in patients with thyroid-associated ophthalmopathy
  193. Forecast of pain degree of lumbar disc herniation based on back propagation neural network
  194. SPA-UNet: A liver tumor segmentation network based on fused multi-scale features
  195. Systematic evaluation of clinical efficacy of CYP1B1 gene polymorphism in EGFR mutant non-small cell lung cancer observed by medical image
  196. Rehabilitation effect of intelligent rehabilitation training system on hemiplegic limb spasms after stroke
  197. A novel approach for minimising anti-aliasing effects in EEG data acquisition
  198. ErbB4 promotes M2 activation of macrophages in idiopathic pulmonary fibrosis
  199. Clinical role of CYP1B1 gene polymorphism in prediction of postoperative chemotherapy efficacy in NSCLC based on individualized health model
  200. Lung nodule segmentation via semi-residual multi-resolution neural networks
  201. Evaluation of brain nerve function in ICU patients with Delirium by deep learning algorithm-based resting state MRI
  202. A data mining technique for detecting malignant mesothelioma cancer using multiple regression analysis
  203. Markov model combined with MR diffusion tensor imaging for predicting the onset of Alzheimer’s disease
  204. Effectiveness of the treatment of depression associated with cancer and neuroimaging changes in depression-related brain regions in patients treated with the mediator-deuterium acupuncture method
  205. Molecular mechanism of colorectal cancer and screening of molecular markers based on bioinformatics analysis
  206. Monitoring and evaluation of anesthesia depth status data based on neuroscience
  207. Exploring the conformational dynamics and thermodynamics of EGFR S768I and G719X + S768I mutations in non-small cell lung cancer: An in silico approaches
  208. Optimised feature selection-driven convolutional neural network using gray level co-occurrence matrix for detection of cervical cancer
  209. Incidence of different pressure patterns of spinal cerebellar ataxia and analysis of imaging and genetic diagnosis
  210. Pathogenic bacteria and treatment resistance in older cardiovascular disease patients with lung infection and risk prediction model
  211. Adoption value of support vector machine algorithm-based computed tomography imaging in the diagnosis of secondary pulmonary fungal infections in patients with malignant hematological disorders
  212. From slides to insights: Harnessing deep learning for prognostic survival prediction in human colorectal cancer histology
  213. Ecology and Environmental Science
  214. Monitoring of hourly carbon dioxide concentration under different land use types in arid ecosystem
  215. Comparing the differences of prokaryotic microbial community between pit walls and bottom from Chinese liquor revealed by 16S rRNA gene sequencing
  216. Effects of cadmium stress on fruits germination and growth of two herbage species
  217. Bamboo charcoal affects soil properties and bacterial community in tea plantations
  218. Optimization of biogas potential using kinetic models, response surface methodology, and instrumental evidence for biodegradation of tannery fleshings during anaerobic digestion
  219. Understory vegetation diversity patterns of Platycladus orientalis and Pinus elliottii communities in Central and Southern China
  220. Studies on macrofungi diversity and discovery of new species of Abortiporus from Baotianman World Biosphere Reserve
  221. Food Science
  222. Effect of berrycactus fruit (Myrtillocactus geometrizans) on glutamate, glutamine, and GABA levels in the frontal cortex of rats fed with a high-fat diet
  223. Guesstimate of thymoquinone diversity in Nigella sativa L. genotypes and elite varieties collected from Indian states using HPTLC technique
  224. Analysis of bacterial community structure of Fuzhuan tea with different processing techniques
  225. Untargeted metabolomics reveals sour jujube kernel benefiting the nutritional value and flavor of Morchella esculenta
  226. Mycobiota in Slovak wine grapes: A case study from the small Carpathians wine region
  227. Elemental analysis of Fadogia ancylantha leaves used as a nutraceutical in Mashonaland West Province, Zimbabwe
  228. Microbiological transglutaminase: Biotechnological application in the food industry
  229. Influence of solvent-free extraction of fish oil from catfish (Clarias magur) heads using a Taguchi orthogonal array design: A qualitative and quantitative approach
  230. Chromatographic analysis of the chemical composition and anticancer activities of Curcuma longa extract cultivated in Palestine
  231. The potential for the use of leghemoglobin and plant ferritin as sources of iron
  232. Investigating the association between dietary patterns and glycemic control among children and adolescents with T1DM
  233. Bioengineering and Biotechnology
  234. Biocompatibility and osteointegration capability of β-TCP manufactured by stereolithography 3D printing: In vitro study
  235. Clinical characteristics and the prognosis of diabetic foot in Tibet: A single center, retrospective study
  236. Agriculture
  237. Biofertilizer and NPSB fertilizer application effects on nodulation and productivity of common bean (Phaseolus vulgaris L.) at Sodo Zuria, Southern Ethiopia
  238. On correlation between canopy vegetation and growth indexes of maize varieties with different nitrogen efficiencies
  239. Exopolysaccharides from Pseudomonas tolaasii inhibit the growth of Pleurotus ostreatus mycelia
  240. A transcriptomic evaluation of the mechanism of programmed cell death of the replaceable bud in Chinese chestnut
  241. Melatonin enhances salt tolerance in sorghum by modulating photosynthetic performance, osmoregulation, antioxidant defense, and ion homeostasis
  242. Effects of plant density on alfalfa (Medicago sativa L.) seed yield in western Heilongjiang areas
  243. Identification of rice leaf diseases and deficiency disorders using a novel DeepBatch technique
  244. Artificial intelligence and internet of things oriented sustainable precision farming: Towards modern agriculture
  245. Animal Sciences
  246. Effect of ketogenic diet on exercise tolerance and transcriptome of gastrocnemius in mice
  247. Combined analysis of mRNA–miRNA from testis tissue in Tibetan sheep with different FecB genotypes
  248. Isolation, identification, and drug resistance of a partially isolated bacterium from the gill of Siniperca chuatsi
  249. Tracking behavioral changes of confined sows from the first mating to the third parity
  250. The sequencing of the key genes and end products in the TLR4 signaling pathway from the kidney of Rana dybowskii exposed to Aeromonas hydrophila
  251. Development of a new candidate vaccine against piglet diarrhea caused by Escherichia coli
  252. Plant Sciences
  253. Crown and diameter structure of pure Pinus massoniana Lamb. forest in Hunan province, China
  254. Genetic evaluation and germplasm identification analysis on ITS2, trnL-F, and psbA-trnH of alfalfa varieties germplasm resources
  255. Tissue culture and rapid propagation technology for Gentiana rhodantha
  256. Effects of cadmium on the synthesis of active ingredients in Salvia miltiorrhiza
  257. Cloning and expression analysis of VrNAC13 gene in mung bean
  258. Chlorate-induced molecular floral transition revealed by transcriptomes
  259. Effects of warming and drought on growth and development of soybean in Hailun region
  260. Effects of different light conditions on transient expression and biomass in Nicotiana benthamiana leaves
  261. Comparative analysis of the rhizosphere microbiome and medicinally active ingredients of Atractylodes lancea from different geographical origins
  262. Distinguish Dianthus species or varieties based on chloroplast genomes
  263. Comparative transcriptomes reveal molecular mechanisms of apple blossoms of different tolerance genotypes to chilling injury
  264. Study on fresh processing key technology and quality influence of Cut Ophiopogonis Radix based on multi-index evaluation
  265. An advanced approach for fig leaf disease detection and classification: Leveraging image processing and enhanced support vector machine methodology
  266. Erratum
  267. Erratum to “Protein Z modulates the metastasis of lung adenocarcinoma cells”
  268. Erratum to “BRCA1 subcellular localization regulated by PI3K signaling pathway in triple-negative breast cancer MDA-MB-231 cells and hormone-sensitive T47D cells”
  269. Retraction
  270. Retraction to “Protocatechuic acid attenuates cerebral aneurysm formation and progression by inhibiting TNF-alpha/Nrf-2/NF-kB-mediated inflammatory mechanisms in experimental rats”
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Heruntergeladen am 6.9.2025 von https://www.degruyterbrill.com/document/doi/10.1515/biol-2022-0781/html
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