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Lysophosphatidic acid 2 alleviates deep vein thrombosis via protective endothelial barrier function

  • Ruifeng Bai , Xinyang Yue , Xuan Tian , Huiru Zhao , Ying Liu , Tian Li and Jun Wu EMAIL logo
Published/Copyright: February 6, 2025
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Open Medicine
From the journal Open Medicine Volume 20 Issue 1

Abstract

Background

The specific role of lysophosphatidic acid 2 (LPA2) in deep vein thrombosis (DVT) remains unclear.

Methods

An inferior vena cava annulus retraction model of DVT was established in wild-type (WT) and global LPA2 knockout (Lpar2 −/− ) mice. We examined the incidence of DVT, wet weight of thrombus, length of thrombus, assessed endothelial permeability through Evans blue dye assay in vivo, cell viability, and endothelial cell (EC) permeability of mouse inferior vena cava ECs in vitro. Proteomics, histopathology, immunohistochemistry, and western blotting were employed to investigate the role of LPA2 in DVT.

Results

Lpar2 deficiency increased vascular endothelial permeability and promoted the progression of DVT. Histological examination revealed aggravated inflammation in the thrombus of Lpar2 −/− DVT mice. In vitro, Lpar2 −/− resulted in increased permeability of ECs. Proteomic results indicated that DVT after Lpar2 −/− may be related to tight junction (TJ) protein. LPA2 agonist, 2-[4-(1,3-dioxo-1H,3H-benzoisoquinolin-2-yl)butylsulfamoyl] benzoic acid, significantly reduced vascular endothelial permeability as well as increased expression of the vascular endothelial TJ protein zonula occludens-1.

Conclusion

These data provide a novel mechanism of endothelial barrier protection of LPA2 in DVT.

Keywords: deep vein thrombosis; lysophosphatidic acid 2; vascular endothelial permeability; endothelial cells; zonula occludens-1

1 Introduction

Deep vein thrombosis (DVT) was a common complication after orthopedic trauma. Clinical data show that DVT was the third most common cause of vascular death after heart disease and stroke [1], and the incidence of DVT reaches 35% after hip or knee replacement [2], with a mortality of 10% [3]. Effective treatments for DVT included oral anticoagulant drugs such as warfarin and the new representative rivaroxaban, or interventional inferior vena cava filter implantation, whereas 50% of the DVT patients still developed post-thrombotic syndrome [4]. At present, it was recognized that blood flow retardation, blood hypercoagulability, and vascular inner wall injury proposed by Virchow are the three major factors of DVT formation.

Endothelial cell (EC) dysfunction caused by damage to the endovascular wall is a leading cause of DVT [5]. When the endothelial barrier function was damaged, endothelial permeability was enhanced, tissue factor (TF) stored in the lower layer of the endothelium was exposed, and the clotting pathway was activated to induce thrombosis by the von Willebrand factor, platelets, and factor VII [6]. Although it was known that the occurrence and development of DVT were closely related to the formation of endothelial permeability, the mechanism of regulating endothelial permeability and then affecting DVT was not clear. Therefore, an in-depth study of the mechanism by which weakening permeability protects endothelial function is of great significance for the development of new drug targets for DVT.

Lysophosphatidic acid 2 (LPA2) was reported to stabilize endothelial barrier function in vitro, reduce EC permeability [7,8], and stimulate angiogenesis in vivo [9,10,11]. Studies have shown that LPA therapy partially improved lipopolysaccharide-induced epithelial barrier breakdown. Another study also supports the role of LPA in endothelial barrier function. LPA acyltransferase inhibitors can reduce LPA degradation and protect lung leakage in vivo [12], enhance the barrier function of corneal ECs, and play a protective role in airway inflammation and airway remodeling [13].

There are six subtypes of LPA receptors, namely LPA1–6. Our research group has previously found that the expression of LPA2 in the heart after myocardial infarction is increased, mainly from ECs, and the results showed that the cardiac vascular permeability is significantly increased in Lpar2 −/− mice. In addition, our study found that the expression of LPA2 in pulmonary microvascular ECs was increased after acute septic lung injury, and the pulmonary vascular permeability of Lpar2 −/− mice was significantly increased. At the same time, LPA2 from carotid vessels increased by 6.2 times after carotid artery ligation [14]. In addition, LPA2 had a hundredfold or more affinity with LPA than other LPA receptors [15,16]. In conclusion, it was believed that the upregulated expression of LPA2 in ECs under injury conditions had an important regulatory effect on vascular ECs. Therefore, in this study, Lpar2 −/− mice were used as the model animal and WT mice as the control group, and endothelial permeability was taken as the focus of DVT research.

2 Materials and methods

2.1 ECs

The mice (purchased from the Animal Center of Capital Medical University) were sacrificed using carbon dioxide. The whole chest and abdominal cavity were dissected layer by layer through the median incision of the chest and abdomen to reveal the entire chest and abdominal cavity. The artery envelope and surrounding adipose tissue were carefully separated under a 10-fold microscope. It was cut into a 1 mm × 1 mm blood vessel graft and attached to the inner side of the blood vessel to the 6-hole plate. After standing for 5–10 min in a 5% CO2 incubator at 37°C, ECM complete culture medium containing 20% FBS was added and continued to be cultured in the incubator [17]. The culture medium was changed every 3 days, and flow cytometry was performed with a CD31 label. All cells used in this experiment ranged from P2 to P6.

2.2 Endothelial permeability

The cells of the transwell culture plate (coated with 1% gelatin) were incubated at 37°C for 30 min. The stable growth of EC cells of 2–6 generations was digested with pancreatic enzymes and inoculated in the transwell chamber at a density of 1 × 104 (200 μL), and 1 ml of complete culture medium was added into the lower chamber. The cells were cultured in a 5% CO2 incubator at 37°C for 24 h, and the serum of DVT mice was stimulated for 48 h after starvation for 12 h. The cells were washed twice with PBS, and 100 μL of phenol-red free DMEM (containing 1 μg/mL of FITC-d-glucoside) was added to the top chamber of the double-layer chamber, and 600 μL of phenol-red free DMEM was added to the bottom chamber of the double-layer chamber, and cultured in the incubator for 45 min. The fluorescence intensity of FITC-dextran was measured by placing 100 μL of liquid in a 96-well plate with a black transparent bottom.

2.3 Animal experiments

Mice were anesthetized by isoflurane. The skin was disinfected, and the inferior vena cava and abdominal aorta below the liver were exposed by microsurgical forceps. Ligation of small branches of the inferior vena cava to prevent the establishment of collateral circulation affects thrombosis. The inferior vena cava was wrapped with a 7-0 suture close to the left renal vein, a 27G needle was placed close to the inferior vena cava, and the needle and inferior vena cava were tied together with a 7-0 suture wrapped around inferior vena cava. After the 27G needle was extracted, the inferior vena cava could restore partial blood flow. Using 5-0 sutures to close the abdomen layer by layer, the mice were safely returned to the cage. Phenotypic assessment was performed at the sampling time point, and blood was taken from the eyeball under anesthesia by intraperitoneal injection of tribromoethanol, and then sampling was performed.

2.4 Evans blue dye (EBD)

EBD solution (normal saline, 0.5%) was prepared, 200 μL was injected into the tail vein of each mouse 30 min before sampling, and the mice were killed by neck removal (to reduce the interference of anesthetic drugs on the vascular permeability of mice, the faster the action is, the better), the vena cava was removed, weighed, and added with 500 μL formamide, and the supernatant was centrifugally removed after 48 h of 55°C water bath. Using formamide as blank, the supernatants were measured at 620–740 nm spectrophotometrically.

2.5 Hematoxylin and eosin staining

The inferior vena cava was isolated and fixed by immersion in 4% paraformaldehyde, embedded in paraffin, and sectioned at 5 μm thickness. The slices were roasted, dewaxed, hydrated, and then stained with hematoxylin. Then, the slides were separated with 1% hydrochloric acid alcohol, and the cytoplasm and other components were further stained with an eosin staining solution. The excess staining solution was rinsed with running water, and the staining effect was observed under a microscope. The nucleus was blue, and the cytoplasm and other interstitial spaces were red. The slides were further dehydrated and sealed with neutral gum. Pathological changes in the lung tissues were examined under a light microscope.

2.6 Immunohistochemistry staining

The slicing preparation process is described above [18]. Inferior vena cava was embedded in paraffin, sectioned (5 mm), and mounted on glass slides. After dewaxing, antigen retrieval was performed using citrate buffer and then permeabilized with 0.1% Triton X-100 for 10 min. After being blocked by hydrogen peroxide, the slides were immunostained with an anti-fibrinogen antibody (1:100, Abcam, ab34269) overnight at 4°C and rewarmed at 37°C for 30 min. Subsequently, sections were incubated with ready-to-use undiluted secondary antibodies conjugated with HRP for 30 min at 37°C. Subsequently, diaminobenzidine staining was used for 5 min at room temperature, and the nuclei were stained with hematoxylin for 2.5 min at room temperature. The stained sections were observed under a light microscope. Images were analyzed using the Image-J software.

2.7 Western blotting

The left lung obtained from each group was frozen in liquid nitrogen and stored at −80°C. Tissue samples from various groups were homogenized with protein extraction reagents containing protease inhibitors. For ECs of different groups, the cell samples were rinsed twice with 1× PBS and lysed with the lysis buffer. The treated cells were mechanically scraped off with a rubber scraper and centrifuged at 12,000 g for 25 min, and the supernatant was collected. Protein concentrations of both tissues and ECs were determined by using Pierce TM BCA Protein Assay Kit (Thermo Fisher Scientific, USA, 23225). Samples of supernatant containing 40 μg protein were heated to 72°C for 10 min and then separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis in 10% gels. Protein bands were electroblotted onto polyvinylidene difluoride membrane and blocked with 5% BSA for 1 h. The membranes were incubated with primary rabbit polyclonal antibody anti-VE-cadherin (1:1,000, Abcam, ab205336), anti-zonula occludens-1 (ZO-1; 1:1,000, Abcam, ab216880), and anti-claudin-5 (1:1,000, ThermoFisher, 35-2500). Primary antibodies were diluted in 5% BSA overnight at 4°C before the membranes were incubated with the secondary antibodies. The immunoblots were detected by using SuperSignal West Pico Plus (ThermoFisher Scientific, 34577). The protein band intensity was measured using Image J software.

2.8 Statistical analysis

GraphPad Prism 8 and SPSS 21.0 software were used for statistical analysis. The data are expressed as mean ± SD. One-way ANOVA, together with the Tukey test for multiple comparisons after the variance homogeneity test, was used to assess significant differences among groups. Differences were considered statistically significant when p < 0.05.

  1. Ethical statement: The Animal Care & Use Committee of Jishuitan Hospital approved this study (JL-K2022-016), which was conducted in accordance with the “Regulation to the Care and Use of Experimental Animals (1996)” guidelines of the Beijing Animal Care Council. The authors are accountable for all aspects of the work and for ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

3 Results

3.1 LPA2 deficiency causes increased incidence of DVT in mice

HE staining showed that the vascular ECs in blank and blank groups were intact and orderly, and no inflammatory cell infiltration was observed. Mice in the WT-DVT group and the Lpar2 −/−-DVT group revealed red thrombus with infiltration of neutrophils, monocytes, macrophages, and other inflammatory cells around the thrombus wall, and inflammatory cells in the Lpar2 −/−-DVT group were significantly increased (Figure 1a). Compared with the WT-DVT group, the wet weight and length of thrombosis in the Lpar2 −/−-DVT group were significantly increased (Figure 1b). Compared with the WT-DVT group, the APTT, PT, FIB, and TT in the Lpar2 −/−-DVT group were decreased (Figure 1c). It is suggested that LPA2 reduced the occurrence of DVT.

Figure 1 LPA2 deletion causes more DVT production in mice. (a) HE staining showed that DVT and inflammatory cell infiltration increased in Lpar2 −/− mice. Scale bar = 100 μm. (b) Statistical charts of thrombus length and wet weight in each group. (c) Changes in APTT, PT, FIB, and TT in plasma. Compared with mice in the WT-DVT group, *p < 0.05 and **p < 0.01.
Figure 1

LPA2 deletion causes more DVT production in mice. (a) HE staining showed that DVT and inflammatory cell infiltration increased in Lpar2 −/− mice. Scale bar = 100 μm. (b) Statistical charts of thrombus length and wet weight in each group. (c) Changes in APTT, PT, FIB, and TT in plasma. Compared with mice in the WT-DVT group, *p < 0.05 and **p < 0.01.

3.2 Increase of DVT after LPA2 deletion may be related to the enhancement of endothelial permeability

Disruption of endothelial function resulted in changes in vascular permeability, and excessive increase in vascular permeability resulted in vascular leakage. TF stored in the subendothelial layer exposes blood and promotes DVT production. Compared with the WT-DVT group, the vascular permeability of the inferior vena cava of mice in the Lpar2 −/−-DVT group was significantly enhanced (Figure 2a). The expressions of VE-cadherin, ZO-1, and claudin-5, which reflect endothelial permeability were decreased in the Lpar2 −/−-DVT group (Figure 2b and C). The primary vascular ECs of WT and Lpar2 −/− mice were separated, and the results of studies in vitro showed that cell activity of Lpar2 −/− mice ECs decreased more under injury conditions (Figure 2e), suggesting that the loss of Lpar2 may affect the activity and function of ECs, lead to enhanced vascular permeability (Figure 2f), and increase the production of DVT. These results suggested that the loss of Lpar2 disrupts vascular homeostasis and leads to the breakdown of vascular endothelial barrier function, which might be a pivotal reason for the increased formation of DVT in Lpar2 −/− mice.

Figure 2 LPA2 deletion induced enhanced endothelial permeability of inferior vena cava in mice. (a) Evans Blue assay found that the vascular permeability of inferior vena cava in mice in the Lpar2 −/−-DVT group was significantly enhanced. (b) The detection of connexin, which reflects endothelial permeability, showed that the expressions of VE-cadherin, ZO-1, and claudin-5 in the inferior vena cava of mice in the Lpar2 −/−-DVT group were lower than those in the WT-DVT group. (c) Statistical analysis of VE-cadherin, ZO-1, and claudin-5 results. (d) Optical microscopic representation of primary vascular ECs. Scale bar = 50 μm. (e) CCK-8 activity of isolated primary aortic ECs and serum-induced cell damage in mice after DVT. (f) ECs were spread in the transwell chamber, and 70 kDa FITC-dextran was added to detect the permeability of ECs in each group. Compared with mice in the WT-DVT group, *p < 0.05 and **p < 0.01.
Figure 2

LPA2 deletion induced enhanced endothelial permeability of inferior vena cava in mice. (a) Evans Blue assay found that the vascular permeability of inferior vena cava in mice in the Lpar2 −/−-DVT group was significantly enhanced. (b) The detection of connexin, which reflects endothelial permeability, showed that the expressions of VE-cadherin, ZO-1, and claudin-5 in the inferior vena cava of mice in the Lpar2 −/−-DVT group were lower than those in the WT-DVT group. (c) Statistical analysis of VE-cadherin, ZO-1, and claudin-5 results. (d) Optical microscopic representation of primary vascular ECs. Scale bar = 50 μm. (e) CCK-8 activity of isolated primary aortic ECs and serum-induced cell damage in mice after DVT. (f) ECs were spread in the transwell chamber, and 70 kDa FITC-dextran was added to detect the permeability of ECs in each group. Compared with mice in the WT-DVT group, *p < 0.05 and **p < 0.01.

3.3 LPA2 endothelium-specific deletion causes an increased incidence of DVT in mice

To determine the functional significance of LPA2 in DVT, we introduced LPA2 endothelium-specific knockout mice. By gross observation, venous thrombosis was formed in both the WT-DVT group and the Lpar2-cKO-DVT group. The vascular wall adhesion to the surrounding tissue was light in the Lpar2 f/f -DVT group and seriousness in the Lpar2-cKO-DVT group (Figure 3a). Fibrinogen promotes platelet aggregation, increases blood viscosity and peripheral resistance, causes EC damage, migrates chemotactic monocytes/macrophages to the intima, and promotes red blood cell adhesion and thrombosis. Immunohistochemical staining results showed that fibrinogen increased in the thrombi of Lpar2-cKO-DVT group mice (Figure 3b). Compared with the Lpar2 f/f -DVT group, the wet weight and length of the thrombus in the Lpar2-cKO-DVT group were significantly increased. Fibrinogen increased in the Lpar2-cKO-DVT group (Figure 3c). The thrombus formation rate of Lpar2 f/f mice and Lpar2-cKO mice was compared by ligation of the inferior vena cava-induced DVT model. The experimental results showed that the thrombolytic rate of WT was 45%, and that of Lpar2 −/− mice was 60%. LPA2 inhibited the occurrence of DVT (Figure 3d).

Figure 3 Increased release of inflammatory cytokines from LPA2-deficient ECs. (a) A visual view of thrombus. (b) Immunohistochemical staining of thrombus. Scale bar = 100 μm. (c) Statistical charts of thrombus length and wet weight in each group. (d) Thrombosis rate of mice in each group. Compared with mice in the Lpar2 f/f group, *p < 0.05 and **p < 0.01.
Figure 3

Increased release of inflammatory cytokines from LPA2-deficient ECs. (a) A visual view of thrombus. (b) Immunohistochemical staining of thrombus. Scale bar = 100 μm. (c) Statistical charts of thrombus length and wet weight in each group. (d) Thrombosis rate of mice in each group. Compared with mice in the Lpar2 f/f group, *p < 0.05 and **p < 0.01.

3.4 Enhanced endothelial permeability of Lpar2-cKO mice was associated with tight junction (TJ) proteins

In order to further explore the reasons for increased DVT formation in mice after endothelium-specific knockout of LPA2, we performed proteomic analysis on the inferior vena cava of Lpar2-cKO and Lpar2 f/f mice. The results showed that the TJ protein pathway was downregulated in Lpar2-cKO-DVT mice (Figure 4a and b). For further verification, we tested the vascular permeability of mice inferior vena cava, and the results showed that the endothelial permeability was enhanced in Lpar2-cKO-DVT mice, indicating that LPA2 indeed plays an important role in endothelial function (Figure 4c–e).

Figure 4 Endothelial permeability upregulated in Lpar2-cKO mice. (a) P value of the downregulated pathway. (b) Each group down pathway enrichment. (c) Detection of vascular permeability of mice inferior vena cava. (d) Expressions of ZO-1, occludin, and claudin-5 in the inferior vena cava of mice. (e) Statistical analysis of ZO-1, occludin, and claudin-5.Compared with mice in the Lpar2 f/f group, *p < 0.05 and **p < 0.01.
Figure 4

Endothelial permeability upregulated in Lpar2-cKO mice. (a) P value of the downregulated pathway. (b) Each group down pathway enrichment. (c) Detection of vascular permeability of mice inferior vena cava. (d) Expressions of ZO-1, occludin, and claudin-5 in the inferior vena cava of mice. (e) Statistical analysis of ZO-1, occludin, and claudin-5.Compared with mice in the Lpar2 f/f group, *p < 0.05 and **p < 0.01.

3.5 Endothelial permeability was weakened after LPA2 drug activation or adenovirus overexpression

The results in vivo showed that the vascular permeability of the inferior vena cava was significantly weakened after 2-[4-(1,3-dioxo-1H,3H-benzoisoquinolin-2-yl)butylsulfamoyl] benzoic acid (DBIBB) activation or LPA2 adenovirus overexpression in Lpar2 f/f mice (Figure 5a). The same results were shown in primary ECs extracted in vitro after DBIBB activation or LPA2 adenovirus overexpression (Figure 5b), suggesting that overexpression of LPA2 affected EC function. These results suggested that adenovirus overexpression of DBIBB and LPA2 improved endothelial function and effectively maintained endothelial homeostasis, which played an important role in maintaining the vascular barrier and thus reducing the production of DVT.

Figure 5 Reduced endothelial damage due to LPA2 overexpression. (a) Detection of vascular permeability of mice inferior vena cava. (b) Isolation of primary mouse inferior vena cava vascular ECs to induce permeability detection after cell injury. Compared with mice in the Lpar2 f/f group, *p < 0.05 and **p < 0.01.
Figure 5

Reduced endothelial damage due to LPA2 overexpression. (a) Detection of vascular permeability of mice inferior vena cava. (b) Isolation of primary mouse inferior vena cava vascular ECs to induce permeability detection after cell injury. Compared with mice in the Lpar2 f/f group, *p < 0.05 and **p < 0.01.

4 Discussion

4.1 Main interpretation

Vascular endothelium plays a very important role in thrombotic diseases [19,20]. In this study, we demonstrated that LPA2 played a protective role in inferior vena cava annulus retraction-induced DVT, which was associated with endothelial barrier function. Lpar2 deficiency increased vascular endothelial permeability in the inferior vena cava. In vitro, activation of LPA2 with DBIBB mitigated DVT by decreased endothelial permeability (Figure 6).

Figure 6 Graphic abstract. LPA2 upregulates the expression of TJ proteins ZO-1, occludin, and claudin-5, maintains endothelial barrier function, and decreases DVT. DVT reduced overexpression of LPA2 by Ad-Lpar2/DBIBB.
Figure 6

Graphic abstract. LPA2 upregulates the expression of TJ proteins ZO-1, occludin, and claudin-5, maintains endothelial barrier function, and decreases DVT. DVT reduced overexpression of LPA2 by Ad-Lpar2/DBIBB.

The endothelial barrier function played a critical role in modulating DVT. Previous studies reported a 6.2-fold increase of LPA2 in carotid artery LPA2 after carotid artery ligation [14,21]. Our group found that LPA2 was upregulated in mice after myocardial infarction and that elevated LPA2 levels were mainly due to increased LPA2 expression in vascular ECs [22]. This attracted our interest because it highlighted the potential role of LPA2 in the pathogenesis of DVT. Prior to our findings, no data were available regarding the role of LPA2 in DVT. How LPA2 was involved in the pathogenesis of DVT is our big concern.

ECs play a pivotal role in the maintenance of vascular homeostasis. An increase in vascular permeability leads to exposure of subcutaneous collagen, activation of platelets and coagulation factor XII, and initiation of the endogenous coagulation system. The injured ECs released TF, activated clotting factor Ⅶ, and activated the exogenous clotting system. Lpar2 deficiency led to a marked induction in vascular endothelial permeability of the inferior vena cava. By applying the inferior vena cava annulus retraction-induced DVT model in Lpar2−/− mice, we showed that LPA2 was required for vascular endothelial permeability, further confirming the substantial role of LPA2 in endothelial barrier function. Cultured primary ECs from Lpar2−/− mice showed an increase in endothelial permeability characterized by relative fluorescence intensity. These results indicated that Loss of Lpar2 caused an increase in mortality after DVT, possibly due to the destruction of endothelial barrier function, resulting in increased vascular endothelial permeability.

Although it was suggested that LPA played a protective role in endothelial barrier function [7,23,24], it was unclear which LPA receptors helped to mediate the key steps of vascular endothelial permeability in veins. Studies suggested that the knockdown of LPA1 increased lung endothelial permeability [25]. LPA via LPAR6 induced actin stress fiber formation and increased brain capillary EC permeability [12,26]. Our previous study showed the potential benefit of LPA2 in vascular endothelial homeostasis following cardiac ischemia [22]. These observations provided evidence that different LPA receptors are used for various functions of ECs. In our current research, we demonstrated that the function of LPA2 in endothelium permeability by using Lpar2 −/− mice could stimulate the expression of VE-cadherin, ZO-1, and claudin-5. All these results indicated that LPA-LPA2 plays an important protective role in DVT.

DBIBB is an agonist of LPA2, and it has been reported that DBIBB can increase intestinal crypt survival and enterocyte proliferation and decrease apoptosis, thus reducing gastrointestinal radiation syndrome [16]. DBIBB could also contribute to vascular endothelium homeostasis and protect cardiac function and myocardial remodeling in mice after ischemic injury [22]. In our study, DBIBB reduced endothelial permeability in WT mice. These results suggested that LPA2 is an original regulator for DVT, which was similar to the gastrointestinal radiation syndrome study [16].

5 Limitations

The present study has some limitations. First, we focused on the study that LPA2 inhibited DVT by acting in the endothelium and thus inhibited DVT; whether it regulated coagulation is something that we have only preliminarily explored. Second, our study demonstrated that increased DVT after endothelial-specific knockdown of LPA2 was associated with the TJ proteins ZO-1, occludin, and claudin-5, whereas the one that played the most pivotal role is unknown. Finally, the specific pathway by which LPA2 regulates TJ proteins on the endothelium remained unknown. Further studies are needed in the future to better understand the exact mechanisms.

6 Conclusion

In conclusion, our data revealed for the first time a novel, selective, and causal role of LPA2 activation in mediating endothelial barrier dysfunction in the DVT model in vivo and in vitro. The beneficial effects of LPA2 were mediated by the restoration of endothelial AJ and TJ proteins, VE-cadherin, ZO-1, and claudin-5. The activation of LPA2 with DBIBB protected against endothelial barrier function and improved DVT. These findings suggested that targeting LPA2 and its downstream signaling pathways may prove to be an innovative therapeutic strategy for the treatment of DVT.

# Equal contribution.

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Acknowledgements

The current work received funding through grants obtained from the Natural Science Foundation of Beijing (7232077) and Beijing JST Research Funding (ZR-202202).

  1. Author contributions: BRF, YXY, and WJ initiated the report ideas and concepts. BRF wrote the first draft of the manuscript, supervised by YXY and WJ. TX, LT, and ZHR are responsible for treating the mice. LY is responsible for the literature background investigation. All authors have critically reviewed and approved the final version of the manuscript.

  2. Conflict of interest: Author state that no conflict of interest declare.

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

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Received: 2024-07-03
Revised: 2024-12-09
Accepted: 2024-12-20
Published Online: 2025-02-06

© 2025 the author(s), published by De Gruyter

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

Articles in the same Issue

  1. Research Articles
  2. Network pharmacological analysis and in vitro testing of the rutin effects on triple-negative breast cancer
  3. Impact of diabetes on long-term survival in elderly liver cancer patients: A retrospective study
  4. Knockdown of CCNB1 alleviates high glucose-triggered trophoblast dysfunction during gestational diabetes via Wnt/β-catenin signaling pathway
  5. Risk factors for severe adverse drug reactions in hospitalized patients
  6. Analysis of the effect of ALA-PDT on macrophages in footpad model of mice infected with Fonsecaea monophora based on single-cell sequencing
  7. Development and validation of headspace gas chromatography with a flame ionization detector method for the determination of ethanol in the vitreous humor
  8. CMSP exerts anti-tumor effects on small cell lung cancer cells by inducing mitochondrial dysfunction and ferroptosis
  9. Predictive value of plasma sB7-H3 and YKL-40 in pediatric refractory Mycoplasma pneumoniae pneumonia
  10. Antiangiogenic potential of Elaeagnus umbellata extracts and molecular docking study by targeting VEGFR-2 pathway
  11. Comparison of the effectiveness of nurse-led preoperative counseling and postoperative follow-up care vs standard care for patients with gastric cancer
  12. Comparing the therapeutic efficacy of endoscopic minimally invasive surgery and traditional surgery for early-stage breast cancer: A meta-analysis
  13. Adhered macrophages as an additional marker of cardiomyocyte injury in biopsies of patients with dilated cardiomyopathy
  14. Association between statin administration and outcome in patients with sepsis: A retrospective study
  15. Exploration of the association between estimated glucose disposal rate and osteoarthritis in middle-aged and older adults: An analysis of NHANES data from 2011 to 2018
  16. A comparative analysis of the binary and multiclass classified chest X-ray images of pneumonia and COVID-19 with ML and DL models
  17. Lysophosphatidic acid 2 alleviates deep vein thrombosis via protective endothelial barrier function
  18. Transcription factor A, mitochondrial promotes lymph node metastasis and lymphangiogenesis in epithelial ovarian carcinoma
  19. Serum PM20D1 levels are associated with nutritional status and inflammatory factors in gastric cancer patients undergoing early enteral nutrition
  20. Hydromorphone reduced the incidence of emergence agitation after adenotonsillectomy in children with obstructive sleep apnea: A randomized, double-blind study
  21. Vitamin D replacement therapy may regulate sleep habits in patients with restless leg syndrome
  22. The first-line antihypertensive nitrendipine potentiated the therapeutic effect of oxaliplatin by downregulating CACNA1D in colorectal cancer
  23. Health literacy and health-related quality of life: The mediating role of irrational happiness
  24. Modulatory effects of Lycium barbarum polysaccharide on bone cell dynamics in osteoporosis
  25. Mechanism research on inhibition of gastric cancer in vitro by the extract of Pinellia ternata based on network pharmacology and cellular metabolomics
  26. Examination of the causal role of immune cells in non-alcoholic fatty liver disease by a bidirectional Mendelian randomization study
  27. Clinical analysis of ten cases of HIV infection combined with acute leukemia
  28. Investigating the cardioprotective potential of quercetin against tacrolimus-induced cardiotoxicity in Wistar rats: A mechanistic insights
  29. Clinical observation of probiotics combined with mesalazine and Yiyi Baitouweng Decoction retention enema in treating mild-to-moderate ulcerative colitis
  30. Diagnostic value of ratio of blood inflammation to coagulation markers in periprosthetic joint infection
  31. Sex-specific associations of sex hormone binding globulin and risk of bladder cancer
  32. Core muscle strength and stability-oriented breathing training reduces inter-recti distance in postpartum women
  33. The ERAS nursing care strategy for patients undergoing transsphenoidal endoscopic pituitary tumor resection: A randomized blinded controlled trial
  34. The serum IL-17A levels in patients with traumatic bowel rupture post-surgery and its predictive value for patient prognosis
  35. Impact of Kolb’s experiential learning theory-based nursing on caregiver burden and psychological state of caregivers of dementia patients
  36. Analysis of serum NLR combined with intraoperative margin condition to predict the prognosis of cervical HSIL patients undergoing LEEP surgery
  37. Commiphora gileadensis ameliorate infertility and erectile dysfunction in diabetic male mice
  38. The correlation between epithelial–mesenchymal transition classification and MMP2 expression of circulating tumor cells and prognosis of advanced or metastatic nasopharyngeal carcinoma
  39. Tetrahydropalmatine improves mitochondrial function in vascular smooth muscle cells of atherosclerosis in vitro by inhibiting Ras homolog gene family A/Rho-associated protein kinase-1 signaling pathway
  40. A cross-sectional study: Relationship between serum oxidative stress levels and arteriovenous fistula maturation in maintenance dialysis patients
  41. A comparative analysis of the impact of repeated administration of flavan 3-ol on brown, subcutaneous, and visceral adipose tissue
  42. Identifying early screening factors for depression in middle-aged and older adults: A cohort study
  43. Perform tumor-specific survival analysis for Merkel cell carcinoma patients undergoing surgical resection based on the SEER database by constructing a nomogram chart
  44. Unveiling the role of CXCL10 in pancreatic cancer progression: A novel prognostic indicator
  45. High-dose preoperative intraperitoneal erythropoietin and intravenous methylprednisolone in acute traumatic spinal cord injuries following decompression surgeries
  46. RAB39B: A novel biomarker for acute myeloid leukemia identified via multi-omics and functional validation
  47. Impact of peripheral conditioning on reperfusion injury following primary percutaneous coronary intervention in diabetic and non-diabetic STEMI patients
  48. Clinical efficacy of azacitidine in the treatment of middle- and high-risk myelodysplastic syndrome in middle-aged and elderly patients: A retrospective study
  49. The effect of ambulatory blood pressure load on mitral regurgitation in continuous ambulatory peritoneal dialysis patients
  50. Expression and clinical significance of ITGA3 in breast cancer
  51. Single-nucleus RNA sequencing reveals ARHGAP28 expression of podocytes as a biomarker in human diabetic nephropathy
  52. rSIG combined with NLR in the prognostic assessment of patients with multiple injuries
  53. Toxic metals and metalloids in collagen supplements of fish and jellyfish origin: Risk assessment for daily intake
  54. Exploring causal relationship between 41 inflammatory cytokines and marginal zone lymphoma: A bidirectional Mendelian randomization study
  55. Gender beliefs and legitimization of dating violence in adolescents
  56. Effect of serum IL-6, CRP, and MMP-9 levels on the efficacy of modified preperitoneal Kugel repair in patients with inguinal hernia
  57. Effect of smoking and smoking cessation on hematological parameters in polycythemic patients
  58. Pathogen surveillance and risk factors for pulmonary infection in patients with lung cancer: A retrospective single-center study
  59. Necroptosis of hippocampal neurons in paclitaxel chemotherapy-induced cognitive impairment mediates microglial activation via TLR4/MyD88 signaling pathway
  60. Celastrol suppresses neovascularization in rat aortic vascular endothelial cells stimulated by inflammatory tenocytes via modulating the NLRP3 pathway
  61. Cord-lamina angle and foraminal diameter as key predictors of C5 palsy after anterior cervical decompression and fusion surgery
  62. GATA1: A key biomarker for predicting the prognosis of patients with diffuse large B-cell lymphoma
  63. Influencing factors of false lumen thrombosis in type B aortic dissection: A single-center retrospective study
  64. MZB1 regulates the immune microenvironment and inhibits ovarian cancer cell migration
  65. Integrating experimental and network pharmacology to explore the pharmacological mechanisms of Dioscin against glioblastoma
  66. Trends in research on preterm birth in twin pregnancy based on bibliometrics
  67. Four-week IgE/baseline IgE ratio combined with tryptase predicts clinical outcome in omalizumab-treated children with moderate-to-severe asthma
  68. Single-cell transcriptomic analysis identifies a stress response Schwann cell subtype
  69. Acute pancreatitis risk in the diagnosis and management of inflammatory bowel disease: A critical focus
  70. Effect of subclinical esketamine on NLRP3 and cognitive dysfunction in elderly ischemic stroke patients
  71. Interleukin-37 mediates the anti-oral tumor activity in oral cancer through STAT3
  72. CA199 and CEA expression levels, and minimally invasive postoperative prognosis analysis in esophageal squamous carcinoma patients
  73. Efficacy of a novel drainage catheter in the treatment of CSF leak after posterior spine surgery: A retrospective cohort study
  74. Comprehensive biomedicine assessment of Apteranthes tuberculata extracts: Phytochemical analysis and multifaceted pharmacological evaluation in animal models
  75. Relation of time in range to severity of coronary artery disease in patients with type 2 diabetes: A cross-sectional study
  76. Dopamine attenuates ethanol-induced neuronal apoptosis by stimulating electrical activity in the developing rat retina
  77. Correlation between albumin levels during the third trimester and the risk of postpartum levator ani muscle rupture
  78. Factors associated with maternal attention and distraction during breastfeeding and childcare: A cross-sectional study in the west of Iran
  79. Mechanisms of hesperetin in treating metabolic dysfunction-associated steatosis liver disease via network pharmacology and in vitro experiments
  80. The law on oncological oblivion in the Italian and European context: How to best uphold the cancer patients’ rights to privacy and self-determination?
  81. The prognostic value of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and prognostic nutritional index for survival in patients with colorectal cancer
  82. Factors affecting the measurements of peripheral oxygen saturation values in healthy young adults
  83. Comparison and correlations between findings of hysteroscopy and vaginal color Doppler ultrasonography for detection of uterine abnormalities in patients with recurrent implantation failure
  84. The effects of different types of RAGT on balance function in stroke patients with low levels of independent walking in a convalescent rehabilitation hospital
  85. Causal relationship between asthma and ankylosing spondylitis: A bidirectional two-sample univariable and multivariable Mendelian randomization study
  86. Correlations of health literacy with individuals’ understanding and use of medications in Southern Taiwan
  87. Correlation of serum calprotectin with outcome of acute cerebral infarction
  88. Comparison of computed tomography and guided bronchoscopy in the diagnosis of pulmonary nodules: A systematic review and meta-analysis
  89. Curdione protects vascular endothelial cells and atherosclerosis via the regulation of DNMT1-mediated ERBB4 promoter methylation
  90. The identification of novel missense variant in ChAT gene in a patient with gestational diabetes denotes plausible genetic association
  91. Molecular genotyping of multi-system rare blood types in foreign blood donors based on DNA sequencing and its clinical significance
  92. Exploring the role of succinyl carnitine in the association between CD39⁺ CD4⁺ T cell and ulcerative colitis: A Mendelian randomization study
  93. Dexmedetomidine suppresses microglial activation in postoperative cognitive dysfunction via the mmu-miRNA-125/TRAF6 signaling axis
  94. Analysis of serum metabolomics in patients with different types of chronic heart failure
  95. Diagnostic value of hematological parameters in the early diagnosis of acute cholecystitis
  96. Pachymaran alleviates fat accumulation, hepatocyte degeneration, and injury in mice with nonalcoholic fatty liver disease
  97. Decrease in CD4 and CD8 lymphocytes are predictors of severe clinical picture and unfavorable outcome of the disease in patients with COVID-19
  98. METTL3 blocked the progression of diabetic retinopathy through m6A-modified SOX2
  99. The predictive significance of anti-RO-52 antibody in patients with interstitial pneumonia after treatment of malignant tumors
  100. Exploring cerebrospinal fluid metabolites, cognitive function, and brain atrophy: Insights from Mendelian randomization
  101. Development and validation of potential molecular subtypes and signatures of ocular sarcoidosis based on autophagy-related gene analysis
  102. Widespread venous thrombosis: Unveiling a complex case of Behçet’s disease with a literature perspective
  103. Uterine fibroid embolization: An analysis of clinical outcomes and impact on patients’ quality of life
  104. Discovery of lipid metabolism-related diagnostic biomarkers and construction of diagnostic model in steroid-induced osteonecrosis of femoral head
  105. Serum-derived exomiR-188-3p is a promising novel biomarker for early-stage ovarian cancer
  106. Enhancing chronic back pain management: A comparative study of ultrasound–MRI fusion guidance for paravertebral nerve block
  107. Peptide CCAT1-70aa promotes hepatocellular carcinoma proliferation and invasion via the MAPK/ERK pathway
  108. Electroacupuncture-induced reduction of myocardial ischemia–reperfusion injury via FTO-dependent m6A methylation modulation
  109. Hemorrhoids and cardiovascular disease: A bidirectional Mendelian randomization study
  110. Cell-free adipose extract inhibits hypertrophic scar formation through collagen remodeling and antiangiogenesis
  111. HALP score in Demodex blepharitis: A case–control study
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  124. The application of augmented reality in robotic general surgery: A mini-review
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  151. Corrigendum
  152. Corrigendum to “Empagliflozin improves aortic injury in obese mice by regulating fatty acid metabolism”
  153. Corrigendum to “Comparing the therapeutic efficacy of endoscopic minimally invasive surgery and traditional surgery for early-stage breast cancer: A meta-analysis”
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  170. Special Issue Diabetes
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https://doi.org/10.1515/med-2024-1137
Keywords for this article
deep vein thrombosis; lysophosphatidic acid 2; vascular endothelial permeability; endothelial cells; zonula occludens-1
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Articles
  2. Network pharmacological analysis and in vitro testing of the rutin effects on triple-negative breast cancer
  3. Impact of diabetes on long-term survival in elderly liver cancer patients: A retrospective study
  4. Knockdown of CCNB1 alleviates high glucose-triggered trophoblast dysfunction during gestational diabetes via Wnt/β-catenin signaling pathway
  5. Risk factors for severe adverse drug reactions in hospitalized patients
  6. Analysis of the effect of ALA-PDT on macrophages in footpad model of mice infected with Fonsecaea monophora based on single-cell sequencing
  7. Development and validation of headspace gas chromatography with a flame ionization detector method for the determination of ethanol in the vitreous humor
  8. CMSP exerts anti-tumor effects on small cell lung cancer cells by inducing mitochondrial dysfunction and ferroptosis
  9. Predictive value of plasma sB7-H3 and YKL-40 in pediatric refractory Mycoplasma pneumoniae pneumonia
  10. Antiangiogenic potential of Elaeagnus umbellata extracts and molecular docking study by targeting VEGFR-2 pathway
  11. Comparison of the effectiveness of nurse-led preoperative counseling and postoperative follow-up care vs standard care for patients with gastric cancer
  12. Comparing the therapeutic efficacy of endoscopic minimally invasive surgery and traditional surgery for early-stage breast cancer: A meta-analysis
  13. Adhered macrophages as an additional marker of cardiomyocyte injury in biopsies of patients with dilated cardiomyopathy
  14. Association between statin administration and outcome in patients with sepsis: A retrospective study
  15. Exploration of the association between estimated glucose disposal rate and osteoarthritis in middle-aged and older adults: An analysis of NHANES data from 2011 to 2018
  16. A comparative analysis of the binary and multiclass classified chest X-ray images of pneumonia and COVID-19 with ML and DL models
  17. Lysophosphatidic acid 2 alleviates deep vein thrombosis via protective endothelial barrier function
  18. Transcription factor A, mitochondrial promotes lymph node metastasis and lymphangiogenesis in epithelial ovarian carcinoma
  19. Serum PM20D1 levels are associated with nutritional status and inflammatory factors in gastric cancer patients undergoing early enteral nutrition
  20. Hydromorphone reduced the incidence of emergence agitation after adenotonsillectomy in children with obstructive sleep apnea: A randomized, double-blind study
  21. Vitamin D replacement therapy may regulate sleep habits in patients with restless leg syndrome
  22. The first-line antihypertensive nitrendipine potentiated the therapeutic effect of oxaliplatin by downregulating CACNA1D in colorectal cancer
  23. Health literacy and health-related quality of life: The mediating role of irrational happiness
  24. Modulatory effects of Lycium barbarum polysaccharide on bone cell dynamics in osteoporosis
  25. Mechanism research on inhibition of gastric cancer in vitro by the extract of Pinellia ternata based on network pharmacology and cellular metabolomics
  26. Examination of the causal role of immune cells in non-alcoholic fatty liver disease by a bidirectional Mendelian randomization study
  27. Clinical analysis of ten cases of HIV infection combined with acute leukemia
  28. Investigating the cardioprotective potential of quercetin against tacrolimus-induced cardiotoxicity in Wistar rats: A mechanistic insights
  29. Clinical observation of probiotics combined with mesalazine and Yiyi Baitouweng Decoction retention enema in treating mild-to-moderate ulcerative colitis
  30. Diagnostic value of ratio of blood inflammation to coagulation markers in periprosthetic joint infection
  31. Sex-specific associations of sex hormone binding globulin and risk of bladder cancer
  32. Core muscle strength and stability-oriented breathing training reduces inter-recti distance in postpartum women
  33. The ERAS nursing care strategy for patients undergoing transsphenoidal endoscopic pituitary tumor resection: A randomized blinded controlled trial
  34. The serum IL-17A levels in patients with traumatic bowel rupture post-surgery and its predictive value for patient prognosis
  35. Impact of Kolb’s experiential learning theory-based nursing on caregiver burden and psychological state of caregivers of dementia patients
  36. Analysis of serum NLR combined with intraoperative margin condition to predict the prognosis of cervical HSIL patients undergoing LEEP surgery
  37. Commiphora gileadensis ameliorate infertility and erectile dysfunction in diabetic male mice
  38. The correlation between epithelial–mesenchymal transition classification and MMP2 expression of circulating tumor cells and prognosis of advanced or metastatic nasopharyngeal carcinoma
  39. Tetrahydropalmatine improves mitochondrial function in vascular smooth muscle cells of atherosclerosis in vitro by inhibiting Ras homolog gene family A/Rho-associated protein kinase-1 signaling pathway
  40. A cross-sectional study: Relationship between serum oxidative stress levels and arteriovenous fistula maturation in maintenance dialysis patients
  41. A comparative analysis of the impact of repeated administration of flavan 3-ol on brown, subcutaneous, and visceral adipose tissue
  42. Identifying early screening factors for depression in middle-aged and older adults: A cohort study
  43. Perform tumor-specific survival analysis for Merkel cell carcinoma patients undergoing surgical resection based on the SEER database by constructing a nomogram chart
  44. Unveiling the role of CXCL10 in pancreatic cancer progression: A novel prognostic indicator
  45. High-dose preoperative intraperitoneal erythropoietin and intravenous methylprednisolone in acute traumatic spinal cord injuries following decompression surgeries
  46. RAB39B: A novel biomarker for acute myeloid leukemia identified via multi-omics and functional validation
  47. Impact of peripheral conditioning on reperfusion injury following primary percutaneous coronary intervention in diabetic and non-diabetic STEMI patients
  48. Clinical efficacy of azacitidine in the treatment of middle- and high-risk myelodysplastic syndrome in middle-aged and elderly patients: A retrospective study
  49. The effect of ambulatory blood pressure load on mitral regurgitation in continuous ambulatory peritoneal dialysis patients
  50. Expression and clinical significance of ITGA3 in breast cancer
  51. Single-nucleus RNA sequencing reveals ARHGAP28 expression of podocytes as a biomarker in human diabetic nephropathy
  52. rSIG combined with NLR in the prognostic assessment of patients with multiple injuries
  53. Toxic metals and metalloids in collagen supplements of fish and jellyfish origin: Risk assessment for daily intake
  54. Exploring causal relationship between 41 inflammatory cytokines and marginal zone lymphoma: A bidirectional Mendelian randomization study
  55. Gender beliefs and legitimization of dating violence in adolescents
  56. Effect of serum IL-6, CRP, and MMP-9 levels on the efficacy of modified preperitoneal Kugel repair in patients with inguinal hernia
  57. Effect of smoking and smoking cessation on hematological parameters in polycythemic patients
  58. Pathogen surveillance and risk factors for pulmonary infection in patients with lung cancer: A retrospective single-center study
  59. Necroptosis of hippocampal neurons in paclitaxel chemotherapy-induced cognitive impairment mediates microglial activation via TLR4/MyD88 signaling pathway
  60. Celastrol suppresses neovascularization in rat aortic vascular endothelial cells stimulated by inflammatory tenocytes via modulating the NLRP3 pathway
  61. Cord-lamina angle and foraminal diameter as key predictors of C5 palsy after anterior cervical decompression and fusion surgery
  62. GATA1: A key biomarker for predicting the prognosis of patients with diffuse large B-cell lymphoma
  63. Influencing factors of false lumen thrombosis in type B aortic dissection: A single-center retrospective study
  64. MZB1 regulates the immune microenvironment and inhibits ovarian cancer cell migration
  65. Integrating experimental and network pharmacology to explore the pharmacological mechanisms of Dioscin against glioblastoma
  66. Trends in research on preterm birth in twin pregnancy based on bibliometrics
  67. Four-week IgE/baseline IgE ratio combined with tryptase predicts clinical outcome in omalizumab-treated children with moderate-to-severe asthma
  68. Single-cell transcriptomic analysis identifies a stress response Schwann cell subtype
  69. Acute pancreatitis risk in the diagnosis and management of inflammatory bowel disease: A critical focus
  70. Effect of subclinical esketamine on NLRP3 and cognitive dysfunction in elderly ischemic stroke patients
  71. Interleukin-37 mediates the anti-oral tumor activity in oral cancer through STAT3
  72. CA199 and CEA expression levels, and minimally invasive postoperative prognosis analysis in esophageal squamous carcinoma patients
  73. Efficacy of a novel drainage catheter in the treatment of CSF leak after posterior spine surgery: A retrospective cohort study
  74. Comprehensive biomedicine assessment of Apteranthes tuberculata extracts: Phytochemical analysis and multifaceted pharmacological evaluation in animal models
  75. Relation of time in range to severity of coronary artery disease in patients with type 2 diabetes: A cross-sectional study
  76. Dopamine attenuates ethanol-induced neuronal apoptosis by stimulating electrical activity in the developing rat retina
  77. Correlation between albumin levels during the third trimester and the risk of postpartum levator ani muscle rupture
  78. Factors associated with maternal attention and distraction during breastfeeding and childcare: A cross-sectional study in the west of Iran
  79. Mechanisms of hesperetin in treating metabolic dysfunction-associated steatosis liver disease via network pharmacology and in vitro experiments
  80. The law on oncological oblivion in the Italian and European context: How to best uphold the cancer patients’ rights to privacy and self-determination?
  81. The prognostic value of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and prognostic nutritional index for survival in patients with colorectal cancer
  82. Factors affecting the measurements of peripheral oxygen saturation values in healthy young adults
  83. Comparison and correlations between findings of hysteroscopy and vaginal color Doppler ultrasonography for detection of uterine abnormalities in patients with recurrent implantation failure
  84. The effects of different types of RAGT on balance function in stroke patients with low levels of independent walking in a convalescent rehabilitation hospital
  85. Causal relationship between asthma and ankylosing spondylitis: A bidirectional two-sample univariable and multivariable Mendelian randomization study
  86. Correlations of health literacy with individuals’ understanding and use of medications in Southern Taiwan
  87. Correlation of serum calprotectin with outcome of acute cerebral infarction
  88. Comparison of computed tomography and guided bronchoscopy in the diagnosis of pulmonary nodules: A systematic review and meta-analysis
  89. Curdione protects vascular endothelial cells and atherosclerosis via the regulation of DNMT1-mediated ERBB4 promoter methylation
  90. The identification of novel missense variant in ChAT gene in a patient with gestational diabetes denotes plausible genetic association
  91. Molecular genotyping of multi-system rare blood types in foreign blood donors based on DNA sequencing and its clinical significance
  92. Exploring the role of succinyl carnitine in the association between CD39⁺ CD4⁺ T cell and ulcerative colitis: A Mendelian randomization study
  93. Dexmedetomidine suppresses microglial activation in postoperative cognitive dysfunction via the mmu-miRNA-125/TRAF6 signaling axis
  94. Analysis of serum metabolomics in patients with different types of chronic heart failure
  95. Diagnostic value of hematological parameters in the early diagnosis of acute cholecystitis
  96. Pachymaran alleviates fat accumulation, hepatocyte degeneration, and injury in mice with nonalcoholic fatty liver disease
  97. Decrease in CD4 and CD8 lymphocytes are predictors of severe clinical picture and unfavorable outcome of the disease in patients with COVID-19
  98. METTL3 blocked the progression of diabetic retinopathy through m6A-modified SOX2
  99. The predictive significance of anti-RO-52 antibody in patients with interstitial pneumonia after treatment of malignant tumors
  100. Exploring cerebrospinal fluid metabolites, cognitive function, and brain atrophy: Insights from Mendelian randomization
  101. Development and validation of potential molecular subtypes and signatures of ocular sarcoidosis based on autophagy-related gene analysis
  102. Widespread venous thrombosis: Unveiling a complex case of Behçet’s disease with a literature perspective
  103. Uterine fibroid embolization: An analysis of clinical outcomes and impact on patients’ quality of life
  104. Discovery of lipid metabolism-related diagnostic biomarkers and construction of diagnostic model in steroid-induced osteonecrosis of femoral head
  105. Serum-derived exomiR-188-3p is a promising novel biomarker for early-stage ovarian cancer
  106. Enhancing chronic back pain management: A comparative study of ultrasound–MRI fusion guidance for paravertebral nerve block
  107. Peptide CCAT1-70aa promotes hepatocellular carcinoma proliferation and invasion via the MAPK/ERK pathway
  108. Electroacupuncture-induced reduction of myocardial ischemia–reperfusion injury via FTO-dependent m6A methylation modulation
  109. Hemorrhoids and cardiovascular disease: A bidirectional Mendelian randomization study
  110. Cell-free adipose extract inhibits hypertrophic scar formation through collagen remodeling and antiangiogenesis
  111. HALP score in Demodex blepharitis: A case–control study
  112. Assessment of SOX2 performance as a marker for circulating cancer stem-like cells (CCSCs) identification in advanced breast cancer patients using CytoTrack system
  113. Risk and prognosis for brain metastasis in primary metastatic cervical cancer patients: A population-based study
  114. Comparison of the two intestinal anastomosis methods in pediatric patients
  115. Factors influencing hematological toxicity and adverse effects of perioperative hyperthermic intraperitoneal vs intraperitoneal chemotherapy in gastrointestinal cancer
  116. Endotoxin tolerance inhibits NLRP3 inflammasome activation in macrophages of septic mice by restoring autophagic flux through TRIM26
  117. Review Articles
  118. The effects of enhanced external counter-pulsation on post-acute sequelae of COVID-19: A narrative review
  119. Diabetes-related cognitive impairment: Mechanisms, symptoms, and treatments
  120. Microscopic changes and gross morphology of placenta in women affected by gestational diabetes mellitus in dietary treatment: A systematic review
  121. Review of mechanisms and frontier applications in IL-17A-induced hypertension
  122. Research progress on the correlation between islet amyloid peptides and type 2 diabetes mellitus
  123. The safety and efficacy of BCG combined with mitomycin C compared with BCG monotherapy in patients with non-muscle-invasive bladder cancer: A systematic review and meta-analysis
  124. The application of augmented reality in robotic general surgery: A mini-review
  125. The effect of Greek mountain tea extract and wheat germ extract on peripheral blood flow and eicosanoid metabolism in mammals
  126. Neurogasobiology of migraine: Carbon monoxide, hydrogen sulfide, and nitric oxide as emerging pathophysiological trinacrium relevant to nociception regulation
  127. Plant polyphenols, terpenes, and terpenoids in oral health
  128. Laboratory medicine between technological innovation, rights safeguarding, and patient safety: A bioethical perspective
  129. End-of-life in cancer patients: Medicolegal implications and ethical challenges in Europe
  130. The maternal factors during pregnancy for intrauterine growth retardation: An umbrella review
  131. Intra-abdominal hypertension/abdominal compartment syndrome of pediatric patients in critical care settings
  132. PI3K/Akt pathway and neuroinflammation in sepsis-associated encephalopathy
  133. Screening of Group B Streptococcus in pregnancy: A systematic review for the laboratory detection
  134. Giant borderline ovarian tumours – review of the literature
  135. Leveraging artificial intelligence for collaborative care planning: Innovations and impacts in shared decision-making – A systematic review
  136. Cholera epidemiology analysis through the experience of the 1973 Naples epidemic
  137. Case Reports
  138. Delayed graft function after renal transplantation
  139. Semaglutide treatment for type 2 diabetes in a patient with chronic myeloid leukemia: A case report and review of the literature
  140. Diverse electrophysiological demyelinating features in a late-onset glycogen storage disease type IIIa case
  141. Giant right atrial hemangioma presenting with ascites: A case report
  142. Laser excision of a large granular cell tumor of the vocal cord with subglottic extension: A case report
  143. Rapid Communication
  144. Biological properties of valve materials using RGD and EC
  145. Letter to the Editor
  146. Role of enhanced external counterpulsation in long COVID
  147. Expression of Concern
  148. Expression of concern “A ceRNA network mediated by LINC00475 in papillary thyroid carcinoma”
  149. Expression of concern “Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway”
  150. Expression of concern “circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8”
  151. Corrigendum
  152. Corrigendum to “Empagliflozin improves aortic injury in obese mice by regulating fatty acid metabolism”
  153. Corrigendum to “Comparing the therapeutic efficacy of endoscopic minimally invasive surgery and traditional surgery for early-stage breast cancer: A meta-analysis”
  154. Corrigendum to “The progress of autoimmune hepatitis research and future challenges”
  155. Retraction
  156. Retraction of “miR-654-5p promotes gastric cancer progression via the GPRIN1/NF-κB pathway”
  157. Special Issue Advancements in oncology: bridging clinical and experimental research - Part II
  158. Unveiling novel biomarkers for platinum chemoresistance in ovarian cancer
  159. Lathyrol affects the expression of AR and PSA and inhibits the malignant behavior of RCC cells
  160. The era of increasing cancer survivorship: Trends in fertility preservation, medico-legal implications, and ethical challenges
  161. Bone scintigraphy and positron emission tomography in the early diagnosis of MRONJ
  162. Meta-analysis of clinical efficacy and safety of immunotherapy combined with chemotherapy in non-small cell lung cancer
  163. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part IV
  164. Exploration of mRNA-modifying METTL3 oncogene as momentous prognostic biomarker responsible for colorectal cancer development
  165. Special Issue The evolving saga of RNAs from bench to bedside - Part III
  166. Interaction and verification of ferroptosis-related RNAs Rela and Stat3 in promoting sepsis-associated acute kidney injury
  167. Special Issue Exploring the biological mechanism of human diseases based on MultiOmics Technology - Part II
  168. Dynamic changes in lactate-related genes in microglia and their role in immune cell interactions after ischemic stroke
  169. A prognostic model correlated with fatty acid metabolism in Ewing’s sarcoma based on bioinformatics analysis
  170. Special Issue Diabetes
  171. Nutritional risk assessment and nutritional support in children with congenital diabetes during surgery
  172. Correlation of the differential expressions of RANK, RANKL, and OPG with obesity in the elderly population in Xinjiang
  173. Special Issue Biomarker Discovery and Precision Medicine
  174. CircASH1L-mediated tumor progression in triple-negative breast cancer: PI3K/AKT pathway mechanisms
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