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Cell-free adipose extract inhibits hypertrophic scar formation through collagen remodeling and antiangiogenesis

  • Junchao Sun , Yujie Zhao , Zhoujiang Qu , Shudong Sun EMAIL logo and Kun Wang EMAIL logo
Published/Copyright: August 22, 2025
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Open Medicine
From the journal Open Medicine Volume 20 Issue 1

Abstract

Objective

Hypertrophic scars (HS) are a fibrotic proliferative disorder that results from an abnormal wound healing process, presenting significant challenges for clinical intervention. The primary characteristics of HS include excessive collagen deposition and angiogenesis. In recent years, the study of mesenchymal stem cells (MSCs) and their derived exosomes has emerged as a prominent area of research within the academic community. However, the therapeutic application of MSCs is impeded by several challenges, including immune rejection, sourcing limitations, ethical dilemmas, and difficulties related to the scalability of exosome production. Cell-free adipose extract (CEFAE), a novel bioproduct derived from adipose tissue, is rich in various active protein factors that are essential for MSCs and their exosomes. CEFAE presents several advantages, including low immunogenicity, non-tumorigenicity, and a high degree of clinical safety. However, the application of CEFAE in the prevention and treatment of scar formation has not been adequately validated through experimental studies.

Methods

This research established a rabbit ear scar model, establishing a control group, a low-concentration CEFAE group (L-CEFAE), and a high-concentration CEFAE group (H-CEFAE) to evaluate wound treatment. Observations of scar changes were conducted at 14 and 28 days post-treatment, supplemented by histological and immunohistochemical analyses.

Results

Histological analysis revealed that the H-CEFAE group achieved optimal outcomes, with the lowest collagen deposition, thinnest epidermal/dermal thickness, and the most orderly collagen alignment. Furthermore, the formation of new blood vessels in the H-CEFAE group showed a significant reduction over time, resulting in decreased blood supply, which is beneficial for suppressing scar tissue development. Quantification of COL I, COL III, and vascular endothelial growth factor also supports these results.

Conclusion

The findings indicated that high-concentration CEFAE has a beneficial preventive and therapeutic effect on scar proliferation. Furthermore, the study explored the potential mechanisms by which CEFAE inhibits scar proliferation, thereby providing novel therapeutic strategies for the prevention and management of clinical scars.

Keywords: hypertrophic scar; cell-free adipose extract; CEFAE; collagen; angiogenesis; antiangiogenesis

1 Introduction

Hypertrophic scars (HS) typically develop following severe burns or skin injuries and are classified as a fibrotic proliferative disorder that occurs during the skin wound healing process [1,2,3,4]. These scars are characterized by excessive proliferation of fibroblasts, fibrosis, chronic inflammation, and an overabundance of extracellular matrix (ECM) proteins produced by fibroblasts, particularly type I and type III collagen [5,6,7,8,9,10]. HS not only cause cosmetic concerns but may also lead to functional impairments, resulting in both physiological and psychological issues. Currently, there are various treatment methods for scars in clinical practice, commonly including surgical excision, laser therapy, pressure therapy, local injection of corticosteroids, and functional dressings [11,12,13,14,15]. Since there has not been an effective treatment plan that can completely resolve the issue of scars, there is an urgent need to explore new clinical intervention approaches.

In recent years, mesenchymal stem cells (MSCs) and their derived exosomes have emerged as a prominent area of research in academia [16,17,18,19,20]. For instance, exosomes derived from human adipose-derived MSCs have been utilized to mitigate HS fibrosis [21]. Nevertheless, MSC therapy continues to encounter numerous unresolved challenges, including immune rejection, sourcing limitations, ethical controversies, and difficulties in scaling up exosome production [17,22,23]. These factors collectively hinder the advancement of stem cells and exosomes in clinical applications. Research has demonstrated that stem cells can facilitate tissue repair by secreting growth factors [21,24,25,26,27,28]. However, the low yield of cytokines and the high cost of treatment present significant barriers to their widespread application.

Fat tissue has been extensively utilized in the treatment of various diseases after undergoing processing through physical or chemical methods as they are rich in cytokines [29,30,31,32]. Cell-free adipose extract (CEFAE) is an emerging biological product derived from adipose tissue that has garnered attention in regenerative medicine. Unlike traditional fat grafting or stem cell therapies, CEFAE is processed to remove intact cells (e.g., adipocytes, stromal vascular fraction cells) while retaining a concentrated mixture of bioactive components, including growth factors [e.g., vascular endothelial growth factor (VEGF), FGF, TGF-β], cytokines, extracellular vesicles, and other soluble proteins [33,34,35,36,37,38]. The extract is typically prepared through mechanical emulsification, centrifugation, and filtration of lipoaspirated fat, resulting in a liquid formulation enriched with regenerative molecules but devoid of cellular debris or risks associated with whole-cell transplantation. Furthermore, CEFAE offers several advantages, including autologous origin, low immunogenicity, non-tumorigenicity, high clinical safety, and minimal ethical concerns [39,40,41,42,43,44]. However, the application of CEFAE in the prevention and treatment of scar formation lacks robust experimental validation. This study employs a rabbit ear scar model to investigate the preventive and therapeutic effects of CEFAE on scar hyperplasia and further explores its potential mechanisms for inhibiting scar hyperplasia, thereby providing new treatment strategies for the prevention and management of clinical scars.

2 Materials and methods

2.1 Preparation of CEFAE

A total of 24 male New Zealand rabbits aged 8–10 weeks were used in this study and purchased from Qingdao Kangda Aibo Biotechnology Co., Ltd. (Qingdao, China). The animals were housed under controlled conditions (24 ± 2°C, 50 ± 10% humidity, 12 h light/dark cycle) and acclimatized for 1 week. All experiments and procedures were approved by the Animal Research Committee of the Clinical Medical College of Shandong Second Medical University.

Using negative pressure suction technology, 5 mL of adipose tissue was collected from the groin area of a rabbit. The collected adipose tissue was rinsed with physiological saline and then centrifuged at 1,200 rpm for 3 min. The excess washing liquid from the lower layer was drained, and the above steps were repeated for a total of three cycles. After centrifugation, the adipose tissue was divided into 10 mL syringes using a fat emulsifier. One end of the emulsifier was connected to a 10 mL syringe, while the other end was connected to an empty 10 mL syringe. After manually pushing and pulling the fat 60 times, the emulsified fat was transferred to a new syringe, the stopper was tightened, and the syringe piston shaft was broken off. The remaining fat was processed in the same manner until all the fat was handled. During the emulsification process, if larger fat clumps or obvious white fascia were observed, they could be removed and discarded using sterile gauze or tweezers. After balancing the emulsified fat, it was symmetrically placed in a centrifuge and centrifuged at 2,000 rpm for 10 min. Following centrifugation, a three-layer structure should form, with the bottom layer being CEFAE, the middle layer being fat, and the top layer being oil. The top two layers were removed to obtain pure CEFAE. Finally, the obtained CEFAE was filtered using a 0.22 micron sterilizing filter, and the filtrate was aliquoted into 1 mL sterile tubes for future use.

2.2 Establishment and treatment of rabbit ear scar model

The experimental rabbits were anesthetized using inhalation of 2–2.5% isoflurane. Once adequate anesthesia was confirmed, three circular defects, each with a diameter of 8 mm, were created on the inner surface of the ventral side of each ear, removing the dermis, epidermis, and perichondrium.

These three defects were randomly assigned to three groups: the top group received high concentration CEFAE with 3 mg/mL (H-CEFAE group) treatment, the middle group received low concentration CEFAE with 1 mg/mL (L-CEFAE group) treatment, and the bottom group served as the PBS control group. At a distance of 1 mm from the outer edge of the wound, each group received a subcutaneous injection of H-CEFAE, L-CEFAE, or PBS, with an injection volume of 100 µL for each.

After a 14-day observation period, twelve experimental rabbits (four in each group) were anesthetized using 2–2.5% isoflurane. Subsequently, sterile ophthalmic scissors were employed to incise the muscle layer, allowing for the excision of the wound and the surrounding tissue within a 3 mm margin. The fresh wound tissue was immediately fixed in 4% formaldehyde for subsequent dehydration and paraffin block preparation. After 28 days, the same procedure was conducted on the remaining twelve rabbits.

2.3 Scar elevation index (SEI)

The SEI is utilized to evaluate the condition of scars and the process of wound healing. This index is determined by measuring the distance from the highest point of the vertical scar tissue (a) to the surface of the surrounding normal skin (b) and to the surface of the ear cartilage. The specific methodology involves using ImageJ software for measurement, where SEI is calculated as SEI = a/b. In this formula, ‘a’ represents the vertical distance from the highest point of the scar tissue to the surface of the ear cartilage, while ‘b’ denotes the vertical distance from the surface of the surrounding normal skin to the surface of the ear cartilage. The assessment of the SEI is performed prior to injection and again at 14 and 28 days post-injection.

2.4 Histopathological examination

Fix the samples in 4% paraformaldehyde, followed by embedding in paraffin. Then, cut the samples into sections with a thickness of 5 µm and mount them on glass slides. The slices are processed through the following steps: first, they undergo routine deparaffinization and hydration treatment, then they are soaked in hematoxylin for 5 min, followed by rinsing with tap water. Next, the slices are immersed in a hydrochloric acid-ethanol solution for 30 s, rinsed again with tap water, and then stained with eosin for 2 min, followed by another rinse with tap water. After that, a gradient concentration ethanol dehydration treatment is performed, and finally, they are cleaned in xylene and mounted with neutral balsam. The final results are observed under a microscope.

The tissue sections were subjected to staining with Ponceau acid fuchsin for a duration of 10 min, followed by rinsing with distilled water. Subsequently, the sections were immersed in a phosphomolybdic acid solution for 5 min, after which they were stained with aniline blue for an additional 5 min and treated with 1% acetic acid for 2 min. Following these procedures, the sections underwent dehydration, clarification, and mounting before being examined under a microscope.

2.5 Immunohistochemistry and Immunofluorescence staining

Fix the samples in 4% paraformaldehyde, followed by embedding in paraffin. Then, cut the samples into sections with a thickness of 5 µm and mount them on glass slides. After deparaffinization with xylene, the sections underwent gradient alcohol hydration and were heated in a microwave to promote antigen retrieval. Next, the sections were incubated in a 3% H2O2 solution for 15 min to eliminate endogenous peroxidase activity. Subsequently, the sections were blocked with goat serum for 1 h to prevent non-specific binding. The sections were incubated overnight with the primary antibody at 4°C, followed by a 2 h incubation with the secondary antibody. The color development process used diaminobenzidine. After counterstaining with hematoxylin, the sections were dehydrated and cleared, and finally sealed with resin.

Tissue sections are placed in a repair box filled with EDTA antigen retrieval buffer (pH 9.0) and subjected to antigen retrieval in a microwave. Heat on high for 3 min until boiling, then switch to low for 9 min. After natural cooling, the slides are washed once in PBS for 5 min. After gently shaking off excess liquid, 10% rabbit serum is added to evenly cover the tissue, and the slides are incubated in a 37°C oven for 30 min. The blocking solution is gently discarded, and PBS with a prepared primary antibody is added to the slides, which are then placed in a humid box and incubated overnight at 4°C. The slides are washed in PBS three times, with each wash lasting 5 min. After gently shaking off excess liquid, a secondary antibody is added to cover the tissue and incubated at 37°C for 45 min in the dark. The slides are washed in PBS four times, with each wash lasting 5 min, and after gently shaking off excess liquid, DAPI staining solution is added and incubated at room temperature for 10 min in the dark. The slides are washed in distilled water three times, with each wash lasting 5 min. After gently shaking off excess liquid, the slides are mounted with an anti-fade mounting medium. The slides are observed under an inverted fluorescence microscope, and images are collected. The results were analyzed using ImageJ software.

2.6 Statistical analysis

Differences in quantitative data were analyzed using SPSS 23. A p-value of less than 0.05 was considered statistically significant.

  1. Ethical approval: The study protocol was reviewed and approved by the Shandong Second Medical University Research Ethics Committee and Weifang People’s Hospital Research Ethics Committee.

3 Results

3.1 In vivo treatment

Before starting the treatment, all rabbits were successfully modeled, and three circular wounds with a diameter of 0.8 cm were made on each rabbit's ear, and the cartilage membrane was removed. Comprehensive observations indicated that by the 14th day following surgery, the wound healing rates in both the H-CEFAE and L-CEFAE groups surpassed those of the Blank group. By the 28th day, all groups achieved complete wound closure; however, the Blank and L-CEFAE groups exhibited notable scar characteristics, including elevation, contraction, erythema, and palpable scars. In contrast, the H-CEFAE group presented with flatter scars, demonstrating less contraction and reduced erythema (Figure 1). A quantitative measure of the SEI was significantly lower in the H-CEFAE group (1.15 ± 0.08) compared to the L-CEFAE (3.03 ± 0.12) and blank (4.28 ± 0.17) groups at day 28. These findings suggest that the CEFAE effectively reduces scar hypertrophy and promotes regenerative healing.

Figure 1 Treatment of HS: (a) Gross view, (b) Wound trance of Blank, L-CEFAE, and H-CEFAE group at 0, 14, and 28 days; (c) SEI assay calculated from HE staining (*P < 0.05).
Figure 1

Treatment of HS: (a) Gross view, (b) Wound trance of Blank, L-CEFAE, and H-CEFAE group at 0, 14, and 28 days; (c) SEI assay calculated from HE staining (*P < 0.05).

3.2 Histopathological, immunohistochemistry and ommunofluorescence staining

Histological analysis revealed that the H-CEFAE group achieved optimal outcomes, with the lowest collagen deposition, thinnest epidermal/dermal thickness, and the most orderly collagen alignment. The L-CEFAE group showed intermediate efficacy, demonstrating comparatively reduced scar severity and improved ECM organization (Figures 2–4). In contrast, blank group scars exhibited thickened epidermal and dermal layers, irregular collagen fiber organization, and excessive ECM accumulation. Furthermore, the formation of new blood vessels in the H-CEFAE group showed a significant reduction over time, resulting in decreased blood supply, which is beneficial for suppressing scar tissue development. Although the L-CEFAE group demonstrated a greater quantity of new blood vessels compared to the H-CEFAE group, it also exhibited a tendency toward vascular inhibition (Figure 5). Quantification of COL I, COL III, and VEGF also supports these results (Figure 6).

Figure 2 HE staining of blank, L-CEFAE and H-CEFAE with 14 and 28 days.
Figure 2

HE staining of blank, L-CEFAE and H-CEFAE with 14 and 28 days.

Figure 3 Masson staining of blank, L-CEFAE, and H-CEFAE at 14 and 28 days.
Figure 3

Masson staining of blank, L-CEFAE, and H-CEFAE at 14 and 28 days.

Figure 4 COL I and COL III staining of blank, L-CEFAE, and H-CEFAE at 14 and 28 days.
Figure 4

COL I and COL III staining of blank, L-CEFAE, and H-CEFAE at 14 and 28 days.

Figure 5 VEGF staining of blank, L-CEFAE, and H-CEFAE at 14 and 28 days.
Figure 5

VEGF staining of blank, L-CEFAE, and H-CEFAE at 14 and 28 days.

Figure 6 Quantification of COL I, COL III, and VEGF.
Figure 6

Quantification of COL I, COL III, and VEGF.

4 Discussion

HS develop due to an aberrant wound-healing response characterized by excessive fibroblast proliferation, collagen deposition, and disrupted ECM remodeling. Central to this pathology is the aberrant behavior of COL I and COL III. Early in healing, COL III – a thinner, more flexible collagen variant – is overproduced, forming a provisional matrix that is later replaced by the thicker, sturdier COL I in healthy tissue. However, in HS, this transition is disrupted: COL III remains overly abundant initially, while COL I eventually dominates but is deposited in dense, parallel bundles rather than the basket-weave pattern of normal skin. VEGF promotes excessive microvascular proliferation, contributing to scar erythema and rigidity. Genetic predisposition and environmental factors (e.g., wound infection, delayed epithelialization) further amplify these pathways, culminating in raised, erythematous, and inelastic scars confined to the original wound boundaries. Unlike keloids, HS lack invasive growth but share overlapping molecular drivers.

Recent research advances in the treatment of HS using stem cells and exosomes have focused on harnessing their regenerative and anti-fibrotic properties to target the pathological mechanisms underlying scar formation [45]. MSCs, sourced from adipose tissue, bone marrow, or umbilical cord, are increasingly recognized for their ability to modulate inflammation, reduce fibroblast overactivity, and promote collagen remodeling. Studies highlight that MSCs inhibit HS progression by suppressing the TGF-β1/Smad pathway, a key driver of fibrosis, while enhancing the expression of anti-fibrotic factors like HGF and MMPs to degrade excess collagen. Innovations in delivery systems, such as 3D-printed scaffolds or injectable hydrogels, have improved MSC retention and localized therapeutic effects in scar tissue, addressing earlier challenges like poor cell survival. Exosomes, nanosized EVs derived from MSCs, have emerged as a safer, cell-free alternative, circumventing risks associated with whole-cell therapies. These vesicles are enriched with bioactive molecules, including miRNAs (e.g., miR-29a, miR-21, and miR-196a), proteins, and lipids, which regulate fibroblast proliferation, collagen synthesis, and inflammation. Preclinical models demonstrate that exosome treatment reduces scar thickness, improves collagen alignment, and normalizes ECM composition by silencing pro-fibrotic genes and promoting apoptosis in hyperactive fibroblasts. Advances in bioengineering, such as modifying exosomes to enhance targeting or loading them with specific anti-scarring miRNAs, have boosted their therapeutic precision. Techniques like exosome-laden microneedling patches or hybrid hydrogels enable sustained, controlled release into dense scar tissue, improving efficacy.

Despite their therapeutic potential, stem cell and exosome therapies for HS face significant challenges. Stem cells, particularly MSCs, struggle with low survival and engraftment rates in the harsh fibrotic scar microenvironment, where hypoxia and inflammation limit their effectiveness. Additionally, heterogeneity in MSCs sources and potency, along with risks of unintended differentiation or rare tumorigenic effects, raises safety and consistency concerns. Exosomes, while safer as cell-free alternatives, confront hurdles in standardization, as isolation methods yield variable purity and cargo composition. Their natural molecular cargo – miRNAs, proteins, and lipids – can include unintended pro-fibrotic elements, and engineering exosomes to enrich specific therapeutic molecules without compromising stability remains technically difficult. Both therapies face delivery challenges, as dense scar tissue impedes penetration, and current strategies (e.g., hydrogels, microneedling) only partially improve localized retention.

CEFAE is a cell-free biologic derived from processed adipose tissue, enriched with growth factors, cytokines, EVs, and signaling molecules. Its therapeutic potential for HS lies in its ability to target multiple pathological processes simultaneously. Angiogenesis is enhanced through VEGF and FGF, improving blood flow and reducing hypoxia-driven fibrosis. Simultaneously, CEFAE remodels the ECM by stimulating elastin and hyaluronic acid synthesis, which restores skin elasticity, while EV-mediated delivery of MMPs and miRNAs (e.g., miR-196a) degrades disorganized collagen and promotes healthy ECM alignment.

The results indicate that both low and high concentrations of CEFAE have a significant regulatory effect on collagen, particularly under high concentration conditions. Specifically, in the high concentration group, the content of COL III exhibits a decreasing trend, while the content of COL I gradually increases over time. CEFAE effectively rebalances collagen dynamics in HS by targeting both type 1 and COL III. It suppresses excessive COL I synthesis – associated with scar rigidity, while promoting the production of COL III, which enhances skin elasticity, through regenerative factors such as VEGF and FGF. We speculate that CEFAE upregulates matrix metalloproteinases (MMPs-1/3) to degrade overabundant COL I and ensures balanced degradation of COL III, maintaining a healthy collagen ratio simultaneously. This will be further validated in our future experiments. This dual modulation restores the collagen architecture to a natural, organized basket-weave pattern, improving scar pliability and tensile strength. Long-term, CEFAE sustains ECM homeostasis via bioactive molecules like adiponectin and miRNAs, which fine-tune collagen gene expression and prevent scar recurrence. By harmonizing collagen reduction and regeneration, CEFAE transforms HS into softer, thinner, and more functional tissue resembling healthy skin.

In comparison to the other cell and active factor therapies previously discussed, CEFAE presents several significant advantages. First, CEFAE circumvents the ethical challenges associated with MSCs. Currently, the use of allogeneic MSCs necessitates rigorous donor screening and informed consent, while the use of embryonically derived MSCs raises ethical concerns regarding the beginning of life. Moreover, traditional cell therapies often require in vitro expansion, which carries the risk of tumorigenesis. A notable advantage of CEFAE is that it does not involve the transplantation of live cells, thereby mitigating the risks of tumor formation and immune rejection. Additionally, CEFAE does not depend on the viability of donor cells, facilitating the establishment of a storage bank and eliminating the human leukocyte antigen matching issues commonly associated with MSCs. This study evaluated the safety and efficacy of rabbit autologous CEFAE, thereby establishing a foundational basis for its conceptual validation in human applications. Future research will concentrate on developing the production process for human-derived CEFAE and investigating its mechanisms for enhancing healing in chronic wound models. This acellular therapy model is anticipated to address the challenges associated with cell therapies, particularly in the realms of ethics, regulation, and industrialization.

However, challenges remain, including variability in CEFAE composition due to donor differences and processing methods, limited penetration into dense scars, and incomplete understanding of how individual components synergize. Compared to cell-based therapies, CEFAE avoids risks like tumorigenicity and offers a broader bioactive profile than isolated exosomes, but standardization and delivery optimization (e.g., combining with microneedling) are needed. Overall, CEFAE represents a promising, multi-target approach to scar treatment, though further clinical validation and mechanistic studies are essential to solidify its role in practice.

5 Conclusion

In conclusion, CEFAE demonstrates significant preventive and therapeutic efficacy in the rabbit ear HS model, effectively restoring homeostasis in collagen metabolism and inhibiting abnormal neovascularization associated with altered angiogenic regulators. These findings highlight the dual mechanisms through which CEFAE functions, particularly in the regulation of collagen remodeling and the angiogenesis process. This study supports the potential of CEFAE as a cell-free therapeutic intervention for HS, offering a promising approach for alleviating this condition. Future research will aim to further optimize the effective concentration of CEFAE.

Acknowledgments

This research was supported by the Science and Technology Project of Traditional Chinese Medicine of Shandong Province (M-2022055), and the Traditional Chinese Medicine Research Project of Weifang Health Commission (WFZYY2022-03-013).

  1. Funding information: Authors state no funding involved.

  2. Author contributions: All authors contributed to the conception, design, and data analysis of this study. Junchao Sun contributed to the acquisition and interpretation of data and drafted the manuscript. Yujie Zhao contributed to the design of the study, performed statistical analyses and improved the manuscript. Zhoujiang Qu contributed to the data collection, interpretation and provided constructive feedback on the manuscript. Shudong Sun contributed to the study design, data analysis, and revised the manuscript. Kun Wang contributed to the interpretation of data and provided significant revisions to the manuscript. All authors have approved the final version of the manuscript and have agreed to be accountable for all aspects of the work. This ensures that any inquiries regarding the accuracy or integrity of the study are adequately addressed and resolved.

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

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

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Received: 2025-03-17
Revised: 2025-07-05
Accepted: 2025-07-06
Published Online: 2025-08-22

© 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

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  4. Knockdown of CCNB1 alleviates high glucose-triggered trophoblast dysfunction during gestational diabetes via Wnt/β-catenin signaling pathway
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https://doi.org/10.1515/med-2025-1249
Keywords for this article
hypertrophic scar; cell-free adipose extract; CEFAE; collagen; angiogenesis; antiangiogenesis
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. Lateral transperitoneal laparoscopic adrenalectomy: A single-centre experience of 21 procedures
  118. Petunidin attenuates lipopolysaccharide-induced retinal microglia inflammatory response in diabetic retinopathy by targeting OGT/NF-κB/LCN2 axis
  119. Procalcitonin and C-reactive protein as biomarkers for diagnosing and assessing the severity of acute cholecystitis
  120. Factors determining the number of sessions in successful extracorporeal shock wave lithotripsy patients
  121. Development of a nomogram for predicting cancer-specific survival in patients with renal pelvic cancer following surgery
  122. Inhibition of ATG7 promotes orthodontic tooth movement by regulating the RANKL/OPG ratio under compression force
  123. A machine learning-based prognostic model integrating mRNA stemness index, hypoxia, and glycolysis‑related biomarkers for colorectal cancer
  124. Glutathione attenuates sepsis-associated encephalopathy via dual modulation of NF-κB and PKA/CREB pathways
  125. FAHD1 prevents neuronal ferroptosis by modulating R-loop and the cGAS–STING pathway
  126. Association of placenta weight and morphology with term low birth weight: A case–control study
  127. Investigation of the pathogenic variants induced Sjogren’s syndrome in Turkish population
  128. Nucleotide metabolic abnormalities in post-COVID-19 condition and type 2 diabetes mellitus patients and their association with endocrine dysfunction
  129. TGF-β–Smad2/3 signaling in high-altitude pulmonary hypertension in rats: Role and mechanisms via macrophage M2 polarization
  130. Ultrasound-guided unilateral versus bilateral erector spinae plane block for postoperative analgesia of patients undergoing laparoscopic cholecystectomy
  131. Profiling gut microbiome dynamics in subacute thyroiditis: Implications for pathogenesis, diagnosis, and treatment
  132. Delta neutrophil index, CRP/albumin ratio, procalcitonin, immature granulocytes, and HALP score in acute appendicitis: Best performing biomarker?
  133. Anticancer activity mechanism of novelly synthesized and characterized benzofuran ring-linked 3-nitrophenyl chalcone derivative on colon cancer cells
  134. H2valdien3 arrests the cell cycle and induces apoptosis of gastric cancer
  135. Prognostic relevance of PRSS2 and its immune correlates in papillary thyroid carcinoma
  136. Association of SGLT2 inhibition with psychiatric disorders: A Mendelian randomization study
  137. Motivational interviewing for alcohol use reduction in Thai patients
  138. Luteolin alleviates oxygen-glucose deprivation/reoxygenation-induced neuron injury by regulating NLRP3/IL-1β signaling
  139. Polyphyllin II inhibits thyroid cancer cell growth by simultaneously inhibiting glycolysis and oxidative phosphorylation
  140. Relationship between the expression of copper death promoting factor SLC31A1 in papillary thyroid carcinoma and clinicopathological indicators and prognosis
  141. CSF2 polarized neutrophils and invaded renal cancer cells in vitro influence
  142. Proton pump inhibitors-induced thrombocytopenia: A systematic literature analysis of case reports
  143. The current status and influence factors of research ability among community nurses: A sequential qualitative–quantitative study
  144. OKAIN: A comprehensive oncology knowledge base for the interpretation of clinically actionable alterations
  145. The relationship between serum CA50, CA242, and SAA levels and clinical pathological characteristics and prognosis in patients with pancreatic cancer
  146. Identification and external validation of a prognostic signature based on hypoxia–glycolysis-related genes for kidney renal clear cell carcinoma
  147. Engineered RBC-derived nanovesicles functionalized with tumor-targeting ligands: A comparative study on breast cancer targeting efficiency and biocompatibility
  148. Relationship of resting echocardiography combined with serum micronutrients to the severity of low-gradient severe aortic stenosis
  149. Effect of vibration on pain during subcutaneous heparin injection: A randomized, single-blind, placebo-controlled trial
  150. The diagnostic performance of machine learning-based FFRCT for coronary artery disease: A meta-analysis
  151. Comparing biofeedback device vs diaphragmatic breathing for bloating relief: A randomized controlled trial
  152. Serum uric acid to albumin ratio and C-reactive protein as predictive biomarkers for chronic total occlusion and coronary collateral circulation quality
  153. Multiple organ scoring systems for predicting in-hospital mortality of sepsis patients in the intensive care unit
  154. Single-cell RNA sequencing data analysis of the inner ear in gentamicin-treated mice via intraperitoneal injection
  155. Review Articles
  156. The effects of enhanced external counter-pulsation on post-acute sequelae of COVID-19: A narrative review
  157. Diabetes-related cognitive impairment: Mechanisms, symptoms, and treatments
  158. Microscopic changes and gross morphology of placenta in women affected by gestational diabetes mellitus in dietary treatment: A systematic review
  159. Review of mechanisms and frontier applications in IL-17A-induced hypertension
  160. Research progress on the correlation between islet amyloid peptides and type 2 diabetes mellitus
  161. 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
  162. The application of augmented reality in robotic general surgery: A mini-review
  163. The effect of Greek mountain tea extract and wheat germ extract on peripheral blood flow and eicosanoid metabolism in mammals
  164. Neurogasobiology of migraine: Carbon monoxide, hydrogen sulfide, and nitric oxide as emerging pathophysiological trinacrium relevant to nociception regulation
  165. Plant polyphenols, terpenes, and terpenoids in oral health
  166. Laboratory medicine between technological innovation, rights safeguarding, and patient safety: A bioethical perspective
  167. End-of-life in cancer patients: Medicolegal implications and ethical challenges in Europe
  168. The maternal factors during pregnancy for intrauterine growth retardation: An umbrella review
  169. Intra-abdominal hypertension/abdominal compartment syndrome of pediatric patients in critical care settings
  170. PI3K/Akt pathway and neuroinflammation in sepsis-associated encephalopathy
  171. Screening of Group B Streptococcus in pregnancy: A systematic review for the laboratory detection
  172. Giant borderline ovarian tumours – review of the literature
  173. Leveraging artificial intelligence for collaborative care planning: Innovations and impacts in shared decision-making – A systematic review
  174. Cholera epidemiology analysis through the experience of the 1973 Naples epidemic
  175. Risk factors of frailty/sarcopenia in community older adults: Meta-analysis
  176. Supplement strategies for infertility in overweight women: Evidence and legal insights
  177. Scurvy, a not obsolete disorder: Clinical report in eight young children and literature review
  178. A meta-analysis of the effects of DBS on cognitive function in patients with advanced PD
  179. Protective role of selenium in sepsis: Mechanisms and potential therapeutic strategies
  180. Strategies for hyperkalemia management in dialysis patients: A systematic review
  181. C-reactive protein-to-albumin ratio in peripheral artery disease
  182. Case Reports
  183. Delayed graft function after renal transplantation
  184. Semaglutide treatment for type 2 diabetes in a patient with chronic myeloid leukemia: A case report and review of the literature
  185. Diverse electrophysiological demyelinating features in a late-onset glycogen storage disease type IIIa case
  186. Giant right atrial hemangioma presenting with ascites: A case report
  187. Laser excision of a large granular cell tumor of the vocal cord with subglottic extension: A case report
  188. EsoFLIP-assisted dilation for dysphagia in systemic sclerosis: Highlighting the role of multimodal esophageal evaluation
  189. Molecular hydrogen-rhodiola as an adjuvant therapy for ischemic stroke in internal carotid artery occlusion: A case report
  190. Coronary artery anomalies: A case of the “malignant” left coronary artery and its surgical management
  191. Rapid Communication
  192. Biological properties of valve materials using RGD and EC
  193. A single oral administration of flavanols enhances short-term memory in mice along with increased brain-derived neurotrophic factor
  194. Letter to the Editor
  195. Role of enhanced external counterpulsation in long COVID
  196. Expression of Concern
  197. Expression of concern “A ceRNA network mediated by LINC00475 in papillary thyroid carcinoma”
  198. Expression of concern “Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway”
  199. Expression of concern “circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8”
  200. Corrigendum
  201. Corrigendum to “Empagliflozin improves aortic injury in obese mice by regulating fatty acid metabolism”
  202. Corrigendum to “Comparing the therapeutic efficacy of endoscopic minimally invasive surgery and traditional surgery for early-stage breast cancer: A meta-analysis”
  203. Corrigendum to “The progress of autoimmune hepatitis research and future challenges”
  204. Retraction
  205. Retraction of “miR-654-5p promotes gastric cancer progression via the GPRIN1/NF-κB pathway”
  206. Retraction of: “LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through downregulating SP-A by sponging to miR-424”
  207. Retraction of: “SCARA5 inhibits oral squamous cell carcinoma via inactivating the STAT3 and PI3K/AKT signaling pathways”
  208. Special Issue Advancements in oncology: bridging clinical and experimental research - Part II
  209. Unveiling novel biomarkers for platinum chemoresistance in ovarian cancer
  210. Lathyrol affects the expression of AR and PSA and inhibits the malignant behavior of RCC cells
  211. The era of increasing cancer survivorship: Trends in fertility preservation, medico-legal implications, and ethical challenges
  212. Bone scintigraphy and positron emission tomography in the early diagnosis of MRONJ
  213. Meta-analysis of clinical efficacy and safety of immunotherapy combined with chemotherapy in non-small cell lung cancer
  214. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part IV
  215. Exploration of mRNA-modifying METTL3 oncogene as momentous prognostic biomarker responsible for colorectal cancer development
  216. Special Issue The evolving saga of RNAs from bench to bedside - Part III
  217. Interaction and verification of ferroptosis-related RNAs Rela and Stat3 in promoting sepsis-associated acute kidney injury
  218. The mRNA MOXD1: Link to oxidative stress and prognostic significance in gastric cancer
  219. Special Issue Exploring the biological mechanism of human diseases based on MultiOmics Technology - Part II
  220. Dynamic changes in lactate-related genes in microglia and their role in immune cell interactions after ischemic stroke
  221. A prognostic model correlated with fatty acid metabolism in Ewing’s sarcoma based on bioinformatics analysis
  222. Red cell distribution width predicts early kidney injury: A NHANES cross-sectional study
  223. Special Issue Diabetes mellitus: pathophysiology, complications & treatment
  224. Nutritional risk assessment and nutritional support in children with congenital diabetes during surgery
  225. Correlation of the differential expressions of RANK, RANKL, and OPG with obesity in the elderly population in Xinjiang
  226. A discussion on the application of fluorescence micro-optical sectioning tomography in the research of cognitive dysfunction in diabetes
  227. A review of brain research on T2DM-related cognitive dysfunction
  228. Metformin and estrogen modulation in LABC with T2DM: A 36-month randomized trial
  229. Special Issue Innovative Biomarker Discovery and Precision Medicine in Cancer Diagnostics
  230. CircASH1L-mediated tumor progression in triple-negative breast cancer: PI3K/AKT pathway mechanisms
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