ABSTRACT
BACKGROUND: This study evaluated the use of metformin or pioglitazone in preventing or reducing the development of post-operative intra-abdominal adhesion (PIAA) by employing histopathological, immunohistochemical, and biochemical analyses in an experimental adhesion model. METHODS: Fifty Wistar-Albino rats were divided into five groups: Group I (Control), Group II (Sham Treatment), Group III (Hy-aluronic Acid), Group IV (Metformin), and Group V (Pioglitazone). Adhesions were induced in the experimental groups, except for the sham group, using the scraping method. After 10 days, rats were euthanized for evaluation. Macroscopic adhesion degrees were assessed using Nair's scoring system. Immunohistochemical and enzyme-linked immunosorbent assay (ELISA) methods were utilized to assess serum, peritoneal lavage, and intestinal tissue samples. Fructosamine, interleukin-6 (IL-6), transforming growth factor-beta (TGF-ß), and fibronectin levels were measured in serum and peritoneal lavage samples. RESULTS: The groups exhibited similar Nair scores and Type I or Type III Collagen staining scores (all, p>0.05). Pioglitazone significantly reduced serum IL-6 and TGF-ß levels compared to controls (p=0.002 and p=0.008, respectively). Both metformin and pioglitazone groups showed elevated IL-6 in peritoneal lavage relative to controls, while fibronectin levels in the lavage were lower in pioglitazone-treated rats compared to the sham group (all, p<0.005). CONCLUSION: Pioglitazone, but not metformin, demonstrated a positive biochemical impact on preventing PIAA formation in an experimental rat model, although histological impacts were not observed. Further experimental studies employing different dose/duration regimens of pioglitazone are needed to enhance our understanding of its effect on PIAA formation.
Subject(s)
Disease Models, Animal , Metformin , Pioglitazone , Rats, Wistar , Animals , Pioglitazone/pharmacology , Metformin/pharmacology , Tissue Adhesions/prevention & control , Tissue Adhesions/drug therapy , Rats , Hypoglycemic Agents/pharmacology , Male , Thiazolidinediones/pharmacology , Postoperative Complications/prevention & controlABSTRACT
The purpose of this study was to explore the effect of Semaglutide on intrauterine adhesions and discover new drugs for such adhesions. In this study, the cell model was simulated by TGF-ß1-induced human endometrial epithelial cells, and the animal model was established through mechanical curettage and inflammatory stimulation. After co-culturing with TGF-ß1 with or without different concentrations of Semaglutide for 48 h, cells were collected for RT-qPCR and Western blotting analyses. Three doses were subcutaneously injected into experimental mice once a day for two weeks, while the control group received sterile ddH2O. The serum and uterine tissues of the mice were collected. HE and Masson staining were used for the uterine histomorphological and pathological analyses. RT-qPCR and Western blotting were used for mRNA and protein expression analyses. Serum indicators were detected using ELISA kits. The results showed that Semaglutide significantly reduced the mRNA levels of fibrosis indicators ACTA2, COL1A1, and FN and inflammatory indicators TNF-α, IL-6, and NF-κB in the two models. Semaglutide improved endometrium morphology, increased the number of endometrial glands, and reduced collagen deposition in IUA mice. The results also showed that Semaglutide could inhibit vimentin, E-Cadherin, and N-Cadherin in the two models. In summary, Semaglutide can ameliorate fibrosis and inflammation of intrauterine adhesions as well as inhibit epithelial-mesenchymal transition in IUA models.
Subject(s)
Disease Models, Animal , Epithelial-Mesenchymal Transition , Fibrosis , Glucagon-Like Peptides , Animals , Female , Epithelial-Mesenchymal Transition/drug effects , Tissue Adhesions/drug therapy , Tissue Adhesions/metabolism , Tissue Adhesions/pathology , Tissue Adhesions/prevention & control , Mice , Glucagon-Like Peptides/pharmacology , Humans , Endometrium/drug effects , Endometrium/pathology , Endometrium/metabolism , Transforming Growth Factor beta1/metabolism , Transforming Growth Factor beta1/genetics , Uterus/drug effects , Uterus/pathology , Uterus/metabolismABSTRACT
The development of novel therapeutic approaches to facilitate endometrial repair and regeneration while preventing adhesion recurrence is a crucial research objective aimed at enhancing clinical outcomes for women with intrauterine adhesions (IUA). In this study, we introduced an injectable Alg-GMA/PTSB zwitterionic hydrogel, characterized by excellent biocompatibility, anti-protein adsorption properties, and biodegradability. In a rat model, the hydrogel significantly promoted the regeneration and angiogenesis of damaged endometrial tissue, leading to improved recovery of epithelial cells, glands, proliferation, and vascularization. Furthermore, it exhibited the ability to suppress cellular apoptosis and collagen deposition, thereby mitigating fibrosis. Additionally, the hydrogel restored the expression of estrogen/progesterone receptors and endometrial receptivity markers, contributing to enhanced embryo implantation and fertility. These findings underscore the potential of the hydrogel as a promising therapeutic strategy for addressing endometrial injury, reducing fibrosis, restoring fertility, and ultimately improving outcomes for women with IUA.
Subject(s)
Alginates , Endometrium , Fertility , Hydrogels , Female , Hydrogels/chemistry , Hydrogels/pharmacology , Animals , Endometrium/drug effects , Endometrium/metabolism , Alginates/chemistry , Alginates/pharmacology , Rats , Fertility/drug effects , Tissue Adhesions/prevention & control , Tissue Adhesions/drug therapy , Rats, Sprague-Dawley , Injections , Regeneration/drug effects , HumansABSTRACT
Postoperative intra-abdominal adhesions represent a significant post-surgical problem. Its complications can cause a considerable clinical and cost burden. Herein, our study aimed to investigate the effect of Everolimus on peritoneal adhesion formation after inducing adhesions in rats. In this experimental study, adhesion bands were induced by intraperitoneal injection of 3 ml of 10% sterile talc solution in 64 male albino rats. The first group served as the control group. The second one received oral Prednisolone (1 mg/kg/day), the third received Everolimus (0.1 mg/kg/day), and group four received both drugs with similar dosages for four consecutive weeks. The formation of adhesion bands was qualitatively graded according to the Nair classification. The rats in the control group had extensive adhesions between the abdominal wall and the organs. Regarding substantial adhesion formation, 50% (8/16) of animals in the control group had substantial adhesions, while this rate in the groups receiving Prednisolone, Everolimus, and combination treatment was 31%, 31%, and 31%, respectively. Also, 68.75% (5/11) of the Prednisolone recipients had insubstantial adhesions, the same as Everolimus recipients, while in the combination group, 66.66% (10/15) rats had insubstantial adhesions. Everolimus demonstrated satisfactory results in reducing the rates of induced peritoneal adhesion in an experimental model, similar to Prednisolone and superior to a combination regime.
Subject(s)
Everolimus , Prednisolone , Animals , Everolimus/pharmacology , Everolimus/administration & dosage , Tissue Adhesions/drug therapy , Tissue Adhesions/prevention & control , Tissue Adhesions/pathology , Prednisolone/pharmacology , Prednisolone/administration & dosage , Rats , Male , Drug Therapy, Combination , Disease Models, Animal , Peritoneum/pathology , Peritoneum/drug effects , Peritoneal Diseases/drug therapy , Peritoneal Diseases/pathology , Peritoneal Diseases/prevention & control , Peritoneal Diseases/etiology , Postoperative Complications/prevention & control , Postoperative Complications/drug therapyABSTRACT
Current interest in adhesion formation stems from its global impact on the function and quality of life, spanning a spectrum of subtle impairments to significant disabilities, based on the affected area and the extent of adhesion. Yet therapeutic agents are restricted to prophylactic anti-inflammatories, revision surgeries, and biological and physical techniques, none of which grant a decent outcome. Recent advancements in tissue- engineered biomaterials, drug delivery systems, and fabricating technologies such as nanoparticles, hydrogels, and weaving or braiding demonstrate potential for improved outcomes. However, none of the mentioned methods have reliable outcomes, thus this study aims to elucidate the mechanisms involved in the pathophysiology of tendon adhesion and post-surgical adhesion band formation (PSAB), with a closer look at inflammatory pathways stimulating the process. This article consolidates information on diverse therapeutic and prophylactic methods and cutting-edge technologies, aiming to provide a comprehensive update on this topic, and providing researchers an avenue for new and innovative ideas for further investigations.
Subject(s)
Tendons , Humans , Tissue Adhesions/prevention & control , Tissue Adhesions/drug therapy , Tendons/surgery , Tendons/drug effects , Animals , Drug Delivery Systems , Biocompatible Materials/chemistry , Biocompatible Materials/pharmacologyABSTRACT
OBJECTIVES: The study aimed to examine the histopathological and biomechanical effects of papaverine administered intraperitoneally and locally on Achilles tendon healing in a rat model. MATERIALS AND METHODS: Forty-eight adult male Sprague-Dawley rats (range, 300 to 400 g) were used in this study conducted between October and November 2022. The rats were divided into three groups, with each group further subdivided into two for sacrifice on either the 15th (early period) or 30th (late period) day after surgery. The first (control) group received no treatment following Achilles tendon repair, while papaverine was intraperitoneally administered every other day for 10 days in the second group and locally in the third group after surgery. On the 15th and 30th days, the rats were sacrificed, and their Achilles tendons were subjected to biomechanical testing and histopathological evaluation. RESULTS: Histopathologically, there were no significant differences among the groups on the 15th day. However, on the 30th day, the locally applied papaverine group exhibited superior histopathological outcomes compared to the control group (p<0.05). Concerning the highest tensile strength values before rupture, the biomechanical assessment showed that the group receiving local papaverine treatment in the early period and both the group with systemic papaverine treatment and the one with local papaverine treatment in the late period displayed a statistically significant advantage compared to the control group (p<0.05). CONCLUSION: Locally administered papaverine has positive biomechanical effects in the early period and exhibits a positive correlation both histopathologically and biomechanically in the late period. Novel therapeutic options may be provided for patients through these findings.
Subject(s)
Achilles Tendon , Papaverine , Rats, Sprague-Dawley , Tendon Injuries , Wound Healing , Animals , Achilles Tendon/injuries , Achilles Tendon/drug effects , Achilles Tendon/pathology , Achilles Tendon/surgery , Papaverine/pharmacology , Papaverine/administration & dosage , Papaverine/therapeutic use , Male , Tissue Adhesions/drug therapy , Tissue Adhesions/pathology , Wound Healing/drug effects , Tendon Injuries/drug therapy , Tendon Injuries/pathology , Tendon Injuries/surgery , Rats , Tensile Strength/drug effects , Injections, Intraperitoneal , Biomechanical Phenomena/drug effects , Disease Models, AnimalABSTRACT
Cluster-like collective cell migration of fibroblasts is one of the main factors of adhesion in injured tissues. In this research, a microdot biomaterial system is constructed using α-helical polypeptide nanoparticles and anti-inflammatory micelles, which are prepared by ring-opening polymerization of α-amino acids-N-carboxylic anhydrides (NCAs) and lactide, respectively. The microdot biomaterial system slowly releases functionalized polypeptides targeting mitochondria and promoting the influx of extracellular calcium ions under the inflammatory environment, thus inhibiting the expression of N-cadherin mediating cell-cell interaction, and promoting apoptosis of cluster fibroblasts, synergistically inhibiting the migration of fibroblast clusters at the site of tendon injury. Meanwhile, the anti-inflammatory micelles are celecoxib (Cex) solubilized by PEG/polyester, which can improve the inflammatory microenvironment at the injury site for a long time. In vitro, the microdot biomaterial system can effectively inhibit the migration of the cluster fibroblasts by inhibiting the expression of N-cadherin between cell-cell and promoting apoptosis. In vivo, the microdot biomaterial system can promote apoptosis while achieving long-acting anti-inflammation effects, and reduce the expression of vimentin and α-smooth muscle actin (α-SMA) in fibroblasts. Thus, this microdot biomaterial system provides new ideas for the prevention and treatment of tendon adhesion by inhibiting the cluster migration of fibroblasts.
Subject(s)
Biocompatible Materials , Cell Movement , Fibroblasts , Cell Movement/drug effects , Biocompatible Materials/chemistry , Biocompatible Materials/pharmacology , Fibroblasts/drug effects , Fibroblasts/cytology , Animals , Nanoparticles/chemistry , Peptides/chemistry , Peptides/pharmacology , Apoptosis/drug effects , Celecoxib/pharmacology , Celecoxib/chemistry , Cadherins/metabolism , Mice , Tendon Injuries/drug therapy , Tendon Injuries/pathology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Cell Adhesion/drug effects , Tissue Adhesions/prevention & control , Tissue Adhesions/drug therapyABSTRACT
Intrauterine adhesion (IUA), a major cause of uterine infertility, is pathologically characterized by endometrial fibrosis. Current treatments for IUA have poor efficacy with high recurrence rate, and restoring uterine functions is difficult. We aimed to determine the therapeutic efficacy of photobiomodulation (PBM) therapy on IUA and elucidate its underlying mechanisms. A rat IUA model was established via mechanical injury, and PBM was applied intrauterinely. The uterine structure and function were evaluated using ultrasonography, histology, and fertility tests. PBM therapy induced a thicker, more intact, and less fibrotic endometrium. PBM also partly recovered endometrial receptivity and fertility in IUA rats. A cellular fibrosis model was then established with human endometrial stromal cells (ESCs) cultured in the presence of TGF-ß1. PBM alleviated TGF-ß1-induced fibrosis and triggered cAMP/PKA/CREB signaling in ESCs. Pretreatment with the inhibitors targeting this pathway weakened PBM's protective efficacy in the IUA rats and ESCs. Therefore, we conclude that PBM improved endometrial fibrosis and fertility via activating cAMP/PKA/CREB signaling in IUA uterus. This study sheds more lights on the efficacy of PBM as a potential treatment for IUA.
Subject(s)
Low-Level Light Therapy , Uterine Diseases , Female , Rats , Animals , Humans , Transforming Growth Factor beta1/metabolism , Uterine Diseases/therapy , Uterine Diseases/metabolism , Uterine Diseases/pathology , Endometrium/metabolism , Endometrium/pathology , Tissue Adhesions/drug therapy , Tissue Adhesions/pathologyABSTRACT
Metabolic reprogramming is defined as the skill of cells to change their metabolism to support the induced energy demand due to continuous growth. Metabolic reprogramming is a well- known occurrence in the progression of neoplastic cells, although, evidence has shown that it is present in fibrotic disorders. Post-surgical adhesion as a fibrotic disorder is a medical challenge and is defined by fibrotic bands connected between organs with the abdominal wall. Despite many investigations carried out about the pathogenesis of the disorder but there are many unknowns, therefore, targeting special pathways may have the potential to prevent the formation of fibrotic bands post-operative. Glycolysis is a necessary metabolic pathway in living cells. In hypoxic conditions, it is the dominant pathway in the production of energy for different types of cells such as fibroblasts, immune cells, and endothelial cells. Also, glycolysis is a main downstream target for transforming growth factor ß (TGF-ß) and upregulates during fibrotic conditions. Furthermore, this is noteworthy that hypoxia induces factor 1 alpha (HIF-1α) as a transcription factor, elevated during the hypoxia condition stimulates different signaling pathways such as TGF-ß/SMAD, nuclear factor kappa B (NF-kB), and mTOR pathway to control glycolytic metabolism and T-cell trafficking for immune cell migration. Different evidence has indicated that the administration of glycolytic inhibitors has the potential to prevent the development of fibrotic markers. In this review, we pointed out the role of the glycolysis pathway and its connection to profibrotic cytokines to promote inflammatory and fibrotic pathways. Based on the results of studies related to fibrotic disorders we hypothesized that targeting glycolysis may have therapeutic potential in the prevention of postoperative adhesions.
Subject(s)
Endothelial Cells , Signal Transduction , Humans , Tissue Adhesions/drug therapy , Endothelial Cells/metabolism , Transforming Growth Factor beta/metabolism , HypoxiaABSTRACT
BACKGROUND: Hysteroscopic adhesiolysis is the preferred primary method for intrauterine adhesion. However, there is about a 60% of chance of re-adhesion after surgery. The objectives of the study were to evaluate the efficacy and safety of Yangmo decoction as a secondary treatment in preventing intrauterine re-adhesion against those of hyaluronic acid gel. METHODS: Women received oral Yangmo decoction (YD cohort, n = 105) or intrauterine hyaluronic acid gel (HA cohort, n = 125) or did not receive secondary re-adhesion prevention treatments (EP cohort, n = 165) after hysteroscopic adhesiolysis for 6 months. In addition, all women have received 3 mg of oral estrogen and 20 mg oral progesterone combination after hysteroscopic adhesiolysis for 3 months. Intrauterine re-adhesion after hysteroscopic adhesiolysis after 6 months with or without secondary treatment(s) was detected using hysteroscopy. The extent of the cavity, type of adhesion, and the menstrual pattern were included to define the American Fertility Society classification of intrauterine re-adhesions (AFS) score. RESULTS: Fewer numbers of women suffered from intrauterine re-adhesion after hysteroscopic adhesiolysis in the YD cohort than those of the HA (15(14%) vs. 40(32%), p = 0.0019) and the EP (15(14%) vs. 58(35%). p = 0.0001) cohorts. Among women who developed intrauterine re-adhesion, AFS score was fewer for women of the YD cohort than those of HA (2(2-1) vs. 4(4-3), p < 0.001) and the EP (2(2-1) vs. 4(4-4), p < 0.001) cohorts. AFS score after surgery was fewer for women of the HA cohort than those of the EP cohort (p < 0.05). Higher numbers of women of the YD cohort retained pregnancies after 6-months of treatment than those of the HA (55(52%) vs. 45(36%), p = 0.0161) and EP (55(52%) vs. 35(21%), p < 0.0001) cohorts. Among women who develop re-adhesion, 10(10%) women of the YD cohort only had successful pregnancies. CONCLUSIONS: Yangmo decoction for 6 months after hysteroscopic adhesiolysis can reduce AFS score, prevent intrauterine re-adhesion, and increases the chances of successful pregnancies of women. LEVEL OF EVIDENCE: IV. TECHNICAL EFFICACY: Stage 5.
Subject(s)
Hyaluronic Acid , Uterine Diseases , Pregnancy , Humans , Female , Male , Hyaluronic Acid/therapeutic use , Retrospective Studies , Hysteroscopy , Fertility , Tissue Adhesions/drug therapy , Tissue Adhesions/prevention & control , Tissue Adhesions/surgeryABSTRACT
BACKGROUND: Topical estrogen treatment has been considered the first-line treatment of labial adhesions in prepubertal girls. However, the effect of topical estrogen cream is different according to studies, and no study compared estrogen cream to observation. OBJECTIVE: This study aims to investigate the efficacy of topical estrogen cream treatment compared with observation in prepubertal girls with labial adhesions. STUDY DESIGN: The medical records of prepubertal girls diagnosed with labial adhesions from April 2005 to June 2019 were retrospectively analyzed. Baseline characteristics such as age at diagnosis and initial symptoms were collected. The primary outcome was the resolution of labial adhesion. Secondary outcomes were recurrence and side effects. RESULTS: A total of 114 patients were enrolled and divided into two groups, topical estrogen cream (n = 94), and observation (n = 20). Girls who were treated with estrogen cream had older age (24.6 ± 19.0 vs. 16.7 ± 15.3 months, p = 0.037) and higher resolution rate than the observation group (100.0% vs. 85.0%, respectively, p = 0.005). Girls younger than 23.3 months showed a significantly higher resolution rate to topical estrogen treatment (100% vs. 86.7%, p = 0.043). Side effects and recurrences occurred exclusively in children treated with topical estrogen therapy without significant differences compared to the observation group. CONCLUSION: Topical estrogen therapy showed a higher resolution rate than observation for the treatment of prepubertal girls with labial adhesions, especially in younger girls.
Subject(s)
Estrogens , Vulvar Diseases , Child , Female , Humans , Retrospective Studies , Tissue Adhesions/drug therapy , Vulvar Diseases/drug therapy , Administration, TopicalABSTRACT
Postoperative adhesion (PA) is currently one of the most unpleasant complications following surgical procedures. Researchers have developed several new strategies to alleviate the formation of PA to a great extent, but so far, no single measure or treatment can meet the expectations and requirements of clinical patients needing complete PA prevention. Chinese medicine (CM) has been widely used for thousands of years based on its remarkable efficacy and indispensable advantages CM treatments are gradually being accepted by modern medicine. Therefore, this review summarizes the formating process of PA and the efficacy and action mechanism of CM treatments, including their pharmacological effects, therapeutic mechanisms and advantages in PA prevention. We aim to improve the understanding of clinicians and researchers on CM prevention in the development of PA and promote the in-depth development and industrialization process of related drugs.
Subject(s)
Drugs, Chinese Herbal , Medicine, Chinese Traditional , Humans , Tissue Adhesions/drug therapy , Tissue Adhesions/prevention & control , Industrial Development , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic useABSTRACT
The prevention and treatment of post-traumatic peritendinous adhesion (PA) have always been a great difficulty for orthopedic surgeons. Current treatments include resecting surgery, non-steroidal anti-inflammatory drugs (NSAIDs) usage and implantable membranes, often target single disease pathogenic processes, resulting in unfavorable therapeutic outcomes. Here a polylactic acid (PLA)-dicumarol conjugates-electrospun nanofiber membrane (ENM) (PCD) is generated, which can achieve spatial accuracy and temporal sustainability in drug release. It is further demonstrated that PCD possesses a significantly higher and more sustainable drug release profile than traditional drug-loading ENM. By providing a physical barrier and continuous releasing of dicumarol, PCD implantation significantly reduces tissue adhesion by 25%, decreases fibroblasts activity and inhibits key fibrogenic cytokine transforming growth factor beta (TGFß) production by 30%, and improves the biomechanical tendon property by 14.69%. Mechanistically, PCD potently inhibits the connexin43 (Cx43) and thereby tunes down the fibroblastic TGFß/Smad3 signaling pathway. Thus, this approach leverages the anti-adhesion effect of dicumarol and drug release properties of grafted copolymer ENM by esters to provide a promising therapeutic strategy for patients who suffer from PA.
Subject(s)
Nanofibers , Polymers , Humans , Polymers/therapeutic use , Dicumarol/therapeutic use , Delayed-Action Preparations/pharmacology , Tissue Adhesions/drug therapy , Tissue Adhesions/prevention & control , Tissue Adhesions/pathology , Nanofibers/therapeutic use , Transforming Growth Factor betaABSTRACT
Intrauterine adhesions (IUA), which is characterized by endometrial fibrosis, continue to be the most common cause of uterine infertility globally. Our work revealed that 3 fibrotic progression markers (Vimentin, COL5A2, and COL1A1) were significantly increased in the endometrium of IUA patients. Mesenchymal stem cell-derived exosomes (EXOs) have been recently revealed as a cell-free therapy for fibrosis diseases. Nevertheless, the application of EXOs is restricted by the short residency duration in the target tissue. To overcome this limitation, herein, we reported an exosome-based regimen (EXOs-HP) that thermosensitive poloxamer hydrogel possessed the ability to efficiently promote the residency duration of EXOs in the uterine cavity. By downregulating fibrotic progression markers (Vimentin, COL5A2, and COL1A1), EXOs-HP could significantly restore the function and structure of the injured endometrium in the IUA model. Our work provides the theoretical and experimental foundation of EXOs-HP in treating IUA, highlighting the clinical potential of topical EXOs-HP delivery system in IUA patients.
Subject(s)
Exosomes , Uterine Diseases , Female , Humans , Biomarkers , Collagen , Endometrium , Exosomes/transplantation , Fibrosis , Tissue Adhesions/drug therapy , Tissue Adhesions/pathology , Uterine Diseases/therapy , Uterine Diseases/pathology , Vimentin/therapeutic useABSTRACT
BACKGROUND: Adhesion band formation is a common cause of morbidity for patients undergoing surgeries. Anti-inflammatory and anti-fibrotic properties of curcumin, a pharmacologically active component of Curcuma longa, have been investigated in several studies. The aim of this study is to explore the therapeutic potential of curcumin in attenuating post-operative adhesion band (PSAB) formation in both peritoneal and peritendinous surgeries in animal models. METHODS: Bio-mechanical, histological and quantitative evaluation of inflammation, and total fibrosis scores were graded and measured in the presence and absence of phytosomal curcumin. RESULTS: Results showed that phytosomal curcumin significantly decreased severity, length, density and tolerance of mobility of peritendinous adhesions as well as incidence and severity of abdominal fibrotic bands post-surgery. Curcumin may decrease inflammation by attenuating recruitment of inflammatory cells and regulating oxidant/anti-oxidant balance in post-operative tissue samples. Moreover, markedly lower fibrosis scores were obtained in the adhesive tissues of phytosomal curcumin-treated groups which correlated with a significant decrease in quantity, quality and grading of fibers, and collagen deposition in animal models. CONCLUSION: These results suggest that protective effects of phytosomal curcumin against PSAB formation is partially mediated by decreasing inflammation and fibrosis at site of surgery. Further studies are needed to investigate the therapeutic potential of this molecule in preventing PSAB.
Subject(s)
Curcumin , Animals , Curcumin/pharmacology , Tissue Adhesions/drug therapy , Inflammation , Models, AnimalABSTRACT
OBJECTIVES: The main treatment for intrauterine adhesion (IUA) is hysteroscopic adhesiolysis (HA), which most of treatment frequently employs estrogen and progesterone cycle therapy. The growth and coverage of endometrium after operation is a difficult problem, and several hospitals in China have performed growth hormone (GH) in empirically treating IUA, which has achieved excellent curative effects. Unfortunately, the mechanism of action has not yet been clearly elucidated. In previous study, an IUA animal model after surgical abortion and curettage in pregnant rats has been successfully established. In this experiment, the IUA animal model after surgical abortion and curettage in pregnant rats, which is more in line with the mechanism of human intrauterine adhesion, was used for the first time to investigate the therapeutic effect of GH on IUA in the pregnant rat curettage model. The expression of signal transducers and activators of transcription 3(STAT3), phosphorylated STAT3 (p-STAT3), STAT5 and p-STAT5 content were detected by immunohistochemistry to preliminarily explore the possible mechanism of GH involving in promoting endometrial growth of IUA, and to provide a theoretical basis for clinical medication and treatment. METHODS: Pregnant rats were anesthetized, and the bilateral embryos were removed completely. Then the rat endometrium was scraped with a curette in 4 different directions (front, back, left, and right). After the IUA animal model was established, the rats were randomly divided into 3 groups (n=5): a control group, a GH group, and a GH + AG490 group. Normal saline (0.4 mL/100 g) was injected subcutaneously at the 7th day after curettage in the control groupï¼0.15 U/100 g of GH was injected subcutaneously at the 7th day after curettage in the GH group; 0.15 U/100 g of GH was injected subcutaneously and 1 mg/100 g AG490 was injected intraperitoneally at the 7th day after curettage in the GH+ AG490 group. All the rats were injected continuously for 5 days. The rats in each group were sacrificed at the 14th day. The uterus of rats in each group was stained with HE staining to explore the endometrial morphology and the number of endometrial glands in each group, and Masson staining was utilized to observe the degree of endometrial fibrosis. The levels of STAT3, p-STAT3, STAT5 and p-STAT5 were detected by immunohistochemistry. RESULTS: 1) The number of glands in the GH group was more than that in the control group on the 14th day, with statistical difference (P<0.05). However, the number of endometrial glands in the AG490+GH group was decreased compared with the GH group on the 14th day (P<0.05). 2) The fibrosis ratio in the GH group was less than that in the control group at the 14th day after operation (P<0.05). However, the area of endometrial interstitial fibrosis in the AG490+GH group was much higher than that in the GH group 14 days after operation (P<0.05). 3) Compared with the control group, there was not significant difference in the levels of STAT3 and STAT5 in GH group (both P>0.05), while the levels of protein p-STAT3 and p-STAT5 were increased in the GH group (both P<0.05). Compared with the GH group, there was not significant difference in the levels of STAT3 and STAT5 in the AG490+GH group (both P>0.05), while the levels of p-STAT3 and p-STAT5 were decreased in the AG490+GH group (both P<0.05). CONCLUSIONS: GH can not only promote the growth of endometrial glands in the IUA model, but also reduce the degree of fibrosis and play a role in the treatment of IUA, which may be related to the activation of the Janus kinase (JAK), JAK/STAT3 and STAT5 signaling pathways.
Subject(s)
Endometrium , Growth Hormone , Tissue Adhesions , Animals , Rats , China , Endometrium/pathology , Tissue Adhesions/drug therapyABSTRACT
We previously demonstrated that transplantation of menstrual blood-derived stromal cells (MenSCs) is a safe and effective therapy for treating intrauterine adhesions (IUA). However, improving the colonization and therapeutic efficiency of MenSCs is still needed before full clinical application. Here, we established an amniotic membrane extract (AME)-enriched RGD hydrogel, and evaluated the therapeutic effect of this adjuvant combined with MenSCs transplantation in an IUA rat model. Our results indicated that AME promoted the proliferation and secretion of MenSCs in vitro, up-regulated the expression of apoptosis-suppressing gene BCL2 and down-regulated the expression of apoptosis-related genes Caspase-3 and Caspase-8. The AME-enriched hydrogel was biocompatible, and improved the survival of MenSCs in vitro and in vivo. It also promoted the retention of MenSCs in IUA uterus and augmented the effects of MenSCs on improving uterus morphology, endometrial proliferation, endometrial receptivity and fibrosis suppression. In addition, co-transplantation of MenSCs with AME-enriched hydrogel markedly down-regulated the expressions of inflammation-related genes IL10 and TGFß while up-regulated the IL4/IFN-γ ratio in the IUA endometrium, and improved the expressions of cell proliferation-related antigen, gland-regeneration-related marker leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), angiogenesis-related marker platelet and endothelial cell adhesion molecule 1 (PECAM1), endometrial receptivity related genes ITGα5 and ITGß3. Our study suggested that AME and MenSCs had a synergistic effect. Co-transplantation of MenSCs with AME-enriched hydrogel provided a promising approach for stem cell-based IUA treatment.
Subject(s)
Amnion , Uterine Diseases , Animals , Female , Humans , Rats , Hydrogels/metabolism , Stromal Cells , Tissue Adhesions/drug therapy , Uterine Diseases/metabolismABSTRACT
Estrogen combined with physical barrier therapy may be a prospective method to repair a damaged endometrium and prevent postsurgical re-adhesion in the treatment of intrauterine adhesions (IUAs), but there lacks a suitable scaffold with good biocompatibility, appropriate mechanical properties, and drug-releasing kinetics. Herein, a mechanically robust and stable barrier based on the poly(hydroxyethyl methacrylate) (PHEMA) hydrogel combined with estradiol-loaded mesoporous silica is designed. The network is formed by covalent bonds and noncovalent coordination bonds, which endow the hydrogel with superior mechanical properties to most reported PHEMA-based hydrogels. Meanwhile, the covalent bonds impart excellent stability to the hydrogel, which maintains its structure and mechanical properties in a simulated uterine fluid for 30 days. The excellent mechanical properties and stability are comparable to those of a typical barrier material intrauterine device (IUD), enabling the hydrogel to be retained in the uterus and removed intact like an IUD. In vitro and in vivo experiments show that the hydrogel possesses good biocompatibility similar to pure PHEMA hydrogels. In addition, the hydrogel releases estradiol continuously and stably, and exhibits a good therapeutic effect in promoting the proliferation of endometrial cells and inhibiting the progression of fibrosis. Therefore, the combinational advantages make the present hydrogel very promising in IUA treatment.
Subject(s)
Estradiol , Polyhydroxyethyl Methacrylate , Female , Humans , Polyhydroxyethyl Methacrylate/chemistry , Estradiol/pharmacology , Estradiol/therapeutic use , Hydrogels/chemistry , Tissue Adhesions/drug therapy , Tissue Adhesions/prevention & control , Endometrium/pathologyABSTRACT
Most treatments for spinal cancer are accompanied by serious side effects including subsequent tumor recurrence, spinal cord compression, and tissue adhesion, thus a highly effective treatment is crucial for preserving spinal and neurological functionalities. Herein, trilayered electrospun doxorubicin@bovine serum albumin/poly(ε-caprolactone)/manganese dioxide (DOX@BSA/PCL/MnO2) nanofibers with excellent antiadhesion ability, dual glutathione/hydrogen peroxide (GSH/H2O2) responsiveness, and cascade release of Mn2+/DOX was fabricated for realizing an efficient spinal tumor therapy. In detail, Fenton-like reactions between MnO2 in the fibers outermost layer and intra-/extracellular glutathione within tumors promoted the first-order release of Mn2+. Then, sustained release of DOX from the fibers' core layer occurred along with the infiltration of degradation fluid. Such release behavior avoided toxic side effects of drugs, regulated inflammatory tumor microenvironment, amplified tumor elimination efficiency through synergistic chemo-/chemodynamic therapies, and inhibited recurrence of spinal tumors. More interestingly, magnetic resonance and photoacoustic dual-modal imaging enabled visualizations of tumor therapy and material degradation in vivo, achieving rapid pathological analysis and diagnosis. On the whole, such versatile hierarchical-structured nanofibers provided a reference for rapid and potent theranostic of spinal cancer in future clinical translations.
Subject(s)
Nanofibers , Nanoparticles , Neoplasms , Spinal Neoplasms , Humans , Manganese Compounds/pharmacology , Spinal Neoplasms/drug therapy , Hydrogen Peroxide , Serum Albumin, Bovine , Oxides , Tissue Adhesions/drug therapy , Delayed-Action Preparations , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , Neoplasms/therapy , Glutathione/metabolism , Cell Line, Tumor , Tumor MicroenvironmentABSTRACT
Background: Scarless healing comprises the ultimate goal after an injury. Since tendon healing results in a fibrotic scar, an injured tendon can never regain the mechanical potential and strength of its uninjured form. A wide variety of studies focus on the tendon healing with an absent or minimal peritendinous adhesions. However, no simple method has managed it at all. Possible complex actions and peritendinous environmental events take place during the tendon healing process. Tamoxifen (TAM), besides its breast cancer-related usage, is a potent antifibrotic drug. Here, we aimed to reduce the peritendinous adhesion with TAM administration. Methods: Achilles tendons of 44 Wistar albino rats were randomly distributed in 4 groups. In group 1, bilateral lower extremities were used as control and sham. Groups 2 and 3 were comprised of low-dose (1 mg/kg) and high-dose (40 mg/kg) systemic administration of TAM, respectively. Group 4 included local administration (1 mg/kg) of TAM. Biomechanical, macroscopical, and histopathological analyses were done and compared statistically. Biomechanically, the maximum force that led to tendon rupture was determined, and tensile force data were recorded via tensile testing device. Macroscopical and histopathological analysis were composed of the quantity, quality, and grade of peritendinous adhesions. Results: Macroscopic and histopathologic findings revealed that groups 2 and 3 had a variety of values ranging between slight to severe adhesions. In group 2, almost half of the animals had moderate adhesions, whereas in group 3, the majority of the animals had moderate adhesions. There were no animals with moderate or severe adhesions in group 4. Statistically significant values were calculated between sham and control groups. Biomechanically, group 2 showed the most significant result. The tendons in group 2 had the highest stiffness when maximal force was applied to rupture the tendons. Henceforth, all these consequences were proven statistically. Conclusion: We achieved less peritendinous adhesion with the local administration of TAM when compared to systemic administration of TAM. A better understanding of the peritendinous environmental process will reveal to develop new therapies in the prevention of peritendinous adhesions.