Phytosomal curcumin elicits potent protective responses in post-surgical adhesion band formation by decreasing inflammation and fibrosis

Phytosomal curcumin elicits potent protective responses in post-surgical adhesion band formation by decreasing inflammation and fibrosis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Phytosomal curcumin elicits potent protective responses in post-surgical adhesion band formation by decreasing inflammation and fibrosis Mohammad-Mostafa Askarnia-Faal, Sayyed-Hadi Sayyed-Hosseinian, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1561463/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background In this study we investigated the therapeutic potential of the phytosomal form of pharmacologically active component of Curcuma longa, curcumin, in attenuating Post-operative adhesion bands (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 Our 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. We showed that curcumin could 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 the anti-inflammatory and anti-fibrotic properties of phytosomal curcumin, has therapeutic potential for preventing PSAB formation.” Phytosomal curcumin Peritendinous adhesion Peritoneal fibrosis Post-surgical adhesion bands Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Post-operative adhesion bands (PSAB) are fibrotic tissues generated by impaired fibrinolysis and cellular exudates following injury to the operated area such as abdominal cavity 1 , flexor and Achilles tendons 2 . Current therapeutic strategy utilizes solid barriers such as Interceed and Seprafilm at reducing adhesion band formation at injury sites. However, the accurate prediction of the damaged area following surgery limits usage of this method 3 , 4 . Intra-abdominal adhesions develop in over 90% of patients with peritoneal or gynecological surgeries 5 , 6 . The formation of these fibrotic bands is usually asymptomatic 7 . This condition is accompanied by post-surgical complications including pelvic pain, infertility, and intestinal obstruction 8 . Similarly, peritendinous adhesions are a serious complication of flexor tendon injury associated with a high personal and economic burden for patients 9 . Tendons are dense fibrillary connective tissues made up of parallel collagen fiber bundles and low cellular populations 10 . Flexor tendons serve as energy-saving elastic springs absorbing external forces and stabilize joint motion and biomechanical function of the musculoskeletal system 11 . Current therapeutic options for reducing or preventing tendon adhesions are ineffective and not routine in clinical medicine. Thus, it is necessary to attain a greater understanding of the adhesion formation process and to develop an effective treatment 10 . Curcumin, also known as diferuloylmethane, is a polyphenol extract of turmeric ( Curcuma longa L. rhizome) and has been used for centuries in traditional Chinese and Indian medicine 12 . Curcumin exerts its therapeutic effects by modulating transcription factors, cell adhesion molecules, enzymes, and cytokines 12 . However, the applicability of curcumin is limited due to low solubility in aqueous mediums, instability at physiological pH, and rapid clearance 13 . To enhance curcumin's bioavailability and its therapeutic effects, the formulated phytosomal curcumin (curcumin-phosphatidylcholine complex) has been provided by Sami Labs Ltd. (Bangalore, India) and was used in our previous publications 14 – 16 . Aberrant regulation of the inflammatory response and fibrosis are major factors in adhesion band formation 9 , 17 . Anti-inflammatory activities of phytosomal curcumin have been reported to have positive effects in various diseases such as cancers 16 and hepatic disorders 18 , 19 . In addition, several studies illustrated the protective effects of phytosomal curcumin against liver fibrosis and non-alcoholic fatty liver diseases 20 – 22 . In this study we aim to investigate the protective effects of phytosomal curcumin on post-operative peritoneal and peritendinous adhesions. Materials And Methods Materials Phytosomal curcumin was obtained from Sami Labs Ltd. (Bangalore, India). All reagents for malondialdehyde (MDA), total thiol, catalase (CAT), and superoxide dismutase (SOD) were purchased from Sigma-Aldrich Chemical Co. (St. Louis, MO, USA). Animal experiment Animal experiments were carried out in line with the guidelines for Care and Use of Laboratory Animals from Mashhad University of Medical Sciences (reference number: IR.MUMS.MEDICAL.REC.1399.067). Male Wistar rats (weighing 200–250 g) were obtained from the laboratory animals center of medical school, Mashhad University of Medical Sciences. They were housed according to the protocol approved by Institutional Animal Care Guidelines. All animals had free access to drinking water and were fed standard rat chow. They were kept at a normal temperature of 22–25°C and a standard 12-hr light/dark cycle . The post-operational adhesion band models General anesthesia was induced with an intraperitoneal injection of ketamine/xylazine. Post-operational peritendinous adhesion model was induced according to a protocol established by Tang et al 23 . Briefly after shaving the right hind limb, a longitudinal incision was made in the Achilles tendon, inducing peritendinous adhesion. The tendon was sutured using the Kessler–Kirchmeyer technique. Abdominal adhesion formation was induced by surgical procedure according to protocol by Hemadeh et al 24 . Briefly, the peritoneal was opened by a U-shaped incision. Using a medical electric scalpel, the cecal and the interior abdomen surfaces were gently rubbed to generate partial petechial hemorrhages and adhesion band formation. Animals in each model were randomly divided into 3 groups (n = 6) as described below: (A) sham group with surgical incision but no adhesion, (B) positive control group with total surgical transection and adhesion receiving normal saline daily, (C) phytosomal curcumin group which is the same as group B except that rats were treated with 25 mg/kg/day curcumin orally 16 , 25 for either 7 or 21 days in peritoneal or tendon adhesion models, respectively. At the end of the experiments, rats were anesthetized, sacrificed, and tissue samples were collected (quickly frozen in liquid nitrogen or stored at 10% formalin) for further assessments. Evaluation of adhesion scores The macroscopic grading (Table 1 ) and the severity of the tendon adhesion bands (Table 2 ) were carried out using the Tang et al. 23 and Ishiyama et al. 26 adhesion scoring system, respectively. The Nair 27 and Leach 28 scoring systems were used for evaluating the incidence and stability of intraperitoneal adhesions, respectively (Table 3 ). Table 1 Tang et al. Macroscopic grading of peritendinous adhesion bands Grading Tang et al. Macroscopic grading Length(quantity) 0 1 2 3 No adhesions 10 mm Density and tolerance for mobility(quality) 0 1 2 3 No adhesions Loose, elastic, mobile Moderate mobility Rigid, dense, immobile Grading of adhesions 0 1 to 2 3 to 4 5 to 6 Absent Inferior Medium Severe Table 2 Ishiyama et al Macroscopic grading scores for peritendinous adhesion bands Grading Ishiyama et al grading scores Grade 1 No adhesion formation Grade 2 Adhesion could be separated by blunt dissection alone Grade 3 Sharp dissection was needed to separate no more than 50% of adhesion tissues Grade 4 Adhesion could be separated by sharp dissection was required to separate 51-97.5% of adhesion tissues Grade 5 Sharp dissection was required to separated > 97.5% of adhesion tissues Table 3 Intra-peritoneal adhesion score system for macroscopic evaluation 0 to 4 Adhesion grade (Nair's et al) Adhesion grade (Leach et al) 0 Complete absence of adhesion No adhesions 1 Single band of adhesion, between viscera or from viscera to abdominal wall If the adhesions separated from tissue with gentle traction 2 Two bands, either or from viscera to abdominal wall Requiring moderate traction 3 More than two bands, between viscera or viscera to abdominal wall Requiring sharp dissection 4 Viscera directly adherent to abdominal wall, irrespective of number and extent of adhesive bands Histological staining Tissue specimens were fixed in 10% formalin, processed, and embedded in paraffin. Next, tissues were stained with either hematoxylin/eosin (H&E) or Masson’s trichrome staining. H&E staining was performed to analyze general tissue structure and the inflammatory cells infiltration whereas trichrome staining was utilized to explore the collagen deposition, reflecting the severity of fibrosis. Inflammatory cell infiltration was quantified using Moran et al. (Table 4 ) 29 scoring system. Histological grading scores for the peritendinous adhesion bands were completed according to the Tang et al. system 23 (Table 5 ). Table 4 Moran et al. grading scores for inflammatory cells infiltration to the injury site Grading Moran et al. scores Grade 0 None Grade 1 Leukocyte infiltration within fibro-osseous sheath Grade 2 Infiltration of synovium and epitenon Grade 3 Infiltration of endotenon Grade 4 Diffuse inflammation extending within tendon and beyond sheath Table 5 Tang et al. Histological grading scores for the peritendinous adhesion bands Grading Tang et al. Histological score Quantity 0 1 2 3 No apparent adhesions A number of scattered filaments A large number of filaments countless filaments Quality 0 1 2 3 No apparent adhesions Regular, elongated, fine, filamentous Irregular, mixed, shortened, filamentous Dense, not filamentous Grading of adhesions 0 2 3 to 4 5 to 6 None Slight Moderate Severe Oxidative stress markers analysis Assessment of the antioxidant effect of phytosomal curcumin was performed by measuring MDA and total thiol concentrations as well as SOD and catalase enzyme activities in tissue samples as described 7 , 8 . Biomechanical testing of tendon repairs Achilles tendon tissue mechanical properties were analyzed as described previously 30 , 31 . In summary, the calcaneus-tendon-muscle complex of rats was dissected and hydrated in phosphate buffered saline (PBS) for one hour. Samples were immediately mounted on a tensile testing machine (SANTAM-STM20) using specific metal clamps. The angle between the calcaneus and Achilles tendon corresponded to 30º dorsiflexion of the foot. A 500 N load cell and a 5 mm/min speed were used at a maintained temperature of 25 ± 2ºC. The sample’s properties were computed using the load-elongation and stress-strain curves obtained during the final load-to-failure tests. The load-elongation curve represents structural parameters including ultimate load (N), elongation (%), energy absorbed, and stiffness. First the tendon tissues of the specimens were tensioned to the point of failure. The maximum longitudinal changes and the maximum load values exerted before tissue rupture are defined as ultimate elongation (mm) and ultimate load (N), respectively 32 . Mechanical data from the stress-stain curve includes ultimate stress (MPa), ultimate strain (%), and tangent modulus (MPa) 31 . Ultimate stress (MPa) is formulated by dividing ultimate load value (N) by cross-sectional area (CSA). Ultimate strain (%) is expressed as elongation rate/initial length (ΔL/L0) x 100. Tangent modulus (MPa) is defined as the ratio of induced stress to strain (the slope of the linear) at each loading cycle, indicating the ability of specimens to resist deformation. Thus, a higher tangent modulus generates higher stress for a given strain 33 . Statistical analysis Results were expressed as mean ± standard error of the mean (SEM). Statistical analysis was performed using one-way ANOVA and Shapiro-Wilk normality test. A P-value of < 0.05 was considered significant. All statistical assessments were performed using the SPSS software (SPSS Inc., Chicago, IL, USA). Results Phytosomal curcumin attenuates frequency and structural properties of adhesion bands Anesthetic induction and surgical procedures were successful with all rats surviving to the end of the study. Results showed that curcumin significantly decreased adhesion band formation in both the tendon (Fig. 1 A) and abdominal surgeries (Fig. 1 B). We used Tang 23 and Ishiyama grading 26 system to evaluate the properties and severity of peritendinous adhesions, and Nair 27 and Leach 28 scoring systems for evaluating the presence and rigidity of peritoneal adhesions. Using Tang macroscopic grading scores of peritendinous adhesion bands (Table 1 ), curcumin-treated rats showed decreased length (Fig. 2 A), density and tolerance for mobility (Fig. 2 B), and grading of adhesion score (Fig. 2 C) compared to the positive control group. Consistent with these findings, the Ishiyama macroscopic scoring system (Table 2 ) also indicated that curcumin treatment decreased the severity of adhesions formation (Fig. 2 E). Next, we used Nair and Leach scoring systems (Table 3 ) to investigate the protective effects of curcumin on abdominal adhesion bands formation. Results showed that curcumin significantly decreased both the incidence (Fig. 2 F) and severity (Fig. 2 G) of fibrotic bands compared to positive control rats. No adhesion fibers were found in the sham group. Phytosomal curcumin inhibits post-surgical inflammation in peritendinous and intraperitoneal adhesion models Inflammation is one of the key factors in the pathogenesis of post-surgical adhesion band formation. To determine the protective effect of phytosomal curcumin on adhesion band-associated inflammation, either tendon or abdominal adhesion tissues were stained with H&E to examine the morphological and histological changes in adhesion rat models. As we previously suggested that 25 mg/Kg phytosomal curcumin has potential therapeutic effects 15 , 16 , here we showed that the selective dose of phytosomal curcumin at 25 mg/Kg decreased infiltration of inflammatory cells into the injured site in the tendon adhesions (Fig. 3 A). We quantified the results and showed a decrease in fibrosis using the Moran 29 grading score, which is specific for tendon but not abdominal surgeries (Table 4 ) (Fig. 3 B). In terms of peritoneal adhesions, H&E results also demonstrated a decrease in adhesion-related inflammation based on a lower influx of inflammatory cells into the surgical area (Fig. 3 C). Phytosomal curcumin suppresses inflammation by counterbalancing oxidative stress Evaluation of oxidative stress markers was used to further investigate the anti-inflammatory activity of curcumin in post-surgical adhesion band models. Compared to the positive control group, curcumin treatment significantly reduced the level of MDA, an oxidative marker of fatty acid peroxidation, in both peritendinous (Fig. 4 A), and abdominal adhesion tissue homogenates (Fig. 4 E). Next, the total thiol (Fig. 4 B, and F) concentration and the activities of SOD (Fig. 4 C, and G) and CAT (Fig. 4 D, and H) enzymes, all anti-oxidant markers, were measured in the Achilles tendon and abdominal adhesion tissues. Our results clearly showed that the level and activity of all these anti-oxidant markers was increased in the curcumin-treated group, supporting the anti-inflammatory effects of phytosomal curcumin in post-surgical adhesion rat models. The effects of curcumin on fibrosis as a key element in post-surgical adhesion band formation We stained tissues with Masson's trichrome in both post-surgical models to determine the effect of curcumin on fibrosis and collagen deposition at the site of surgery, Results showed that compared to the positive control rats, curcumin suppressed fibrosis and collagen content in peritendinous adhesion tissues (Fig. 5 A). Moreover, by using Tang Histological (microscopic) grading score (Fig. 5 E) (Table 5 ), consisting of quantity (Fig. 5 B), quality (Fig. 5 C), and grading (Fig. 5 D) of fibrosis, we showed that curcumin significantly decreased the overall fibrosis score when compared with the positive control group in peritendinous adhesion. Similarly, using Masson's trichrome staining, the efficacy of phytosomal curcumin on fibrosis of peritoneal tissues was investigated and results showed potent protective activities of curcumin against fibrosis at site of surgery (Fig. 5 F). These results suggest that inhibition of fibrosis is a mechanism by which curcumin decreases adhesion band formation post-surgeries. Effects of phytosomal curcumin on mechanical properties of tendons To obtain the effects of phytosomal curcumin on structural and mechanical properties of tendon adhesion tissues, we plotted the load-elongation and the stress-strain curves, using a SANTAM-STM20 testing machine. Cross-sectional area (CSA) was also measured to evaluate possible modifications in mechanical features of the Achilles tendon in response to the phytosomal curcumin. In this study, we investigated the structural properties of tendon adhesion tissues by measurement of ultimate load between different groups. Our results showed that in comparison to the positive control group, phytosomal curcumin improved the structural properties of damaged tissues, including maximum load (N) in tendons (Table 6 ). However, these results were not statistically significant. Table 6 Comparing structural/mechanical properties of the Achilles tendon between groups. Values are expressed as means ± standard deviation. Group Ultimate Load (N) Ultimate Stress (MPa) Ultimate Strain (%) Tangent Modulus (MPa) Sham 40.6 ± 5.126 12.92 ± 1.632 34.56 ± 9.621 54.19 ± 18.74 Positive Control 35.5 ± 4.083 2.232 ± 0.256 40.94 ± 16.4 6.694 ± 2.89 Phy-curcumin 41.55 ± 5.541 3.663 ± 0.488 40.05 ± 20.58 8.487 ± 5.493 Since the load-elongation curve depends on size, volume, and shape of tissue samples, we normalized the quantities using the stress-strain curve analyzing the ultimate stress (MPa), ultimate strain (%), and tangent modulus (MPa) indexes. As expected, in the sham group, the level of ultimate stress and ultimate strain is higher and lower than positive control group, respectively. We showed that phytosomal curcumin improved ultimate stress and strain when compared to the positive control group. Consistently, compared to the positive control group, treatment with phytosomal curcumin increased tangent modulus which is an index indicating the ability of specimens to resist deformation (Table 6 ). Discussion In this study, we analyzed the protective effects of oral phytosomal curcumin in decreasing adhesion formation post tendon and abdominal surgeries in animal models. Our results suggested that phytosomal curcumin significantly decreased post-operational adhesion band formation in both rat models. We showed that phytosomal curcumin reduced adhesion-related inflammatory responses by decreasing infiltration of inflammatory cells and regulating the oxidant/anti-oxidant balance at surgery sites. Moreover, our results showed that phytosomal curcumin potently exhibited anti-fibrotic activities by attenuating fibrotic bundle thickness and collagen deposition. These findings support the therapeutic potential of phytosomal curcumin in decreasing post-surgical adhesion band formation. Adhesion band formation post tendon and abdominal injuries are common surgery-associated complications in patients worldwide 34 – 37 . Inflammation is a key physio-pathological factor in post-surgical adhesion band formation 38 , 39 . The anti-inflammatory properties of phytosomal curcumin and its safety have been validated in numerous human disorders including osteoarthritis, diabetes, cancer, retinopathy, and other diseases 40 – 42 . It has been shown that curcumin down-regulates expression of several inflammatory mediators including IL-6, TNF-α, nuclear factor kappa-B (NF-κB)-regulated gene products such as cyclooxygenase (COX)-2, IL-1, cell adhesion molecules, and C-reactive protein (CRP) 12 . Similarly, Vizzutti et al. showed that production of reactive oxygen species (ROS) was reduced in curcumin-treated mice in a steato-hepatitis model 43 . We recently showed that the anti-cancer property of phytosomal curcumin is partially mediated by eliciting anti-inflammatory responses in colorectal cancer 15 . We also previously showed that phytosomal curcumin potentiates the anti-inflammatory activity of 5-fluorouracil (5-FU), leading to a significant reduction in inflammation and histo-pathological scores in colitis-associated colorectal cancer using in vitro and in vivo models 16 . In another study we demonstrated the anti-oxidant activities of phytosomal curcumin in a xenograft mice model of breast cancer 44 . Consistent with these findings, here we showed that curcumin elicits significant anti-inflammatory activity by decreasing inflammatory cell infiltration and increasing levels and activities of anti-oxidant markers in both peritendinous and abdominal surgeries. Our results suggest that a decreased inflammatory response post-surgery could be a mechanism by which curcumin elicits its therapeutic potency at site of injuries. Although surgical-induced adhesions and inflammatory responses occur early during the adhesions formations, fibrosis appears as a late event with a major impact on tissues dysfunction 9 , 17 . In line with this, Kang et al. evaluated the protective effects of curcumin on synthesis of collagen in both cellular and animal models. Results showed a lower thickness of smooth muscle alpha-actin and collagen fibers and lower mRNA expression of type I collagen in curcumin-treated groups 45 . Furthermore, it has been shown that the high density of fibrillar extracellular matrix (ECM) and the gene expression level of pro-collagen type I were reduced via curcumin treatment inhibiting the fibrogenic progression in sinusoids and perivenular areas in steatohepatitis mice 43 . Consistently, in this study we showed that curcumin via reducing fibrosis quantity, fibrosis quality, grading of adhesion, and the collagen deposition could decrease total fibrosis score in tissue adhesions in rat model. Taken together, the current study introduced anti-inflammatory and anti-fibrotic phytosomal curcumin as a promising treatment for inhibition or reduction of post-surgical adhesion band formation. The exact protective functions of phytosomal curcumin in adhesion models have not been yet understood. Further animal and clinical studies are needed to clarify these underlying mechanisms and validate these results in patients. Conclusion Our results suggest that the anti-inflammatory and anti-fibrotic properties of phytosomal curcumin, has therapeutic potential for preventing PSAB formation The particular protective roles of phytosomal curcumin in adhesion models have not been yet completely understood. Supplementary animal and clinical studies are required to elucidate these underlying mechanisms and confirm these results in patients. Abbreviations PSAB Post-operative adhesion bands MDA Malondialdehyde CAT Catalase SOD Superoxide dismutase H&E Hematoxylin/eosin PBS Phosphate buffered saline SEM Standard error of mean IL-1 Interlukine-1 IL-6 Interlukine-6 TNF-α Tumor necrosis factor Alpha NF-κB Nuclear factor kappa B COX-2 Cyclooxygenase-2 CRP C-reactive protein ROS Reactive oxygen species 5-FU 5 Fluorouracil Declarations The funding agencies had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Ethics approval and consent to participate: Animal experiments were carried out in line with the guidelines for Care and Use of Laboratory Animals from Mashhad University of Medical Sciences (reference number: IR.MUMS.MEDICAL.REC.1399.067). Consent to publish: All authors give their consent for the publication of identifiable details within the text to be published in this Journal. Availability of data and materials: All data and materials are available upon request to corresponding author via sending e-mail to [email protected] Competing interests: The authors declare no conflict of interest. Funding: This study was supported by grants awarded by the Mashhad University of Medical Sciences (981180) to S.M.H. Authors Contributions: M. A. with support from M. E., and M. A. designed and performed cellular and molecular experiments. S. E. N, and F. A. with support from H. G. and H. N. and A. A. designed and performed animal experiments. A. S. and S. M. H. with support from M. R wrote the manuscript. A. A., R. M., and S. S. analyzed data and contributed to the clinical interpretation of the results. S. M. H. and M. K. designed the study plan and supervised the project. All authors discussed the results and contributed to the final manuscript. Acknowledgements: N/A. References Soltany, S. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1561463","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":101426306,"identity":"09072269-43a1-4fb0-afb1-958bb84c91fc","order_by":0,"name":"Mohammad-Mostafa Askarnia-Faal","email":"","orcid":"","institution":"Mashhad University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mohammad-Mostafa","middleName":"","lastName":"Askarnia-Faal","suffix":""},{"id":101426307,"identity":"c98a4277-af01-4d18-b42f-e1d57071d6ca","order_by":1,"name":"Sayyed-Hadi Sayyed-Hosseinian","email":"","orcid":"","institution":"Mashhad University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sayyed-Hadi","middleName":"","lastName":"Sayyed-Hosseinian","suffix":""},{"id":101426308,"identity":"9e49b812-62ee-43ae-b29d-2f5bd5492f71","order_by":2,"name":"Seyedeh Elnaz Nazari","email":"","orcid":"","institution":"Mashhad University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Seyedeh","middleName":"Elnaz","lastName":"Nazari","suffix":""},{"id":101426309,"identity":"4b916ccc-a97b-4b35-b505-5d3b253d8f60","order_by":3,"name":"Fereshteh Asgharzadeh","email":"","orcid":"","institution":"Mashhad University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Fereshteh","middleName":"","lastName":"Asgharzadeh","suffix":""},{"id":101426310,"identity":"05850a96-8eca-46ea-94b8-ed92a6c2ef01","order_by":4,"name":"Haniyeh Ghasemi","email":"","orcid":"","institution":"Mashhad University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Haniyeh","middleName":"","lastName":"Ghasemi","suffix":""},{"id":101426311,"identity":"6932804f-eb96-4187-87fd-c6dae88c3cc5","order_by":5,"name":"Amir Avan","email":"","orcid":"","institution":"Mashhad University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Amir","middleName":"","lastName":"Avan","suffix":""},{"id":101426312,"identity":"6e7dea03-6974-444f-aae2-1698ac1e7891","order_by":6,"name":"Moein Eskandari","email":"","orcid":"","institution":"Mashhad University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Moein","middleName":"","lastName":"Eskandari","suffix":""},{"id":101426313,"identity":"88e31b2b-e058-4f4f-8da4-ac62976b5764","order_by":7,"name":"Maryam Alaei","email":"","orcid":"","institution":"Mashhad University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Maryam","middleName":"","lastName":"Alaei","suffix":""},{"id":101426314,"identity":"e14875c0-6cee-4f53-9ef1-9683ee0b21cb","order_by":8,"name":"Hamideh Naimi","email":"","orcid":"","institution":"Mashhad University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hamideh","middleName":"","lastName":"Naimi","suffix":""},{"id":101426315,"identity":"93756557-6954-4c0c-9e1a-dbb28daf336c","order_by":9,"name":"Atena Soleimani","email":"","orcid":"","institution":"Mashhad University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Atena","middleName":"","lastName":"Soleimani","suffix":""},{"id":101426316,"identity":"522dca29-749b-4f38-b633-b9d16a0b7434","order_by":10,"name":"Abbas Alalikhan","email":"","orcid":"","institution":"Mashhad University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Abbas","middleName":"","lastName":"Alalikhan","suffix":""},{"id":101426317,"identity":"d94df702-ba56-44bd-a7f2-0517018842bd","order_by":11,"name":"Reza Mohammadzadeh","email":"","orcid":"","institution":"University of Maragheh","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Reza","middleName":"","lastName":"Mohammadzadeh","suffix":""},{"id":101426318,"identity":"3f37cd66-ef80-4e84-bad2-2b0c163b066d","order_by":12,"name":"Seyed Mahdi Hassanian","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7klEQVRIiWNgGAWjYBACAwTJA8QVcAkJYrWcIVoLA1QLYxsRDjNnP/7wc0GBXZ5ue++xTzfnbUtc23+A8cMPBot8XFose3KMpWcYJBebnTmXPDt32+3EbTcSmCV7GCQsG3A57EAOgzSPATNQZY4xM0QLA4M00C8GOHQwGJx//vg3j0F94rb7b4Ba5gC1nD/A/BuvlhsJZkBbDgMN5wFqaQBqOZDAht+WG2/MrHkMjiduOwN0WM6x28bbbiS2WfYY4HNY+uPbPH+qE7cdPwPUUnNbdtv5w4dv/Kiow6kFG2BsQImvUTAKRsEoGAWkAwBxK1iA40qP/QAAAABJRU5ErkJggg==","orcid":"","institution":"Mashhad University of Medical Sciences","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Seyed","middleName":"Mahdi","lastName":"Hassanian","suffix":""},{"id":101426319,"identity":"1333f46a-d964-4d79-b3f2-9fd6f4445047","order_by":13,"name":"Majid Khazei","email":"","orcid":"","institution":"Mashhad University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Majid","middleName":"","lastName":"Khazei","suffix":""}],"badges":[],"createdAt":"2022-04-15 11:59:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1561463/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1561463/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":20883193,"identity":"760a2247-b52c-425d-9e59-f6b2471fb3ad","added_by":"auto","created_at":"2022-04-28 16:02:21","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":149760,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePhytosomal curcumin attenuated the formation of adhesion bands. \u003c/strong\u003e(A-B)\u003cstrong\u003e \u003c/strong\u003eThe macroscopic illustration of adhesion bands formation in different groups of peritendinous (A), and peritoneal (B) post-surgical adhesion models.\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1561463/v1/931a520b8ae1c44a55f140fd.jpg"},{"id":20883886,"identity":"966cc8d5-dc59-4d05-b461-6f4785731ceb","added_by":"auto","created_at":"2022-04-28 16:07:21","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":83975,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePhytosomal curcumin attenuates macroscopic grading of post-operational adhesion bands score. \u003c/strong\u003e(A-D) The macroscopic adhesion grading based on Tang et al. scoring system (Table 1) for peritendinous adhesion bands. (E) The same as (A-D) except that severity of adhesion bands was scored according to Ishiyama et al. grading system (Table 2). (F-G) The efficacy of phytosomal curcumin on reduction of Nair (F) and Leach (G) grading systems (Table 3) in abdominal post-surgery. **P\u0026lt;0.01, ***P\u0026lt;0.001.\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1561463/v1/9d447f005ec84ee291c0bad1.jpg"},{"id":20883887,"identity":"4a8434e5-575f-4c5d-acbb-9b218f8ce537","added_by":"auto","created_at":"2022-04-28 16:07:21","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":244537,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePhytosomal curcumin reduced inflammatory cells infiltration to the site of surgeries. \u003c/strong\u003e(A) Hematoxylin and Eosin (H\u0026amp;E) staining of Achilles tendon adhesion tissues showed a lower leukocytes infiltration (arrows) into the tendon tissue in phytosomal curcumin-treated group. (B) Quantification of inflammation score based on Moran et al. scoring system (Table 4). (C) The effect of phytosomal curcumin was also compared between abdominal adhesion groups, using H\u0026amp;E staining. Arrows indicate inflammatory cells infiltration ***P\u0026lt;0.001\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"Fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1561463/v1/5e0af5d321aaba1abf9daa3f.jpg"},{"id":20883192,"identity":"00926e38-36e7-4142-bde3-b50d0348fd47","added_by":"auto","created_at":"2022-04-28 16:02:21","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":112654,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe effect of phytosomal curcumin on oxidant/ anti-oxidant balance in adhesive tissue samples. \u003c/strong\u003e(A-D) The concentration of MDA (A) and total thiol (B), as well as superoxide dismutase (C) and catalase (D) enzyme activities, were compared between different groups in peritendinous adhesions. (E-H) The protective effect of phytosomal curcumin on counterbalancing of oxidative stress was performed by measuring oxidative stress markers in abdominal tissue homogenates. ***P\u0026lt;0.001.\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"Fig4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1561463/v1/1ea731139b6115b3351e8368.jpg"},{"id":20883204,"identity":"49b707d0-6599-4ac0-9e2e-587cfb0d2d57","added_by":"auto","created_at":"2022-04-28 16:02:21","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":203785,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePhytosomal curcumin decreased post-surgical fibrosis in animal models\u003c/strong\u003e. (A) Results of Masson’s trichrome staining showed a significant reduction of collagen deposition in curcumin-treated rats compared to the positive control group in tendon adhesion tissues. (B-E) Tang Histological (microscopic) grading score (Fig. 5E) (Table 5), consisting of quantity (Fig. 5B), quality (Fig. 5C), and grading (Fig. 5D) of fibrosis, was compared between different groups in post-operational peritendinous adhesion band formation. (F) Masson’s trichrome staining showed that phytosomal curcumin attenuated collagen deposition in post-surgical peritoneal adhesions. Arrows show deposition of collagen. **P\u0026lt;0.01, ***P\u0026lt;0.001.\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"Fig5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1561463/v1/e85608a9038da03b4a93868f.jpg"},{"id":20883888,"identity":"72835379-5fc3-4423-b922-9661be302fc2","added_by":"auto","created_at":"2022-04-28 16:07:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1397036,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1561463/v1/4e4be82e-8076-4c4f-a0fd-748eefe99541.pdf"},{"id":20883207,"identity":"4a8a2163-ebb7-4d83-9282-514fd6891f88","added_by":"auto","created_at":"2022-04-28 16:02:21","extension":"docx","order_by":14,"title":"","display":"","copyAsset":false,"role":"supplement","size":13376,"visible":true,"origin":"","legend":"","description":"","filename":"Highlights.docx","url":"https://assets-eu.researchsquare.com/files/rs-1561463/v1/8e3c722c1e56970279b04b5b.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Phytosomal curcumin elicits potent protective responses in post-surgical adhesion band formation by decreasing inflammation and fibrosis","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePost-operative adhesion bands (PSAB) are fibrotic tissues generated by impaired fibrinolysis and cellular exudates following injury to the operated area such as abdominal cavity \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e, flexor and Achilles tendons \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Current therapeutic strategy utilizes solid barriers such as Interceed and Seprafilm at reducing adhesion band formation at injury sites. However, the accurate prediction of the damaged area following surgery limits usage of this method \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Intra-abdominal adhesions develop in over 90% of patients with peritoneal or gynecological surgeries \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. The formation of these fibrotic bands is usually asymptomatic \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. This condition is accompanied by post-surgical complications including pelvic pain, infertility, and intestinal obstruction \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSimilarly, peritendinous adhesions are a serious complication of flexor tendon injury associated with a high personal and economic burden for patients \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Tendons are dense fibrillary connective tissues made up of parallel collagen fiber bundles and low cellular populations \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Flexor tendons serve as energy-saving elastic springs absorbing external forces and stabilize joint motion and biomechanical function of the musculoskeletal system \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Current therapeutic options for reducing or preventing tendon adhesions are ineffective and not routine in clinical medicine. Thus, it is necessary to attain a greater understanding of the adhesion formation process and to develop an effective treatment \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCurcumin, also known as diferuloylmethane, is a polyphenol extract of turmeric (\u003cem\u003eCurcuma longa\u003c/em\u003e L. rhizome) and has been used for centuries in traditional Chinese and Indian medicine \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Curcumin exerts its therapeutic effects by modulating transcription factors, cell adhesion molecules, enzymes, and cytokines \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. However, the applicability of curcumin is limited due to low solubility in aqueous mediums, instability at physiological pH, and rapid clearance \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. To enhance curcumin's bioavailability and its therapeutic effects, the formulated phytosomal curcumin (curcumin-phosphatidylcholine complex) has been provided by Sami Labs Ltd. (Bangalore, India) and was used in our previous publications \u003csup\u003e\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAberrant regulation of the inflammatory response and fibrosis are major factors in adhesion band formation \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Anti-inflammatory activities of phytosomal curcumin have been reported to have positive effects in various diseases such as cancers \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e and hepatic disorders \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. In addition, several studies illustrated the protective effects of phytosomal curcumin against liver fibrosis and non-alcoholic fatty liver diseases \u003csup\u003e\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. In this study we aim to investigate the protective effects of phytosomal curcumin on post-operative peritoneal and peritendinous adhesions.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eMaterials\u003c/h2\u003e \u003cp\u003ePhytosomal curcumin was obtained from Sami Labs Ltd. (Bangalore, India). All reagents for malondialdehyde (MDA), total thiol, catalase (CAT), and superoxide dismutase (SOD) were purchased from Sigma-Aldrich Chemical Co. (St. Louis, MO, USA).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eAnimal experiment\u003c/h2\u003e \u003cp\u003e Animal experiments were carried out in line with the guidelines for Care and Use of Laboratory Animals from Mashhad University of Medical Sciences (reference number: IR.MUMS.MEDICAL.REC.1399.067). Male Wistar rats (weighing 200\u0026ndash;250 g) were obtained from the laboratory animals center of medical school, Mashhad University of Medical Sciences. They were housed according to the protocol approved by Institutional Animal Care Guidelines. All animals had free access to drinking water and were fed standard rat chow. They were kept at a normal temperature of 22\u0026ndash;25\u0026deg;C and a standard 12-hr light/dark cycle .\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eThe post-operational adhesion band models\u003c/h2\u003e \u003cp\u003eGeneral anesthesia was induced with an intraperitoneal injection of ketamine/xylazine. Post-operational peritendinous adhesion model was induced according to a protocol established by Tang et al \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Briefly after shaving the right hind limb, a longitudinal incision was made in the Achilles tendon, inducing peritendinous adhesion. The tendon was sutured using the Kessler\u0026ndash;Kirchmeyer technique. Abdominal adhesion formation was induced by surgical procedure according to protocol by Hemadeh et al \u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. Briefly, the peritoneal was opened by a U-shaped incision. Using a medical electric scalpel, the cecal and the interior abdomen surfaces were gently rubbed to generate partial petechial hemorrhages and adhesion band formation.\u003c/p\u003e \u003cp\u003eAnimals in each model were randomly divided into 3 groups (n\u0026thinsp;=\u0026thinsp;6) as described below: (A) sham group with surgical incision but no adhesion, (B) positive control group with total surgical transection and adhesion receiving normal saline daily, (C) phytosomal curcumin group which is the same as group B except that rats were treated with 25 mg/kg/day curcumin orally \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e for either 7 or 21 days in peritoneal or tendon adhesion models, respectively. At the end of the experiments, rats were anesthetized, sacrificed, and tissue samples were collected (quickly frozen in liquid nitrogen or stored at 10% formalin) for further assessments.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eEvaluation of adhesion scores\u003c/h2\u003e \u003cp\u003eThe macroscopic grading (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) and the severity of the tendon adhesion bands (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) were carried out using the Tang et al. \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e and Ishiyama et al. \u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e adhesion scoring system, respectively. The Nair \u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e and Leach \u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e scoring systems were used for evaluating the incidence and stability of intraperitoneal adhesions, respectively (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTang et al. Macroscopic grading of peritendinous adhesion bands\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eGrading\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eTang et al. Macroscopic grading\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLength(quantity)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo adhesions\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;5mm\u003c/p\u003e \u003cp\u003e5 to 10 mm\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;10 mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDensity and tolerance for mobility(quality)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo adhesions\u003c/p\u003e \u003cp\u003eLoose, elastic, mobile\u003c/p\u003e \u003cp\u003eModerate mobility\u003c/p\u003e \u003cp\u003eRigid, dense, immobile\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGrading of adhesions\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e1 to 2\u003c/p\u003e \u003cp\u003e3 to 4\u003c/p\u003e \u003cp\u003e5 to 6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAbsent\u003c/p\u003e \u003cp\u003eInferior\u003c/p\u003e \u003cp\u003eMedium\u003c/p\u003e \u003cp\u003eSevere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eIshiyama et al Macroscopic grading scores for peritendinous adhesion bands\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrading\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIshiyama et al grading scores\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGrade 1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo adhesion formation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGrade 2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdhesion could be separated by blunt dissection alone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGrade 3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSharp dissection was needed to separate no more than 50% of adhesion tissues\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGrade 4\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdhesion could be separated by sharp dissection was required to separate 51-97.5% of adhesion tissues\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGrade 5\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSharp dissection was required to separated\u0026thinsp;\u0026gt;\u0026thinsp;97.5% of adhesion tissues\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eIntra-peritoneal adhesion score system for macroscopic evaluation\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0 to 4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdhesion grade (Nair's et al)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAdhesion grade (Leach et al)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eComplete absence of adhesion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo adhesions\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSingle band of adhesion, between viscera or from viscera to abdominal wall\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIf the adhesions separated from tissue with gentle traction\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTwo bands, either or from viscera to abdominal wall\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRequiring moderate traction\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMore than two bands, between viscera or viscera to abdominal wall\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRequiring sharp dissection\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eViscera directly adherent to abdominal wall, irrespective of number and extent of adhesive bands\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eHistological staining\u003c/h2\u003e \u003cp\u003eTissue specimens were fixed in 10% formalin, processed, and embedded in paraffin. Next, tissues were stained with either hematoxylin/eosin (H\u0026amp;E) or Masson\u0026rsquo;s trichrome staining. H\u0026amp;E staining was performed to analyze general tissue structure and the inflammatory cells infiltration whereas trichrome staining was utilized to explore the collagen deposition, reflecting the severity of fibrosis. Inflammatory cell infiltration was quantified using Moran et al. (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) \u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e scoring system. Histological grading scores for the peritendinous adhesion bands were completed according to the Tang et al. system \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMoran et al. grading scores for inflammatory cells infiltration to the injury site\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrading\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMoran et al. scores\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGrade 0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGrade 1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLeukocyte infiltration within fibro-osseous sheath\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGrade 2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInfiltration of synovium and epitenon\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGrade 3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInfiltration of endotenon\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGrade 4\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDiffuse inflammation extending within tendon and beyond sheath\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTang et al. Histological grading scores for the peritendinous adhesion bands\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrading\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eTang et al. Histological score\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eQuantity\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo apparent adhesions\u003c/p\u003e \u003cp\u003eA number of scattered filaments\u003c/p\u003e \u003cp\u003eA large number of filaments\u003c/p\u003e \u003cp\u003ecountless filaments\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eQuality\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo apparent adhesions\u003c/p\u003e \u003cp\u003eRegular, elongated, fine, filamentous\u003c/p\u003e \u003cp\u003eIrregular, mixed, shortened, filamentous\u003c/p\u003e \u003cp\u003eDense, not filamentous\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGrading of adhesions\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e3 to 4\u003c/p\u003e \u003cp\u003e5 to 6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003cp\u003eSlight\u003c/p\u003e \u003cp\u003eModerate\u003c/p\u003e \u003cp\u003eSevere\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eOxidative stress markers analysis\u003c/h2\u003e \u003cp\u003eAssessment of the antioxidant effect of phytosomal curcumin was performed by measuring MDA and total thiol concentrations as well as SOD and catalase enzyme activities in tissue samples as described \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eBiomechanical testing of tendon repairs\u003c/h2\u003e \u003cp\u003eAchilles tendon tissue mechanical properties were analyzed as described previously \u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. In summary, the calcaneus-tendon-muscle complex of rats was dissected and hydrated in phosphate buffered saline (PBS) for one hour. Samples were immediately mounted on a tensile testing machine (SANTAM-STM20) using specific metal clamps. The angle between the calcaneus and Achilles tendon corresponded to 30\u0026ordm; dorsiflexion of the foot. A 500 N load cell and a 5 mm/min speed were used at a maintained temperature of 25\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u0026ordm;C. The sample\u0026rsquo;s properties were computed using the load-elongation and stress-strain curves obtained during the final load-to-failure tests. The load-elongation curve represents structural parameters including ultimate load (N), elongation (%), energy absorbed, and stiffness. First the tendon tissues of the specimens were tensioned to the point of failure. The maximum longitudinal changes and the maximum load values exerted before tissue rupture are defined as ultimate elongation (mm) and ultimate load (N), respectively \u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. Mechanical data from the stress-stain curve includes ultimate stress (MPa), ultimate strain (%), and tangent modulus (MPa) \u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. Ultimate stress (MPa) is formulated by dividing ultimate load value (N) by cross-sectional area (CSA). Ultimate strain (%) is expressed as elongation rate/initial length (ΔL/L0) x 100. Tangent modulus (MPa) is defined as the ratio of induced stress to strain (the slope of the linear) at each loading cycle, indicating the ability of specimens to resist deformation. Thus, a higher tangent modulus generates higher stress for a given strain \u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eResults were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard error of the mean (SEM). Statistical analysis was performed using one-way ANOVA and Shapiro-Wilk normality test. A P-value of \u0026lt;\u0026thinsp;0.05 was considered significant. All statistical assessments were performed using the SPSS software (SPSS Inc., Chicago, IL, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePhytosomal curcumin attenuates frequency and structural properties of adhesion bands\u003c/h2\u003e \u003cp\u003eAnesthetic induction and surgical procedures were successful with all rats surviving to the end of the study. Results showed that curcumin significantly decreased adhesion band formation in both the tendon (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA) and abdominal surgeries (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). We used Tang \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e and Ishiyama grading \u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e system to evaluate the properties and severity of peritendinous adhesions, and Nair \u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e and Leach \u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e scoring systems for evaluating the presence and rigidity of peritoneal adhesions.\u003c/p\u003e\u003cp\u003eUsing Tang macroscopic grading scores of peritendinous adhesion bands (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), curcumin-treated rats showed decreased length (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA), density and tolerance for mobility (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB), and grading of adhesion score (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC) compared to the positive control group. Consistent with these findings, the Ishiyama macroscopic scoring system (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) also indicated that curcumin treatment decreased the severity of adhesions formation (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE).\u003c/p\u003e\u003cp\u003eNext, we used Nair and Leach scoring systems (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) to investigate the protective effects of curcumin on abdominal adhesion bands formation. Results showed that curcumin significantly decreased both the incidence (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eF) and severity (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eG) of fibrotic bands compared to positive control rats. No adhesion fibers were found in the sham group.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003ePhytosomal curcumin inhibits post-surgical inflammation in peritendinous and intraperitoneal adhesion models\u003c/h2\u003e \u003cp\u003e Inflammation is one of the key factors in the pathogenesis of post-surgical adhesion band formation. To determine the protective effect of phytosomal curcumin on adhesion band-associated inflammation, either tendon or abdominal adhesion tissues were stained with H\u0026amp;E to examine the morphological and histological changes in adhesion rat models. As we previously suggested that 25 mg/Kg phytosomal curcumin has potential therapeutic effects \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e, here we showed that the selective dose of phytosomal curcumin at 25 mg/Kg decreased infiltration of inflammatory cells into the injured site in the tendon adhesions (Fig. \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). We quantified the results and showed a decrease in fibrosis using the Moran \u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e grading score, which is specific for tendon but not abdominal surgeries (Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) (Fig. \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). In terms of peritoneal adhesions, H\u0026amp;E results also demonstrated a decrease in adhesion-related inflammation based on a lower influx of inflammatory cells into the surgical area (Fig. \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC).\u003c/p\u003e\u003cdiv id=\"Sec14\" class=\"Section3\"\u003e \u003ch2\u003ePhytosomal curcumin suppresses inflammation by counterbalancing oxidative stress\u003c/h2\u003e \u003cp\u003eEvaluation of oxidative stress markers was used to further investigate the anti-inflammatory activity of curcumin in post-surgical adhesion band models. Compared to the positive control group, curcumin treatment significantly reduced the level of MDA, an oxidative marker of fatty acid peroxidation, in both peritendinous (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA), and abdominal adhesion tissue homogenates (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eE).\u003c/p\u003e\u003cp\u003eNext, the total thiol (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB, and F) concentration and the activities of SOD (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC, and G) and CAT (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eD, and H) enzymes, all anti-oxidant markers, were measured in the Achilles tendon and abdominal adhesion tissues. Our results clearly showed that the level and activity of all these anti-oxidant markers was increased in the curcumin-treated group, supporting the anti-inflammatory effects of phytosomal curcumin in post-surgical adhesion rat models.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eThe effects of curcumin on fibrosis as a key element in post-surgical adhesion band formation\u003c/h2\u003e \u003cp\u003eWe stained tissues with Masson's trichrome in both post-surgical models to determine the effect of curcumin on fibrosis and collagen deposition at the site of surgery, Results showed that compared to the positive control rats, curcumin suppressed fibrosis and collagen content in peritendinous adhesion tissues (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA). Moreover, by using Tang Histological (microscopic) grading score (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eE) (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e), consisting of quantity (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eB), quality (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eC), and grading (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eD) of fibrosis, we showed that curcumin significantly decreased the overall fibrosis score when compared with the positive control group in peritendinous adhesion. Similarly, using Masson's trichrome staining, the efficacy of phytosomal curcumin on fibrosis of peritoneal tissues was investigated and results showed potent protective activities of curcumin against fibrosis at site of surgery (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eF). These results suggest that inhibition of fibrosis is a mechanism by which curcumin decreases adhesion band formation post-surgeries.\u003c/p\u003e\u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eEffects of phytosomal curcumin on mechanical properties of tendons\u003c/h2\u003e \u003cp\u003eTo obtain the effects of phytosomal curcumin on structural and mechanical properties of tendon adhesion tissues, we plotted the load-elongation and the stress-strain curves, using a SANTAM-STM20 testing machine. Cross-sectional area (CSA) was also measured to evaluate possible modifications in mechanical features of the Achilles tendon in response to the phytosomal curcumin. In this study, we investigated the structural properties of tendon adhesion tissues by measurement of ultimate load between different groups. Our results showed that in comparison to the positive control group, phytosomal curcumin improved the structural properties of damaged tissues, including maximum load (N) in tendons (Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). However, these results were not statistically significant.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparing structural/mechanical properties of the Achilles tendon between groups. Values are expressed as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUltimate Load (N)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUltimate Stress (MPa)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUltimate Strain (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTangent Modulus (MPa)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSham\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e40.6\u0026thinsp;\u0026plusmn;\u0026thinsp;5.126\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e12.92\u0026thinsp;\u0026plusmn;\u0026thinsp;1.632\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e34.56\u0026thinsp;\u0026plusmn;\u0026thinsp;9.621\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e54.19\u0026thinsp;\u0026plusmn;\u0026thinsp;18.74\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePositive Control\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e35.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.083\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e2.232\u0026thinsp;\u0026plusmn;\u0026thinsp;0.256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e40.94\u0026thinsp;\u0026plusmn;\u0026thinsp;16.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e6.694\u0026thinsp;\u0026plusmn;\u0026thinsp;2.89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePhy-curcumin\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e41.55\u0026thinsp;\u0026plusmn;\u0026thinsp;5.541\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e3.663\u0026thinsp;\u0026plusmn;\u0026thinsp;0.488\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e40.05\u0026thinsp;\u0026plusmn;\u0026thinsp;20.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e8.487\u0026thinsp;\u0026plusmn;\u0026thinsp;5.493\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eSince the load-elongation curve depends on size, volume, and shape of tissue samples, we normalized the quantities using the stress-strain curve analyzing the ultimate stress (MPa), ultimate strain (%), and tangent modulus (MPa) indexes. As expected, in the sham group, the level of ultimate stress and ultimate strain is higher and lower than positive control group, respectively. We showed that phytosomal curcumin improved ultimate stress and strain when compared to the positive control group. Consistently, compared to the positive control group, treatment with phytosomal curcumin increased tangent modulus which is an index indicating the ability of specimens to resist deformation (Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we analyzed the protective effects of oral phytosomal curcumin in decreasing adhesion formation post tendon and abdominal surgeries in animal models. Our results suggested that phytosomal curcumin significantly decreased post-operational adhesion band formation in both rat models. We showed that phytosomal curcumin reduced adhesion-related inflammatory responses by decreasing infiltration of inflammatory cells and regulating the oxidant/anti-oxidant balance at surgery sites. Moreover, our results showed that phytosomal curcumin potently exhibited anti-fibrotic activities by attenuating fibrotic bundle thickness and collagen deposition. These findings support the therapeutic potential of phytosomal curcumin in decreasing post-surgical adhesion band formation.\u003c/p\u003e \u003cp\u003eAdhesion band formation post tendon and abdominal injuries are common surgery-associated complications in patients worldwide \u003csup\u003e\u003cspan additionalcitationids=\"CR35 CR36\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. Inflammation is a key physio-pathological factor in post-surgical adhesion band formation \u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. The anti-inflammatory properties of phytosomal curcumin and its safety have been validated in numerous human disorders including osteoarthritis, diabetes, cancer, retinopathy, and other diseases \u003csup\u003e\u003cspan additionalcitationids=\"CR41\" citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e. It has been shown that curcumin down-regulates expression of several inflammatory mediators including IL-6, TNF-α, nuclear factor kappa-B (NF-κB)-regulated gene products such as cyclooxygenase (COX)-2, IL-1, cell adhesion molecules, and C-reactive protein (CRP) \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Similarly, Vizzutti et al. showed that production of reactive oxygen species (ROS) was reduced in curcumin-treated mice in a steato-hepatitis model \u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. We recently showed that the anti-cancer property of phytosomal curcumin is partially mediated by eliciting anti-inflammatory responses in colorectal cancer \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. We also previously showed that phytosomal curcumin potentiates the anti-inflammatory activity of 5-fluorouracil (5-FU), leading to a significant reduction in inflammation and histo-pathological scores in colitis-associated colorectal cancer using \u003cem\u003ein vitro\u003c/em\u003e and \u003cem\u003ein vivo\u003c/em\u003e models \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. In another study we demonstrated the anti-oxidant activities of phytosomal curcumin in a xenograft mice model of breast cancer \u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e. Consistent with these findings, here we showed that curcumin elicits significant anti-inflammatory activity by decreasing inflammatory cell infiltration and increasing levels and activities of anti-oxidant markers in both peritendinous and abdominal surgeries. Our results suggest that a decreased inflammatory response post-surgery could be a mechanism by which curcumin elicits its therapeutic potency at site of injuries.\u003c/p\u003e \u003cp\u003eAlthough surgical-induced adhesions and inflammatory responses occur early during the adhesions formations, fibrosis appears as a late event with a major impact on tissues dysfunction \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. In line with this, Kang et al. evaluated the protective effects of curcumin on synthesis of collagen in both cellular and animal models. Results showed a lower thickness of smooth muscle alpha-actin and collagen fibers and lower mRNA expression of type I collagen in curcumin-treated groups \u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e. Furthermore, it has been shown that the high density of fibrillar extracellular matrix (ECM) and the gene expression level of pro-collagen type I were reduced via curcumin treatment inhibiting the fibrogenic progression in sinusoids and perivenular areas in steatohepatitis mice \u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. Consistently, in this study we showed that curcumin via reducing fibrosis quantity, fibrosis quality, grading of adhesion, and the collagen deposition could decrease total fibrosis score in tissue adhesions in rat model.\u003c/p\u003e \u003cp\u003eTaken together, the current study introduced anti-inflammatory and anti-fibrotic phytosomal curcumin as a promising treatment for inhibition or reduction of post-surgical adhesion band formation. The exact protective functions of phytosomal curcumin in adhesion models have not been yet understood. Further animal and clinical studies are needed to clarify these underlying mechanisms and validate these results in patients.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur results suggest that the anti-inflammatory and anti-fibrotic properties of phytosomal curcumin, has therapeutic potential for preventing PSAB formation The particular protective roles of phytosomal curcumin in adhesion models have not been yet completely understood. Supplementary animal and clinical studies are required to elucidate these underlying mechanisms and confirm these results in patients.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePSAB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePost-operative adhesion bands\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMDA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMalondialdehyde\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCAT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCatalase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSOD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSuperoxide dismutase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eH\u0026amp;E\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHematoxylin/eosin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePBS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePhosphate buffered saline\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSEM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eStandard error of mean\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIL-1\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInterlukine-1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIL-6\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInterlukine-6\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTNF-α\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTumor necrosis factor Alpha\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNF-κB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNuclear factor kappa B\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCOX-2\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCyclooxygenase-2\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCRP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eC-reactive protein\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eROS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eReactive oxygen species\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e5-FU\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e5 Fluorouracil\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eThe funding agencies had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnimal experiments were carried out in line with the guidelines for Care and Use of Laboratory Animals from Mashhad University of Medical Sciences (reference number: IR.MUMS.MEDICAL.REC.1399.067).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors give their consent for the publication of identifiable details within the text to be published in this Journal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data and materials are available upon request to corresponding author via sending e-mail to [email protected]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by grants awarded by\u0026nbsp;the Mashhad University of Medical Sciences (981180) to S.M.H.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors Contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eM. A. with support from M. E., and M. A. designed and performed cellular and molecular experiments. S. E. N, and F. A. with support from H. G. and H. N. and A. A. designed and performed animal experiments. A. S. and S. M. H. with support from M. R wrote the manuscript. A. A., R. M., and S. S. analyzed data and contributed to the clinical interpretation of the results.\u003c/p\u003e\n\u003cp\u003eS. M. H. and M. K. designed the study plan and supervised the project. All authors discussed the results and contributed to the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eN/A.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSoltany, S. Postoperative peritoneal adhesion: an update on physiopathology and novel traditional herbal and modern medical therapeutics. 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Pharmacol. \u003cb\u003e54\u003c/b\u003e, 119\u0026ndash;126, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1211/0022357021771823\u003c/span\u003e\u003cspan address=\"10.1211/0022357021771823\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2002).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Phytosomal curcumin, Peritendinous adhesion, Peritoneal fibrosis, Post-surgical adhesion bands ","lastPublishedDoi":"10.21203/rs.3.rs-1561463/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1561463/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eIn this study we investigated the therapeutic potential of the phytosomal form of pharmacologically active component of Curcuma longa, curcumin, in attenuating Post-operative adhesion bands (PSAB) formation in both peritoneal and peritendinous surgeries in animal models.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eBio-mechanical, Histological and quantitative evaluation of inflammation, and total fibrosis scores were graded and measured in the presence and absence of phytosomal curcumin.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOur 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. We showed that curcumin could 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.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThese results suggest that the anti-inflammatory and anti-fibrotic properties of phytosomal curcumin, has therapeutic potential for preventing PSAB formation.\u0026rdquo;\u003c/p\u003e","manuscriptTitle":"Phytosomal curcumin elicits potent protective responses in post-surgical adhesion band formation by decreasing inflammation and fibrosis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-04-28 16:02:19","doi":"10.21203/rs.3.rs-1561463/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0acc7e0b-4d2f-41ad-91d1-a9997beecede","owner":[],"postedDate":"April 28th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-05-14T12:29:11+00:00","versionOfRecord":[],"versionCreatedAt":"2022-04-28 16:02:19","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1561463","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1561463","identity":"rs-1561463","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}