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Exploring new therapeutic potentials of curcumin against post-surgical adhesion bands

Abstract

Background

Adhesion band formation is a common cause of morbidity for patients undergoing surgeries. Anti-inflammatory and anti-fibrotic properties of curcumin, a pharmacologically active component of Curcuma longa, have been investigated in several studies. The aim of this study is to explore the therapeutic potential of curcumin in attenuating post-operative adhesion band (PSAB) formation in both peritoneal and peritendinous surgeries in animal models.

Methods

Bio-mechanical, histological and quantitative evaluation of inflammation, and total fibrosis scores were graded and measured in the presence and absence of phytosomal curcumin.

Results

Results showed that phytosomal curcumin significantly decreased severity, length, density and tolerance of mobility of peritendinous adhesions as well as incidence and severity of abdominal fibrotic bands post-surgery. Curcumin may decrease inflammation by attenuating recruitment of inflammatory cells and regulating oxidant/anti-oxidant balance in post-operative tissue samples. Moreover, markedly lower fibrosis scores were obtained in the adhesive tissues of phytosomal curcumin-treated groups which correlated with a significant decrease in quantity, quality and grading of fibers, and collagen deposition in animal models.

Conclusion

These results suggest that protective effects of phytosomal curcumin against PSAB formation is partially mediated by decreasing inflammation and fibrosis at site of surgery. Further studies are needed to investigate the therapeutic potential of this molecule in preventing PSAB.

Peer Review reports

Introduction

Post-operative adhesion bands (PSAB) are fibrotic tissues generated by impaired fibrinolysis and cellular exudates following injury to operated areas such as abdominal cavity [1], flexor and Achilles tendon [2]. Current therapeutic strategy utilizes solid barriers such as Interceed and Seprafilm at reducing adhesion band formation at injury sites. However, accurate prediction of damag levels at injury sites following surgery limits the usage of this method [3, 4]. Peritoneal adhesion bands develop in 93% of patients undergoing a general surgery and up to 97% of patients undergoing an open gynecological pelvic operation [5,6,7]. The formation of these fibrotic bands is usually asymptomatic [8]. This condition is accompanied by post-surgical complications including pelvic pain, infertility, and intestinal obstruction [9]. Adhesiolysis operations place a significant burden on public health and they are responsible for 3–5% of patient’s death post surgeries. It has been shown that dhesiolysis accounted for 303,836 hospitalizations and more than $1.33 billion in hospitalization and surgeon expenditures [10].

Similarly, peritendinous adhesions are a serious complication of flexor tendon injury associated with a high personal and economic burden for patients [11]. Tendons are dense fibrillary connective tissues made up of parallel collagen fiber bundles and low cellular populations [12]. Flexor tendons serve as energy-saving elastic springs absorbing external forces and stabilizing joint motion and biomechanical function of the musculoskeletal system [13]. Current therapeutic options for reducing or preventing tendon adhesions are ineffective and not routine in clinical medicine. Thus, it is necessary to attain greater understanding of adhesion formation process and develop an effective treatment [12].

Currently, various complementary and alternative medicine methods have been used for human diseases [14, 15]. In line with this, therapeutic potency of many phytochemicals have been investigated to attenuating post-surgical adhesion band formation [15,16,17,18]. 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 [19]. Curcumin exerts its therapeutic effects by modulating transcription factors, cell adhesion molecules, enzymes, and cytokines [19]. However, the applicability of curcumin is limited due to low solubility in aqueous mediums, instability at physiological pH, and rapid clearance [20]. 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 previous publications [21,22,23].

Aberrant regulation of the inflammatory response and fibrosis are major factors in adhesion band formation [11, 16]. Anti-inflammatory activities of phytosomal curcumin have been reported to have positive effects in various diseases such as cancers [23] and hepatic disorders [24, 25]. In addition, several studies illustrated the protective effects of phytosomal curcumin against liver fibrosis and non-alcoholic fatty liver diseases [26,27,28]. Previous studies investigating curcumin as a potent anti-inflammatory and antioxidant agent have demonstrated its ability to reduce intra-abdominal adhesion formation induced by dimethyl sulfoxide [29]. In addition, another study showed curcumin improved the quality of tendon rupture healing, which indicates that curcumin holds promise as a treatment for injured tendon tissue [30, 31]. Curcumin is a strong anti-oxidant and anti-inflammatory agent that has different pharmacological effects [20]. In addition, several studies have shown curcumin to be safe at doses up to 8 g per day, however, because of its low solubility in water and rapid metabolism, it does not have high oral bioavailability [20]. Bioavailability of curcumin has been shown to be improved with phytosomal formulations (curcumin complexed with phosphatidylcholine). Phytosomes in complex withphospholipids, exhibit specific physicochemical properties, such as amphiphilicity, allowing them to disperse in hydrophilic and lipophilic media [20]. The efficacy and safety of curcumin phytosomes have not been studied at attenuating post-operative peritoneal and peritendinous adhesions. The aim of this study is 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 study

Male Wistar rats (weighing 200–250 g) were obtained from the laboratory animals center of the medical school at Mashhad University of Medical Sciences. Animals 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.

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 [32]. 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 [33]. 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 [23, 34] 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 collected (rapid freezing by liquid nitrogen or stored in 10% formalin) for further assessments.

Evaluation of adhesion scores

The macroscopic grading and the severity of the tendon adhesion bands were carried out using the Tang et al. [32] and Ishiyama et al. [35] adhesion scoring system, respectively. The Nair [36] and Leach [37] scoring systems were used for evaluating the incidence and stability of intraperitoneal adhesions, respectively.

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. [38] scoring system. Histological grading scores for the peritendinous adhesion bands were completed according to the Tang et al. system [32].

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 [8, 9].

Biomechanical testing of tendon repairs

Achilles tendon tissue mechanical properties were analyzed as described previously [39, 40]. In summary, the calcaneus-tendon-muscle complex of rats was dissected and hydrated in phosphate buffered saline (PBS) for 1 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° dorsiflexion of the foot. A 500 N load cell and a 5 mm/min speed were used at a maintained temperature of 25 ± 2 °C. The sample 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. Tendon tissues of the specimens were first 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 [41]. Mechanical data from the stress-stain curve includes ultimate stress (MPa), ultimate strain (%), and tangent modulus (MPa) [40]. 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) × 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 [42].

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. 1A) and abdominal surgeries (Fig. 1B). Tang [32] and Ishiyama grading [35] system were used to evaluate the properties and severity of peritendinous adhesions, and Nair [36] and Leach [37] scoring systems for evaluating the presence and rigidity of peritoneal adhesions.

Fig. 1
figure 1

Phytosomal curcumin attenuated the formation of adhesion bands. a-b The macroscopic illustration of adhesion bands formation in different groups of peritendinous (a), and peritoneal (b) post-surgical adhesion models

Using Tang macroscopic grading scores of peritendinous adhesion bands [32], curcumin-treated rats showed decreased length (Fig. 2A), density and tolerance for mobility (Fig. 2B), and grading of adhesion score (Fig. 2C) compared to the positive control group. Consistent with these findings, the Tang and Ishiyama macroscopic scoring system [32, 35] also indicated that curcumin treatment decreased the severity of adhesions formation (Fig. 2D and E).

Fig. 2
figure 2

Phytosomal curcumin attenuates macroscopic grading of post-operational adhesion bands score. a-d The macroscopic adhesion grading based on Tang et al. scoring system [32] 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 [35]. f-g The efficacy of phytosomal curcumin on reduction of Nair [36] (f) and Leach [37] (g) grading systems in abdominal post-surgery. **P < 0.01, ***P < 0.001

Next, Nair [36] and Leach scoring systems [37] were used to investigate the protective effects of curcumin on abdominal adhesion bands formation. Results showed that curcumin significantly decreased both the incidence (Fig. 2F) and severity (Fig. 2G) 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. It has been suggested that 25 mg/Kg phytosomal curcumin has potential therapeutic effects [22, 23]. Results showed that using the same dose of curcumin potently decreased infiltration of inflammatory cells into the injury site (Fig. 3A) and decreased fibrosis in the tendon adhesions (Fig. 3B). 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. 3C).

Fig. 3
figure 3

Phytosomal curcumin reduced inflammatory cells infiltration to the site of surgeries. a Hematoxylin and Eosin (H&E) staining of Achilles tendon adhesion tissues showed a lower leukocyte infiltration (arrows) into the tendon tissue in phytosomal curcumin-treated group. b Quantification of inflammation score based on Moran et al. scoring system [38]. c The effect of phytosomal curcumin was also compared between abdominal adhesion groups, using H&E staining. Arrows indicate inflammatory cells infiltration ***P < 0.001

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. 4A) and abdominal adhesion tissue homogenates (Fig. 4E).

Fig. 4
figure 4

The effect of phytosomal curcumin on oxidant/ anti-oxidant balance in adhesive tissue samples. 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 < 0.001

Next, total thiol (Fig. 4B, and F) concentration and activities of SOD (Fig. 4C, and G) and CAT (Fig. 4D, and H) enzymes, all anti-oxidant markers, were measured in the Achilles tendon and abdominal adhesion tissues. These 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

Tissues were stained with Masson’s trichrome to determine the effect of curcumin on fibrosis and collagen deposition at the surgery site. Results showed that compared to the positive control rats, curcumin suppressed fibrosis and collagen content in peritendinous adhesion tissues (Fig. 5A). Moreover, by using Tang Histological (microscopic) grading score [32] (Fig. 5E), consisting of quantity (Fig. 5B), quality (Fig. 5C), and grading (Fig. 5D) of fibrosis, 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 surgery site (Fig. 5F). These results suggest that inhibition of fibrosis is a mechanism by which curcumin decreases post-surgery adhesion band formation.

Fig. 5
figure 5

Phytosomal curcumin decreased post-surgical fibrosis in animal models. 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 [32] (e), consisting of quantity (b), quality (c), and grading (d) 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 < 0.01, ***P < 0.001

Effects of phytosomal curcumin on mechanical properties of tendons

To ascertain the effects of phytosomal curcumin on structural and mechanical properties of tendon adhesion tissues, the load-elongation and the stress-strain curves were plotted. Cross-sectional area (CSA) was also measured to evaluate possible modifications in mechanical features of the Achilles tendon in response to phytosomal curcumin. 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 1). However, these results were not statistically significant.

Table 1 Comparing structural/mechanical properties of the Achilles tendon between groups. Values are expressed as means ± standard deviation

Since the load-elongation curve depends on size, volume, and shape of tissue samples, the quantities were normalized by 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. Moreover, 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 1).

Discussion

In this study the protective effects of oral phytosomal curcumin in decreasing adhesion formation post tendon and abdominal surgeries were investigated in animal models. Results suggested that phytosomal curcumin significantly decreased post-operational adhesion band formation in both rat models. Moreover, phytosomal curcumin reduced adhesion-related inflammatory responses by decreasing infiltration of inflammatory cells and regulating the oxidant/anti-oxidant balance at surgery sites. Furthermore, 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 [43,44,45,46]. Inflammation is a key physio-pathological factor in post-surgical adhesion band formation [47, 48]. 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 [49,50,51]. 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) [19]. Similarly, Vizzutti et al. showed that production of reactive oxygen species (ROS) was reduced in curcumin-treated mice in a steato-hepatitis model [52]. It has been recently shown that the anti-cancer property of phytosomal curcumin is partially mediated by eliciting anti-inflammatory responses in colorectal cancer [22]. Consistent with these findings Marjaneh et al. 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 [23]. In another study we demonstrated the anti-oxidant activities of phytosomal curcumin in a xenograft mice model of breast cancer [21]. Consistent with these findings, results of this study 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. These results suggest that a decreased inflammatory response post-surgery could be a mechanism by which curcumin elicits its therapeutic potency at injury sites.

Although surgically-induced adhesions and inflammatory responses occur early during the adhesions formations, fibrosis appears as a late event with a major impact on tissues dysfunction [11, 16]. 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 [53]. Furthermore, it has been shown that the high density of fibrillar extracellular matrix (ECM) and the gene expression levels of pro-collagen type I were reduced via curcumin treatment inhibiting fibrogenic progression in sinusoids and perivenular areas in steatohepatitis mice [52]. Consistently, results of this study showed that curcumin via reduction of fibrosis quantity, fibrosis quality, grading of adhesion, and collagen deposition could decrease total fibrosis score in tissue adhesions in rat model.

These results suggest that protective response of phytosomal curcumin against PSAB formation is partially mediated by decreasing inflammation and fibrosis at site of surgery. Further studies are needed to investigate therapeutic potential of this molecule in preventing PSAB.”. The exact protective mechanisms of phytosomal curcumin in adhesion models have yet to be understood. Further animal and clinical studies are needed to clarify these underlying mechanisms and validate these results in patients.

Conclusion

Results of this study suggest that the protective response of phytosomal curcumin against PSAB formation is partially mediated by decreasing inflammation and fibrosis at surgery sites. Supplementary animal and clinical studies are required to elucidate these underlying mechanisms and confirm these results in patients.

Availability of data and materials

All data and materials are available upon request to corresponding author via sending e-mail to hasanianmehrm@mums.ac.ir.

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

References

  1. Soltany S. Postoperative peritoneal adhesion: an update on physiopathology and novel traditional herbal and modern medical therapeutics. Naunyn Schmiedeberg's Arch Pharmacol. 2021;394:317–36.

    Article  CAS  Google Scholar 

  2. Chen S, et al. RelA/p65 inhibition prevents tendon adhesion by modulating inflammation, cell proliferation, and apoptosis. Cell Death Dis. 2017;8:e2710. https://doi.org/10.1038/cddis.2017.135.

    Article  Google Scholar 

  3. Cai X, et al. Transglutaminase-catalyzed preparation of crosslinked carboxymethyl chitosan/carboxymethyl cellulose/collagen composite membrane for postsurgical peritoneal adhesion prevention. Carbohydr Polym. 2018;201:201–10. https://doi.org/10.1016/j.carbpol.2018.08.065.

    Article  CAS  Google Scholar 

  4. Yurdakul Sıkar E, Sıkar HE, Top H, Aygıt AC. Effects of Hyalobarrier gel and Seprafilm in preventing peritendinous adhesions following crush-type injury in a rat model. Turk J Trauma Emerg Surg. 2019;25:93–8.

    Google Scholar 

  5. Liakakos T, Thomakos N, Fine PM, Dervenis C, Young RL. Peritoneal adhesions: etiology, pathophysiology, and clinical significance. Dig Surg. 2001;18:260–73.

    Article  CAS  Google Scholar 

  6. Tabibian N, Swehli E, Boyd A, Umbreen A, Tabibian J. Abdominal adhesions: a practical review of an often overlooked entity. Ann Med Surg. 2017;15:9–13.

    Article  CAS  Google Scholar 

  7. Berríos-Torres SI, et al. Centers for disease control and prevention guideline for the prevention of surgical site infection, 2017. JAMA Surg. 2017;152:784–91.

    Article  Google Scholar 

  8. Soleimani A, et al. Novel oral transforming growth factor-β signaling inhibitor potently inhibits postsurgical adhesion band formation. J Cell Physiol. 2020;235:1349–57.

    Article  CAS  Google Scholar 

  9. Arjmand M-H, et al. Intraperitoneal administration of telmisartan prevents postsurgical adhesion band formation. J Surg Res. 2020;248:171–81.

    Article  CAS  Google Scholar 

  10. Ward BC, Panitch A. Abdominal adhesions: current and novel therapies. J Surg Res. 2011;165:91–111.

    Article  Google Scholar 

  11. Titan AL, Foster DS, Chang J, Longaker MT. Flexor tendon: development, healing, adhesion formation, and contributing growth factors. Plast Reconstr Surg. 2019;144:639e.

    Article  CAS  Google Scholar 

  12. Legrand A, Kaufman Y, Long C, Fox PM. Molecular biology of flexor tendon healing in relation to reduction of tendon adhesions. J Hand Surg. 2017;42:722–6.

    Article  Google Scholar 

  13. Aeberhard PA, et al. Efficient decellularization of equine tendon with preserved biomechanical properties and cytocompatibility for human tendon surgery indications. Artif Organs. 2020;44:E161–71.

    Article  CAS  Google Scholar 

  14. Hashemi MS, et al. Efficacy of pomegranate seed powder on glucose and lipid metabolism in patients with type 2 diabetes: a prospective randomized double-blind placebo-controlled clinical trial. Complement Med Res. 2021;28:226–33.

    Article  Google Scholar 

  15. Afrasiabian F, et al. Aloysia citriodora Palau (lemon verbena) for insomnia patients: a randomized, double-blind, placebo-controlled clinical trial of efficacy and safety. Phytother Res. 2019;33:350–9.

    Article  CAS  Google Scholar 

  16. Arjmand MH, et al. Therapeutic potential of active components of saffron in post-surgical adhesion band formation. J Tradit Complement Med. 2021;11:328–35. https://doi.org/10.1016/j.jtcme.2021.01.002.

    Article  Google Scholar 

  17. Jamshidi-Adegani F, et al. Prevention of post-surgical adhesion bands by local administration of frankincense n-hexane extract. J Tradit Complement Med. 2022;12:367–74. https://doi.org/10.1016/j.jtcme.2021.10.004.

    Article  Google Scholar 

  18. Karimi M, Parsaei P, Shafiei-Alavijeh S, Rafieian-Kopaei M, Asadi SY. Effect of silymarin alcoholic extract on surgery-induced intraperitoneal adhesion in rats. Surg Pract. 2016;20:27–33.

    Article  Google Scholar 

  19. Strimpakos AS, Sharma RA. Curcumin: preventive and therapeutic properties in laboratory studies and clinical trials. Antioxid Redox Signal. 2008;10:511–45. https://doi.org/10.1089/ars.2007.1769.

    Article  CAS  Google Scholar 

  20. Mirzaei H, et al. Phytosomal curcumin: a review of pharmacokinetic, experimental and clinical studies. Biomed Pharmacother. 2017;85:102–12. https://doi.org/10.1016/j.biopha.2016.11.098.

    Article  CAS  Google Scholar 

  21. Hashemzehi M, et al. Phytosomal-curcumin antagonizes cell growth and migration, induced by thrombin through AMP-kinase in breast cancer. J Cell Biochem. 2018;119:5996–6007.

    Article  CAS  Google Scholar 

  22. Moradi-Marjaneh R, et al. Phytosomal curcumin elicits anti-tumor properties through suppression of angiogenesis, cell proliferation and induction of oxidative stress in colorectal cancer. Curr Pharm Des. 2018;24:4626–38.

    Article  CAS  Google Scholar 

  23. Marjaneh RM, et al. Phytosomal curcumin inhibits tumor growth in colitis-associated colorectal cancer. J Cell Physiol. 2018;233:6785–98.

    Article  CAS  Google Scholar 

  24. Cicero AF, et al. Effects of phytosomal curcumin on anthropometric parameters, insulin resistance, cortisolemia and non-alcoholic fatty liver disease indices: a double-blind, placebo-controlled clinical trial. Eur J Nutr. 2020;59:477–83.

    Article  CAS  Google Scholar 

  25. Teng C-F, et al. Chemopreventive effect of phytosomal curcumin on hepatitis B virus-related hepatocellular carcinoma in a transgenic mouse model. Sci Rep. 2019;9:1–13.

    Article  Google Scholar 

  26. Panahi Y, et al. Efficacy and safety of phytosomal curcumin in non-alcoholic fatty liver disease: a randomized controlled trial. Drug Res. 2017;67:244–51.

    Article  CAS  Google Scholar 

  27. Mirhafez SR, et al. Efficacy of phytosomal curcumin among patients with non-alcoholic fatty liver disease. Int J Vitam Nutr Res. 2021;91:278-86.

  28. Mirhafez SR, et al. The effect of curcumin Phytosome on the treatment of patients with non-alcoholic fatty liver disease: a double-blind, randomized, placebo-controlled. Adv Exp Med Biol. 2021;1308:25-35.

  29. Sarigoz T, et al. Protective effects of curcumin on postoperative adhesions in rat models. Chirurgia. 2017;30:191–5.

    Article  Google Scholar 

  30. Güleç A, et al. Effect of curcumin on tendon healing: an experimental study in a rat model of Achilles tendon injury. Int Orthop. 2018;42:1905–10. https://doi.org/10.1007/s00264-018-4017-5.

    Article  Google Scholar 

  31. Jiang D, Gao P, Lin H, Geng H. Curcumin improves tendon healing in rats: a histological, biochemical, and functional evaluation. Connect Tissue Res. 2016;57:20–7. https://doi.org/10.3109/03008207.2015.1087517.

    Article  CAS  Google Scholar 

  32. Tang JB, Shi D, Zhang QG. Biomechanical and histologic evaluation of tendon sheath management. J Hand Surg. 1996;21:900–8.

    Article  CAS  Google Scholar 

  33. Hemadeh O, Chilukuri S, Bonet V, Hussein S, Chaudry IH. Prevention of peritoneal adhesions by administration of sodium carboxymethyl cellulose and oral vitamin E. Surgery. 1993;114:907–10.

    CAS  Google Scholar 

  34. Tian R, et al. Apoptosis exerts a vital role in the treatment of colitis-associated cancer by herbal medicine. Front Pharmacol. 2020;11:438.

    Article  CAS  Google Scholar 

  35. Ishiyama N, et al. The prevention of peritendinous adhesions by a phospholipid polymer hydrogel formed in situ by spontaneous intermolecular interactions. Biomaterials. 2010;31:4009–16.

    Article  CAS  Google Scholar 

  36. Nair SK, Bhat IK, Aurora AL. Role of proteolytic enzyme in the prevention of postoperative intraperitoneal adhesions. Arch Surg. 1974;108:849–53.

    Article  CAS  Google Scholar 

  37. Leach RE, Burns JW, Dawe EJ, SmithBarbour MD, Diamond MP. Reduction of postsurgical adhesion formation in the rabbit uterine horn model with use of hyaluronate/carboxymethylcellulose gel. Fertil Steril. 1998;69:415–8.

    Article  CAS  Google Scholar 

  38. Moran SL, Ryan CK, Orlando GS, Pratt CE, Michalko KB. Effects of 5-fluorouracil on flexor tendon repair. J Hand Surg Am. 2000;25:242–51. https://doi.org/10.1053/jhsu.2000.jhsu25a0242.

    Article  CAS  Google Scholar 

  39. Lee S-Y, et al. Characteristics of sonography in a rat Achilles tendinopathy model: possible non-invasive predictors of biomechanics. Sci Rep. 2017;7:1–11.

    Google Scholar 

  40. Jung H-J, Fisher MB, Woo SL. Role of biomechanics in the understanding of normal, injured, and healing ligaments and tendons. BMC Sports Sci Med Rehabil. 2009;1:1–17.

    Article  Google Scholar 

  41. Chatzistergos P, et al. The fracture stress of rat Achilles tendons. Scand J Lab Anim Sci. 2010;37:149–56.

    CAS  Google Scholar 

  42. Dunkman AA, et al. Decorin expression is important for age-related changes in tendon structure and mechanical properties. Matrix Biol. 2013;32:3–13. https://doi.org/10.1016/j.matbio.2012.11.005.

    Article  CAS  Google Scholar 

  43. Järvinen TA, et al. Achilles tendon injuries. Curr Opin Rheumatol. 2001;13:150–5. https://doi.org/10.1097/00002281-200103000-00009.

    Article  Google Scholar 

  44. Leppilahti J, Orava S. Total Achilles tendon rupture. A review. Sports Med. 1998;25:79–100. https://doi.org/10.2165/00007256-199825020-00002.

    Article  CAS  Google Scholar 

  45. Raikin SM, Garras DN, Krapchev PV. Achilles tendon injuries in a United States population. Foot Ankle Int. 2013;34:475–80. https://doi.org/10.1177/1071100713477621.

    Article  Google Scholar 

  46. Hu Q, et al. A review of physiological and cellular mechanisms underlying fibrotic postoperative adhesion. Int J Biol Sci. 2021;17:298.

    Article  CAS  Google Scholar 

  47. Galatz LM, Gerstenfeld L, Heber-Katz E, Rodeo SA. Tendon regeneration and scar formation: the concept of scarless healing. J Orthop Res. 2015;33:823–31. https://doi.org/10.1002/jor.22853.

    Article  Google Scholar 

  48. Fu F, Hou Y, Jiang W, Wang R, Liu K. Escin: inhibiting inflammation and promoting gastrointestinal transit to attenuate formation of postoperative adhesions. World J Surg. 2005;29:1614–20.

    Article  Google Scholar 

  49. Gupta NK, Dixit VK. Bioavailability enhancement of curcumin by complexation with phosphatidyl choline. J Pharm Sci. 2011;100:1987–95. https://doi.org/10.1002/jps.22393.

    Article  CAS  Google Scholar 

  50. Liu W, et al. Oral bioavailability of curcumin: problems and advancements. J Drug Target. 2016;24:694–702. https://doi.org/10.3109/1061186x.2016.1157883.

    Article  CAS  Google Scholar 

  51. Gupta SC, Patchva S, Aggarwal BB. Therapeutic roles of curcumin: lessons learned from clinical trials. AAPS J. 2013;15:195–218. https://doi.org/10.1208/s12248-012-9432-8.

    Article  CAS  Google Scholar 

  52. Vizzutti F, et al. Curcumin limits the fibrogenic evolution of experimental steatohepatitis. Lab Investig. 2010;90:104–15.

    Article  CAS  Google Scholar 

  53. Kang HC, et al. Curcumin inhibits collagen synthesis and hepatic stellate cell activation in-vivo and in-vitro. J Pharm Pharmacol. 2002;54:119–26. https://doi.org/10.1211/0022357021771823.

    Article  CAS  Google Scholar 

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Acknowledgements

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Funding

This study was supported by grants awarded by the Mashhad University of Medical Sciences (981180) to S.M.H.

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Authors and Affiliations

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. The author(s) read and approved the final manuscript.

Corresponding authors

Correspondence to Majid Khazaei or Seyed Mahdi Hassanian.

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All animal experiments were carried out in accordance with the guidelines of National Institute of Health for the Care and Use of Laboratory Animals (NIH Publication No. 80–23; revised 1978) and were approved by the Ethics Committee of Mashhad University of Medical Sciences (IR.MUMS.MEDICAL.REC.1399.067). All methods are reported in accordance with ARRIVE guidelines for the reporting of animal experiments.

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Askarnia-Faal, MM., Sayyed-Hosseinian, SH., Nazari, S.E. et al. Exploring new therapeutic potentials of curcumin against post-surgical adhesion bands. BMC Complement Med Ther 23, 27 (2023). https://doi.org/10.1186/s12906-022-03808-6

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