Challenges and opportunities of medicines for treating tendon inflammation and fibrosis: A comprehensive and mechanistic review.

BACKGROUND: Tendinopathy refers to conditions characterized by collagen degeneration within tendon tissue, accompanied by the proliferation of capillaries and arteries, resulting in reduced mechanical function, pain, and swelling. While inflammation in tendinopathy can play a role in preventing infection, uncontrolled inflammation can hinder tissue regeneration and lead to fibrosis and impaired movement. OBJECTIVES: The inability to regulate inflammation poses a significant limitation in tendinopathy treatment. Therefore, an ideal treatment strategy should involve modulation of the inflammatory process while promoting tissue regeneration. METHODS: The current review article was prepared by searching PubMed, Scopus, Web of Science, and Google Scholar databases. Several treatment approaches based on biomaterials have been developed. RESULTS: This review examines various treatment methods utilizing small molecules, biological compounds, herbal medicine-inspired approaches, immunotherapy, gene therapy, cell-based therapy, tissue engineering, nanotechnology, and phototherapy. CONCLUSION: These treatments work through mechanisms of action involving signaling pathways such as transforming growth factor-beta (TGF-ß), mitogen-activated protein kinases (MAPKs), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), all of which contribute to the repair of injured tendons.

Niosome as a promising tool for increasing the effectiveness of anti-inflammatory compounds.

Niosomes are drug delivery systems with widespread applications in pharmaceutical research and the cosmetic industry. Niosomes are vesicles of one or more bilayers made of non-ionic surfactants, cholesterol, and charge inducers. Because of their bilayer characteristics, similar to liposomes, niosomes can be loaded with lipophilic and hydrophilic cargos. Therefore, they are more stable and cheaper in preparation than liposomes. They can be classified into four categories according to their sizes and structures, namely small unilamellar vesicles (SUVs), large unilamellar vesicles (LUVs,), multilamellar vesicles (MLVs), and multivesicular vesicles (MVVs). There are many methods for niosome preparation, such as thin-film hydration, solvent injection, and heating method. The current study focuses on the preparation methods and pharmacological effects of niosomes loaded with natural and chemical anti-inflammatory compounds in kinds of literature during the past decade. We found that most research was carried out to load anti-inflammatory agents like non-steroidal anti-inflammatory drugs (NSAIDs) into niosome vesicles. The studies revealed that niosomes could improve anti-inflammatory agents' physicochemical properties, including solubility, cellular uptake, stability, encapsulation, drug release and liberation, efficiency, and oral bioavailability or topical absorption. See also the graphical abstract(Fig. 1).

Preparation and characterization of vaginal suppository of semisynthetic derivatives of ergot alkaloids cabergoline.

Background: There is evidence that vaginal cabergoline can help to prevent ovarian hyperstimulation syndrome. Therefore, the vaginal suppository may be a good choice because it can be administered directly into the vagina and has no adverse effects on the stomach. In this regard we developed a cabergoline suppository as an alternative to cabergoline tablets. Design-Expert was used to determine the most suitable concentrations of PEG 6000/400, and Tween 80 to obtain a stable suppository. Specific ratios of PEG6000/400 and Tween 80 were entered as factors, and release, melting time, and hardness were evaluated as responses. In addition, the final formulation was evaluated for weight changes, pH, drug content, degradation time, deformation time, in vitro drug release, DSC analysis, infrared spectroscopy, and stability properties. Results: The suppositories were all smooth and white. They all had a weight that averaged less than 5 %. The formulations showed a pH between 6 and 6.5. The active ingredient content ranged between 79.666 ± 8.54 % and 99.67 ± 6.55 %. Suppository stiffness was between 2.74 ± 0.04 and 4.20 ± 0.03. The decomposition time of the suppositories varied between 11.25 ± 0.15 to 20.19 ± 0.08 min. The deformation time was between 26.11 ± 0.06 to 38.59 ± 0.47 min. Cabergoline content was released over 45 min from formulations of F10 (∼46 %), F2 (∼64 %), F6 (∼69 %), F4 (∼79 %), F1 (∼88 %), and F7 (∼93 %). However, other formulations released more than 95 % within 45 min. Conclusions: All variables except melting time significantly affected our responses. In vitro studies have indicated that the optimized cabergoline formula could be an excellent alternative to cabergoline oral formulations.

Preparation and characterization of solid lipid nanoparticles encapsulated noscapine and evaluation of its protective effects against imiquimod-induced psoriasis-like skin lesions.

Psoriasis is a chronic inflammatory skin disease characterized by thickening the epidermis with erythema, scaling, and proliferation. Noscapine (NOS) has several anti-inflammatory, anti-angiogenic, and anti-fibrotic effects, but its low solubility and large size results in its lower efficacy in the clinic. In this regard, solid lipid nanoparticles (SLN) encapsulated NOS (SLN-NOS) were fabricated using the well-known response surface method based on the central composite design and modified high-shear homogenization and ultrasound method. As a result, Precirol® was selected as the best lipid base for the SLN formulation based on Hildebrand-Hansen solubility parameters, in which SLN-NOS 1 % had the best zeta potential (-35.74 ± 2.59 mV), average particle size (245.66 ± 17 nm), polydispersity index (PDI, 0.226 ± 0.09), high entrapment efficiency (89.77 %), and ICH-based stability results. After 72 h, the SLN-NOS 1 % released 83.23 % and 58.49 % of the NOS at pH 5.8 and 7.4, respectively. Moreover, Franz diffusion cell's results indicated that the skin levels of NOS for SLN and cream formulations were 46.88 % and 13.5 % of the total amount, respectively. Our pharmacological assessments revealed that treatment with SLN-NOS 1 % significantly attenuated clinical parameters, namely ear thickness, length, and psoriasis area and severity index, compared to the IMQ group. Interestingly, SLN-NOS 1 % reduced the levels of interleukin (IL)-17, tumor necrosis factor-α, and transforming growth factor-ß, while elevating IL-10, compared to the IMQ group. Histology studies also showed that topical application of SLN-NOS 1 % significantly decreased parakeratosis, hyperkeratosis, acanthosis, and inflammation compared to the IMQ group. Taken together, SLN-NOS 1 % showed a high potential to attenuate skin inflammation.

A promising impact of oral administration of noscapine against imiquimod-induced psoriasis-like skin lesions.

Objective: Psoriasis is a chronic inflammatory autoimmune disease. The effectiveness of noscapine has been employed as a helpful treatment for various disorders and subjected to recent theoretical breakthroughs. Materials and Methods: Psoriasis-like lesions were induced by topical application of 5% imiquimod (IMQ) (10 mg/cm2 of skin) in male Balb/c mice and then medicated with a single oral dose of methotrexate (MET) as a positive control or daily oral treatment of noscapine (5, 15 and 45 mg/kg). In this way, skin inflammation intensity, psoriatic itchiness, psoriasis area severity index (PASI) score, ear length, thickness, and organ weight were daily measured. At the end of the study, histological and immunohistochemical and enzyme-linked immunosorbent assays (ELISA, for pro-/anti-inflammatory factors) were performed in each ear. Results: IMQ caused psoriasis-like lesions. Noscapine markedly alleviated macroscopic parameters, namely ear thickness, ear length, skin inflammation, itching, and organ weight, as well as microscopic parameters including, pathology and Ki67 and p53, and tissue immunological mediators, such as tumour necrosis factor (TNF-α), interleukin (IL)-10, transforming growth factor (TGF-ß), interferon-γ (IFN-γ), IL-6, IL-17, and IL-23p19 in the psoriatic skin in a concentration manner (p<0.05-<0.001). Conclusion: Therefore, noscapine with good pharmacological properties has considerable effects on psoriasis inflammation.

Boswellia serrata inhibits LPS-induced cardiotoxicity in H9c2 cells: Investigating role of anti-inflammatory and antioxidant effects.

Sepsis-induced myocardial dysfunction is the main reason for mortality and morbidity. Recent investigations have shown that inflammation and oxidative stress play a central role in lipopolysaccharide (LPS)-induced cardiac injury pathophysiology. Gum-resin extracts of Boswellia serrata have been traditionally used in folk medicine for centuries to treat various chronic inflammatory diseases. The present study aimed to investigate the effects of B. serrata pretreatment on LPS-induced cardiac damage in H9c2 cells. The cells were pretreated with various concentrations of B. serrata (5-45 µg/ml) for 24 h and then stimulated with LPS (10 µg/ml) for another 24 h. Afterward, the levels of cell viability, tumor necrosis factor (TNF)-α, prostaglandin (PGE)-2, interleukin (IL)-1ß, IL-6, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, nitric oxide (NO) and glutathione (GSH) were determined using enzyme-linked immunosorbent assay (ELISA), real time-PCR or appropriated biochemical methods. Our results demonstrated that LPS treatment caused a remarkable decrease in cell viability and GSH, and on the contrary, it led to a significant increase in the levels of gene and protein expression of inflammatory markers and NO. However, pretreatment of B. serrata (5, 15, and 45 µg/ml) decreased the levels of TNF-α, PGE2, IL-1ß, COX-2, iNOS, IL-6, and NO production, while cell viability and GSH levels were increased. Taken together, our results demonstrated that B. serrata might be a potential therapeutic agent against LPS and endotoxemia-induced cardiac injury, through its anti-inflammatory and antioxidant properties.

Peritoneal lavage with Glycyrrhiza glabra is effective in preventing peritoneal adhesion in a rat model.

BACKGROUND: Intraperitoneal adhesion formation is a significant problem following surgeries, resulting in substantial clinical and economic consequences. Glycyrrhiza glabra has several pharmacological properties consisting of anti-inflammatory, anti-microbial, anti-oxidant, anti-cancer, and immunomodulatory activities. AIM: Therefore, we aimed to investigate the impacts of G. glabra on the development of post-operative abdominal adhesion in a rat model. METHODS: Male Wistar rats weighing 200-250 g were divided into six groups (n = 8): Group 1: normal group (non-surgical), and the surgical groups including Group 2: control group received the vehicle, Group 3: G. glabra 0.5% w/v, Group 4: G. glabra 1% w/v, Group 5: G. glabra 2% w/v, and Group 6: dexamethasone, 0.4% w/v. The intra-abdominal adhesion was performed utilizing soft sterilized sandpaper on one side of the cecum, and the peritoneum was slightly washed with 2 ml of the extract or vehicle. In addition, macroscopic examination of adhesion scoring and the levels of inflammatory mediators [interferon (IFN)-γ, prostaglandin E2 (PGE2)], fibrosis markers [interleukin (IL)-4, transforming growth factor (TGF)-ꞵ], and oxidative factors [malondialdehyde (MDA), nitric oxide metabolites (NO), and reduced glutathione (GSH)] were evaluated. In vitro toxicities were also done on mouse fibroblast L929 and NIH/3T3 cell lines. RESULTS: We found higher levels of adhesion (P < 0.001), IFN-γ(P < 0.001), PGE2(P < 0.001), IL-4(P < 0.001), TGF-ß(P < 0.001), MDA(P < 0.001), and NO(P < 0.001), and lower levels of GSH(P < 0.001) in the control group. In contrast, G. glabra concentration dependent and dexamethasone alleviated the levels of adhesion (P < 0.05), inflammatory mediators (P < 0.001-0.05), fibrosis (P < 0.001-0.05), and oxidative (P < 0.001-0.05) factors, while propagating the anti-oxidant marker (P < 0.001-0.05) in comparison to the control group. Results also showed that the extract did not significantly reduce cell viability up to 300 µg/ml (P > 0.05). CONCLUSION: G. glabra could concentration-dependently mitigate peritoneal adhesion formation through its anti-inflammatory, anti-fibrosis, and anti-oxidant properties. However, further clinical investigations are required to approve that G. glabra may be a promising candidate against post-surgical adhesive complications.

Crocetin regulates Th1/Th2 and Th17/Treg balances, nitric oxide production, and nuclear localization of NF-κB in Th2-provoked and normal situations in human-isolated lymphocytes.

Crocetin is a natural carotenoid dicarboxylic acid derived from Crocus sativus. It has been utilized as natural biomedicine with healing effects. The immunoregulatory and anti-inflammatory properties may cause the biological activities of crocetin. Nevertheless, it is not still clear how this compound acts and causes an immune-modulatory impact on human lymphocytes. The effects of three concentrations (5, 10, and 20 µM) of crocetin or dexamethasone (0.1 mM) were assessed on gene expression and secretion of cytokines, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) level, and nitric oxide (NO) production in phytohaemagglutinin (PHA)-stimulated and non-stimulated lymphocytes. By incubation with PHA, gene expression and cytokine concentration comprising interferon (IFN)-γ, interleukin (IL)-17A, IL-10, and IL-4 were increased, along with NF-κB concentration and NO production (all, p < 0.001). In comparison with the controls, an alteration occurred in the T-helper (Th)2/Th1 and Th17/Treg balance in the stimulated lymphocyte toward a Th2 and Th17 response. In stimulated cells, crocetin and dexamethasone decreased pro-inflammatory significantly and increased anti-inflammatory cytokines and related gene expression, respectively. Moreover, Th17/Treg and Th1/Th2 balance was changed toward Treg and Th1 significantly reducing NF-κB and NO levels (p < 0.05 to p < 0.001). Promoting effects were represented by crocetin on T-cell subsets to Treg and Th1. Hence, it can have therapeutic value for treating predominant diseases of Th2 or Th17 cells.

Preparation of porous PCL-PEG-PCL scaffolds using supercritical carbon dioxide.

In this study, the Supercritical Carbon Dioxide (scCO2) gas foaming procedure was used in the preparation of scaffolds containing the model drug dexamethasone (DXMT). The method used did not include an organic solvent thus making it a safe method. The ring-opening polymerization of PCL-PEG-PCL (PCEC) triblock was conducted using an organocatalyst [1,8 diazabicyclo [5.4.0] undec-7-ene (DBU)]. After mixing 5.0 g of DXMT with 50.0 g of PCEC, hydraulic pressure was applied to compress the mixed powder into disc-like tablets. The tablet-like scaffold of the triblock containing DXMT was inserted into a scCO2 gas-foaming device. The peak porosity percentage of the synthesized triblock was found to be 55.58 %. Pressure, temperature, soaking time and the time required to depressurize were recorded as 198 bar, 50 °C, 2.0 h, and 28 min respectively. After treatment with scCO2, the scaffolds experienced an almost full release of DXMT in vitro after 30 days (83.74 ± 1.54 % vs 52.24 ± 2.03 % before scCO2 treatment). In conclusion, the results proved that the scCO2 gas foaming procedure could be employed for constructing modifiable PCEC scaffolds with plausible porosity and structural and morphological features which can manipulate drug release.

Carnosol Attenuates LPS-Induced Inflammation of Cardiomyoblasts by Inhibiting NF-κB: A Mechanistic in Vitro and in Silico Study.

Carnosol possesses several beneficial pharmacological properties. However, its role in lipopolysaccharide (LPS) induced inflammation and cardiomyocyte cell line (H9C2) has never been investigated. Therefore, the effect of carnosol and an NF-κB inhibitor BAY 11-7082 was examined, and the underlying role of the NF-κB-dependent inflammatory pathway was analyzed as the target enzyme. Cell viability, inflammatory cytokines levels (tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6, and prostaglandin E 2 (PGE2)), and related gene expression (TNF-α, IL-1ß, IL-6, and cyclooxygenase-2 (COX-2)) were analyzed by ELISA and real-time PCR. In addition, docking studies analyzed carnosol's molecular interactions and binding modes to NF-κB and IKK. We report that LPS caused the reduction of cell viability while enhancing both cytokines protein and mRNA levels (P < 0.001, for all cases). However, the BAY 11-7082 pretreatment of the cells and carnosol increased cell viability and reduced cytokine protein and mRNA levels (P < 0.001 vs. LPS, for all cases). Furthermore, our in silico analyses also supported the modulation of NF-κB and IKK by carnosol. This evidence highlights the defensive effects of carnosol against sepsis-induced myocardial dysfunction and, contextually, paved the rationale for the next in vitro and in vivo studies aimed to precisely describe its mechanism(s) of action.

Topical Formulation of Noscapine, a Benzylisoquinoline Alkaloid, Ameliorates Imiquimod-Induced Psoriasis-Like Skin Lesions.

Psoriasis is considered an autoimmune inflammatory disease. The disease is spread and diagnosed by the infiltration of inflammatory mediators and cells into the epidermis. Recent theoretical developments have focused on the effectiveness of noscapine (NOS) as a potential alkaloid for being used as a valuable treatment for different diseases. In the present study, psoriasis-like dermatitis was induced on the right ear pinna surface of male Balb/c mice by topical application of imiquimod (IMQ) for ten consecutive days, which was treated with noscapine (0.3, 1, 3, and 10% w/v) or clobetasol (0.05% w/v) as a positive control. The levels of ear length, thickness, severity of skin inflammation, psoriatic itch, psoriasis area severity index (PASI) score, and body weight were measured daily. On the 10th day of study, each ear was investigated for inflammation, fibrosis, proliferation, and apoptosis using histopathological (H&E and Masson's trichrome staining) and immunohistochemistry (Ki67 and p53 staining) assays. Furthermore, the levels of inflammatory biomarkers were characterized by an enzyme-linked immunosorbent assay (ELISA). The results confirmed IMQ-induced psoriasis for five consecutive days. In contrast, noscapine significantly reduced the ear length, thickness, severity of skin inflammation, psoriatic itch and body weight, tumor necrosis factor-α (TNF-α), transforming growth factor-ß (TGF-ß), interferon-gamma (IFN-γ), interleukin 6 (IL-6), IL-17, and IL-23p19 in a concentration-dependent manner (P < 0.001-0.05 for all cases). Overall, topical noscapine significantly ameliorated both the macroscopical and microscopical features of psoriasis. However, further clinical investigations are required to translate the effects to clinics.

Preparation, characterization, and evaluation of anti-tyrosinase activity of solid lipid nanoparticles containing Undecylenoyl phenylalanine (Sepiwhite®).

BACKGROUND: Hyperpigmentation is darkened patches or spots on the skin occurred by increased melanin. Undecylenoyl phenylalanine (Sepiwhite®), as a commercial lipophilic derivative of phenylalanine, is a powerful new brightener that can be used in the treatment of skin pigmentation disorders. AIMS: Solid lipid nanoparticles (SLNs) increase the efficiency of hydrophobic drugs. The current study aimed to prepare and characterize SLNs containing Sepiwhite (SEPI-SLN). METHODS: In this study, an optimized SEPI-SLN formulation was selected by applying the response surface method. In vitro drug loading content, the release profile of SEPI, and cell viability were investigated. The permeation rate of SEPI-SLN was also compared to conventional cream containing Sepiwhite (SEPI-CREAM). Furthermore, the anti-tyrosinase activity of Sepiwhite was also evaluated. RESULTS: The optimized formulation showed a spherical morphology with particle size and entrapment efficiency of 218.6 ± 11.1 nm and % 87.31 ± 0.65, respectively. Differential scanning calorimetry (DSC) analysis confirmed SEPI-loaded SLN formulation with no drug-lipid incompatibility. The in vitro permeation experiment revealed the enhanced cutaneous uptake of SEPI-SLN. The results also showed that Sepiwhite could stop melanogenesis with inhibition of the tyrosinase enzyme. CONCLUSION: Our findings confirm that SLNs could be a proper nanocarrier for the relevant usage of Sepiwhite as a powerful brightener agent.

Noscapine, an Emerging Medication for Different Diseases: A Mechanistic Review.

Noscapine is a benzylisoquinoline alkaloid isolated from poppy extract, used as an antitussive since the 1950s, and has no addictive or euphoric effects. Various studies have shown that noscapine has excellent anti-inflammatory effects and potentiates the antioxidant defences by inhibiting nitric oxide (NO) metabolites and reactive oxygen species (ROS) levels and increasing total glutathione (GSH). Furthermore, noscapine has indicated antiangiogenic and antimetastatic effects. Noscapine induces apoptosis in many cancerous cell types and provides favourable antitumour activities and inhibitory cell proliferation in solid tumours, even drug-resistant strains, via mitochondrial pathways. Moreover, this compound attenuates the dynamic properties of microtubules and arrests the cell cycle in the G2/M phase. Noscapine can reduce endothelial cell migration in the brain by inhibiting endothelial cell activator interleukin 8 (IL-8). In fact, this study aimed to elaborate on the possible mechanisms of noscapine against different disorders.

Intraperitoneal Lavage with Crocus sativus Prevents Postoperative-Induced Peritoneal Adhesion in a Rat Model: Evidence from Animal and Cellular Studies.

Postoperative peritoneal adhesions are considered the major complication following abdominal surgeries. The primary clinical complications of peritoneal adhesion are intestinal obstruction, infertility, pelvic pain, and postoperative mortality. In this study, regarding the anti-inflammatory and antioxidant activities of Crocus sativus, we aimed to evaluate the effects of Crocus sativus on the prevention of postsurgical-induced peritoneal adhesion. Male Wistar-Albino rats were used to investigate the preventive effects of C. sativus extract (0.5%, 0.25% and 0.125% w/v) against postsurgical-induced peritoneal adhesion compared to pirfenidone (PFD, 7.5% w/v). We also investigated the protective effects of PFD (100 µg/ml) and C. sativus extract (100, 200, and 400 µg/ml) in TGF-ß1-induced fibrotic macrophage polarization. The levels of cell proliferation and oxidative, antioxidative, inflammatory and anti-inflammatory, fibrosis, and angiogenesis biomarkers were evaluated both in vivo and in vitro models. C. sativus extract ameliorates postoperational-induced peritoneal adhesion development by attenuating oxidative stress [malondialdehyde (MDA)]; inflammatory mediators [interleukin- (IL-) 6, tumour necrosis factor- (TNF-) α, and prostaglandin E2 (PGE2)]; fibrosis [transforming growth factor- (TGF-) ß1, IL-4, and plasminogen activator inhibitor (PAI)]; and angiogenesis [vascular endothelial growth factor (VEGF)] markers, while propagating antioxidant [glutathione (GSH)], anti-inflammatory (IL-10), and fibrinolytic [tissue plasminogen activator (tPA)] markers and tPA/PAI ratio. In a cellular model, we revealed that the extract, without any toxicity, regulated the levels of cell proliferation and inflammatory (TNF-α), angiogenesis (VEGF), anti-inflammatory (IL-10), M1 [inducible nitric oxide synthase (iNOS)] and M2 [arginase-1 (Arg 1)] biomarkers, and iNOS/Arg-1 ratio towards antifibrotic M1 phenotype of macrophage, in a concentration-dependent manner. Taken together, the current study indicated that C. sativus reduces peritoneal adhesion formation by modulating the macrophage polarization from M2 towards M1 cells.

Thermosensitive Chitosan-ß-Glycerophosphate Hydrogels as Targeted Drug Delivery Systems: An Overview on Preparation and Their Applications.

Today, with the advances in technology and science, more advanced drug delivery formulations are required. One of these new systems is an intelligent hydrogel. These systems are affected by the environment or conditions that become a gel, stay in the circumstance for a certain period, and slowly release the drug. As an advantage, only a lower dose of the drug is required, and it provides less toxicity and minor damage to other tissues. Hydrogels are of different types, including temperature-sensitive, pH-sensitive, ion change-sensitive, and magnetic field-sensitive. In this study, we investigated a kind of temperature-sensitive smart hydrogel, which has a liquid form at room temperature and becomes gel with increasing temperature. Chitosan-ß-glycerophosphate hydrogels have been researched and used in many studies. This study investigates the various factors that influence the gelation mechanism, such as gel formation rates, temperature, pH, time, and gel specificity. Hydrogels are used in many drug delivery systems and diseases, including nasal drug delivery, vaginal drug delivery, wound healing, peritoneal adhesion, ophthalmic drug delivery, tissue engineering, and peptide and protein delivery. Overall, the chitosan-ß-glycerophosphate hydrogel is a suitable drug carrier for a wide range of drugs. It shows little toxicity to the body, is biodegradable, and is compatible with other organs. This system can be used in different conditions and different medication ways, such as oral, nasal, and injection.

Evaluation of the Effects of Peritoneal Lavage with Rosmarinus officinalis Extract against the Prevention of Postsurgical-Induced Peritoneal Adhesion.

Postoperative adhesions are regarded as the major complication following abdominal surgery. Rosmarinus officinalis has shown antioxidative and anti-inflammatory effects. Therefore, we aimed to assess the influence of 70% v/v hydro-ethanolic extract of the aerial parts of R. officinalis against postoperative abdominal adhesions in a rat model. Forty-eight male Wistar rats (190 ± 20 g) were divided into six groups of eight: group 1 = normal group, without any surgical procedures, group 2 = control group, group 3 = vehicle group, and groups 3, 4, and 5 = experimental groups receiving 2 mL of 4, 2, or 1% w/v R. officinalis treatment. Adhesion levels were macroscopically examined. Additionally, the levels of inflammatory cytokines (interleukin-6, interleukin-1ß, and TNF-α), growth factors (transforming growth factor-ß1, and vascular endothelial growth factor), oxidative (NO, nitric oxide and MDA, malondialdehyde), and antioxidative (GSH, glutathione) factors were evaluated. Our results revealed that the adhesion score, interleukin-6, interleukin-1ß, TNF-α, transforming growth factor-ß1, vascular endothelial growth factor, NO, and MDA levels were significantly increased in the vehicle group, while the GSH level was diminished. R. officinalis treatment notably ameliorated the adhesion score following postoperative abdominal adhesions compared with the vehicle group. Our results also revealed that R. officinalis markedly reduced inflammatory cytokines, oxidative factors, fibrosis, and angiogenesis biomarkers, whereas it increased the antioxidative factor. Therefore, R. officinalis may be a potential candidate for the management of postoperative peritoneal adhesion.

A Systematic Review on Prevention and Treatment of Nipple Pain and Fissure: Are They Curable?

Averagely 80% to 90% of breastfeeding women experience the nipple pain and fissures. The important factor for successful breastfeeding is to treat this problem. This study has done as a review with the aim of analysis of the clinical trials in the field of the prevention and treatment of the nipple fissures and pain due to the importance of breastfeeding. For this purpose, the key words of sore, nipples, fissure, trauma, wound, prevention, treatment, therapeutics, therapy, clinical trial, breastfeeding and their Persian synonyms and all of their possible combinations were searched in the national databases: SID and Iran Medex and Magiran, and in the international databases: PubMed, Scopus, Medline, Science direct by May 2017. The Jadad criterion was used to assess the quality of the articles and the articles with a score of 3 or more were included in this study. Finally, 48 clinical trials were reviewed that 17 of them (sample size 1801) scored 3 or more based on the Jadad criterion. Seven articles were also in the non- drug treatment group (sample size 491) and 2 articles in the drug treatment group (sample size 337) and 8 articles in the herbal treatment group (sample size 973).The results show that menthol and warm water compress as well as teaching the correct breastfeeding methods are effective treatments to prevent and treat the nipple pain and fissures. Moreover, applying the herbal medicine for prevention and treatment of the issues raised from breastfeeding may have beneficial such as Aloe vera, Portulaca olearacea. However, more studies with a great methodology are necessary to obtain more accurate evidence.

Protective effects of hydro-ethanolic extract of Terminalia chebula on primary microglia cells and their polarization (M1/M2 balance).

Teminalia chebula (TC) has been traditionally used in the Iranian traditional medicine (ITM) and Ayurvedic medicine primarily for neurologic disorders and inflammation. Mainly, its fruits have been applied for CNS disorders. The effects of Terminalia chebula as herbal medicine with anti-inflammatory and anti-oxidant properties were aimed on lipopolysaccharide (LPS)-induced microglial inflammation. Cytotoxicity of TC extract (0-80) µg/ml on microglial cells was evaluated using the MTT assay. Also, the protective effect of TC extract concentrations with specified amount of LPS-induced mice microglial cells was studied. The concentrations of TNF-α (Tumor Necrosis Factor-α), IL-1ß (Interleukin-1ß), IL-6 and PGE-2 (Prostaglandin-E2) were evaluated using ELISA. Gene expression of TNF-α, IL-1ß, IL-6, COX-2 (Cyclooxygenase-2), iNOS and arginase-1 was also evaluated using the Real-Time PCR method. Nitrite oxide and urea were measured using biochemical methods. The studied concentrations of TC extract did not affect the viability of microglial cells but significantly protected the viability after treatment with LPS. The concentrations and expression levels of pro-inflammatory factors (TNF-α, IL-1ß, IL-6, PGE-2, COX-2) were significantly decreased after TC extract treatment in LPS-induced microglial cells with dose dependent manner. The extract also significantly decreased the levels of nitric oxide, increased urea and down regulated the expression of nitric oxide synthesis while arginase-1 expression was enhanced. Our results suggest that TC extract reduces inflammation in microglial cells and can be used as a potential anti-inflammatory agent in central nervous system inflammatory diseases.

Evaluation of the effects of Iranian propolis on the severity of post operational-induced peritoneal adhesion in rats.

BACKGROUND: Peritoneal adhesion is a major complication of surgery that can lead to serious problems such as bowel obstruction, pain, infertility and even mortality. Propolis is a honey bee product with anti-inflammatory and anti-oxidant activities that could potentially protect against adhesive surgical complications. METHODS: Forty 8-weeks-old rats (275 ±â€¯25 g) were divided into five groups: normal group without any surgical procedure, and experimental groups treated with normal saline, 50 mg/kg, 100 mg/kg and 200 mg/kg of propolis. Peritoneal adhesions were examined macroscopically and also, the levels of inflammatory factors (IL-6, IL-1ß and TNF-α), growth factors (TGF-ß1 and VEGF) were evaluated in the study groups using ELISA. Biochemical indices of oxidative status including Nitric Oxide (NO), Malondialdehyde (MDA) and Glutathione (GSH) were also measured. RESULTS: Peritoneal adhesion scores, IL-1ß, IL-6, TNF-α, TGF-ß1, VEGF, NO, GSH and MDA levels were significantly different between the study groups (p < 0.001). Propolis treatment reduced peritoneal adhesion (p < 0.001), TNF-α (p < 0.001), IL-1ß (p < 0.001), IL-6 (p < 0.001), TGF-ß1 (p < 0.001), VEGF (p < 0.001), NO (p < 0.001) and MDA (p < 0.001), while GSH levels were increased (p < 0.001) compared with the vehicle group. Our results showed that higher dose of propolis was associated with significantly greater reductions in peritoneal adhesion (p < 0.001), TNF-α (p < 0.001), IL-1ß (p < 0.001), IL-6 (p < 0.001), VEGF (p < 0.001), NO (p < 0.001) and MDA (p < 0.001), a greater increase in GSH levels (p < 0.001) compared with the lower dose. CONCLUSIONS: Propolis treatment can dose-dependently reduce peritoneal adhesion through its anti-inflammatory, anti-angiogenic and antioxidant properties. Therefore, propolis might serve as a protective agent against post-surgical adhesive complications.

ß-Amyrin, the cannabinoid receptors agonist, abrogates mice brain microglial cells inflammation induced by lipopolysaccharide/interferon-γ and regulates Mφ1/Mφ2 balances.

BACKGROUND: Inflammation is a primary response to infection that can pathologically lead to various diseases including neurodegenerative diseases. The purpose of this study was to evaluate the effect of ß-Amyrin, a naturally occurring pentacyclic triterpenoid compound, on inflammation induced by lipopolysaccharide (LPS) and interferone-γ (IFN-γ) in rat microglial cells. MATERIALS AND METHODS: Cytotoxicity of ß-Amyrin (3-100) µM on microglial cells was evaluated using the MTT assay. Also, the protective effect of various ß-Amyrin (2-16 µM) concentrations with LPS/IFN-γ-induced mice microglial cells was studied. The concentrations of TNF-α (Tumor Necrosis Factor-α), IL-1ß (Interleukin-1ß), IL-6 (Interleukin-6) and PGE-2 (Prostaglandin E2) were evaluated using ELISA. Gene expressions of TNF-α, IL-1ß, IL-6, COX-2 (Cyclooxygenase-2), iNOS and arginase-1 were also evaluated using the Real-Time PCR method. Nitrite oxide and urea were measured using biochemical methods. RESULTS: The studied concentrations ​​of ß-Amyrin had no significant effects on the viability of microglial cells. Interestingly, ß-Amyrin concentration dependently and significantly increased the reduced cell proliferation concerning to LPS/IFN-γ exposure (p < 0.001). The concentrations and expression levels of pro-inflammatory factors including TNF-α, IL-1ß, IL-6, PGE-2, COX-2 were significantly reduced after ß-Amyrin treatment in LPS/IFN-γ-induced microglial cells (p < 0.05-0.001). ß-Amyrin also decreased the levels of nitric oxide, increased urea and down regulated the expression of nitric oxide synthesis while arginase-1 expression was enhanced (p < 0.001). The ratio of NO/urea and iNOS/Arg1 were also markedly increased in comparison to the LPS/IFN-g group (p < 0.001). CONCLUSION: ß-Amyrin reduces inflammation in microglial cells and can be used as a potential anti-inflammatory agent in central nervous system neurodegenerative diseases such as Alzheimer and multiple sclerosis, by affecting the inflammatory cytokine and differentiation of microglia as resident CNS macrophages.