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.

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.

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.

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.

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.

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.

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.