The Role of Cannabinoid-1 Receptor Ligands in the Ovalbumin-Induced Mouse Model of Allergic Asthma: Is It Related to Transient Receptor Potential Vanilloid-1 Channels?

Objectives: The aim of this study was to investigate the role of cannabinoid (CB1) receptors on airway inflammation and hypersensitivity in allergic asthma and the potential interactions with TRPV1 channels. Materials and Methods: BALB/c mice were sensitized and provoked with ovalbumin to create a model of allergic asthma. CB1 selective agonist arachidonoyl 2'-chloroethylamide (ACEA) was administered intraperitoneally at doses of 0.5, 3, and 5 mg/kg. Receptor antagonism studies were performed utilizing selective CB1 antagonists AM251 at a dose of 3 mg/kg. TRPV1 channel was selectively blocked by capsazepine at a dose of 2.5 mg/kg. Penh values were recorded in vivo by a whole-body plethysmograph under methacholine challenge. Inflammatory cell count was performed in bronchoalveolar lavage fluid (BALF). Serum levels of proinflammatory cytokines were measured by Enzyme-Linked ImmunoSorbent Assay (ELISA). Inflammation in the lung tissue was scored histopathologically. Statistical significance was determined using one-way analysis of variance or Kruskal-Wallis test and expressed as p<0.05. Results: In sensitized animals, provocation with inhaled ovalbumin increased Penh values, serum interleukin (IL)-4, IL-5, IL-13 levels, eosinophil, neutrophil, lymphocyte, macrophage counts in BALF, and inflammation in the lung tissue. ACEA applications did not significantly alter Penh values, BALF inflammatory cell levels, and histological changes related to inflammation in the lung tissue according to the disease group; however, only at a dose of 5 mg/kg, it reduced the levels of the inflammatory cytokine IL-4. AM251 decreased Penh values, eosinophil and neutrophil migration in BALF, and inflammation score of lung tissue compared with the disease group. Although BALF inflammatory cell levels and Penh values were higher in the AM251+ACEA group than in the AM251 group, the differences were insignificant. In the CPZ+ACEA group, Penh values were significantly higher, and serum IL-4 and IL-13 levels and BALF eosinophil counts were lower than that in the CPZ group. Conclusions: This study demonstrated an important role of the CB1 receptors in allergic asthma. CB1 antagonism reduced airway hyperresponsiveness and inflammation and showed immunomodulatory effects. The effect of the CB1 agonist ACEA on asthma does not appear to be related to TRPV1 channels.

The Anti-Apoptotic Effect of Ranolazine on Cerebral Protection during Cardiopulmonary Bypass and Carotid Artery Surgery.

Background: We aimed to determine the usability of ranolazine (Rn) as a neuroprotective during cardiac surgeries and carotid artery interventions where cerebral blood flow is interrupted. Methods: Female Wistar albino rats were used. The rats were divided into 4 groups of 8 rats each. The first group (Group 1) was the control group. Group 2 underwent ischemia induction but was not treated with Rn. Group 3 received 25 mg/kg/day and Group 4 50 mg/kg/day Rn intraperitoneally, starting 3 days before ischemia induction. Bilateral carotid arteries were explored and clamped simultaneously. Ischemia was induced for 15 minutes. After 72 hours, the experimental animals were sacrificed. Results: Superoxide dismutase, alkaline phosphatase, and interleukin 6 levels were similar among the 4 groups. Acetylcholine esterase (Group 3: p = 0.007, Group 4: p = 0.002), tumor necrosis factor-alpha (Group 4: p = 0.01), and annexin V (Group 3: p = 0.001) levels were statistically significantly lower in the Rn-treated groups. Malondialdehyde (Group 3: p = 0.003, Group 4: p = 0.009), reduced glutathione (Group 4: p = 0.04), acid phosphatase (Group 3: p = 0.04), noradrenaline (Group 3: p = 0.01), and Bcl-2 (Group 4: p = 0.004) levels were significantly higher in the Rn-treated groups. Conclusions: The results of this study demonstrated the antiapoptotic effect of Rn in a brain ischemia-reperfusion model of rats receiving Rn before the procedure.

Fenofibrate attenuates asthma features in an ovalbumin-induced mouse model via suppressing NF-κB binding activity.

BACKGROUND/AIM: Asthma is a chronic inflammatory disease of the airways with a high prevalence. Asthma has a complex pathophysiology and about 5-10% of patients are not fully responsive to the currently available treatments. The aim of this study is to investigate the involvement of NF-κB in the effects of fenofibrate on a mouse model of allergic asthma. MATERIALS AND METHODS: A total of 49 BALB/c mice were randomly distributed into 7 groups (n = 7). Allergic asthma model was created by administering i.p. injections of ovalbumin on days 0, 14 and 21, followed by provocation with inhaled ovalbumin on days 28, 29 and 30. Fenofibrate was orally given in 3 different doses; 1, 10 and 30 mg/kg through days 21-30 of the experiment. On day 31, pulmonary function test using whole body plethysmography was performed. The mice were sacrificed 24 h later. Blood samples were obtained, and serum of each sample was separated for IgE determination. Bronchoalveolar lavage fluid (BALF) and lung tissues were collected to measure IL-5 and IL-13 levels. Nuclear extracts of lung tissues were employed to assess nuclear factor kappa B (NF-κB) p65 binding activity. RESULTS: Enhanced Pause (Penh) values were significantly increased in ovalbumin-sensitized and challenged mice (p < 0.01). Administration of fenofibrate (10 and 30 mg/kg) resulted in improved pulmonary function as shown by significantly lower Penh values (p < 0.01). Interleukin (IL) - 5 and IL-13 levels in BALF and lung tissues and immunoglobulin E (IgE) levels in serum were significantly elevated in the allergic mice. IL-5 levels in the lung tissues of mice treated with 1 mg/kg fenofibrate (FEN1) group were significantly reduced (p < 0.01). BALF and lung tissue IL-5 and IL-13 levels in mice treated with 10 and 30 mg/kg fenofibrate, FEN10 and FEN30, respectively, were significantly diminished when compared to the ovalbumin-treated (OVA) group, whereas treatment with 1 mg/kg fenofibrate resulted in insignificant changes. IgE levels in the serum of FEN30 group mice have shown a prominent reduction (p < 0.01). NF-κB p65 binding activity was higher in mice sensitized and challenged with ovalbumin (p < 0.01). NF-κB p65 binding activity was significantly reduced in allergic mice treated with 30 mg/kg (p < 0.01) fenofibrate. CONCLUSIONS: In this study, we showed that administration of 10 and 30 mg/kg fenofibrate effectively attenuated airway hyperresponsiveness and inflammation in a mouse model of allergic asthma, possibly through inhibition of NF-κB binding activity.

Lymphangiectatic Variant of Low-Grade Malignant Eccrine Spiradenoma.

Low-grade malignant eccrine spiradenoma (spiradenocarcinoma) is a rare sweat gland tumor, which usually arises from a pre-existing benign eccrine spiradenoma. This paper presents the case of a 55-year-old male who had a lesion in his right elbow for 10 years. The microscopic examination revealed a well-demarcated, multilobulated tumor in the dermis and subcutis, which presented with many blood-filled vessels and extensive hemorrhage. The tumor was composed of hyperchromatic, round to oval cells with nucleolar prominence, mild to moderate atypia, and increased mitotic index. Additionally, lymphangiectatic appearance was observed in areas with prominent stromal lymphedema. P53 and Ki-67 had high positivity. Surgical excision of the lesion was performed with adequate surgical margins, and the dissected lymph nodes in the axilla were tumor-negative. After 15 months of follow-up, there was no recurrence or distant metastasis.

Hydroxychloroquine induces endothelium-dependent and endothelium-independent relaxation of rat aorta.

BACKGROUND: Hydroxychloroquine (HCQ) is an antimalarial that is widely used in the management of rheumatoid arthritis and other autoimmune diseases. In this study, we aimed to examine the vascular effects of HCQ on rat aorta (RA). METHODS: The RA rings were suspended in isolated organ baths and tension was recorded isometrically. HCQ-induced relaxations were tested in the presence of the nitric oxide synthase inhibitor, nitro-L-arginine methyl ester (L-NAME, 100 mM); the cyclooxygenase enzyme inhibitor, indomethacin (10 mM); the calcium (Ca2+) ion channel blocker, nilvadipine (10 µM); and the K+ ion channel inhibitors, tetraethylammonium (1 mM), glibenclamide (10 mM), 4-aminopyridine (1 mM), and barium chloride (30 mM). The effect of HCQ on Ca2+ channels was examined using Ca2+-free Krebs solution, and adding calcium chloride (CaCl2 , 10-5- 10-2 M) cumulatively to baths incubated with HCQ. RESULTS: Removing the endothelium resulted in less relaxation of RA rings compared to endothelium-intact rings (p < 0.05). The effect of endothelium was supported by using L-NAME where HCQ produced-vasorelaxation was decreased (p < 0.05). The contraction of vascular rings was inhibited to a significant degree following the addition of CaCl2 , PE, or KCl on HCQ-incubated RA rings (p < 0.05). The incubation of the RA rings with the Ca2+ channel blocker, the K+ channel blockers, and the COX inhibitor, indomethacin did not significantly affect vascular relaxation induced by HCQ. DISCUSSION: HCQ produced relaxation of RA rings. The relaxation mechanism differs according to the concentration of HCQ. At con-centrations of 10-6 and 10-5 M, the relaxation is endothelium-dependent and mediated by NO. We strongly suggest that Ca2+ channel inhibition is involved at concentrations of 10-5 and 10-4 M, as well as NO.

Extract of Glycyrrhiza glabra root attenuates nociception in experimental pain models: the role of BKCa channels / Extracto de raíz de Glycyrrhiza glabra atenúa la nocicepción en modelos experimentales de dolor: el rol de los canales BKCa

Abstract: The aim of this study was to evaluate the functional interaction of Glycyrrhiza glabra root extract (GGRE) on the large conductance Ca 2+ - activated K + (BKCa) channels expressed in the peripheral nervo us system by using nociception and inflammation models in rodents in vivo . Besides toxicity studies and open field tests, nociception and inflammation tests were performed on rodents. Different doses of GGRE were given orally to rats and mice. Naloxone, in domethacin, morphine, NS1619 and iberiotoxin (IbTX) were administered. GGRE had both anti - nociceptive and anti - inflammatory activity in rats and mice. GGRE exhibited an analgesic effect by decreasing the time - course of the pain threshold or reaction time i n some nociceptive tests. Furthermore, GGRE reduced level of pro - inflammatory cytokines, including TNF - α and IL - 1ß. As a conclusion, GGRE can alleviate the pain sensation of the afferent nerves and can reduce inflammation and associated pain by activating B KCa channels and reducing the levels of TNF - α, IL1ß

Resumen: El objetivo de este estudio fue evaluar la interacción funcional del extracto de raíz de Glycyrr hiza glabra (GGRE) en los canales de K + (BKCa) activados por Ca 2+ de gran conductancia expresados en el sistema nervioso periférico mediante el uso de modelos de nocicepción e inflamación en roedores in vivo . Además de los estudios de toxicidad y las prueb as de campo abierto, se realizaron pruebas de nocicepción e inflamación en roedores. Se administraron por vía oral diferentes dosis de GGRE a ratas y ratones. Se administraron naloxona, indometacina, morfina, NS1619 e iberiotoxina (IbTX). GGRE tenía activi dad tanto antinociceptiva como antiinflamatoria en ratas y ratones. GGRE mostró un efecto analgésico al disminuir la evolución temporal del umbral del dolor o el tiempo de reacción en algunas pruebas nociceptivas. Además, GGRE redujo el nivel de citocinas proinflamatorias, incluidas TNF - α e IL - 1ß. Como conclusión, GGRE puede aliviar la sensación de dolor de los nervios aferentes y puede reducir la inflamación y el dolor asociado activando los canales BKCa y reduciendo los niveles de TNF - α, IL1ß.

Carbamazepine protects the endometrium against negative effects of estrogen in rats.

Carbamazepine (CMZ) increases estrogen metabolism by inducing cytochrome P450 (CYP3A4). We investigated whether CMZ is protective against endometrial hyperplasia (EH). We used 32 female Wistar albino rats divided into four equal groups: the control group received drinking water, the estradiol valerate (EV) group was given EV, the CMZ group was given CMZ, and the EV + CMZ group was given both EV and CMZ. After 30 days the uteri of the rats were removed and serum estrogen and progesterone levels were measured, and endometrial tissue characteristics were evaluated. CYP3A4 expression was assessed using immunohistochemistry. Serum estrogen levels were lowest in the EV group and highest in the CMZ group. Serum progesterone levels were similar among all groups. Glandular density, a proxy measure of EH, was highest in the EV group and lowest in the EV + CMZ group. EH was detected in six of eight rats (75%) in the EV group and two of eight rats (25%) in the EV + CMZ group. Immunohistochemical staining revealed no significant difference in CYP3A4 expression among the four groups. CMZ reduced the negative effect of high dose estrogen that is not balanced by progesterone on the endometrium in rats. The effect likely is probably due to the CYP3A4 enzyme activator effect. CMZ may be protective against EH in high risk women, although confirmation is required.

The effect of carbamazepine, which increases oestrogen destruction, on the endometriotic implants; an experimental rat model.

We planned this experimental study to investigate the effect of carbamazepine (CMZ) on the endometriotic implants. Rats were randomised into four groups after endometriosis surgery. Drinking water was given to the sham group, 0.2 mg/kg oestradiol valerate (EV) to the EV group, 100 mg/kg/day CMZ to the CMZ group, and 0.2 mg/kg EV and 100 mg/kg/day CMZ to the EV-CMZ group. The endometrium of the rats using CMZ stained more intensely with cytochrome P450-3A4 (CYP3A4) enzyme. No endometrial hyperplasia was found in these rats. Endometriotic implants weight was found to be higher in these rats. There was no difference between the groups in terms of staining of the endometriotic implants with CYP3A4 enzyme. Endometriotic implants were less stained with the CYP3A4 enzyme than the endometrium. According to our results, CMZ does not increase the destruction of oestrogen in the endometriotic implants, unlike the endometrium. It may even cause the lesion to enlarge.Impact statementWhat is already known on this subject? Endometriosis is an oestrogen-dependent, progressive disease. Carbamazepine (CMZ) is known to increase oestrogen degradation by activating the cytochrome P450-3A4 (CYP3A4) enzyme. CMZ can be used in the treatment of endometriosis because it increases oestrogen breakdown in tissues.What do the results of this study add? CMZ can protect the endometrium against hyperplasia by increasing the amount of CYP3A4 enzyme in the endometrium. This effect could not be demonstrated in the endometriotic implants. The presence of CYP3A4 enzyme less in the endometriotic implants than in the endometrium may explain this situation. In addition, the fact that CMZ does not increase the enzyme in the endometriotic implants may contribute to this situation.What are the implications of these findings for clinical practice and/or further research? CMZ may not be a suitable alternative in the treatment of endometriosis. However, it may protect against endometrial hyperplasia. Clinical studies are needed for this effect.

Resveratrol as an anti-asthmatic agent: could this stilbenoid help against COVID-19 in any way? a meta-analysis / Resveratrol como agente antiasmático: ¿podría este estilbenoide ayudar contra el COVID-19 de alguna manera? un metaanálisis

Resveratrol is a phenolic phytoconstituent found in many plants. This molecule has always caught the attention of scientists because of biological potentials such as inhibition of inflammation, oxidative stress and platelet aggregation as well as to prevent/protect against cardiovascular and neurodegenerative disease/disorders. Literature search have been conducted over resveratrol in covid-19 and asthma studies published in Pubmed and Google Scholars until 30 September 2020. The criteria used in the literature review were determined and were reviewed works on resveratrol including 368 articles and 47 articles on covid-19 and asthma, respectively. As a result of meta-analysis, TNF-α values of the studies showed a significant difference (heterogeneity) of I2=68.39% from each other in total (Cohran Q:6.33, p<0.0423). This study shows that resveratrol would have a potential to reduce ARDS symptoms, by suppressing the cytokine storm and severe inflammation caused by SARS-CoV-2, and by showing strong activity against various types of DNA/RNA viruses.

El resveratrol es un fitoconstituyente fenólico que se encuentra en muchas plantas. Esta molécula siempre ha llamado la atención de los científicos debido a sus potenciales biológicos como la inhibición de la inflamación, el estrés oxidativo y la agregación plaquetaria, así como para prevenir/proteger contra enfermedades/trastornos cardiovasculares y neurodegenerativos. Se han realizado búsquedas bibliográficas sobre resveratrol en covid-19 y estudios sobre asma publicados en Pubmed y Google Scholars hasta el 30 de septiembre de 2020. Se determinaron los criterios utilizados en la revisión bibliográfica y se revisaron trabajos sobre resveratrol que incluyen 368 artículos y 47 artículos sobre covid-19 y asma, respectivamente. Como resultado del metanálisis, los valores de TNF-α de los estudios mostraron una diferencia significativa (heterogeneidad) de I2=68,39% entre sí en total (Cohran Q: 6,33, p<0,0423). Este estudio muestra que el resveratrol podría reducir los síntomas del ARDS al suprimir la tormenta de citocinas y la inflamación severa causada por el SARS-CoV-2, y al mostrar una fuerte actividad contra varios tipos de virus de ADN/ARN.

A Probable Covid-19 Case Presented with Acute Upper Limb Ischemia.

The arterial revascularization procedure is still a challenging issue in Covid-19 associated limb ischemia. Herein we aimed to present a case of a 64 year-old woman with acute ischemic signs in upper extremity who was diagnosed as a probable Covid-19 case incidentally after admission. Although late admission and failed recurrent embolectomies lead to an eventful course, intra-arterial thrombolysis seemed to present a benefitable treatment option for our patient.

Glabridin Relaxes Vascular Smooth Muscles by Activating BKCa Channels and Inhibiting Phosphodiesterase in Human Saphenous Vein.

The aim of the current study was to investigate the pharmacological activity of glabridin on the isolated human saphenous vein (SV) and explore the underlying mechanisms. Samples of patients' SVs were removed during bypass surgery, and 4-mm lengths of the vessels were placed in Krebs solution at +4°C and hung in an isolated organ bath to assess their contraction/relaxation responses. The contraction/relaxation responses were recorded to observe if the cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) pathway mediates the relaxant effect of glabridin after treatment with blockers like ODQ (a guanylate cyclase inhibitor), KT5823 (a PKG inhibitor), isobutylmethylxanthine [IBMX, a phosphodiesterase (PDE) inhibitor], and cantharidin [Cant, a myosin light-chain phosphatase (MLCP) inhibitor]. Moreover, nitric oxide (NO), cGMP, and PKG levels in SV tissues were determined by ELISA after incubation with glabridin, N(ω)-nitro-L-arginine methyl ester (L-Name, a NO synthetase inhibitor), phenylephrine (PE), ODQ, IBMX, and KT5823. The results showed that glabridin relaxed the vascular smooth muscle of human SV pretreated with PE in a dose-dependent manner, which was independent of the endothelium. The vasorelaxant effect of glabridin was only inhibited by iberiotoxin (IbTX), Cant, and KT5823. Glabridin increased cGMP and PKG levels in SV homogenates, whereas it did not alter the NO level. The enhancing effects of cGMP and PKG levels by glabridin were abolished by ODQ and KT5823. In conclusion, glabridin has a vasorelaxant effect, which is associated with the activation of BKCa channels and inhibition of PDE.

An uncommon cause of massive haemothorax and treatment under cardiopulmonary bypass.

Pulmonary sequestration is defined as nonfunctioning lung tissue that is not in normal continuity with the tracheobronchial tree and that has a systemic arterial blood supply. Herein, we aimed to present a case of a 34-year-old male patient who had massive left-sided haemothorax on admission due to a giant intralobar pulmonary sequestration. An emergent repair was performed under cardiopulmonary bypass with axillofemoral cannulation.

Effects of cannabinoid receptor 2 synthetic agonist, AM1241, on bleomycin induced pulmonary fibrosis.

Bleomycin (BLM) is a chemotherapeutic agent that can cause pulmonary fibrosis. Little is known about the possible protective role of the CB2 receptor agonist, AM1241. We investigated the effects of CB2 receptor activation by AM1241 on BLM induced lung fibrosis in a rat model. BLM was administered via the trachea. Adult female Wistar rats were divided into five groups: saline (control group), BLM (BLM group), CB2 agonist (AM1241) + BLM (BLMA group), CB2 antagonist (AM630) and CB2 agonist (AM1241) + BLM (BLMA + A group), and vehicle (dimethylsulfoxide) + BLM (BLM + vehicle group). Hydroxyproline, collagen type 1, total protein, glutathione (GSH), malondialdehyde (MDA), interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels were measured in lung fibrosis and control tissue using standard methods. We investigated the histopathology of lung tissue to determine the extent of fibrosis. We found significantly higher levels of hydroxyproline, TNF-α, IL-6 and total protein in the BLM group compared to the BLMA group. The level of GSH also was higher in the BLMA group compared to the BLM group. Inflammation and fibrotic changes were significantly reduced in the BLMA group. Our findings suggest that CB2 receptor activation provided protection against BLM induced pulmonary fibrosis by suppressing oxidative stress and increasing cytokines.

Investigation of the Effect of Preoperative Hypoalbuminemia, Blood Urea Nitrogen and Creatinine Levels on Postoperative Atrial Fibrillation on Off-Pump Coronary Bypass Surgery Patients.

BACKGROUND: Postoperative atrial fibrillation (PoAF) is one of the most common complications to occur after open heart surgery. It has been shown that hypoalbuminemia accompanies some cardiovascular disorders. The present study evaluates the effects of pre-procedural albumin, blood urea nitrogen (BUN), and creatinine levels on PoAF. METHODS: The data of 81 patients who underwent off-pump coronary artery bypass graft (CABG) surgery was evaluated. Patients who developed atrial fibrillation (AF) in the first 48 hours post surgery constituted the PoAF (+) group, while those without AF constituted the PoAF (-) group. The pre-procedural hematological parameters of patients in both groups were included in the analysis. RESULTS: The PoAF (+) group was comprised of 57 patients (70.3%) with a mean age of 65.5 ± 9.8 years, while the PoAF (-) group was comprised of 24 patients (29.7%) with a mean age of 60.6 ± 9.6 years. A comparison of the demographic characteristics of the two groups showed that age (P = .036), frequency of renal failure (P = .007), and frequency of DM (P = .001) were higher in the PoAF (+) group. An examination of the laboratory data revealed a negative correlation between Hct (P = .001) and albumin (P = .000) levels and presence of PoAF. Also, the MPV (P = .02), BUN (P = .007), and Cr (P = .043) values were higher in the PoAF (+) group. CONCLUSION: The present study, whose focus was on the effects of albumin levels on the occurrence of PoAF, found that low levels of pre-procedural albumin, as one of the major proteins in the blood, is a risk factor for the development of PoAF.

CB2 Agonist (AM1241) Improving Effect on Ovalbumin-Induced Asthma in Rats.

Asthma is a disease characterized by spontaneous contraction of the airways in response to a wide variety of endogenous and exogenous stimuli. Many asthma models are used to mimic the human asthma model in the literature. In order to better understand the role of the cannabinoid (CB) 2 receptor in the ovalbumin (OVA)-induced asthma model, a combination of both selective CB2 agonist (AM1241) and antagonist (AM630) was used to improve inflammatory hypersensitivity and edema in rats. In the present study, it was found that OVA decreased body weight (p < 0.05), increased lung weights (p < 0.05), increased diastolic and systolic blood pressure (p < 0.001), and caused irregularity in pulmonary functions (p < 0.001). Moreover, CB2 agonist was found not to reduce body weight, cause blood pressure and respiratory irregularities (p < 0.05). OVA led to increase in IgE, TNF-α, IL-4, MDA level (p < 0.001), and total WBC count (p < .05). CB2 treatment caused to reduce the number of total WBC and the level of total protein in BALF, to hinder to increase level of MDA, IgE, TNF-α, and IL-4 (p < 0.05) in BALF or serum or lung tissue. But CB2-antagonist treatment prevented the protective effect of CB2 agonist. The aim of this study was to study the role of the CB2 receptor in the OVA induced asthma model, to improve inflammatory hypersensitivity, and edema in the rats. The results suggested that CB2 agonist administration to OVA induced asthmatic rats via anti-asthmatic potential through inhibition of parameters such as IgE, IL-4, TNF-α, microvascular escape, and oxidative stress.

Glabridin attenuates airway inflammation and hyperresponsiveness in a mice model of ovalbumin-induced asthma.

Asthma is an inflammatory disease of the airways of the lungs, which is characterized by airflow obstruction and bronchospasms. Glabridin is a major flavonoid, especially found in root of Glycyrrhiza glabra, and has several pharmacological activities, including antioxidant and anti-inflammatory effects. The anti-asthmatic effect and possible mechanism of glabridin, however, have not been revealed so far. The aim of this study is to investigate the effects and possible mechanisms of glabridin against ovalbumin (OVA)-induced airway hyperresponsiveness (AHR) and inflammation in mice. In male BALB/c mice, asthma was induced by intraperitoneal (i.p) injection of OVA mixed with 2 mg aluminium hydroxide on days 0, 14 and boosted with OVA aerosol challenge on days 21, 22, and 23. Mice were either treated with dexamethasone (i.p, 1 mg/kg) or glabridin (10, 20, and 30 mg/kg) from days 18-23. Pulmonary function parameters such as peak inspiratory flow, peak expiratory flow, tidal volume, expiratory volume, the frequency of breathing, enhanced pause values were evaluated by using whole-body plethysmography. Measurements were performed at baseline and following methacholine (50 mg/mL) challenges. In addition, white blood cells (WBC) count, total protein, and IgE levels were measured in bronchial alveolar lavage fluid (BALF), lung, and serum, respectively. Glabridin (20 or 30 mg/kg) significantly attenuated (p < 0.05) OVA-induced alteration in respiratory parameters. Elevated counts of total WBC, differential WBC (neutrophils, lymphocytes, monocytes, and eosinophils) in BALF and the total protein in lungs and BALF were significantly decreased (p < 0.05) by glabridin (20 or 30 mg/kg). It also significantly attenuated the increased serum IgE levels (p < 0.05). As glabridin reduces the level of serum IgE, the total protein and the count of WBC and improves respiratory function, it may be a novel therapeutic agent in asthma.

Thymoquinone reduces ischemia and reperfusion-induced intestinal injury in rats, through anti-oxidative and anti-inflammatory effects.

OBJECTIVES: The aim of the present study was to investigate the effect of thymoquinone on ischemia/reperfusion (I/R) injury at 150 min or/and 24 h of reperfusion in male Wistar Rats. MATERIAL AND METHODS: The therapeutic value of thymoquinone on cellular damage caused by reactive oxygene species or inflammatory processes during intestinal ischemia/reperfusion was investigated using pharmacological function studies on smooth muscle contractile responses of acetylcholine (Ach) and KCl, along with myeloperoxidase activity, malondialdehyhde, glutathione and cytokine levels such as tumor necrosis factor (TNF)-α and interleukin (IL)-1ß in serum and ileum tissue of rats. Thymoquinone was administered at a dose of 50 mg/kg orally for three times: 30 min, 24 h and 48 h prior to the surgical procedure. Soon after reperfusion timing (150 min or 24 h), the contractility traces to KCl and acetylcholine of the ileum smooth muscle were recorded through isolated organ bath. RESULTS: Pretreatment with thymoquinone reversed the disrupted contractility of the ileum smooth muscle at the 24 h reperfusion. Increased malondialdehyde and depleted glutathione levels and high myeloperoxidase activity determined in the ileum I/R tissue returned to reasonable amounts by pretreatment of Thymoquinone, which attenuated malondialdehyde quantity, restored glutathione level and inhibited myeloperoxidase activity. In addition, both serum and tissue TNF-α and IL-1ß activities were modulated by thymoquinone at 24 h of intestinal I/R. CONCLUSION: The results indicate that thymoquinone may have therapeutic value due to its immunomodulating, radical scavenging and/or antioxidant effects in intestinal I/R injury including oxidant damage mechanisms.

Glabridin Alleviates Inflammation and Nociception in Rodents by Activating BKCa Channels and Reducing NO Levels.

Inflammation, and the pain that accompanies it, is a natural response of the body. The licorice plant (Glycyrrhiza glabra) have demonstrated anti-inflammatory, anti-edematous, and anti-nociceptive effects of its extracts. The effective ingredient remains unidentified; however, one possibility is the unique isoflavone glabridin. The anti-nociceptive, and anti-inflammatory effects of glabridin and its possible mechanism with focus on the large conductance Ca2+-activated K+ (BKCa) channels and L-arginine-nitric oxide (NO) pathway were examined by using different tests. In order to determine the anti-edematous, anti-nociceptive, and anti-oxidative effects of glabradin, some tests such as the tail flick, hotplate, carrageenan-induced paw edema, air pouch, acetic-acid-induced writhing, formalin, and capsaicin tests, as well as toxicity and open field tests were made. Glabridin was administered to rats (n = 8) or mice (n = 8) for 3 d at 3 doses (10, 20, and 40 mg/kg). Glabridin inhibited cytokine production and showed an anti-nociceptive response via the activating of BKCa channels and downregulating NO level and partially transient receptor potential vanilloid-1 pathways. It also demonstrated anti-inflammatory effects by inhibiting cyclooxygenase (COX) activity, while showing no cytotoxicity. Glabridin, however, showed no anti-nociceptive effect in the neurogenic phase. Glabridin is a promising substance in terms of its anti-nociceptive and anti-inflammatory effects by disrupting peripheral NO production, inhibiting cyclic guanosine monophosphate (cGMP) activation and activating BKCa channels and its lack of acute and subacute toxic effects.

The curative effect of cannabinoid 2 receptor agonist on functional failure and disruptive inflammation caused by intestinal ischemia and reperfusion.

Ischemia and reperfusion of intestinal tissue (intestinal I/R) induce disruption of ileal contractility and chain responses of inflammatory. The aim of this study was to reveal whether therapeutic value of cannabinoid 2 (CB2) receptor activity in the intestinal I/R, via to the exogenous administration of CB2 agonist (AM-1241). Intestinal I/R injury were performed through 30-min ischemia and 150-min reperfusion of mesenteric artery in Wistar rats. The pre-administered doses of 0.1, 1, and 5 mg/kg of CB2 agonist were studied to inhibit inflammation of intestinal I/R injury including ileum smooth muscle contractility, polymorphonuclear cell migration, oxidant/antioxidant defense system, and provocative cytokines. Pre-administration with CB2 receptor agonist ensured to consider improving the disrupted contractile responses in ileum smooth muscle along with decreased the formation of MDA that production of lipid peroxidation, reversed the depleted glutathione, inhibited the expression of TNF-α and of IL-1ß in the intestinal I/R of rats. Taken together results of this research, the agonistic activity of CB2 receptor for healing of intestinal I/R injury is ensuring associated with anti-inflammatory mechanisms such as the inhibiting of migration of inflammatory polymorphonuclear cells that origin of acute and initial responses of inflammation, the inhibiting of production of provocative and pro-inflammatory cytokines like TNF-α and IL-1ß, the rebalancing of oxidant/antioxidant redox system disrupted in injury of reperfusion period and the supporting of physiologic defensive systems in endothelial and inducible inflammatory cells.

Glabridin alleviates ischemia/reperfusion-induced functional failure of smooth muscle of rat ileum by upregulating the cAMP / Glabridin alivia la falla funcional inducida por isquemia/reperfusión del músculo liso de ileum murino regulando el incremento de cAMP

Despite the development of modern medicine, alternative medicine, which has not lost its timeliness, remains attractive for the treatment of various diseases. Glabridin, a major flavonoid of Glycyrrhiza glabra, is known for its antioxidant and anti-inflammatory activity. The aim of this study was: 1) to determine the possible protective role of glabridin against ischemia/reperfusion (I/R) injury of the intestine; 2) to evaluate the in vitrocontractile responses of ileum smooth muscles to acetylcholine after an intestinal I/R; and 3) to explain the underlying molecular mechanism of its effect. Rats were assigned to groups of six rats each; 1) I/R, 2) gla10, 3) gla20, 4) gla40, 5) N5-[imino(nitroamino)methyl]-L-ornithine, methyl ester monohydrochloride (L-NAME)+gla40, and 6) Sham group. The healing effect of glabridin was abolished by L-NAME. Glabridin did not cause contractility of the smooth muscles to acetylcholine-induced contractile responses in intestinal I/R. Yet, it increased to spontaneous basal activity.

A pesar del desarrollo de la medicina moderna, la medicina alternativa, sin perder su vigencia, sigue siendo atractiva para el tratamiento de varias enfermedades. Glabradina, el flavonoide mayoritario de Glycyrrhiza glabra, es conocido por su actividad antioxidante y antiinflamatoria. Los propósitos de este estudio fueron: 1) Determinar el posible rol protector de glabradina ante daños intestinales por isquemia/reperfusion (I/R) 2) Evaluar in vitrolas respuestas de contracción de los músculos lisos del ileum ante acetilcolina después de I/R intestinal; y 3) Explicar el mecanismo molecular subyacente de este efecto. Se asignaron grupos de seis ratas: 1) I/R, 2) gla10, 3) gla20, 4) gla40, 5) N5-[imino(nitroamino)metil]-L-ornithina, metil ester monohidrochloruro (L-NAME)+gla40, y 6) Grupo testigo. El efecto curativo de glabridina fue abolido por L-NAME. Glabridina no causó contracción en el músculo liso como respuesta acetilcolina-inducida I/R. Además, incrementa la actividad basal expontánea.