Immuno-modulatory effects of methanolic extract of Ferula szowitsiana on isolated human Th1/Th2/Treg cytokines levels, and their genes expression and nitric oxide production.

BACKGROUND: Anti-inflammatory and anti-oxidants activities of Ferula szowitsiana L. (F. szowitsiana) were shown in ancient texts and assayed by modern studies. However, immunomodulatory properties of the plant are poorly understood. METHODS: The effects of F. szowitsiana extract (10, 40 and 160 µg/ml), dexamethasone and vehicle were investigated on nitric oxide (NO) level, cell proliferation, and cytokines (IL-4, IL10 and IFN-γ) expression at gene and protein levels in non-stimulated and phytohaemagglutinin-stimulated human lymphocytes (n = 15 in each group). RESULTS: Cell proliferation, cytokines secretion, NO production and levels of genes expression were significantly inhibited but IFN-γ/IL-4 and IL-10/IL-4 ratios (T helper 1/Th2 and Treg/Th2 balances respectively) were increased by dexamethasone and all three concentrations of the extract compared to control group in stimulated lymphocytes (P < 0.001 for all cases). The effect of three concentrations of the extract in all experiments was significantly lower than dexamethasone (P < 0.001 for all cases). CONCLUSION: The extract of F. szowitsiana concentration-dependently decreased NO level but increased Th1/Th2 and Treg/Th2 ratios toward Th1 and Treg. These results suggest the therapeutic potential of the plant's extract in inflammatory diseases with dominant Th2 polarization such as asthma or cancers.

Safety and tolerability of carvacrol in healthy subjects: a phase I clinical study.

This study was designed to assess safety and tolerability of carvacrol in healthy individuals. Subjects were randomly divided into two groups receiving 1 and 2 mg/kg/day carvacrol. Before and after carvacrol administration, routine blood and urine laboratory tests and spirometry were performed for all participants. The results showed that one-month treatment with carvacrol did not significantly affect the measured variables. In the group receiving 1 mg/kg/day carvacrol, calcium, erythrocyte sedimentation rate (ESR), mean cell volume (MCV), hemoglobin (Hb), and hematocrit (HCT) levels were significantly reduced but creatinine phosphokinase (CPK) was significantly increased, after treatment compared to baseline values (p < 0.05-p < 0.001). There was significant reductions in high-density lipoprotein cholesterol (HDL), total bilirubin, amylase, iron, red blood cells (RBC) count, and HCT after one-month treatment with 2 mg/kg/day carvacrol compared to pretreatment values (p < 0.05-p < 0.01). Although, triglyceride (TG), phosphorus, lactate dehydrogenase (LDH), prothrombin time (PT), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) were significantly increased after treatment with carvacrol 1 mg/kg/day (p < 0.05-p < 0.001), all post-treatment measured parameters were within normal range. Treatment with carvacrol 2 mg/kg/day for one month increased FEV1 (p < 0.05). Nevertheless, there was no significant difference in measured variables except LDH, MCH, MCHC, and MCV (p < 0.05-p < 0.01), between the two groups. The results of this phase I study regarding carvacrol effects on healthy subjects, showed clinical safety and tolerability for this agent.

Zataria multiflora affects clinical symptoms, oxidative stress and cytokines in asthmatic patient: A randomized, double blind, placebo-controlled, phase II clinical trial.

BACKGROUND: Z. multiflora effect on clinical symptoms, pulmonary function tests (PFT), oxidative stress and cytokine levels in asthmatic patients were evaluated. METHODS: 36 asthmatic patients were divided to; placebo group (P), two groups treated with Z. multiflora extract (5 and 10 mg/kg/day, as Z5 and Z10, respectively), (n = 12 in each group). Medications were administered three times a day for two months and several parameters were evaluated before treatment (step 0), one (step 1) and two months (step 2) after treatment. RESULTS: Clinical symptoms and PFTs were significantly improved in Z5 and Z10 groups in steps 1 and 2 compared to step 0 (p < 0.05 to p < 0.001). Improvement of oxidative stress, cytokines levels and their gene expression after treatment with both doses of extract were observed in step 2 compared to step 0 (p < 0.05 to p < 0.001). CONCLUSION: These results indicated therapeutic value of Z. multiflora for the management of asthma.

Possible therapeutic effect of carvacrol on asthmatic patients: A randomized, double blind, placebo-controlled, Phase II clinical trial.

The relaxant effects of carvacrol, a phenolic monoterpene, on tracheal smooth muscle and its preventive effect on asthmatic animals were reported. The effect of carvacrol in asthmatic patients was examined in the placebo group (Group P, n = 11) receiving placebo and treatment group (Group C, n = 12), which received carvacrol capsule (1.2 mg/kg/day) for 2 months in a double-blind manner. Pulmonary function tests, respiratory symptoms, hematological indices, and high-sensitivity C-reactive protein (hs-CRP) were measured before, 1 and 2 months after starting treatment. At the end of treatment period, Pulmonary function tests values in Group C were significantly increased (p < .05 to p < .001). Most respiratory symptoms were also significantly reduced in Group C at the end of 2-month treatment (p < .05 to p < .001). Total and differential white blood cell (p < .05 to p < .001), as well as serum levels of hs-CRP in Group C were also significantly reduced after 2-month treatment with carvacrol (p < .001). Mean corpuscular hemoglobin concentration and hematocrit were changed in Group C (p < .05 and p < .01, respectively). However, in Group P, there was no significant changes in the evaluated parameters. Pulmonary function tests were increased but respiratory symptoms, inflammatory cells, and hs-CRP were reduced in asthmatic patients who received carvacrol that indicates its therapeutic effect on asthma.

Antiinflammatory, antioxidant, and immunological effects of Carum copticum L. and some of its constituents.

Carum copticum L. has been used traditionally for its various therapeutic effects. The plant contains various components such as thymol and carvacrol. Different therapeutic effects such as antifungal, antioxidant, antibacterial, antiparasitic, and antilipidemic were described for the plant and its constituents. Therefore, antiinflammatory, antioxidant, and immunological effects of C. copticum and its constituents, thymol and carvacrol, were discussed in the present review. Previous studies have shown potent antiinflammatory, antioxidant, and immunological effects for C. copticum and its constituents, thymol and carvacrol. Therefore, the plant and its constituents have therapeutic values in several inflammatory and immunological disorders as well as in the oxidative stress conditions.

Zataria multiflora extract influenced asthmatic patients by improving respiratory symptoms, pulmonary function tests and lung inflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Anti-inflammatory and anti-oxidant effects of Zataria multiflora Boiss (Z. multiflora) were reported in previous studies which is using in traditional and modern medicine. This plant is traditional used as an anti-tussive agent and for the management of respiratory disorders. AIM OF THE STUDY: The preventive effect of the extract of leaves and stems of Z. multiflora on respiratory symptoms, pulmonary function tests, hematological indices, high sensitivity C-reactive protein (hs-CRP), level of interleukin-10 (IL-10) in the serum and supernatant of cultured peripheral blood mononuclear cells (PBMC) and gene expression of IL-10 in these cells in asthmatic patients was studied. MATERIALS AND METHODS: 36 asthmatic patients in three groups (randomly divided) of placebo group (P), two groups treated with 5 and 10 mg/kg/day doses of Z. multiflora (Z5 and Z10) for two months completed the study. Drugs were administered double-blindly and different variables were assessed before and after (one and two months) starting treatment including respiratory symptoms, pulmonary function tests (PFT), hematological indices, hs-CRP, serum and supernatant levels as well as gene expression of IL-10. RESULTS: Two months treatment with Z5 and Z10 led to significant reduction of respiratory symptoms (p < 0.05 to p < 0.001). Pulmonary function test values in treated groups were also significantly increased two months after starting treatment (p < 0.05 to p < 0.001). Total WBC, monocytes and eosinophils were also decreased in treated groups with the extract at the end of study period (p < 0.05 to p < 0.01). Hemoglobin and hematocrit in Z10 treated group (p < 0.05 and p < 0.01, respectively) and mean corpuscular volume (MCV) in both treated groups (p < 0.05 to p < 0.01) were significantly reduced. In addition, the level of hs-CRP in both treated groups was significantly reduced after two months (p < 0.05 to p < 0.01). IL-10 concentration in Z10 treated group in supernatant of PBMC was also significantly enhanced (p < 0.01). All comparisons were made compared to the baseline (beginning of the treatment) values. CONCLUSION: Z. multiflora improved respiratory symptoms and increased pulmonary function tests in asthmatic patients. In addition, the plant was effective in decrement of inflammatory cells and hs-CRP as well as enhanced IL-10. Therefore, the plant showed possible preventive therapeutic effect on asthma.

Zataria multiflora induced bronchodilatoion comparable to theophylline syrup in asthmatic patients.

OBJECTIVE: The bronchodilatory effect of hydro-ethanolic extract of Z. multiflora was examined in asthmatic patients. DESIGN: Pulmonary function tests (PFTs) were measured before and 15, 30, 60, 90, 120, 150, and 180 min after administration of the extract (20 mg/kg) in 18 asthmatics and after theophylline syrup (6 mg/kg) in 12 patients. MAIN OUTCOME MEASURES: The extract of Z. multiflora significantly increased all PFT values, 30 to 180 min post-administration similar to the effect of theophylline (all, p<0.001). Increased PFT values due to the extract were significantly declined 180 min but the effects of theophylline were declined 150 min after administration (p<0.05 to p<0.001). Values of PFTs at baseline, 30 and 180 min after drugs administration were not singnificantly different between the extract and theophylline. CONCLUSIONS: Z. multiflora showed a bronchodilatory effect in asthmatic patients comparable to theophylline effect but with a longer duration of action.

Carvacrol improves pulmonary function tests, oxidant/antioxidant parameters and cytokine levels in asthmatic patients: A randomized, double-blind, clinical trial.

BACKGROUND: Carvacrol effects on inflammatory mediators, lung pathology and tracheal responsiveness were indicated in animal models of pulmonary diseases. PURPOSE: To evaluate carvacrol effects on respiratory symptoms, pulmonary function tests (PFT), oxidative stress markers and cytokine levels in asthmatic patients. STUDY DESIGN: This study was a randomized, placebo-controlled double-blind, clinical trial. METHODS: Thirty-three moderate asthmatic patients were divided to the two groups of: placebo group (n = 16) and carvacrol group (1.2 mg/kg/day, n = 17). Prepared capsules were taken for two months along, 3 times/day along with routine medications. Respiratory symptoms, PFT, and oxidative stress markers were evaluated before the treatment (step 0), and one (step I) and two months (step II) after the beginning of the treatment. However, cytokine levels in serum and supernatant of peripheral blood mononuclear cells (PBMC), and their gene expression were evaluated in step 0 and II. RESULTS: In carvacrol-treated group, respiratory symptoms significantly decreased after one- and two-month treatment with carvacrol compared to pre-treatment values (p < 0.05 to p < 0.001). Compared to step 0, PFT values were significantly increased in step I and II, in treated group with carvacrol (p < 0.05 to p < 0.001). Most oxidative stress markers were improved following carvacrol treatment (p < 0.05 to p < 0.001). Treatment with carvacrol for two-month also significantly improved cytokine levels in serum and supernatant of PBMC, compared to step 0 (p < 0.05 to p < 0.001). However, no significant changes were observed in the above-noted parameters in the placebo group. CONCLUSION: Due to anti-inflammatory and antioxidant effect, carvacrol could be suggested as a therapeutic agent for asthma.

Effect of Zataria multiflora on serum cytokine levels and pulmonary function tests in sulfur mustard-induced lung disorders: A randomized double-blind clinical trial.

ETHNOPHARMACOLOGICAL RELEVANCE: Zataria multiflora (Z. multiflora) belongs to the Lamiaceae family and has several traditional uses owing to its antiseptic, aesthetic, antispasmodic, analgesic, and antidiarrheal properties. AIM OF THE STUDY: We aimed to investigate the effect of Z. multiflora on serum cytokine levels and pulmonary function tests (PFT) in patients exposed to sulfur mustard (SM) for a long term (27-30 years). MATERIALS AND METHODS: Thirty-five patients were randomly assigned to the placebo group (P) and two experimental groups treated with Z. multiflora extracts, i.e., 5 and 10 mg/kg/day (Z5 and Z10). Serum levels of cytokines including IL (2, 4, 6, 8, and 10) and IFN-γ as well as PFT indices such as maximum mid-expiratory flow (MMEF) and maximum expiratory flow at 25, 50, and 75% of vital capacity (VC) (MEF25, 50, and 75) were assessed at the beginning (phase 0) and at the end of 4 and 8 weeks (phases I and II, respectively) after starting the treatment. RESULTS: Serum levels of IL-2, IL-6, and IL-8 were significantly decreased, while serum levels of IL-10 and IFN-γ were significantly increased in the Z5 and Z10 treatment groups in phases I and II as compared to those in phase 0 (p < 0.05 to p < 0.001). MMEF and MEF25, 50, and 75 values were significantly increased in the Z5 group in phase II and in the Z10 group in phases I and II compared to those in phase 0 (p < 0.05 to p < 0.001). The percent change in serum cytokine levels and the change in MEF25, 50, and 75 during the two-month treatment period were significantly higher in the treatment groups than in the placebo group. CONCLUSIONS: Two months of treatment with Z. multiflora reduced inflammation, while it enhanced anti-inflammatory cytokines and improved PFT indices in SM-exposed patients.

The prevalence of asthma and related symptoms in Middle East countries.

OBJECTIVES: Asthma is a chronic inflammatory airway disease characterized by reversible airway constriction and airway hyperresponsiveness. Asthma is a worldwide problem and its prevalence varies among different parts of the world. There are insufficient data about the prevalence and risk factors of this disease in Middle East countries. DATA SOURCE: The objective of this review article was to determine the prevalence of asthma in Middle East countries by searching EMBASE, Medline, Web of Science and Google Scholar for articles about asthma prevalence in children and adults in this region. STUDY SELECTION: The prevalence of asthma in different countries and different cities of each country in the Middle East was reviewed in children and adults of both sexes. The possible risk factors for asthma in different areas were also reviewed from 1985 to 2012. RESULTS: The highest asthma prevalence in children and adults was 35.4% in Tehran, Iran by ISAAC phase I and 15% in Kuwait by self-designed questionnaire and the lowest prevalence was 1% in Kermanshah, Iran by ISAAC and 2% in Tehran, Iran by ECRHS questionnaire, respectively. Most studies showed that the prevalence of this common disease declines with increasing age. CONCLUSION: The data showed that the prevalence of asthma varies among different countries and even among different cities of the same country. The common risk factors for this disease were genetic predisposition, cigarette smoking, family history of asthma and allergic diseases.

Pharmacological effects of Zataria multiflora Boiss L. and its constituents focus on their anti-inflammatory, antioxidant, and immunomodulatory effects.

Zataria multiflora Boiss (Z. multiflora) belongs to the Lamiaceae family is used traditionally for culinary and medicinal purposes. Different pharmacological effects have been described for the plant including; bronchodilation, vasodilation, and effect on lung inflammation. The plant is also used as a remedy against cough in the traditional medicine. In this article, 'pharmacological effects of Z. multiflora and its constituents focusing on their anti-inflammatory, antioxidant, and immunomodulatory properties were reviewed' by searching various databases until 'June' 2016. The anti-inflammatory effects of the plant such as decreased total white blood cell, neutrophils, and eosinophils counts were demonstrated. The sprotective effects of Z. multiflora on serum levels of phospholipase A2 and total protein were showed. In addition, constituents of the plant, such as flavonoids and carvacrol, also showed anti-inflammatory effects. Z. multiflora also reduced oxidative stress by scavenging free radicals and can be used in the therapy of oxidative damage. Decreased level of malondialdehyde and protective effects of Z. multiflora on serum levels of nitric oxide were also shown. Improvement of the serum levels of IgE, reduction in pro-inflammatory cytokine (IL-4, TGF-ß, and IL-17), and increased anti-inflammatory cytokines (IFN-γ and FOXP3) were shown for Z. multiflora and its constituents, carvacrol and thymol. These results indicated that carvacrol and thymol could be used for treatment of inflammatory diseases as new anti-inflammatory agents. Therefore, Z. multiflora showed anti-inflammatory, antioxidant, and immunomodulatory effects which could be used for treatment of inflammatory and immune dysregulation diseases or disorders associated with increased oxidative stress.

The effect of Zataria multiflora and carvacrol on wheezing, FEV1 and plasma levels of nitrite in asthmatic patients.

OBJECTIVE: The preventive effect of Zataria multiflora in animal models of asthma has been reported. In the present study, its effect on wheezing, forced expiratory volume in 1 second, and plasma nitrite (NO2-) in asthmatic patients was studied. MATERIALS AND METHODS: In this study, forty asthmatic patients including 15 males and 25 females (aged 45.8±6.21 years) were randomly allocated in four groups including placebo group (P), and three treatment groups which received two doses of Z. multiflora (groups Z low and Z high that received 5 and 10 mg/kg/day, respectively) and carvacrol (group C treated with 1.2 mg/kg/day). All patients were treated for two months in a double-blind manner. At three time points (before starting the treatment (pretreatment), and one and two month after treatment), wheezing during day and exercise, forced expiratory volume in 1 second and NO2- were measured. RESULTS: Day wheeze and exercise wheeze were significantly reduced in treated groups with carvacrol and both doses of Z. multiflora compared to pretreatment (p<0.05 to p<0.01). However, FEV1% was significantly increased in treated groups with carvacrol and both doses of Z. multiflora (p<0.05 to p<0.001). Plasma level of NO2- was also significantly decreased in Z high and carvacrol groups after two months of treatment (p<0.01 to p<0.001). However, most of evaluated parameters in placebo group did not show significant changes during the study. CONCLUSION: Z. multiflora and its constituent, carvacrol, improved FEV1% while reduced wheezing and plasma level of NO2- in asthmatic patients. Therefore, a possible therapeutic potential for this plant and its constituent, carvacrol could be suggested to be used against asthma.

The Effect of Zataria multiflora on Th1/Th2 and Th17/T Regulatory in a Mouse Model of Allergic Asthma.

Asthma is a chronic inflammatory disease with no definite treatment and more research is needed to overcome this condition. The aim of this study was to investigate the effect of the extract of Zataria multiflora (Z. multiflora) as a medicinal plant on cytokine genes expression in an experimental mouse model of asthma. Adult mice were randomly divided into the following groups: control (C), untreated asthma (A), asthmatic groups treated with dexamethasone (D) and Z. multiflora extract (200, 400, and 800 µg/mL; Z1, Z2, and Z3, respectively), (for groups C, A, and D n = 5 and for groups Z1, Z2, and Z3 n = 6). For induction of the mouse model of asthma, animals were sensitized with intraperitoneal injection and inhalation of ovalbumin (OVA). The number of T helper (Th) subtype cells (using flow cytometry) and the levels of IFN-γ, FOXP3, IL-4, TGF-ß, IL-17 gene expression (by real time PCR) were assessed in mice splenocytes. The observed changes in spleen cells of group A compared to group C were increased number of Th2 and Th17 cells, enhancement of gene expression of IL-4, IL-17, and TGF-ß (p < 0.001 for all cases), reduction of Th1 cells and Th1/Th2 ratio (p < 0.001 for both cases) and decrease in gene expression of IFN-γ, FOXP3 and IFN-γ/IL-4 ratio (p < 0.01 for IFN-γ and p < 0.001 for other cases). The observed changes in spleen cells of treated compared to untreated A group were enhancement of Treg cells and Th1/Th2 ratio (p < 0.001 for both cases), increase in IFN-γ (p < 0.05) and FOXP3 (p < 0.001) gene expression and IFN-γ/IL-4 ratio (p < 0.01) as well as reduction of Th2 and Th17 cells (p < 0.01 to p < 0.001), decrease gene expression of IL-4, IL-17, and TGF-ß (p < 0.05 to p < 0.001). The findings showed that the extract of Z. multiflora decreased pro-inflammatory cytokines in asthma (IL-4 and IL-17 and TGF-ß) but increased anti-inflammatory cytokines (IFN-γ) gene expression and the number of Treg (FOXP3) in splenocytes of asthmatic mice which may indicate the specific therapeutic effect of the plant extract in allergy, autoimmunity, and infectious diseases via potentiating Th1 and suppressing Th2 and Th17 cells.

Carum copticum L.: a herbal medicine with various pharmacological effects.

Carum copticum L. commonly known as "Ajwain" is cultivated in many regions of the world including Iran and India, states of Gujarat and Rajasthan. Traditionally, C. copticum has been used in the past for various therapeutic effects including bloating, fatigue, diarrhea, abdominal tumors, abdominal pain, respiratory distress, and loss of appetite. It has other health benefits such as antifungal, antioxidant, antibacterial, antiparasitic, and hypolipidemic effects. This plant contains different important components such as carbohydrates, glucosides, saponins and phenolic compounds (carvacrol), volatile oils (thymol), terpiene, paracymene and beta-pinene, protein, fat, fiber, and minerals including calcium, phosphorus, iron, and nicotinic acid (niacin). In the previous studies, several pharmacological effects were shown for C. copticum. Therefore, in this paper, the pharmacological effects of the plant were reviewed.