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Ethnopharmacological Relevance: The herbicide paraquat (PQ) is highly toxic, capable of inducing severe lung inflammation and oxidative stress, resulting in lung fibrosis and respiratory failure. Previous research has demonstrated a range of pharmacological effects associated with Crocus sativus. L (Cs) through its anti-inflammatory, antioxidant and immunomodulatory properties. Pharmacological studies support the widespread use of Cs in traditional medicine to treat respiratory disorders such as coughs and asthma., Aim of Study: This study aimed to investigate the preventive impact of Cs extract and pioglitazone (Pio) on lung inflammation, oxidative stress, pathological alterations, and tracheal reactivity induced by inhaled PQ in rats as compared to dexamethasone (Dexa)., Methods: The control (Ctrl) group of rats was administered with saline aerosol, while the remaining six groups received PQ aerosol eight times every other day. The six PQ exposure groups were treated daily during the exposure period to PQ with either; saline alone, low dose Cs, High dose Cs, Pio alone, Pio combined with low dose Cs, or Dexa of 16 days., Results: In the PQ group, the levels of superoxide dismutase (SOD), catalase (CAT), and thiol in the bronchoalveolar lavage fluid (BALF) were declined whereas, the levels of MDA, total and differential WBC, and lung tissue levels of tumor necrosis factor (TNF-α) and Interleukin 10 (IL-10), tracheal responsiveness (TR) to methacholine and lung pathological changes were enhanced. The measured variables showed significant improvement in all treated groups, except for a few variables in Cs (L). The combined Cs (L) + Pio showed higher effects than Cs (L) and Pio alone. For all comparisons, p values were <0.05 to <0.001., Conclusions: The results showed preventive effect of Cs comparable to that of Dexa and the potential additive preventive capabilities of the Cs and Pio indicate that the involvement of the PPARγ receptor is implicated in the effects induced by Cs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Control rats were exposed to saline aerosol, two groups were exposed to paraquat (PQ), 27 (PQ-L) and 54 (PQ-H) mg/m 3 aerosols and six groups were treated with carvacrol, 20 (C-L) and 80 (C-H) mg/kg/day, pioglitazone, 5 (Pio-L) and 10 (Pio-H) mg/kg/day, C-L+Pio-L and dexamethasone, 0.03 mg/kg/day, for 16 days after the end of exposure to PQ-H. Different variables were measured after the end of treatment period. Total and differential white blood cells counts, nitrite, malondialdehyde, interleukin (IL)-10, and interferon-gamma levels were significant increased, but thiol, superoxide dismutase, catalase, IL-17, and tumor necrosis factor alpha were decreased in the blood due to both doses of PQ (p < 0.05-p < 0.001). Most measured parameters were significantly improved in treated groups with both doses of carvacrol, pioglitazone, the combination of C-L+Pio-L and dexamethasone compared to PQ-H group (p < 0.05-p < 0.001). Treatment with C-L+Pio-L showed significantly higher effects compared to each one alone (p < 0.05-p < 0.001). Systemic oxidative stress and inflammation due to inhaled PQ were improved by carvacrol and pioglitazone. Higher effects of C-L+Pio-L than each one alone suggests carvacrol modulating PPAR-γ receptors., (© 2021 International Union of Biochemistry and Molecular Biology.)

The immediate and the late effects of inhaled Paraquat (PQ) on systemic and lung inflammation and oxidative stress were investigated. Rats were exposed to saline (control group) and two doses of inhaled PQ (27 and 54 mg/m 3 ) and studied variables were measured: 1) one day after the end of PQ exposure as "immediate condition", 2) 16 days after the end of PQ exposure as "late condition". Total and differential white blood cells (WBC) counts, lipid peroxidation and nitrite were increased but thiol, superoxide dismutase and catalase in the blood and BALF as well as methacholine EC50 was reduced in both conditions in the animals exposed to PQ compared to control groups (p < 0. 05 to p < 0.001). Most studied parameters in the immediate condition were significantly higher than the late condition (p < 0.05 to p < 0.001). Systemic and lung inflammation and oxidative stress due to inhaled PQ in both the immediate and the late conditions were shown. Although most measured parameters in the immediate condition were higher, all variables were significantly different with the control group even in late condition, indicating a long-term effect of inhaled PQ toxicity, which may help in a more effective treatment of PQ poising in the future., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: The present study aimed to assess the impact of the aqueous-ethanolic extract of Zataria multiflora (ZM), carvacrol (Car), and their co-administration with a PPAR activator, pioglitazone (Pio), on oxidative stress and inflammation induced by paraquat (PQ) inhalation at a systemic level. Materials and Methods: The rats in the control group were exposed to saline and those of other groups to PQ (54 mg/m³) aerosols for 8 times on alternate days. Nine PQ groups were treated with saline, Car (20 and 80 mg/kg/day), ZM (200 and 800 mg/kg/day), Pio (5 mg/kg/day), dexamethasone (Dexa, 0.03 mg/kg/day), and low-dose ZM or Car + Pio for 16 days during the period of PQ exposure (n=6). Results: Differential and total WBC counts, and malondialdehyde (MDA), interleukin (IL)-10, and tumor necrosis factor (TNF)-α levels were enhanced but catalase (CAT), thiol, and superoxide dismutase (SOD) levels were reduced in the blood in the PQ group (p<0.01 to p<0.001). All measured variables improved in groups treated with both doses of ZM, Car, Pio, ZM + Pio, Car+Pio, and Dexa vs the PQ group (p<0.05 to p<0.001). Most variables were more improved in combined treatment groups in comparison with three agents alone. The combination of ZM or Car, and Pio showed an impact on PQ inhalation-induced systemic changes. Conclusion: The synergistic effect between Pio with ZM or Car indicates that these substances work together to enhance their individual effects. [ABSTRACT FROM AUTHOR]

Objective(s): The effects of Crocus sativus, safranal, and pioglitazone on aerosolized paraquat (PQ)- induced systemic changes were examined. Materials and Methods: Control (Ctrl) and PQ groups of rats were exposed to saline or PQ (27 and 54 mg/m3, PQ-L and PQ-H) aerosols eight times on alternate days. Nine PQ-H groups were treated with dexamethasone (0.03 mg/kg/day, Dexa), two doses of C. sativus extract (20 and 80 mg/kg/day, CS-L and CS-H), safranal (0.8 and 3.2 mg/kg/day, Saf-L and Saf-H), pioglitazone (5 and 10 mg/kg/day, Pio-L and Pio-H), and the combination of low dose of the pioglitazone and extract or safranal (Pio + CS and Pio + Saf) after the end of PQ exposure. Results: Interferon-gamma (INF-γ), interleukin 10 (IL-10), superoxide dismutase (SOD), catalase (CAT), and thiol serum levels were reduced, but tumor necrosis factor (TNF-α), malondialdehyde (MDA), and total and differential WBC were increased in both PQ groups (P<0.05 to P<0.001). All measured variables were improved in all treated groups (P<0.05 to P<0.001). The effects of high dose of C. sativus and safranal on measured parameters were higher than dexamethasone (P<0.05 to P<0.001). The effects of Pio + CS and Pio + Saf treatment on most variables were significantly higher than three agents alone (P<0.05 to P<0.001). Conclusion: C. sativus and safranal improved inhaled PQ-induced systemic inflammation and oxidative stress similar to those of dexamethasone and showed synergic effects with pioglitazone suggesting the possible PPARγ receptor-mediated effects of the plant and its constituent. [ABSTRACT FROM AUTHOR]

Objective: Comparative effect of Curcuma longa (C. longa) ethanolic extract and curcumin on paraquat (PQ)-induced systemic and lung oxidative stress and inflammation were evaluated in the present study. Materials and Methods: Control animals were exposed to normal saline and PQ group to 54 mg/m3 PQ aerosols (8 times, each time for 30 min). Treatment groups were exposed to PQ and treated with 150 and 600 mg/kg/day C. longa, or 30 and 120 mg/kg/day curcumin after PQ exposure period for 16 days. Total and differential white blood cells (WBC) and oxidative markers were measured both in bronchoalveolar lavage (BALF) and blood at the end of the study. Results: Total and differential WBC counts as well as malondialdehyde (MDA) level were significantly increased but total thiol content and the activities of catalase (CAT) and superoxide dismutase (SOD) were reduced in both the BALF and blood of the PQ group in comparison with the control group (p<0.05 to p<0.001). Both doses of C. longa and curcumin diminished MDA level, total and differential WBC counts in the blood and BALF but increased CAT and SOD activities in both of them compared to PQ group (p<0.05 to p<0.001). The effects of C. longa and curcumin high dose on most variables were markedly more than low dose (p<0.05 to p<0.001). Furthermore, the effects of curcumin on some variables were markedly more than C. longa (p<0.05 to p<0.001). Conclusion: Both C. longa and curcumin improved PQ-induced systemic and lung inflammation and oxidative stress, but the effect of curcumin was more prominent. [ABSTRACT FROM AUTHOR]

Objectives: The effects of hydroalcoholic extract of Zataria multiflora (Z. multiflora) on memory changes, as well as lung injury due to inhaled paraqut (PQ) in rat, were examined. Method: Control group of rat with saline aerosol administration, PQ groups with PQ aerosol (27 and 54 mg/m3) administration, PQ groups treated with two doses of the extract (200 and 800 mg/kg/day) and dexamethasone (0.03 mg/kg/day) were studied. Shuttle box and Morris Water Maze (MWM) tests were carried out as well as oxidant, anti-oxidant markers, total and differential white blood cell (WBC) counts and cytokine levels in broncho-alveolar lavage (BALF). Results: Inhaled PQ significantly increased the escape latency and travelled distance in MWM test, but the time spent in the target quadrant on the probe day was significantly reduced (p < 0.05 to p < 0.001). The latency to enter the dark room at 3, 24, and 48 h after an electrical shock was reduced due to PQ (p < 0.05 to p < 0.001). Exposure to PQ significantly increased total WBC, neutrophil, eosinophil, lymphocyte, and monocyte counts, IL-10, interferon gama (INF-γ), nitrite (NO2), and malondialdehyde (MDA) levels, but catalase (CAT), superoxide dismutase (SOD), and thiol levels were decreased (p < 0.05 to p < 0.00). Z. multiflora and dexamethasone treatment significantly improved all behavioral as well as lung changes induced by inhaled PQ (p < 0.05 to p < 0.01). Conclusion:Z. multiflora treatment improved learning and memory impairment as well as lung inflammation and oxidative stress induced by inhaled PQ. [ABSTRACT FROM AUTHOR]

The effects of Zataria multiflora (Z. multiflora) and pioglitazone (a PPAR-γ agonist) alone and in combination, on systemic inflammation and oxidative stress induced by inhaled paraquat (PQ) as a herbicide, which induced inflammation in rats, were examined. Rats were exposed to (1) saline (control) and (2) 54 mg/m3 PQ aerosols (8 times, every other day, each time for 30 min) without treatment or treated with (3 and 4) two doses of Z. multiflora (200 and 800 mg/kg/day), (5 and 6) two doses of pioglitazone (5 and 10 mg/kg/day), (7) low doses of Z. m u l t i f l o r a + pioglitazone , (Pio-5+Z-200 mg/kg/day) or (8) dexamethasone (0.03 mg/kg/day) for 16 days, after the last PQ exposure. Different variables were measured at the end of the treatment period. Exposure to PQ significantly increased total and differential white blood cells (WBC) counts, serum levels of nitrite (NO2), malondialdehyde (MDA), interleukin- (IL) 17, and tumor necrosis factor alpha (TNF-α), but reduced thiol, superoxide dismutase (SOD), catalase (CAT), IL-10, and interferon-gamma (INF-γ) (p < 0.05 to p < 0.001). Most measured parameters were significantly improved in groups treated with either doses of the extract, pioglitazone, Pio-5+Z-200 mg/kg/day, or dexamethasone compared to the PQ group (p < 0.05 to p < 0.001). The combination of low doses of Pio-5+Z-200 mg/kg/day showed significantly higher effects compared to each one alone (p < 0.05 to p < 0.001). Systemic oxidative stress and inflammation due to inhaled PQ were improved by Z. multiflora and pioglitazone. Higher effects of Pio-5+Z-200 mg/kg/day compared to each one alone suggest modulation of PPAR-γ receptors by the plant extract, but further studies using PPAR-γ antagonists need to be done in this regard. [ABSTRACT FROM AUTHOR]

Objective: Paraquat (PQ) is a herbicide which induces oxidative stress and inflammation. Anti-inflammatory and anti-oxidant effects were shown for Zataria multiflora (Z. multiflora) and carvacrol previously. The effects of Z. multiflora hydroalcoholic extract and carvacrol on systemic inflammation and oxidative stress induced by inhaled PQ were examined in this study. Materials and Methods: Six groups of male rats used in this study were as follows: control group exposed to normal saline aerosol, one group exposed to PQ 54 mg/m³ aerosol, animals exposed to PQ 54 mg/m³ and treated with Z. multiflora (200 and 800 mg/kg/day) or carvacrol (20 and 80 mg/kg/day) for 16 days after the end of exposure to PQ. Exposure to PQ was performed 8 times, every other day, each time for 30 min. After the end of the treatment period, different variables were measured. Results: Significant increases in nitrite (NO2), malondialdehyde (MDA) and interleukin (IL)-6 serum levels but significant reduction interferon-gamma (IFN-γ) serum levels as well as IFN-γ/IL-6 ratio were observed in PQ-exposed compared to control group (p<0.01 for MDA and IL-6, p<0.001 for other cases). Treatment with both doses of the extract and carvacrol specially at high dose, reduced MDA, NO2, and IL-6 but increased IFN-γ and IFN-γ/IL-6 ratio compared to un-treated PQ exposed group (p<0.05 to p<0.001). Conclusion: Treatment with Z. multiflora and carvacrol improved systemic inflammation oxidative biomarkers induced by inhaled PQ which may indicate therapeutic potential of the plant and its constituent, carvacrol in systemic inflammation and oxidative biomarkers induced by inhaled PQ. [ABSTRACT FROM AUTHOR]

Objective(s): The effects of PPAR-γ agonist alone and in combination with carvacrol and Zataria multiflora on inhaled paraquat (PQ) induced-systemic inflammation and oxidative stress were examined. Materials and Methods: Control group exposed to normal saline aerosol, one group exposed to 54 mg/m3 PQ aerosol and four groups exposed to PQ aerosol and treated with 5 mg/kg/ day pioglitazone, pioglitazone + 200 mg/kg/day Z. multiflora extract, pioglitazone + 20 mg/kg/day carvacrol, and 0.03 mg /kg/day dexamethasone for 16 days after the end of exposure to PQ were studied. Exposure to normal saline or PQ was performed every other days for 30 min (8 times). Different variables were measured after the end of treatment period. Results: PQ exposure significantly increased serum levels of NO2, MDA and IL-6 but dexreased CAT and IFN-γ levels and IFN-γ/IL-6 ratio compared to control group (P<0.01 to P<0.001). Treatment with pioglitazone only improved serum level of MDA (P<0.01). Treatment with combination of pioglitazone and carvacrol as well as treatment with dexamethasone improved all measured variables compared to PQ exposed group (P<0.05 to P<0.001). The effects of pioglitazone + Z. multiflura and pioglitazone + carvacrol on almost all measured variables were significantly higher than pioglitazone alone (P<0.05 toP<0.001). Conclusion: The effects of combination therapy of pioglitazone with Z. multiflora or carvacrol on inhaled paraquat (PQ) induced-oxidative stress and systemic inflammation were higher than the effects of pioglitazone alone. These results suggested that the effects of the extract and carvacrol may mediated through PPAR-γ receptors. [ABSTRACT FROM AUTHOR]

• Inhaled paraquat induced lung injury and inflammation in rat. • Zataria multiflora improved inflammation induced by paraquat similar to dexamethasone effect. • Pioglitazone, a PPARγ agonist, also improved inflammation induced by inhaled paraquat. • Zataria multiflora extract showed synergic effects with pioglitazone. The effects of a PPAR-γ agonist, pioglitazone and Zataria multiflora (Z. multiflora) on inhaled paraquat (PQ)-induced lung oxidative stress, inflammation, pathological changes and tracheal responsiveness were examined. The study was carried out in control rats exposed to normal aerosol of saline, PQl and PQh groups exposed to aerosols of 27 and 54 mg/m3 PQ, groups exposed to high PQ concentration (PQh) and treated with 200 and 800 mg/kg/day Z. multiflora , 5 and 10 mg/kg/day pioglitazone, low doses of Z. multiflora + pioglitazone, and 0.03 mg/kg/day dexamethasone. Increased tracheal responsiveness, transforming growth factor beta (TGF-ß) and lung pathological changes due to PQh were significantly improved by high doses of Z. multiflora and pioglitazone, dexamethasone and extract + pioglitazone, (p < 0.05 to p < 0.001). In group treated with low doses of the extract + pioglitazone, the improvements of most measured variables were significantly higher than the low dose of two agents alone (p < 0.05 to p < 0.001). Z. multiflora improved lung injury induced by inhaled PQ similar to dexamethasone and pioglitazone which could be mediated by PPAR-γ receptor. [ABSTRACT FROM AUTHOR]

Paraquat is a green liquid toxin that is used in agriculture and can induce multi-organ including lung injury. Various pharmacological effects of Crocus sativus (C. sativus) were indicated in previous studies. In this research, the effects of C. sativus extract and pioglitazone on inhaled paraquat-induced lung inflammation, oxidative stress, pathological changes, and tracheal responsiveness were studied in rats. Eight groups of rats (n = 7 in each) including control (Ctrl), untreated paraquat aerosol exposed group (54 mg/m3, 8 times in alternate days), paraquat treated groups with dexamethasone (0.03 mg/kg/day, Dexa) as positive control, two doses of C. sativus extract (20 and 80 mg/kg/day, CS-20 and CS-80), pioglitazone (5 and 10 mg/kg/day, Pio-5 and Pio-10), and the combination of CS-20 + Pio-5 were studied. Total and differential WBC, levels of oxidant and antioxidant biomarkers in the BALF, lung tissue cytokine levels, tracheal responsiveness (TR), and pathological changes were measured. The levels of IFN-γ, IL-10, SOD, CAT, thiol, and EC 50 were reduced, but MDA level, total and differential WBC count in the BALF and lung pathological changes were increased in the paraquat group (all, p < 0.001). The levels of IFN-γ, IL-10, SOD, CAT, thiol and EC 50 were increased but BALF MDA level, lung pathological changes, total and differential WBC counts were reduced in all treated groups. The effects of C. sativus high dose and combination groups on measured parameters were equal or even higher than dexamethasone (p < 0.05 to p < 0.001). The effects of the combination of CS-20 + Pio-5 on most variables were significantly higher than CS-20 and Pio-5 alone (p < 0.05 to p < 0.001). C. sativus treatment improved inhaled paraquat-induced lung injury similar to dexamethasone and showed a synergistic effect with pioglitazone, suggesting possible PPAR-γ receptor-mediated effects of the plant. [Display omitted] • The effect of C. sativus on inhaled PQ-induced lung injury were studied. • Treatment with C. sativus extract improved PQ induced lung injury. • The effect of the extract were similar to those of pioglitazone and dexamethasone. • There was a synergic effect between the extract with pioglitazone. • Possible PPARγ receptor-mediated effects of the plant was suggested. [ABSTRACT FROM AUTHOR]

The effect of Curcuma longa (Cl) ethanolic extract, nano-curcumin (Cu) and a PPARγ activator, pioglitazone on inhaled paraquat (PQ)-induced systemic inflammation and oxidative stress was examined in the present study. Control rats were exposed to normal saline and PQ groups to 27 and 54 mg/m3 (PQ-L and PQ-H) aerosols. Nine other PQ-H groups were treated with Curcuma longa (Cl, 150 and 600 mg/kg/day), nano-curcumin (Cu, 2 and 8 mg/kg/day), pioglitazone (Pio, 5 and 10 mg/kg), low dose of Pio + Cl and Cu and dexamethasone (0.03 mg/kg/day) for 16 days after PQ exposure period (n = 8). Total and differential WBC counts, malondialdehyde (MDA) and TNF-α levels were increased but thiol, catalase (CAT), superoxide dismutase (SOD), IL-10 and IFN-γ levels were decreased in the blood in the both PQ groups (p < 0.05 to p < 0.001). Treatment with Dexa and both doses of Cl, Cu, and Pio improved all measured variables compared to the PQ-H group (p < 0.05 to p < 0.001). The improvements of most variables in the treated group with low dose of Pio + Cl and Cu were higher than the effects of three agents alone. Systemic inflammation and oxidative stress induced by inhaled PQ were improved by Cl, Cu and Pio. In addition, a synergic effect between Pio with those of Cl and Cu was shown, suggesting PPARγ mediated effects of the plant and its derivative Cu. [Display omitted] • Inhaled paraquat (PQ)-induced systemic inflammation and oxidative stress was examined. • Inhaled PQ significantly changed systemic oxidative stress and inflammatory indices. • Extract and curcumin improved measured variables more than dexamethasone. • Pioglitazone showed synergic effect, Curcuma longa and nano-curcumin. • Extract and curcumin ameliorated systemic insults induced by inhaled PQ. [ABSTRACT FROM AUTHOR]