The effect of aqueous extract of Rosa damascena on formaldehyde-induced toxicity in mice testes

Context: Rosa damascena L. (Rosaceae) (RD) essential oil and extracts are commonly used as a flavour in herbal medicine which increase libido. Previous studies have shown inhalation of RD flower’s oil increases libido and causes protective effects in formaldehyde (FA)-induced testicular damage.

Objective: The protective effects of aqueous extract of RD on the male reproductive system of mice were examined following FA-induced damage.

Materials and methods: Forty-eight adult NMRI male mice were randomly assigned to six groups (n?=?8): control (normal saline, 10?mg/kg); RD40 (40?mg/kg, p.o.); FA treated (10?mg/kg of 10%, i.p.) and FA?+?RD treated at 10, 20 and 40?mg/kg (FA?+?RD10), (FA?+?RD20) and (FA?+?RD40), respectively, for 40 days. At the end of treatment regimes, serum testosterone (T) level and the reproductive activity, viz. body/organ weights, testicular structure and sperm characteristics were studied.

Results: Formaldehyde administration significantly decreased serum T level (p?p?p?Discussion and conclusions: We may conclude that RD flower extract can withstand effects of FA in the male reproductive system of mice possibly due to its antioxidative properties.     

The effects of Melissa officinalis (lemon balm) pretreatment on the resistance of the heart to myocardial injury

Context: The antihyperlipidemic, antiarrhythmic, neuroprotective and hepatoprotective effects of Melissa officinalis L. (Lamiaceae) have been reported. However, no study has examined its effects on the resistance of the heart to stressful conditions.

Objective: The objective of this study is to evaluate the effects of aqueous extract of M. officinalis aerial parts on Wistar rat heart with/without cardiac injury.

Materials and methods: Animals were grouped as control, isoproterenol (ISO), M. officinalis without (M50, M100, and M200) and with isoproterenol (M50?+?ISO, M100?+?ISO, and M200?+?ISO). The aqueous extract of M. officinalis was orally administered at dosages of 50, 100, and 200?mg/kg/d, respectively, for 7 consecutive days. On the 6th and 7th day, ISO, M50?+?ISO, M100?+?ISO, and M200?+?ISO groups received 85?mg/kg of isoproterenol for myocardial injury induction. On day 8, hemodynamic parameters were recorded and samplings were done.

Results: The extract (50, 100, and 200?mg/kg) significantly reduced the heart rate (264?±?5, 259?±?5 and 281?±?3 versus 377?±?13 in control group, p?<?0.01). Blood pressure was significantly decreased in M50?+?ISO (75?±?5) versus M50 (110?±?6) and M100?+?ISO (72?±?6) versus M100 (105?±?5?mmHg, p?<?0.01). The malondialdehyde levels of the injured hearts were lower in M50?+?ISO and M100?+?ISO groups than in the ISO group (p?<?0.05). Serum cardiac troponin I was higher in the M200?+?ISO group (5.1?±?1.7) than in the ISO group (2.7?±?0.7?ng/ml, p?<?0.05).

Conclusion: The lower dose of extract, by improving the balance of the redox system and by reducing the heart rate, may increase the heart resistance to injury. However, the higher doses of extract may intensify the injury of ischemic heart.     

Antifungal properties of hypericin,hypericin tetrasulphonic acid and fagopyrin on pathogenic fungi and spoilage yeasts

Context: The role of hypericin-mediated photodynamic antimicrobial properties on pathogenic fungi and photodynamic therapy for human cancer cells is known. Antifungal properties of Hypericum perforatum L. (Hypericaceae) and Fagopyrum esculentum Moench. (Polygonaceae) extracts were also studied. The different polarities of solvents can cause complication in the identification of antifungal effects of separate biologically active compounds. In recent experimental work, we compared antifungal properties of purified hypericin, hypericin tetrasulphonic acid (hypericin?+?S) and fagopyrin, which is analogue of hypericin.

Objective: The antifungal properties of aromatic polyketide derivatives such as hypericin, hypericin?+?S and fagopyrin on the selected pathogenic fungi and spoilage yeasts have been studied.

Materials and methods: The antifungal properties of hypericin, hypericin?+?S and fagopyrin were determined using the broth microdilution method against a set of pathogenic fungi and spoilage yeasts including: Microsporum canis, Trichophyton rubrum, Fusarium oxysporum, Exophiala dermatitidis, Candida albicans, Kluyveromyces marxianus, Pichia fermentans and Saccharomyces cerevisiae. The tested concentrations of hypericin, hypericin?+?S and fagopyrin ranged from 750 to 0.011?μg/mL and MIC values were evaluated after 48?h incubation at 30?°C.

Results: The results confirm different antifungal properties of hypericin, hypericin?+?S and fagopyrin on the selected pathogenic fungi and spoilage yeasts. For pathogenic fungi, the minimum inhibitory concentrations of hypericin ranged 0.18–46.9?μg/mL, hypericin?+?S 0.18–750?μg/mL and fagopyrin 11.7–46.9?μg/mL. For spoilage yeasts, the MICs of hypericin and hypericin?+?S ranged 0.18–46.9 and 0.011–0.73?μg/mL, respectively.

Discussion and conclusion: The results obtained herein indicate that various chemical structures of hypericin, hypericin?+?S and fagopyrin can develop different antifungal properties.     

Role of GABAB receptors and p38MAPK/NF-κB pathway in paclitaxel-induced apoptosis of hippocampal neurons

Context: The effects of the anticancer drug paclitaxel on learning and memory are rarely studied.

Objective: This study investigated changes in GABA_B receptor expression during paclitaxel-induced apoptosis of hippocampal neurons and the role of the p38MAPK/NF-κB pathway in this process.

Materials and methods: Hippocampal neurons isolated from neonatal Sprague–Dawley rats were divided into six groups: Control (C), SB (10?µL of 10-µmol/L SB203580), SN (53?µg/mL SN50), N (1?µmol/L paclitaxel), SB?+?N (10?µmol/L SB203580?+?1?µmol/L paclitaxel) and SN?+?N (53?µg/mL SN50?+?1?µmol/L paclitaxel). Cells in different groups were treated with corresponding agents for 24?h at 37?°C. The apoptosis rate and protein levels of GABA_B1 receptors and NF-κB p65 were evaluated. Rat models of neuropathic pain was induced by paclitaxel and were divided into four groups such as N, B?+?N, SN?+?N and SN?+?B?+?N groups. Rats in the N group received intrathecal injections of normal saline solution. Rats in the B?+?N group received intrathecal injections of 10?μL baclofen (0.05?μg/μL). Rats in the SN?+?N and SN?+?B?+?N groups received intrathecal injections of SN50 and SN50 plus baclofen, respectively. Spatial learning and memory were evaluated in rat models based on the escape latency and the number of crossings over the platform and protein levels of GABA_B1 receptors, NF-κB, IL-1β and TNFα were measured by immunohistochemistry assay and western blot.

Results: The neuronal apoptosis rate was significantly increased in N (49.16?±?3.12)%, SB?+?N (31.18?±?3.02)% and SN?+?N (28.47?±?3.75)% groups, accompanied by increased levels of GABA_B1 receptors and NF-κB p65 (p?p?B1:9.0?±?1.6, NF-κB p65:29.6?±?2.4, IL-1β: 30.4?±?3.4, TNFα: 31.0?±?3.4), B?+?N, SN?+?N and SN?+?B?+?N groups evidently increased levels of GABA_B1 receptor (B?+?N:SN?+?N:SN?+?B?+?N?=?19.4?±?2.1:20.8?±?1.9:28.0?±?1.9) but significantly decreased levels of NF-κB p65 (B?+?N:SN?+?N:SN?+?B?+?N?=?21.2?±?1.5:18.6?±?2.1:12.6?±?1.5), IL-1β (B?+?N:SN?+?N:SN?+?B?+?N?=?22.0?±?1.0:19.6?±?1.8:14.6?±?1.5) and TNF α (B?+?N:SN?+?N:SN?+?B?+?N?=?23.0?±?1.6:22.2?±?0.8:16.6?±?1.7). Similar findings were found in western blot analysis.

Discussions and conclusions: Paclitaxel may reduce cognitive function in rats through the p38MAPK/NF-κB pathway and GABA_B1 receptors.     

Dynamic changes of mononuclear phagocytes in circulating,pulmonary alveolar and interstitial compartments in a mouse model of experimental silicosis

Context: Silicosis is a devastating, irreversible lung fibrosis condition exposed to crystalline silica. The mononuclear phagocyte system plays an important role in the pathogenesis of silicosis.

Objective: The present study was aimed to explore the dynamic changes of mononuclear phagocytes in circulating, pulmonary alveolar and interstitial compartments in experimental silicosis model.

Materials and methods: A mouse model of lung fibrosis was developed with crystalline silica particles (2?mg/40?μL via oropharyngeal instillation) using male C57BL/6 mice, and were killed on days 1, 3, 7, 14, and 28. The lung inflammation and fibrosis was investigated using hematoxylin–eosin staining and bronchoalveolar lavage fluid (BALF) analysis, Masson’s trichrome staining, and immunofluorescence. Circulating monocyte subsets (Ly6C^hi and Ly6C^lo), polarization state of BALF-derived alveolar macrophages (AM?) and lung interstitial macrophages (IM?, derived from enzymatically digested lung tissue) were analyzed by flow cytometry.

Results: The percentage of Ly6C^hi monocytes significantly increased on day 1 after silica exposure, which reached the peak level from day 7 till day 28. Moreover, M2 (alternative activation) AM? (PI???CD64?+?CD206+) was dramatically and progressively increased from day 1 to day 28. A parallel increase in IM? with M2 polarization (PI-CD64?+?CD11b?+?CD206+) was also observed from day 1 to day 28.

Conclusion: Our data demonstrate a dynamic view of mononuclear phagocyte change in three compartments after silica challenge, which highlights the remodeling of mononuclear phagocyte system as a potential therapeutic target for silicosis.     

Paracetamol-induced nephrotoxicity and oxidative stress in rats: the protective role of Nigella sativa

Context Nigella sativa L. (Ranunculaceae) (NS) is traditionally used to treat many conditions such as inflammation.

Objective This study evaluates the effects of NS seeds ethanol extract in paracetamol-induced acute nephrotoxicity in rats.

Materials and methods Forty-eight female Wistar Albino rats were divided into eight groups: I?=?sham; II?=?sham?+?1000?mg/kg NS; III?=?sham?+?140?mg/kg (N-acetyl cysteine) NAC; IV?=?2?g/kg paracetamol; V?=?2?g/kg paracetamol?+?140?mg/kg NAC; VI, VII and VIII?=?2?g/kg paracetamol?+?250, 500 and 1000?mg/kg NS, respectively. Paracetamol administration (oral) was carried out 1?h after NS and NAC administrations (oral), and all animals were sacrificed 24?h later.

Results Paracetamol administration significantly increased serum urea (88.05?U/L) and creatinine (0.80?U/L) when compared with the sham group (49.80 and 0.31?U/L, respectively). However, serum urea level was reduced to 65.60, 56.00 and 54.18?U/L, with 250, 500 and 1000?mg/kg doses of the extract, respectively. Also, serum creatinine level was reduced to 0.64, 0.57 and 0.52?U/L with 250, 500 and 1000?mg/kg doses of the extract, respectively. NS administration increased superoxide dismutase and glutathione, and decreased malondialdehyde levels in the kidneys. Kidney histopathological examinations showed that NS administration antagonized paracetamol-induced kidney pathological damage.

Discussion and conclusions The results suggest NS has a significant nephroprotective activity on paracetamol-induced nephrotoxicity. It may be suggested that the antiinflammatory and antioxidant effects of NS ethanolic extract originated from different compounds of its black seeds.     

Fenofibrate,simvastatin and their combination in the management of dyslipidaemia in type 2 diabetic patients

ABSTRACT

Objective: To evaluate the efficacy of fenofibrate, simvastatin or their combination in type 2 diabetic patients with combined dyslipidaemia.

Research design and methods: 241 patients, who had never previously taken lipid-lowering medications, received fenofibrate 145?mg/day, or simvastatin 40?mg/day, or fenofibrate 145?mg/day?+?simvastatin 40?mg/day?combination for 12 months. We evaluated lipids, glycaemic, haemostatic, and inflammatory variables at baseline, and after 6 and 12 months.

Results: After 12 months total cholesterol (TC), LDL cholesterol (LDL-C) and triglycerides (Tg) decreased while HDL cholesterol (HDL-C) increased in all groups, even if the values obtained with fenofibrate?+?simvastatin were the best. At the end of the study apolipoprotein A-1 (Apo A-1) increased with fenofibrate?+?simvastatin, while apolipoprotein B (Apo B) decreased in all groups compared to baseline. Plasminogen activator inhibitor-1 (PAI-1) and high-sensitivity C reactive protein (hs-CRP) decreased after 12 months compared to baseline with simvastatin, and with fenofibrate?+?simvastatin even if the value obtained with fenofibrate–simvastatin was the lowest. After 12 months, fibrinogen (Fg) decreased compared to baseline with fenofibrate?+?simvastatin.

Limitations: This study has some limitations. The first one is the relatively small sample of studied patients. The second one is the lack of an advanced lipid proteins evaluation, such as lipoprotein subfraction changes in the different treatment regimen. Finally, we have not selected patients that could show the best response to fibrate (i.e.: hypertriglyceridemics) or statins (i.e.: hypercholesterolemics) monotherapy, so the effect of these drugs administered alone may have been partly attenuated.

Conclusions: Fenofibrate?+?simvastatin association improved lipid parameters, prothrombotic and inflammatory factors, and appeared to have a good tolerability profile over 12 months of therapy.     

Statin plus ezetimibe treatment in clinical practice: the SI-SPECT (Slovenia (SI) Statin Plus Ezetimibe in Cholesterol Treatment) monitoring of clinical practice study

ABSTRACT

Background: Poor results from lipid-lowering therapy are mainly due to inadequate dosing and increased adverse effects with high-dose statin monotherapy or drug combinations.

Objectives: The SI-SPECT (Slovenia (SI) Statin Plus Ezetimibe in Cholesterol Treatment) study evaluated the effectiveness of either ezetimibe (EZE) 10?mg as monotherapy or co-administered with on-going statin treatment (S?+?EZE) in clinical practice.

Design and methods: A total of 1053 dyslipidaemic patients (52% men, age 60.3 years, 42.9% with CHD, 32.0% with diabetes mellitus and 69.6% with hypertension) were enrolled. The majority (n?=?986; 93.6%) were treated with EZE as ‘add-on’ to their already prescribed statin, the rest only received EZE (n?=?67).

Main outcome measures: Baseline lipid levels were compared with those obtained 16 weeks after initiating treatment.

Results: Total (TC) and low density lipoprotein cholesterol (LDL-C), as well as triglycerides (TG) decreased significantly with S?+?EZE (by 25.3%, 31.4% and 28.9%, respectively; p?<?0.0001 for all comparisons), while monotherapy with EZE resulted in a decrease of 20.8% for TC (?p?<?0.0001), 28.0% for LDL-C (?p?<?0.0001) and 28.8% for TG (?p?=?0.016). At the end of the study 43.9% of patients achieved target TC (<?5.0?mmol/L for primary prevention and <?4.5?mmol/L for secondary prevention), 50.5% target LDL-C (<?3.0?mmol/L for primary prevention and <?2.5?mmol/L for secondary prevention) and 61.6% target TG (<?2.0?mmol/L). The overall incidence of adverse effects during the treatment period, and probably related to EZE use, was low (n?=?6, 0.6% of patients).

Conclusions: (1) S?+?EZE combination therapy was effective and safe irrespective of the statin used, (2) the S?+?EZE combination resulted in significantly more patients reaching their recommended target lipid levels and (3) the lipid-lowering efficacy of EZE in monotherapy as well as of the S?+?EZE combination was related to initial lipid values. The much greater decrease of TG than expected could be, at least in part, due to better control/compliance regarding diet and drug treatment during the study and adherence to the need for an overnight fast before sampling.     

七氟醚麻醉对新生鼠学习与记忆的影响

目的 探索用七氟醚麻醉发育期小鼠是否会引起成长过程中学习记忆障碍。 方法 实验包括122只新生鼠(出生后7 d)。其中72只分别经七氟醚1.0或0.5最低肺泡有效浓度(minimum alveolar concentration,MAC)麻醉或吸入40% O₂ 2 h,4周或12周行水迷宫实验,记录训练各天潜伏期和游泳速度,以及探索期平台滞留时间和平台穿越次数。另外50只小鼠用于测定七氟醚麻醉(1.0或0.5 MAC)过程(0、1、2 h)中动脉血血气分析。 结果 新生鼠在整个麻醉过程中,pH值、PaCO₂、PaO₂和SaO₂均保持稳定,P>0.05。麻醉后4周,训练期后3 d,对照组小鼠潜伏期明显低于麻醉组,且后2 d,0.5 MAC组小鼠的潜伏期明显短于1.0 MAC组。探索期,对照组小鼠平台停留时间和平台穿越次数均明显高于2组麻醉组。麻醉后12周,1.0 MAC组小鼠在训练第5天潜伏期仍明显延长。探索期,对照组小鼠平台停留时间和(或)平台穿越次数均明显高于麻醉组。 结论 七氟醚麻醉引起新生鼠成长过程中学习与记忆障碍,其程度与药物浓度有关,且随时间推移减弱。     

Evaluation of protective effects of diosmin (a citrus flavonoid) in chemical-induced urolithiasis in experimental rats

Context There have not been any conclusive studies of the effects of diosmin, a modified flavanone glycoside obtained from Teucrium gnaphalodes L’Her (Lamiaceae), on urolithiasis.

Objective To evaluate anti-urolithiatic effects of diosmin in ammonium chloride and ethylene glycol-induced renal stone in experimental animals.

Materials and methods Thirty Sprague-Dawley were divided into five groups (n=6) receiving the following treatments, respectively, p.o. for 15 consecutive days: distilled water, 0.75% v/v ethylene glycol?+?2% w/v ammonium chloride, 0.75% v/v ethylene glycol?+?2% w/v ammonium chloride?+?cystone® 750?mg/kg, 0.75% v/v ethylene glycol?+?2% w/v ammonium chloride?+?diosmin 10?mg/kg or 0.75% v/v ethylene glycol?+?2% w/v ammonium chloride?+?diosmin 20?mg/kg. Different biomarkers of urolithiasis in urine and serum were evaluated and histopathological examination of kidney was done.

Results Animals treated with diosmin (both 10 and 20?mg/kg) had significantly (p?<?0.005) decreased in kidney weight, urinary pH, total urinary protein, urinary calcium, phosphorus, serum potassium, sodium, magnesium, creatinine, uric acid and blood urea nitrogen levels and significantly (p?<?0.005) increased in urinary volume, urinary magnesium, potassium, sodium, creatinine, uric acid and serum calcium levels in comparison to animals treated with ethylene glycol and ammonium chloride. However, results were better with diosmin 20?mg/kg in comparison to the control group.

Conclusion Diosmin (10 and 20?mg/kg) has very good anti-urolithiatic activity similar to the standard drug cystone®.     

Protective effect of Nigella sativa oil against acetamiprid induced reproductive toxicity in male rats

The present study was designed to investigate the adverse reproductive effects of acetamiprid, besides the possible protective role of Nigella sativa oil (NSO), as a potential antioxidant agent. Thirty-two male Wistar rats were allocated into four equal groups of eight, control (CRL), acetamiprid (ACMP, 27?mg/kg), Nigella sativa oil (NSO, 0.5?ml/kg) and in combination (ACMP?+?NSO). The experimental animals were dosed by gavage (5?days per week) for 45 consecutive days. Body weight gain, reproductive organs weights, sperm characteristics, testosterone, and thiobarbutiric acid-reactive substances (TBARS) levels were investigated. The obtained results showed that ACMP decreased significantly (p?p?p?p?相似文献   

Dexamethasone phosphate in antibiotic ear drops for the treatment of acute bacterial otitis externa

ABSTRACT

Objectives: To compare the efficacy and safety of polymyxin sulfate 7500?IU/neomycin sulfate 3500?IU/dexamethasone phosphate 0.1% (PN?+?Dx) otic solution with polymyxin sulfate 7500?IU/neomycin sulfate 3500?IU (PN???Dx) in patients with acute bacterial otitis externa (AOE), in order to determine the possible benefit of the addition of dexamethasone.

Research design and methods: Active controlled, double-blind, randomized, parallel group, multi-center clinical trial in ear, nose, and throat (ENT) specialist practices with a planned interim analysis for sample size adaptation. In total, 338 patients aged 18–76 who had a previous episode of otitis externa within the last year were randomized to receive 10?±?2 days of treatment with two drops, three times daily, of either PN?+?Dx or PN???Dx.

Main outcome measures: Change in the clinical symptom score (consisting of the subscores redness, swelling, pain, and secretion) and of the visual analogue scale (VAS) rating for pain from Visit 1 (Day 1) to Visit 2 (Day 4?±?1), patient's assessment of efficacy at Visit 3 (Day 10?±?2), and the frequency and type of adverse events.

Results: There was a significantly greater reduction of swelling from Visit 1 to Visit 2 with PN?+?Dx, and more patients rated the efficacy of PN?+?Dx as ‘very good’ or ‘good’ at Visit 3 (p?=?0.03). There was also a significantly greater decrease in the clinical symptom score from Visit 1 to Visit 2 in the PN?+?Dx group in patients who had at least a moderately severe symptom score with more than seven points at Visit 1 (p?=?0.01) and in patients suffering from their current episode of otitis externa for more than 2 days (p?=?0.02). In total, 14 adverse events were reported during the study period with no related adverse drug reactions for PN?+?Dx.

Conclusions: The addition of dexamethasone phosphate to polymyxin B/neomycin significantly reduces swelling in patients with AOE and leads to significantly higher patient's ratings of treatment efficacy. It especially leads to an overall reduction of symptoms in cases of moderately or more severe otitis externa and cases lasting for more than 2 days.     

Effects of safflower injection on the pharmacodynamics and pharmacokinetics of warfarin in rats

1.?Safflower injection (SI) is extracted from Chinese herbal medicine safflower that comprises many active components. Warfarin is a common anticoagulant and has exhibited drug interactions with several herbal products. This study aimed to investigate the effects of SI on pharmacodynamics and pharmacokinetics of warfarin in rats.

2.?Wistar rats were randomly divided into blank control group, SI group, warfarin control group and SI?+?warfarin group, respectively. In SI and SI?+?warfarin groups, rats were injected with SI (1.6?mL/kg/d, i.p.) for 14?days. Warfarin (0.2?mg/kg) was given orally on the eighth day. Saline was given as control. The blood samples were collected at various time points. Prothrombin time (PT) and activated partial thromboplastin time (APTT) were measured. UPLC-MS/MS was used to determine the plasma concentrations of S(R)-warfarin, and the pharmacokinetic parameters were calculated.

3.?PT, APTT in SI and SI?+?warfarin rats increased significantly compared with corresponding control rats. The pharmacokinetic parameters including C_max, t_1/2, AUC_0-t and AUC_0-∞ of S-warfarin and R-warfarin in SI?+?warfarin rats were higher than those in warfarin control rats.

4.?These findings suggest that SI significantly increases the anticoagulant effect of warfarin by affecting its pharmacodynamic and pharmacokinetic parameters.     

Effects of glycyrrhizin on the pharmacokinetics of asiatic acid in rats and its potential mechanism

Context: Asiatic acid has been reported to possess a wide range of pharmacological activities.

Objective: This study investigates the effects of glycyrrhizin on the pharmacokinetics of asiatic acid in rats and its potential mechanism.

Materials and methods: The pharmacokinetics of orally administered asiatic acid (20?mg/kg) with or without glycyrrhizin pretreatment (100?mg/kg/day for seven days) were investigated using a LC–MS method. Additionally, the Caco-2 cell transwell model and rat liver microsome incubation systems were used to investigate the potential mechanism of glycyrrhizin’s effects on the pharmacokinetics of asiatic acid.

Results: The results showed that the C_max (221.33?±?21.06 vs. 324.67?±?28.64?ng/mL), AUC_0–inf (496.12?±?109.31 vs. 749.15?±?163.95?μg·h/L) and the t_1/2 (1.21?±?0.27 vs. 2.04?±?0.32?h) of asiatic acid decreased significantly (p?p?Discussion and conclusions: In conclusion, these results indicated that glycyrrhizin could decrease the system exposure of asiatic acid, possibly by inducing the activity of P-gp or CYP450 enzyme.     

Changes in pharmacokinetic profiles of acetaminophen and its glucuronide after pretreatment with combinations of N-acetylcysteine and either glycyrrhizin,silibinin or spironolactone in rat

Abstract

1. The present study was to investigate the effects of giving N-acetylcysteine (NAC) alone and in combination with either glycyrrhizin (GL), silibinin (SIB) or spironolactone (SL) on the plasma pharmacokinetic (PK) profiles, hepatic exposure, biliary excretion and urinary excretion of acetaminophen (APAP) and its major metabolite, acetaminophen glucuronide (AG).

2. Groups of rats (n?=?5) were pretreated with oral doses of either NAC, NAC?+?GL, NAC?+?SIB or NAC?+?SL on five occasions every 12?h. At 1?h, after the last dose, they received APAP (200?mg/kg) by intraperitoneal injection. Blood, bile, liver and urine samples were collected at various times after APAP injection and analyzed for APAP and AG by HPLC. NAC alone and NAC?+?SIB did not significantly change the PK profiles of APAP and AG. In contrast, NAC?+?GL decreased the biliary excretion of APAP and AG leading to accumulation of APAP in the liver and systemic circulation whereas NAC?+?SL [multidrug resistance associated 2 (Mrp2) inducer] increased the biliary excretion of AG and decreased the hepatic exposure to APAP and AG.

3. Our results suggest that Mrp2 inhibitor GL should be discouraged with NAC to treat APAP hepatotoxicity. Such PK drug–drug interactions should be considered in the treatment of APAP-induced liver injury.     

Ameliorative effect of quercetin against arsenic-induced sperm DNA damage and daily sperm production in adult male rats

In this study, the protective effect of quercetin was evaluated against arsenic induced reproductive ailments in male rats. For this purpose, male rats (n?=?5/group) weighing 180–250?g were used. First group served as control, second group received arsenic (50?ppm) in drinking water. Third group was treated with quercetin (50?mg/kg) alone, while fourth group received arsenic?+?quercetin. All treatments were carried out for 49 days. After treatment, animals were killed by decapitation; testis and epididymis were dissected out. Right epididymis was minced immediately for comet assay, while left epididymis was processed for histology. Similarly, right testis was homogenized for estimation of daily sperm production (DSP) and detection of metal concentration. The results of our research revealed that arsenic treatment did not cause any significant change in body weight and testicular volume. Quercetin treatment significantly prevented tissue deposition of arsenic within the testis. Arsenic treatment caused a significant reduction in DSP, however, in the arsenic?+?quercetin-treated group and quercetin alone-treated group, DSP was significantly high as compared to the arsenic-treated group. Histological study of epididymis showed empty lumen in arsenic-treated group while in arsenic?+?quercetin-treated group and quercetin alone-treated group, lumen were filled with sperm and were comparable to control. Sperm DNA damage, induced by arsenic, was significantly reversed toward control levels by supplementation of quercetin. These results suggest that quercetin not only prevents deposition of arsenic in tissues, but can also protect the sperm DNA damage.     

Protective effect of MOTILIPERM in varicocele-induced oxidative injury in rat testis by activating phosphorylated inositol requiring kinase 1α (p-IRE1α) and phosphorylated c-Jun N-terminal kinase (p-JNK) pathways

Context: MOTILIPERM was prepared as a mixture of extracts of three medicinal herbs [roots of Morinda officinalis How (Rubiaceae), outer scales of Allium cepa L. (Liliaceae) and seeds of Cuscuta chinensis Lamark (Convolvulaceae)].

Objective: To investigate the role of reactive oxygen species (ROS)-based endoplasmic reticulum (ER) stress in a rat model of varicocele and the therapeutic efficacy of MOTILIPERM in this model.

Materials and methods: Sixty male rats were divided into five experimental groups: a normal control group (CTR?+?vehicle), a control group administered MOTILIPERM 200?mg/kg (CTR?+?M 200), a varicocele-induced control group (VC?+?vehicle) and two varicocele-induced groups administered MOTILIPERM 100 (VC?+?M 100) or 200 (VC?+?M 200) mg/kg for 4 weeks. Testis weights were recorded and serums were assayed for hormone concentrations. Tissues were subjected to semen analysis, histopathology, analyses of ER response protein expression levels and oxidative stress were assessed by measuring ROS, reactive nitrogen species (RNS), malondialdehyde (MDA) level and ratios of total glutathione (GSH)/oxidized GSH (GSSG).

Results: MOTILIPERM treatment of varicocele-induced groups significantly increased left testis weight, testosterone level, sperm motility, count and spermatogenic cell density. ER-response protein expression levels were dose-dependently decreased in VC?+?M 200 group compared with VC?+?vehicle group. MOTILIPERM treatment also decreased MDA and ROS/RNS level but increased GSH/GSSG ratio.

Discussion and conclusions: This study suggests that ROS-related ER stress may play a major role in varicocele-induced infertility and MOTILIPERM, a novel compound targeting ROS-based ER stress, may be therapeutically useful in treatment of varicocele, or as a supplement for the treatment of infertility.     

Potential mechanisms of neurobehavioral disturbances in mice caused by sub-chronic exposure to low-dose VOCs

Abstract

To investigate effects of neurobehavioral disturbances in mice caused by sub-chronic exposure to low-dose volatile organic compounds (VOCs) and the possible mechanism for these effects, 60 male Kunming mice were exposed in 5 similar static chambers, 0 (control) and 4 different doses of VOCs mixture (G1–4) for consecutively 90?d at 2?h/d. The concentrations of VOCs mixture were as follows: formaldehyde, benzene, toluene, and xylene 0.05?+?0.05?+?0.10?+?0.10?mg/m³, 0.10?+?0.11?+?0.20?+?0.20?mg/m³, 0.50?+?0.55?+?1.00?+?1.00?mg/m³, 1.00?+1.10?+?2.00?+?2.00?mg/m³, respectively, which corresponded to 1/2, 1, 5, and 10 times of indoor air quality standard in China. Morris water maze (MWM) and Grip strength (GS) test were performed in the last 7 weeks. One day following VOCs exposure, oxidative stress markers, neurotransmitters, and cholinergic system enzymes in brain were examined. In addition, the expressions of N-methyl-d-aspartate (NMDA) receptor in hippocampus were determined. VOCs exposure induced behavioral impairment of mice in MWM and GS test. The levels of reactive oxygen species (ROS), malondialdehyde (MDA) and glutamic acid (Glu) were significantly increased, while the acetylcholinesterase (AChE), choline acetyltransferase (ChAT) and acetylcholine (ACh) levels, and the expression of NMDA receptor were significantly decreased in VOCs exposed groups. Results showed that sub-chronic exposure to low-dose VOCs induced damage on physique and motor function, as well as impairment on learning and memory capacity of mice. Oxidative damage, abnormal metabolism of neurotransmitters and cholinergic system enzymes, and the alternation of NMDA receptor expression may be the possible mechanism for VOCs-induced neurotoxicity.     

The acute effects of waterpipe smoking on lung function and exercise capacity in a pilot study of healthy participants

Abstract

Context: Waterpipe tobacco smoking (WTS) has gained popularity, but its physiologic effects have not been extensively studied: rather, studies have focused on WTS’s chronic effects or have evaluated limited respiratory/cardiac parameters.

Objective: We sought to characterize in a more detailed manner the acute effects of WTS on lung function and exercise capacity.

Method: We recruited 24 healthy WTS males. We used a pilot single-group pre-test (abstained from WTS for ≥48?h) post-test (within 0.5?h of a 45-min WTS session) design. We performed spirometry, diffusing lung capacity and time-limited CPE testing (CPET; cycloergometer; 2-min 20-Watt warm-up and 25-Watt increase every 2-min for 10?min).

Results: Mean age was 20.4 years; Post-WTS, the following significant changes were observed: CO level increased from 3.7?ppm to 24.4; oxygen consumption decreased (from 1.86?L/min to 1.7); baseline respiratory rate increased (from 17.7 breath/min to 19.7); forced expiratory flow over the middle half of the forced vital capacity decreased (from 5.51?L to 5.29); and perceived exertion (measured by Borg scale) at mid and peak exercise increased. Baseline resting systolic blood pressure, pulse pressure, and pulse pressure product increased post-WTS (from 118.9?mmHg to 129.2; from 45.3?mmHg to 55.6; and from 9.9?mmHg/min to 11.1 post-WTS, respectively). During exercise, a decrease in oxygen pulse was observed post-WTS (from 10.89?ml/beat to 9.97), while the heart rate-oxygen consumption relationship increased post-WTS (from 3.52 beats/ml/kg to 3.91).

Conclusion: Acute WTS appears to induce impairment in lung function and exercise capacity. Larger studies are warranted to further characterize the nature and extent of such impairment.     

Protective effect of Pycnogenol on cisplatin-induced ototoxicity in rats

Context: Pycnogenol^®, which is French maritime pine bark extract, is a potent antioxidant. It is used in medical conditions caused by oxidative stress. Cisplatin (cis-diamminedichloroplatinum II) is an antineoplastic agent. However, its serious side effects such as ototoxicity limit its usage.

Objective: Antioxidants can be used to prevent ototoxicity. We investigated the effect of Pycnogenol^® on cisplatin-induced ototoxicity.

Materials and methods: Rats were randomly assigned to four groups of five. Distortion product-evoked otoacoustic emissions (DPOAE) test was performed for each rat. The experimental groups were as follows: Control Group, Pycnogenol^® Group: 10?mg/kg Pycnogenol^® intraperitoneally for 7 days, Cisplatin Group: intraperitoneally 15?mg/kg single injection of cisplatin on the fifth day, Cisplatin?+?Pycnogenol^® Group: intraperitoneally 10?mg/kg Pycnogenol^® treatment for 7 days, additionally on the fifth day, 15?mg/kg single injection of cisplatin was given. On the eighth day, DPOAE was re-performed and rats were sacrificed. Apoptosis was evaluated histopathologically.

Results: Mean percentage of apoptotic cells was 1.5, 3, 30 and 11% in organ of Corti and 2, 2, 40, 15% in spiral ganglion neurons in Control Group, Pycnogenol^® Group, Cisplatin Group and Cisplatin?+?Pycnogenol^® Group, respectively. Cisplatin Group and Cisplatin?+?Pycnogenol^® Group were significantly different when compared to Control Group histopathologically both in organ of Corti and spiral ganglion neuron (p?<0.001, p?=?0.019, p?=?0.001, p?=?0.015). DPOAE results showed that Cisplatin?+?Pycnogenol^® Group was significantly different when compared to Cisplatin Group at 3, 6 and 8?kHz (p?<?0.05).

Conclusion: Pycnogenol protected against cisplatin ototoxicity. Also, pycnogenol is not ototoxic.