Differential mRNA expression of acetylcholinesterase in the central nervous system of rats with acute and chronic exposure of sarin & physostigmine

A time‐course study was carried out to measure the acetylcholinesterase (AChE) gene expression in the brain of female rats exposed to different doses of sarin and physostigmine. Short‐term effects were studied with an acute single subcutaneous dose (s.c.) of 80 µg kg^?1 (0.5 × LD₅₀) sarin. Cortex and cerebellum showed a significant decline in AChE mRNA expression at 2.5, 24 and 72 h. Biochemical studies showed that plasma butrylcholinesterase (BChE) and brain AChE activities were significantly decreased at 2.5 h, which came back to near control values by 24 h in both cases. For long‐term chronic studies, three groups of female rats received daily doses of physostigmine (0.1 mg kg^?1 day^?1) intramuscularly (i.m.), sarin (15 µg kg^?1 day^?1) s.c. independently and a combined dose of physostigmine (i.m.) (0.1 mg kg^?1 day^?1) followed by sarin (s.c.) (15 µg kg^?1 day^?1) continuously for 30 days. Differential AChE mRNA levels in cortex and cerebellum of rat brain were observed after 30 days and after a lag period of another 30 days with no further administration. Plasma (BChE) and brain (AChE) showed irregular inhibition profile in biochemical studies at 30 days and returned to control levels after 60 days. The acute single subcutaneous administration of sarin for short‐term as well as chronic long‐term studies showed that AChE inhibition alone does not lead to observed changes in mRNA expression of AChE gene. These observations further suggest that route of administration as well as dose exposure regimen also contributes to the regulation of AChE mRNA expression. Copyright © 2009 John Wiley & Sons, Ltd.     

Increased expression of the testicular estrogen receptor alpha in adult mice exposed to low doses of methiocarb

Methiocarb is a widely used carbamate pesticide and a suspected endocrine disrupter. The objective of this study was to examine the in vivo effects of methiocarb at low doses on testicular expression of steroid receptors, spermatogenesis and sperm quality in adult mice. Eighteen‐week‐old DBA/2 males were treated with daily intraperitoneal injection of methiocarb (0, 0.03, 0.3, 1.0 or 3.0 µg kg^?1 of body weight) for 20 days. Kidney and liver weights were significantly increased in the 1.0 or 3.0 µg kg^?1 treatment groups (P < 0.05). The testicular expression of estrogen receptor α (ERα) was significantly increased in mice treated with methiocarb as confirmed by Western blot analysis. The sperm production and sperm quality of the methiocarb‐exposed mice were not significantly altered as determined using a computer‐assisted sperm analysis system. Therefore, these results demonstrate, that although the exposure to methiocarb at low doses alters testicular ERα expression in adult mice, both sperm production and quality remain unaffected. Copyright © 2009 John Wiley & Sons, Ltd.     

Evaluation of cytotoxic concentration–time response in A549 cells exposed to respirable α‐quartz

A causal pathway between quartz, silicosis and lung cancer has been postulated. The aim of our study was to assess cytotoxic effects induced in a human lung epithelial cell line (A549) by exposure to α‐quartz. Cells were exposed to respirable α‐quartz (SRM1878a, NIST) at 25, 50 or 100 µg ml^?1 for 24 h and at 50 or 100 µg ml^?1 for 48 h. Cytotoxic effects were analyzed by scanning electron microscopy (SEM), apoptotic morphology analysis with Hoechst staining and lactate dehydrogenase (LDH) release assay. In cells exposed to α‐quartz for 24 h, a concentration‐dependent bleb development and in particular the localization of blebs at the cell edge at higher concentrations were observed. The blebbing phenomenon was more evident after 48 h of exposure to 50 or to 100 µg ml^?1 of α‐quartz and large blebs were localized at the cell edge. At the same concentrations surface smoothing was also observed. Moreover the presence of holes and tears was detected at the highest concentration both at 24 and 48 h. Results of morphological analysis with Hoechst stain evidenced an increase concentration–time dependent of apoptotic cell percentage that was more marked after 48 h exposure to 100 µg ml^?1 and a prevalence of late apoptosis stage with the increase of exposure time and concentration. Cells exposed to 50 or 100 µg ml^?1 of α‐quartz for 24 and 48 h produced a significant increase in LDH release. The concentration–time‐dependent bleb induction evidenced by SEM correlates with the increase of apoptotic cells and LDH activity release, demonstrating the onset of cytotoxic effects in human lung cells exposed to α‐quartz. Copyright © 2009 John Wiley & Sons, Ltd.     

Selective blockade of mGlu5 metabotropic glutamate receptors is hepatoprotective against fulminant hepatic failure induced by lipopolysaccharide and d‐galactosamine in mice

This study was designed to investigate the influence of 2‐methyl‐6‐phenylethynyl pyridine hydrochloride (MPEP), an antagonist of metabotropic glutamate receptor subtype 5, in lipopolysaccharide (LPS) and d‐ galactosamine (d‐ GalN)‐induced fulminant hepatic failure in mice. Mice were given an intraperitoneal injection of 50 µg kg^?1 LPS and 500 mg kg^?1 d‐ GalN. MPEP (1, 5 and 25 mg kg^?1) was administered intraperitoneally 1 h before LPS/d‐ GalN injection. Twenty‐four hours after administration of LPS/d‐ GalN, plasma was collected and used for biochemical assays. Mice were euthanized and histological analysis and toxicological parameters were carried out in the liver. MPEP, at all doses tested, protected against the increase in aspartate and alanine aminotransferase activities induced by LPS/d‐ GalN exposure. Ascorbic acid levels were not altered in all experimental groups. Glutathione S‐transferase activity was increased by administration of LPS/d‐ GalN and MPEP did not modify the enzyme activity in mice. MPEP, at the doses of 5 and 25 mg kg^?1, was effective in protecting against the decrease in catalase activity caused by LPS/d‐ GalN administration in mice. The histological data showed that sections of liver from LPS/d‐ GalN‐exposed mice presented extensive injuries. MPEP, at all doses tested, reduced the scores of liver damage and markedly ameliorated the degree of liver damage. The hepatoprotective effect of MPEP on fulminant hepatic failure induced by LPS and d‐ GalN in mice was demonstrated. Copyright © 2009 John Wiley & Sons, Ltd.     

Subchronic hepatotoxicity evaluation of bromobenzene in Fischer 344 rats

Male Fischer 344 (F344) rats were exposed to bromobenzene (BB) for 5 days and 2, 4 and 13 weeks. BB was administered by gavage (corn oil vehicle) at doses of 0, 25, 100, 200, 300 and 400 mg kg^?1 per day. Endpoints evaluated included clinical observations, body weights, liver weights, serum chemistry, blood BB, gross pathology and liver histopathology. There were no BB exposure‐related clinical signs of toxicity. Mean body weight decreased by 5–10% compared with control in the 400 mg kg^?1 per day group. Liver weight increases were dose‐ and exposure time‐related and statistically significant at ≥25 mg kg^?1 per day. Incidence and severity of centrilobular cytoplasmic alteration and hepatocyte hypertrophy were related to dose and exposure time. At early time points (5 days and 2 weeks), centrilobular inflammation, including granulomatous areas, and necrotic and anisokaryocytic hepatocytes were observed in rats of the two highest BB dose groups. Blood BB concentrations increased linearly with dose and at 13 weeks ranged from 8 to 136 µg ml^?1 (25–400 mg kg^?1 per day). In conclusion, rats administered BB doses up to 400 mg kg^?1 per day for up to 13 weeks had mild liver effects. A NOAEL of 200 mg kg^?1 per day was selected based on the statistically significant incidence of hepatocyte hypertrophy at doses ≥ 400 mg kg^?1 per day. Copyright © 2012 John Wiley & Sons, Ltd.     

Urinary levels,tissue concentrations and lung inflammation after nose‐only exposure to three different chemical forms of beryllium

This study aimed to determine the toxicity and toxicokinetic of three Be chemical species A total of 120 mice (four groups of 30) were nose‐only exposed. The first group was used as a control while the three others were exposed to 250 μg m^?3 of fine particles of three different Be species (Be metal, Be–F; Be oxide, BeO–F; Be aluminium, BeAl–F). Exposure lasted over three consecutive weeks, five days per week and 6 h per day. Blood and several tissues were collected one week after exposure. Urines were collected before the beginning of exposure, at the end of every week of exposure and one week after exposure. Results showed that urine concentrations were different from one Be species to another and that excretion continued after the end of exposure. Except for BeO–F, where Be urine concentrations were stable during the three weeks of exposure, concentrations of Be–F and BeAl–F reached a peak after the first week. According to particle size, BeO–F obtained the highest theoretical pulmonary deposition rate, which partially led to the highest Be lung concentration. This group also presented the lowest urine concentration but that did not lead to more severe lung inflammation. Moreover, even if BeAl–F obtained the lowest percentage theoretical pulmonary deposition, it showed the highest Be urinary concentration, the lowest Be lung concentration and the lowest lung toxicity. In this specific case, a high Be concentration in urine did not reflect a high exposure or a severe toxic effect. Copyright © 2010 John Wiley & Sons, Ltd.     

Toxicokinetic study of melamine in the presence and absence of cyanuric acid in rats

Several lines of evidence show that the nephrotoxic effect of melamine (MEL) in animals is consistent with combined ingestion of MEL and cyanuric acid (CYA). The aim of the present study was to compare the toxicokinetics of MEL in the presence and absence of CYA, and to elucidate the correlation between toxicity and kinetic properties of MEL. Sprague–Dawley rats were administered a single oral dose of MEL (100 mg kg^?1) with or without CYA (100 mg kg^?1). Plasma and tissue samples were analyzed by liquid chromatography–tandem mass spectrometric (LC–MS/MS) assay. Significant changes in toxicokinetic parameters of MEL such as lower maximum concentration (7.4 ± 3.5 vs 78.0 ± 11.0 µg ml^?1) and area under curve (94.9 ± 53.5 vs 295.1 ± 93.7 µg h ml^?1), higher plasma elimination half‐life (7.0 ± 3.3 vs 2.5 ± 0.3 h) and volume of distribution (11 505.5 ± 5030.3 vs 1312.7 ± 337.7 ml kg^?1), as well as significantly higher concentration of MEL in rat kidney (2.96–274.15 vs < 1 µg g^?1) were detected in the CYA co‐administration group when compared with MEL alone group (P < 0.05). The differences in kinetic parameters between the two groups meant that CYA co‐administration could lower absorption, slow excretion and induce tissue accumulation of MEL, which correlated well with the generation and development of renal toxicity. In conclusion, co‐administration with CYA leads to the alteration of the kinetic characteristics of MEL, which provides an additional explanation for renal toxicity. Copyright © 2011 John Wiley & Sons, Ltd.     

Lack of interaction between metoclopramide and morphine in vitro and in mice

1.?This study examined interactions via common metabolism or via common pharmacodynamic pathways between frequently co-prescribed metoclopramide (a prokinetic) and morphine (an opioid analgesic).

2.?In human liver microsomes, morphine 3-glucuronide and morphine 6-glucuronide formation had V_max estimates of 6.2 ± 0.07 and 0.75 ± 0.01 (nmole min^?1 mg^?1 protein) and K_m estimates of 1080 ± 37 and 665 ± 55 (µM), respectively. The in vitro K_i for morphine 3-glucuronide formation in the presence of metoclopramide in human liver microsomes or recombinant uridine diphosphoglucuronosyltransferase 2B7 predicted a lack of in vivo interaction.

3.?Morphine (2 mg kg^?1 subcutaneously) delayed gastrointestinal meal transit in mice, metoclopramide (10 mg kg^?1 subcutaneously) had no effect on meal transit, and metoclopramide did not alter this effect of morphine.

4.?Morphine (2 or 5 mg kg^?1 subcutaneously) was antinociceptive in mice (hot plate test) and metoclopramide (10 mg kg^?1 subcutaneously) did not alter the antinociceptive effects of morphine.

5.?Together, the data suggest a lack of interaction between morphine and metoclopramide.     

EBHU18, a novel derivative of fatty acid bile acid conjugates, prevents cholesterol gallstone formation in experimental mice

In this study, we tested whether the oral administration of EBHU18, one of the newly synthesized fatty acid bile acid conjugates (FABACs), was able to prevent the development of cholesterol gallstones. In the first study, gallstone-susceptible C57BL/6 mice were fed a lithogenic diet for 8?weeks, and then treated with ursodeoxycholic acid (UDCA, 10?mg?kg^?1?day^?1, i.g.), EBHU18-L (0.5?mg?kg^?1?day^?1 i.g.), or EBHU18-H (3?mg?kg^?1?day^?1 i.g.). In the second study, C57BL/6 mice were fed the lithogenic diet for 8?weeks and then treated with EBHU18 at a daily dose of 3?mg (EBHU18-H) or 0.5?mg (EBHU18-L) or with 10?mg of UDCA for another 8?weeks. Pre-treatment or post-treatment with EBHU18 at 3?mg?kg^?1?day^?1 significantly decreased gallstone formation and the fatty liver score. In the first study, EBHU18-H significantly decreased gallstone formation compared with the control animals. The fatty liver score decreased from a mean of 1.6?±?1.02 in the controls to 0.5?±?0.67 in the EBHU18-L group (P?<?0.05) and 0.3?±?0.64 in the EBHU18-H group (P?<?0.01). In the second study, the drug significantly lowered the gallstone formation rate in the EBHU18-H group. The fatty liver score decreased from a mean of 1.6?±?0.98 in the controls to 0.67?±?0.90 in the EBHU18-L group (P?<?0.05) and 0.4?±?0.74 in the EBHU18-H group (P?<?0.01). EBHU18 can prevent and reduce gallstone formation and/or fatty liver and can be developed as a potential therapeutic candidate for anti-gallstone therapy.     

The anti-tumor effect of folate-targeted liposome microbubbles loaded with oridonin as ultrasound-triggered tumor-targeted therapeutic carrier system

In this study, folate receptor (FR) targeted liposome microbubbles loaded with oridonin (ORI) (F-LMB-ORI), liposome loaded with ORI (L-ORI) and liposome microbubbles loaded with ORI (LMB-ORI) were prepared. In vitro release properties, cellular uptake and cytotoxicity in HepG-2 cells as well as in vivo antitumor effects in HepG-2 cells tumor-bearing mice of F-LMB-ORI, L-ORI and LMB-ORI were evaluated upon ultrasound exposure. Results showed cytotoxicity assay on F-LMB-ORI gave IC₅₀ of 0.508?±?0.018?µmol/mL on HepG-2 cells and LMB-ORI; L-ORI gave IC₅₀ of 2.424?±?0.116?µmol/mL, 3.031?±?0.122?µmol/mL in vitro, respectively. These drug delivery carriers were able to control the release of ORI. F-LMB-ORI exhibited higher binding to HepG-2 cells in comparison to LMB-ORI and L-ORI. F-LMB-ORI improved antitumor activity of ORI obviously in comparison to L-ORI, LMB-ORI under in vivo ultrasound. After the treatment for 14 d, the tumor inhibition ratio for F-LMB-ORI (the dose of ORI: 1.5?×?10^?2?g·kg^?1, once a day) was 87.6%, obviously higher than that of LMB-ORI group, L-ORI group and free ORI (the dose of ORI: 1.5?×?10^?2?g·kg^?1, once a day) which were 71.5%, 64.3% and 43.4%, respectively.     

Influence of ketanserin on the effects of methylenedioxymethamphetamine on body temperature in the mouse

相似文献   

ROLE OF EXTRACELLULAR Na+, Ca2+-ACTIVATED Cl- CHANNELS AND BK CHANNELS IN THE CONTRACTION OF Ca2+ STORE-DEPLETED TRACHEAL SMOOTH MUSCLE

• 1 In the present study, we investigated the series of events involved in the contraction of tracheal smooth muscle induced by the re‐addition of Ca²⁺ in an in vitro experimental model in which Ca²⁺ stores had been depleted and their refilling had been blocked by thapsigargin.
• 2 Mean (±SEM) contraction was diminished by: (i) inhibitors of store‐operated calcium channels (SOCC), namely 100  µ mol/L SKF‐96365 and 100  µ mol/L 1‐(2‐trifluoromethylphenyl) imidazole (to 66.3 ± 4.4 and 41.3 ± 5.2% of control, respectively); (ii) inhibitors of voltage‐gated Ca²⁺ channels Ca_V1.2 channels, namely 1  µ mol/L nifedipine and 10  µ mol/L verapamil (to 86.2 ± 3.4 and 76.9 ± 5.9% of control, respectively); and (iii) 20  µ mol/L niflumic acid, a non‐selective inhibitor of Ca²⁺‐dependent Cl^? channels (to 41.1 ± 9.8% of control). In contrast, contraction was increased 2.3‐fold by 100 nmol/L iberiotoxin, a blocker of the large‐conductance Ca²⁺‐activated K⁺ (BK) channels.
• 3 Furthermore, contraction was significantly inhibited when Na⁺ in the bathing solution was replaced by N‐methyl–d ‐glucamine (NMDG⁺) to 39.9 ± 7.2% of control, but not when it was replaced by Li⁺ (114.5 ± 24.4% of control). In addition, when Na⁺ had been replaced by NMDG⁺, contractions were further inhibited by both nifedipine and niflumic acid (to 3.0 ± 1.8 and 24.4 ± 8.1% of control, respectively). Nifedipine also reduced contractions when Na⁺ had been replaced by Li⁺ (to 10.7 ± 3.4% to control), the niflumic acid had no effect (116.0 ± 4.5% of control).
• 4 In conclusion, the data of the present study demonstrate the roles of SOCC, BK channels and Ca_V1.2 channels in the contractions induced by the re‐addition of Ca²⁺ to the solution bathing guinea‐pig tracheal rings under conditions of Ca²⁺‐depleted sacroplasmic reticulum and inhibition of sarcoplasmic/endoplasmic reticulum calcium ATPase. The contractions were highly dependent on extracellular Na⁺, suggesting a role for SOCC in mediating the Na⁺ influx.

     

Pharmacokinetic study of two acetylcholinesterase reactivators, trimedoxime and newly synthesized oxime K027, in rat plasma

K027 [1‐(4‐hydroxyiminomethylpyridinium)‐3‐(4‐carbamoylpyridinium)–propane dibromide] is a promising new reactivator of organophosphate‐ or organophosphonate‐inhibited acetylcholinesterase (AChE) with low acute toxicity and broad spectrum efficacy. The aim of the present study was to compare the pharmacokinetics of both compounds. Male Wistar rats (body weight = 320 ± 10 g) were administered a single intramuscular dose of K027 (22.07 mg kg^?1) and an equimolar dose of trimedoxime. Blood was collected at various time intervals until 180 min. Plasma samples were analyzed by reversed‐phase HPLC with ultraviolet (UV) detection. The recovery of both oximes from the plasma was approximately 90% and a linear relationship (R² > 0.998) was observed between the peak areas and concentrations of calibrated standards in the range 1–100 µg ml^?1. Near‐identical plasma profiles were obtained for both compounds. No differences were found in the mean ± SD values of C_max (18.6 ± 2.5 vs 20.0 ± 6.3 µg ml^?1, P = 0.72) and AUC_0–180min (2290 ± 304 vs 2269 ± 197 min µg ml^?1, P = 0.84). However, the percentage coefficient of variation of the first‐order rate constant of absorption (k_a) was 3‐fold higher (P < 0.01) providing evidence for more erratic absorption of intramuscular trimedoxime as compared with K027. In conclusion, oxime K027 might have superior pK properties that may be translated in its faster absorption and subsequent tissue distribution. Copyright © 2011 John Wiley & Sons, Ltd.     

Integration of mechanistic and pharmacokinetic information to derive oral reference dose and margin‐of‐exposure values for hexavalent chromium

The current US Environmental Protection Agency (EPA) reference dose (RfD) for oral exposure to chromium, 0.003 mg kg^?1 day^?1, is based on a no‐observable‐adverse‐effect‐level from a 1958 bioassay of rats exposed to ≤25 ppm hexavalent chromium [Cr(VI)] in drinking water. EPA characterizes the confidence in this RfD as “low.” A more recent cancer bioassay indicates that Cr(VI) in drinking water is carcinogenic to mice at ≥30 ppm. To assess whether the existing RfD is health protective, neoplastic and non‐neoplastic lesions from the 2 year cancer bioassay were modeled in a three‐step process. First, a rodent physiological‐based pharmacokinetic (PBPK) model was used to estimate internal dose metrics relevant to each lesion. Second, benchmark dose modeling was conducted on each lesion using the internal dose metrics. Third, a human PBPK model was used to estimate the daily mg kg^?1 dose that would produce the same internal dose metric in both normal and susceptible humans. Mechanistic research into the mode of action for Cr(VI)‐induced intestinal tumors in mice supports a threshold mechanism involving intestinal wounding and chronic regenerative hyperplasia. As such, an RfD was developed using incidence data for the precursor lesion diffuse epithelial hyperplasia. This RfD was compared to RfDs for other non‐cancer endpoints; all RfD values ranged 0.003–0.02 mg kg^?1 day^?1. The lowest of these values is identical to EPA's existing RfD value. Although the RfD value remains 0.003 mg kg^?1 day^?1, the confidence is greatly improved due to the use of a 2‐year bioassay, mechanistic data, PBPK models and benchmark dose modeling.     

Protective effects of lemongrass (Cymbopogon citratus STAPF) essential oil on DNA damage and carcinogenesis in female Balb/C mice

This study investigated the protective effect of oral treatment with lemongrass (Cymbopogon citratus STAPF) essential oil (LGEO) on leukocyte DNA damage induced by N‐methyl‐N‐nitrosurea (MNU). Also, the anticarcinogenic activity of LGEO was investigated in a multi‐organ carcinogenesis bioassay induced by 7,12‐dimethylbenz(a)antracene, 1,2‐dimethylhydrazine and N‐butyl‐N‐(4‐hydroxibuthyl)nitrosamine in Balb/C female Balb/c mice (DDB‐initiated mice). In the short‐term study, the animals were allocated into three groups: vehicle group (negative control), MNU group (positive control) and LGEO 500 mg kg^?1 (five times per week for 5 weeks) plus MNU group (test group). Blood samples were collected to analyze leukocyte DNA damage by comet assay 4 h after each MNU application at the end of weeks 3 and 5. The LGEO 500 mg kg^?1 treated group showed significantly lower (P < 0.01) leukocyte DNA damage than its respective positive group exposed to MNU alone at week 3. In the medium‐term study, DDB‐initiated mice were allocated into three groups: vehicle group (positive control) and LGEO 125 or 500 mg kg^?1 (five times per week for 6 weeks; test groups). At week 20, all animals were euthanized and mammary glands, colon and urinary bladder were processed for histopathological analyses for detection of preneoplastic and neoplastic lesions. A slight non‐significant effect of treatment with LGEO 500 mg kg^?1 in reducing development of alveolar and ductal mammary hyperplasia was found (P = 0.075). Our findings indicate that lemongrass essential oil provided protective action against MNU‐induced DNA damage and a potential anticarcinogenic activity against mammary carcinogenesis in DDB‐initiated female Balb/C mice. Copyright © 2010 John Wiley & Sons, Ltd.     

The adverse effects of low‐dose exposure to Di(2‐ethylhexyl) phthalate during adolescence on sperm function in adult rats

Di(2‐ethylhexyl) phthalate (DEHP) is the most crucial phthalate derivative added to polyvinyl chloride as a plasticizer. This study examined the effects of low‐dose exposure to DEHP during adolescence on sperm function in adult rats. The male rats were daily gavaged with 30, 100, 300, and 1000 µg kg^?1 of DEHP or corn oil from postnatal day (PND) 42 until PND 105. The selection of DEHP doses ranged from the mean daily intake by the normal‐population exposure levels to no‐observed‐adverse‐effect level of DEHP for the endpoints evaluated until adulthood. Significant increases in the percentage of sperm with tail abnormality, tendency for sperm DNA fragmentation index (DFI) and percentage of sperm with DFI were found in those exposed to 100, 300, and 1000 µg kg^?1 (P < 0.05). We observed a significant increase of hydrogen peroxide (H₂O₂) generation in the sperm of the 1000 µg kg^?1 group compared with the control group (P < 0.05). The excessive production of sperm H₂O₂ coincided with an increase in sperm DFI. In this study, the lowest‐observed‐adverse‐effect level for sperm toxicity was considered to be 100 µg DEHP/kg/day in sperm morphology and chromatin DNA damage. Further research is necessary to clarify the mechanisms of DEHP‐related sperm ROS generation on sperm DNA damage. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 706–712, 2016.     

Natural Products: Anti-hyperalgesic Effect of an Ethanolic Extract of Propolis in Mice and Rats

Propolis, or bee glue, which contains a complex mixture of secondary metabolites, has long been used in many countries for the management of several diseases. The purpose of this study was to evaluate, by means of several pharmacological models, the anti-hyperalgesic effect of propolis collected in the south of Brazil. The abdominal constrictions induced in mice by intraperitoneal injection of acetic acid (0.6%), kaolin (50 mg kg^?1) or zymosan (40 mg kg^?1) were inhibited to different extents by an extract of propolis (1–60 mg kg^?1) administered intraperitoneally 30 min earlier; mean ID50 (concentrations resulting in 50% inhibition) values were 2.7, 10.8 and 10.7 mg kg^?1, respectively, and maximum inhibition was 58 ± 5, 57 ± 10 and 51 ± 5%, respectively. Given orally (25–200 mg kg^?1, 1 h previously) propolis also inhibited the abdominal constrictions induced by acetic acid (maximum inhibition 43 ±5%). When injected intraperitoneally (3–60 mg kg^?1, 30 min previously), propolis attenuated both the neurogenic (first phase) and inflammatory (second phase) pain responses and paw oedema caused by intraplantar injection of formalin (2.5%); maximum inhibition was 32 ±5, 43 ±6 and 19 ±2%, respectively. Oral administration of propolis (25–200 mg kg^?1, 1 h previously) inhibited both phases and reduced the oedema formation associated with the second phase of the formalin test (maximum inhibition 22±5, 33 ±6 and 26±3%) and extract of propolis (3–30 mg kg^?1 i.p. or 25–100 mg kg^?1 p.o., respectively 30 min and 1 h previously) significantly inhibited capsaicin-induced pain with maximum inhibition of 39±8 and 41 ±8%, respectively. When assessed in the Randall–Sellito test of pain, the extract of propolis (3–30 mg kg^?1, i.p., 30 min previously) significantly reversed the hyperalgesia induced by intraplantar injection of bradykinin (3 nmol per paw) in rats (P < 0.01). In contrast with morphine the extract of propolis (. 100 mg kg^?1, 30 min previously) was ineffective when assessed in the tail-flick and hot-plate thermal assays. Naloxone (5 mg kg^?1 i.p.) reversed (P < 0.01) the effect of morphine (5 mg kg^?1 s.c.) by 70 and 94% respectively in the first and second phases of the formalin test, but did not interfere with the analgesic effect of propolis (10 mg kg^?1 i.p., 30 min previously). These results show that ethanolic extract of propolis, given systemically, has significant anti-hyperalgesic action when assessed in chemical, but not thermal, models of nociception in mice and rats. Its analgesic action seems to be unrelated to release or activation of the opioid system.     

Modulation of aryl hydrocarbon receptor‐regulated genes by acute administration of ammonium metavanadate in kidney,lung and heart of C57BL/6 mice

We recently reported that vanadium (V⁵⁺) was able to decrease the 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD)‐mediated induction of Cyp1a1 and Nqo1 at mRNA, protein and catalytic activity levels in mouse hepatoma Hepa 1c1c7 and human hepatoma HepG2 cells. However, little is known regarding the in vivo effects. Thus, the objective of this study was to investigate whether similar effects would occur at the in vivo level. Therefore, we examined the effect of exposure to V⁵⁺ (5 mg kg^?1) with or without TCDD (15 µg kg^?1) on the AhR‐regulated genes in kidney, lung and heart of C57BL/6 J mice. Our results demonstrated that V⁵⁺ alone significantly decreased Cyp1b1 protein and catalytic activity levels in kidney at 24 h. Moreover, it significantly potentiated Nqo1 and Gsta1 gene expression in the heart, and only Gsta1 gene expression in the lung. Upon co‐exposure, we found that V⁵⁺significantly inhibited the TCDD‐mediated induction of Cyp1a1, Cyp1a2 and Cyp1b1 mRNA, protein and catalytic activity levels in the kidney at 24 h. On the other hand, V⁵⁺ significantly potentiated the TCDD‐mediated induction of Nqo1 and Gsta1 protein and activity levels in the kidney. Cyp1a1, Cyp1b1, Nqo1 mRNA, protein and catalytic activity levels in the lung were significantly potentiated at 6 h. Interestingly, all tested genes in the heart were significantly decreased at 6 h with the exception of Gsta1 mRNA. The present study demonstrates that V⁵⁺ modulates TCDD‐induced AhR‐regulated genes. Furthermore, the effect on one of these enzymes could not be generalized to other enzymes even if it was in the same organ. Copyright © 2012 John Wiley & Sons, Ltd.     

Chronic trimethyltin chloride exposure and the development of kidney stones in rats

We recently reported that occupational exposure to trimethyltin (TMT) is a risk factor for developing kidney stones. To further examine the association between TMT exposure and the formation of kidney stones, we conducted a 180‐day animal study and exposed the randomly grouped Sprague–Dawley (SD) rats to TMT in the drinking water at doses of 0, 8.2, 32.8 and 131.3 µg kg^–1 day^–1. Transient behavioral changes were observed in the high‐dose group during the first 2 weeks of exposure. TMT exposure led to a significant dose‐dependent inhibition of renal H⁺/K⁺‐ATPase and an increase in urinary pH. In comparison to no kidney stones being identified in the control and the lowest dose group, 1 rat in the 32.8 µg kg^–1 day^–1 dose group and 3 out of 9 rats in the 131.3 µg kg^–1 day^–1 dose group were found to have stones in the kidney/urinary tract. Pathological analysis showed that more wide spread calcium disposition was observed in kidneys of rats with TMT exposure compared with the rats in the control group. However, X‐ray diffraction (XRD) analysis found that the kidney stones were mainly composed of struvite with the formula: NH4MgPO4 6H₂O, while calcium‐containing components were also detected. Together, this study further demonstrates through animal studies that chronic exposure to a relatively low level of TMT induces nephrotoxicity and increases the risk for developing kidney stones. Copyright © 2014 John Wiley & Sons, Ltd.