Toxicity value for 3-monochloropropane-1,2-diol using a benchmark dose methodology

3-Monochloropropane-1,2-diol (α-chlorohydrin, 3-MCPD) is a well-known contaminant that has been detected in a wide range of foods, and that is principally generated in foods prepared by hydrochloric acid hydrolysis, such as acid-hydrolyzed vegetable protein (acid-HVP). 3-MCPD is nephrotoxic to animals at high doses and induced tumors in some organs in both sexes of rodents. NITR have recently reported on the carcinogenicity of 3-MCPD in SD rats that were exposed for 2 years to drinking water. We considered that the kidney was the main target organ for 3-MCPD in SD rats and that renal tubular hyperplasia was the most sensitive endpoint. Benchmark dose analysis of the dose–response data for renal tubular hyperplasia in male and female rats exposed to 3-MCPD in drinking water for 2 years was conducted. We applied this to the benchmark dose (BMD) methodology to yield a point of departure for developing tolerable daily intakes (TDIs). The calculated BMDs and lower-bound confidence limits (BMDLs) for the critical endpoint were estimated using the seven different models. Predicted doses associated with 10% extra risk were calculated. The smallest Akaike’s Information Criterion (AIC) was used in selecting the appropriate model. The model chosen by AIC for males was the logistic and for females it was the multistage. In summary, the predicted BMD₁₀ and BMDL₁₀ were 1.21 mg/kg bw/day and 0.87 mg/kg bw/day for the male rat incidence data, and values for female rats were 26.31 mg/kg bw/day and 19.47 mg/kg bw/day. In this study, the BMDL₁₀ of 0.87 mg/kg bw/day for male rats was suggested as the point of departure for deriving the human tolerable daily intake level of 3-MCPD.     

Differential expression of neuronal and inducible nitric oxide synthase in rat brain after subchronic administration of 3-monochloro-1,2-propanediol.

The compound 3-monochloro-1,2-propanediol (3-MCPD) is a contaminant of acid-hydrolyzed vegetable protein foodstuffs. Several reports have suggested that chronic exposure to 3-MCPD can produce neurotoxicity or neurobehavioral effects in experimental animals. We sought to further explore the neurotoxic effects of 3-MCPD (10 or 30 mg/kg) administered for 13 weeks on the expression of two forms of nitric oxide synthase (NOS), neuronal NOS (nNOS), and inducible NOS (iNOS), in rat cerebral cortex and striatum. Using immunocytochemistry, the number of nNOS-expressing neurons or the optical density of iNOS staining in sections from three coronal levels (bregma 1.0, -0.4, and -2.3 mm) were compared between 3-MCPD-treated and control rats. At bregma level 1.0 mm, the number of nNOS-expressing neurons was significantly decreased in the 10 and 30 mg/kg groups. At bregma level -0.4 mm, nNOS expression was significantly decreased only in the 30 mg/kg group, in the cortex and striatum. However, at bregma level -2.3 mm, 3-MCPD administration produced no significant difference in the number of nNOS-expressing neurons in the cortex or striatum. In contrast, iNOS expression was significantly increased in the neocortex and striatum at all three rostrocaudal levels following subchronic 3-MCPD administration. These data suggest that subchronic 3-MCPD exposure may involve compensatory mechanisms acting on nNOS and iNOS expression to maintain nitric oxide homeostasis in the rostral part of the neocortex and striatum. However, in the caudal brain, increased iNOS expression did not profoundly suppress nNOS expression. Thus, the present study suggests that 3-MCPD-induced neurotoxicity is mediated, at least in part, through disturbances in the nitric oxide signaling pathway and exhibits a rostrocaudal difference, through differential expression of nNOS and iNOS in the neocortex and striatum.     

Pathological and genotoxic effects of atrazine in male Japanese quail (<Emphasis Type="Italic">Coturnix japonica</Emphasis>)

The objective of the present study was to determine the pathological and genotoxic effects of atrazine (ATZ) in male Japanese quail. Adult male Japanese quail were administered ATZ daily at 0–500 mg/kg bw (A–H groups) orally for 45 days. The blood and morbid tissues were collected at day 15, 30, and 45 of the treatment. A significant decrease in feed intake, body weight, erythrocyte counts, hemoglobin and hematocrit values were observed at high ATZ dose compared to control. Leukocyte counts decreased significantly throughout the experiment in groups E–H (50–500 mg/kg bw). Grossly, testes from ATZ treated birds were comparatively smaller in size. Histologically, seminiferous tubules of testes in group H (500 mg/kg bw) exhibited decreased number of spermatocytes, necrotic nuclei of spermatids, and lesser number or absence of spermatozoa. Biliary hyperplasia and vacuolar degeneration in liver and mild renal tubular necrosis was observed in birds higher doses. Significantly longer comet tails of DNA damage in leukocytes and isolated hepatocytes were recorded with 500 mg/kg bw ATZ.     

The effect of dietary supplements on chronic bitterweed (Hymenoxys odorata) poisoning in sheep.

Two experiments were designed to establish a chronic bitterweed dose in sheep and to study the prevention of chronic bitterweed poisoning with dietary supplements of high protein (20% crude protein) and sodium sulfate. The first experiment consisted of 5 lambs in each of 3 groups. The low dose received up to 5.0 g bitterweed/kg/day which was equivalent to 10 mg hymenoxon/kg bw. The high dose group received a maximum bitterweed dose of 1 g/kg/day or 20 mg hymenoxon/kg. The final average weights of the low (29 kg) and the high (30 kg) dose groups were significantly different from the control (40 kg) group. The prophylactic experiment consisted of 5 groups of 4 sheep each. Each group received a different combination of bitterweed, a basal ration, soybean meal, urea, or sodium sulfate. The soybean meal and urea were used to adjust the ration to 20% crude protein, and each animal received 1.2 g bitterweed/kg/day. The high protein-sodium sulfate diet did not prevent chronic bitterweed toxicity, but soybean meal-sodium sulfate combination had the greatest effect on the reduction of bitterweed toxicity. Urea potentiated the toxic effects of bitterweed.     

Characterization of the effect of deoxynivalenol on selected male reproductive endpoints.

The effect of deoxynivalenol (DON) exposure on male reproductive function was assessed in the rat. Male rats were divided into a control group (n=15 rats) and four treatment groups (0.5 mg/kg, n=15; 1.0 mg/kg, n=15; 2.5 mg/kg, n=15; and 5.0 mg/kg DON, n=16) and exposed to DON daily for 28 days via gastric intubation. Both body weight gain and the final body weight of animals in the 5.0 mg/kg dose group and feed consumption in animals in the 2.5 mg/kg and 5.0 mg/kg dose groups were significantly reduced compared to controls. Fluid consumption was not affected in any of the treated groups. Epididymal and seminal vesicle weights expressed per gram of body weight and brain weight were significantly reduced, compared to control weights, in animals from the 2.5 and 5.0 mg/kg dose groups while prostate weight expressed per gram of brain weight and body weight was significantly lower than controls only in the 5.0 mg/kg dose group. A statistically significant, dose-related decrease in homogenization resistant testicular spermatid counts, spermatid numbers, absolute cauda epididymal sperm numbers and cauda epididymal sperm numbers per gram of cauda epididymis was observed in the 5.0 mg/kg DON treatment group. Sperm tail abnormalities (broken tails) in the 5.0 mg/kg dose group were significantly higher than in the control group. Sperm swimming speed (VSL and VCL) was significantly increased only in the 2.5 mg/kg dose group. Serum FSH and LH concentrations were increased in a dose dependent manner across all treated groups while serum testosterone concentrations were decreased in a dose-related manner across all dose groups. An increase in germ cell degeneration, sperm retention and abnormal nuclear morphology was observed in the 2.5 mg/kg and 5.0 mg/kg dose groups. Treatment related effects included lesions in the non-glandular stomach, thymic lymphoid depletion and splenic hematopoiesis in the 5.0 mg/kg treatment group.     

Soy isoflavones have antimutagenic activity on DNA damage induced by the antileishmanial Glucantime (meglumine antimoniate)

Isoflavones are phytoestrogens reported to be potent antioxidant agents. In contrast, the antileishmanial meglumine antimoniate has mutagenic activities. This study evaluated the ability of soy isoflavones to reduce DNA damage induced by meglumine antimoniate. Antimutagenic effects (by micronucleus test) were tested using Swiss mice divided into seven groups treated with meglumine antimoniate (425?mg/kg bw pentavalent antimony); cyclophosphamide (50?mg/kg bw); water (negative control); single isoflavones dose (1.6?mg/kg bw), and three groups received one dose of isoflavones via gavage (0.4?mg/kg bw, 0.8?mg/kg bw or 1.6?mg/kg bw) plus meglumine antimoniate via intraperitoneal, simultaneously. To evaluate antigenotoxicity (by Comet assay), each group with 10 animals received the above-mentioned control doses; single dose of isoflavones 0.8?mg/kg bw, and three groups received isoflavones (0.8?mg/kg bw) by gavage along with intraperitoneal meglumine antimoniate, which were treated with isoflavones 24?h before or after receiving meglumine antimoniate (pre-treatment and post-treatment, respectively) or simultaneously. Cells were harvested 24?h after the treatment, and the data were evaluated by ANOVA followed by Tukey’s test (p?相似文献   

No toxicological effects on acute and repeated oral gavage doses of single-wall or multi-wall carbon nanotube in rats

Three female Crl:CD(SD) rats/group were dosed with single wall carbon nanotube (SWCNT) or multi wall carbon nanotube (MWCNT) four times by gavage at a total of 50 mg/kg bw or 200 mg/kg bw (four equally divided doses at one-hour intervals). Acute oral doses of SWCNT and MWCNT caused neither death nor toxicological effects, and thus the oral LD50 values for SWCNT and MWCNT were considered to be greater than 50 mg/kg bw and 200 mg/kg bw, in rats respectively. Five or ten Crl:CD(SD) rats/sex were dosed with SWCNT once daily by gavage at a dose of 0 (control), 0.125, 1.25 or 12.5 mg/kg bw/day for 28 days with a 14-day recovery period (0 and 12.5 mg/kg bw/day groups). Six or twelve Crl:CD(SD) rats/sex were dosed with MWCNT once daily by gavage at a dose of 0 (control), 0.5, 5.0 or 50 mg/kg bw/day for 28 days with a 14-day recovery period (0 and 50 mg/kg bw/day groups). Based on no toxicological effects, the no observed adverse effect levels (NOAELs) of repeated dose toxicity of SWCNT and MWCNT were considered to be 12.5 mg/kg bw/day and 50 mg/kg bw/day (the highest dose tested), respectively. It was suggested that SWCNT and MWCNT dosed by gavage reached the gastro-intestinal tract as agglomerates and were mostly excreted via feces.     

Acute oral toxicity of 3-MCPD mono- and di-palmitic esters in Swiss mice and their cytotoxicity in NRK-52E rat kidney cells

The acute oral toxicity of 1-palmitoyl-3-chloropropanediol (3-MCPD 1-monopalmitate) and 1,2-bis-palmitoyl-3-chloropropanediol (3-MCPD dipalmitate) in Swiss mice were examined, along with their cytotoxicity in NRK-52E rat kidney cells. LD₅₀ (median lethal dose) value of 3-MCPD 1-monopalmitate was determined 2676.81 mg/kg body weight (BW). The results showed that 3-MCPD 1-monopalmitate dose-dependently decreased the mean body weight, and caused significant increase of serum urea nitrogen and creatinine in dead mice compared to the control and survived mice. Major histopathological changes in mice fed 3-MCPD 1-monopalmitate were renal tubular necrosis, protein casts and spermatids decrease in the seminiferous tubules. According to the limit test for 3-MCPD dipalmitate, LD₅₀ value of 3-MCPD dipalmitate was presumed to be greater than 5000 mg/kg BW. Obvious changes were not observed on mean body weight, absolute and relative organ weight or serum urea nitrogen and creatinine levels in mice fed 3-MCPD dipalmitate. However, renal tubular necrosis, protein casts and spermatids decrease were also observed in the dead mice. In addition, MTT and LDH assay results only showed the cytotoxicity of 3-MCPD 1-monopalmitate in NRK-52E rat kidney cells in a dose-dependent manner. Together, the results indicated a greater toxicity of 3-MCPD 1-monopalmitate compared to 3-MCPD dipalmitate.     

A 28-day oral gavage toxicity study of 3-monochloropropane-1,2-diol (3-MCPD) in CB6F1-non-Tg rasH2 mice

3-Monochloro-1,2-propanediol (3-MCPD) is a well-known contaminant of foods containing hydrolyzed vegetable protein. However, limited toxicity data are available for the risk assessment of 3-MCPD and its carcinogenic potential is controversial. To evaluate the potential toxicity and determine the dose levels for a 26-week carcinogenicity test using Tg rasH2 mice, 3-MCPD was administered once daily by oral gavage at doses of 0, 25, 50, and 100 mg/kg body weight (b.w.)/day for 28 days to male and female CB6F1-non-Tg rasH2 mice (N = 5 males and females per dose). The standard toxicological evaluations were conducted during the in-life and post-mortem phase. In the 100 mg/kg b.w./day group, 3 males and 1 female died during the study and showed clinical signs such as thin appearance and subdued behavior accompanied by significant decreases in mean b.w. Microscopy revealed tubular basophilia in the kidneys, exfoliated degenerative germ cells in the lumen of the seminiferous tubule of the testes, vacuolation in the brain, axonal degeneration of the sciatic nerve, and cardiomyopathy in the 100, ≥25, ≥50, 100, and 100 mg/kg b.w./day groups, respectively. In conclusion, 3-MCPD's target organs were the kidneys, testes, brain, sciatic nerve, and heart. The “no-observed-adverse-effect level” (NOAEL) of 3-MCPD was ≤25 and 25 mg/kg b.w./day in males and females, respectively.     

PI3K/Akt pathway activation was involved in acute ethanol-induced fatty liver in mice

Accumulating evidences support the important roles of sterol regulatory element-binding protein-1 (SREBP-1) activation in ethanol-induced fatty liver, but the underlying mechanisms for its activation are not fully understood. Recent studies have demonstrated that phosphatidylinositol 3 kinase (PI3K)/Akt pathway activation could enhance SREBP-1 activity. The current study was designed to investigate the potential roles of PI3K/Akt pathway in acute ethanol-induced fatty liver in mice. In the first experiment, mice were treated with ethanol (2.5 or 5 g/kg bw) or isocaloric/isovolumetric maltose-dextrin solution, and sacrificed at several time points after ethanol exposure. As expected, ethanol dose-dependently increased the hepatic triglyceride (TG) levels and the protein levels of the mature form of SREBP-1 (n-SREBP-1). The phosphorylation of Akt and glycogen synthase kinase-3β (GSK-3β) was significantly increased in mice treated with ethanol (5 g/kg bw), while the protein levels of PI3K-p85 were significantly reduced. To confirm the roles of PI3K/Akt pathway, mice were then pretreated with wortmannin (0.7 or 1.4 mg/kg bw), a specific PI3K/Akt pathway inhibitor, before exposure to ethanol. Interestingly, a dual effect of wortmannin was observed. Low dose of wortmannin significantly reduced the hepatic TG levels, while high dose of wortmannin aggravated ethanol-induced fatty liver. The ratio of LC3II/LC3I of wortmannin (1.4 mg/kg bw) group mice was significantly increased, while the p62 protein level was significantly decreased compared to those of ethanol group, which indicated that wortmannin (1.4 mg/kg bw) might suppress the lipid degradation by autophagy. These results supported the hypothesis that PI3K/Akt activation might be involved in acute ethanol-induced fatty liver, and PI3K/Akt inhibitors might have therapeutic potential for the treatment of ethanol-induced fatty liver.     

Effect of carbaryl on some biochemical changes in rats: The ameliorative effect of bee pollen

In this study, 42 female Wistar albino rats, weighing between 200 and 250 g, were used and they were divided into six equal groups. Group 1 was allocated as the control group. Rats included in groups 2 and 3 were administered a water-solubilized extract of bee pollen at a dose of 50 mg/kg bw/day and 100 mg/kg bw/day, respectively. Group 4 received 225 mg/kg bw/day carbaryl. Groups 5 and 6 were given a water-solubilized extract of bee pollen at a dose of 50 mg/kg bw/day and 100 mg/kg bw/day, respectively, plus 225 mg/kg bw/day carbaryl. The indicated administrations were continued for 21 days for groups 1–6 by gavage. MDA levels and the activities of CAT, SOD and GSH-Px were analysed in blood and tissues (liver, kidney, brain and heart). At the same time, levels/activities of total protein, albumin, glucose, triglyceride, T-cholesterol, T-bilirubin, BUN, creatinine, uric acid, GGT, LDH, AST, ALT and ALP, magnesium, sodium, potassium and chloride were evaluated in serum samples. In conclusion, carbaryl was determined to cause negative changes in most of the oxidative stress markers and serum biochemical parameters investigated. These effects were observed to alleviate with the administration of bee pollen.     

Hershberger assay for antiandrogenic effects of phthalates

The antiandrogenic effects of seven phthalates, di(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), butyl benzyl phthalate (BBP), di-isononyl phthalate (DINP), di-isodecyl phthalate (DIDP), di-n-heptyl phthalate (DnHP), and mono-2-ethyhexyl phthalate (MEHP), were investigated by Hershberger assay in castrated male SD rats. An androgen agonist, testosterone (0.4 mg/kg/d), was administered for 10 consecutive days by subcutaneous (s.c.) injection as a positive control. Additionally, 20, 100, or 500 mg/kg body weight (bw)/d of 6 phthalates (DEHP, DBP, BBP, DINP, DIDP, or DnHP) or 10, 50, or 250 mg/kg bw/d of MEHP, the primary metabolite of DEHP, were also administered orally in combination with testosterone (0.4 mg/kg/d, s.c.) for 10 consecutive days, respectively. In the testosterone-treated groups, glans penis, seminal vesicles, ventral prostate, and levator ani/bulbocavernosus muscles (LABC) weights were found to be significantly increased. Ventral prostate weights were significantly decreased in animals treated with DEHP or DBP at doses of 20 mg/kg bw/d or above, 500 mg/kg bw/d DIDP, and 250 mg/kg bw/d MEHP. Seminal vesicles weights were also significantly decreased by DEHP at > 100 mg/kg bw/d, DINP at > 20 mg/kg bw/d, DIDP at 500 mg/kg bw/d, or MEHP at 50 or 250 mg/kg bw/d, respectively. In addition, LABC weights were decreased by DEHP at 500 mg/kg bw/d, DINP at 500 mg/kg bw/d, and MEHP at 50 or 100 mg/kg bw/d. These data suggest that some phthalates possess antiandrogenic activity, and that multiple cross-talk between androgen, estrogen, and steroid hormone receptors occurs.     

Combined repeated dose and reproductive/developmental toxicity screening test of the nitrophenolic herbicide dinoseb, 2-sec-butyl-4,6-dinitrophenol, in rats

In a combined repeated dose toxicity study with reproduction/developmental toxicity screening test, Crj:CD(SD)IGS rats were dosed with dinoseb, 2-sec-butyl-4,6-dinitrophenol, by gavage at 0 (vehicle), 0.78, 2.33, or 7.0 mg/kg bw/day. Six males per group were dosed for a total of 42 days beginning 14 days before mating. Twelve females per group were dosed for a total of 44-48 days beginning 14 days before mating to day 6 of lactation throughout the mating and gestation period. Recovery groups of six males per group and nonpregnant six females per group were dosed for 42 days followed by a 14-day recovery period. No deaths were observed in males of any dose group or in females of the recovery groups. At 7.0 mg/kg bw/day, eight females died and two animals were moribund during late pregnancy, and a significant decrease in body weight gain was found in both sexes. Hematocrit was significantly higher at 0.78 mg/kg bw/day and above in the main group males at the end of administration period. Reduction in extramedullary hematopoiesis in the spleen was significant at 2.33 mg/kg bw/day in the main group females. Sperm analysis revealed a decrease in sperm motility and an increase in the rates of abnormal sperm, abnormal tail, and abnormal head at 7.0 mg/kg bw/day. A number of dams delivered their pups and of dams with live pups at delivery was significantly lowered in the 7.0 mg/kg bw/day group. Based on these findings, the LOAEL for males and NOAEL for females were 0.78 mg/kg bw/day, and the NOAEL for reproductive/developmental toxicity was considered to be 2.33 mg/kg bw/day.     

Effects of cypermethrin, propetamphos, and combination involving cypermethrin and propetamphos on lipid peroxidation in mice

Insecticides are the chemicals widely used in agriculture, environmental health, human-and animal-health fields. Exposure to insecticides has been associated with many hazardous effects, including antioxidative metabolism. In the current study, the effect of cypermethrin (CYP), propetamphos (PRO) and their mixtures on oxidative stress in mice to understand the possible health effects to animals and human beings was investigated. In the present study, 245 male Albino mice weighing 35-40 g were used. The mice were divided into seven groups. The first group served as the control group. The second and third groups were administered CYP at doses of 5 mg/kg/bw and 10 mg/kg/bw, respectively, and the fourth and fifth groups were given PRO at doses of 2.5 mg/kg/bw and 5.0 mg/kg/bw, respectively. The sixth and seventh groups received combination regimens containing 5 mg/kg/bw CYP plus 2.5 mg/kg/bw PRO and 10 mg/kg/bw CYP plus 5 mg/kg/bw PRO, respectively, in feed for 60 days. Blood samples were collected by cardiac puncture on the 15th, 45th and 60th days. Serum nitric oxide (NO) and plasma malondialdehyde (MDA) levels and erythrocyte superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities were measured. In conclusion, the alterations observed in the MDA and NO levels and SOD, CAT, and GSH-Px activities of the trial groups, demonstrate the administration of certain doses of CYP and PRO, either alone or combined, to mice for a period of 60 days to produce oxidative stress. The degree of oxidative stress was found to be related to the dose administered, the duration of exposure and the administration of the indicated compounds either alone or as a combination.     

Allicin modulates diclofenac sodium induced hepatonephro toxicity in rats via reducing oxidative stress and caspase 3 protein expression

PurposeThis study was designed to evaluate the protective effects of allicin against diclofenac sodium induced hepatonephro toxicity in rats.MethodsSixty male Wister albino rats were assigned into six groups. The control group received calcium carbonate and corn starch. 2^nd group received diclofenac sodium (2 mg/kg bw orally) for 30 days. 3^rd group received allicin (45 mg/kg bw orally) for 30 days. 4^th group administrated diclofenac sodium as in the 2^nd group and allicin (15 mg/kg bw orally) for 30 days. 5^th group received diclofenac sodium as in the 2^nd group and allicin (30 mg/kg bw orally) for 30 days. 6^th group received diclofenac sodium as 2^nd and allicin (45 mg/kg bw orally) for 30 days.ResultsDiclofenac sodium significantly elevated activities of serum aspartate aminotransferase and alanine aminotransferase and serum levels of creatinine and urea. In addition, it induced hyperglycemia, lipid peroxidation, pathological alteration and caspase 3 protein expression in hepatic and renal tissues. However, it decreased reduced glutathione concentration and proliferating cell nuclear antigen protein expression in hepatic tissues. In contrast, allicin modulated the diclofenac sodium induced alteration in liver and kidney functions and structures dose dependently.ConclusionThis study indicated that allicin had potential preventive effects against diclofenac sodium induced hepatonephro toxicity in rats.     

丹皮酚、 三七总皂苷组方对急性心肌梗死大鼠心脏内 Ⅰ、 Ⅲ型胶原表达的影响

摘要： 目的 研究丹皮酚、 三七总皂苷组方用药对急性心肌梗死 （AMI） 大鼠心脏内Ⅰ、 Ⅲ型胶原表达的影响, 并探讨其改善心肌纤维化的分子机制。方法 通过结扎大鼠左冠状动脉前降支的方法复制急性心肌梗死模型, 根据干预方式不同分为模型组、 丹皮酚 （8 mg/kg） 组 （n=8）、 三七总皂苷 （40 mg/kg） 组 （n=7）、 组方低剂量（丹皮酚4 mg/kg+三七总皂苷 20 mg/kg） 组 （n=8）、 组方高剂量 （丹皮酚 8 mg/kg+三七总皂苷 40 mg/kg） 组 （n=9）, 卡托普利 （10 mg/kg） 组 （n= 8）。假手术组 （n=10）, 只穿线不结扎。连续给药 28 d 后取材测定左心指数, Masson 染色观察各组大鼠心肌间质纤维化情况; Western blot 和 RT-PCR 检测Ⅰ、 Ⅲ型胶原蛋白和 mRNA 的表达。结果 模型组左心指数较假手术组及各用药组均有不同程度升高; 与丹皮酚组和三七总皂苷组相比, 组方低、 高剂量组左心指数明显下降, 且组方高剂量组下降更明显 （均 P＜0.01）。模型组呈病理改变, 各用药组均有不同程度的病理结构改善, 组方低、 高剂量组和卡托普利组改善最明显。模型组较假手术组和各用药组Ⅰ、 Ⅲ型胶原蛋白和 mRNA 表达水平均不同程度增强; 与丹皮酚和三七总皂苷组相比, 组方低、 高剂量组Ⅰ、 Ⅲ型胶原蛋白和 mRNA 表达明显降低, 且组方高剂量组降低更明显 （均 P＜0.05）。结论 丹皮酚、 三七总皂苷组方能改善心肌梗死大鼠心肌纤维化, 且具有协同作用, 其机制可能与组方用药可降低Ⅰ、 Ⅲ型胶原表达有关。     

Therapeutic role of quercetin on oxidative damage induced by acrylamide in rat brain

Context Quercetin (QE), a bioflavonoid present abundantly in fruits and vegetables, has been reported to possess antioxidant properties. Acrylamide (ACR) is formed in foods during cooking and is known to be neurotoxic.

Objective The present study was designed to evaluate the protective effect of QE against neurotoxicity induced by ACR.

Materials and methods Four groups of Wistar rats consisting of six rats each: (i) control group; (ii) acrylamide treated group (50?mg/kg body weight as single dose); (iii) quercetin group: rats were treated intraperitoneally (i.p.) with QE (10?mg/kg body weight alone every day for 5 d); (iv) quercetin?+?acrylamide group: quercetin (10?mg/kg bw) was given i.p. every day for 5 d followed by acrylamide i.p. injection (50?mg/kg bw) on fifth day (single dose). Rats were killed after 48?h.

Results Administration of ACR (50?mg/kg bw) in Wistar rats resulted in significant increase of dopamine, interferon-γ and 8-hydroxyguanosine with concomitant decrease of serotonin (p?<?0.001) in the rat brain. Treatment of rats with QE intraperitonealy (10?mg/kg body weight) before ACR assault resulted in the diminution of ACR-mediated neurotoxicity as evident from decreased levels of dopamine, interferon-γ (p?<?0.001) and 8-hydroxyguanosine with concomitant restoration of serotonin levels (p?<?0.001).

Discussion and conclusion On the basis of the above results, the present study suggests that quercetin may be a potential therapeutic agent for restoration of oxidative damage to neurons.     

Prolonged survival after experimental paraquat intoxication: role of alternative antioxidants

Since paraquat poisoning causes multiorgan damage through the generation of several redox products, the usual therapy includes antioxidative drugs, such as N-acetylcysteine. We investigated whether selected antioxidative drugs can improve survival from acute paraquat toxicity. Forty-eight male 2-3-mo-old Wistar rats were divided into 4 groups receiving paraquat dichloride in a single injection (11 mg/kg bw ip) I h before the administration of normal saline (control ip), S-carboxymethylcysteine (600 mg/kg bw po), propofol (100 mg/kg bw ip) or trimetazidine (10 mg/kg bw po). Animals were observed for 7 d. The median survival time in the control group was 3 d whereas it was 4 (p = 0.15), 4.5 (p < 0.05) or 5 (p < 0.05) d for the trimetazidine, S-carboxymethylcysteine or propofol-treated groups, respectively.     

水飞蓟护肝胶囊对抗结核药物所致肝损伤大鼠模型的影响

目的 研究水飞蓟护肝胶囊对抗结核药物所致肝损伤大鼠模型的的影响.方法 取SD大鼠50只,随机分成5组,每组10只,分别为:模型对照组、阳性药对照组、水飞蓟护肝胶囊高剂量组、水飞蓟护肝胶囊中剂量组、水飞蓟护肝胶囊低剂量组.上述动物均通过联合用药异烟肼80 mg/kg、利福平160 mg/kg、乙胺丁醇8 mg/kg、吡嗪酰胺8 mg/kg,连续28 d建立抗结核药物所致肝损伤大鼠模型,另取SD大鼠10只作为空白对照组.模型建立后各组动物分别给予相应药物,其中空白对照组与模型对照组给予等体积饮用水,阳性对照组给予双环醇13.5 mg/kg.连续给药14 d,实验结束时10％水合氯醛3 ml/kg麻醉动物后称重,腹主动脉取血检测肝功能指标,摘取肝脏称重并计算肝脏指数.结果 与空白组比较,模型组大鼠肝脏指数显著降低,血清谷丙转氨酶、谷草转氨酶均显著升高,差异有统计学意义(P＜0.01).与模型组比较,阳性对照组、水飞蓟护肝胶囊高、中剂量组大鼠肝脏指数显著升高,血清谷丙转氨酶、谷草转氨酶均显著降低,差异有统计学意义(P＜ 0.05或P＜0.01).结论 水飞蓟护肝胶囊能够改善抗结核药物所致肝损伤.     

Developmental toxicity evaluation of triclopyr butoxyethyl ester and triclopyr triethylamine salt in the CD rat

Triclopyr (3,5,6-trichloro-2-pyridyloxyacetic acid) is an herbicide used extensively in the control of woody plants and broadleaf weeds, and is often formulated as a triethylamine salt (T-TEA) or butoxyethyl ester (T-BEE). This study evaluated the developmental toxicity of T-TEA or T-BEE in time-mated CD rats gavaged on gestation days 6-15 with 0, 30, 100 or 300 mg/kg body weight(bw)/day. The doses of each compound were equimolar and equivalent to 22, 76, 216 mg/kg bw/day of triclopyr, based on prior studies indicating rapid cleavage of the salt or ester and equivalent pharmacokinetics for the active ingredient. T-TEA caused maternal toxicity, evidenced by the death of one high-dose dam, reduced body weight gain, increased relative liver and kidney weights (300 mg/kg bw/day), reduced feed consumption, and increased water consumption (100 and 300 mg/kg bw/day). Developmental effects were limited to slightly decreased fetal body weight and reduced skeletal ossification at the high dose level. T-BEE caused similar, albeit slightly more severe, maternal toxicity, with three maternal deaths at 300 mg/kg bw/day, and slight maternal effects at 30 mg/kg bw/day. Due to an equivocal increase in malformations, which were mainly clustered in litters from three high dose dams with marked maternal toxicity, the T-BEE study was repeated using 30 dams/group, investigator-blind fetal evaluations, and an additional dose group (5 mg/kg bw/day). In the repeat study, the only reproducible fetal effect was an increased incidence of 14th thoracolumbar rib at 300 mg/kg bw/day. Overall analysis of the two T-BEE studies suggested that the fetal malformations unique to the initial study likely reflected a combination of spontaneous events, exacerbated by marked maternal toxicity. The combined weight of evidence from these developmental toxicity studies, coupled with their known pharmacokinetic equivalence, indicates that T-BEE and T-TEA are not selectively toxic to the fetus. The respective maternal toxicity no-observed effect levels (NOEL) for T-BEE and T-TEA were 5 and 30 mg/kg bw/day, while the NOEL for developmental toxicity was 100 mg/kg bw/day for both compounds.