Activity and gene expression profile of certain antioxidant enzymes to microcystin-LR induced oxidative stress in mice

Microcystins are cyclic heptapeptide toxins produced by certain strains of Microcystis aeruginosa and microcystin-LR (MC-LR) is the most toxic among the 70 variants isolated so far. These toxins have been implicated in both human and livestock mortality. In the present study we investigated the microcystin-LR induced oxidative stress in mice in terms of its effect on activity and gene expression profile of certain antioxidant enzymes and expression of heat shock protein-70 (HSP-70). Mice were treated with 0.5 LD₅₀ (38.31 μg/kg) and 1 LD₅₀ (76.62 μg/kg) and the biochemical variables were determined at 1, 3, 7 days and 15, 30, 60 and 120 min post-exposure for 0.5 and 1 LD₅₀ dose, respectively. A significant time-dependent increase in HSP-70 expression over control was observed at 1 LD₅₀ dose. The toxin induced significant increase in liver body weight index, hepatic lipid perxoidation and depletion of GSH levels at 1 LD₅₀ compared to control group. There was significant decrease in the activity of antioxidant enzymes glutathione peroxidase (GPX), superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR) and glutathione-S-transferase (GST) at 1 LD₅₀. Except catalase, there was no effect on other antioxidant enzymes at 0.5 LD₅₀ dose. In contrast to activity of antioxidant enzymes the gene expression profile did not show any significant difference compared to control at 1 LD₅₀. GR showed significant decrease in expression at 1, 3 and 7 days in animals dosed with 0.5 LD₅₀ MC-LR. The results of our in vivo study clearly show the oxidative stress induced by MC-LR, and a correlation with activity and regulation at gene expression level of antioxidant enzymes.     

Toxicity of the dialyzable fraction of the venom of the yellow scorpion, Leiurus quinquestriatus, to the migratory locust

Dialysis was carried out on redissolved freeze-dried venom of the scorpion Leiurus quinquestriatus H. and E. The mortality rate of Locusta migratoria migratorioides R. & F. injected with the dialyzable portion was used for calculating the regression equation and the LD₅₀. It was found that the LD₅₀ per female locust (mean weight 1·8 g) was that amount which was dialyzed out of 161 μg of whole venom, which means that the dialyzable portion has 2·67 per cent of the lethality of the whole venom. The toxic dose of the dialyzed venom was found not to differ from that of the whole venom.     

Effects of sarin on the operant behavior of guinea pigs

The present study evaluated the dose–response effects of subacute exposure to sublethal doses of the organophosphorus (OP) chemical warfare nerve agent (CWNA) sarin (GB) on the operant behavior of guinea pigs. Dietary restricted guinea pigs, trained to respond for food under a progressive ratio (PR) schedule of reinforcement, were injected five times per week (Monday–Friday) for 2 weeks with fractions (0.1, 0.2, and 0.4) of the established LD₅₀ of GB (42 μg/kg). Changes in body weight, whole blood (WB) acetylcholinesterase (AChE) levels, and operant performances were monitored over the 2 weeks of GB exposure and for an additional 2 weeks following the termination of exposures. There were dose-related changes in body weight and WB AChE levels throughout the exposure and post-exposure periods. Several parameters of PR performance were disrupted during exposure to 0.4 LD₅₀ GB, however, concurrent weight loss indicated the presence of overt toxicity. PR performance recovered following the termination of exposures. Lower doses (0.1 and 0.2 LD₅₀) of GB failed to produce reliable effects on operant performance during the exposure period. Overall responding decreased during exposure to 0.4 LD₅₀ GB, resulting in reduced response rates and break points. The decrease in overall response rates was attributed to an increase in pausing since there was no decrease in running rate. Motor effects of 0.4 LD₅₀ GB were evident as an increase in the proportion of lever press durations ≥ 1.0 s. In the present study, doses of GB lower than 0.4 LD₅₀ produced no marked alteration of operant performance in guinea pigs, although WB AChE levels were maximally inhibited to 20% of control.     

Acute oral toxicity test and assessment of rhynchophylline in mice

As the main alkaloid constituent of Uncaria species, rhynchophylline has drawn extensive attention in recent years for its antihypertensive and neuroprotective activities. However, toxicity study of the rhynchophylline is still lacking. In the present study, oral acute toxicity of rhynchophylline was conducted in Kunming mice. The mice were orally treated with 520.00, 442.00, 375.70, 319.34 and 271.44 mg/kg of rhynchophylline for 14 d. The general behavior, body weight changes, toxic reaction, and death were recorded, and histopathological analyses were performed. The acute toxicity was evaluated by the assessment of the median lethal dose (LD₅₀). The acute toxicity study showed that no significant difference was found in the body weight of the mice in the control group and those in the drug group. However, the mice treated with rhynchophylline showed obvious abnormal symptoms and mortality. The median lethal dose (LD₅₀) of orally administered rhynchophylline was 308.08 mg/kg. The histopathological results showed that the mice in the high-dose rhynchophylline group displayed toxic effects in the brain, liver, lung, and kidney. The results of the current study indicated that rhynchophylline could not be taken at a high dose. Collectively, our current findings provided a strong basis for further clinical investigation.     

Experimental evidence for toxic damage induced by a dimeric anthracenone: diast T-514 (peroxisomicine A2)

Dimeric anthracenones obtained from the genus Karwinskia (Rhamnaceae) are characteristic compounds isolated from the plants of this species. Previous toxicity studies demonstrated Diast T-514 to be toxic to animals in experimental settings. Diast T-514 extracted and characterized from Karwinskia parvifolia, was studied in CD1 mice. The LD₅₀ for this compound was determined. Animals were testedwith Diast T-514 following enteral and parenteral administration. An LD₅₀ dose by both oral and intraperitoneal administration showed selective damage to target organs.     

Preliminary studies of nematocysts from the jellyfish Stomolophus meleagris

Nematocysts from the jellyfish Stomolophus meleagris were found to be of the type—heterotrichous microbasic euryteles. The nematocysts were not ruptured by various physical or chemical means, but were disrupted by homogenization in a Braun homogenizing mill. The toxin(s) which contained 11·2 per cent protein and 7·25 per cent nitrogen, had an LD₅₀ in mice of 0·85 μg N₂/g mouse when injected intravenously. The toxin(s) were heat labile and rapidly destroyed when incubated with trypsin, indicating that they were protein.     

In vitro cytotoxicity tests for the prediction of acute toxicity in vivo

Investigations of the use of in vitro cytotoxicity tests for the prediction of acute toxicity in vivo have been reviewed with particular emphasis on those studies that have been published during the past 5 years. Numerous cell types, endpoints and exposure periods have been used in cytotoxicity tests, although these appear generally to have little effect on the resulting correlation between in vitro IC₅₀ values and in vivo LD₅₀ values. The in vitro data correlate better with rodent parenteral (ip or iv) LD₅₀ values than with oral LD₅₀ values due to kinetic considerations. For certain groups of related chemicals (e.g. antitumour compounds, metal salts), and for some sets of unrelated chemicals, the in vitro data correlate very well with LD₅₀ values. However, while cytotoxicity tests are useful for screening chemicals for their intrinsic and relative toxicities, it is impossible to tell whether predictions based on cytotoxicity data alone would be sufficiently accurate for labelling and classifying a new chemical according to its likely acute toxicity in vivo. The in vitro endpoints need to be of greater relevance to the possible mechanisms of chemically-induced acute toxicity in vivo than most of those that are used at present.     

Effect of atropine on cyanide-induced acute lethality in mice

The effects of atropine on acute lethality induced by cyanide were investigated in mice. The LD₅₀ value of cyanide (s.c. injection) was 8.4 (7.6–9.3) mg/kg. However, the LD₅₀ value of cyanide (s.c.) was significantly increased by 1.5-fold when atropine (32 mg/kg) was injected s.c. in mice. Furthermore, the combined administration of atropine (32 mg/kg). Ca²⁺ (500 mg/kg) and sodium thiosulfate (1 g/kg) tremendously increased the LD₅₀ value by 5.6-fold in mice although sodium thiosulfate or Ca²⁺ alone increased the LD₅₀ 2.5- or 1.5-fold. On the other hand, although the LD₅₀ value of cyanide (intracerebroventricular injection (i.v.t.)) was 52.0 (47.4–57.0) μ/brain, the LD₅₀ value of cyanide (i.v.t.) was significantly increased by 1.3- or 1.61-fold in mice 10 min after s.c. injection of atropine (32 mg/kg) or Ca²⁺ (500 mg/kg). Furthermore, the combined administration of atropine and Ca²⁺ increased the LD₅₀ value of cyanide by 2.1-fold. These results suggest that atropine inhibits cyanide-induced acute lethality and promotes the antagonistic effect of thiosulfate and Ca²⁺ in mice.     

Zootoxicological properties of venom L-amino acid oxidase

L-amino acid oxidase prepared from Crotalus adamanteus venom after the method of and does not contribute to the production of the profound fall in systemic arterial pressure usually seen following injection of crude Crotalus venom, nor does it provoke any early deleterious changes in the dependent variables of the cardiovascular system.

The enzyme has no effect on neuromuscular transmission in the mammal. Its LD₅₀ is 9·13 (7·83–10·35) mg per kg test animal body weight.     

Experimental envenoming of mice with venom from the scorpion Centruroides limpidus limpidus: differences in mortality and symptoms with and without antibody therapy relating to differences in age, sex and strain of mouse

C57Bl/6J and BALB/cAnN inbred strains of mice differed significantly in mortality and symptoms when intoxicated subcutaneously with one LD₅₀ of venom from Centruroides limpidus limpidus. Higher mortality was observed in C57Bl/6J than in BALB/cAnN. Also, C57Bl/6J mice more quickly developed muscular and respiratory collapse whilst BALB/cAnN mice were hyperactive before dying. Also, the symptoms in the survivors lasted for 24 h in C57Bl/6J and for 2 h in BALB/cAnN. The age and sex of mice were also related to mortality: younger mice were more resistant than older mice and females were more susceptible than males, especially in the younger groups. Antivenom (horse F(ab′)₂) administration 5–10 min after envenoming of mice with one LD₅₀ rescued 60% of BALB/cAnN and 52% of C57Bl/6J mice, respectively. Results indicate that genetic background, gender and age differences are of consequence in the pathogenesis of C. limpidus scorpion envenomation in mice, and that timely treatment with active antivenom F(ab′)₂ saves a significant fraction of intoxicated mice without statistically significant distinction of strains.     

不同剂量吡唑啉酮希夫碱衍生物铜配合物对小鼠的急性毒性实验

目的: 研究吡唑啉酮希夫碱衍生物铜配合物[Cu(PMPP-SAL)(EtOH)]对小鼠腹腔注射后急性毒性反应,评估其安全性。方法: 采取腹腔注射法给小鼠一次性给药,观察15 d内12.5,25,50,200,400,800 mg·kg^-1共6个剂量组小鼠的生长发育、行为变化、血液学变化。计算[Cu(PMPP-SAL)(EtOH)]腹腔注射半数致死率(LD₅₀)及95%的可信区间。结果: 高剂量组中毒小鼠均出现不同程度的呼吸心跳加快、抽搐等症状。经腹腔注射[Cu(PMPP-SAL)(EtOH)] LD₅₀为:33 mg·kg^-1,95%的可信限为:25.5~43 mg·kg^-1。25 mg·kg^-1剂量组与阳性药物(顺铂,DDP,12.5 mg·kg^-1)组相比具有相似的毒性作用。结论: 低浓度的[Cu(PMPP-SAL)(EtOH)]毒性较小,具有较好的安全性。     

Isolation and purification of a toxin from Millepora dichotoma

A water-soluble, non-dialyzable toxin has been isolated from the hydrozoan coral, Millepora dichotoma, collected at Eniwetok Atoll. The toxin was purified by anion exchange chromatography. The ₅₀ for 20 g mice is 38 μg protein per kg body wt. The toxin is compared and contrasted with that isolated from the West Indian and Caribbean hydrozoan, Millepora alcicornis.     

度洛西汀对小鼠急性毒性及遗传毒性的研究

目的:探讨度洛西汀对成年雄性小鼠的急性毒性及遗传毒性.方法:采用小鼠急性毒性试验观察致死率及半数致死量(LD50).采用小鼠骨髓微核试验、小鼠精子畸变试验及生殖与淋巴器官重量指数检测方法,将小鼠均分为6组,即阴性对照组、阳性对照组,度洛西汀1、2、3和4组(分别给予度洛西汀5、10、20和40 mg/kg),观察度洛西...     

Partial purification of Lophozozymus pictor toxin

An aqueous extract of a coral reef crab Lophozozymus pictor was subjected to a 6-stage purification and chemical testing procedure. The semi-purified toxin had a molecular weight between 1000 and 5000 and gave reactions that suggested it contained free amino and phenolic groups. The ₅₀ for mice was 377 μg/kg. The dose-death time relationships for the crab toxin, saxitoxin and tetrodotoxin were determined. The relationship for the crab toxin differed markedly from those for the other two toxins, the crab toxin being slower in its action.     

A comparison of the safety margins of botulinum neurotoxin serotypes A, B, and F in mice

This study compared the respective intramuscular (IM) safety margins of two preparations of botulinum toxin (BTX) serotype A and one preparation each of BTX serotypes B and F in mice. Mice received an IM injection (0–200 U kg⁻¹ body weight) of BTX-A (BOTOX® or DYSPORT®), an experimental preparation of BTX-B (WAKO Chemicals, Inc.), or an experimental preparation of BTX-F (WAKO). An observer who was masked to treatment scored muscle weakness using the Digit Abduction Scoring (DAS) assay. Peak DAS responses were plotted and IM ED₅₀ values calculated. The safety margin for each BTX preparation was calculated as a ratio of the IM median lethal dose after hind limb injection to the median effective dose in the DAS assay (IM LD₅₀/IM ED₅₀). Experiments were repeated 4–6-times for each preparation (10 mice/dose). Mean safety margin values were highest for BTX-F (WAKO; 16.7±3.9) and one of the BTX-A preparations (BOTOX®; 13.9±1.7). Mean safety margins values for the other BTX-A preparation (DYSPORT®) and BTX-B (WAKO) were significantly lower (7.6±0.9 and 4.8±1.1, respectively). Thus, the BTX preparations exhibited different safety margins in mice. These results support the hypothesis that the preparations are unique therapeutics and are not interchangeable based on a simple dose ratio.     

Antifungal activity of a new benzothiazole derivative against Candida in vitro and in vivo

The antifungal activity of 6-amino-2-n-pentylthiobenzothiazole (APB) against 26 strains of the genus Candida in vitro was studied. Susceptibility of 17 strains was IC₅₀ ≤ 40 μmol/ml, of 7 strains IC₅₀ = 40−80 μmol/ml and of 2 strains IC₅₀ = 80−200 μmol/ml. Generalized candidosis of mice was treated with APB (doses 50, 100, 250 mg/kg) and ketoconazole (KET, 50 mg/kg of body weight). The optimal dose of APB was shown to be 100 mg/kg; 25% of mice survived after 14 days as compared to control animals. C. albicans was not found in the kidney of the sacrificed mice. 80% of mice survived after KET therapy. However, C. albicans was present in the kidney in an amount of 10⁵−10⁶ CFU/g of tissue. C. albicans did not reappear in the kidney 7 days after the discontinuation of APB treatment, but it was found there after KET therapy.     

-Hydroperoxy diethyl peroxide, an unusual natural compound isolated from an ascidian (Phallusia mammillata): acute toxicity in DDY mice

-Hydroperoxy diethyl peroxide, a novel compound found in the tunic of ascidians, has two peroxide moieties per molecule. Since ascidians are a widely served food item in Japan, human exposure to this compound potentially exists in the seafood preparation industries. No toxicological data have so far been published on this compound, and so we determined the intraperitoneal 6-day LD₅₀ in mice and conducted histopathological examinations. The 6-day LD₅₀, was found to be 199 mg/kg with 95% confidence limits of 126–314 mg/kg. Histopathological examination revealed necrosis induced in a variety of cells that had been directly exposed to the compound. These cells included hepatocytes, parenchymal pancreatic cells and fat cells. It is concluded that direct contact with this compound is likely to elicit cellular necrosis of various organs. The specific toxicological effects are probably dependent on the route of exposure.     

Interaction study between Ocimum sanctum and Glimepiride(sulfonylurea derivative) in diabetic rats

The present study was intended to discover the interaction between Ocimum sanctum(O. sanctum) and Glimepiride, a sulfonylurea derivative used in the treatment of type-2 diabetes, in diabetic rats to suggest an alteration in the dose of Glimepiride in case of hypoglycaemia. LD50 studies for the aqueous extract of O. sanctum leaf were carried out in albino mice up to the dose level of 2000 mg/kg. O. sanctum at low, medium and high doses(100, 200 and 400 mg/kg, per oral), respectively and Glimepiride ?(half) therapeutic dose, therapeutic dose and 2 time therapeutic dose(0.036, 0.072 and 0.144 mg/200 g, per oral) were selected. After the treatment with O. sanctum and Glimepiride as single doses and in various combinations of these two drugs in streptozotocin-induced diabetic rats serum glucose levels in all the groups were analysed by the glucose oxidase-peroxidase method. When administered alone as single doses both aqueous extract of O. sanctum leaf and Glimepiride produced a significant anti-diabetic effect in diabetic rats. The anti-diabetic effect observed with combination of aqueous extract of O. sanctum leaf and Glimepiride was significant and more when compared to either of the drugs given alone. There was a definite interaction that necessitates dose readjustment of Glimepiride and further glucose levels are to be frequently monitored to avoid complication of hypoglycemic condition with aqueous extract of O. sanctum leaf and Glimepiride combination.     

Some pharmacological characteristics of the venom of the alphabet cone, Conus spurius atlanticus

Lyophilized venom of the alphabet cone, Conus spurius atlanticus, was tested on the crabs Uca sp. and Cardisoma guanhumi. The venom induced ataxia, muscle spasms, paralysis, and death in Uca pugilator ( ₅₀ ca. 100 μg per crab).

The venom may have interfered with conduction between the cardiac ganglion and the contractile elements of the heart in C. guanhumi.     

Analgesic and Anti-Inflammatory Effects of Alangium salvifolium

The methanol extract of Alangium salvifolium plant roots has been studied for analgesic and anti-inflammatory activities in animal models. The methanol extract produced significant dose-dependent inhibition of carrageenan-induced rat paw edema. The extract also showed marked analgesic activity. Acute toxicity studies with mice showed no mortality up to 1 g/kg body weight when administered intraperitoneally.