华西广医1号急性毒性、鼻黏膜刺激性和增强免疫功能的研究

为初步了解拟开发医院雾化制剂华西广医1号的安全性和有效性,通过小鼠急性毒性试验、大鼠鼻黏膜刺激性试验和增强免疫功能的药效学试验方法研究了华西广医1号安全性和药效。结果表明:以0.34 g/mL药液24 h内雾化给药,对小鼠无明显急性毒性;对大鼠经鼻腔给药无明显刺激性;以0.068 g/mL雾化给药,有升高幼龄小鼠的胸腺指数的作用趋势;可升高环磷酰胺致免疫功能低下小鼠的巨噬细胞碳粒廓清指数K、校正指数α和外周血白细胞数目(white blood cell,WBC),红细胞数目(red blood cell,RBC)和血红蛋白浓度(hemoglobin,HGB)水平,并可升高溶血素值。可见,华西广医1号雾化给药小鼠的最大给药量为34 g/kg,无明显鼻黏膜刺激性,0.068 g/mL雾化给药有增强免疫功能,可用于预防上呼吸道感染。

食蟹猴重复给予溶瘤病毒药物HSV-1/hPD-1的毒性研究

目的:考察食蟹猴重复给予溶瘤病毒药物HSV-1/hPD-1后的体内毒性,探索安全剂量范围,为后续临床试验提供参考信息。方法:30只食蟹猴随机分成3组,包括溶媒对照组和低、高剂量(1.0×10^(8)、4.0×10^(8)pfu)组,每组10只,雌雄各半。采用肌肉注射给药,每周给药2次,连续给药6周,恢复期8周。试验期间,每天观察动物的临床症状和摄食量,每次给药后1~2天观察注射部位症状,每周称量体重。分别在检疫期、首次给药后、给药期结束、恢复期结束的不同时间点进行安全药理(体温、血压、心电图)测定、临床病理(血液学、血凝、血清生化、尿生化)检查、免疫学(T淋巴细胞、细胞因子、免疫原性)测定、组织病理学检查和脏器称重。结果:给药后,动物未见异常症状、注射部位刺激性、体重和摄食量改变,未见安全药理和临床病理指标有意义的变化。与溶媒对照组比较,第41天,低剂量会引起动物CD3^(+)CD4^(+)T细胞比例升高,高剂量未见明显变化。第13至97天,低、高剂量均能引起动物产生抗载体结合抗体、抗抗体,以及个别动物检出hPD-1表达产物。证明药物在体内产生免疫活性和介导免疫原性。组织病理学检查显示,给药期结束时,低、高剂量组动物注射部位极轻度至中度混合细胞浸润,高剂量组动物坐骨神经极轻度髓鞘/轴突变性;恢复期结束时注射部位病变减为极轻度,坐骨神经病变未见恢复趋势。低、高剂量组动物未见组织脏器重量改变。结论:食蟹猴重复给予溶瘤病毒药物HSV-1/hPD-1后,动物体内耐受良好,受试物未见毒性反应剂量(NOAEL)是1.0×10^(8)pfu。上述研究结果为药物开展临床试验提供了数据支持。

Glutaredoxin-1 alleviates acetaminophen-induced liver injury by decreasing its toxic metabolites

Excessive N-acetyl-p-benzoquinone imine(NAPQI)formation is a starting event that triggers oxidative stress and subsequent hepatocyte necrosis in acetaminophen(APAP)overdose caused acute liver failure(ALF).S-glutathionylation is a reversible redox post-translational modification and a prospective mechanism of APAP hepatotoxicity.Glutaredoxin-1(Glrx1),a glutathione-specific thioltransferase,is a primary enzyme to catalyze deglutathionylation.The objective of this study was to explored whether and how Glrx1 is associated with the development of ALF induced by APAP.The Glrx1 knockout mice(Glrx1^(-/-))and liver-specific overexpression of Glrx1(AAV8-Glrx1)mice were produced and underwent APAPinduced ALF.Pirfenidone(PFD),a potential inducer of Glrx1,was administrated preceding APAP to assess its protective effects.Our results revealed that the hepatic total protein S-glutathionylation(PSSG)increased and the Glrx1 level reduced in mice after APAP toxicity.Glrx1^(-/-)mice were more sensitive to APAP overdose,with higher oxidative stress and more toxic metabolites of APAP.This was attributed to Glrx1 deficiency increasing the total hepatic PSSG and the S-glutathionylation of cytochrome p4503a11(Cyp3a11),which likely increased the activity of Cyp3a11.Conversely,AAV8-Glrx1 mice were defended against liver damage caused by APAP overdose by inhibiting the S-glutathionylation and activity of Cyp3a11,which reduced the toxic metabolites of APAP and oxidative stress.PFD precede administration upregulated Glrx1 expression and alleviated APAP-induced ALF by decreasing oxidative stress.We have identified the function of Glrx1 mediated PSSG in liver injury caused by APAP overdose.Increasing Glrx1 expression may be investigated for the medical treatment of APAP-caused hepatic injury.

Differential Expression of Iron Deficiency Responsive Rice Genes under Low Phosphorus and Iron Toxicity Conditions and Association of OsIRO3 with Yield in Acidic Soils

With the hypothesis that iron(Fe) deficiency responsive genes may play a role in Fe toxicity conditions,we studied five such genes OsNAS1,OsNAS3,OsIRO2,OsIRO3 and OsYSL16 across six contrasting rice genotypes for expression under high Fe and low phosphorus(P) conditions,and sequence polymorphism.Genotypes Sahbhagi Dhan,Chakhao Poirieton and Shasharang were high yielders with no bronzing symptom visible under Fe toxic field conditions,and BAM350 and BAM811 were low yielders but did not show bronzing symptoms.Hydroponic screening revealed that the number of crown roots and root length can be traits for consideration for identifying Fe toxicity tolerance in rice genotypes.Fe contents in rice roots and shoots of a high-yielding genotype KMR3 showing leaf bronzing were significantly high.In response to 24 h high Fe stress,the expression levels of OsNAS3 were up-regulated in all genotypes except KMR3.In response to 48 h high Fe stress,the expression levels of OsNAS1 were3-fold higher in tolerant Shasharang,whereas in KMR3,it was significantly down-regulated.Even in response to 7 d excess Fe stress,the transcript abundances of OsIRO2 and OsNAS3 were contrasting in genotypes Shasharang and KMR3.This suggested that the reported Fe deficiency genes had a role in Fe toxicity and that in genotype KMR3 under excess Fe stress,there was disruption of metal homeostasis.Under the 48 h low P conditions,OsIRO2 and OsYSL16 were significantly up-regulated in Fe tolerant genotype Shasharang and in low P tolerant genotype Chakhao Poirieton,respectively.In silico sequence analysis across 3 024 rice genotypes revealed polymorphism for 4 genes.Sequencing across OsIRO3and OsNAS3 revealed nucleotide polymorphism between tolerant and susceptible genotypes for Fe toxicity.Non-synonymous single nucleotide polymorphisms and insertion/deletions(InDels) differing in tolerant and susceptible genotypes were identified.A marker targeting 25-bp InDel in OsIRO3,when run on a diverse panel of 43 rice genotypes and a biparental population,was associated with superior performance for yield under acidic lowland field conditions.This study highlights the potential of one of the vital genes involved in Fe homeostasis as a genic target for improving rice yield in acidic soils.

Ferrostatin-1 protects HT-22 cells from oxidative toxicity

Ferroptosis is a type of programmed cell death dependent on iron.It is different from other forms of cell death such as apoptosis,classic necrosis and autophagy.Ferroptosis is involved in many neurodegenerative diseases.The role of ferroptosis in glutamate-induced neuronal toxicity is not fully understood.To test its toxicity,glutamate(1.25–20 mM)was applied to HT-22 cells for 12 to 48 hours.The optimal experimental conditions occurred at 12 hours after incubation with 5 mM glutamate.Cells were cultured with 3–12μM ferrostatin-1,an inhibitor of ferroptosis,for 12 hours before exposure to glutamate.The cell viability was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.Autophagy was determined by monodansylcadaverine staining and apoptosis by caspase 3 activity.Damage to cell structures was observed under light and by transmission electron microscopy.The release of lactate dehydrogenase was detected by the commercial kit.Reactive oxygen species were measured by flow cytometry.Glutathione peroxidase activity,superoxide dismutase activity and malondialdehyde level were detected by the appropriate commercial kit.Prostaglandin peroxidase synthase 2 and glutathione peroxidase 4 gene expression was detected by real-time quantitative polymerase chain reaction.Glutathione peroxidase 4 and nuclear factor erythroid-derived-like 2 protein expression was detected by western blot analysis.Results showed that ferrostatin-1 can significantly counter the effects of glutamate on HT-22 cells,improving the survival rate,reducing the release of lactate dehydrogenase and reducing the damage to mitochondrial ultrastructure.However,it did not affect the caspase-3 expression and monodansylcadaverine-positive staining in glutamate-injured HT-22 cells.Ferrostatin-1 reduced the levels of reactive oxygen species and malondialdehyde and enhanced superoxide dismutase activity.It decreased gene expression of prostaglandin peroxidase synthase 2 and increased gene expression of glutathione peroxidase 4 and protein expressions of glutathione peroxidase 4 and nuclear factor(erythroid-derived)-like 2 in glutamate-injured HT-22 cells.Treatment of cultured cells with the apoptosis inhibitor Z-Val-Ala-Asp(OMe)-fluoromethyl ketone(2–8μM),autophagy inhibitor 3-methyladenine(100–400μM)or necrosis inhibitor necrostatin-1(10–40μM)had no effect on glutamate induced cell damage.However,the iron chelator deferoxamine mesylate salt inhibited glutamate induced cell death.Thus,the results suggested that ferroptosis is caused by glutamate-induced toxicity and that ferrostatin-1 protects HT-22 cells from glutamate-induced oxidative toxicity by inhibiting the oxidative stress.

UGT1A1 gene polymorphism: Impact on toxicity and efficacy of irinotecan-based regimens in metastatic colorectal cancer

AIM: To investigate the correlation between uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) gene polymorphisms and irinotecan-associated side effects and parameters of drug efficacy in patients with metastatic colorectal cancer (mCRC) receiving a low-dose weekly irinotecan chemotherapeutic regimen. METHODS: Genotypes were retrospectively evaluated by gene scan analysis on the ABI 310 sequencer of the TATAA box in the promoter region of the UGT1A1 gene in blood samples from 105 patients who had received 1st line irinotecan-based chemotherapy for mCRC. RESULTS: The distribution of the genotypes was as follows: wild type genotype (WT) (6/6 ) 39.0%, heterozygous genotype (6/7) 49.5%, and homozygous genotype (7/7) 9.5%. The overall response rate (OR) was similar between patients carrying the (6/7, 7/7) or the WT genotype (6/6) (44.3% vs 43.2%, P = 0.75). Neither time to progression [(TTP) 8.1 vs 8.2 mo, P = 0.97] nor overall survival [(OS) 21.2 vs 18.9 mo, P = 0.73] differed significantly in patients who carried the(6/6) when compared to the (6/7, 7/7) genotype. No significant differences in toxicity were observed: Grade 3 and 4 delayed diarrhoea [(6/7, 7/7) vs (6/6); 13.0% vs 6.2%, P =0.08], treatment delays [(6/7, 7/7) vs (6/6); 25.1% vs 19.3%, P = 0.24] or dose reductions [(6/7, 7/7) vs (6/6); 21.5% vs 27.2%, P = 0.07].CONCLUSION: This analysis demonstrates the non-significant influence of the UGT1A1 gene polymorphism on efficacy and rate of irinotecan-associated toxicity in mCRC patients receiving low-dose irinotecan based chemotherapy.

Severe irinotecan-induced toxicity in a patient with UGT1A1*28 and UGT1A1*6 polymorphisms

Many studies have demonstrated the impact of UGT1A1 on toxicity of irinotecan. In particular, patients bear-ing UGT1A1*28 (TA 7/7) have a higher risk of severe neutropenia and diarrhea. Based on this, prescribers of irinotecan are advised that patients with UGT1A1*28 (TA 7/7) should start with a reduced dose of irinotecan, although a particular dose is not specified. Research in Asian countries has shown a lower incidence of UG-T1A1*28 (TA 7/7), while UGT1A1*6 (A/A) is more often found and is associated with severe irinotecan-related neutropenia. We report here a case of a metastatic colorectal cancer patient who is heterozygous for the UGT1A1*28 polymorphism (TA 6/7) as well as the UG-T1A1*6 polymorphism (G/A). The patient was treated with FOLFIRI for 9 cycles and underwent two irinote-can dose reductions according to pharmacokinetic data regarding exposure to the active metabolite, SN-38. Simultaneous heterozygous UGT1A1*28 and UGT1A1*6 polymorphisms may produce higher exposure to SN-38 and a higher risk of adverse effects related to irinote-can. Additional studies will be necessary to determine the optimal starting dose of irinotecan for patients with both UGT1A1*28 and UGT1A1*6 polymorphisms.

Study of the Toxicity of 1-Bromo-3-Chloro-5,5-Dimethylhydantoin to Zebrafish

Objective 1-Bromo-3-chloro-5,5-dimethylhydantoin （BCDMH） is a solid oxidizing biocide for water disinfection.The objective of this study was to investigate the toxic effect of BCDMH on zebrafish.Methods The developmental toxicity of BCDMH on zebrafish embryos and the dose-effect relationship was determined.The effect of BCDMH exposure on histopathology and tissue antioxidant activity of adult zebrafish were observed over time.Results Exposure to 4 mg/L BCDMH post-fertilization was sufficient to induce a number of developmental malformations,such as edema,axial malformations,and reductions in heart rate and hatching rate.The no observable effects concentration of BCDMH on zebrafish embryo was 0.5 mg/L.After 96 h exposure,the 50% lethal concentration （95% confidence interval （CI）） of BCDMH on zebrafish embryo was 8.10 mg/L （6.15-11.16 mg/L）.The 50% inhibitory concentration （95% CI） of BCDMH on hatching rate was 7.37 mg/L （6.33-8.35 mg/L）.Histopathology showed two types of responses induced by BCDMH,defensive and compensatory.The extreme responses were marked hyperplasia of the gill epithelium with lamellar fusion and epidermal peeling.The histopathologic changes in the gills after 10 days exposure were accompanied by significantly higher catalase activity and lipid peroxidation.Conclusion These results have important implications for studies on the toxicity and use of BCDMH and its analogs.

Study on Acute Toxicity of Purified Protein HAS1 Expression in KM Mice

[Objectives]The antifungal protein HAS1 newly obtained was evaluated for acute toxicity safety in KM mice according to relevant national regulations,so as to eliminate people s concerns about the safety of transgenic plants.[Methods]The acute toxicity of the purified protein HAS1 was observed by intragastric administration of mice,and the poisoning symptoms,poisoning degree,recovery and death were observed.[Results]No abnormal toxicity symptoms were observed in the test group,the vehicle control group and the blank control group.The main tissues and organs were not abnormal in gross anatomy.The average body weight of each group showed an increasing trend compared with before administration at 1,3,7,11 and 14 d after administration.It was found that after giving the purified protein HAS1 to KM mice at a cumulative dose of 64 mg/kg a day,no obvious toxicity was observed in the acute toxicity test,indicating that the test substance was non-toxic by oral administration.[Conclusions]This study provides a basis for further use of the protein and its coding genes.

曲妥珠单抗联合放化疗对HER2阳性乳腺癌患者血清CEA、 CA153、ICAM-1水平的影响

目的探究曲妥珠单抗联合放化疗对人表皮生长因子受体2(HER2)阳性乳腺癌患者癌胚抗原(CEA)、癌相关糖蛋白抗原(CA153)和细胞间黏附因子-1(ICAM-1)的影响。方法按照信封抽签法将110例HER2阳性乳腺癌患者分为观察组(55例,采用放化疗+曲妥珠单抗的治疗方式)与对照组(55例,采用放化疗的治疗方式),比较两组患者的临床疗效、生存时间及质量、血清肿瘤标志物水平和用药安全性。结果对照组患者经治疗后疾病缓解率(43.64%)明显低于观察组(76.36%)(P<0.05);对照组的肿瘤总生存期、无进展生存期和QOL评分等各项数据都明显低于观察组(P<0.05);两组患者治疗后CEA、CA153、ICAM-13均降低,且观察组降低幅度更显著(P<0.05);总不良反应发生率观察组(27.27%)与对照组(23.64%)比较无统计学意义(P>0.05)。结论曲妥珠单抗联合放化疗能够有效改善患者的血清CEA、CA153、ICAM-1水平,提高HER2阳性乳腺癌患者的临床疗效,且不会增加患者机体的不良反应。

硫酸氨基葡萄糖联合美洛昔康对膝骨关节炎患者血清FGF-2、TGF-β、IGF-1水平及膝关节运动功能的影响

目的 探究硫酸氨基葡萄糖联合美洛昔康对膝骨关节炎患者血清成纤维细胞生长因子-2(fibroblast growth factor-2, FGF-2)、转化生长因子-β(transforming growth factor-β, TGF-β)、胰岛素样生长因子-1(insulin-like growth factor-1, IGF-1)水平及膝关节运动功能的影响。方法 选择2021年6月-2023年6月就诊的膝骨关节炎114例,以随机数字表法分为联合组和美洛昔康组各57例。美洛昔康组予美洛昔康片治疗,联合组在美洛昔康组基础上加用硫酸氨基葡萄糖胶囊治疗,均治疗6周后观察疗效,比较2组治疗前、治疗6周后膝关节运动功能、炎性因子、生长因子水平及治疗期间安全性。结果 治疗6周后,联合组总有效率为91.23%(52/57)高于美洛昔康组的73.68%(42/57)(P<0.05)。治疗6周后,2组5次坐立试验、2.4 m起立行走试验所需时间短于治疗前,且联合组短于美洛昔康组(P<0.05,P<0.01);西安大略和麦克马斯特大学骨关节炎指数评分及血清前列腺素E2、白细胞介素-17、基质金属蛋白酶-3水平低于治疗前,且联合组低于美洛昔康组(P<0.05,P<0.01)。治疗6周后,2组血清FGF-2、TGF-β、IGF-1水平均高于治疗前,且联合组高于美洛昔康组(P<0.05,P<0.01)。2组治疗期间总不良反应发生率比较差异无统计学意义(P>0.05)。结论 硫酸氨基葡萄糖联合美洛昔康可有效升高膝骨关节炎患者血清FGF-2、TGF-β、IGF-1水平,延缓软骨退行性病变,控制机体炎症反应,进而有效改善患者膝关节运动功能,疗效显著,安全性良好。

程序性细胞死亡配体1、泛免疫炎症值、血小板与淋巴细胞比值和肠道菌群构成与晚期非小细胞肺癌化疗联合免疫治疗获益及毒副反应的关系

目的探讨程序性细胞死亡配体1(programmed cell death ligand 1,PD-L1)、泛免疫炎症值(panimmune inflammatory value,PIV)、血小板与淋巴细胞比值(platelet lymphocyte ratio,PLR)和肠道菌群构成与晚期非小细胞肺癌化疗联合免疫治疗获益及毒副反应的关系。方法选取2021年1月至2023年1月在河北中石油中心医院接受治疗的晚期非小细胞肺癌患者112例,所有患者均给予化疗联合免疫治疗。分析治疗有效组和治疗无效组、毒副反应Ⅰ~Ⅱ级组和毒副反应Ⅲ~Ⅳ级组患者治疗前后PD-L1、PIV、PLR和肠道菌群构成差异。结果69例患者治疗有效,治疗有效率为61.61%。毒副反应达到Ⅲ~Ⅳ级患者38例,毒副反应达到Ⅰ~Ⅱ级患者74例。治疗有效组患者治疗后1个月PD-L1、PIV、PLR、肠球菌及大肠埃希菌含量均显著低于治疗无效组(均P<0.05),而双歧杆菌、乳酸杆菌含量均显著高于治疗无效组(均P<0.05)。毒副反应Ⅲ~Ⅳ级组患者美国东部肿瘤协作组评分2分比例、TNM分期Ⅳ期比例分别为58.14%和46.51%,均显著高于毒副反应Ⅰ~Ⅱ级组(均P<0.05)。毒副反应Ⅰ~Ⅱ级组患者治疗后1个月PD-L1、PIV、PLR均显著高于毒副反应Ⅰ~Ⅱ级组(均P<0.05),而双歧杆菌、乳酸杆菌含量均显著低于毒副反应Ⅰ~Ⅱ级组(均P<0.05)。结论在化疗联合免疫治疗有效的晚期非小细胞肺癌患者中,治疗后PD-L1、PIV和PLR显著降低,肠道菌群明显改善,同时在毒副反应Ⅰ~Ⅱ级患者中存在相同现象。

Definition of Planarian Mortality in an Acute Toxicity Test:A Case Study on Dugesia japonica Exposed to 1-Octyl-3-methylimidazolium Bromide

In order to define the mortality criteria of planarian objectively,a case study of Dugesia japonica exposed to 1-octyl-3-methylimidazolium bromide([C8mim]Br)was performed followed by a recovery culture.The results showed that defining planarian mortality in light of its body disintegration was appropriate.If the disintegrated tissue of a planarian was more than 1/4 of its body length,it would completely degenerate.However,a planarian would regenerate the lost tissue and return to normal after a few days’recovery culture if the disintegrated part was less than 1/4 of body length.Therefore,we propose to use body disintegration as the endpoint of planarian mortality,i.e.,1/4 body length degenerated is the critical threshold of mortality and survival of planarians when exposed to toxicants.This criterion could be adapted in the standardization of testing protocols and comparability of acute toxicity test or other toxicological research using planarian as the test animal.

Neurotoxicity of the pesticide rotenone on neuronal polarization: a mechanistic approach

Neurons are the most extensive and polarized cells that display a unique single long axon and multiple dendrites, which are compartments exhibiting structural and functional differences. Polarity occurs early in neuronal development and it is maintained by complex subcellular mechanisms throughout cell life. A well-defined and controlled spatio-temporal program of cellular and molecular events strictly regulates the formation of the axon and dendrites from a non-polarized cell. This event is critical for an adequate neuronal wiring and therefore for the normal functioning of the nervous system. Neuronal polarity is very sensitive to the harmful effects of different factors present in the environment. In this regard, rotenone is a crystalline, colorless and odorless isoflavone used as insecticide, piscicide and broad spectrum pesticide commonly used earlier in agriculture. In the present review we will summarize the toxicity mechanism caused by this pesticide in different neuronal cell types, focusing on a particular biological mechanism whereby rotenone could impair neuronal polarization in cultured hippocampal neurons. Recent advances suggest that the inhibition of axonogenesis produced by rotenone could be related with its effect on microtubule dynamics, the actin cytoskeleton and their regulatory pathways, particularly affecting the small RhoGTPase RhoA. Unveiling the mechanism by which rotenone produces neurotoxicity will be instrumental to understand the cellular mechanisms involved in neurodegenerative diseases influenced by this environmental pollutant, which may lead to research focused on the design of new therapeutic strategies.

Effects of bifenthrin on Daphnia magna during chronic toxicity test and the recovery test

The acute and chronic toxic effects of bifenthrin on Daphnia magna were studied. The results showed that 24 h-EC 50 , 48 h-LC 50 and 96 h-LC 50 of bifenthrin on D. magna were 3.24, 12.40 and 1.40 μg/L respectively. And the LOEC and NOEC of bifenthrin were 0.02 and 0.004 μg/L respectively. The recovery test of bifenthrin on Daphnia magna was presented. Daphnia magna(F 0 generation) were exposed during 21 d to different bifenthrin concentrations. Offspring(animals from the first and third brood: F 1(1st) and F 1(3rd), respectively) were transferred to a free pesticide medium during a 21 d recovery period. In this recovery study, survival, growth, reproduction(mean total young per female, onset of reproduction and number broods per female) and the intrinsic rate of natural increase (r) were assessed as parameters. Reproduction such as number of young per female as well as length was still reduced in F 1(1st) generation daphnids from parentals(F 0) exposed to the bifenthrin. However F 1(3rd) individuals from parentals exposed to pesticide concentrations were able to restore reproduction when a recovery period of 21 d was allowed, but the length of F 1(3rd) from parentals exposed to the 0.5 and 0.75 μg/L bifenthrin concentration was still significantly effected(P<0.05).

In vitro anti oxidant activity and acute oral toxicity of Terminalia paniculata bark ethanolic extract on Sprague Dawley rats

Objective:To ensure the safety and evaluate the anti oxidant activity of Terminalia paniculata(T.paniculata)ethanolic extract in Sprague Dawley rats.Methods:The solvent extracts(hexane,ethyl acetate and ethanol)of T.paniculata were subjected to phytochemical analysis and their DPPH radical scavenging activity was assayed.The oral acute toxicity was evaluated using ethanolic extract of T.paniculata.Results:Ethyl acetate and elhanolic extracts showed more phytochemicals,whereas highest DPPH scavenging activity was found in ethanolic extract.In an acute toxicity study,T.paniculata ethanolic extract was orally administered(1000 mg/kg body weight)to rats and observed for72 h for any toxic symptoms and the dose was continued up to 14 d.On the 15th day rats were sacrificed and blood samples were collected from control and test animals and analyzed for some biochemical parameters.We did not observe any behavioral changes in test groups in comparison with their controls.Also,there were no significant alterations in biochemical,hematological(hemoglobin content and blood cells count)and liver function parameters such as serum glutamate pyruvate transaminase,serum glutamate oxaloacetate transaminase,alkaline phosphatase,total proteins,albumin and bilirubin levels between T.paniculata ethanolic extract treated and normal control groups.Conclusions:Together our results demonstrated that T.paniculala ethanolic possessed potent antioxidant activity and it was safer and non toxic to rats even at higher doses and therefore could be well considered for further investigation for its medicinal and therapeutic efficacy.

Negundoside,an irridiod glycoside from leaves of Vitex negundo,protects human liver cells against calcium-mediated toxicity induced by carbon tetrachloride

AIM： To evaluate the protective effect of 2′-p-hydroxy benzoylmussaenosidic acid [negundoside （NG）, against carbon tetrachloride （CCl4）-induced toxicity in HUH-7 cel Is.METHODS： CCI4 is a well characterized hepatotoxin, and inducer of cytochrome P450 2E1 （CYP2E1）-mediated oxidative stress. In addition, lipid peroxidation and accumulation of intracellular calcium are important steps in the pathway involved in CCl4 toxicity. Liver cells （HUH-7） were treated with CCI4, and the mechanism of the cytoprotective effect of NG was assessed. Silymarin, a known hepatoprotective drug, was used as control. RESULTS： NG protected HUH-7 cells against CCl4 toxicity and loss of viability without modulating CYP2E1 activity. Prevention of CCl4 toxicity was associated with a reduction in oxidative damage as reflected by decreased generation of reactive oxygen species （ROS）, a decrease in lipid peroxidation and accumulation of intracellular Ca^2＋ levels and maintenance of intracellular glutathione homeostasis. Decreased mitochondrial membrane potential （MMP）, induction of caspases mediated DNA fragmentation and cell cycle arrest, as a result of CCl4 treatment, were also blocked by NG. The protection afforded by NG seemed to be mediated by activation of cyclic adenosine monophosphate （cAMP） synthesis and inhibition of phospholipases （cPLA2）. CONCLUSION： NG exerts a protective effect on CYP2E1-dependent CCl4 toxicity via inhibition of lipid peroxidation, followed by an improved intracellular calcium homeostasis and inhibition of Ca^2＋-dependent proteases.

Determination and QSAR Study on the Toxicity of Substituted Phenol against Qinghaiensis sp (Q67)

Toxicities （-1gEC50） of 16 phenolic compounds against Q67 were determined, and structural parameters as well as thermodynamic parameters of these compounds were obtained through fully optimized calculations by using B3LYP method of density functional theory （DFT） at the 6-311G^＊＊ level. Moreover, a 3-parameter （molecular average polarizability （α）, heat energy corrected value （Eth） and the most positive hydrogen atomic charge （qH^＋）） correlation model with R^2 = 0.981 and q^2 = 0.967 to predict -1gEC50 was obtained from experimental data based on the above-mentioned parameters as theoretical descriptors. Therein a was the most significant on -1gEC50. Variance Inflation Factors （VIF）, t-value and cross-validation were applied to verify the model, confirming that the resultant model has fairly better stability and predictive ability to predict -1gEC50 of similar compounds.

微生物法针对毒性位点降解黄曲霉毒素B_(1)的研究进展

文章主要探究了黄曲霉毒素B_(1)(AFB_(1))的毒性位点及毒性机理,并对比了微生物法破坏AFB_(1)毒性位点从而降解AFB_(1)的优势。重点综述了微生物法中的脱毒酶法对AFB_(1)的降解机制。同时,对脱毒酶法联合其他方法的复合应用进行展望。

Neuroprotective effects of exogenous brain-derived neurotrophic factor on amyloid-beta 1-40-induced retinal degeneration

Amyloid-beta(Aβ)-related alterations,similar to those found in the brains of patients with Alzheimer's disease,have been observed in the retina of patients with glaucoma.Decreased levels of brain-derived neurotrophic factor(BDNF)are believed to be associated with the neurotoxic effects of Aβpeptide.To investigate the mechanism underlying the neuroprotective effects of BDNF on Aβ_(1-40)-induced retinal injury in Sprague-Dawley rats,we treated rats by intravitreal administration of phosphate-buffered saline(control),Aβ_(1-40)(5 nM),or Aβ_(1-40)(5 nM)combined with BDNF(1μg/mL).We found that intravitreal administration of Aβ_(1-40)induced retinal ganglion cell apoptosis.Fluoro-Gold staining showed a significantly lower number of retinal ganglion cells in the Aβ_(1-40)group than in the control and BDNF groups.In the Aβ_(1-40)group,low number of RGCs was associated with increased caspase-3 expression and reduced TrkB and ERK1/2 expression.BDNF abolished Aβ_(1-40)-induced increase in the expression of caspase-3 at the gene and protein levels in the retina and upregulated TrkB and ERK1/2 expression.These findings suggest that treatment with BDNF prevents RGC apoptosis induced by Aβ_(1-40)by activating the BDNF-TrkB signaling pathway in rats.