辐射致癌的分子机理

辐射致癌的分子机理０５００１１河北省肿瘤医院祝淑钗，郭宝仲辐射可以致癌，但是人们对辐射致癌的分子机理认识较少。１９９１年国际原子能机构（ＩＡＥＡ）组织专家讨论了辐射致癌的机理［１］，对射线引起的癌瘤发生、癌瘤进展以及它对癌瘤的促进作用进行了初步的探讨...     

抗流行性感冒中草药及动物模型研究进展

流行性感冒（简称流感）是人类常见疾病,中草药是较理想的抗流感病毒药物。为进一步深入研究流感的防治,建立良好的动物模型是重要基础。该文介绍了动物模型研究进展,对其建模原则、模型鉴定方法、动物选择等方面进行归纳,比较了小鼠模型、雪貂模型、大鼠模型、猪模型和非人灵长类动物模型等各自的优点和缺点,提出小鼠模型是目前流感病毒模型的主要类型,但将来雪貂模型有可能会取代小鼠模型的地位。     

抗痛风中草药的研究进展

随着社会发展和人类生活水平的提高,痛风疾病的发病率不断增加并且还伴着发病年龄出现低龄化趋势。痛风是一种以高尿酸血症导致尿酸钠晶体在关节及其周围组织沉积为特征的嘌呤代谢性疾病。在西药上常用来抗痛风的药物有秋水仙碱、非甾体类抗炎药、促肾上腺皮质激素、糖皮质激素等。近年来抗痛风药物中草药的研究也取得很大进步,本文就有关抗痛风中草药的研究进行综述。     

抗心肌缺血再灌注损伤的中草药研究进展

目的:介绍中草药防治心肌缺血再灌注损伤方面的研究进展。方法:根据近几年的研究文献,总结中草药防治心肌缺血再灌注损伤方面的研究及作用机理。结果:三七皂甙、纹股蓝总甙、人参皂甙、槲皮素、丹参素、川芎嗪、茶多酚;银各叶、水芹、丹参水提物;炙甘草汤、生脉散、四逆汤;丹参注射液、灯盏花注射液、当归注射液、654-2注射液、川芎嗪注射液有良好的抗心肌缺血再灌注损伤作用。作用机理包括:抗氧自由基损伤、抗脂质过氧化作用、钙通道阻滞作用,防止钙超载,抑制肾素活性,降低TXA_2/PEI_2比值,升高心肌SOD活性,增加心肌营养血流量等。结论:中草药抗心肌缺血再灌注损伤作用肯定,前景广阔,但应用于临床,仍需深入研究。     

抗心肌缺血再灌注损伤的中草药研究进展

目的:介绍中草药防治心肌缺血再灌注损伤方面的研究进展。方法:根据近几年的研究文献,总结中草药防治心肌缺血再灌注损伤方面的研究及作用机理。结果:三七皂甙、纹股蓝总甙、人参皂甙、槲皮素、丹参素、川芎嗪、茶多酚;银各叶、水芹、丹参水提物;炙甘草汤、生脉散、四逆汤;丹参注射液、灯盏花注射液、当归注射液、654-2注射液、川芎嗪注射液有良好的抗心肌缺血再灌注损伤作用。作用机理包括:抗氧自由基损伤、抗脂质过氧化作用、钙通道阻滞作用,防止钙超载,抑制肾素活性,降低TXA_2/PEI_2比值,升高心肌SOD活性,增加心肌营养血流量等。结论:中草药抗心肌缺血再灌注损伤作用肯定,前景广阔,但应用于临床,仍需深入研究。     

中草药美白及有效成分的研究进展

目的综述近年来中草药美白及有效成分的研究进展。方法查阅相关文献,进行归纳总结。结果有美白功效的中草药中主要含有黄酮类、二苯乙烯类、多糖类、果酸类等有效成分。含有美白功效的中草药主要有芦荟、花粉、胎盘、冬虫夏草、甘草、桑叶、白芷、人参。结论中草药美白可能是未来几年皮肤美容研究领域的重点。应重视相关的学习和研究。     

中草药体外杀精子抗生育作用的研究进展

综述了单味中草药以及中草药有效成分（包括皂甙、生物碱、萜类、酚酸和脂肪酸类及其他成分）体外杀精子抗生育作用的国内外研究进展。     

HPV16致癌分子机制的研究进展

人乳头瘤病毒 (Ｈｕｍａｎｐａｐｉｌｌｏｍａｖｉｒｕｓｅｓ,ＨＰＶ)是一类分子长度大约为 8ｋｂ左右的小分子环状双股ＤＮＡ病毒。通过ＤＮＡ序列分析 ,至今已发现人乳头瘤病毒大约有 70多型 ,不同型ＨＰＶ常常分布于不同组织的上皮表面 ,大约有 2 0多型ＨＰＶ嗜好感染粘膜上皮 ,特别是生殖道的粘膜上皮[1] 。大量分子流行病学研究资料表明 ,人乳头瘤病毒 16型(ＨＰＶ16 )与生殖道肿瘤密切相关 ,在宫颈癌活检组织中 ,ＨＰＶ16的阳性检出率显著高于正常宫颈组织[2 ] 。动物致癌实验发现 ,ＨＰＶ16及其Ｅ6Ｅ7基因可明显诱导小鼠宫颈癌的发生…     

抗病毒中草药研究进展

病毒性疾病已成为目前传染性疾病中的突出问题,因此寻找有效的抗病毒药物仍然是目前的迫切任务。近廿余年来研究寻找到有抗病毒活性的、临床疗效突出的合成药物为数不多,且有些尚存在轻重各异的不良反应和耐药性。我国中草药资源丰富,从中发     

抗衰老中草药成分在植物科属中的存在及药理作用机理研究进展

<正> 中草药能补益健身,延缓衰老,历代医药书籍中均有记载。但其作用机理尚不清楚。直到19世纪,通过科学实验,人们对中草药及其成分的抗衰老作用有了初步认识,证实许多中草药及其成分确能增强生命活力,延缓衰老。本文概述近年来抗衰老中草药成分在植物科属中的存在及药理作用机理研究的新进展。抗衰老中草药成分在植物科属中的存在     

Phosphorylation of p53 by Cdk5 contributes to benzo[a]pyrene-induced neuronal apoptosis

Benzo[a]pyrene (B[a]P) is a ubiquitous carcinogenic pollutant in the environment, however, the potential neurotoxic effects of B[a]P has not been elucidated clearly. In the present study, we explored the potential involvement of p53 phosphorylation by Cdk5 in B[a]P-induced neuronal apoptosis at both in vitro and in vivo settings. For in vitro studies, primary cortical neurons isolated from the brains of Sprague Dawley (SD) rat pup were exposed to 0, 10, 20, and 40 μM of B[a]P for 12, 24, or 48 h. For in vivo studies, SD rats were injected intraperitoneally with 0, 1.0, 2.5, and 6.25 mg/kg of B[a]P every other day for 1, 2, or 3 months. Our results demonstrated that exposure to B[a]P caused a dose- and a time-dependent increase in neuronal apoptotic ratio in both in vitro and in vivo studies. There was also a dose- and a time-dependent upregulation of p35, p25, Cdk5, and phosphorylated p53 at Ser15 after B[a]P exposure. In order to explore whether B[a]P-induced increased neuronal apoptosis was through Cdk5/p53 pathway, roscovitine, a specific Cdk5 inhibitor, was applied to pretreat neurons prior to B[a]P exposure. The results showed that pretreatment of neurons with roscovitine partially rescued cells from B[a]P-induced apoptosis, and alleviated B[a]P-induced upregulation of phosphorylated p53 at Ser15. Our results suggest that Cdk5/p53 signaling pathway may be involved in B[a]P-induced neuronal apoptosis, which will provide information to further elucidate the molecular mechanisms of B[a]P-induced neurotoxicity.     

Preliminary physiologically based pharmacokinetic models for benzo[a]pyrene and dibenzo[def,p]chrysene in rodents

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants generated as byproducts of natural and anthropogenic combustion processes. Despite significant public health concern, physiologically based pharmacokinetic (PBPK) modeling efforts for PAHs have so far been limited to naphthalene, plus simpler PK models for pyrene, nitropyrene, and benzo[a]pyrene (B[a]P). The dearth of published models is due in part to the high lipophilicity, low volatility, and myriad metabolic pathways for PAHs, all of which present analytical and experimental challenges. Our research efforts have focused upon experimental approaches and initial development of PBPK models for the prototypic PAH, B[a]P, and the more potent, albeit less studied transplacental carcinogen, dibenzo[def,p]chrysene (DBC). For both compounds, model compartments included arterial and venous blood, flow limited lung, liver, richly perfused and poorly perfused tissues, diffusion limited fat, and a two compartment theoretical gut (for oral exposures). Hepatic and pulmonary metabolism was described for both compounds, as were fractional binding in blood and fecal clearance. Partition coefficients for parent PAH along with their diol and tetraol metabolites were estimated using published algorithms and verified experimentally for the hydroxylated metabolites. The preliminary PBPK models were able to describe many, but not all, of the available data sets, comprising multiple routes of exposure (oral, intravenous) and nominal doses spanning several orders of magnitude. Supported by Award Number P42 ES016465 from the National Institute of Environmental Health Sciences.     

中药醋炙增效减毒机理的现代研究进展

醋炙法多用于具有疏肝解郁、散瘀止痛、攻下逐水功效的中药。醋炙可引药入肝,增强疏肝解郁、散瘀止痛中药的作用,降低峻下逐水中药的毒性。本文在查阅大量文献的基础上,从化学、药理和毒理角度对醋炙增效减毒的机理进行总结论述,为醋炙中药的临床合理应用提供参考。     

Mdm2 as a Sensitive and Mechanistically Informative Marker for Genotoxicity Induced by Benzo[a]pyrene and Dibenzo[a,l]pyrene

Mdm2 is an oncoprotein interacting with p53 and maintaininglow p53 levels in unstressed cells. Here we investigated theeffect of genotoxic compounds on Mdm2 phosphorylation levels.Employing the Mdm2 2A10 antibody and phosphatase treatment wefound that Mdm2 accumulated in HepG2 cells when exposed to lowconcentrations of genotoxic compounds such as mitomycin C, etoposide,5-fluorouracil, and benzo[a]pyrene (BP). The low-dose responseswere not accompanied by p53 accumulation and the effect of lowconcentrations of BP on Mdm2 was not affected by small interferingRNA for p53. In human lymphoblasts 10nM BP induced an Mdm2 response.Low concentrations of BP also induced binding of Mdm2 to chromatinin HepG2 cells, but no p53 binding or H2AX phosphorylation.The more mutagenic dibenzo[a,l]pyrene as well as higher BP concentrationsinstead induced H2AX and p53 Ser15 association with chromatin.Acrolein potentiated the effect of BP on p53 stabilization andchromatin binding. Taken together, these data suggest that (1)Mdm2 is a sensitive biomarker for certain types of genotoxicity,and (2) that polycyclic aromatic hydrocarbons-induced Mdm2 bindingto chromatin reflects repairable damage, whereas chromatin bindingof p53 Ser15 and H2AX indicates more persistent DNA damage.The analysis of Mdm2 and related endpoints might be useful forevaluating mutagenic potentials of DNA damages. It is suggestedthat patterns documented here can be used for separating BPdoses that induce readily repaired DNA adducts from doses thatoverwhelm this capacity.     

毒死蜱致雄性生殖毒性及其机制的研究进展

【摘要】毒死蜱（chlorpyrifos,CPF）系有机磷农药（organophosphates,OPs）,广泛应用于农业生产和居住环境。毒死蜱不仅具有急性毒性,其慢性毒性和潜在危害日益引起业界关注。有研究提示CPF为可疑的环境内分泌干扰物（EEDs）,具有生殖发育毒性。CPF的雄性生殖毒性主要表现为组织病理学、精子质量、激素水平和睾丸标志酶活性等发生变化,提示可能机制以脂质过氧化损伤机制研究居多。本文就CPF的雄性生殖毒性及其可能机制进行综述。     

Activity of rat UGT1A1 towards benzo[a]pyrene phenols and dihydrodiols

Four UDP-glucuronosyltransferases from the rat UGT1A family were tested for activity towards benzo[a]pyrene phenols and dihydrodiols. UGT1A1 and UGT1A7 were found to be broadly active towards BaP metabolites. Antisera recognizing rat UGT1A1 and UGT1A7 were used to assess UGT levels in relation to UGT activity towards benzo[a]pyrene-7,8-dihydrodiol (BPD). The rank BPD UGT activities were liver = intestine  kidney, whereas UGT1A1 was highest in liver and UGT1A7 was highest in intestine. Phenobarbital, an inducer of hepatic UGT1A1, only slightly increased BPD UGT activity, whereas UGT1A7 inducers more potently increased the activity. Inhibition studies using the differential UGT1A1 inhibitor, bilirubin, suggest that UGT1A1 is not a major contributor to the constitutive BPD glucuronidating activity of control rat liver microsomes. These data suggest that multiple UGT1A enzymes contribute to glucuronidation of BPD and other BaP metabolites, and that their relative contributions depend on tissue- and environmental-specific factors.     

Acute and subchronic oral toxicities of benzo[a]pyrene in F-344 rats.

We have studied the acute and subchronic oral toxicities of benzo[a]pyrene (BaP) in male and female F-344 rats. Single acute BaP doses of 0, 100, 600, and 1000 mg /kg dissolved in peanut oil were administered by oral gavage. Subchronic doses of 0, 5, 50, and 100 mg/kg/day were administered for 90 days in the animal diet. The major toxicological endpoints examined included animal body weight, selected tissue weights, and histopathological examinations (liver, kidney, stomach, prostate, testes, and ovaries). In addition, we examined blood elements: red blood cells (RBC), white blood cells (WBC), hemoglobin (Hgb), hematocrit (Hct), mean cell volume (MCV), mean cell hematocrit (MCH), and mean cell hemoglobin concentration (MCHC), blood chemistry (ALT, AST, and BUN), and urine chemistry (glucose, bilirubin, specific gravity, pH, protein, urobilinogen, nitrite, occult blood, and leucocytes). In the acute study, WBC were significantly decreased and mean cell-hemoglobin concentration was significantly increased, both in males only. The liver:body weight ratio was significantly increased in males and females (up to 30%). None of the blood chemistry or urine parameters were significantly affected. In the subchronic study, mean body weight was significantly decreased in males only (13%), and the liver:body weight ratio in males was significantly increased. Several of the blood elements were significantly decreased in males and females after 90 days; RBCs (up to 10%), Hct (up to 12%), and Hgb (up to 12%). For blood chemistry parameters (AST, ALT, BUN), only BUN in males was significantly increased in the high dose group (100 mg/kg) at the 90 day time point. The histopathological examination of selected tissues showed significant abnormalities (tubular casts) only in the male kidney, at the 2 highest doses, after 90 days. These studies indicate that the acute and subchronic toxicities of BaP are relatively low, BaP affects specific blood elements and organs, and BaP has a greater effect on males than females. The induction of non-carcinogenic kidney abnormalities in males only may be indicative of renal dysfunction and further substantiates an apparent sex difference in tolerance to BAP:     

Benzo[a]pyrene induced p53‐mediated cell cycle arrest,DNA repair,and apoptosis pathways in Chinese rare minnow (Gobiocypris rarus)

The p53 pathways play an important role in carcinogenesis. In mammals, p53 and p53 target genes have been extensively studied, but little is known about their functions and regulation in fish. In this study, the cDNA fragments of p53 network genes, including p53, p21, mdm2, gadd45α, gadd45β, igfbp‐3, and bax, were cloned from Chinese rare minnow (Gobiocypris rarus). These genes displayed high amino acid sequence identities with their zebrafish orthologs. The mRNA levels of p53 network genes and pathological changes in the liver were determined after adult rare minnow were exposed to 0.4, 2, and 10 µg/L of benzo[a]pyrene (BaP) for 28 days. The results showed that p53, p21, mdm2, gadd45α, and bax mRNA expressions in the livers from males and females were significantly upregulated compared with those of the controls (p < 0.05), but gadd45β and igfbp‐3 expression was not significantly changed. Microphotographs revealed enlargement of the cell nuclei and cellular degeneration in males, while atrophy and vacuolization of hepatocytes were observed in females (10 µg/L). These results suggested that BaP induced liver DNA repair and apoptosis pathways and caused adverse pathological changes in rare minnow. The strongly responsive p53 network genes in the livers suggest that rare minnow is suitable as an experimental fish to screen environmental carcinogens. In addition, the p53 network genes in rare minnow could feasibly be used to identify the mechanism of environmental carcinogenesis. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 979–988, 2017.     

Synthesis and Biological Evaluation of [1,2,4]Triazolo[3,4‐a]phthalazine and Tetrazolo[5,1‐a]phthalazine Derivatives Bearing Substituted Benzylpiperazine Moieties as Positive Inotropic Agents

Two series of [1,2,4]triazolo[3,4‐a]phthalazine and tetrazolo[5,1‐a]phthalazine derivatives bearing substituted benzylpiperazine moieties have been synthesized and evaluated for their positive inotropic activity by measuring left atrium stroke volume on isolated rabbit heart preparations. The majority of the derivatives exhibited better in vitro activity than the existing drug, milrinone, and 6‐((4‐(4‐methoxyphenyl)piperazin‐1‐yl)methyl)tetrazolo[5,1‐a]phthalazine. 8 m in particular was identified as the most potent with an increased stroke volume of 12.02 ± 0.20% (milrinone: 2.46 ± 0.07%) at a concentration of 3 × 10^–5 m . The chronotropic effects of the compounds that exhibited good potency were also evaluated.     

浅谈中药配伍减毒及现代研究

中药以配伍来减毒主要反映在两个方面:一是运用七情中"相杀"、"相畏"的关系,即一种药物能减轻另一种药物的毒副作用,如生姜能减轻和消除半夏的毒性,砂仁能减轻熟地滋腻碍脾的副作用等。二是多味功用相近药物同时配伍运用,这种方式既可利用相近功用药物的协同作用,又能有效减轻毒副作用的发生,如十枣汤之甘遂、大戟、芫花。本文从温热药、寒凉药的相关配伍减毒实例及现代研究进展来浅谈配伍的妙处。