Metformin prevents hormonal and metabolic disturbances and 1,2-dimethylhydrazine-induced colon carcinogenesis in non-diabetic rats

Effects of two doses of the anti-diabetic drug, metformin （MF）, on hormonal and metabolic levels of serum of non-diabetic male Wistar rats with 1,2-dimethylhydrazine （DMH）-induced colon tumor adenocarcinomas were studied. Carcinogenesis in the animals was also observed. Rats with DMH-induced colon adenocarcinomas had elevated levels of serum glucose, insulin, insulin- like growth factor-l, total cholesterol, triglycerides, catalase, malonic dialdehyde, glycated hemoglobin, aspartate aminotransferase, and alanine aminotransferase and decreased hemoglobin. Treatment with two doses of MF normalized maiority of these changes in DMH-treated rats, whereas the drug was ineffective in rats without DMH treatment. The only exception was the decreased triglyceride levels in MF-treated rats. A 100 mg/kg dose of MF increased DMH-induced exophytic colon carcinomas and decreased endophytic tumors compared with untreated rats. Moreover, both MF doses increased DMH-induced and highly differentiated tumors and decreased the invasiveness of colon carcinomas compared with rats provided with DMH and water. Therefore, effects of MF on metabolic homeostasis are critical for preventing colon cancer.

Increased paracellular permeability of tumor-adjacent areas in 1,2-dimethylhydrazine-induced colon carcinogenesis in rats

Objective: The morphology and functions of the proximal and distal large intestine are not the same. The incidence of colorectal cancer in these regions is also different, as tumors more often appear in the descending colon than in the ascending colon.Inflammatory bowel disease and colorectal cancer can increase transepithelial permeability, which is a sign of reduced intestinal barrier function. However, there is not enough evidence to establish a connection between the difference in colorectal cancer incidence in the proximal and distal colon and intestinal permeability or the effects of carcinogenesis on the barrier properties in various areas of the colon. The aim of the study was to assess the permeability of different segments of the large intestine according to a developed mapping methodology in healthy rats and rats with 1,2-dimethylhydrazine(DMH)-induced colon adenocarcinoma.Methods: The short circuit current, the transepithelial electrical resistance and the paracellular permeability to fluorescein of large intestine wall of male Wistar rats were examined in the Ussing chambers. The optical density of the solution from the serosa side to assess the concentration of the diffused fluorescein from mucosa to serosa was analyzed by spectrophotometry. The morphometric and histological studies were performed by optical microscopy.Results: Rats with DMH-induced colon adenocarcinomas showed elevated transepithelial electrical resistance in the areas of neoplasm development. In contrast, there was no change in the electrophysiological properties of tumor adjacent areas, however,the paracellular permeability of these areas to fluorescein was increased compared to the control rats and was characterized by sharply reduced barrier function.Conclusions: The barrier properties of the colon vary depending on tumor location. The tumors were less permeable than the intact intestinal wall and probably have a negative influence on tumor-adjacent tissues by disrupting their barrier function.

A novel mouse model for colitis-associated colon carcinogenesis induced by 1,2-dimethylhydrazine and dextran sulfate sodium

AIM: To develop an efficient animal colitis-associated carcinogenesis model and to detect the expression of β-catenin and p53 in this new model. METHODS: Dysplasia and cancer were investigated in mice pretreated with a single intraperitoneal injection of 20 mg/kg body mass of 1,2-dimethylhydrazine prior to three repetitive oral administrations of 30 g/L dextran sulfate sodium to give conditions similar to the clinically observed active and remission phases. Immunohistochemical staining of β-catenin and p53 was performed on paraffin-imbedded specimens of animals with cancer and/or dysplasia, those without dysplasia and the normal control animals. RESULTS: At wk 11, four early-invasive adenocarcinomas and 36 dysplasia were found in 10 (90.9%) of the 11 mice that underwent 1,2-dimethylhydrazine-pretreatment with 3 cycles of 30 g/L dextran sulfate sodium-exposure. Dysplasia and/or cancer occurred as flat lesions or as dysplasia-associated lesion or mass (DALM) as observed in humans. Colorectal carcinogenesis occurred primarily on the distal portion of the large intestine. No dysplasia and/or cancer lesion was observed in the control groups with 1,2-dimethylhydrazine pretreatment or 3 cycles of 30 g/L dextran sulfate sodium exposure alone. Immunohistochemical investigation revealed that β-catenin was translocated from cell membrane to cytoplasm and/or nucleus in 100% of cases with dysplasia and neoplasm, while normal membrane staining was observed in cases without dysplasia and the normal control animals. Nuclear expression of p53 was not detected in specimens. CONCLUSION: A single dose of procarcinogen followed by induction of chronic ulcerative colitis results in a high incidence of colorectal dysplasia and cancer. Abnormalexpression of β-catenin occurs frequently in dysplasia and cancer. This novel mouse model may provide an excellent vehicle for studying colitis-related colon carcinogenesis.

Lack of inhibitory effects of Lactic acid bacteria on 1,2-dimethylhydrazine-induced colon tumors in rats

AIM: A myriad of healthful effects has been attributed to the probiotic lactic acid bacteria, perhaps the most controversial issue remains that of anticancer activity. This study was aimed at investigating the putative anti-cancer effects of lactic acid bacteria strains on the progression of colon tumor in 1,2-dimethylhydrazine (DMH)-treated animals.METHODS: The strain of lactic acid bacteria used in this study was lactic acid bacteria NZ9000 that conformed to the characteristics of plasmid free. Sixty male Wistar rats were given subcutaneous injections of DMH at a dose of 40 mg/kg body wt or saline once a week for 10 weeks. The rats were divided into 6 experimental groups. After the last DMH injection,animals in groups 1 and 4 were gavaged with 1 mi of lactic acid bacteria at a dose of 5×109 per day or vehide until sacrifice at the end of week 22 or week 52. Animals in groups 1-3 were killed at the end of week 22 for histopathological examination.The whole period of experimental observation was 52 weeks.RESULTS: By the end of 22nd week, final average body weights of the rats treated with DMH alone and all animals receiving lactic acid bacteria were significantly decreased compared with the vehicle control (P＜0.05). No differences in tumor inridence, multiplicity, dimensions and stage in the colonic mucosa were observed among the groups. At week 52, the survival rate of the rats administered lactic acid bacteria was lower than that of the rats treated with DMH that were fed on control fluids of non-lactococcus lactis. The mean survival time of lactic acid bacteria-treated animals was 39 weeks.CONCLUSION: These results indicate that lactic acid bacteria lacks inhibitory effects on the progression of colon tumor in DMH-treated animals, and does not support the hypothesis that alteration of colonic flora may exert an influence on the progression of colon tumor.

1,2-环己烷二甲酸醇醚酯结构与增塑PVC性能的关系

以1,2-环己烷二甲酸酐(HHPA)、乙二醇醚(乙二醇甲醚系列、乙二醇丁醚系列)为原料,通过直接酯化法合成了1,2-环己烷二甲酸二(乙二醇醚)酯(简称醇醚酯,下同)。利用FTIR和^(1)HNMR对产物进行了表征,并对醇醚酯增塑后的聚氯乙烯(PVC)制品的力学性能、微观形貌、热稳定性、耐迁移性、耐挥发性和耐候性进行了测试。结果表明,当醇醚酯的单侧乙氧基数目≤3时,其增塑效果与乙氧基数目呈正相关;与邻苯二甲酸二辛酯(DOP)增塑后的PVC制品(DOP/PVC)相比,1,2-环己烷二甲酸二(三乙二醇甲醚)酯(HHPTEM)增塑后PVC制品(HHPTEM/PVC)的断裂伸长率提升88.0%,5%热失重温度提高了20.2℃,在正己烷和甲苯中的质量损失率分别下降7.6%和4.9%,70℃下挥发性测试中,质量损失率下降1.9%,10 d紫外老化后断裂伸长率保持率提升8.6%。

重组体pET-28a-C12O/E.coli降解菲的功能研究

多环芳烃污染在石油及页岩油开采过程中不可避免,以多环芳烃菲作为标准降解底物,利用实验室初期从大庆石油采油三厂中分离得到的石油降解菌HL-1(Acinetobacter calcoaceticus)。以菌株HL-1为模板,通过PCR扩增的方法得到邻苯二酚1,2双加氧酶(C12O)。将C12O通过连接到表达载体pET-28a,在E.coli BL21中得到成功表达。在温度为30℃、摇床转速恒定在150 r/min,培养的初始pH值为7.0,菲浓度为2000 mg/L的高浓度下,经过7 d的降解,其降解率为15.9%。因此,通过基因工程技术在应对多环芳烃的污染方面有着较好的应用前景。

以2-硝基糖烯为中间体合成1,2-顺式-2-氨基-2-脱氧糖的研究进展

糖疫苗因具有预防肺炎、脑膜炎和婴儿败血症等疾病的作用,近年来受到广泛关注。1,2-顺式-2-氨基-2-脱氧糖苷是一种重要的糖类衍生物,许多糖缀合疫苗中含有这种化合物结构,合成该结构对糖疫苗的研发非常关键。由2-硝基糖烯合成1,2-顺式-2-氨基-2-脱氧糖,其合成条件比较温和、环保,是理想的合成前体,因此开发一种高效合成2-硝基糖烯的方法至关重要。本文综述了2-硝基糖烯的合成以及以2-硝基糖烯为中间体合成1,2-顺式-2-氨基-2-脱氧糖苷的研究进展,为糖疫苗的研发提供理论参考。

基于(金刚烷)-1,2-二氧环丁烷结构的化学发光探针检测生物酶的研究进展

目前,在生理条件下基于(金刚烷)-1,2-二氧环丁烷结构的化学发光性能大幅提升,其化学发光方法检测各类小分子和生物大分子获得了广泛关注。利用该结构获得的化学发光探针具有无需外源激发光源、没有生物背景信号干扰、无光损伤、光漂白和高灵敏度等优点。本文综述了近几年来基于(金刚烷)-1,2-二氧环丁烷结构的化学发光检测生物酶的研究进展,并讨论了该化学发光平台在生物检测方面潜在的挑战和前景。

葛根粉中1,2-丙二醇和1,3-丙二醇的测定

目的:建立气相色谱-氢火焰离子化检测法(Gas Chromatography-Flame Ionization Detector,GC-FID)和气相色谱-质谱法(Gas Chromatography-Mass Spectrometry,GC-MS)同时检测葛根粉中1,2-丙二醇和1,3-丙二醇的分析方法。方法:试样经乙腈提取,提取液过滤后,上机测定。结果:采用GC-FID法和GC-MS法测定时,目标物质分别在0~50.00μg·mL^(-1)以及0~10.00μg·mL^(-1)线性范围内线性关系良好,相关系数r均大于0.9999;1,2-丙二醇的检出限分别为5 mg·kg^(-1)、1 mg·kg^(-1),1,3-丙二醇的检出限分别为8 mg·kg^(-1)、1 mg·kg^(-1);两种方法对应目标物质的平均加标回收率均≥89.2%,相对标准偏差均<5%。结论:GC-FID法与GC-MS法的灵敏度均较高、回收率高、重现性好,且操作简单快捷,适合于葛根粉中1,2-丙二醇和1,3-丙二醇的测定,可适应不同检测机构的需要。

铜催化草酸二甲酯加氢副产物1,2-丙二醇生成机理的DFT研究

利用密度泛函理论对Cu(111)及Cu_(2)O(111)表面上草酸二甲酯加氢副产物1,2-丙二醇(1,2-PDO)的生成机理进行了探究,计算了两种表面上1,2-PDO生成的不同反应路径基元步骤的热力学数据以及所涉及物种的吸附行为,进行了局域态密度以及差分电荷密度分析,阐明了铜催化剂的主要活性位点及1,2-PDO生成的主要路径。结果表明,1,2-PDO主要由乙二醇和甲醇于Cu_(2)O(111)表面通过Guerbet醇缩合反应生成,具体包括醇脱氢、羟醛缩合以及不饱和醛加氢三个过程。Cu_(2)O(111)表面Cu_(us)^(+)及O_(suf)^(-)位点形成的Lewis酸碱对能够促进反应物、产物及反应中间体的吸附且对于1,2-PDO生成过程的整体催化活性更高。Cu_(2)O(111)表面的O_(suf)^(-)位点是醇类脱氢生成醛、羟醛缩合过程中生成烯醇物种以及不饱和醛类中间体加氢的主要活性中心,而C-C偶联反应则发生在Cu_(us)^(+)金属位点上。论文研究结果可为铜催化剂设计和改性以及草酸酯加氢工艺的优化提供理论指导。

N-聚糖合成通路中内质网α-1,2甘露糖苷酶和α-甘露糖苷酶Ⅱ基因对家蚕胚胎滞育的调控作用

家蚕滞育是基因与环境协同作用的结果,其调控网络十分复杂,至今仍未完全阐明。为了解家蚕N-聚糖生物合成通路是否参与胚胎滞育调控,调查家蚕不同化性品系蛹期、胚胎发育早期以及滞育激素(DH)、蜕皮激素(20E)处理后BmN细胞中内质网α-1,2甘露糖苷酶基因(BmMAN1B)和α-甘露糖苷酶Ⅱ基因(BmMAN2)的转录水平。qRT-PCR结果显示:这2个基因在不同化性品系中的转录水平存在较大差异,蛹晚期的转录水平高于早期;分别用100 nmol/L DH和10 ng/mL 20E处理BmN细胞,BmMAN1B和BmMAN2的转录水平都极显著上调,提示2个基因与家蚕滞育密切相关。对BmN细胞和家蚕二化性品系秋丰165℃催青产非滞育卵组(QFLT)蛹期2 d雌蛹进行BmMAN1B和BmMAN2基因的RNA干扰,结果发现滞育相关基因BmDH、BmDHR-1、BmTRE2和BmSDH-2a等的转录水平发生了变化;当在个体水平进行BmMAN1B和BmMAN2基因的共同干扰时,382%的子代卵由非滞育转变为滞育。结果表明,BmMAN1B和BmMAN2在家蚕胚胎滞育中具有重要的调控作用。

两步法合成1,4-二(2-苯并咪唑)苯及其与不同溶剂分子的晶体结构

以邻苯二胺和对苯二甲醛为原料,在乙醇溶剂中于4℃的冰箱内反应制备新化合物1,4-二[苯胺-2-(E)-亚甲氨基]苯中间体,该中间体在体积比为5∶1的乙酸乙酯与甲醇的混合溶剂中于室温下与空气反应得到产物1,4-二[2-苯并咪唑基]苯,产物分别在N,N-二甲基甲酰胺及体积比为1∶1的三氟乙酸水溶液中析出晶体,其结构通过单晶X-射线衍射进行表征。实验结果表明,两步法合成实验操作简便、成本低廉,目标产物可与不同的溶剂及水分子形成三元结合物,且均为三斜晶系,P-1空间群。

乙二醇和1,2-丁二醇混合物与丙醛的缩合反应动力学

采用阳离子交换树脂催化剂KRD001,在釜式反应器中对EG(乙二醇)和1,2-BDO(1,2-丁二醇)混合物与丙醛的缩合反应动力学进行研究,考察传质阻力、催化剂用量、进料摩尔比和反应温度等对反应速率的影响,分析反应机理,建立反应动力学模型,并回归得到相应的动力学参数。结果表明:醛醇进料摩尔比对EG、1,2-BDO的平衡转化率和反应选择性差异影响较大。反应体系中同时发生EG与丙醛的缩合反应、1,2-BDO与丙醛的缩合反应及半缩醛(AC_(1))与1,2-BDO生成半缩醛(AC_(2))和EG的缩醛交换反应。缩醛反应过程放热,丙醛与EG的反应焓为-18.73 kJ/mol,丙醛与1,2-BDO的反应焓为-37.31 kJ/mol。二阶拟均相模型对实验数据具有良好的拟合效果,EG与丙醛正、逆反应的活化能分别是43.7和62.4 kJ/mol;1,2-BDO与丙醛正、逆反应的活化能分别是50.0和87.3 kJ/mol。

4,5-二氢吡咯并[1,2-a]喹喔啉化合物研究进展

4,5-二氢吡咯并[1,2-a]喹喔啉类化合物是一类具有广泛药理活性的含氮杂环化合物,因而,对4,5-二氢吡咯并[1,2-a]喹喔啉骨架合成研究具有重要的理论和实际研究意义。本文综述了近几十年的4,5-二氢吡咯并[1,2-a]喹喔啉的制备方法,并总结了当前合成方法的优点和局限性并对今后的发展作出了展望。

气相色谱-质谱法测定镇痛泵中增塑剂环己烷1,2-二甲酸二异壬基酯迁移量

建立气相色谱-质谱法测定镇痛泵在枸橼酸舒芬太尼模拟液中增塑剂环己烷1,2-二甲酸二异壬基酯(DINCH)迁移量,并为该产品的安全性评价提供依据。以二氯甲烷作萃取剂,萃取枸橼酸舒芬太尼模拟液中的DINCH,萃取液经HP-5MS型色谱柱(30 m×0.25 mm,0.25μm)分离,采用气相色谱-质谱法检测,外标法定量。环己烷1,2-二甲酸二异壬基酯在质量浓度为0.128~1.281µg/mL范围内与定量离子色谱峰面积线性关系良好,相关系数r为0.9992,方法检出限为0.0387µg/mL,定量限为0.174µg/mL。环己烷1,2-二甲酸二异壬基酯在模拟液中的加标回收率为93.2%,测定结果的相对标准偏差为3.5%(n=9)。该方法的灵敏度高、重复性好,适用于镇痛泵中DINCH迁移量的测定。DINCH在枸橼酸舒芬太尼模拟液中的迁移量较低,发生迁移的风险较小,相对比较安全。

可见光促进三组分合成C3-芳甲基取代的咪唑并[1,2-a]吡啶衍生物

C3-芳甲基取代的咪唑并[1,2-a]吡啶衍生物在材料及药物化学领域有着广泛应用。基于自由基对亚胺C=N键的插入串联环化策略,以2-氨基吡啶衍生物、芳基甲醛为原料、芳基溴乙炔为自由基源,在可见光促进和路易斯酸协同作用下,通过三组分串联反应,以70%~78%的产率实现了C3-芳甲基取代的咪唑并[1,2-a]吡啶衍生物的构建。目标产物结构经^(1)H NMR、^(13)C NMR和HR-MS确证。本方法无需额外添加光催化剂,操作简便、反应条件温和,具有较好的底物适用性和官能团耐受性,并且可以应用于唑吡坦的一步合成。

1,2-二氯乙烷催化裂解制氯乙烯催化剂及反应工艺研究

本文在固定床反应装置上,考察了以SAPO-34分子筛为活性组分制备的催化剂催化裂解1,2-二氯乙烷(EDC)制氯乙烯的催化反应性能,考察了空速、反应温度、载体对催化裂解1,2二氯乙烷制氯乙烯的影响,得到了优化的反应工艺条件:在350℃,常压,EDC空速为2 h^(-1)时,EDC转化率达到57%,氯乙烯选择性达98.5%。

含1,2-苯并噻嗪结构的杂原子取代薁类衍生物的合成及其抗肿瘤活性

以吡罗昔康甲基物为原料,利用生物电子等排和活性拼接等药物设计原理,设计并合成10个结构新颖的目标化合物,其结构经1H NMR、MS等表征。通过测定对胰腺癌细胞Capan-1、白血病细胞L1210和人肝癌细胞SMMC-7721的抑制活性,评价目标化合物的体外抗肿瘤活性。结果表明,化合物6f(IC_(50)=4.8±0.5μmol/L)对胰腺癌细胞Capan-1表现出较好的抑制活性;化合物6b(IC_(50)=2.6±0.3μmol/L)对白血病细胞L1210表现出较好的抑制活性;化合物6c(IC_(50)=2.1±0.2μmol/L)对人肝癌细胞SMMC-7721表现出较好的抑制活性。初步的抗肿瘤活性实验结果表明,薁类衍生物的引入,对提高该类化合物的抗肿瘤活性有一定的作用。

纤维带与无头加压螺钉治疗第1,2跖骨近端粉碎性骨折Lisfranc损伤

背景:Lisfranc韧带是维持足部横弓与纵弓的重要结构,Lisfranc损伤为一种严重的中足损伤。Lisfranc韧带损伤是复杂的,其治疗以及首选的固定方法有争议。目的:比较钢板联合Suturetape与钢板联合无头加压螺钉治疗第1,2跖骨近端粉碎性骨折Lisfranc损伤的短期疗效。方法:回顾性分析东莞市中医院骨七科2019年1月至2022年6月因第1,2跖骨近端粉碎性骨折Lisfranc损伤患者48例,其中25例采用钢板联合Suture tape固定(观察组),23例采用钢板联合无头加压螺钉固定(对照组)。术前参照影像学资料,根据Myerson分类系统进行分型;术后随访根据骨折愈合时间、目测类比评分、美国足踝外科学会标准评估足功能恢复情况,并对两组术后并发症进行比较分析。结果与结论:①两组患者均顺利完成手术并获得随访,随访时间12-36个月,平均(18.0±5.42)个月;②两组患者手术时间、术中出血量比较差异均无显著性意义(P>0.05);③观察组较对照组骨折愈合时间稍长,差异有显著性意义(P<0.05);④术后3,6,12个月随访,观察组较对照组目测类比评分明显降低(P<0.05);⑤术后6,12个月,观察组术后各时间点随访足功能AOFAS评分较螺钉组明显改善(P<0.05),且均较术前显著提高(P<0.05);⑥术后观察组出现1例创伤性关节炎,对照组出现1例切口感染、1例螺钉断裂及2例创伤性关节炎,两组比较差异无显著性意义(P>0.05),考虑与样本量偏少有关;⑦提示对于第1,2跖骨近端粉碎性骨折Lisfranc损伤,实施钢板联合Suture tape内固定治疗Lisfranc关节损伤效果可靠,可改善患者足关节功能,且具有手术创伤小、术后并发症少、远期医源性创伤性关节炎风险低的优势,较无头加压钉更有利于足功能的恢复。

食品污染物3-氯-1,2-丙二醇的来源、毒代动力学及毒性研究进展

氯丙醇类化合物的污染和超标等食品安全问题引起了国内外的广泛关注。3-氯-1,2-丙二醇(3-Monochloropropane-1,2-diol,3-MCPD)作为氯丙醇类食品污染物中最常见的代表,在酱油、植物油、婴幼儿配方奶粉、谷物食品、咖啡等多种食品中广泛存在,所以其摄入很难避免。摄入的3-MCPD经吸收后,通过血液循环分布到全身各器官和组织,从而造成健康风险。3-MCPD暴露可诱发机体产生肾毒性、肝毒性、生殖毒性、神经毒性、免疫毒性、致癌性等,但其致毒机制较为复杂,目前尚未研究清楚,其中关于3-MCPD诱导的肾毒性和生殖毒性方面研究最为广泛。该文从3-MCPD的理化性质、来源、毒代动力学、毒性及其作用机制进行综述,重点阐述了3-MCPD的毒性及其机制,以期为3-MCPD的毒性研究和控制提供依据,并为防控氯丙醇类化合物带来的食品安全问题以及健康风险评估提供参考。