Effects of histidine and n-acetylcysteine on experimental lesions induced by doxorubicin in sciatic nerve of rats

In this study, the effect of separate and combined intraperitoneal (i.p.) injections of histidine and n-acetylcysteine were investigated on experimental damage induced by doxorubicin (DOX) in sciatic nerve of rats. DOX was i.p. injected at a dose of 4?mg/kg once weekly for four weeks. Histidine and n-acetylcysteine were i.p. injected at a same dose of 20?mg/kg. Cold and mechanical allodynia were recorded using acetone spray and von Frey filaments tests, respectively. The sciatic nerve damage was evaluated by light microscopy. Plasma levels of malondialdehyde (MDA) and total antioxidant capacity (TAC) were measured. Histidine and especially n-acetylcysteine at a same dose of 20?mg/kg suppressed cold and mechanical allodynia, improved sciatic nerve lesions and reversed MDA and TAC levels in DOX-treated groups. Combination treatment with histidine and n-acetylcysteine showed better responses when compared with them used alone. The results of the present study showed peripheral neuroprotective effects for histidine and n-acetylcysteine. Reduction of free radical-induced toxic effects may have a role in neuroprotective properties of histidine and n-acetylcysteine.     

洋参御糖丸对糖尿病大鼠心肌微血管病变的干预作用

目的观察洋参御糖丸对糖尿病大鼠心肌微血管病变的干预作用。方法高糖高脂联合腹腔注射链脲佐菌素建立糖尿病大鼠心肌微血管损伤模型,筛选成模大鼠并将其随机分为模型组、二甲双胍组以及洋参御糖丸高、低剂量组,各组大鼠相应给予4周蒸馏水、二甲双胍70 mg/(kg·d)、洋参御糖丸2.7 g/(kg·d)、洋参御糖丸1.35 g/(kg·d)干预后,检测血糖、糖化血红蛋白,观察大鼠心肌超微结构以及对大鼠心肌AGEs、VEGF、VCAM-1的影响。结果洋参御糖丸高剂量组、二甲双胍组与模型组相比血糖、HbA1c均显著下降;心肌AGEs、VEGF、VCAM-1表达明显降低;电镜下心肌纤维排列整齐,肌丝结构正常,细胞核线粒体结构清晰,心肌微血管数目正常。结论洋参御糖丸在降糖同时能够修复心肌超微结构的损伤;并且具有降低AGEs、抑制病理性微血管促新生效应、抑制促内皮细胞黏附积聚作用,进而可能延缓糖尿病微血管病变进程。     

二仙汤对去卵巢大鼠心肌微血管及血液流变学的影响

目的:观察去卵巢大鼠心肌微血管密度、微血管内皮细胞形态及血液流变学的变化并探讨二仙汤的干预作用。方法:选用健康10周龄雌性SPF级SD大鼠32只,随机分为假手术组、模型组、雌激素组(戊酸雌二醇,0.18 mg·kg~(-1)),二仙汤组(9 g·kg~(-1))。去卵巢后2周开始灌胃给药,1次/d,连续16周。二仙汤组及雌激素组分别给予二仙汤或戊酸雌二醇灌胃,假手术组和模型组灌胃等体积纯净水。给药16周末,无创超声心动图(UCG)检测心功能;CD34免疫荧光染色法检测心肌微血管密度;透射电镜观测心肌微血管超微结构;放射免疫分析法检测血浆雌二醇(E_2)含量;酶联免疫吸附测定(ELISA)检测血浆内皮素-1(ET-1),前列环素I_2(PGI_2),血栓素A_2(TXA_2),血管内皮生长因子(VEGF)和血管性血友病因子(vWF)水平;凝固法检测凝血四项;血液流变学检测全血黏度和血浆黏度。结果:与假手术组比较,模型组左室射血分数(EF)显著降低(P0.01),左室短轴缩短率(FS)显著降低(P0.01),左室收缩末期容积(LVVols)显著升高(P0.01);心肌微血管密度显著减少(P0.01);心肌微血管内皮细胞肿胀明显,胞浆空化;血浆E_2含量显著降低(P0.01);ET-1,VEGF,vWF含量显著升高(P0.01),前列环素I_2/血栓素A_2(PGI_2/TXA_2)显著降低(P0.01);血浆活化部分凝血酶原时间(APTT)显著降低(P0.01),纤维蛋白原(FIB)含量显著升高(P0.01);全血黏度、血浆黏度、卡松黏度显著升高(P0.01),全血高、低切指数和红细胞聚集指数明显升高(P0.05)。与模型组比较,二仙汤组大鼠EF,FS明显升高(P0.05),LVVols明显降低(P0.05);微血管密度显著增多(P0.01);心肌微血管内皮细胞水肿改善,运输小泡清晰可见;血浆E_2显著升高(P0.01);ET-1,VEGF显著降低(P0.01),PGI_2/TXA_2显著升高(P0.01);APTT显著升高(P0.01);全血黏度、全血高切相对指数、红细胞聚集指数明显降低(P0.05),卡松黏度、血浆黏度显著降低(P0.01)。结论:二仙汤增加去卵巢大鼠心肌微血管密度、保护微血管内皮细胞结构的完整性,改善其内皮分泌功能和血液流变学,保护心功能。     

Pyridostigmine bromide and its relation to Gulf War illness

Abstract

Pyridostigmine bromide acts as a reversible cholinesterase inhibitor that is used at relatively high doses in treatment of Myasthenia gravis and in low dose regimens as prophylaxis against nerve agents poisoning during the Gulf War. The manifestation of late nonspecific symptoms commonly called Gulf War illness has led to the discussion about the role of pyridostigmine bromide in the pathogenesis of this illness. In our study, we described plasma absorption profile of pyridostigmine bromide after p.o. administration in rats; subsequently, changes in blood biochemical and oxidative stress markers were measured. Pyridostigmine bromide was applied p.o. at the dose of 5.82?mg/kg b.w. according to the previously published recommendations. The absorption of pyridostigmine was relatively fast; the C_max in plasma was 110.20?±?15.12?ng/ml at T_max of 197.12?±?17.14?min. The bioavailability expressed as AUC_total was 44,348?±?7608?min ng/ml. The prolongation of pyridostigmine in circulation is in agreement with relatively long half-life that was 179.00?±?28.54?min. Several blood biochemical markers were altered, including glucose, creatinine, creatine kinase, alanine aminotransferase, aspartate aminotransferase, interleukin-6, triglycerides, and cholesterol. However, the changes could be considered as mild. Thiobarbituric acid reactive substances and ferric reducing ability of plasma indicate suppression of basal metabolism. The results of blood biochemical and oxidative stress markers imply that long-term use might possibly change the basal metabolism and cause cellular damage with inflammatory changes.     

Evaluation of fosphenytoin,levetiracetam, and propofol as treatments for nerve agent-induced seizures in pediatric and adult rats

Multiple recent instances of nerve agent (NA) exposure in civilian populations have occurred, resulting in a variety of negative effects and lethality in both adult and pediatric populations. Seizures are a prominent effect of NAs that can result in neurological damage and contribute to their lethality. Current anticonvulsant treatments for NAs are approved for adults, but no approved pediatric treatments exist. Further, the vast majority of NA-related research in animals has been conducted in adult male subjects. There is a need for research that includes female and pediatric populations in testing. In this project, adult and pediatric male and female rats were challenged with sarin or VX and then treated with fosphenytoin, levetiracetam, or propofol. In this study, fosphenytoin and levetiracetam failed to terminate seizure activity when animals were treated 5 min after seizure onset. Propofol was effective, exhibiting high efficacy and potency for terminating seizure activity quickly in pediatric and adult animals, suggesting it may be an effective anticonvulsant for NA-induced seizures in pediatric populations.     

Comparison of dendritic cells obtained from autoimmunty-prone and resistant rats

Dendritic cells (DC) are responsible for the initiation and shaping of the adaptive immune response and are in the focus of autoimmunity research. We were interested in comparison of DC obtained from autoimmunity-prone Dark Agouti (DA) rats and autoimmunity-resistant Albino Oxford (AO) rats. DC were generated from bone marrow precursors and matured (mDC) by lipopolysaccharide. Tolerogenic DC (tolDC) obtained by vitamin D3 treatment were studied in parallel. Profile of cytokine production was different in AO and DA mDC and tolDC. Expression of MHC class II molecules and CD86 were higher in DA DC, while vitamin D3 reduced their expression in dendritic cells of both strains. Allogeneic proliferation of CD4⁺ T cells was reduced by AO tolDC, but not with DA tolDC in comparison to respective mDC. Finally, expression of various genes identified as differentially expressed in human mDC and tolDC was also analyzed in AO and DA DC. Again, AO and DA DC differed in the expression of the analyzed genes. To conclude, AO and DA DC differ in production of cytokines, expression of antigen presentation-related molecules and in regulation of CD4⁺ T proliferation. The difference is valuable for understanding the divergence of the strains in their susceptibility to autoimmunity.     

基于代谢组学探讨艾灸关元穴对老年大鼠肾能量代谢的影响＊

目的 通过UHPLC-Q-TOF-MS代谢组学探讨艾灸关元穴对老年大鼠肾代谢物的影响，进而为艾灸关元穴的作用机制提供参考。方法 将8月龄SD雄性大鼠设为成年对照组（8只），21月龄SD雄性大鼠随机分为老年对照组（8只）、老年金匮肾气丸组（7只）、老年艾灸组（8只）。老年金匮肾气丸组每日按体重给药，老年艾灸组每日艾灸关元穴15 min，均每周5天。实验持续13周后检测大鼠肾组织线粒体呼吸耗氧速率、琥珀酸脱氢酶（SDH）活性以及血清肾功能指标，观察肾脏病理变化，结合UHPLC-Q-TOF-MS技术对大鼠的肾组织进行代谢轮廓分析，筛选代谢差异物并进行鉴定。结果 与老年对照组比较，老年艾灸组大鼠肾线粒体的呼吸耗氧速率和SDH酶的活力显著提高（P<0.01）。代谢组学结果显示，肾组织中筛选出13个共同差异化合物，分别是丁酸十二烷基酯、亚油酰胺、5-甲基四氢叶酸、PC（16∶0/22∶5（7Z，10Z，13Z，16Z，19Z））、6，8-二羟基嘌呤、1，2，3-丙烷三羧酸、3-（4-甲氧基苯基）-2-氧代丙酸、吲哚-3-乙酰甘氨酸、亚麻油酸、9，10-环氧十八烷酸、二十二碳五烯酸（22n-6）、牛磺胆酸、LysoPS （18∶0/0∶0）。结论 艾灸关元穴可通过调控老年大鼠的牛磺酸和亚牛磺酸代谢、α-亚麻酸代谢、亚油酸代谢、甘油磷脂代谢来调节肾的能量代谢。