茜草醇提物对佐剂性关节炎大鼠肝脏、脾脏损伤及Foxp3的影响

目的:以茜草醇提物干预AIA大鼠模型,探讨茜草醇提物对佐剂性关节炎(AIA)大鼠模型肝脏、脾脏损伤及脾脏组织中叉状头/翅膀状螺旋转录因子3(Foxp3)的影响。方法:将72只Wistar大鼠随机分为正常组、模型组、地塞米松(0.125 mg·kg-1)组和茜草醇提物低、中、高剂量组(2.5,5,10 g·kg-1),每组12只。适应性喂养7 d后,于其余5组大鼠右后足跖皮下注射弗氏完全佐剂(CFA)0.1 m L致炎,复制AIA模型,正常组给予等体积的蒸馏水,连续灌胃给药21 d。给药期间,用排水法测定致炎侧大鼠足体积,观察大鼠行为、体质量增长情况。给药21 d后,计算大鼠足肿胀度、脏器指数,检测肝脏组织中超氧化物歧化酶(SOD),丙二醛(MDA),髓过氧化物酶(MPO),一氧化氮(NO)水平,苏木素-伊红(HE)染色观察肝脏、脾脏病理组织学变化,免疫组化法检测大鼠脾脏组织内Foxp3蛋白表达情况。结果:与正常组比较,模型组大鼠足肿胀显著升高,脾脏、肝脏脏器指数明显降低,肝脏组织中MDA和MPO含量明显增加,脾脏中Foxp3蛋白水平显著降低(P0.05,P0.01)。与模型组比较,茜草醇提物中、高剂量组及地塞米松组大鼠足肿胀明显降低(P0.05,P0.01),但茜草醇提物低剂量组无显著性差异;茜草醇提物低、中、高剂量组大鼠脾脏、肝脏脏器指数显著增加(P0.01);改善肝脏及脾脏组织炎症变化,茜草醇提物低、高剂量组及地塞米松组均可以明显降低MDA和MPO的含量(P0.05,P0.01),仅茜草醇提物高剂量组及地塞米松组显著升高SOD活性和降低NO的含量(P0.01),茜草醇提物中、高剂量组及地塞米松组明显上调脾脏中Foxp3蛋白水平(P0.05,P0.01)。结论:茜草醇提物具有较好的抗炎作用,表明茜草醇提物可以改善AIA大鼠肝脏及脾脏损伤,增加肝脏中MDA和MPO的含量,并提高脾脏组织中Foxp3的表达水平来增强机体的免疫耐受能力。     

A novel vaccinological evaluation of intranasal vaccine and adjuvant safety for preclinical tests

Vaccines are administered to healthy humans, including infants, so the safety and efficacy must be very high. Therefore, evaluating vaccine safety in preclinical and clinical studies, according to World Health Organization guidelines, is crucial for vaccine development and clinical use. A change in the route of administration is considered to alter a vaccine’s immunogenicity. Several adjuvants have also been developed and approved for use in vaccines. However, the addition of adjuvants to vaccines may cause unwanted immune responses, including facial nerve paralysis and narcolepsy. Therefore, a more accurate and comprehensive strategy must be used to develope next-generation vaccines for ensuring vaccine safety. Previously, we have developed a system with which to evaluate vaccine safety in rats using a systematic vaccinological approach and 20 marker genes. In this study, we developed a safety evaluation system for nasally administered influenza vaccines and adjuvanted influenza vaccines using these marker genes. Expression of these genes increased dose-dependent manner when mice were intranasally administered the toxicity reference vaccine. When the adjuvant CpG K3 or a CpG-K3-combined influenza vaccine was administered intranasally, marker gene expression increased in a CpG-K3-dose-dependent way. A histopathological analysis indicated that marker gene expression correlated with vaccine- or adjuvant-induced phenotypic changes in the lung and nasal mucosa. We believe that the marker genes expression analyses will be useful in preclinical testing, adjuvant development, and selecting the appropriate dose of adjuvant in nasal administration vaccines.     

Pomegranate juice intake attenuates the increase in oxidative stress induced by intravenous iron during hemodialysis

The hemodialysis (HD) procedure induces oxidative stress (OS), which is further aggravated by intravenous (IV) iron administration, aimed at correcting anemia of patients with HD. We have recently shown that 1 year of pomegranate juice (PJ) intake attenuated OS and inflammation in patients with HD. In the current study, we hypothesized that a single dose of PJ can attenuate the enhanced OS and inflammation induced by both the dialysis procedure and IV iron administration during HD session. Twenty-seven patients with HD were randomized to receive PJ or placebo during 1 dialysis session with IV iron. Blood samples were drawn before and after the session to asses OS biomarkers such as advanced oxidation protein products and myeloperoxidase (MPO), whereas polymorphonuclear leukocyte (PMNL) counts served as an indirect measure of inflammation. At the end of the dialysis session, an increase in advanced oxidation protein products and MPO levels as well as a decrease in PMNLs counts were observed in the placebo group, whereas no significant changes occurred in the PJ group. The postdialysis increase in MPO levels in the placebo group is a direct result of PMNL degranulation, associated with postdialysis decrease in PMNL counts. Degranulation of PMNLs leads to the release of other cell moieties, such as inflammatory mediators and proteases that enhance inflammation. We conclude that PJ intake attenuated the increase in systemic OS and inflammation induced by IV iron administration during the dialysis session. These beneficial effects illuminate the previously observed attenuation in OS and inflammation in patients with HD on prolonged PJ intake.     

卡托普利对大鼠局灶性脑缺血再灌注损伤后炎症反应的影响

目的观察血管紧张素转化酶抑制药卡托普利对大鼠局灶性脑缺血再灌注损伤后炎症反应的影响。方法采用血管内栓线阻断法制备大鼠局灶性脑缺血再灌注损伤模型,于脑缺血1 h、再灌注24 h后测定脑组织中髓过氧化物酶(MPO)活性,免疫组织化学方法测定细胞间黏附分子(ICAM-1)表达。结果卡托普利可明显抑制MPO活性及ICAM-1的表达。结论卡托普利可抑制脑缺血再灌注损伤后炎症反应。     

Curcumin ameliorates hepatic chronic inflammation induced by bile duct obstruction in mice through the activation of heme oxygenase-1

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Investigation into the role of the cholinergic system in radiation-induced damage in the rat liver and ileum

It has been previously shown that acetylcholine (ACh) may affect pro-inflammatory and anti-inflammatory cytokines. The role of the cholinergic system in radiation-induced inflammatory responses and tissue damage remains unclear. Therefore, the present study was designed to determine the radio-protective properties of the cholinergic system in the ileum and the liver of rats. Rats were exposed to 8-Gy single-fraction whole-abdominal irradiation and were then decapitated at either 36 h or 10 d post-irradiation. The rats were treated either with intraperitoneal physiological saline (1 ml/kg), physostigmine (80 µg/kg) or atropine (50 μg/kg) twice daily for 36 h or 10 d. Cardiac blood samples and liver and ileal tissues were obtained in which TNF-α, IL-1β and IL-10 levels were assayed using ELISA. In the liver and ileal homogenates, caspase-3 immunoblots were performed and myeloperoxidase (MPO) activity was analyzed. Plasma levels of IL-1β and TNF-α increased significantly following radiation (P < 0.01 and P < 0.001, respectively) as compared with non-irradiated controls, and physostigmine treatment prevented the increase in the pro-inflammatory cytokines (P < 0.01 and P < 0.001, respectively). Plasma IL-10 levels were not found to be significantly changed following radiation, whereas physostigmine augmented IL-10 levels during the late phase (P < 0.01). In the liver and ileum homogenates, IL-1β and TNF-α levels were also elevated following radiation, and this effect was inhibited by physostigmine treatment but not by atropine. Similarly, physostigmine also reversed the changes in MPO activity and in the caspase-3 levels in the liver and ileum. Histological examination revealed related changes. Physostigmine experiments suggested that ACh has a radio-protective effect not involving the muscarinic receptors.     

支气管哮喘患儿MPO、PMN及MCP-4的血清水平及临床意义

目的 探讨外周血清过氧化物酶(myeloperoxidase,MPO)、中性粒细胞(neutrophils,PMN)及单核细胞趋化蛋白-4(monocyte chemoattractant protein-4,MCP-4)在小儿支气管哮喘的血清水平,为临床有效防治提供有效参考。方法 采用酶联免疫吸附法分别测定67例支气管哮喘患儿(哮喘组)和30例健康儿童(正常对照组)血清MPO、PMN及MCP-4水平,并进行比较。结果 1)MPO的血清水平在支气管哮喘急性发作期为[(878.43±18.77)U/L] 高于哮喘缓解组[(678.62±33.36)U/L]及健康对照组[(703.17±18.26)U/L](P均＜0.05);2)MCP-4在支气管哮喘急性发作期患儿血清水平[(117.34±18.77)pg/mL]高于哮喘缓解组[(55.67±6.13)pg/mL]及健康对照组[(33.74±2.98)pg/mL](P均＜0.05)。3)PMN绝对值在支气管哮喘急性发作期[(10.31±1.98)×10⁹/L]高于哮喘缓解组[(4.63±1.51)×10⁹/L]及健康对照组[(4.82±1.51)×10⁹/L](P均＜0.05)。MPO、PMN及MCP-4的升高程度与病情严重程度相关,且两者之间呈正相关(r=0.976,0.989;P均<0.01)。结论 MPO、PMN及MCP-4在支气管哮喘中发挥了重要作用,与气道炎症反应有关,血清MPO、PMN及MCP-4可做为支气管哮喘的生化检测指标。哮喘缓解期仍存在慢性炎症反应。     

Optimization of novel tocopheryl acetate nanoemulsions for parenteral delivery of curcumin for therapeutic intervention of sepsis

Objective: The objective of this study is to develop a nanostructured parenteral delivery system, laden with curcumin (CUR), for the therapeutic intervention of sepsis and associated pathologies.

Methods: Nanoemulsions were fabricated using sonication and speed homogenization. Size and zeta potential were evaluated by dynamic light scattering and transmission electron microscopy analysis. Pharmacodynamic and pharmacokinetic studies were performed on a rat model of lipopolysaccharide (LPS)-induced sepsis.

Results: The drug content of optimized nanoemulsion (F5) formulation (particle size 246 ± 08 nm, polydispersity index (PDI) of 0.120, zeta potential of ?41.1 ± 1.2 mV) was found to be 1.25 mg/ml. In vitro release studies demonstrated that F5 was able to sustain the release of CUR for up to 24 h. Minimal hemolysis and cellular toxicity demonstrated its suitability for intravenous administration. Significant reduction of inflammatory mediator levels was mediated through enhanced uptake by in RAW 264.7 and THP-1 in absence/presence of LPS. Nanoemulsion resulted in an improvement of plasma concentration (AUC_F5/AUC _CUR = 8.80) and tissue distribution of CUR in rats leading to a reduction in LPS-induced lung and liver injury due to less neutrophil migration, reduced TNF-α levels and oxidative stress (demonstrated by levels of lipid peroxides as well as carbonylated proteins) as confirmed by histopathological studies.

Conclusion: The findings suggest that the therapeutic performance (i.e., reduction in oxidative damage in tissues) of CUR can be enhanced by employing tocol acetate nanoemulsions (via improving pharmacokinetics and tissue distribution) as a platform for drug delivery in sepsis-induced organ injury.     

Modulatory effects of sesamol in dinitrochlorobenzene-induced inflammatory bowel disorder in albino rats

BackgroundInflammatory bowel disease (IBD) is a chronic inflammatory condition of gastrointestinal tract of immune, genetic and environmental origin. In the present study, we examined the effect of sesamol (SES), the main anti-oxidative constituent of Sesamum indicum (sesame seed) Linn. in the dinitrochlorobenzene (DNCB)-induced model for IBD in rats.MethodsThe groups were divided into normal control, DNCB control, SES and sulfasalazine (SS). On day 24, the rats were killed, colon removed and the macroscopic, biochemical and histopathological evaluations were performed.ResultsThe levels of MPO, TBARS and nitrite increased significantly (p < 0.05) in the DNCB group, whereas reduced significantly in the SES, SS treated groups. Serum nitrite levels were found to be insignificant between the different groups. IL-6 and TNF-α levels were significantly high in the DNCB group.ConclusionsWe conclude the mucosal protective effect of SES on colon due to its potent antioxidant actions. Further investigation is required in a chronic model of different rodent strain for its role involved in the cytokine pathway.