Effects of sildenafil on inflammatory injury of the lung in sodium taurocholate-induced severe acute pancreatitis rats

BackgroundInflammatory response and acute lung injury (ALI) occur in sodium taurocholate-induced severe acute pancreatitis (SAP). Because sildenafil has anti-inflammatory, anti-oxidant and immune-modulating effects, we investigated its effect on inflammatory and lung injury in sodium taurocholate-induced SAP-associated ALI rat lung.MethodsSodium taurocholate-induced SAP rats received sildenafil (100 mg/kg) or not and were compared to age-matched normal control animals. We evaluated inflammatory response by detecting the expression of inflammatory factors including IL-1β, IL-6 and TNF-α, and detected the level of lung injury through histopathological evaluation. Moreover, we also tested the protein expression of PCNA, P21, Bcl-2 and Bax in the lung.ResultsSildenafil administration rats had a low level of lung injury and inflammation. In addition, sildenafil significantly increased the expression of proliferation-related markers and decreased the expression of apoptosis-related markers in lung tissue.ConclusionsSildenafil administration may attenuate inflammation and lung injury by promoting proliferation and suppressing apoptosis in SAP rats.     

Pathologically triggered in situ aggregation of nanoparticles for inflammation-targeting amplification and therapeutic potentiation

Uncontrolled and persistent inflammation is closely related to numerous acute and chronic diseases. However, effective targeting delivery systems remain to be developed for precision therapy of inflammatory diseases. Herein we report a novel strategy for engineering inflammation-accumulation nanoparticles via phenolic functionalization. Different phenol-functionalized nanoparticles were first developed, which can undergo in situ aggregation upon triggering by the inflammatory/oxidative microenvironment. Phenolic compound-decorated poly (lactide-co-glycolide) nanoparticles, in particular tyramine (Tyr)-coated nanoparticles, showed significantly enhanced accumulation at inflammatory sites in mouse models of colitis, acute liver injury, and acute lung injury, mainly resulting from in situ cross-linking and tissue anchoring of nanoparticles triggered by local myeloperoxidase and reactive oxygen species. By combining a cyclodextrin-derived bioactive material with Tyr decoration, a multifunctional nanotherapy (TTN) was further developed, which displayed enhanced cellular uptake, anti-inflammatory activities, and inflammatory tissue accumulation, thereby affording amplified therapeutic effects in mice with colitis or acute liver injury. Moreover, TTN can serve as a bioactive and inflammation-targeting nanoplatform for site-specifically delivering a therapeutic peptide to the inflamed colon post oral administration, leading to considerably potentiated in vivo efficacies. Preliminary studies also revealed good safety of orally delivered TTN. Consequently, Tyr-based functionalization is promising for inflammation targeting amplification and therapeutic potentiation of nanotherapies.     

羟乙基淀粉对大鼠心肌缺血再灌注后无复流的影响

 目的: 探讨羟乙基淀粉(HES 130/0.4)对大鼠心肌缺血再灌注中无复流现象的影响及机制。方法: 36只SD大鼠随机分为缺血-再灌注组(IR组),生理盐水组(NS-IR组),羟乙基淀粉组(HES-IR组)和假手术组(sham组)。NS-IR和HES-IR组在缺血30 min时分别静注生理盐水和HES 130/0.4,再灌注180 min后以Evans blue、Thilflavin S和TTC染色测定心肌梗死面积与无复流范围,同时检测心肌肌酸激酶同工酶(CK-MB)、心肌肌钙蛋白I(cTnI)含量和髓过氧化物酶(MPO)活性。培养心肌微血管内皮细胞,随机分为正常对照组(Con组),缺氧-复氧组(H/R组),生理盐水组(NS-H/R组)和羟乙基淀粉组(HES-H/R组),以缺氧复氧法模拟急性缺血再灌注,测定游离钙离子浓度、细胞活力和凋亡率。结果: HES-IR组大鼠心肌梗死面积、无复流范围、心肌酶CK-MB、cTnI和MPO与IR组相比均减少(P<0.05)。HES-H/R组细胞内游离钙离子浓度和细胞凋亡率较H/R组亦明显减少(P<0.05),而细胞活力增高(P<0.05)。结论: HES 130/0.4能改善心肌缺血-再灌注后的无复流现象,其机制不仅涉及对中性粒细胞激活、浸润的抑制,还与减轻内皮细胞钙超载有关。     

IgA nephropathy with myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO ANCA): a discrepancy between the histological activity and MPO ANCA

Anti-neutrophil cytoplasmic antibodies (ANCA) of the immunoglobulin (Ig)G type are associated with rapidly progressive glomerulonephritis. Such antibodies have been detected only rarely in patients with Henoch-Schönlein purpura (HSP) or IgA nephropathy (IgAN). We report a patient with biopsy-proven IgAN with fibrous crescents in whom high titers of IgG ANCA occurred and were confirmed to be anti-myeloperoxidase antibodies (MPO ANCA) by solid-phase enzyme-linked immunosorbent assay (ELISA) and inhibition studies. During a 1-year follow-up period, high titers of MPO ANCA persisted but creatinine clearance remained over 50 ml/min per 1.48 m.² This case suggests the lack of a reliable association between fulminant outcome of IgAN with crescents and high titers of IgG MPO ANCA, and indicates the involvement of subsets of IgG MPO ANCA which recognize important or unimportant epitopes of MPO in the pathogenesis.     

胞浆内抗原CD_3、CD_(22)、MPO的检测方法及临床意义

目的 :探讨和明确胞浆内抗原 CD3、CD2 2 、MPO的检测方法及其在白血病诊断中的意义。方法 :采用多聚甲醛和甲醇联合固定细胞 ,单抗间接荧光法标记细胞内相应的抗原 ,在荧光显微镜下检测计数 ,并将结果与形态学和细胞表面抗原检测结果进行对照研究。结果 :19例初诊患者中 ,11例 MPO阳性 ,6例 Cy CD2 2 阳性 ,1例Cy CD3阳性 ,1例 3项均为阴性 ,结合形态学和表面抗原分析 ,全部病例获得明确诊断。结论 :胞浆内 CD3、CD2 2 、MPO的检测简便、准确、灵敏度高 ,可在临床广泛开展使用 ,对白血病的诊断和鉴别诊断具有重要意义     

脑缺血后处理对缺血再灌注脑组织细胞间黏附因子-1和髓过氧化物酶的影响

目的探讨脑缺血后处理对缺血再灌注损伤脑组织的保护机制。方法将20只SD大鼠随机分为假手术组、缺血-再灌注组、缺血后处理组及延迟缺血后处理组。采用Longa大鼠MCAO模型方法,于缺血30min、再灌注24h后应用2%氯化三苯基四氮唑染色检测梗死体积,比色法检测髓过氧化物酶活性变化,RT-PCR法检测细胞间黏附因子-1(ICAM-1)的表达。结果脑缺血后处理明显减少脑梗死体积(P0.05),降低髓过氧化物酶活性(P0.05),可抑制缺血再灌注所诱导的ICAM-1mRNA的表达(P0.05);延迟脑缺血后处理组与缺血再灌注相比无明显改变。结论脑缺血后处理有脑保护作用,其保护作用有时间依赖性,可能通过抑制细胞间黏附因子-1活性和中性粒细胞浸润起到脑保护作用。     

Association of colorectal cancer with pathogenic Escherichia coli: Focus on mechanisms using optical imaging

AIM: To investigate the molecular or cellular mechanisms related to the infection of epithelial colonic mucosa by pks-positive Escherichia coli (E. coli) using optical imaging. METHODS: We choose to evaluate the tumor metabolic activity using a fluorodeoxyglucose analogue as 2-deoxyglucosone fluorescent probes and to correlate it with tumoral volume (mm³). Inflammation measuring myeloperoxidase (MPO) activity and reactive oxygen species production was monitored by a bioluminescent (BLI) inflammation probe and related to histological examination and MPO levels by enzyme-linked immunosorbent assay (ELISA) on tumor specimens. The detection and quantitation of these two signals were validated on a xenograft model of human colon adenocarcinoma epithelial cells (HCT116) in nude mice infected with a pks-positive E. coli. The inflammatory BLI signal was validated intra-digestively in the colitis-CEABAC10 DSS models, which mimicked Crohn’s disease. RESULTS: Using a 2-deoxyglucosone fluorescent probe, we observed a high and specific HCT116 tumor uptake in correlation with tumoral volume (P = 0.0036). Using the inflammation probe targeting MPO, we detected a rapid systemic elimination and a significant increase of the BLI signal in the pks-positive E. coli-infected HCT116 xenograft group (P < 0.005). ELISA confirmed that MPO levels were significantly higher (1556 ± 313.6 vs 234.6 ± 121.6 ng/mL P = 0.001) in xenografts infected with the pathogenic E. coli strain. Moreover, histological examination of tumor samples confirmed massive infiltration of pks-positive E. coli-infected HCT116 tumors by inflammatory cells compared to the uninfected group. These data showed that infection with the pathogenic E. coli strain enhanced inflammation and ROS production in tumors before tumor growth. Moreover, we demonstrated that the intra-digestive monitoring of inflammation is feasible in a reference colitis murine model (CEABAC10/DSS). CONCLUSION: Using BLI and fluorescence optical imaging, we provided tools to better understand host-pathogen interactions at the early stage of disease, such as inflammatory bowel disease and colorectal cancer.     

Increased myeloperoxidase enzyme activity in plasma is an indicator of inflammation and onset of sepsis

Introduction

Circulating lipopolysaccharides released from bacteria may activate both neutrophils and monocytes. The activated neutrophils release myeloperoxidase (MPO), a specific enzyme with strong oxidative activity. The aim of this study was to evaluate MPO enzyme activity in plasma of critically ill patients and to check the hypothesis that these concentrations in plasma would be higher in sepsis and systemic inflammatory conditions, as neutrophils release their contents before proliferating in response to stress.

Material and Methods

Blood samples were collected from 105 critically ill patients admitted to the intensive care unit, consisting of those with systemic inflammatory response syndrome (n = 42), sepsis (n = 37), and septic shock (n = 26). Plasma MPO enzyme activity was determined by o-dianisidine-H₂O₂ method, modified for 96-well plates.

Results

The plasma MPO enzyme activity in sepsis patients was significantly higher than that in the control group (mean, 2.4 ± 1.8 in sepsis and 1.86 ± 1.2 nmol per milligram protein per 10 minutes in systemic inflammatory response syndrome vs 0.32 ± 0.11 nmol per milligram protein per 10 minutes in healthy controls). Mean plasma lactate levels in sepsis (7.8 ± 1.2 mmol/L) and shock patients (9.5 ± 1.2 mmol/L) and cytokines like tumor necrosis factor–α, interleukin-8, and interleukin-1β were simultaneously evaluated to establish onset of inflammation and sepsis. These results show that neutrophil activation occurring during inflammation and sepsis could be detected by plasma MPO concentration.

Conclusion

The plasma MPO concentrations may be a marker of the neutrophil proliferation and severity of inflammation.     

Neuroprotective effects of alpha-lipoic acid in experimental spinal cord injury in rats

Background:

Oxidative stress is a mediator of secondary injury to the spinal cord following trauma.

Objective:

To investigate the putative neuroprotective effect of α-lipoic acid (LA), a powerful antioxidant, in a rat model of spinal cord injury (SCI).

Methods:

Wistar albino rats were divided as control, vehicle-treated SCI, and LA-treated SCI groups. To induce SCI, a standard weight-drop method that induced a moderately severe injury (100 g/cm force) at T10 was used. Injured animals were given either 50 mg/kg LA or saline at 30 minutes postinjury by intraperitoneal injection. At 7 days postinjury, neurologic examination was performed, and rats were decapitated. Spinal cord samples were taken for histologic examination or determination of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity, and DNA fragmentation. Formation of reactive oxygen species in spinal cord tissue samples was monitored by using a chemiluminescence (CL) technique.

Results:

SCI caused a significant decrease in spinal cord GSH content, which was accompanied with significant increases in luminol CL and MDA levels, MPO activity, and DNA damage. Furthermore, LA treatment reversed all these biochemical parameters as well as SCI-induced histopathologic alterations. Conversely, impairment of the neurologic function caused by SCI remained unchanged.

Conclusion:

The present study suggests that LA reduces SCI-induced oxidative stress and exerts neuroprotection by inhibiting lipid peroxidation, glutathione depletion, and DNA fragmentation.