Prostaglandins and cyclooxygenases in glial cells during brain inflammation

Many brain disorders such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Huntington, stroke, head trauma, and infection, are associated with inflammation that is involved in neuropathologenesis and hyperalgesis. Microglia and astrocytes act as immune cells in the inflamed brain. Both cell types, but especially microglia, are thought to contribute to the onset of inflammation in many brain diseases by producing deleterious proinflammatory mediators. Prostaglandins (PGs), which are critical mediators of physiologic processes and inflammation, are largely produced by activated microglia and reactive astrocytes during brain inflammation. These compounds are converted from arachnoidic acid (AA) by two isoforms of the cyclooxygenase (COX) enzyme, namely COX-1 and COX-2. In particular, the action of COX-2 and PGs in CNS inflammation has gained much attention recently. PGs have been found to act neuroprotectively by elevating intracellular cAMP levels in neurons. These molecules also function as anti-inflammatory molecules to reduce the production of nitric oxide and proinflammatory cytokines, and to increase the expression of anti-inflammatory cytokines. However, accumulating evidence also shows that COX inhibitors alleviate various types of brain damage via suppressing inflammatory reactions. Accordingly, the roles of two COX enzymes in mediating inflammation and anti-inflammation have recently been debated. We provide here a review of recent findings indicating that the reciprocal interaction of glial cell activation, COX enzymes and PGs mediates neurodegeneration and neuroprotection during brain inflammation. In addition, the mechanism by which PGs mediate signaling is discussed.     

Oxidative stress,inflammation and angiogenesis markers in elite female water polo athletes throughout a season

Elite athletes undergo heavy training programs throughout the year. The aim of the present study was to evaluate blood biomarkers of redox status, oxidative stress, inflammation and angiogenesis over the course of a competitive season in elite female water polo players. The biomarkers were evaluated in four distinct phases of an athletic season. It was found that the reduced glutathione (GSH) concentration was significantly increased, whereas catalase activity was decreased in erythrocytes in phases 3 and 4 compared to phase 2. Plasma concentration of thiobarbituric acid reactive substances (TBARS) was increased in phases 3 and 4 compared to phases 1 and 2, the concentration of protein carbonyls was increased in phase 4, and total antioxidant capacity (TAC) was decreased in phases 2 and 3. Plasma monocyte chemoattractant protein-1 (MCP-1) was decreased in phases 3 and 4; interleukin-10 (IL-10) was increased in phase 4, whereas no change was observed for adiponectin and endoglin. The findings of this study indicate that oxidative stress and inflammation varies over the season in elite female water polo athletes and this information might be used to apply remedies for optimizing athletic performance and accelerating training recovery.     

术后替莫唑胺联合三维适形放疗治疗高级别胶质细胞瘤的疗效

目的探讨术后替莫唑胺(TMZ)联合三维适形放疗治疗高级别胶质细胞瘤的临床疗效。方法回顾性分析30例行术后三维适形放疗的高级别胶质细胞瘤患者的临床资料。患者分为观察组(20例,放疗联合TMZ化疗)和对照组(10例,仅行放疗),比较其近期疗效及生存率。结果观察组近期临床缓解率及1、2年生存率分别为75%(15/20)、70%(14/20)、45%(9/20),明显高于对照组的40%(4/10)、40%(4/10)、20%(2/10)(P<0.05)。结论术后TMZ联合三维适形放疗治疗高级别胶质细胞瘤疗效优于单用放疗。     

替莫唑胺联合全脑放疗治疗脑转移瘤的疗效评价

目的:评价替莫唑胺联合全脑放疗治疗脑转移瘤患者的疗效及安全性。方法:将55例脑转移瘤患者(转移灶>3个)随机分为替莫唑胺联合放疗组及放疗组。替莫唑胺联合放疗组予以常规分割行全脑放疗,DT:40 Gy(2 Gy.d-1,每周5 d),于放疗d1开始给予替莫唑胺口服治疗(75 mg.m-2.d-1),放疗结束后每28 d予以替莫唑胺口服5 d(200 mg.m-2.d-1)化疗,共6周期。放疗组全脑放疗,DT:40 Gy(2 Gy.d-1,每周5 d)。使用Kaplan-Meier方法计算生存率、无进展生存率及生存曲线,组间生存率比较应用Log-rank检验。结果:替莫唑胺联合放疗组与放疗组的客观缓解率分别为76.9%和48.0%(P=0.033);中位生存期分别为8.0和5.5个月,差异达统计学显著性(P=0.025);中位无进展生存期为分别为5.0和3.1个月,差异达统计学显著性(P=0.020)。替莫唑胺联合放疗组发生恶心、呕吐的患者显著高于单纯放疗组,但大部分患者可耐受。结论:替莫唑胺联合全脑放疗有可能提高脑转移瘤患者的局部控制及远期生存,且耐受性良好。     

动态增强-磁共振成像技术对于鼻咽癌放疗后复发与放疗后炎症的鉴别价值研究

目的观察动态增强-磁共振成像技术(DCE-MRI)在鉴定鼻咽癌放疗后复发与放疗后炎症的鉴别临床应用价值。方法选取我院20例鼻咽癌放疗后复发患者与20例鼻咽癌放疗后放射性炎症患者进行动态增强磁共振检查,观察2组患者在动态增强磁共振检查中的表现特征。结果 20例鼻咽癌放疗后复发患者均表现为鼻咽腔不对称狭窄或肿物隆突、鼻咽黏膜或浸润区多表现为凹凸不平,黏膜层和肌层、肌间隙受累、MRI中病变的信号呈稍长T1稍长T2信号,且信号不均匀,多处骨质破坏。20例鼻咽癌放疗后炎症患者中有18例表现为原鼻咽癌放疗区黏膜及组织肿胀,病变的信号呈稍长T1长T2信号,信号欠均匀。结论 DCE-MRI能够很好地区别鼻咽癌放疗后复发与放疗后炎症的鉴别,能够很好地在临床诊断中应用。     

Nicotine: specific role in angiogenesis,proliferation and apoptosis

Nowadays, tobacco smoking is the cause of ~5–6 million deaths per year, counting 31% and 6% of all cancer deaths (affecting 18 different organs) in middle-aged men and women, respectively. Nicotine is the addictive component of tobacco acting on neuronal nicotinic receptors (nAChR). Functional nAChR, are also present on endothelial, haematological and epithelial cells. Although nicotine itself is regularly not referred to as a carcinogen, there is an ongoing debate whether nicotine functions as a ‘tumour promoter’. Nicotine, with its specific binding to nAChR, deregulates essential biological processes like regulation of cell proliferation, apoptosis, migration, invasion, angiogenesis, inflammation and cell-mediated immunity in a wide variety of cells including foetal (regulation of development), embryonic and adult stem cells, adult tissues as well as cancer cells. Nicotine seems involved in fundamental aspects of the biology of malignant diseases, as well as of neurodegeneration. Investigating the biological effects of nicotine may provide new tools for therapeutic interventions and for the understanding of neurodegenerative diseases and tumour biology.     

Nicotine: specific role in angiogenesis, proliferation and apoptosis

Nowadays, tobacco smoking is the cause of ~5-6 million deaths per year, counting 31% and 6% of all cancer deaths (affecting 18 different organs) in middle-aged men and women, respectively. Nicotine is the addictive component of tobacco acting on neuronal nicotinic receptors (nAChR). Functional nAChR, are also present on endothelial, haematological and epithelial cells. Although nicotine itself is regularly not referred to as a carcinogen, there is an ongoing debate whether nicotine functions as a 'tumour promoter'. Nicotine, with its specific binding to nAChR, deregulates essential biological processes like regulation of cell proliferation, apoptosis, migration, invasion, angiogenesis, inflammation and cell-mediated immunity in a wide variety of cells including foetal (regulation of development), embryonic and adult stem cells, adult tissues as well as cancer cells. Nicotine seems involved in fundamental aspects of the biology of malignant diseases, as well as of neurodegeneration. Investigating the biological effects of nicotine may provide new tools for therapeutic interventions and for the understanding of neurodegenerative diseases and tumour biology.     

Radiotherapy and sequential temozolomide compared with radiotherapy with concomitant and sequential temozolomide in the treatment of newly diagnosed glioblastoma multiforme

Our objective was to determine and compare effects of sequential temozolomide vs. concomitant plus sequential temozolomide with conventional radiotherapy, in patients with newly diagnosed glioblastoma multiforme, comparing two independent trials. Sixty-four patients were treated on two consecutive separate phase II studies that used identical eligibility criteria and the same radiotherapy (60 Gy, 2 Gy/day, after surgery) and adjuvant temozolomide (200 mg/m/day for 5 days/28 days until progression), but differed in the absence or presence of a concomitant treatment with temozolomide (75 mg/m/day) during radiotherapy. In the first protocol (1999-2002), 21 patients (median age of 64 years) received radiotherapy alone and sequential temozolomide; in the succeeding protocol (2002-2004), 43 patients (median age of 61 years) with similar characteristics received radiotherapy with concomitant and sequential temozolomide. Median number of adjuvant cycles was five in both trials. Median survival was similar in both studies (18 vs. 17.4 months); overall survival rates at 6, 12, 18 and 24 months of all the population were 89, 69, 45 and 24%. No statistically significant differences were found among prognostic factors considered. Hematologic toxicities were mild and similar, with grade 3-4 neutropenia in 5-7% and grade 3-4 thrombocytopenia in 7-10% of patients in the sequential phases, and grade 3-4 thrombocytopenia in 7% in the concomitant phase of temozolomide. We confirmed that temozolomide combined with radiotherapy is well tolerated and provides a survival advantage compared with historical data using radiotherapy alone. Nevertheless, a concomitant use of temozolomide during radiotherapy does not seem to improve survival, although it does not increase toxicity.     

放疗联合替莫唑胺对照尼莫斯汀同步化疗治疗脑恶性胶质瘤疗效观察

目的观察脑胶质瘤术后放疗联合替莫唑胺（TMZ）与放疗联合尼莫司汀（ACNU）的近期疗效及安全性。方法经手术后病理确诊的高级别脑胶质瘤患者36例,根据患者的意愿及经济情况分为放疗联合替莫唑胺组（RT—TMZ组）18例与放疗联合尼莫司汀组（RT—ACNU组）18例,分别应用替莫唑胺（TMZ）和尼莫司汀（ACNU）化疗4～6个周期。同时进行放疗,总照射剂量60Gy,2Gy／次,1次／d,5次／周。结果两组患者观察期内均未出现Ⅲ度以上毒性反应,RT—TMZ组的I。Ⅱ度不良反应发生率较RT—ACNU组为低（P〈0．05）。RT—TMZ组有效率、控制率（83．3％,88．9％）均明显高于RT—ACNU组（55．6％,66．7％）,两组差异具统计学意义（P〈0．05）。RT—TMZ组的中1、2年生存率分别为77．8％、55．6％,优于RT—ACNU组的61．1％、33-3％（P〈O．05）。结论与放疗联合ACNU组相比,放疔联合TMZ联合组对脑胶质瘤术后患者更安全、有效。脑恶性胶质瘤患者术后放疗联合TMZ化疗疗效较好,毒副作用较轻,且TMZ口服应用方便,有较好的临床应用前景。     

Involvement of mast cells in angiogenesis and chronic inflammation

Mast cells (MC) are granulated secretory cells that have long been recognized as a rich source of biologically highly active mediators such as biogenic amines, prostaglandins, leukotrienes, proteases, cytokines and chemokines. Most of their biological functions however has been rather elusive. There are now emerging data assigning these cells a relevant role in orchestrating angiogenesis, both in normal and pathological conditions. MC indeed synthesize and release a large array of proangiogenic factors upon different stimulation pathways. In addition, MC have been recognized as key cells in mediating host innate and adaptive immune responses. This review summarizes the most recent acquisitions concerning MC involvement in angiogenic processes and chronic inflammatory reactions.     

Adipose tissue macrophages, low grade inflammation and insulin resistance in human obesity

Obesity was first described as a low-grade inflammatory condition more than a decade ago. However, it is only relatively recently that obese individuals have been described with increased macrophage infiltration of adipose tissue, as well as an increase in the number of "M1" or "classically activated" macrophages. Furthermore, macrophages have been identified as the primary source of many of the circulating inflammatory molecules that are detected in the obese state and are postulated to be causal both in the development of insulin resistance and in the progression to type 2 diabetes. There is also novel evidence to suggest that macrophages inhibit adipocyte differentiation, potentially leading to adipocyte hypertrophy, altered secretion of adipokines and ectopic storage of lipid within liver, muscle and other non-adipose tissues. Currently, it is not clear what causes increased macrophage infiltration of adipose tissue in obese individuals. Theories include altered signalling by adipocytes, nutritional induction of metabolic endotoxemia or reduced angiogenesis and local adipose cell hypoxia. Importantly, PPAR-gamma agonists have been shown to alter macrophage phenotype to "M2" or an "alternatively activated" anti-inflammatory phenotype and may induce macrophage specific cell death. Consequently, excitement surrounds the potential for specific inhibition of macrophage infiltration of adipose tissue via pharmacotherapy for obese patients and more particularly as adjunct therapy to improve insulin sensitivity in obese individuals with insulin resistance and overt type 2 diabetes.     

Resveratrol, a polyphenol found in grapes, suppresses oxidative damage and stimulates apoptosis during early colonic inflammation in rats

Oxidative stress, neutrophil infiltration, proinflammatory cytokines and eicosanoid generation are clearly involved in the pathogenesis of intestinal bowel disease. Resveratrol, a polyphenolic compound found in grapes and wine, has been shown to have anti-inflammatory, antioxidant, antitumour and immunomodulatory activities, however, its effects on experimental colitis remain unknown. We have investigated the effects of resveratrol on the colon injury caused by intracolonic instillation of trinitrobenzenesulphonic acid (TNBS) in rats. We determined the production of prostaglandin (PG)E(2) and PGD(2) in colon mucosa and the expression of cyclo-oxygenases (COX)-1 and -2 immunohistochemically. The inflammatory response was assessed by histology and myeloperoxidase activity, as an index of neutrophil infiltration. Interleukin-1 beta production, histological and histochemical analysis of the lesions were also carried out. Finally, since resveratrol has been found to modulate apoptosis we intended to elucidate its effects on colonic mucosa under early acute inflammatory conditions. Resveratrol (5-10mg/kg/day) significantly reduced the degree of colonic injury, the index of neutrophil infiltration and the levels of the cytokine. Resveratrol did not revert the increased PGE(2) levels but produced a significant fall in the PGD(2) concentration. Compared with inflamed colon, no changes in staining for COX-1 were observed in colon of resveratrol and TNBS-treated rats. In contrast, COX-2 expression was decreased. Furthermore, resveratrol enhanced apoptosis compared with already high level induced by TNBS. In conclusion, resveratrol reduces the damage in experimentally induced colitis, alleviates the oxidative events and stimulates apoptosis.     

Pycnogenol modulates apoptosis by suppressing oxidative stress and inflammation in high glucose-treated renal tubular cells

Compelling evidence indicates that polyphenolic antioxidants protect against diabetic nephropathy. Pycnogenol is made up of flavonoids, mainly procyanidins and phenolic compounds, and is a known powerful antioxidant. Hyperglycemia is characteristic of diabetic nephropathy and induces renal tubular cell apoptosis. Thus, in this study, we used high glucose-treated renal tubular cells to investigate the protective action of pycnogenol against high glucose-induced apoptosis and diabetic nephropathy. We also sought to further delineate the underlying mechanisms elicited by oxidative stress and inflammation and suppressed by pycnogenol. Results show that pycnogenol significantly suppressed the high glucose-induced morphological changes and the reduction in cell viability associated with cytotoxicity. Bcl2/Bax protein levels indicated pycnogenol’s anti-apoptotic effect against high glucose-induced apoptotic cell death. In addition, several key markers of oxidative stress and inflammation were measured for pycnogenol’s beneficial effects. Results indicate pycnogenol’s anti-oxidative and anti-inflammatory efficacy in suppressing lipid peroxidation, total reactive species (RS), superoxide (O₂), nitric oxide (NO), peroxynitrite (ONOO⁻), pro-inflammatory inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and nuclear factor-kappa B (NF-κB) nuclear translocation. Based on these results, we conclude that pycnogenol’s anti-oxidative and anti-inflammatory properties underlie its anti-apoptotic effects, suggesting further investigation of pycnogenol as a promising treatment against diabetic nephropathy.     

Natural and synthetic agents targeting inflammation and angiogenesis for chemoprevention of prostate cancer

Prostate cancer is the most common cancer in men and one of the leading causes of cancer-related deaths in Western countries. The extraordinary biological heterogeneity, the increasing incidence of this disease, and the presence of putative premalignant conditions make prostate cancer a crucial pathology to study and test pharmacological or nutritional chemopreventive strategies. It has been demonstrated that the incidence of prostate cancer is lower in Asian people, and that it increases in Asian men living in Western countries; these data point to a pivotal role of diet in the onset of prostate cancer. A large amount of work has been done in investigating chemopreventive properties of dietary compounds widely used in Asian countries (i.e. soy, soybeans, green tea, fish) in respect of the oxidants- and meat-rich diet typical of Western people, particularly of central and northern Europe. Some dietary products appear promising as chemo-preventive agents for prostate cancer, because they display both anti-oxidant and anti-inflammatory activity - and inflammation is crucial for the aetiology of adeno-carcinoma of the prostate. There is increasing evidence for close correlation between inflammation, the microenvironment and tumour-associated neo-angiogenesis causing the adverse outcomes of prostate cancer. It may thus be useful to develop new strategies to couple the treatment of inflammation-related prostate cancer and the generation of angiopreventive or antiinflammatory molecules to prevent this disease. The search for compounds with few or no adverse effects - particularly cardiovascular - as compared with the agents currently in use is therefore of greatest relevance.     

The development of inhibitors of heparanase, a key enzyme involved in tumour metastasis, angiogenesis and inflammation

Heparanase is an endo-beta-glucuronidase that degrades the glycosaminoglycan heparan sulfate, a major component of the extracellular matrix and basement membranes, and has been implicated in such processes as inflammation, angiogenesis and metastasis. The identification of inhibitors of heparanase is an attractive approach towards developing new therapeutics for metastatic tumours and chronic inflammatory diseases. This review focuses on heparanase inhibitors that have been isolated or synthesised to date. More recent developments in the understanding of heparanase structure and function that may ultimately aid in the future design of inhibitors with improved potency and specificity, are also discussed.     

心肌梗死中涉及炎症和凋亡的机制

由心肌梗死引起的炎症反应和细胞凋亡对病程的发展和预后有着极其重要的作用,炎症可以通过肿瘤坏死因子α(TNF-α)、CCAAT/增强子结合蛋白同源蛋白(CHOP)、白细胞介素10(IL-10)、α7烟酸型乙酰胆碱受体(α7nAChR)信号途径对细胞的凋亡进行调控,凋亡反馈可影响炎症的严重程度,两者共同影响了心肌梗死面积的大小和心功能的恢复。抑制炎症和减少凋亡已经成为心肌梗死后预防心室重构、调节心功能紊乱的重要环节,对其深入研究具有广阔的前景。     

Plasma biomarkers of liver injury and inflammation demonstrate a lack of apoptosis during obstructive cholestasis in mice

Cholestasis is a pathological common component of numerous liver diseases that results in hepatotoxicity, inflammation, and cirrhosis when untreated. While the predominant hypothesis in cholestatic liver injury remains hepatocyte apoptosis due to direct toxicity of hydrophobic bile acid exposure, recent work suggests that the injury occurs through inflammatory necrosis. In order to resolve this controversy, we used novel plasma biomarkers to assess the mechanisms of cell death during early cholestatic liver injury. C57Bl/6 mice underwent bile duct ligation (BDL) for 6–72 h, or sham operation. Another group of mice were given d-galactosamine and endotoxin as a positive control for apoptosis and inflammatory necrosis. Plasma levels of full length cytokeratin-18 (FL-K18), microRNA-122 (miR-122) and high mobility group box-1 protein (HMGB1) increased progressively after BDL with peak levels observed after 48 h. These results indicate extensive cell necrosis after BDL, which is supported by the time course of plasma alanine aminotransferase activities and histology. In contrast, plasma caspase-3 activity, cleaved caspase-3 protein and caspase-cleaved cytokeratin-18 fragments (cK18) were not elevated at any time during BDL suggesting the absence of apoptosis. In contrast, all plasma biomarkers of necrosis and apoptosis were elevated 6 h after Gal/End treatment. In addition, acetylated HMGB1, a marker for macrophage and monocyte activation, was increased as early as 12 h but mainly at 48–72 h. However, progressive neutrophil accumulation in the area of necrosis started at 6 h after BDL. In conclusion, these data indicate that early cholestatic liver injury in mice is an inflammatory event, and occurs through necrosis with little evidence for apoptosis.     

Role of simvastatin and/or antioxidant vitamins in therapeutic angiogenesis in experimental diabetic hindlimb ischemia: effects on capillary density, angiogenesis markers, and oxidative stress

Therapeutic angiogenesis has emerged as an attractive approach for the management of peripheral arterial disease in diabetic patients. Oxidative stress generated and aggravated by prolonged hyperglycemia may interfere with and destroy the newly formed blood vessels. Angiogenic effect of simvastatin has been reported; however, its exact mechanism is yet to be evaluated. In addition, the exact role of antioxidant vitamins in diabetic peripheral arterial disease is still controversial. The present study was undertaken to investigate the therapeutic potential of simvastatin and antioxidant vitamins (E and C) and their combined effects on angiogenesis in diabetic hind-limb ischemia. Streptozotocin diabetic rats were treated for 6 weeks with simvastatin either alone or in combination with vitamin E or vitamin C. Parameters of angiogenesis, nitric oxide, heme oxygenase-1 (HO-1), and oxidative stress markers were evaluated. CD31 immunostaining revealed an increased capillary density in ischemic gastrocnemious tissue of diabetic rats treated with either simvastatin or its combination with vitamin C. This effect was accompanied by up-regulated plasma levels of HO-1, nitric oxide, vascular endothelial growth factor (VEGF) and its intra-muscular receptor type-2 (Flk-1). Tissue reduced glutathione and antioxidant enzymes activities were normalized in groups treated with antioxidant vitamins or their combination with simvastatin with concomitant blunting of lipid peroxidation. Vitamins E and C, through their antioxidant effects, evidently enhanced the angiogenic effect of simvastatin in ischemic diabetic muscle. Hence, the use of antioxidant vitamins combined with statins to induce therapeutic angiogenesis is a promising strategy in the management of diabetes-associated peripheral arterial disease.     

米非司酮对人子宫内膜细胞凋亡及促血管生成因子表达的影响

目的为了解米非司酮对子宫内膜细胞的毒性,探讨使用米非司酮后子宫内膜细胞凋亡情况以及促血管生成因子水平变化情况。方法取培养的人子宫内膜细胞,观察不同浓度米非司酮的细胞毒性情况,以染色流式细胞术检查细胞凋亡的全科,同时使用实时荧光定量聚合酶链反应观察米非司酮对促血管生成因子水平的影响。结果发现随着药物浓度上升,细胞死亡率增加、细胞解体、排列紊乱现象严重;米非司酮对基因pro-Caspase3表达有抑制作用,药物对Ang-1表达有抑制效果,对VEGF、Ang-2表达有促进效果。结论米非司酮可能通过调控pro-Caspase3表达促进人子宫内膜细胞凋亡有效果,同时此药抑制机体Ang-1表达、增加VEGF、Ang-2表达。     

Role of Fas-ligand induced apoptosis in pulmonary inflammation and injury

In the lung, inflammation followed by the loss of epithelial cell precursors beyond a safeguard threshold, leads to increased mesenchymal repair and autonomous fibrosis. Fas-Fas ligand induced apoptosis promotes IL-1beta secretion, neutrophil extravasation, and loss of epithelial cells. In models of lung disease, inflammation and fibrosis can be controlled by interfering with either Fas-Fas ligand interaction, or with downstream caspase activation. These results suggest that the Fas-Fas ligand pathway is a target for the design of new therapeutic strategies for lung diseases.