A(₂A) adenosine receptor (A(₂A)AR) as a therapeutic target in diabetic retinopathy

In diabetic retinopathy (DR), abnormalities in vascular and neuronal function are closely related to the local production of inflammatory mediators whose potential source is microglia. A_2A adenosine receptor (A_2AAR) has been shown to possess anti-inflammatory properties that have not been studied in DR. Here, we evaluate the role of A_2AAR and its underlying signaling in retinal complications associated with diabetes. Initial studies in wild-type mice revealed that the treatment with the A_2AAR agonist resulted in marked decreases in hyperglycemia-induced retinal cell death and tumor necrosis factor (TNF)-α release. To further assess the role of A_2AAR in DR, we studied the effects of A_2AAR ablation on diabetes-induced retinal abnormalities. Diabetic A_2AAR^−/− mice had significantly more terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells, TNF-α release, and intercellular adhesion molecule-1 expression compared with diabetic wild-type mice. To explore a potential mechanism by which A_2AAR signaling regulates inflammation in DR, we performed additional studies using microglial cells treated with Amadori-glycated albumin, a risk factor in diabetic disorders. The results showed that activation of A_2AAR attenuated Amadori-glycated albumin-induced TNF-α release in a cAMP/exchange protein directly activated by cAMP-dependent mechanism and significantly repressed the inflammatory cascade, C-Raf/extracellular signal-regulated kinase (ERK), in activated microglia. Collectively, this work provides pharmacological and genetic evidence for A_2AAR signaling as a control point of cell death in DR and suggests that the retinal protective effect of A_2AAR is mediated by abrogating the inflammatory response that occurs in microglia via interaction with C-Raf/ERK pathway.Diabetic retinopathy (DR) is the leading cause of blindness in the Western world and the most common complication of diabetes.^1,2 DR has been categorized as a vascular-neuroinflammatory disease. Early features of DR include signs of retinal inflammatory reactions, breakdown of the blood-retinal barrier function and loss of retinal neurons.^3–5 Under these conditions, normally quiescent microglial cells become activated.^6,7 Activated microglia release glutamate, reactive oxygen species, and proinflammatory mediators, such as tumor necrosis factor (TNF)-α.^8–10 The retinal expression of TNF-α has been reported to be associated with neuronal and endothelial cell death, hallmark features of the disease,^5,11 and inhibition of TNF-α has demonstrated beneficial effects in the prevention of early DR.¹² Thus, research on retinal microglia activation may provide insights into the pathogenesis of DR.¹³Adenosine has been proposed to modulate a variety of physiological responses.¹⁴ Under stress conditions, the local levels of extracellular adenosine are increased due to the increased need for energy supplied by ATP¹⁵ and the increased degradation of released ATP.¹⁶ The increased adenosine at inflamed sites can protect against cellular damage by activating A_2A adenosine receptor (A_2AAR), a Gs-coupled receptor.¹⁷ Treatment with an A_2AAR agonist blocked the inflammation and functional changes associated with diabetic nephropathy in wild-type diabetic mice, but not in the diabetic A_2AAR^{−/− mice}.¹⁸Recent efforts to understand how neurotoxic inflammatory cytokines are produced have shown that Ras/Raf/MEK/extracellular signal-regulated kinase (ERK) cascade is one of the attractive targets for intervention in human inflammatory-associated diseases, such as diabetes. However, this cascade does not operate alone, but rather interacts with other signaling systems, such as Gs-coupled receptor transducing pathway. Activation of this pathway results in accumulation of cAMP that interacts with the Ras/Raf/MEK/ERK kinase signaling to regulate cell functions.¹⁹Previously we demonstrated the anti-inflammatory effect of A_2AAR in acute retinal inflammation.²⁰ Currently, we seek to determine the contribution of A_2AAR in retinal protection against diabetes-induced retinal inflammation and injury. Moreover, we pursue to gain insight into the underlying signaling involved therein. Here, we report evidence that activation of A_2AAR plays a protective role in diabetes-induced retinal cell death by enhancing the anti-inflammatory signaling, including the interaction with C-Raf/ERK cascade. These findings suggest that A_2AAR agonists may be promising innovative agents in the treatment of diabetic retinopathy.     

重组蛋白A

重组蛋白A(recombinational protein A)是recA基因的产物,简称recA蛋白,又称X蛋白(protein X)。早在六十年代末就已发现rec基因组并证明它与遗传重组有着密切的关系。1975年,Radman在大肠杆菌中(E.coll)发现了一种新的DNA损伤后的修复系统——“SOS”修复。深入研究表明,这种活动都与rec基因的作用有关,而且都是recA基因产物,即recA蛋白直接作用的结果。后来,许多体内、外的实验证明,此recA蛋白具有极为活跃的生物活性。因此,本文将就recA蛋白及其生物学作用作一简要的综述。     

Corallopyronin A – A promising antibiotic for treatment of filariasis

Lymphatic filariasis and onchocerciasis are diseases of severe morbidity that affect the poorest of the poor in the world. The diseases are caused by filarial nematodes that are transmitted by mosquitoes or biting blackflies and are endemic to more than 80 countries worldwide, mainly in the tropics and sub-tropics. Current control programs aim to eliminate the diseases by distributing antifilarial drugs. However, the primary effect of the drugs is to kill the microfilariae in the blood or skin, thus preventing uptake by the obligate insect vector. Since the adult worms live 10 years or longer, drug distribution requires many years of treatment, which is a heavy burden on the burgeoning health care systems. Sub-optimal response, possible resistance and inadequate population coverage lessen the chances for successful elimination in all endemic areas. The search for new drugs that could enhance elimination by permanently sterilizing or killing adult worms has identified the Wolbachia intracellular bacteria of filarial nematodes as a target. Depleting the obligate endosymbionts from the worms with doxycycline or rifampicin causes a permanent block in oogenesis, embryogenesis and development, and in slow death of the adult worms. These two antibiotics are suitable for individual drug administration, but caveats exist for their inclusion in broader drug administration programs. Here we review Wolbachia as targets for antifilarial drug discovery and highlight the natural product corallopyronin A as an effective drug that is currently being developed specifically for use against filarial nematodes.     

A case of hemorrhagic colitis after influenza A infection

The pandemic (H1N1) influenza virus continues to be the predominant circulating virus in both the northern and southern hemispheres. In February 2009, during the early stage of the worldwide H1N1 influenza virus (influenza A) pandemic, we experienced a case of hemorrhagic colitis after infection with influenza A. A 21-year-old man with no serious disease in his past history visited our hospital with chief complaints of a high body temperature and pharyngeal pain. A diagnosis of influenza A was made using a rapid diagnosis kit (Capilia Flu A+B), and the patient was admitted to our hospital. After admission, the patient complained of a lower abdominal pain, diarrhea, and hematochezia. An emergency colonoscopy revealed active bleeding colitis from the sigmoid to descending colon. Hemorrhagic colitis was confirmed by the pathological findings of a punch biopsy specimen. After the administration of an antiviral drug, zanamivir hydrate (10 mg/d), the patient's general condition and colonoscopic findings improved significantly. The findings of both sequential colonoscopies and intestinal histology strongly suggested that infection with influenza A could induce hemorrhagic colitis, though the incidence is quite low.     

曲古柳菌素A对肺癌A549细胞凋亡的影响

目的:检测不同浓度的组蛋白去乙酰化酶抑制剂古曲柳菌素A(TSA)对A549细胞周期及细胞凋亡的影响,探讨TSA抑制A549肺癌细胞的分子机制.方法:以流式细胞术分析,Annexin V/PI 法,免疫印迹研究 TSA 对A549 细胞的细胞周期、凋亡及Bax蛋白水平变化的影响.结果:TSA处理后,100nmol/L和400nmol/L引起细胞G0/G1及G2/M期阻滞.Annexin V/PI法显示TSA可诱导细胞凋亡.Bax蛋白的表达随着TSA浓度的增高而增强.结论:不同浓度的TSA对A549细胞周期阻滞影响不同,低浓度可诱导细胞凋亡.     

维生素A与免疫

近些年来，越来越多的实验资料证实维生素Ａ与机体免疫功能的关系密切。维生素Ａ缺乏能从多方面影响免疫系统的功能，使淋巴器官萎缩、ＮＫ细胞活性降低、细胞免疫反应下降。更重要的是，维生素Ａ缺乏使机体对细菌、病毒、寄生虫等抗原成分产生的特异性抗体明显减少。维生素Ａ正常水平的动物，给予维生素Ａ，可以发挥佐剂作用，提高机体对特异抗原的抗体应答，并能增强细胞免疫，产生抗肿瘤作用。     

内皮素A受体阻滞剂

内皮素Ａ受体阻滞剂可抑制内皮素引起血管暂时舒张后的持续性收缩，使血管舒张，可治疗与内皮素有关的血管收缩性疾病。ＳＢ２０９６７０除抑制ＥＴＡＲ，ＥＴＢ１Ｒ外，还能抑制介导收缩反应的ＥＴＢ２Ｒ，能更全面地阻滞收缩反应；ＢＱ－１５３和ＢＱ－１２３等扩张血管时不影响血压；ＦＲ１３９３１抑制平滑肌细胞增殖，可能对ＥＴ－１引起的肺动脉高压有效；具有口服活性的Ｌ－７４４４５３，Ｌ－７５４１４２，Ａ－１２７７２２，ＰＤ０１２５２７，ＰＤ１５５０８０，ＳＢ２１７２４２，ＳＢ２０９６７０，ＢＭＳ－１８２７４等治疗更方便；ＰＤ１５１２４２可形成放射性结合物，使其应用更广。     

微乳剂环孢素A

微乳剂环孢素Ａ加拿大报道对一个老药作了一点改变将会对接受器官移植患者产生巨大影响。微乳剂环孢素Ａ是已被广泛应用的免疫抑制剂的一种新剂型。药物的有效成分是相同的，但作了改变使之更容易被人体吸收。以往，存在的一个大问题在于，一些患者，特别是接受肾移植者或...     

维生素A与免疫

近些年来，越来越多的实验资料证实维生素Ａ与机体免疫功能的关系密切。维生素Ａ缺乏能从多方面影响免疫系统的功能，使淋巴器官萎缩、ＮＫ细胞活性降低，细胞免疫反应下降。更重要的是，维生素Ａ缺乏使机体对细菌、病毒、寄生虫等抗原成分产生的特异性抗体明显减少。维生素Ａ正常水平的动物，给予维生素Ａ，可以发挥佐剂作用，提高机体对特异抗原的抗体应答，并能增强细胞免疫，产生抗肿瘤作用。     

大鼠运动核内5-羟色胺1A、2A、5A受体的定位分布

为了阐明５ 羟色胺在中枢神经系统内与运动神经元结合的精确部位,本研究用免疫细胞化学技术分别观察了大鼠躯体运动核和内脏运动核内５ 羟色胺１Ａ、２Ａ、５Ａ 受体的定位分布。在躯体运动核内观察到：（１）５ 羟色胺１Ａ 受体样阳性神经元和纤维主要分布于动眼神经核、滑车神经核、三叉神经运动核、面神经核、舌下神经核和脊髓前角;（２）５ 羟色胺２Ａ 受体样阳性神经元主要见于动眼神经核、三叉神经运动核、面神经核、舌下神经核和脊髓前角,但阳性纤维和终末却密集地分布于三叉神经运动核、面神经核、舌下神经核和脊髓前角等处,除此之外动眼神经核、滑车神经核、展神经核和疑核内也能见到中等密度的阳性纤维和终末,纤维和终末的分布范围和染色浓度、密度都较神经元为明显;（３）少量淡染的５ 羟色胺５Ａ 受体样阳性神经元和稀疏的阳性纤维及终末主要见于三叉神经运动核、面神经核、舌下神经核和脊髓前角。在内脏运动核内观察的结果是：（１）动眼神经副交感核（Ｅ Ｗ 核）、上涎核、迷走神经背核、骶髓副交感核和胸髓侧角内仅有少量５ 羟色胺１Ａ 受体样阳性神经元、纤维和终末分布;（２）５ 羟色胺２Ａ 受体样阳性神经元和较密集的阳性纤维和终末见于Ｅ Ｗ 核、迷走神经背核、骶?     

S100A8和S100A9的天然免疫作用

天然免疫是机体免疫的第一道防线,小分子肽S100钙结合蛋白A8(S100A8)即钙粒蛋白A (calgranulin A)和S100A9在先天防御中有多效性。S100A8和S100A9可由粒细胞、单核细胞及上皮细胞等产生,是低分子量钙结合蛋白,常可形成二聚体,与肿瘤、抗菌、损伤修复等活动密切相关,并且在修复作用中可能对损伤引起的炎症反应有反馈调节并激活指纹图谱重编程。我们主要总结了S100A8和S100A9在肿瘤、黏膜防御、损伤修复中的天然免疫作用研究进展。     

A unilateral additional right renal artery and vein – A case report

IntroductionProper knowledge of variations of the vessels of the kidney is essential to radiologist and surgeons.MethodsOne such variation was observed during dissection of a 68-year-old male cadaver at Medical College, Kolkata. The cadaver was preserved and dissected by following proper steps.ObservationOn right side in addition to normal renal artery, an additional renal artery originated from the abdominal aorta and entered into the kidney through the lower part of its hilum. The additional renal vein emerged from the lowermost point of the hilum, passed medially to end in the posterior part of inferior vena cava below the opening of normal right renal vein.ConclusionThe comprehensive knowledge of different vascular patterns is the key issue in determining the technical feasibility of different surgical interventions.