一氧化氮与乙型肝炎病毒感染状态的关系初探

一氧化氮 (ｎｉｔｒｉｃｏｘｉｄｅ ,ＮＯ)是一种新型的生物活性分子 ,在神经信息传递、心脑血管调节、抗感染免疫和抗肿瘤免疫方面起重要作用。一氧化氮合成酶 (ｎｉｔｒｉｃｏｘｉｄｅｓｙｎｔｈａｓｅ ,ＮＯＳ)是催化Ｌ 精氨酸生成ＮＯ的酶类。目前 ,有关ＮＯ和ＮＯＳ在肝细胞损伤和肝病发病机理中的作用已有相关报道 ,但多局限于动物实验 ,且报道各不一致。有关ＮＯ和ＮＯＳ在乙型肝炎病毒 (ＨＢＶ)感染过程中的作用尚少见报道。我们试图通过分析ＨＢＶ不同感染状态患者血清中ＮＯ和ＮＯＳ的含量 ,来探讨ＮＯ和ＮＯＳ在ＨＢＶ感染过程中…     

诱导型一氧化氮合酶(iNOS)与动脉血压的调节

一氧化氮（ｎｉｔｒｉｃｏｘｉｄｅ,ＮＯ）具有强大的扩血管作用,体内ＮＯ的合成由一氧化氮合酶（ｎｉｔｒｉｃｏｘｉｄｅｓｙｎｔｈａｓｅ,ＮＯＳ）催化底物精氨酸（Ｌ－ａｒｇｉｎｉｎｅ,Ｌ－Ａｒｇ）的氨基上的Ｎ与分子氧（Ｏ２）结合生成。目前已经证明至少存在三种ＮＯＳ,即内皮型ＮＯＳ（ｅＮＯＳ）、诱导型ＮＯＳ（ｉＮＯＳ）及神经型ＮＯＳ（ｎＮＯＳ）。虽然大量的研究表明ｅＮＯＳ在血液动力学中具有极其重要的调节作用,但有关ｉＮＯＳ在血液动力学中的作用却知之甚少。我们以前的工作表明,高盐能刺激ＳＤ大鼠ＮＯ的生成及…     

肺内一氧化氮含量的变化与肺纤维化的关系

目的和方法 :为探讨一氧化氮 (ｎｉｔｒｉｃｏｘｉｄｅ ,ＮＯ)在肺纤维化形成中的作用 ,本实验动态观察了气管内注入平阳霉素 (ｂｌｅｏｍｙｃｉｎＡ5,ＢＬＭＡ5) 5ｍｇ/ｋｇ后 7ｄ至 30ｄ ,大鼠出、入肺血ＮＯ代谢终产物ＮＯ-2 /ＮＯ-3 含量、肺间质诱导型一氧化氮合酶 (ｉｎｄｕｃｉｂｌｅｎｉｔｒｉｃｏｘｉｄｅｓｙｎｔｈａｓｅ,ｉＮＯＳ)蛋白表达的变化及其与肺组织羟脯氨酸含量变化间的关系。ＳＤ大鼠 2 4只 ,分为注ＢＬＭＡ5 后 7ｄ、1 4ｄ、30ｄ组 (简称 :ＢＬＭＡ57ｄ、ＢＬＭＡ51 4ｄ、ＢＬＭＡ530ｄ组 )和假手术组 (ｓｈａｍ) ,…     

一氧化氮合酶在人吞噬细胞的表达上调TNF—α生成

本研究用鼠巨噬细胞诱导型一氧化氮合酶（ｉｎｄｕｃｉｂｌｅｎｉｔｒｉｃｏｘｉｄｅｓｙｎｔｈａｓｅ，ｉＮＯＳ）ｃＤＮＡ构建质粒表达载体，由电钻孔方法导入人单核细胞样细胞Ｕ９３７，经抗性标记筛选获得ｉＮＯＳ稳定表达细胞，蛋白印迹法证实，ｉＮＯＳ基因转当细胞表达了鼠巨噬细胞一氧化氮合酶，该细胞可随培养时间延长测得一氧化氮（ｎｉｔｒｉｃｏｘｉｄｅ，ＮＯ）的稳定代谢产物硝酸盐和亚硝酸盐含量积累增加，这种积累增     

高盐对SD大鼠肾组织一氧化氮合酶(NOS)表达的影响

肾脏作为调节水盐代谢的主要器官,对血流动力学具有极为重要的调控作用。一氧化氮（ｎｉｔｒｉｃｏｘｉｄｅ,ＮＯ）是近来所发现的最重要的血管活性物质。我们以前的工作表明肾组织是机体ＮＯ的重要来源之一,肾髓质局部输入一氧化氮合酶（ＮＯＳ）抑制剂ａｍｎｏｇｕａｎｉｄｉｎｅ（ＡＧ）、Ｎω－ｍｏｎｏｍｅｔｈｙｌ－Ｌ－ａｒｇｉｎｉｎｅ（Ｌ－ＮＭＭＡ）等能明显放大高盐所致的ＳＤ大鼠血压升高效应初步证明了肾源性ＮＯ参与了血流动力学的调控。为进一步验证肾源性ＮＯ的这一作用,我们应用Ｗｅｓｔｅｒｎｂｌｏｔ方法检测了给…     

人类血管内皮细胞一氧化氮合成酶基因启动子序列的功能分析

目的 血管内皮细胞一氧化氮合成酶（ｅｎｄｏｔｈｉｌｉａｌ ｎｉｔｒｉｃ ｏｘｉｄｅ ｓｙｎｔｈａｓｅ,ｅｃＮＯＳ）在体内催化一氧化氮合成。为研究一氧化氮合成酶基因转录的调控,对一氧化氮合成酶基因启动子序列进行功能分析。方法 以血管内皮细胞核提取物为材料,采用凝胶迁移实验和ＤＮａｓｅⅠ足迹法实验。结果 启动子序列有３个区域与蛋白／转录因子结合。其中（－１０６～－８８）ＧＣ含量丰富,为转录因子ＳＰ１所     

诱导型一氧化氮合酶与疾病

迟至 2 0世纪 80年代末 ,一氧化氮 (ｎｉｔｒｉｃｏｘｉｄｅ ,ＮＯ)才被认识到是人体内一种生物学活性分子。人体内的ＮＯ有两个来源。一为非酶生 (ｎｏｎ -ｅｎ ｚｙｍｓｔｉｇｅｎｅｓｅ) ,来自体表或者摄入的无机氮的化学降解 /转化 ;一为酶生 (ｅｎｚｙｍｓｔｉｇｅｎｅｓｅ) ,由ＮＯ合酶(ＮＯｓｙｎｔｈａｓｅＮＯＳ)所合成。现已认识到ＮＯ既是一个有细胞毒性效应器作用的分子 ,是组织损伤的诱发因子和各种病变的增强因子 ,有其病理上不好的一面 ;又是生物体许多部分的信号 (ｓｉｇｎａｌ)分子 ,是先天性免疫应答的调节性效应分子 ,作…     

急,慢性缺氧对肺组织一氧化氮合成酶活性的影响

本文利用β－ＮＡＤＰＨ－ｄ组织化学法发现，急性缺氧时肺动脉内皮之一氧化氮合成酶（ｎｉｔｒｉｃｏｘｉｄｅｓｙｎｔｈａｓｅ，ＮＯＳ）阳性着色降低，而肺组织中ＮＯＳ阳性神经纤维数目增及着色明显增强，呈典型串珠状，并可见神经元及丝状神经纤维。同时见支气管上皮的ＮＯＳ着色略降低，慢性缺氧时，肺动脉内皮增厚，充盈，ＮＯＳ着色加深，而支气管上皮ＮＯＳ着色更加降低，因此，急性缺氧所致肺动脉收缩反应可能与内皮ＮＯ生     

2型糖尿病患者血NO/NOS和TNF检测的临床意义

众所周知 ,一氧化氮 (ＮＯ)是一种具有多种生物学活性的物质 ,它具有松驰血管平滑肌、舒张血管、抑制血小板聚集以及抑制内皮细胞增殖作用[1] 。一氧化氮酶 (ｎｉｔｒｉｃＯｘｉｄｅＳｙｎ ｔｈｅｔａｓｅ ,ＮＯＳ)为其催化酶。肿瘤坏死因子 (ＴＮＦ)是一种多肽激素 ,它是由巨噬细胞和单核细胞所分泌的一种细胞因子[2 ] 。近年的研究表明[3 ] ,ＴＮＦ在糖尿病的发生和发展中起着举足轻重的作用。本文对 2型糖尿病患者进行血ＮＯ/ＮＯＳ和ＴＮＦ检测 ,旨在探讨它们在该病的发生、发展中的作用。现将结果报告如下。对象和方法一、对象 :(一 )…     

大鼠小肠肌间神经丛一氧化氮合酶阳性神经元的发育研究

大鼠小肠肌间神经丛一氧化氮合酶阳性神经元的发育研究（第三军医大学组织学与胚胎学教研室，重庆６３００３８肖岚，蔡文琴）近年来的研究提示，一氧化氮为一类特殊的神经递质，并且认为神经系统的一氧化氮合酶（ｎｉｔｒｉｃｏｘｉｄｅｓｙｎｔｈａｓｅ，ＮＯＳ）就是Ｎ...     

Nitric oxide and bone.

Nitric oxide (NO) is a free radical which has important effects on bone cell function. The endothelial isoform of nitric oxide synthase (eNOS) is widely expressed in bone on a constitutive basis, whereas inducible NOS is only expressed in response to inflammatory stimuli. It is currently unclear whether neuronal NOS is expressed by bone cells. Pro-inflammatory cytokines such as IL-1 and TNF cause activation of the iNOS pathway in bone cells and NO derived from this pathway potentiates cytokine and inflammation induced bone loss. These actions of NO are relevant to the pathogenesis of osteoporosis in inflammatory diseases such as rheumatoid arthritis, which are characterized by increased NO production and cytokine activation. Interferon gamma is a particularly potent stimulator of NO production when combined with other cytokines, causing very high concentrations of NO to be produced. These high levels of NO inhibit bone resorption and formation and may act to suppress bone turnover in severe inflammation. The eNOS isoform seems to play a key role in regulating osteoblast activity and bone formation since eNOS knockout mice have osteoporosis due to defective bone formation. Other studies have indicated that the NO derived from the eNOS pathway acts as a mediator of the effects of oestrogen in bone. eNOS also mediates the effects of mechanical loading on the skeleton where it acts along with prostaglandins, to promote bone formation and suppress bone resorption. Pharmacological NO donors have been shown to increase bone mass in experimental animals and preliminary evidence suggests that these agents may also influence bone turnover in man. These data indicate that the L-arginine/NO pathway represents a novel target for therapeutic intervention in the prevention and treatment of bone diseases.     

Efficacy of oral etidronate for skeletal diseases in Japan

Etidronate is an oral bisphosphonate compound that is known to reduce bone resorption through the inhibition of osteoclastic activity. The efficacy of etidronate for involutional (postmenopausal and senile) and glucocorticoid-induced osteoporosis, as well as that for other skeletal diseases, was reviewed in Japanese patients. Cyclical etidronate treatment (200 mg or 400mg/day for 2 weeks about every 3 months) increases the lumbar bone mineral density (BMD) in patients with involutional osteoporosis and prevents incident vertebral fractures in patients with glucocorticoid-induced osteoporosis. The losses of the lumbar BMD in patients with liver cirrhosis and the metacarpal BMD in hemiplegic patients after stroke are prevented, and the lumbar BMD is possibly increased, preventing fragile fractures in adult patients with osteogenesis imperfecta type I. Furthermore, proximal bone resorption around the femoral stem is reduced and some complications may be prevented in patients who undergo cementless total hip arthroplasty. Oral etidronate treatment may also help to transiently relieve metastatic cancer bone pain followed by a decrease in abnormally raised bone resorption in patients with painful bone metastases from primary cancer sites, such as the lung, breast and prostate. Thus, oral etidronate treatment is suggested to be efficacious for osteoporosis, as well as other skeletal diseases associated with increased bone resorption, in Japanese patients. Randomized controlled trials needed to be conducted on a large number of patients to confirm these effects.     

A randomized clinical trial of the effects of isosorbide mononitrate on bone formation and resorption in post-menopausal women: a pilot study

BACKGROUND: Nitric oxide (NO) stimulates bone formation and inhibits bone resorption in vitro. NO donors (nitrates) are inexpensive and widely available, but their value for post-menopausal osteoporosis has never been evaluated in a randomized trial. The objective of this study was to compare the effects of 5 and 20 mg of isosorbide mononitrate (ISMO) on markers of bone turnover in post-menopausal women. METHODS: A prospective randomized trial was carried out in the Department of Obstetrics & Gynecology, Ain Shams University, Egypt. The study included 50 healthy post-menopausal women with a hip bone mineral density T score between 0 and -2.5. Participants were randomly assigned to 5 or 20 mg/day of ISMO for 12 weeks. Urine N-telopeptide (NTx), a marker of bone resorption, and serum bone-specific alkaline phosphatase (BSALP), a marker of bone formation, were measured. Markers were measured immediately before randomization and after 12 weeks of treatment. The percent change in NTx and BSALP for each of the treatment groups (5 mg ISMO and 20 mg ISMO) was calculated. The main outcome measures were serum NTx and BSALP in the 5 and 20 mg ISMO groups after 12 weeks of treatment. RESULTS: Women adhering to 20 mg of ISMO had a 42.03% (95% confidence interval (CI), 20.1-73.7) reduction in NTx and a 29.05% (95% CI, 10.8-48.4) increase in BSALP, and women adhering to 5 mg of ISMO had a 31.12% (95% CI, 8.3-68.2) reduction in NTx and a 28.4% (95% CI, 4.6-52.1) increase in BSALP. CONCLUSION: ISMO, as a NO donor, may be useful for the prevention of post-menopausal osteoporosis.     

Pharmacological management of osteogenesis

Osteogenesis and bone remodeling are complex biological processes that are essential for the formation of new bone tissue and its correct functioning. When the balance between bone resorption and formation is disrupted, bone diseases and disorders such as Paget''s disease, fibrous dysplasia, osteoporosis and fragility fractures may result. Recent advances in bone cell biology have revealed new specific targets for the treatment of bone loss that are based on the inhibition of bone resorption by osteoclasts or the stimulation of bone formation by osteoblasts. Bisphosphonates, antiresorptive agents that reduce bone resorption, are usually recommended as first-line therapy in women with postmenopausal osteoporosis. Numerous studies have shown that bisphosphonates are able to significantly reduce the risk of femoral and vertebral fractures. Other antiresorptive agents indicated for the treatment of osteoporosis include selective estrogen receptor modulators, such as raloxifene. Denosumab, a human monoclonal antibody, is another antiresorptive agent that has been approved in Europe and the USA. This agent blocks the RANK/RANKL/OPG system, which is responsible for osteoclastic activation, thus reducing bone resorption. Other approved agents include bone anabolic agents, such as teriparatide, a recombinant parathyroid hormone that improves bone microarchitecture and strength, and strontium ranelate, considered to be a dual-action drug that acts by both osteoclastic inhibition and osteoblastic stimulation. Currently, anti-catabolic drugs that act through the Wnt-β catenin signaling pathway, serving as Dickkopf-related protein 1 inhibitors and sclerostin antagonists, are also in development. This concise review provides an overview of the drugs most commonly used for the control of osteogenesis in bone diseases.     

Efficacy and Tolerability of Calcitonin in the Prevention and Treatment of Osteoporosis

Calcitonin in general, and, more specifically, salmon calcitonin (salcatonin), has been known for 30 years to be a specific inhibitor of bone resorption. Studies have confirmed its efficacy in metabolic bone diseases characterised by excessive bone resorption, such as osteoporosis. Most randomised studies in which salcatonin and oral calcium were administered for 1 to 5 years to recently postmenopausal women for the prevention of osteoporosis have shown that bone mineral density or bone content of the lumbar spine increased significantly, compared with a reduction among women receiving calcium only. Prospective studies have shown that salcatonin is effective in the treatment of established osteoporosis, reducing significantly the relative risk of new vertebral fractures. The benefits of salcatonin nasal spray therapy were observed in the majority of women studied, and it has been shown to be an effective alternative for osteoporotic women more than 5 years postmenopausal who refuse estrogens, or for whom estrogens are contraindicated. Finally, in established osteoporosis, nasal calcitonin possesses a potent analgesic effect. The well-demonstrated effects of nasal calcitonin permit it to be considered a well tolerated and efficient approach for prevention and treatment of postmenopausal osteoporosis.     

6-Methylprednisolone down-regulates IRAK-M in human and murine osteoclasts and boosts bone-resorbing activity: a putative mechanism for corticoid-induced osteoporosis

Osteoclasts are large, multinucleated cells, which originate from the fusion of macrophages. They play a central role in bone development and remodeling via the resorption of bone and are thus important mediators of bone loss, which leads to osteoporosis. IL-1R-associated kinase (IRAK)-M is a pseudokinase, which acts as a negative modulator of innate immune responses mediated by TLRs and IL-1R. Recently, it has been reported that IRAK-M also participates in the control of macrophage differentiation into osteoclasts. In addition, it was shown that IRAK-M knockout mice develop a strong osteoporosis phenotype, suggesting that down-regulation of this molecule activates osteoclast-mediated bone resorption. We studied the effect of the osteoporosis-inducing glucocorticoid, 6-methylprednisolone (6-MP), on IRAK-M expression in osteoclasts. Our results showed that osteoclasts, derived from THP-1 and RAW cells as well as human blood monocytes, differentiated into osteoclasts, express high levels of IRAK-M at mRNA and protein levels. In addition, 6-MP down-regulates IRAK-M expression, which correlates with an increased activation of bone resorption. These findings suggest a mechanism of corticosteroid-induced osteoporosis and open new avenues for treating this endemic disease of Western societies.     

Parathyroid Hormone in the Treatment of Osteoporosis

Parathyroid hormone (PTH), especially intact human PTH [hPTH(1–84)] and its various fragments [hPTH(1–31), (1–34), (1–36), (1–38) and their modifications], has been used for the treatment of osteoporosis over the last 10 years. Although chronic continuous excess of PTH markedly increases bone resorption, as seen in the typical example of primary hyperparathyroidism and osteitis fibrosa generalisata, intermittent PTH administration has been found to stimulate bone formation in animals, providing a basis for the use of PTH as a therapeutic agent for osteoporosis. In addition to dramatically increasing trabecular bone density and also sustaining cortical bone density, PTH administration increases bone strength and reduces the fracture rate, despite occasional increases in cortical porosity. Administration of PTH in combination with antiresorptive agents such as estrogen, calcitonin, vitamin D and bisphosphonates augments its effect. Because of its bone anabolic action, PTH is expected to be effective for osteoporosis in those of advanced age with suppressed bone remodelling, which might not respond favourably to antiresorptive agents.     

Effects of neridronic acid on osteoclasts derived by physiological dual-cell cultures

Increased osteoclastic activity is observed in many osteopathic disorders - including postmenopausal osteoporosis, Paget's disease, primary bone tumours, lytic bone metastases, multiple myeloma and rheumatoid arthritis - that involve increased bone resorption and a loss of bone mass. Bisphosphonates are highly effective inhibitors of bone resorption that selectively affect the osteoclasts. The aim of this study was to obtain more information about the mechanism of action of bisphosphonates such as neridronic acid using a dual-cell culture model. As a model of osteoclastogenesis we used a murine monocyte/macrophage cell line RAW 264.7 type CRL 2278 co-cultured with murine osteoblasts. The monocyte-osteoblast system allows physiological experimentation of bone anti-resorption drugs, simulating bone turnover in pathologies such as osteoporosis. The direct actions of neridronic acid on cell proliferation and functionality in the co-culture model were examined using tartrate-resistant acid phosphatase (TRAP) assay, immunohistochemical localization of actin, and transmission and scanning electron microscopy (SEM). Results showed that the percentage of TRAP-positive cells, an early marker of osteoclastic differentiation, was significantly higher in control cultures than in co-cultures treated with variable concentrations of neridronic acid. Neridronic acid induced dramatic morphological changes, characterized by the loss of the ruffled border. The actin ring associated with the plasma membrane of the cells treated with neridronic acid was shown to break down. The tissue-specific targeting of neridronic acid to bone mineral suggests that it may inhibit bone resorption by direct effects on osteoclasts or other bone cells in the immediate microenvironment of the osteoclasts. From our study, we conclude that structural alterations induced by neridronic acid in our co-culture system lead to decreased osteoclast function. This may encourage the use of neridronic acid to reduce bone resorption in the therapy of demineralizing metabolic bone disorders.     

雌激素防治骨质疏松症的研究进展

１９４１年Ａｌｂｒｉｇｈｔ首先提出绝经与骨质疏松之间的关系，５０多年来，大量的临床与实验研究证实，雌激素缺乏是绝经后骨质疏松的重要发病因素。低雌激素状态或绝经后补充雌激素，可以预防雌激素低下引起的骨丢失，并对绝经后的多种改变有防治作用，例如绝经后症状...     

康力龙、泼尼松对大鼠骨组织形态学的影响

目的　探讨康力龙和泼尼松对大鼠骨组织形态学的影响。方法　 3月龄雄性SD大鼠 2 4只 ,体重 2 31 7± 33 3g随机分为三组。分别用蒸馏水、泼尼松 4 5mg·kg-1·d-1(每周二次 )和泼尼松 4 5mg·kg-1·d-1加康力龙 0 5mg·kg-1·d-1灌胃(每周 6次 ) ,持续 90天。用图像分析仪测算胫骨近端骨小梁的骨形态计量学指标 ,并在扫描电镜下观察大鼠腰椎的组织结构改变。结果　与对照组比较 ,泼尼松组大鼠胫骨的骨吸收增加 (破骨细胞数 + 92 % ) ,骨小梁间隙 (Tb .Sp)增宽 187% ,骨形成率(BFR/TV)减少 89% ,骨小梁面积 (%Tb .Ar)减少 (- 5 8% )。腰椎的骨小梁变少 ,变细 ,断裂 ,连接不紧密 ,表面常见骨吸收形成的陷窝。与泼尼松组比较 ,康力龙组骨形成增加 (BFR/TV + 75 2 % ) ,骨吸收减少 (破骨细胞数 - 41% ) ,骨量增加 (%Tb .Ar +87% ,Tb .Sp - 5 8% )。腰椎的骨小梁粗大 ,排列整齐 ,连接紧密。结论　长期使用泼尼松可导致骨质疏松 ,康力龙对此有防止作用。