能量代谢分子SIRT1在运动改善2型糖尿病骨代谢中的作用机制

文题释义： 沉默信息调节因子1(silent information regulator 1，SIRT1)：是调控能量代谢的关键因子，其通过细胞氧化还原等途径来介导能量代谢、基因转录、细胞衰老等生理学过程。研究发现，SIRT1在调控成骨细胞和破骨细胞分化、增殖和活性上均扮演重要角色。 骨代谢：骨的功能是为肌肉收缩提供附着处及保护内脏等重要的生命器官。一般认为骨在细胞水平上是不活跃的，事实上骨的细胞在不停地进行着细胞代谢，不仅骨的细胞之间会相互作用，还存在骨髓中的红细胞生成细胞、基质细胞相互作用，以进行骨的改建和重建。 背景：能量代谢调控2型糖尿病骨代谢是近来生命医学领域的研究热点。长期糖、脂等能量代谢的紊乱导致胰岛素抵抗，引发2型糖尿病。而沉默信息调节因子1(SIRT1)作为一种烟酰胺腺嘌呤二核苷酸(NAD+)依赖的组蛋白去乙酰化酶，是调控能量代谢关键因子，还参与骨代谢、基因转录、细胞衰老、凋亡及焦亡等。 目的：分析近年来有关SIRT1在运动改善骨代谢中的作用机制的相关文献，研究其现状和研究进展。 方法：在PubMed、CNKI等数据库进行检索，中文关键词：SIRT1，运动，2型糖尿病，骨形成，骨吸收；英文关键词：SIRT1, exercise, type 2 diabetes, bone formation, bone resorption。 结果与结论：①成骨细胞和破骨细胞的分化和功能发挥以及相互之间的代谢平衡是保障骨代谢稳态的关键。而一旦发生紊乱将会导致骨组织形态结构退化，这也是2型糖尿病并发症骨质疏松发生的重要机制；②能量代谢紊乱是引发2型糖尿病的关键，那么SIRT1作为调控能量代谢关键因子，其可通过Wnt、转化生长因子β等途径介导成骨细胞和破骨细胞分化及功能；③近来，研究发现运动可显著改善2型糖尿病的能量代谢和骨代谢，文章从成骨细胞、破骨细胞出发，通过综述目前国内外相关研究，探究SIRT1在运动改善2型糖尿病骨代谢中的作用机制。 ORCID: 0000-0002-3135-9409(张路遥) 中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程     

生长激素长效制剂的研究概况

人生长激素(human growth hormone,hGH)是由脑垂体前叶中的生长激素细胞合成、存储和分泌的一种肽类激素,主要生理功能为促进身体各组织、器官及骨骼中受体细胞的蛋白质合成和脂肪分解,从而调节机体代谢和生长发育,是人体内最重要的促进生长的激素.生长激素不同于类固醇激素,不会产生糖皮质激素或性激素样的副作用...     

Ghrelin抗心力衰竭的作用及机制研究

Ghrelin是一种由28个氨基酸组成的内源性促生长激素释放肽,其在体内的组织中广泛存在,其与生长激素促分泌物质受体(GHSR)各亚型结合后,不仅能有效地促进生长激素分泌,还能调节内分泌、促进摄食、增加体重、维持能量代谢正平衡、改善恶病质,以及降低血管抵抗、改善血流动力学、抗细胞凋亡,故ghrelin可能从多层次多角度逆转心衰的病理生理过程。     

Obestatin、Ghrelin与血糖调节

肥胖抑制素(obestatin)和生长激素释放肽(ghrelin)能互相拮抗,参与血糖的调节.其中obestatin与GPR-39(G-protein-coupled receptor 39)结合抑制摄食和胃肠排空、促进胰岛β细胞功能,影响胰岛素的分泌;而ghrelin与生长激素促分泌受体(GHSR1a)结合,促进食欲...     

周细胞在骨科治疗领域的应用潜力

文题释义：周细胞：长期以来周细胞被认为可调节血压和促进血管生成，然而现在认为其具有间充质干细胞的特征，已广泛应用于骨科常规疾病的研究，因其广泛存在于人体中，无需体外培养扩增细胞，避免了体外培养的风险，未来在骨科中的运用前景可能优于间充质干细胞。 骨科常见移植物：目前临床上最常见的移植物为自体骨、异体骨、骨形态发生蛋白及骨髓间充质干细胞等，虽已广泛应用于临床，但存在内源性供应不足、造价过高等问题，周细胞大量存在于体内，可能成为一种新的植入物应用于临床。 背景：周细胞和其他血管周围干细胞在骨组织工程中越来越受到关注，长期以来周细胞被认为可调节血压和促进血管生成，然而现在认为其具有间充质干细胞的特征，包括多潜能、自我更新、免疫调节以及组织修复等多种功能，在骨折、骨不连、椎体融合、韧带断裂及软骨损伤等骨科常见疾病中展现出了强大的再生潜力。 目的：总结周细胞在骨科中的相关应用，并探讨其作用机制与其本身存在的优缺点。 方法：以“周细胞，血管周围干细胞，修复，治疗，骨科”为中文检索词，“Pericytes，Perivascular stem cells，repair，therapy，orthopedics”为英文检索词，在 PubMed、Web of Science、中国知网及万方数据库中检索自建库到2019年8月关于周细胞治疗骨科疾病的文献，共检索到112篇相关文献，精读全文后最终选取55篇文献。 结果与结论：①周细胞作为一种新兴的干细胞，已应用于众多的骨科疾病治疗研究中，并展现出了强大的治疗前景；②周细胞在人体内细胞来源丰富，无需体外培养获取细胞；③周细胞的修复作用机制主要以旁分泌介导为主，自身分化为辅，但其具体的机制仍不明确，有待进一步探究。 ORCID: 0000-0003-1654-5323(余名川) 中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程     

Ghrelin研究及其临床意义

Ghrelin是第一个被发现的生长激素促分泌物质受体 (GHS R)的内源性配体 ,由 2 8个氨基酸组成。Ghrelin来源于多种组织细胞 ,其受体广泛分布在中枢及外周组织 ,在调节生长激素释放等方面发挥重要作用 ,可能具有重要的临床意义     

首发精神分裂症患者抗精神病药物治疗与代谢相关指标变化的关系

 目的：观察奥氮平和阿立哌唑治疗前后,首发精神分裂症患者体重指数、瘦素及生长激素刺激肽的变化。方法：共99例门诊或住院的首发精神分裂症患者,随机选用奥氮平或阿立哌唑治疗,均单一用药。分别于治疗前、4周末、8周末及24周末测定体重指数,并进行瘦素和生长激素刺激肽测定,以阳性和阴性症状量表(PANSS)评定病情变化及疗效。结果：经奥氮平或阿立哌唑治疗后精神分裂症患者的血清瘦素水平均有不同程度的升高,并与体重指数呈正相关,且这种变化在治疗初期（4周末）即已显现,并持续至24周末。治疗后生长激素刺激肽与治疗后体重指数的相关性仅在阿立哌唑组观察到（r=-0.291,P<0.05）。结论：首发精神分裂症患者经奥氮平或阿立哌唑治疗,持续存在不同程度的瘦素水平升高;奥氮平组体重指数与血清瘦素水平的相关性较显著,而阿立哌唑组则与生长激素刺激肽水平的相关性较显著;阿立哌唑对体重指数的影响可能通过生长激素刺激肽的作用来实现。     

免疫去势和未去势猪睾丸上生长激素释放肽的定位及其基因表达

目的:探讨生长激素释放肽在猪睾丸中的定位及其基因表达,以及免疫去势对猪睾丸中生长激素释放肽表达的影响.方法:14头9周龄公猪随机分为免疫去势组和对照组(未去势组),25周龄时屠宰,取血清和睾丸组织,放射免疫法检测血清睾酮的水平,免疫组织化学PV-9000两步法确定生长激素释放肽在睾丸中的细胞定位,实时荧光定量PCR法分析睾丸中生长激素释放肽mRNA的变化.结果:免疫去势组猪血清睾酮水平显著地低于未去势组;免疫组织化学显示表达生长激素释放肽的细胞为精原细胞、初级精母细胞、精子细胞、支持细胞和间质细胞,且免疫去势猪阳性细胞数显著多于未去势猪.另外,猪睾丸中有生长激素释放肽mRNA,但免疫去势组与未去势组间差异无统计学意义.结论:猪睾丸中广泛存在生长激素释放肽及其mRNA,免疫去势导致生长激素释放肽的表达增多.     

小鼠骨髓多能成体祖细胞的分离、培养及体外诱导分化为胰岛素分泌细胞的研究

目的：探讨培养骨髓多能成体祖细胞的条件和生物学特性及其向胰岛素分泌细胞分化的可能性。 方法： 采用文献报道的条件培养液培养小鼠骨髓多能成体祖细胞，观察其细胞形态、生长情况、细胞表面标志及mRNA水平，检测其oct-4基因表达，并以含胰高糖素多肽-1的无血清培养液诱导分化细胞，基因水平检测与胰岛素分泌细胞有关的基因表达。 结果： 小鼠骨髓多能成体祖细胞类圆形，细胞核大，胞质少；细胞增殖能力尚可；细胞表面CD13+、CD44-、CD45-、MHCⅡ-；有oct-4基因表达；诱导分化后，可见与胰岛素分泌细胞有关的基因表达。 结论： 成功培养小鼠骨髓多能成体祖细胞，具有与文献报道类似的生物学特征；有被诱导分化为胰岛素分泌细胞的可能性。     

瘦素-瘦素受体与胰岛素抵抗综合征

瘦素(Leptin)是人和动物肥胖基因编码的一种多靶器官、多功能的分泌型蛋白激素,它主要由体内白色脂肪组织合成、分泌,进入血液循环后游离或与瘦素运转蛋白结合,通过与定位于中枢和外周多种组织及其多种形式的瘦素受体结合发挥生物学效应,作为一种机体代谢状态的信号,影响机体许多生理系统及代谢通路。     

Skeletal dysplasias and the growth plate

Skeletal dysplasias are disorders in which there is derangement in the growth or shape of the skeleton. Long bone grows from cartilage that persists near the ends until skeletal maturity as the growth plate. Developmental biology work has identified the major regulatory proteins in growth plate chondroyte function. There are hundreds of skeletal dysplasias, and the molecular genetic etiology of many was defined in the past decade and a half. Now that the causative genes for these disorders have been identified, they can be broadly classified by the function of the protein that these genes encode for into disorders caused by extracellular structural proteins, proteins that regulate normal growth plate chondrocyte differentiation and patterning, and enzymes that process these proteins. There are clinical similarities within each group, and the phenotype can be predicted based on the role of the mutated protein in normal growth plate function. As such, this framework to classify the skeletal dysplasias has practical clinical implications.     

Body weight and plasma levels of ghrelin and leptin during treatment with olanzapine

Although enhanced appetite and weight gain are potential side effects of treatment with antipsychotic agents, particularly olanzapine and clozapine, the mechanisms underlying these side effects are poorly understood. Leptin and ghrelin were recently identified as hormones that play crucial roles in the regulation of energy balance and glucose metabolism. To elucidate relationships between weight change and plasma levels of ghrelin and leptin, we investigated the circulating ghrelin and leptin levels and body weight during olanzapine treatment. Twenty-four patients with schizophrenia were examined during 6-month administration of olanzapine. Ghrelin, leptin, weight and body mass index (BMI) were measured before and after 2, 4, 8, 12, 16, and 24 weeks of olanzapine treatment. The concentration of glucose and various lipid metabolic parameters were measured at baseline and at 24 weeks. Significant increases in weight, BMI and leptin were observed at week 24. On the other hand, the serum levels of ghrelin decreased significantly after olanzapine treatment. In addition, the level of ghrelin was negatively correlated with the leptin level, BMI and weight. The leptin level was positively correlated with both BMI and weight. Ghrelin is associated with metabolic changes, in combination with leptin, during olanzapine treatment. However, further large-scale and longitudinal studies are warranted to elucidate the metabolic changes involving ghrelin, leptin and insulin during treatment with antipsychotics.     

Association between leptin,markers of bone formation and physical growth of newborns

BACKGROUND: The increase of body size and weight depends on metabolism in the bone tissue and accumulation of fat, but the role of many hormones and enzymatic systems that may influence these processes significantly has not been recognized. AIM: An attempt to assess the correlation between the leptin hormone taking part in the regulation of fat tissue reserves, markers of bone formation and selected anthropometric traits in newborns was made. Subjects and methods: Levels of leptin, osteocalcin and C-terminal propeptide type I procollagen (PICP) in the serum of 64 Appropriate for Gestational Age newborns (AGA newborns) with gestational age between 27 and 42 weeks were assessed. In parallel, 15 anthropometric traits were measured and the Quetelet Index was calculated for all the newborns. Statistical analysis was performed using the Student's t-test, Mann-Whitney U test, Pearson's correlation and Spearman's correlation rank test. p < 0.05 was regarded as significant. RESULTS: Statistically significant correlations between leptin, osteocalcin, PICP and selected anthropometric traits in newborns were found. There were no statistically significant correlations between serum levels of leptin and markers of bone formation in the investigated group of children. CONCLUSION: In our study, we documented the association of leptin, osteocalcin and PICP with overall physical growth of AGA newborns. We did not confirm the relationship between leptin and bone formation in this stage of ontogenesis.     

Role of leptin in the regulation of growth and carbohydrate metabolism in the ovine fetus during late gestation

Leptin is an important regulator of appetite and energy expenditure in adulthood, although its role as a nutritional signal in the control of growth and metabolism before birth is poorly understood. This study investigated the effects of leptin on growth, carbohydrate metabolism and insulin signalling in fetal sheep. Crown–rump length-measuring devices and vascular catheters were implanted in 12 sheep fetuses at 105–110 days of gestation (term 145 ± 2 days). The fetuses were infused i.v. either with saline (0.9% NaCl; n = 6) or recombinant ovine leptin (0.5–1.0 mg kg⁻¹ day⁻¹; n = 6) for 5 days from 125 to 130 days when they were humanely killed and tissues collected. Leptin receptor mRNA and protein were expressed in fetal liver, skeletal muscle and perirenal adipose tissue. Throughout infusion, plasma leptin in the leptin-infused fetuses was 3- to 5-fold higher than in the saline-infused fetuses, although plasma concentrations of insulin, glucose, lactate, cortisol, catecholamines and thyroid hormones did not differ between the groups. Leptin infusion did not affect linear skeletal growth or body, placental and organ weights in utero . Hepatic glycogen content and activities of the gluconeogenic enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase in the leptin-infused fetuses were lower than in the saline-infused fetuses by 44, 48 and 36%, respectively; however, there were no differences in hepatic glycogen synthase activity or insulin signalling protein levels. Therefore, before birth, leptin may inhibit endogenous glucose production by the fetal liver when adipose energy stores and transplacental nutrient delivery are sufficient for the metabolic needs of the fetus. These actions of leptin in utero may contribute to the development of neonatal hypoglycaemia in macrosomic babies of diabetic mothers.     

Association between leptin,markers of bone formation and physical growth of newborns

Background : The increase of body size and weight depends on metabolism in the bone tissue and accumulation of fat, but the role of many hormones and enzymatic systems that may influence these processes significantly has not been recognized. Aim : An attempt to assess the correlation between the leptin hormone taking part in the regulation of fat tissue reserves, markers of bone formation and selected anthropometric traits in newborns was made. Subjects and methods : Levels of leptin, osteocalcin and C-terminal propeptide type I procollagen (PICP) in the serum of 64 Appropriate for Gestational Age newborns (AGA newborns) with gestational age between 27 and 42 weeks were assessed. In parallel, 15 anthropometric traits were measured and the Quetelet Index was calculated for all the newborns. Statistical analysis was performed using the Student's t -test, Mann-Whitney U test, Pearson's correlation and Spearman's correlation rank test. p < 0.05 was regarded as significant. Results : Statistically significant correlations between leptin, osteocalcin, PICP and selected anthropometric traits in newborns were found. There were no statistically significant correlations between serum levels of leptin and markers of bone formation in the investigated group of children. Conclusion : In our study, we documented the association of leptin, osteocalcin and PICP with overall physical growth of AGA newborns. We did not confirm the relationship between leptin and bone formation in this stage of ontogenesis.     

The role of connective tissue growth factor (CTGF/CCN2) in skeletogenesis

Connective tissue growth factor (CTGF) is a 38 kDa, cysteine rich, extracellular matrix protein composed of 4 domains or modules. CTGF has been shown to regulate a diverse array of cellular functions and has been implicated in more complex biological processes such as angiogenesis, chondrogenesis, and osteogenesis. A role for CTGF in the development and maintenance of skeletal tissues first came to light in studies demonstrating its expression in cartilage and bone cells, which was dramatically increased during skeletal repair or regeneration. The physiological significance of CTGF in skeletogenesis was confirmed in CTGF-null mice, which exhibited multiple skeletal dysmorphisms as a result of impaired growth plate chondrogenesis, angiogenesis, and bone formation/mineralization. Given the emerging importance of CTGF in osteogenesis and chondrogenesis, this review will focus on its expression in skeletal tissues, its effects on osteoblast and chondrocyte differentiation and function, and the skeletal implications of ablation or over-expression of CTGF in knockout or transgenic mouse models, respectively. In addition, this review will examine the role of integrin-mediated signaling and the regulation of CTGF expression as it relates to skeletogenesis. We will emphasize CTGF studies in bone or bone cells, and will identify opportunities for future investigations concerning CTGF and chondrogenesis/osteogenesis.     

Role of leptin in regulating appetite, neuroendocrine function, and bone remodeling

Leptin, a hormone secreted by adipocytes, acts on the hypothalamus to regulate appetite and neuroendocrine function. In the hypothalamus, both the arcuate nucleus and the ventromedial nucleus express leptin receptors. Specific neurons in the arcuate nucleus regulate appetite and reproduction. In contrast, neurons in the ventromedial nucleus regulate bone mass. The melanocortin system is the downstream pathway for regulating appetite and neuroendocrine function. In contrast, the sympathetic nervous system is the downstream pathway for regulating bone mass. Leptin, in regulating food intake and body weight, acts, in part, by inhibiting the synthesis of neuropeptide Y and its release from the hypothalamus. The leptin and insulin pathways may interact and may be important in the pathogenesis of the metabolic syndrome.     

Modulation of bone growth and remodeling by the sympathetic nervous system: Review of experimental and clinical studies

The purpose of this paper is to review the interactions of the skeletal and sympathetic nervous systems during normal growth and function as well as in pathology. Clinical and experimental studies have shown that the sympathetic nervous system may play a role in the severity of arthritis and in bone lesions evident in reflex sympathetic dystrophy. In experimental animal studies, bone deposition and mineralization significantly decreased, while bone resorption was significantly increased after sympathectomy. The findings form a basis for understanding the effects of autonomic dysfunction on the skeleton and indicate areas in which further research may have implications for the treatment of skeletal disorders.     

Fibroblast growth factor expression during skeletal fracture healing in mice

Fibroblast growth factors (FGFs) are important signaling molecules that regulate many stages of endochondral bone development. During the healing of a skeletal fracture, several features of endochondral bone development are reactivated. To better understand the role of FGFs in skeletal fracture healing, we quantitatively evaluated the temporal expression patterns of Fgfs, Fgf receptors (Fgfrs), and molecular markers of bone development over a 14‐day period following long bone fracture in a mouse model. These studies identify distinct groups of FGFs that are differentially expressed and suggest active stage‐specific roles for FGF signaling during the fracture repair process. Developmental Dynamics 238:766–774, 2009. © 2009 Wiley‐Liss, Inc.