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1.
可逆性胆硷酯酶抑制剂二甲氨基甲酸-5-二氢吲哚酯的合成 总被引:1,自引:0,他引:1
为了深入研究催醒宁类化合物的结构与抑酶活性的关系,设计合成了-系列1-,3-或5-位不同取代的二氢吲哚类衍生物(中间体和终产物共24个新化合物)。中间体1,3-二甲基-5-烷氧基-2-二氢吲哚酮(A)的C3烷化。采用相转移催化方法进行;反应中还分离到三个副产物(Ⅶ~Ⅸ)。初筛结果表明:这些化合物大多有较强的抑酶活性;1,3-或5-位取代基的改变均明显影响其活性。 相似文献
2.
Braffman BH; Coleman BG; Ramchandani P; Arger PH; Nodine CF; Dinsmore BJ; Louie A; Betsch SE 《Radiology》1994,190(3):797
3.
This study was designed to determine whether the somatostatin analogue,
octreotide, could prevent embryonic loss by normalizing increased uterine
insulin-like growth factor-I (IGF-I) action related to hyperoestrogenaemia
following superovulation. Superovulated immature and
oestradiol-17beta-treated adult rats were infused with 100 or 300 microg/ml
of octreotide respectively, or injected daily with 1 or 10 microg of
octreotide from day 1 to day 3 of pregnancy. On day 3, embryos were
collected from the oviducts and uteri. Uterine luminal fluid was subjected
to embryo culture. The amounts of uterine IGF-I and IGF binding proteins
(IGFBP) were determined by radioimmunoassay and ligand binding assay
respectively. Octreotide infusion normalized uterine IGF-I action following
superovulatory and oestradiol-17beta treatment, by reducing IGF-I
concentrations and increasing IGFBP concentrations. Octreotide infusion
increased the number of normal embryos by 2.7-fold and 1.7-fold in
superovulated and oestradiol-17beta- treated rats respectively, and
reversed the detrimental effects of uterine luminal fluid on embryonic
development caused by superovulatory and oestradiol-17beta treatment. Daily
injections with octreotide had similar but reduced effects in all
parameters examined in both treatment groups. In conclusion, octreotide may
reduce embryonic loss, at least in part, by normalizing IGF-I action
following superovulation.
相似文献
4.
S Bydder NA Spry DRH Christie D Roos BH Burmeister H Krawitz S Davis DJ Joseph M Poulsen M Berry 《Journal of Medical Imaging and Radiation Oncology》2003,47(3):284-288
The purpose of this study was to prospectively examine the effectiveness and tolerability of a simple radiotherapy technique for the palliation of symptomatic liver metastases. Twenty‐eight patients with symptomatic liver metastases were enrolled from seven centres, and received targeted (partial or whole) liver irradiation consisting of 10 Gy in two fractions over 2 days. Symptoms at baseline were hepatic pain (27 patients), abdominal distension (19), night sweats (12), nausea (18) and vomiting (eight). Twenty‐two patients (76%) had failed previous treatment with chemotherapy, hormonal therapy and/or high‐dose steroids. Symptoms and potential toxicities were prospectively assessed at the time of treatment, then 2, 6 and 10 weeks later. Individual symptom response rates were 53?66% at 2 weeks. Partial or complete global symptomatic responses were noted in 15 patients (54%) overall. The treatment was well tolerated with two patients (7%) experiencing grade 3 toxicity (one vomiting and one diarrhoea); however, four patients reported temporary worsening of pain shortly after treatment. This simple and well‐tolerated treatment achieves useful palliation. 相似文献
5.
In the human erythrocyte membrane phosphatidylcholine and sphingomyelin reside mainly in the outer leaflet, whereas the aminophospholipids, phosphatidylethanolamine and phosphatidylserine, are mainly found in the inner leaflet. Maintenance of phospholipid asymmetry has been assumed to involve interactions between the aminophospholipids and the membrane skeleton, in particular spectrin. To investigate whether spectrin contributes to maintaining the phospholipid transbilayer distribution and kinetics of redistribution, we studied erythrocytes from hereditary spherocytosis patients whose spectrin levels ranged from 34% to 82% of normal. The phospholipid composition and the accessibility of membrane phospholipids to hydrolysis by phospholipases were in the normal range. Spin-labeled phosphatidylserine and phosphatidylethanolamine analogues that had been introduced into the outer leaflet were rapidly transported at 37 degrees C to the inner leaflet, whereas the redistribution of spin-labeled phosphatidylcholine was slower. The kinetics of transbilayer movement of these spin-labeled phospholipid in all samples was in the normal range and was not affected by the level of spectrin. Although these erythrocyte membranes contained as little as 34% of the normal level of spectrin and were characterized by several physical abnormalities, the composition, distribution, and transbilayer kinetics of the phospholipids were found to be normal. We therefore conclude that spectrin plays, at best, only a minor role in maintaining the distribution of erythrocyte membrane phospholipid. 相似文献
6.
Obesity, regional body fat distribution, and the metabolic syndrome in older men and women 总被引:1,自引:0,他引:1
Goodpaster BH Krishnaswami S Harris TB Katsiaras A Kritchevsky SB Simonsick EM Nevitt M Holvoet P Newman AB 《Archives of internal medicine》2005,165(7):777-783
BACKGROUND: The metabolic syndrome is a disorder that includes dyslipidemia, insulin resistance, and hypertension and is associated with an increased risk of diabetes and cardiovascular disease. We determined whether patterns of regional fat deposition are associated with metabolic syndrome in older adults. METHODS: A cross-sectional study was performed that included a random, population-based, volunteer sample of Medicare-eligible adults within the general communities of Pittsburgh, Pa, and Memphis, Tenn. The subjects consisted of 3035 men and women aged 70 to 79 years, of whom 41.7% were black. Metabolic syndrome was defined by Adult Treatment Panel III criteria, including serum triglyceride level, high-density lipoprotein cholesterol level, glucose level, blood pressure, and waist circumference. Visceral, subcutaneous abdominal, intermuscular, and subcutaneous thigh adipose tissue was measured by computed tomography. RESULTS: Visceral adipose tissue was associated with the metabolic syndrome in men who were of normal weight (odds ratio, 95% confidence interval: 2.1, 1.6-2.9), overweight (1.8, 1.5-2.1), and obese (1.2, 1.0-1.5), and in women who were of normal weight (3.3, 2.4-4.6), overweight (2.4, 2.0-3.0), and obese (1.7, 1.4-2.1), adjusting for race. Subcutaneous abdominal adipose tissue was associated with the metabolic syndrome only in normal-weight men (1.3, 1.1-1.7). Intermuscular adipose tissue was associated with the metabolic syndrome in normal-weight (2.3, 1.6-3.5) and overweight (1.2, 1.1-1.4) men. In contrast, subcutaneous thigh adipose tissue was inversely associated with the metabolic syndrome in obese men (0.9, 0.8-1.0) and women (0.9, 0.9-1.0). CONCLUSION: In addition to general obesity, the distribution of body fat is independently associated with the metabolic syndrome in older men and women, particularly among those of normal body weight. 相似文献
7.
Styles LA; Schalkwijk CG; Aarsman AJ; Vichinsky EP; Lubin BH; Kuypers FA 《Blood》1996,87(6):2573-2578
Acute chest syndrome (ACS) is associated with significant morbidity and is the leading cause of death in patients with sickle cell disease (SCD). Recent reports suggest that bone marrow fat embolism can be detected in many cases of severe ACS. Secretory phospholipase A2 (sPLA2) is an important inflammatory mediator and liberates free fatty acids, which are felt to be responsible for the acute lung injury of the fat embolism syndrome. We measured SPLA2 levels in 35 SCD patients during 20 admissions for ACS, 10 admissions for vaso-occlusive crisis, and during 12 clinic visits when patients were at the steady state. Eleven non-SCD patients with pneumonia were also evaluated. To determine if there was a relationship between sPLA2 and the severity of ACS we correlated SPLA2 levels with the clinical course of the patient. In comparison with normal controls (mean = 3.1 +/- 1.1 ng/mL), the non- SCD patients with pneumonia (mean = 68.6 +/- 82.9 ng/mL) and all three SCD patient groups had an elevation of SPLA2 (steady state mean = 10.0 +/- 8.4 ng/mL; vaso-occlusive crisis mean = 23.7 +/- 40.5 ng/mL; ACS mean = 336 +/- 209 ng/mL). In patients with ACS sPLA2 levels were 100- fold greater than normal control values, 35 times greater than values in SCD patients at baseline, and five times greater than non-SCD patients with pneumonia. The degree of SPLA2 elevation in ACS correlated with three different measures of clinical severity and, in patients followed sequentially, the rise in SPLA2 coincided with the onset of ACS. The dramatic elevation of SPLA2 in patients with ACS but not in patients with vaso-occlusive crisis or non-SCD patients with pneumonia and the correlation between levels of SPLA2 and clinical severity suggest a role for SPLA2 in the diagnosis and, perhaps, in the pathophysiology of patients with ACS. 相似文献
8.
Schaap LA Pluijm SM Deeg DJ Penninx BW Nicklas BJ Lips P Harris TB Newman AB Kritchevsky SB Cauley JA Goodpaster BH Tylavsky FA Yaffe K Visser M;Health ABC study 《Clinical endocrinology》2008,68(1):42-50
Objective Progressive declines in serum levels of testosterone parallel the decline in physical performance and muscle strength in ageing men, although findings are not conclusive. We examined whether levels of testosterone were associated with 3‐year decline in physical performance and muscle strength in older men. Design Longitudinal data were available for 486 men (mean age 74·9 years, SD 6·4) from the Longitudinal Ageing Study Amsterdam (LASA) and 1071 well‐functioning men (mean age 73·7 years, SD 2·8) from the Health, Ageing and Body Composition (Health ABC) study. Measurements Three‐year change in physical performance score and grip strength according to categories of total testosterone (TT) and free testosterone (FT) levels. Results The mean 3‐year change in physical performance was –1·1 (SD 2·7, –13·6%) in LASA and –0·3 (SD 1·5, –2·9%) in Health ABC. The mean 3‐year change in grip strength was –9·7 kg (SD 12·2, –13·2%) in LASA and –4·4 kg (SD 11·4,–5·8%) in Health ABC. Low levels of TT were not associated with decline in physical performance or with decline in muscle strength [e.g. mean change in physical performance –1·09 (SD 0·26) in the lowest quartile (Q1) and –0·88 (0·24) in the highest quartile (Q4) of total testosterone in LASA, and –0·26 (0·07) vs.–0·36 (0·11) in Health ABC]. Similar results were found for FT. Conclusions Low levels of TT and FT were neither associated with 3‐year decline in physical performance nor with 3‐year decline in muscle strength in two independent samples of older men. 相似文献
9.
Mitch T. Sitnick Mahesh K. Basantani Lingzhi Cai Gabriele Schoiswohl Cynthia F. Yazbeck Giovanna Distefano Vladimir Ritov James P. DeLany Renate Schreiber Donna B. Stolz Noah P. Gardner Petra C. Kienesberger Thomas Pulinilkunnil Rudolf Zechner Bret H. Goodpaster Paul Coen Erin E. Kershaw 《Diabetes》2013,62(10):3350-3361
Intramyocellular triacylglycerol (IMTG) accumulation is highly associated with insulin resistance and metabolic complications of obesity (lipotoxicity), whereas comparable IMTG accumulation in endurance-trained athletes is associated with insulin sensitivity (the athlete’s paradox). Despite these findings, it remains unclear whether changes in IMTG accumulation and metabolism per se influence muscle-specific and systemic metabolic homeostasis and insulin responsiveness. By mediating the rate-limiting step in triacylglycerol hydrolysis, adipose triglyceride lipase (ATGL) has been proposed to influence the storage/production of deleterious as well as essential lipid metabolites. However, the physiological relevance of ATGL-mediated triacylglycerol hydrolysis in skeletal muscle remains unknown. To determine the contribution of IMTG hydrolysis to tissue-specific and systemic metabolic phenotypes in the context of obesity, we generated mice with targeted deletion or transgenic overexpression of ATGL exclusively in skeletal muscle. Despite dramatic changes in IMTG content on both chow and high-fat diets, modulation of ATGL-mediated IMTG hydrolysis did not significantly influence systemic energy, lipid, or glucose homeostasis, nor did it influence insulin responsiveness or mitochondrial function. These data argue against a role for altered IMTG accumulation and lipolysis in muscle insulin resistance and metabolic complications of obesity.Obesity is a global public health problem and a major risk factor for insulin resistance and type 2 diabetes. These disorders are characterized by excess lipid accumulation in multiple tissues, primarily as triacylglycerols (TAGs). The lipotoxicity hypothesis suggests that this lipid excess promotes cellular dysfunction and cell death, which ultimately contribute to insulin resistance and metabolic disease (1). However, intracellular TAG accumulation is not always associated with adverse metabolic outcomes, suggesting that TAGs themselves are not pathogenic (2). In contrast, other non-TAG lipid metabolites such as fatty acids (FAs), diacylglycerols (DAGs), and ceramides have been shown to influence glucose homeostasis and insulin action by interfering with insulin signaling and glucose transport, promoting endoplasmic reticulum stress and mitochondrial dysfunction, and activating inflammatory and apoptotic pathways (reviewed in ref. 3). Nevertheless, the precise identities and sources of these bioactive lipid intermediates remain elusive (4,5). Furthermore, whether intracellular TAGs serve as a protective sink or a toxic source of deleterious lipid metabolites that contribute to insulin resistance remains unclear (6).Since skeletal muscle is the major contributor to insulin-mediated glucose disposal, lipid excess in this tissue could have serious implications for systemic glucose homeostasis and insulin responsiveness (7). Indeed, numerous studies have demonstrated a strong association between intramyocellular triacylglycerol (IMTG) accumulation and insulin resistance (reviewed in ref. 8). In contrast, endurance exercise training is characterized by IMTG accumulation and insulin sensitivity (the athlete’s paradox) (2). This variable association between IMTG accumulation and insulin responsiveness has largely been attributed to differences in the balance between lipid delivery and muscle oxidative capacity (8–10). Not surprisingly then, most studies have focused on the impact of muscle FA uptake and/or oxidation on glucose homeostasis and insulin action (11). However, experimental manipulations of these parameters cannot distinguish among the effects of IMTGs, IMTG metabolism, and other lipid intermediates. Furthermore, accumulating evidence suggests that muscle oxidative capacity cannot entirely explain differences in IMTGs or insulin responsiveness (12). These findings have led to speculation that dynamic IMTG metabolism (i.e., TAG synthesis or hydrolysis) may be critically involved in lipid-induced insulin resistance (6). However, few studies have specifically addressed the contribution of IMTG metabolism per se to this process.The regulated storage and release of IMTGs remain poorly understood, but require the coordinated action of synthetic enzymes (i.e., diacylglycerol acyltransferases [DGATs]), hydrolytic enzymes (i.e., adipose triglyceride lipase [ATGL] and hormone sensitive lipase [HSL]), and other lipid droplet proteins (6). Specifically, modulating IMTG synthesis in murine skeletal muscle alters IMTG content and systemic glucose homeostasis, supporting a role for IMTG metabolism in metabolic disease (13–15). However, the metabolic impact of modulating IMTG hydrolysis in vivo remains unclear. Global deletion of either ATGL (16–19) or HSL (20) has produced variable results. The former, but not the latter, results in massive IMTG accumulation with improvement in systemic glucose homeostasis, suggesting that inhibition of ATGL-mediated TAG hydrolysis protects against insulin resistance. In contrast, recent studies in cardiac muscle (21) and other tissues (22,23) indicate that ATGL-mediated TAG hydrolysis is required for mitochondrial function such that enhancing, rather than inhibiting, ATGL action may improve metabolic outcomes. Nevertheless, the autonomous role of skeletal muscle TAG catabolism in influencing muscle-specific and systemic metabolic phenotypes remains unknown.The goal of the current study was to understand the contribution of IMTG hydrolysis to tissue-specific and systemic metabolic phenotypes, particularly glucose homeostasis and insulin action, in the context of obesity. We therefore generated animal models with decreased (skeletal muscle-specific ATGL knockout [SMAKO] mice) and increased (muscle creatine kinase [Ckm]-ATGL transgenic [Tg] mice) ATGL action exclusively in skeletal muscle, and assessed the metabolic consequences at baseline and in response to chronic high-fat feeding. Interestingly, modulation of IMTG hydrolysis via ATGL action did not significantly influence glucose homeostasis, insulin action, or other metabolic phenotypes in the context of obesity despite dramatic changes in IMTG content. 相似文献
10.
Bret H. Goodpaster 《Diabetes》2013,62(4):1032-1035
The specific cellular underpinnings or mechanisms of insulin resistance (IR) are not clear. Here I present evidence to support a causal association between mitochondrial energetics and IR. A large body of literature indicates that mitochondrial capacity for oxidative metabolism is lower in human obesity and type 2 diabetes. Whether or not mitochondria play a causal role in IR is hotly debated. First, IR can be caused by many factors, many of which may or may not involve mitochondria. These include lipid overload, oxidative stress, and inflammation. Thus the first tenet of an argument supporting a role for mitochondria in IR is that mitochondria derangements can cause IR, but IR does not have to involve mitochondria. The second tenet of this argument is that animal models in which oxidative metabolism are completely abolished are not always physiologically or pathologically relevant to human IR, in which small metabolic perturbations can have profound effects over a prolonged period. Lastly, mitochondria are complex organelles, with diverse functions, including links with cell signaling, oxidative stress, and inflammation, which in turn can be connected with IR. In summary, mitochondrial “deficiency” is not merely a reduced energy generation or low fatty acid oxidation; this concept should be expanded to numerous additional important functions, many of which can cause IR if perturbed.The most common forms of human skeletal muscle insulin resistance (IR) are associated with 1) obesity, particularly abdominal obesity and excess accumulation of lipids in nonadipose tissues such as liver and skeletal muscle; and 2) physical inactivity. Identifying a common cellular basis for these conditions, however, remains elusive. Impairments in mitochondrial energetics have been linked to each of these conditions. Obesity has been reported to be associated with reduced mitochondria content and altered mitochondrial performance (1). Physical inactivity is associated with lower mitochondrial biogenesis and content (2). Conversely, exercise is a potent inducer of mitochondria biogenesis (3). Thus it is not surprising that considerable attention has been given to the possibility that mitochondria play a role in IR. But of course associations do not infer that derangements in mitochondria cause IR. Although many of these arguments can be made for other insulin-sensitive tissues such as liver, this line of reasoning to support a role for mitochondria in IR will focus on skeletal muscle. 相似文献