Constituents from the fruiting bodies ofGanoderma applanatum and their aldose reductase inhibitory activity

Eight compounds were isolated from the fruiting bodies of Ganoderma applanatum, and were identified as 2-methoxyfatty acids (1), 5-dihydroergosterol (2), ergosterol peroxide (3) 3beta,7beta, 20,23xi-tetrahydroxy-11,15-dioxolanosta-8-en-26-oic acid (4), 7beta,20,23xi-trihydroxy-3,11,15-trioxolanosta-8-en-26-oic acid (5), cerevisterol (6), 7beta,23xi-dihydroxy-3,11,15-trioxolanosta-8,20E (22)-dien-26-oic acid (7), and 7beta-hydroxy-3,11,15,23-tetraoxolanosta-8,20E(22)-dien-26-oic acid methyl ester (8) by spectral analysis. All compounds were isolated for the first time from this fruiting bodies, and their effect on rat lens aldose reductase (RLAR) activity was tested. Among these eight compounds, ergosterol peroxide (3) was found to exhibit potent RLAR inhibition, its IC50 value being 15.4 microg/mL.     

醛酮还原酶超家族的研究进展

醛糖还原酶是多元醇通路的限速酶,此酶的激活被认为与糖尿病慢性并发症有关。本文主要就醛糖还原酶的基本结构、代谢特点及醛糖还原酶类似蛋白酶1的最新研究进展与糖尿病慢性并发症的关系予以综述。     

微生物来源的醛糖还原酶抑制剂的研究进展

糖尿病并发症与糖代谢多元醇通路激活有关。醛糖还原酶是多元醇代谢通路中的限速酶,醛糖还原酶抑制剂能有效抑制此通路,减慢或改善糖尿病并发症。本文主要概述了微生物来源的醛糖还原酶抑制剂的研究进展。     

Inhibitory activities of the alkaloids from Coptidis Rhizoma against aldose reductase

As part of our ongoing search of natural sources for therapeutic and preventive agents for diabetic complications, the rat lens aldose reductase (RLAR) inhibitory effect of Coptidis Rhizoma (the rhizome of Coptis chinensis Franch) was evaluated. Its extract and fractions exhibited broad and moderate RLAR inhibitory activities of 38.9∼67.5 μg/mL. In an attempt to identify bioactive components, six quaternary protoberberine-type alkaloids (berberine, palmatine, jateorrhizine, epiberberine, coptisine, and groenlandicine) and one quaternary aporphine-type alkaloid (magnoflorine) were isolated from the most active n-BuOH fraction, and the chemical structures therein were elucidated on the basis of spectroscopic evidence and comparison with published data. The anti-diabetic complications capacities of seven C. chinensis-derived alkaloids were evaluated via RLAR and human recombinant AR (HRAR) inhibitory assays. Although berberine and palmatine were previously reported as prime contributors to AR inhibition, these two major components exhibited no AR inhibitory effects at a higher concentration of 50 μg/ml in the present study. Conversely, epiberberine, coptisine, and groenlandicine exhibited moderate inhibitory effects with IC₅₀ values of 100.1, 118.4, 140.1 μM for RLAR and 168.1, 187.3, 154.2 μM for HRAR. The results clearly indicated that the presence of the dioxymethylene group in the D ring and the oxidized form of the dioxymethylene group in the A ring were partly responsible for the AR inhibitory activities of protoberberine-type alkaloids. Therefore, Coptidis Rhizoma, and the alkaloids contained therein, would clearly have beneficial uses in the development of therapeutic and preventive agents for diabetic complications and diabetes mellitus.     

20种天然降压化合物对醛糖还原酶抑制作用的研究

目的:筛选出具有醛糖还原酶抑制作用的防治高血压伴糖尿病的高效低毒的天然降压药物.方法:在构效分析的基础上查阅文献,利用体外酶动学方法测定醛糖还原酶(AR)活性,研究天然降压化合物对牛晶状体醛糖还原酶的抑制作用.结果:芥子碱硫氰酸盐、金丝桃苷、水飞蓟素、丹参酚酸、川芎嗪、黄连素、黄芩素、茶多酚对醛糖还原酶的抑制作用活性最强,IC50值分别为36.9、37.6、39.3、35.9、36.9、35.4、36.8、37.9和39.6 μmol/L.结论:高效低毒的天然降压药物具有较强的醛糖还原酶抑制作用,可以用来防治高血压伴糖尿病.     

冬连胶囊对糖尿病大鼠蛋白非酶糖基化的影响

目的 观察冬连胶囊对蛋白非酶糖基化的干预作用.方法 采用小剂量链脲佐菌素(STZ)腹腔注射,配合高脂饮食制备糖尿病大鼠模型,给药12周后观察冬连胶囊对大鼠血糖、糖化血清蛋白(GSP)、醛糖还原酶(AR)的影响.结果 较空白对照组,模型组血糖明显升高:冬连胶囊高剂量组和西药对照组大鼠血糖有下降趋势,较模型对照组有显著性差异(P＜0.05);冬连胶囊高、低剂量组和西药对照组均能降低大鼠GSP含量、抑制AR活性,较模型对照组有显著性差异(P＜0.01).结论 冬连胶囊对蛋白非酶糖基化反应有抑制作用.     

Erythrocytic sorbitol contents in diabetic patients correlate with blood aldose reductase protein contents and plasma glucose levels, and are normalized by the potent aldose reductase inhibitor fidarestat (SNK-860)

The accumulation of sorbitol by the activated polyol pathway is considered to be a major cause of diabetic neuropathy. Because the erythrocytic sorbitol contents reportedly reflects that in nerves, erythrocytic sorbitol measurement would be useful for confirming the effect of an aldose reductase inhibitor (ARI). In this study, we examined erythrocytic sorbitol contents in healthy subjects and diabetic patients under fasting and postprandial conditions. Then, the contributions of blood aldose reductase (AR) contents and plasma glucose levels to the accumulated erythrocytic sorbitol contents were also analyzed. Erythrocytic sorbitol contents in the healthy subjects were 11.7 and 12.5–12.6 nmol/g Hb in fasting and postprandial status, respectively. In contrast, the erythrocytic sorbitol contents in diabetic patients were apparently higher (approximately 2.5-fold), but fidarestat treatment restored the elevated erythrocytic sorbitol contents to normal. In the diabetic patients, erythrocytic sorbitol contents were highly correlated with blood AR contents multiplied by the plasma glucose levels, whereas in the normal and fidarestat-treated diabetic patients no such correlation was observed. Taken together, these results suggest both the blood AR contents and the plasma glucose levels are factors determining erythrocytic sorbitol contents in diabetic patients. Notably, the potent ARI fidarestat was shown to normalize elevated erythrocytic sorbitol contents.     

醛糖还原酶抑制剂对小鼠胰岛山梨醇代谢的影响

观察了一种醛糖还原酶抑制剂(ICI 128436)对小鼠胰岛体外培养时山梨醇代谢的影响情况。小鼠胰岛培养72小时后,酶抑制剂处理过的胰岛山梨醇水平较对照组显著降低。结果表明小鼠胰岛可以合成山梨醇,其生成水平与醛糖还原酶的活性密切有关。     

Treatment with an aldose reductase inhibitor can reduce the susceptibility of fast axonal transport following nerve compression in the streptozotocin-diabetic rat

Summary The effect of treatment with an aldose reductase inhibitor on the susceptibility of peripheral nerves to compression was studied in rats made diabetic by the injection of streptozotocin (50 mg·kg^–1). The response to nerve compression was determined in untreated diabetic rats after 22 days of diabetes and compared with the response in two similar groups of diabetic rats which had been treated with the aldose reductase inhibitor Statil (ICI 128436; 25 mg·kg^–1· day^–1 orally) either from the induction of diabetes or for 7 days prior to nerve compression. Two groups of non-diabetic rats were treated with Statil for either 22 days or 7 days to act as controls. Inhibition of fast axonally transported proteins was induced by local compression of the sciatic nerves 4 h after application of ³H-leucine to the motor neurone cell bodies in the spinal cord. The inhibition of fast axonal transport was quantified by calculation of a transport block ratio.Compression at 30 mmHg for 3 h induced a significantly greater (p<0.05) inhibition of axonal transport at the site of compression in nerves of untreated diabetic rats (transport block ratio 0.96±0.24, n=8) than in nerves of control rats treated with the aldose reductase inhibitor for either the shorter time of 7 days (0.71±0.17, n=10) or the longer time of 22 days (0.69±0.08, n=5). In diabetic rats treated with the aldose reductase inhibitor for 22 days the inhibition (0.77±0.12, n=6) was significantly less than that in untreated diabetic rats; treatment for 7 days reduced the transport block ratio to 0.85±0.11 (n=8), but the effect was not significant. Treatment for 22 days prevented the marked increase in nerve sorbitol found in the diabetic rats but did not prevent a fall in nerve myo-inositol. The results indicate that treatment with an aldose reductase inhibitor for a sufficient period of time can reduce the increased susceptibility of peripheral nerves to compression in streptozotocin-induced diabetes mellitus in the rat by a mechanism which may be related to the prevention of increases in sorbitol in the nerves.     

Inhibition effects of quinones on aldose reductase: Antidiabetic properties

Diabetes mellitus is a chronic metabolic disease characterized by abnormal glucose metabolism. Aldose reductase (AR) is the first enzyme in the polyol pathway and converts glucose to sorbitol. It plays a vital role as a glucose reducing agent and is involved in the pathophysiology of diabetic complications. In this study, we purified AR from sheep kidney with a specific activity of 2.00 EU/mg protein and 133.33- fold purification After the purification of the AR enzyme, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was performed and the molecular weight of the enzyme was found approximately as 38 kDa. The inhibition effects of eight quinones were studied against AR. The quinones were potent inhibitors of AR with K_i values in the range of 0.07–20.04 μM. Anthraquinone showed the best potential inhibitory effects against AR. All compounds exhibited noncompetitive inhibition against AR. These compounds may be selective inhibitors of this enzyme. AR inhibition is an essential strategy for the attenuation and prevention of diabetic complications.