Protective effect of Tephrosia purpurea in diabetic cataract through aldose reductase inhibitory activity

PurposeTephrosia purpurea (T. purpurea) has been reported to prevent cataract formation in senile cataract model as well as proven effective in STZ induced type 1 diabetes. Aldose reductase (AR) is a key enzyme in the intracellular polyol pathway responsible for the development of diabetic cataract.ObjectiveTo investigate the effects of T. purpurea in the light of inhibition of aldose reductase enzyme in polyol pathway.MethodsWe studied the effects of alcoholic extract and flavonoid fraction of T. purpurea in streptozotocin (STZ, 45 mg/kg, i.v.)-induced type I diabetic cataract in rats. The animals were divided into five groups as control, control treated with alcoholic and flavonoid fraction, diabetic control and diabetic treated with alcoholic and flavonoid fraction. In-vitro aldose reductase inhibitory activity was also evaluated. Further, molecular docking study was performed with crystal structure of aldose reductase and its known chemical constituents of the plant.ResultsThe IC₅₀ value of alcoholic extract for aldose reductase inhibition was found to be 209.13 μg/ml, and that of flavonoid fraction was found to be 46.73 μg/ml. Administration of STZ produced significantly abnormal levels of serum glucose, serum insulin, soluble protein and antioxidants in the lens homogenate. Treatment with alcoholic extract and flavonoid fraction of T. purpurea were able to normalize these levels. Some of the active constituents of T. purpurea showed significant interactions with aldose reductase enzyme in molecular docking studies.ConclusionsOur data suggested that both the extracts might be helpful in delaying the development of diabetic cataract due to the presence of rutin and quercetin. This beneficial effect may be due to its significant inhibition of aldose reductase enzyme and anti-oxidant activity.     

In vitro and in vivo inhibition of aldose reductase and advanced glycation end products by phloretin,epigallocatechin 3-gallate and [6]-gingerol

Hyperglycemic stress activates polyol pathway and aldose reductase (AR) key enzyme responsible for generating secondary complications during diabetes. In this study the therapeutic potential of phloretin, epigallocatechin 3-gallate (EGCG) and [6]-gingerol were evaluated for anti-glycating and AR inhibitory activity in vitro and in vivo systems. Human retinal pigment epithelial (HRPE) cells were induced with high glucose supplemented with the phloretin, EGCG and [6]-gingerol. Aldose reductase activity, total advanced glycation end products (AGEs) and enzyme inhibitor kinetics were assessed. Male C57BL/6J mice were randomly assigned to one of the different treatments (bioactive compounds at 2 concentrations each) with either a low fat diet or high fat diet (HFD). After sixteen weeks, AGE accumulation and AR activity was determined in heart, eyes and kidney. High glucose induced toxicity decreased cell viability compared to the untreated cells and AR activity increased to 2–5 folds from 24 to 96 h. Pre-treatment of cells with phloretin, EGCG and [6]-gingerol improved cell viability and inhibited AR activity. The enzyme inhibition kinetics followed a non-competitive mode of inhibition for phloretin and EGCG whereas [6]-gingerol indicated uncompetitive type of inhibition against AR. Data from the animal studies showed high plasma glucose levels in HFD group over time, compared to the low fat diet. HFD group developed cataract and AR activity increased to 4 folds compared to the group with low fat diet. Administration of EGCG, phloretin and [6]-gingerol significantly reduced blood sugar levels, AGEs accumulation, and AR activity. These findings could provide a basis to consider using the selected dietary components alone or in combination with other therapeutic approaches to prevent diabetes-related complications in humans.     

亚甲基四氢叶酸还原酶基因多态性与河北地区汉族人2型糖尿病肾病易感性的研究

目的　探讨亚甲基四氢叶酸还原酶 (MTHFR)基因多态性与 2型糖尿病肾病 (DN)易感性的关系。方法　利用聚合酶链反应限制性片段长度多态性分析法 (PCR RFLP)检测 175例河北地区汉族人 [12 3例为 2型糖尿病患者 (T2DM ) ,其中 6 9例合并糖尿病肾病 (DN +) ,5 4例不伴肾病 (DN - ) ,5 2例为健康对照者 (HC) ]MTHFR基因第6 77位碱基多态性。分别测定各组MTHFR等位基因和基因型的频率 ,比较各组间频率分布差异是否具有统计学意义。结果　糖尿病肾病 (DN +)患者MTHFR基因纯合突变型 (TT)和等位基因 (T)频率均明显高于糖尿病无肾病(DN - )患者及健康者 (HC) ,分别为 30 .4 3%vs 16 .6 7%、13.4 6 % ,Ρ <0 .0 5 ,和 5 4 .35 %vs 36 .11%、37.5 0 % ,Ρ <0 .0 1。结论　MTHFR基因 6 77C→T突变为河北地区汉族人T2DM患者发生DN的一个遗传易感因素     

羟苯磺酸钙胶囊联合血管紧张素转换酶组织抑制剂对早期糖尿病肾病患者肾功能及血清结缔组织生长因子、金属蛋白酶抑制剂-1水平的影响

目的探讨羟苯磺酸钙胶囊+血管紧张素转换酶抑制剂对早期糖尿病肾病患者肾功能及血清结缔组织生长因子(CTGF)、金属蛋白酶抑制剂-1(TIMP-1)水平的影响。方法将我院2015年1月至2018年1月收治的112例早期糖尿病肾病患者采用随机数字表法分为对照组(n=56)与研究组(n=56)。对照组采取血管紧张素转换酶抑制剂治疗,研究组在对照组基础上采取羟苯磺酸钙胶囊治疗。比较两组临床疗效、治疗前、后血清肌酐(Scr)、尿素氮(BUN)、尿酸(UA)、β2-微球蛋白(β2-MG)、CTGF、TIMP-1水平、24 h尿蛋白定量及不良反应发生情况。结果研究组治疗总有效率高于对照组(P<0.05)。治疗后,研究组血清Scr、BUN、UA、β2-MG、CTGF、TIMP-1水平及24 h尿蛋白定量低于对照组(P<0.05)。两组不良反应总发生率无显著差异(P>0.05)。结论早期糖尿病肾病患者采取羟苯磺酸钙胶囊+血管紧张素转换酶抑制剂治疗效果确切,能改善其肾功能,降低血清CTGF、TIMP-1水平,且安全性高。     

Glutathione, glutathione utilizing enzymes and thioltransferase in platelets of insulin-dependent diabetic patients: relation with platelet aggregation and with microangiopatic complications

Abstract. Reduced glutathione (GSH) and activity of GSH related enzymes play a key role in defence against oxygen free radicals, whose production is, as known, raised in patients affected by diabetes mellitus, and at the same time they may contribute to the process of platelet aggregation. The purpose of this study was to evaluate GSH levels and activity of glutathione peroxidase (GSH-Px), glutathione reduc-tase (GSSG-Red), glutathione transferase (GSH-Tr), glucose-6-phosphate-dehydrogenase (G6PDH), and thioltransferase (TT) in platelets of insulin-dependent diabetic patients in fair metabolic control (mean glycated haemoglobin: 6.5%), as related to presence of retinopathy, neuropathy or nephropathy and to platelet aggregation by arachidonic acid (AA)in vitro. Mean effective dose (ED₅₀) of AA was on average significantly lower in the group of insulin-dependent diabetic patients (0.41 ± 0.02mM (SEM),n= 46) as compared with that of control subjects strictly matched for age, sex and weight (0.77 ± 0.02, n= 51; P= 0.0001). Mean platelet GSH as well as the activity of GSH related enzymes expressed as geometric mean (95% confidence intervals) were similar in diabetic patients and in controls, except for GSSG-Red whose activity was significantly higher in diabetic subjects (28.5 (14.4–57.5) mU 10^-9 platelets vs. 20.3 (8.7–56) mU 10^-9 platelets; P= 0.01). In the diabetic group TT was reduced when compared with healthy controls (3.8 (0.9–12.2) mU 10^-9 platelets vs. 6 (1.6–26.1) mU 10^-9 platelets; P = 004). Moreover TT was significantly reduced in diabetic patients with worse metabolic control or with increased urinary albumin excretion rate (AER ≤ 20 μg min^-1), while neither TT, GSH nor GSH related enzymes were significantly different in patients with retinopathy or neuropathy. In addition TT was significantly related to ED₅₀ of AA (r= 0.51; P= 0.0003). In conclusion GSH is not modified in insulin-dependent diabetic patients in fair metabolic control, probably due to an augmented GSSG-Red activity. Diabetic status, increase in platelet aggregation, and raised urinary AER seem to be altogether associated with a selective reduction in platelet TT activity.     

厄贝沙坦干预糖尿病肾病大鼠白细胞介素8、白细胞介素10的变化

目的观察厄贝沙坦干预对炎症相关细胞因子白细胞介素8(IL-8)和白细胞介素10(IL-10)水平的影响,并从炎症方面探讨其可能的药物作用机制。方法将36只Wistar大鼠随机分为右肾切除对照组、糖尿病肾病组(DN)、厄贝沙坦治疗组(Irb)3组,每组12只。第8周、12周末收集大鼠血、尿标本,测定血液IL-8I、L-10、血糖、肌酐、尿素氮、尿液24小时尿蛋白含量,同时测定肾质量/体质量比值。结果 Irb组和DN组8周、12周的IL-8均高于对照组,而DN组8周、12周的IL-8又高于Irb组(26.51±2.34)ng/L vs(16.12±2.11)ng/L,(59.32±1.28)ng/L vs(21.46±2.59)ng/L(P<0.01);Irb组和DN组12周均高于8周(21.46±2.59)ng/L vs(16.12±2.11)ng/L,(59.32±1.28)ng/L vs(26.51±2.34)ng/L(P<0.01);但Irb组上升幅度小于DN组。Irb组和DN组8周、12周的IL-10均低于对照组,而DN组8周、12周的IL-10又低于Irb组(21.27±2.49)ng/L vs(25.58±3.52)ng/L,(18.05±3.55)ng/L vs(33.22±2.97)ng/L(P<0.01);DN组12周的IL-10低于8周(18.05±3.55)ng/L vs(21.27±2.49)ng/L(P<0.01);而Irb组12周的IL-10高于8周(33.22±2.97)ng/L vs(25.58±3.52)ng/L(P<0.01);C组12周与8周的IL-8I、L-10无明显变化(P>0.05)。IL-8与IL-10显著负相关(r=-0.659,P<0.01);IL-8与血糖、24小时尿蛋白、肌酐、血尿素氮、肾质量/体质量比显著正相关(r=0.596、0.764、0.845、0.635、0.830,P<0.01),而IL-10与血糖、24小时尿蛋白、肌酐、血尿素氮、肾质量/体质量比显著负相关(r=-0.835、-0.739、-0.757、-0.745、-0.810,P<0.01)。结论厄贝沙坦通过抑制免疫炎症反应使促炎症细胞因子IL-8分泌减少,同时刺激分泌抗炎症细胞因子IL-10,改善DN大鼠肾脏肥大程度和尿蛋白排泄,起到保护肾脏的作用。     

Effects of an aldose reductase inhibitor, ONO-2235, insulin and their combination on the altered responsiveness to the nerve stimulation and agonists of the isolated atria of diabetic rats

To determine the effects of an aldose reductase inhibitor (ARI) on diabetes-induced cardiac autonomic nerves disturbance, we examined the effects of ONO-2235, an ARI, as well as insulin on the responsiveness to the nerve stimulation and agonists of the isolated atria of the streptozotocin-induced diabetic rats. Insulin, 4 U/animal/day, was administered s.c. for 4 weeks before the experiment and ARI (ONO-2235), 40 mg/kg/day, was administered p.o. 3 weeks before the experiment. The transmural nerve stimulation (TNS) of sympathetic nerves and parasympathetic nerve was performed in the presence of atropine and metoprolol plus prazocin, respectively. The positive chronotropic and the inotropic responses of the atria to sympathetic TNS and to norepinephrine decreased in the rats diabetic for 8 and 12 weeks. In the rats diabetic for 8 weeks, the insulin treatment restored completely both the positive chronotropic and the inotropic responses to sympathetic TNS, whereas the ARI treatment partially improved the positive chronotropic response and did not improve the positive inotropic response. In the rats diabetic for 12 weeks, the insulin treatment partially improved the positive chronotropic and the inotropic responses to sympathetic TNS, whereas the ARI treatment only slightly improved the positive chronotropic response and did not improve the positive inotropic response to TNS. The combination treatment with insulin and ARI restored completely both the positive chronotropic and the inotropic responses in the rats diabetic for 12 weeks. In rats diabetic for both 8 and 12 weeks, the decreased positive chronotropic and the inotropic responses to norepinephrine recovered completely with the insulin treatment, but did not with the ARI treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of antiplatelet drug dilazep dihydrochloride on anionic sites and extracellular matrix (ecm) components in glomerular basement membrane of stz-induced diabetic rats

A study of anionic sites in the glomerular basement membrane (GBM) of streptozotocin (STZ)-induced diabetic rats with or without treatment by an antiplatelet drug, dilazep dihydrochloride, is described. Expression of glomerular extracellular matrix (ECM) components was examined by immunofluorescence. Renal specimens were immersed in polyethyleneimine (PEI) as a cationic probe and then examined by electron microscopy. Renal specimens were also incubated with rabbit antirat type IV collagen, laminin, and fibronectin antisera and then stained with fluorescein isothiocyanate (FITC)-labeled goat antirabbit IgG antiserum. Mean values of proteinuria in the dilazep-treated diabetic rats were significantly decreased compared with those in nontreated diabetic rats. There was no significant correlation between the levels of proteinuria and those of creatinine clearance (CCr). Number of anionic sites on the GBM in the dilazep-treated diabetic rats were greater than those in diabetic rats. There was no significant difference in the staining of such ECM components between both rat groups. The authors concluded that the dilazep dihydrochloride might prevent anionic charges on the GBM and decrease the urinary excretion of proteins in STZ-induced diabetic rats.     

超声对实验性糖尿病大鼠血糖、血脂及C肽的影响

目的:观察超声波对实验性糖尿病大鼠血糖、血脂及C肽的影响,探讨糖尿病的治疗新的途径。方法:将链脲佐菌素(streptozocin,STZ)按55mg/kg一次性腹腔注射而诱发出糖尿病模型。用3种不同治疗量超声:0,0.6,0.9,1.2W/cm2分别作用于糖尿病大鼠左上腹及左背部的胰腺投影区,每个部位分别作用5min,1次/d。经10d治疗后分别测定空腹血糖、三酰甘油、胆固醇、低密度脂蛋白、高密度脂蛋白及C肽等6项指标。结果:对照组(0W/cm2)与低声强组(0.6W/cm2)及中声强组(0.9W/cm2)与高声强组(0.9W/cm2)的6项指标均无显著性差异(q=2.70,0.99,P均>0.05);但对空腹血糖(mmol/L)在中声强组(10.21±3.61)、高声强组(8.44±3.92)较对照组(18.43±5.71)和低声强组(15.20±5.69)差异有十分显著性意义(q=4.58～5.85,P均<0.01);对三酰甘油、胆固醇和低密度脂蛋白也具有显著降低的效果(H=10.58,10.44,8.80,P均<0.05);同时血中C肽水平也呈显著升高(H=10.35,P<0.05)。高密度脂蛋白(mmol/L)在中、高声强组中均值虽略有增高(0.83±0.22,0.85±0.22),但各组间差异却无显著性(H=7.71,P>0.05)。结论:0.9～1.2W/cm2声强的超声波对糖尿病大鼠具有较好的降糖、降脂效果,并可提高血中C肽水平。     

Plasma homocysteine, methylenetetrahydrofolate reductase gene polymorphism and carotid intima-media thickness in Italian type 2 diabetic patients

BACKGROUND: Moderately elevated levels of homocysteine have been associated with an increased cardiovascular risk in type 2 diabetic patients. The role of methylenetetrahydrofolate reductase gene polymorphism is less clear. MATERIALS AND METHODS: We investigated the contribution of plasma homocysteine levels and the methylenetetrahydrofolate reductase gene polymorphism to the variability of carotid intima-media thickness in 124 consecutive Italian patients with type 2 diabetes mellitus. Fasting plasma homocysteine was measured by high-pressure liquid chromatography with an electrochemical detector; methylenetetrahydrofolate reductase genotypes were determined by polymerase chain reaction and restriction enzyme digestion. The carotid intima-media thickness was evaluated with high-resolution B-mode ultrasonography. RESULTS: Age, creatinine and plasma homocysteine levels showed a positive correlation with mean carotid intima-media thickness values, but only age and creatinine levels were still associated with mean carotid intima-media thickness values in the multivariate analysis. Plasma homocysteine levels were significantly higher in the patients bearing the 677T/677T genotype of the methylenetetrahydrofolate reductase polymorphism; mean carotid intima-media thickness values were not different in the three different methylenetetrahydrofolate reductase genotypes. CONCLUSION: In 124 Italian patients with type 2 diabetes mellitus, basal levels of plasma homocysteine, as well as methylenetetrahydrofolate reductase gene polymorphism, did not explain the variability of mean carotid intima-media thickness.     

The effect of insulin in combination with selenium on blood glucose and GLUT4 expression in the cardiac muscle of streptozotocin‐induced diabetic rats

We evaluated the effect of a combination of low doses of insulin (1 U/kg/day) and selenium (180 μg/kg/day) on general physiological parameters and the level of glucose transporter (GLUT4) in the cardiac muscle of streptozotocin‐induced diabetic rats. Diabetic rats were treated with insulin, selenium and a combination of insulin and selenium for 4 weeks. The levels of blood glucose and hemoglobin A1c were estimated; the level of the GLUT4 in the cardiac muscle was examined by immunoblotting and immunohistochemistry. Insulin in combination with selenium could significantly lower blood glucose and HbA1c levels and could restore disturbances in GLUT4 level in the cardiac muscle. The treatment with insulin was only partially effective in the restoration of diabetic alterations. We conclude that there was cooperation between insulin and selenium, and that the treatment of diabetic rats with combined doses of insulin and selenium was effective in the control of blood glucose and correction of altered GLUT4 distribution in diabetic rat hearts.     

Effect of povidone-iodine on wound healing in control, diabetic and steroid depressed rats

A comparative study was made on the effect of povidone-iodine on wound healing in normal, diabetic and steroid depressed states in the excision wound model in rats. Healing was assessed by the rate of contraction of wounds and epithelialization after three weeks of topical application. Normal and diabetic groups were comparable (P < 0.02) concerning the above-mentioned parameters as well as collagen formation. The steroid group showed significant retardation in healing time (P < 0.001), epithelialization (P < 0.001) and collagen formation (P < 0.001) showing that povidone-iodine did not overcome the steroid effect.     

Role of sorbitol accumulation and myo-inositol depletion in paranodal swelling of large myelinated nerve fibers in the insulin-deficient spontaneously diabetic bio-breeding rat. Reversal by insulin replacement, an aldose reductase inhibitor, and myo-inositol.

Axo-glial dysjunction refers to the disruption of important junctional complexes that anchor terminal loops of myelin to the paranodal axolemma in diabetic human and animal peripheral nerve. Neither axo-glial dysjunction nor the preceeding acute localized paranodal swelling has been specifically attributed to discrete metabolic consequences of insulin deficiency or hyperglycemia. Two metabolic sequelae of hyperglycemia in diabetic nerve, sorbitol accumulation via aldose reductase, and (Na,K)-ATPase deficiency related to myo-inositol depletion, were explored as possible underlying causes of acute paranodal swelling in the spontaneously diabetic bio-breeding rat. 3 wk of insulin replacement, or therapy with an aldose reductase inhibitor or myo-inositol completely reversed paranodal swelling in sural nerve fibers after 3 wk of untreated insulin deficiency. These observations suggest that insulin deficiency and hyperglycemia cause reversible paranodal swelling, and ultimately poorly reversible axo-glial dysjunction, via the myo-inositol-related (Na,K)-ATPase defect rather than by the osmotic effects of sorbitol accumulation within nerve fibers.     

Glutathione and alpha-lipoate in diabetic rats: nerve function, blood flow and oxidative state

BACKGROUND: Increased oxidative stress is considered to be a causal factor in the development of diabetic complications, among which peripheral neuropathy. The pathophysiology of nerve dysfunction in diabetes has been explained both by reduced endoneurial microcirculation and alterations in endoneurial metabolism. It is unclear whether antioxidants primarily improve nerve blood flow or normalise systemic or endoneurial oxidative metabolism. Therefore, we evaluated the effects of the antioxidants glutathione and alpha-lipoic acid on both nerve microcirculation and the antioxidative capacity and lipid peroxidation in experimentally diabetic rats. MATERIALS AND METHODS: Streptozotocin-diabetic rats were treated with different doses of alpha-lipoic acid, reduced glutathione or placebo, and were compared with nondiabetic controls. We measured systemic and endoneurial antioxidants, malondialdehyde and whole blood hydrogen peroxide. Furthermore, we evaluated sciatic and tibial motor and sensory nerve conduction velocity, caudal nerve conduction velocity, and assessed sciatic nerve blood flow and vascular resistance by Laser-Doppler flowmetry. RESULTS: We observed a rise in erythrocyte glutathione by 27 % (P < 0.05), and a trend towards decreased plasma malondialdehyde in alpha-lipoic acid, but not in glutathione-treated animals in comparison with the placebo group. Simultaneously, sciatic nerve blood flow and vascular resistance were improved by daily alpha-lipoic acid administration by 38% (P < 0.05). Peripheral nerve conduction velocity and endoneurial glutathione were not significantly influenced by antioxidant treatment. CONCLUSIONS: Only minor beneficial effects of alpha-lipoic acid on nerve blood flow and oxidative state occur at the given doses; these effects were insufficient to improve nerve conduction deficits.     

脑梗死患者检测纤溶系统及血小板参数的意义

目的探讨纤溶酶原激活剂抑制物-1、组织型纤溶酶原激活物及血小板参数在脑梗死患者中的变化。方法对60例脑梗死患者及60例健康体检者进行血小板及其参数、纤溶酶原激活剂抑制物-1、组织型纤溶酶原激活物的测量。结果与对照组相比,脑梗死患者中血小板、组织型纤溶酶原激活物含量显著低于对照组（P〈0.05）,平均血小板容积及血小板体积分布宽度及纤溶酶原激活剂抑制物-1含量显著高于对照组（P〈0.05）。结论血小板参数及纤溶酶原激活剂抑制物-1、组织型纤溶酶原激活物在脑梗死患者中有显著性改变,提示脑梗死患者存在着血小板活化及纤溶活性减低的现象,凝血系统活性改变在脑梗死患者的病情发展中起着一定的作用。     

Renal synthesis of urokinase type-plasminogen activator, its receptor, and plasminogen activator inhibitor-1 in diabetic nephropathy in rats: modulation by angiotensin-converting-enzyme inhibitor

Plasmin is an important factor in the degradation of extracellular matrix. In the study reported here we examined the expression of plasminogen-activator inhibitor-1 (PAI-1), urokinase-type plasminogen activator (uPA), and uPA receptor (uPAR), as well as the relevance of such expression to the production of type IV collagen, a major component of extracellular matrix, in the renal tissue of rats with streptozotocin-induced diabetes. Because angiotensin II is involved in the synthesis of PAI-1 and uPA, we also examined the effect of benazepril, an angiotensin-converting-enzyme inhibitor, on the expression of PAI-1, uPA, and uPAR messenger RNAs (mRNAs) and type IV collagen protein. Rats with streptozocin-induced diabetes-some untreated and some treated with 30 mg/L benazepril-and nondiabetic control rats were sacrificed at 4, 12, or 24 weeks after induction of diabetes. We examined the expression of PAI-1, uPA, and uPAR mRNAs through the use of in situ hybridization and that of type IV collagen by means of immunohistochemical methods. In control rats, we detected weak signals for PAI-1, uPA, and uPAR mRNAs in glomeruli. Diabetic rats exhibited high levels of expression of PAI-1, uPA, and uPAR mRNAs and type IV collagen protein, mainly in mesangial cells. These mRNAs were synthesized in various renal cells (epithelial, mesangial, and endothelial cells and Bowman's capsule). Benazepril inhibited increases in all 3 mRNAs, especially in the mesangium; reduced type IV collagen expression; and attenuated mesangial expansion. Our results indicated that altered expression of PAI-1, uPA, and uPAR in diabetic nephropathy was associated with mesangial expansion and that the beneficial effects of ACE-I may be at least associated with such expression.     

适龄期孕妇复发性流产与亚甲基四氢叶酸还原酶、纤溶酶原激活物抑制物1基因多态性及血清叶酸浓度关系的研究

目的:探讨适龄期妇女复发性流产（recurrent spontaneous abortion, RSA）与叶酸代谢基因亚甲基四氢叶酸还原酶（methylene Tetrahydrofolate Reductase, MTHFR）、纤溶酶原激活物抑制物1（plasminogen activator inhibitor-1...     

Effects of the sulphydryl donor N-acetyl-L-cysteine on nerve conduction, perfusion, maturation and regeneration following freeze damage in diabetic rats

Abstract. Peripheral nerve conduction velocity deficits in diabetic rats depend on decreased nerve perfusion, which may be related to increased free radical activity and impaired endogenous protection by the glutathione redox cycle. We studied the effect of treatment with the glutathione precursor N -acetyl-L-cysteine on nerve conduction, blood flow, maturation and regeneration. Two months of diabetes in mature rats caused 20% and 48% deficits in sciatic motor conduction velocity and endoneurial blood flow, respectively, which were largely corrected by N -acetyl-L-cysteine treatment during the second month. In young non-diabetic rats, sciatic motor conduction velocity increased by 31% over 6 weeks. Diabetes halved the conduction velocity maturation rate, however N -acetyl-L-cysteine treatment allowed a normal pattern of development. After 1 month of treated or untreated diabetes, the sciatic nerve was lesioned by a liquid nitrogen-cooled probe. Myelinated fibre regeneration distance, determined electrophysiologically, was reduced by 12.2% with diabetes; this was prevented by N -acetyl-L-cysteine treatment. Thus, the data stress the importance of free radical-mediated changes in the aetiology of experimental diabetic neuropathy.     

基质金属蛋白酶2,9及其抑制剂3在脑梗死中的作用

目的通过注入自体血栓形成大鼠脑梗死模型,研究其不同时段基质金属蛋白酶（matrix metalloproteinase,MMP）2、9和基质金属蛋白酶抑制剂（tissue inhibitor metalloproteinase,TIMP）3的表达规律。方法66只成年Sprague Dawley大鼠随机分为3组,空白对照组（6只）、假手术对照组（30只）和手术实验组（30只）。实验组给予自体血栓经颈内动脉注入制备大鼠脑梗死标本;假手术对照组做同样处理,但不给予血栓注入干预,于术后24h,48h,3d,5d,7d麻醉并灌注固定取脑。观察大鼠行为学改变;采用免疫组化方法检测标本MMP-2,MMP-9,TIMP-3表达,了解其与病变之间关系。结果实验组大鼠行为学改变较其他组明显;HE染色下,组织病理变化明显;免疫组化染色显示MMP-2,MMP-9,TIMP-3表达均较其他两组增高,统计学结果显著性差异（P〈0．05）。结论MMP-2和MMP-9在脑梗死中与疾病损伤相关,TIMP-3有对抗作用。