Glycation, ageing and carnosine: are carnivorous diets beneficial?

Non-enzymic protein glycosylation (glycation) plays important roles in ageing and in diabetes and its secondary complications. Dietary constituents may play important roles in accelerating or suppressing glycation. It is suggested that carnivorous diets contain a potential anti-glycating agent, carnosine (beta-alanyl-histidine), whilst vegetarians may lack intake of the dipeptide. The possible beneficial effects of carnosine and related structures on protein carbonyl stress, AGE formation, secondary diabetic complications and age-related neuropathology are discussed.     

A practical method to study functional impairment of proteins by glycation and effects of inhibitors using current coagulation/fibrinolysis reagent kits

Objectives We undertook the present work to device a simple method to study the effects of inhibitors on functional impairment of proteins by the action of glycating agents.Design and methods For that purpose, we first tested the feasibility and optimized the conditions to employ glycation of human plasma coupled with AT III and plasminogen activity measurement, using coagulation test kits available in most clinical laboratories.Results Using D-BUT-CHT-lys-pNA as a plasmin-specific substrate, we show that incubation of plasma with fructose, glyceraldehyde or MG but not glucose decreases plasminogen activity reaching more than 40% in 16 h. A parallel dose-dependent decrease in heparin activation of AT III by up to a 50% was demonstrated using SAR-PRO-ARG-pNA as a specific thrombin substrate. We studied the effects of aminoguanidine, carnosine, quercetin aglycone, alpha tocopherol and ascorbic acid.Conclusion The methods afforded good discrimination between the known different reactivities of glycating sugars as well as the action of known antiglycation agents. They provide a practical system for monitoring the action of putative antiglycation agents.     

Glycation: The angiogenic paradox in aging and age-related disorders and diseases

Angiogenesis is generally a quiescent process which, however, may be modified by different physiological and pathological conditions. The “angiogenic paradox” has been described in diabetes because this disease impairs the angiogenic response in a manner that differs depending on the organs involved and disease evolution. Aging is also associated with pro- and antiangiogenic processes. Glycation, the post-translational modification of proteins, increases with aging and the progression of diabetes. The effect of glycation on angiogenesis depends on the type of glycated proteins and cells involved. This complex link could be responsible for the “angiogenic paradox” in aging and age-related disorders and diseases. Using diabetes as a model, the present work has attempted to review the age-related angiogenic paradox, in particular the effects of glycation on angiogenesis during aging.     

D-半乳糖诱导大鼠肾脏损害的糖基化机制及药物干预作用

目的 D-半乳糖(D-galactose)诱导大鼠体内不同糖基化水平,研究其肾脏损伤发生的机理及药物对其干预作用.方法 采用不同剂量D-半乳糖[150、75、37.5 mg/(kg·d)]分别腹腔注射(ip)处理大鼠8周,诱导糖基化状态和肾脏损伤,同时D-半乳糖高剂量[150 mg/(kg·d)]分别给与氨基胍[150 mg/(kg·d)]和维生素E[150 mg/(kg·d)]处理8周.采用葡萄糖氧化酶法测定大鼠血糖,硫代巴比妥酸(TBA)比色法测定糖化血红蛋白,硝基四氮唑蓝(NBT)比色法测定血清果糖胺;按文献方法分别测定血红细胞醛糖还原酶活性和晚期糖基化终末产物(AGEs)含量及肾脏组织中AGEs含量,羟胺法和比色法分别测定SOD和GSH-Px活性,硫代巴比妥酸法测定MDA含量;采用CBB法测定尿蛋白含量,二乙酰-肟法测定血尿素氮,苦味酸法测定血肌酐;流式细胞仪检测肾脏细胞凋亡情况.结果 D-半乳糖高、中剂量处理8周后,大鼠2 h血糖明显升高,血红细胞醛糖还原酶活性升高,糖化产物形成增多(P<0.01,P<0.05);肾组织中AGEs含量明显升高,SOD及GSH-Px活性下降,MDA含量升高(P<0.01,P<0.05),尿蛋白、血尿素氮和血肌酐量明显增加,肾脏细胞凋亡率明显增加(P<0.01,P<0.05).而氨基胍和维生素E处理后,可明显抑制高剂量D-半乳糖引起的糖基化反应,减少上述物质的生成,并减轻对肾脏组织的损伤作用,尤其是氨基胍作用更为明显.结论 D-半乳糖通过诱导体内蛋白糖基化和肾组织AGEs大量生成,降低抗氧化能力,诱致肾脏细胞凋亡;氨基胍和维生素E对D-半乳糖诱致的肾脏损伤作用具有保护作用.     

High-mobility group box-1 impairs memory in mice through both toll-like receptor 4 and Receptor for Advanced Glycation End Products

High-mobility group box-1 (HMGB1) is a nuclear protein with cytokine-type functions upon its extracellular release. HMGB1 activates inflammatory pathways by stimulating multiple receptors, chiefly toll-like receptor 4 (TLR4) and Receptor for Advanced Glycation End Products (RAGE). TLR4 and RAGE activation has been implicated in memory impairments, although the endogenous ligand subserving these effects is unknown. We examined whether HMGB1 induced memory deficits using novel object recognition test, and which of the two receptor pathways was involved in these effects. Non-spatial long-term memory was examined in wild type, TLR4 knockout, and RAGE knockout mice. Recombinant HMGB1 (10 μg, intracerebroventricularly, i.c.v.) disrupted memory encoding equipotently in wild type, TLR4 knockout and RAGE knockout animals, but affected neither memory consolidation, nor retrieval. Neither TLR4 knockout nor RAGE knockout mice per se, exhibited memory deficits. Blockade of TLR4 in RAGE knockout mice using Rhodobacter sphaeroides lipopolysaccharide (LPS-Rs; 20 μg, i.c.v.) prevented the detrimental effect of HMGB1 on memory. These data show that elevated brain levels of HMGB1 induce memory abnormalities which may be mediated by either TLR4, or RAGE. This mechanism may contribute to memory deficits under various neurological and psychiatric conditions associated with the increased HMGB1 levels, such as epilepsy, Alzheimer's disease and stroke.     

赤芍总苷改善D-半乳糖诱导衰老大鼠学习记忆能力及机制

目的 观察赤芍总苷(TPG)对D-半乳糖(D-gal)诱导学习记忆功能低下衰老大鼠模型学习记忆能力作用,并探讨与衰老相关的氧化应激-自由基损伤、蛋白非酶糖基化反应及醛糖还原酶(AR)活性等作用.方法 采用SD雌性大鼠,腹腔注射D-gal 500mg/kg,每天1次连续70天,诱导衰老大鼠模型;灌胃TGP 300mg...     

The Maillard reaction--illicite (bio)chemistry in tissues and food

We present a review of our early work on the Maillard reaction, at the interface of food chemistry and tissue biochemistry, as well as the reinterpretation of our early findings in the light of recent advances in the chemistry of the involved reactions. These concern specifically the role of lower aldehydes, produced during the glycolytic pathways and especially acetaldehyde. We also review some of our recent findings on the cytotoxic and genotoxic aspect of these “illicit” organic reactions, taking place in tissues (and also in food products) besides the genetically “programmed” metabolic pathways. Some recent results in organic-pharmaceutical chemistry confirm the potential importance of the reviewed reactions both in food chemistry and in tissues as well as the pathological importance of reactions taking place in tissues.     

糖基化终产物诱导心肌细胞炎症反应的研究

目的： 探讨糖基化终产物(AGEs)对乳鼠正常心肌细胞和胰岛素抵抗心肌细胞炎症反应的影响。方法: 原代培养乳鼠心肌细胞并建立胰岛素抵抗心肌细胞模型，用不同浓度葡萄糖孵育的糖化白蛋白（AGE-BSA）干预24 h，采用RT-PCR、免疫细胞化学染色和透射电镜法，观察AGE-BSA对细胞TNF-α mRNA和PPAR-γ mRNA表达、NF-κB活化以及细胞超微结构的影响。结果: AGE-BSA可诱导心肌细胞TNF-α mRNA表达和NF-κB活化,并可抑制PPAR-γ mRNA表达，与对照组及BSA组比较有显著差异（P<0.05）。BSA组与空白对照组比较差异无显著（P>0.05）。随着孵育葡萄糖浓度的增加，各AGE-BSA组间比较有显著差异（P<0.05）。AGE-BSA干预后胞内线粒体和滑面内质网增多、扩大。结论: AGEs能上调心肌细胞TNF-α mRNA表达和NF-κB活化，并可抑制PPAR-γ mRNA表达，提示AGEs在糖尿病心肌病的发生中可能有重要的作用。