Effect of exogenous free N^(ε)-(carboxymethyl)lysine on diabetes-associated cognitive dysfunction:neuroinflammation,and metabolic disorders

Diabetes-associated cognitive dysfunction has already been attracted considerable attention.Advanced glycation end products(AGEs)from daily diets are thought to be a vital contributor to the development of this diseases.However,the effect of one of the best-characterized exogenous AGEs N^(ε)-(carboxymethyl)lysine(CML)on cognitive function is not fully reported.In the present study,diabetical Goto-Kakizaki(GK)rats were treated with free CML for 8-weeks.It was found that oral consumption of exogenous CML significantly aggravated diabetes-associated cognitive dysfunction in behavioral test.In details,exogenous CML increased levels of oxidative stress,promoted the activation of glial cells in the brain,up-regulated the release of inflammatory cytokines interleukin-6,inhibited the protein expression of the brain-derived neurotrophic factor and thus led to neuroinflammation.Furthermore,exogenous CML promoted the amyloidogenesis in the brain of GK rats,and inhibited the expression of GLUT4.Additionally,several tricarboxylic acid cycle and glutamate-glutamine/γ-aminobutyric acid cycle intermediates including pyruvate,succinic acid,glutamine,glutamate were significantly changed in brain of GK rats treated with exogenous free CML.In conclusion,exogenous free CML is a potentially noxious compounds led to aggravated diabetes-associated cognitive dysfunction which could be possibly explained by its effects on neuroinflammation,energy and neurotransmitter amino acid homeostasis.

Advances in Toxicology of Nε-(carboxymethyl)-lysine(CML)

Advanced glycation end-products （AGEs） are products of non-enzymatic glycation of proteins, lipids or nucleic acids and other macromolecules. To be spe- cific, Nε-（carboxymethyl）-Iysine （CML） is one of the most important components of AGEs, which is wildly distributed in the body and can be formed in vivo or in food processing and heating processes. Previous studies have shown that CML is a ma- jor immunological epitope in AGEs and plays an important role in diabetes and its complications, as well as in the development and progression of aging. This review summarized recent advances in major source, toxicological hazard and control mea- sures of CML.

Dietary Nε-(carboxymethyl)lysine affects cardiac glucose metabolism and myocardial remodeling in mice

BACKGROUND Myocardial remodeling is a key factor in the progression of cardiovascular disease to the end stage.In addition to myocardial infarction or stress overload,dietary factors have recently been considered associated with myocardial remodeling.Nε-(carboxymethyl)lysine(CML)is a representative foodborne toxic product,which can be ingested via daily diet.Therefore,there is a marked need to explore the effects of dietary CML on the myocardium.AIM To explore the effects of dietary CML(dCML)on the heart.METHODS C57 BL/6 mice were divided into a control group and a dCML group.The control group and the dCML group were respectively fed a normal diet or diet supplemented with CML for 20 wk.Body weight and blood glucose were recorded every 4 wk.^(18)F-fluorodeoxyglucose(FDG)was used to trace the glucose uptake in mouse myocardium,followed by visualizing with micro-positron emission tomography(PET).Myocardial remodeling and glucose metabolism were also detected.In vitro,H9C2 cardiomyocytes were added to exogenous CML and cultured for 24 h.The effects of exogenous CML on glucose metabolism,collagen I expression,hypertrophy,and apoptosis of cardiomyocytes were analyzed.RESULTS Our results suggest that the levels of fasting blood glucose,fasting insulin,and serum CML were significantly increased after 20 wk of dCML.Micro-PET showed that ^(18)F-FDG accumulated more in the myocardium of the dCML group than in the control group.Histological staining revealed that dCML could lead to myocardial fibrosis and hypertrophy.The indexes of myocardial fibrosis,apoptosis,and hypertrophy were also increased in the dCML group,whereas the activities of glucose metabolism-related pathways and citrate synthase(CS)were significantly inhibited.In cardiomyocytes,collagen I expression and cellular size were significantly increased after the addition of exogenous CML.CML significantly promoted cellular hypertrophy and apoptosis,while pathways involved in glucose metabolism and level of Cs mRNA were significantly inhibited.CONCLUSION This study reveals that dCML alters myocardial glucose metabolism and promotes myocardial remodeling.

Nε-(carboxymethyl)lysine promotes lipid uptake of macrophage via cluster of differentiation 36 and receptor for advanced glycation end products

BACKGROUND Advanced glycation end products(AGEs)are diabetic metabolic toxic products that cannot be ignored.Nε-(carboxymethyl)lysine(CML),a component of AGEs,could increase macrophage lipid uptake,promote foam cell formation,and thereby accelerate atherosclerosis.The receptor for AGEs(RAGE)and cluster of differentiation 36(CD36)were the receptors of CML.However,it is still unknown whether RAGE and CD36 play key roles in CML-promoted lipid uptake.AIM Our study aimed to explore the role of RAGE and CD36 in CML-induced macrophage lipid uptake.METHODS In this study,we examined the effect of CML on lipid uptake by Raw264.7 macrophages.After adding 10 mmol/L CML,the lipid accumulation in macrophages was confirmed by oil red O staining.Expression changes of CD36 and RAGE were detected with immunoblotting and quantitative real-time polymerase chain reaction.The interaction between CML with CD36 and RAGE was verified by immunoprecipitation.We synthesized a novel N-succinimidyl-4-18Ffluorobenzoate-CML radioactive probe.Radioactive receptor-ligand binding assays were performed to test the binding affinity between CML with CD36 and RAGE.The effects of blocking CD36 or RAGE on CML-promoting lipid uptake were also detected.RESULTS The study revealed that CML significantly promoted lipid uptake by macrophages.Immunoprecipitation and radioactive receptor-ligand binding assays indicated that CML could specifically bind to both CD36 and RAGE.CML had a higher affinity for CD36 than RAGE.ARG82,ASN71,and THR70 were the potential interacting amino acids that CD36 binds to CML Anti-CD36 and anti-RAGE could block the uptake of CML by macrophages.The lipid uptake promotion effect of CML was significantly attenuated after blocking CD36 or RAGE.CONCLUSION Our results suggest that the binding of CML with CD36 and RAGE promotes macrophage lipid uptake.

Systematic pharmacology analysis of Sodium 8-(((carboxymethyl)amino)methyl)-4',7-bishydroxy-isoflavone-3'-sulfonate

The purpose of this study is to use the newly synthesized molecule Sodium 8-(((carboxymethyl)amino)methyl)-4',7-bishydroxy-isoflavone-3'-sulfonate(M)as a research object,the pharmacological mechanism of the molecule was analyzed by using a series of Systematic pharmacology methods.The results show that the M molecule has a higher drug-like DL value of 0.59 and better molecular property parameters,namely Hdon=4,Hacc=10 and AlogP=0.94;A total of 11 M molecules related targets,namely F2,ESR1,AR,F10,CA2,DPP4,CCNA2,PRSS1,CDK2,GSK3B and PTPN1;A total of 140 diseases are associated with M molecule targets,and these diseases are mainly related to cancer and cardiovascular diseases;A total of 52 pathways involve the pharmacological mechanisms of M molecules,which are mainly related to cancer and other related diseases;GO-enriched analysis showed that these targets are closely related to the regulation of peptidase activity and biological processes such as blood coagulation and hemostasis.This article clearly demonstrated the pharmacological mechanism of M molecule,which provides references for exploring the pharmacological mechanism of new compounds.

羧甲基-β-环糊精作为手性选择剂对毛细管电泳手性拆分西酞普兰的影响

目的以羧甲基-β-环糊精作为手性选择剂,研究西酞普兰的毛细管电泳手性拆分方法。方法选择和优化了手性选择剂的浓度、缓冲溶液的浓度、pH及分离电压等。电泳石英毛细管柱内径为75μm,总长65 cm,有效长度5 cm;紫外检测波长200 nm;柱温15℃。结果在含0.25%羧甲基-β-环糊精和25 mmol.L-1磷酸盐(pH7.0)的缓冲溶液中,分离电压为30kV时,西酞普兰对映体达到基线分离,分离度为1.6。结论所建方法可以分离分析西酞普兰对映体。

Search for New Antiphytovirucides Ⅷ.Phosphorylation,Sulphonation and Carboxymethylation of Benzimidazole Derivatives and Antiviral Activity of Products

The Iead compound of substituted 2-(4-hydroxyphenyl)benzimidazol were modified by phos-phorylation sulfonation and carboxymethylation. The henzimldazoloamidophosphate (6) (7) have better activi-ty against tobacco mosaic virus (TMV). The benzimldazolophenoxyacetic acid, phenoxysuIfonic acid c0ntaining tri flu0r0methyl, and nitro gr0up have 77% ~85% efflclency f0r wheat rust disease.

Synthesis of novel uracil based 2,5-diaminofurans using multi-component reactions

A simple synthesis of highly functionalized 2,5-diaminofurans based pyrimidine derivatives from 1-（carboxymethyl）uracil via a multi-component reaction is described. The reactive 1：1 intermediate produced from the reaction of tert-butyl isocyanide and dialkyl acetylenedicarboxylates was trapped at room temperature by 1-（carboxymethyl）uracil derivatives to yield polyfunctio- nalized furan rings in fairly good yields.

Advanced glycation end products induce neural tube defects through elevating oxidative stress in mice

Our previous study showed an association between advanced glycation end products （AGEs） and neural tube defects （NTDs）. To understand the molecular mechanisms underlying the effect of AGEs on neural tube development, C57BL/6 female mice were fed for 4 weeks with com- mercial food containing 3% advanced glycation end product bovine serum albumin （AGE-BSA） or 3% bovine serum albumin （BSA） as a control. After mating mice, oxidative stress markers including malondialdehyde and H202 were measured at embryonic day 7.5 （E7.5） of ges- tation, and the level of intracellular reactive oxygen species （ROS） in embryonic cells was determined at E8.5. In addition to evaluating NTDs, an enzyme-linked immunosorbent assay was used to determine the effect of embryonic protein administration on the N-（carboxymethyl） lysine reactivity of acid and carboxyethyl lysine antibodies at E10.5. The results showed a remarkable increase in the incidence of NTDs at El0.5 in embryos of mice fed with AGE-BSA （no hyperglycemia） compared with control mice. Moreover, embryonic protein administration resulted in a noticeable increase in the reactivity of N-（carboxymethyl） lysine and N（ε）-（carboxyethyl） lysine antibodies. Malondialdehyde and H2O2 levels in embryonic cells were increased at E7.5, followed by increased intracellular ROS levels at E8.5. Vitamin E supplementation could partially recover these phenomena. Collectively, these results suggest that AGE-BSA could induce NTDs in the absence of hyperglycemia by an underlying mechanism that is at least partially associated with its capacity to increase embryonic oxidative stress levels.

Chemical Constituents of the Roots of Anemone altaica Fisch. ex C. A. Mey.

The roots of Anemone altaica Fisch. ex C. A. Mey. have been used in the treatment of epilepsia, neurasthenia, and arthritis in Chinese folk medicine for a long time. In order to find new and bioactive compounds, the chemical constituents of the roots of A. altaica were investigated and nine compounds were isolated from the EtOH extract of this plant. On the basis of spectroscopic methods, the structures of these compounds were elucidated as 4-（9H-β-carbolin- 1-yl）-4-oxo-butyric acid （1）, carboxymethyl isoferulate （2）, isoferulic acid （3）, cirsiumaldehyde （4）, 5-hydroxy-4-oxo-pentanoic acid （5）, triacontane （6）, palmic acid （7）, β-sitosterol （8）, and daucosterol （9）. Among them, 1 and 2 were new compounds, and 3 and 4 were obtained from this genus for the first time.