Soluble receptor for advanced glycation end products(sRAGE)acts as a decoy sequestering of RAGE ligands,thus preventing the activation of the ligand-RAGE axis linking human diseases.However,the molecular mechanisms un...Soluble receptor for advanced glycation end products(sRAGE)acts as a decoy sequestering of RAGE ligands,thus preventing the activation of the ligand-RAGE axis linking human diseases.However,the molecular mechanisms underlying sRAGE remain unclear.In this study,THP-1 monocytes were cultured in normal glucose(NG,5.5 mmol/L)and high glucose(HG,15 mmol/L)to investigate the effects of diabetesrelevant glucose concentrations on sRAGE and interleukin-1β(IL-1β)secretion.The modulatory effects of epigallocatechin gallate(EGCG)in response to HG challenge were also evaluated.HG enhanced intracellular reactive oxygen species(ROS)generation and RAGE expression.The secretion of sRAGE,including esRAGE and cRAGE,was reduced under HG conditions,together with the downregulation of a disintegrin and metallopeptidase 10(ADAM10)and nuclear factor erythroid 2-related factor 2(Nrf2)nuclear translocation.Mechanistically,the HG effects were counteracted by siRAGE and exacerbated by siNrf2.Chromatin immunoprecipitation results showed that Nrf2 binding to the ADAM10 promoter and HG interfered with this binding.Our data reinforce the notion that RAGE and Nrf2 might be sRAGE-regulating factors.Under HG conditions,the treatment of EGCG reduced ROS generation and RAGE activation.EGCG-stimulated cRAGE release was likely caused by the upregulation of the Nrf2-ADAM10 pathway.EGCG inhibited HG-mediated NLRP3 inflammasome activation at least partly by stimulating sRAGE,thereby reducing IL-1βrelease.展开更多
The Advanced Glycation End Products(AGE)binding with its receptor can increase reactive oxygen species(ROS)generation through specific signaling mediators.The effect of superoxide(O2-)and O2-mediated ROS and reactive ...The Advanced Glycation End Products(AGE)binding with its receptor can increase reactive oxygen species(ROS)generation through specific signaling mediators.The effect of superoxide(O2-)and O2-mediated ROS and reactive nitrogen species depends on their concentration and location of formation.Nitric oxide(NO)has anti-inflammatory and anticoagulant properties and a vasodilation effect,but NO can be deactivated by reacting with O_(2)^(-).This reaction between NO and O2-produces the potent oxidant ONOO−.Therefore,ONOO-'s regulatory role in AGEs in diabetic cardiovascular complications must considered as a regulator of cardiovascular complications in diabetes.展开更多
The incidence of type 2 diabetes mellitus is growing in epidemic proportions and has become one of the most critical public health concerns.Cardiovascular complications associated with diabetes are the leading cause o...The incidence of type 2 diabetes mellitus is growing in epidemic proportions and has become one of the most critical public health concerns.Cardiovascular complications associated with diabetes are the leading cause of morbidity and mortality.The cardiovascular diseases that accompany diabetes include angina,myocardial infarction,stroke,peripheral artery disease,and congestive heart failure.Among the various risk factors generated secondary to hyperglycemic situations,advanced glycation end products(AGEs)are one of the important targets for future diagnosis and prevention of diabetes.In the last decade,AGEs have drawn a lot of attention due to their involvement in diabetic pathophysiology.AGEs can be derived exogenously and endogenously through various pathways.These are a nonhomogeneous,chemically diverse group of compounds formed nonenzymatically by condensation between carbonyl groups of reducing sugars and free amino groups of protein,lipids,and nucleic acid.AGEs mediate their pathological effects at the cellular and extracellular levels by multiple pathways.At the cellular level,they activate signaling cascades via the receptor for AGEs and initiate a complex series of intracellular signaling resulting in reactive oxygen species generation,inflammation,cellular proliferation,and fibrosis that may possibly exacerbate the damaging effects on cardiac functions in diabetics.AGEs also cause covalent modifications and cross-linking of serum and extracellular matrix proteins;altering their structure,stability,and functions.Early diagnosis of diabetes may prevent its progression to complications and decrease its associated comorbidities.In the present review,we recapitulate the role of AGEs as a crucial mediator of hyperglycemia-mediated detrimental effects in diabetes-associated complications.Furthermore,this review presents an overview of future perspectives for new therapeutic interventions to ameliorate cardiovascular complications in diabetes.展开更多
Advanced glycation end products(AGEs)are a heterogeneous collection of compounds formed during industrial processing and home cooking through a sequence of nonenzymatic glycation reactions.The modern western diet is f...Advanced glycation end products(AGEs)are a heterogeneous collection of compounds formed during industrial processing and home cooking through a sequence of nonenzymatic glycation reactions.The modern western diet is full of heat-treated foods that contribute to AGE intake.Foods high in AGEs in the contemporary diet include processed cereal products.Due to industrialization and marketing strategies,restaurant meals are modified rather than being traditionally or conventionally cooked.Fried,grilled,baked,and boiled foods have the greatest AGE levels.Higher AGE-content foods include dry nuts,roasted walnuts,sunflower seeds,fried chicken,bacon,and beef.Animal proteins and processed plant foods contain furosine,acrylamide,heterocyclic amines,and 5-hydroxymethylfurfural.Furosine(2-furoil-methyl-lysine)is an amino acid found in cooked meat products and other processed foods.High concentrations of carboxymethyl-lysine,carboxyethyl-lysine,and methylglyoxal-O are found in heat-treated nonvegetarian foods,peanut butter,and cereal items.Increased plasma levels of AGEs,which are harmful chemicals that lead to age-related diseases and physiological aging,diabetes,and autoimmune/inflammatory rheumatic diseases such as systemic lupus erythematosus and rheumatoid arthritis.AGEs in the pathophysiology of metabolic diseases have been linked to individuals with diabetes mellitus who have peripheral nerves with high amounts of AGEs and diabetes has been linked to increased myelin glycation.Insulin resistance and hyperglycemia can impact numerous human tissues and organs,leading to long-term difficulties in a number of systems and organs,including the cardiovascular system.Plasma AGE levels are linked to all-cause mortality in individuals with diabetes who have fatal or nonfatal coronary artery disease,such as ventricular dysfunction.High levels of tissue AGEs are independently associated with cardiac systolic dysfunction in diabetic patients with heart failure compared with diabetic patients without heart failure.It is widely recognized that AGEs and oxidative stress play a key role in the cardiovascular complications of diabetes because they both influence and are impacted by oxidative stress.All chronic illnesses involve protein,lipid,or nucleic acid modifications including crosslinked and nondegradable aggregates known as AGEs.Endogenous AGE formation or dietary AGE uptake can result in additional protein modifications and stimulation of several inflammatory signaling pathways.Many of these systems,however,require additional explanation because they are not entirely obvious.This review summarizes the current evidence regarding dietary sources of AGEs and metabolism-related complications associated with AGEs.展开更多
Objective:The main characteristics of diabetic nephropathy(DN)at the early stage are abnormal angiogenesis of glomerular endothelial cells(GECs)and macrophage infiltration.Galectin-3 plays a pivotal role in the pathog...Objective:The main characteristics of diabetic nephropathy(DN)at the early stage are abnormal angiogenesis of glomerular endothelial cells(GECs)and macrophage infiltration.Galectin-3 plays a pivotal role in the pathogenesis of DN via binding with its ligand,advanced glycation end products(AGEs).Catalpol,an iridoid glucoside extracted from Rehmannia glutinosa,has been found to ameliorate vascular inflammation,reduce endothelial permeability,and protect against endothelial damage in diabetic milieu.However,little is known about whether catalpol could exert an anti-angiogenesis and anti-inflammation effect induced by AGEs.Methods:Mouse GECs(mGECs)and RAW 264.7 macrophages were treated with different concentrations of AGEs(0,50,100,200 and 400μg/mL)for different time(0,6,12,24 and 48 h)to determine the optimal concentration of AGEs and treatment time.Cells were treated with catalpol(10μmol/L),GB1107(1μmol/L,galectin-3 inhibitor),PX-478(50μmol/L,HIF-1αinhibitor),adenovirus-green fluorescent protein(Ad-GFP)[3×10^(7)plaque-forming unit(PFU)/mL]or Ad-galectin-3-GFP(2×10^(8)PFU/mL),which was followed by incubation with 50μg/mL AGEs.The levels of galectin-3,vascular endothelial growth factor A(VEGFA)and pro-angiogenic factors angiopoietin-1(Ang-1),angiopoietin-2(Ang-2),tunica interna endothelial cell kinase-2(Tie-2)were detected by enzyme-linked immunosorbent assay(ELISA).Cell counting kit-8(CCK-8)assay was used to evaluate the proliferation of these cells.The expression levels of galectin-3,vascular endothelial growth factor receptor 1(VEGFR1),VEGFR2,and hypoxia-inducible factor-1α(HIF-1α)in mGECs and those of galectin-3 and HIF-1αin RAW 264.7 macrophages were detected by Western blotting and immunofluorescence(IF)staining.The rat DN model was established.Catalpol(100 mg/kg)or GB1107(10 mg/kg)was administered intragastrically once a day for 12 weeks.Ad-galectin-3-GFP(6×10^(7)PFU/mL,0.5 mL)or Ad-GFP(6×10^(6)PFU/mL,0.5 mL)was injected into the tail vein of rats 48 h before the sacrifice of the animals.The expression of galectin-3,VEGFR1,.VEGFR2,and HIF-1αin renal cortices was analyzed by Western blotting.The expression of galectin-3,F4/80(a macrophage biomarker),and CD34(an endothelium biomarker)in renal cortices was detected by IF staining,and collagen accumulation by Masson staining.Results:The expression levels of galectin-3 and VEGFA were significantly higher in mGECs and RAW 264.7 macrophages treated with 50μg/mL AGEs for 48 h than those in untreated cells.Catalpol and GB1107 could block the AGEs-induced proliferation of mGECs and RAW 264.7 macrophages.Over-expression of galectin-3 was found to reduce the inhibitory effect of catalpol on the proliferation of cells.Catalpol could significantly decrease the levels of Ang-1,Ang-2 and Tie-2 released by AGEs-treated mGECs,which could be reversed by over-expression of galectin-3.Catalpol could significantly inhibit AGEs-induced expression of galectin-3,HIF-1α,VEGFR1,and VEGFR2 in mGECs.The inhibitory effect of catalpol on galectin-3 in AGEs-treated mGECs was impaired by PX-478.Moreover,catalpol attenuated the AGEs-activated HIF-1α/galectin-3 pathway in RAW 264.7 macrophages,which was weakened by PX-478.Additionally,catalpol significantly inhibited the expression of galectin-3,macrophage infiltration,collagen accumulation,and angiogenesis in the kidney of diabetic rats.Over-expression of galectin-3 could antagonize these inhibitory effects of catalpol.Conclusion:Catalpol prevented the angiogenesis of mGECs and macrophage proliferation via inhibiting galectin-3.It could prevent the progression of diabetes-induced renal damage.展开更多
Investigation that protein oxidation to the formation of advanced glycation end products(AGEs)after chicken myofibrillar protein glycation is limited.Models of protein oxidation induced by different concentrations of ...Investigation that protein oxidation to the formation of advanced glycation end products(AGEs)after chicken myofibrillar protein glycation is limited.Models of protein oxidation induced by different concentrations of hydroxyl radicals(·OH)were developed after the chicken myofibrillar protein mild glycation(MPG).Results exhibited that levels of AGEs and surface hydrophobicity(H_(0))steadily increased with the a ddition of h ydrogen peroxide(H_(2)O_(2))concentration.However,levels of s ulfhydryl group,free amino group,and particle size gradually decreased with the H_(2)O_(2)concentration.The protein carbonyl value increased in H_(2)O_(2)concentration until 10 mmol/L.Pearson's correlation indicated that MPG structure modification(unfolding and degradation)induced by protein oxidation were significantly positively correlated with AGEs concentration(P<0.05).Finally,a mechanism was proposed to hypothesize t he effect of protein oxidation on the formation of AGEs under MPG conditions.展开更多
Tendinopathy is a challenging complication observed in patients with diabetes mellitus.Tendinopathy usually leads to chronic pain,limited joint motion,and even ruptured tendons.Imaging and histological analyses have r...Tendinopathy is a challenging complication observed in patients with diabetes mellitus.Tendinopathy usually leads to chronic pain,limited joint motion,and even ruptured tendons.Imaging and histological analyses have revealed pathological changes in various tendons of patients with diabetes,including disorganized arrangement of collagen fibers,microtears,calcium nodules,and advanced glycation end product(AGE)deposition.Tendon-derived stem/progenitor cells(TSPCs)were found to maintain hemostasis and to participate in the reversal of tendinopathy.We also discovered the aberrant osteochondrogenesis of TSPCs in vitro.However,the relationship between AGEs and TSPCs in diabetic tendinopathy and the underlying mechanism remain unclear.In this review,we summarize the current findings in this field and hypothesize that AGEs could alter the properties of tendons in patients with diabetes by regulating the proliferation and differentiation of TSPCs in vivo.展开更多
Obesity and type 2 diabetes mellitus(T2DM)are chronic pathologies with a high incidence worldwide.They share some pathological mechanisms,including hyperinsulinemia,the production and release of hormones,and hyperglyc...Obesity and type 2 diabetes mellitus(T2DM)are chronic pathologies with a high incidence worldwide.They share some pathological mechanisms,including hyperinsulinemia,the production and release of hormones,and hyperglycemia.The above,over time,affects other systems of the human body by causing tissue hypoxia,low-grade inflammation,and oxidative stress,which lay the pathophysiological groundwork for cancer.The leading causes of death globally are T2DM and cancer.Other main alterations of this pathological triad include the accumulation of advanced glycation end products and the release of endogenous alarmins due to cell death(i.e.,damage-associated molecular patterns)such as the intracellular proteins high-mobility group box protein 1 and protein S100 that bind to the receptor for advanced glycation products(RAGE)-a multiligand receptor involved in inflammatory and metabolic and neoplastic processes.This review analyzes the latest advanced reports on the role of RAGE in the development of obesity,T2DM,and cancer,with an aim to understand the intracellular signaling mechanisms linked with cancer initiation.This review also explores inflammation,oxidative stress,hypoxia,cellular senescence,RAGE ligands,tumor microenvironment changes,and the“cancer hallmarks”of the leading tumors associated with T2DM.The assimilation of this information could aid in the development of diagnostic and therapeutic approaches to lower the morbidity and mortality associated with these diseases.展开更多
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 ...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.展开更多
Maillard reaction(MR)is a non-enzymatic browning reaction commonly seen in food processing,which occurs between reducing sugars and compounds with amino groups.Despite certain advantages based on Maillard reaction pro...Maillard reaction(MR)is a non-enzymatic browning reaction commonly seen in food processing,which occurs between reducing sugars and compounds with amino groups.Despite certain advantages based on Maillard reaction products(MRPs)found in some food for health and storage application have appeared,however,the MR occurring in human physiological environment can produce advanced glycation end products(AGEs)by non-enzymatic modification of macromolecules such as proteins,lipids and nucleic acid,which could change the structure and functional activity of the molecules themselves.In this review,we take AGEs as our main object,on the one hand,discuss physiologic aging,that is,age-dependent covalent cross-linking and modification of proteins such as collagen that occur in eyes and skin containing connective tissue.On the other hand,pathological aging associated with autoimmune and inflammatory diseases,neurodegenerative diseases,diabetes and diabetic nephropathy,cardiovascular diseases and bone degenerative diseases have been mainly proposed.Based on the series of adverse effects of accelerated aging and disease pathologies caused by MRPs,the possible harm caused by some MR can be slowed down or inhibited by artificial drug intervention,dietary pattern and lifestyle control.It also stimulates people's curiosity to continue to explore the potential link between the MR and human aging and health,which should be paid more attention to for the development of life sciences.展开更多
BACKGROUND Type 2 diabetes mellitus(T2DM)is a metabolic disease of impaired glucose utilization.Uncontrolled high sugar levels lead to advanced glycation end products(AGEs),which affects several metabolic pathways by ...BACKGROUND Type 2 diabetes mellitus(T2DM)is a metabolic disease of impaired glucose utilization.Uncontrolled high sugar levels lead to advanced glycation end products(AGEs),which affects several metabolic pathways by its receptor of advanced glycation end products(RAGE)and causes diabetic complication.MiRNAs are small RNA molecules which regulate genes linked to diabetes and affect AGEs pathogenesis,and target tissues,influencing health and disease processes.AIM To explore miRNA roles in T2DM's metabolic pathways for potential therapeutic and diagnostic advancements in diabetes complications.METHODS We systematically searched the electronic database PubMed using keywords.We included free,full-length research articles that evaluate the role of miRNAs in T2DM and its complications,focusing on genetic and molecular disease mechanisms.After assessing the full-length papers of the shortlisted articles,we included 12 research articles.RESULTS Several types of miRNAs are linked in metabolic pathways which are affected by AGE/RAGE axis in T2DM and its complications.miR-96-5p,miR-7-5p,miR-132,has_circ_0071106,miR-143,miR-21,miR-145-5p,and more are associated with various aspects of T2DM,including disease risk,diagnostic markers,complications,and gene regulation.CONCLUSION Targeting the AGE/RAGE axis,with a focus on miRNA regulation,holds promise for managing T2DM and its complications.MiRNAs have therapeutic potential as they can influence the metabolic pathways affected by AGEs and RAGE,potentially reducing inflammation,oxidative stress,and vascular complications.Additionally,miRNAs may serve as early diagnostic biomarkers for T2DM.Further research in this area may lead to innovative therapeutic strategies for diabetes and its associated complications.展开更多
This study investigated the effect of advanced glycation end products(AGEs) on differentiation of na ve CD4+T cells and the role of the receptor of AGEs(RAGE) and peroxisome proliferator-activated receptors(PPAR...This study investigated the effect of advanced glycation end products(AGEs) on differentiation of na ve CD4+T cells and the role of the receptor of AGEs(RAGE) and peroxisome proliferator-activated receptors(PPARs) activity in the process in order to gain insight into the mechanism of immunological disorders in diabetes. AGEs were prepared by the reaction of bovine serum albumin(BSA) with glucose. Human na ve CD4+T cells, enriched from blood of healthy adult volunteers with negative selection assay, were cultured in vitro and treated with various agents including AGEs, BSA, high glucose, PGJ2 and PD68235 for indicated time. In short hairpin(sh) RNA knock-down experiment, na ve CD4+T cells were transduced with media containing shRNA-lentivirus generated from lentiviral packaging cell line, Lent-XTM293 T cells. Surface and intracellular cytokine stainings were used for examination of CD4+T cell phenotypes, and real-time PCR and Western blotting for detection of transcription factor mRNA and protein expression, respectively. The suppressive function of regulatory T(Treg) cells was determined by a [3H]-thymidine incorporation assay. The results showed that AGEs induced higher pro-inflammatory Th1/Th17 cells differentiated from na ve CD4+T cells than the controls, whereas did not affect anti-inflammatory Treg cells. However, AGEs eliminated suppressive function of Treg cells. In addition, AGEs increased RAGE mRNA expression in na ve CD4+T cells, and RAGE knock-down by shRNA eliminated the effect of AGEs on the differentiation of CD4+T cells and the reduction of suppressive function of Treg cells. Furthermore, AGEs inhibited the mRNA expression of PPARγ, not PPARα; PPARγ agonist, PGJ2, inhibited the effect of AGEs on na ve CD4+T cell differentiation and reversed the AGE-reduced suppressive function of Treg cells; on the other hand, PPARγ antagonist, PD68235, attenuated the blocking effect of RAGE shRNA on the role of AGEs. It was concluded that AGEs may promote CD4+T cells development toward pro-inflammatory state, which is associated with increased RAGE mRNA expression and reduced PPARγ activity. +展开更多
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 developme...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.展开更多
Objective To investigate the effects of hepatocyte growth factor(HGF)on vascular endothelial cells apoptosis induced by advanced glycation end products(AGEs)and its possible mechanism. Methods Human umbilical vein end...Objective To investigate the effects of hepatocyte growth factor(HGF)on vascular endothelial cells apoptosis induced by advanced glycation end products(AGEs)and its possible mechanism. Methods Human umbilical vein endothelial cells(HUVECs)were cultured in vitro and intervened by different concentrations of AGEs and HGF.The cell inhibitory rates of each group with different culture time(12, 24, 48, and 72 hours)were measured by methyl thiazolyl tetrazolium(MTT)assay. The early stage apoptosis was detected by flow cytometry with Annexin V-FITC/PI double staining, morphology of cell apoptosis was observed by hoechst 33258 fluorescence staining, and the expression of apoptosis-associated genes Bax and Bcl-2 were determined by Western blotting.The activity of caspase-3 was detected by enzyme-linked immunosorbent assay (ELISA).Results Morphological observation indicated that high concentration of AGEs induced characteristic apoptotic changes in HUVECs.Within a certain concentration range, HUVECs apoptosis inducing rates by AGEs were in both dose- and time-dependent manners.HGF significantly inhibited the apoptosis of HUVECs induced by AGEs (P< 0.05).AGEs significantly promoted expression of Bax protein, but not Bcl-2.Whereas HGF significantly promoted the expression of Bcl-2(P<0.01)and decreased the activity of caspase-3(P<0.05)without affecting Bax level.Conclusions AGEs can induce the apoptosis of endothelial cells in vitro.HGF may effectively attenuate AGEs-induced endothelial cells apoptosis through upregulating Bcl-2 gene expression and inhibiting caspase-3 activation.展开更多
Advanced glycation end products lead to cell apoptosis, and cause cell death by increasing endoplasmic reticulum stress. Advanced glycation end products alone may also directly cause damage to tissues and cells, but t...Advanced glycation end products lead to cell apoptosis, and cause cell death by increasing endoplasmic reticulum stress. Advanced glycation end products alone may also directly cause damage to tissues and cells, but the precise mechanism remains unknown. This study used primary cultures of rat cerebral cortex neurons, and treated cells with different concentrations of glycation end products (50, 100, 200, 400 mg/L), and with an antibody for the receptor of advanced glycation end products before and after treatment with advanced glycation end products. The results showed that with increasing concentrations of glycation end products, free radical content increased in neurons, and the number of apoptotic cells increased in a dose-dependent manner. Before and after treatment of advanced glycation end products, the addition of the antibody against advanced glycation end-products markedly reduced hydroxyl free radicals, malondialdehyde levels, and inhibited cell apoptosis. This result indicated that the antibody for receptor of advanced glycation end-products in neurons from the rat cerebral cortex can reduce glycation end product-induced oxidative stress damage by suppressing glycation end product receptors. Overall, our study confirms that the advanced glycation end products-advanced glycation end products receptor pathway may be the main signaling pathway leading to neuronal damage.展开更多
AIMTo investigate the association of receptor for advanced glycation end products (RAGE) G82S and vascular endothelial growth factor (VEGF) -634 G/C gene polymorphisms with diabetic retinopathy (DR).METHODSOur cross-s...AIMTo investigate the association of receptor for advanced glycation end products (RAGE) G82S and vascular endothelial growth factor (VEGF) -634 G/C gene polymorphisms with diabetic retinopathy (DR).METHODSOur cross-sectional study included 61 diabetic patients, 12 of them had proliferative diabetic retinopathy (PDR), 15 had non proliferative diabetic retinopathy (NPDR), 34 had no diabetic retinopathy (NDR) and 61 healthy controls. Participants were tested for RAGE G82S and VEGF -634 G/C polymorphisms by polymerase chain reaction-restriction fragment length polymorphism.RESULTSWe found a significant association between VEGF -634 G/C polymorphism and PDR as PDR patients had increased incidence of VEGF -634 CC genotype compared to NDR patients [odds ratio for CC vs (GC+GG)=6.5, 95% CI=1.5-27.8, P=0.021]. Also VEGF -634 CC genotype and C allele were significantly higher in the PDR than in NPDR patients, which is a novel finding in our study (P=0.024, 0.009 respectively). The mean triglycerides level was significantly higher in diabetic patients with CC genotype (P=0.01) as compared to patients with other genotypes. All cases and control subjects were of the same heterozygous RAGE 82G/S genotype.CONCLUSIONPatients carrying VEGF -634 C polymorphism have a higher risk of PDR development, so VEGF -634 G/C polymorphism could be used as a predictive marker for PDR in diabetic patients. We could not find a significant association between RAGE G82S polymorphism and DR.展开更多
The role of protein kinase C (PKC) activation in advanced glycation end products (AGEs)-induced epithelial-mesenchymal transition in renal proximal tubular epithelial cells was investigated. HKC cells were divided...The role of protein kinase C (PKC) activation in advanced glycation end products (AGEs)-induced epithelial-mesenchymal transition in renal proximal tubular epithelial cells was investigated. HKC cells were divided into three groups: normal group, AGE-BSA group (100 mg/L AGE-BSA) and AGE-BSA+PKC inhibitor (10 μmol/L chelerythrine chloride) group. PKC activity was measured by PKC assay kit. The expression of Vimentin, and phosphorylated β-catenin was detected by using Western blotting, and the content of TGF-β1 was examined by ELISA method. The intracellular disposition of Vimentin was observed by fluorescence microscopy. As compared with normal group, PKC activity was increased significantly in AGE-BSA group. The expression of Vimentin, phosphorylated β-catenin, and TGF-β1 was enhanced significantly in AGE-BSA group. The expression of Vimentin, phosphorylated β-catenin, and TGF-β1 was significantly blocked by chelerythrine chloride. High expression of Vimentin, phosphorylated β-catenin, and TGF-β1 induced by AGE-BSA may be mediated via the activation of PKC signal transduction pathway.展开更多
Tea as the most consumed beverage in the world has received enormous attention for its promoting health benefits.The deleterious effect ofα-dicarbonyls and AGEs formed in Maillard reaction is also a longterm challeng...Tea as the most consumed beverage in the world has received enormous attention for its promoting health benefits.The deleterious effect ofα-dicarbonyls and AGEs formed in Maillard reaction is also a longterm challenge.The connection between the two topics was the main aim of this review,to address and update the antiglycation effect and mechanism of tea and tea polyphenols.By analyzing recent publications,we have covered across chemistry models,cell lines and animal studies.Tea polyphenols,particularly catechins,showed outstanding antiglycation effect by trappingα-dicarbonyl compounds and impeding AGEs formation.Reduction of carbonyl stress brought alleviation to aging,diabetes,and collagen related diseases or complications through regulation of RAGE expression and subsequent MAPK and TGF-βpathway.Therefore,tea polyphenols can serve as promising natural candidates in the treatment and/or prevention of nephropathy,retinopathy,hepatopathy,hyperglycemia and obesity among others,by their potent antiglycation effect.Further studies need to address on aspects like exact mechanisms,solution of detection obstacles,balance of practical usage and harmful effects such as potential flavor damage and toxicity in food,to gain a comprehensive understanding of antiglycation activities of tea polyphenols and its actual application.展开更多
BACKGROUND The established cardiovascular risk factors cannot explain the overall risk of coronary artery disease(CAD),especially in women.Therefore,there is a growing need for the assessment of novel biomarkers to id...BACKGROUND The established cardiovascular risk factors cannot explain the overall risk of coronary artery disease(CAD),especially in women.Therefore,there is a growing need for the assessment of novel biomarkers to identify women at risk.The receptor for advanced glycation end products(RAGE)and its interaction with the advanced glycation end product(AGE)ligand have been associated with atherogenesis.The soluble fraction of RAGE(sRAGE)antagonizes RAGE signaling and exerts an antiatherogenic effect.AIM The study aim was to explore the association between plasma levels of sRAGE and CAD in nondiabetic postmenopausal women.METHODS This case-control study included 110 nondiabetic postmenopausal women who were enrolled in two groups.Group I included 55 angiographically proven CAD subjects with>50%stenosis in at least one of the major coronary arteries and Group II included 55 healthy control women who did not have CAD or had<50%stenosis of the coronary arteries.Stenosis was confirmed by invasive angiography.Plasma sRAGE was determined by an enzyme-linked immunosorbent assay.RESULTS We observed significantly lower plasma sRAGE concentrations in subjects with CAD vs healthy controls(P<0.05).Univariate and multivariate logistic regression analysis also revealed a significant correlation between plasma sRAGE levels and CAD(P=0.01).Multivariate odds ratios for CAD revealed that subjects with sRAGE concentrations below 225 pg/mL(lowest quartile)had a 6-fold increase in CAD prevalence independent of other risk factors.CONCLUSION Our findings indicated that low sRAGE levels were independently associated with CAD in nondiabetic postmenopausal women.Risk assessment of CAD in postmenopausal women can be improved by including sRAGE along with other risk factors.展开更多
Objective: To study the adverse effects of advanced glycation end products(AGEs) on chondrocytes and the role of autophagy in this process. Methods: Chondrocytes were harvested from the human articular cartilage tissu...Objective: To study the adverse effects of advanced glycation end products(AGEs) on chondrocytes and the role of autophagy in this process. Methods: Chondrocytes were harvested from the human articular cartilage tissues in surgery. AGEs were administered during chondrocytes culture. The rapamycin was used to induce autophagy. The cell viability was determined by 3-[4,5-dimethylthiazol2-yl]-2,5-diphenyl tetrazolium bromide(MTT) assay.The expression of tumor necrosis factor-α(TNF-α) and nuclear factor-κ B(NF-κ B) was detected by quantitative real-time polymerase chain reaction. The reactive oxygen species(ROS) production and apoptosis of the chondrocytes were determined by fluorescent probe and flow cytometer, respectively. Results: The chondrocytes viability was significantly reduced after 12 h incubation with AGEs(P<0.01)). In contrast, rapamycin pretreatment increased the chondrocytes viability through autophagy. AGEs increased TNF-α and NF-κ B mRNA expression of chondrocytes and autophagy receded or proceeded the change. AGEs increased intracellular ROS accumulation and autophagy reversed the change. AGEs accelerated chondrocytes apoptosis and autophagy suspended apoptosis. Conclusions: Accumulation of AGEs may have an adverse role for chondrocytes by increasing TNF-α and NF-κB expression, ROS accumulation and apoptosis; meanwhile, autophagy ameliorates the AGEsinduced adverse effects.展开更多
文摘Soluble receptor for advanced glycation end products(sRAGE)acts as a decoy sequestering of RAGE ligands,thus preventing the activation of the ligand-RAGE axis linking human diseases.However,the molecular mechanisms underlying sRAGE remain unclear.In this study,THP-1 monocytes were cultured in normal glucose(NG,5.5 mmol/L)and high glucose(HG,15 mmol/L)to investigate the effects of diabetesrelevant glucose concentrations on sRAGE and interleukin-1β(IL-1β)secretion.The modulatory effects of epigallocatechin gallate(EGCG)in response to HG challenge were also evaluated.HG enhanced intracellular reactive oxygen species(ROS)generation and RAGE expression.The secretion of sRAGE,including esRAGE and cRAGE,was reduced under HG conditions,together with the downregulation of a disintegrin and metallopeptidase 10(ADAM10)and nuclear factor erythroid 2-related factor 2(Nrf2)nuclear translocation.Mechanistically,the HG effects were counteracted by siRAGE and exacerbated by siNrf2.Chromatin immunoprecipitation results showed that Nrf2 binding to the ADAM10 promoter and HG interfered with this binding.Our data reinforce the notion that RAGE and Nrf2 might be sRAGE-regulating factors.Under HG conditions,the treatment of EGCG reduced ROS generation and RAGE activation.EGCG-stimulated cRAGE release was likely caused by the upregulation of the Nrf2-ADAM10 pathway.EGCG inhibited HG-mediated NLRP3 inflammasome activation at least partly by stimulating sRAGE,thereby reducing IL-1βrelease.
文摘The Advanced Glycation End Products(AGE)binding with its receptor can increase reactive oxygen species(ROS)generation through specific signaling mediators.The effect of superoxide(O2-)and O2-mediated ROS and reactive nitrogen species depends on their concentration and location of formation.Nitric oxide(NO)has anti-inflammatory and anticoagulant properties and a vasodilation effect,but NO can be deactivated by reacting with O_(2)^(-).This reaction between NO and O2-produces the potent oxidant ONOO−.Therefore,ONOO-'s regulatory role in AGEs in diabetic cardiovascular complications must considered as a regulator of cardiovascular complications in diabetes.
文摘The incidence of type 2 diabetes mellitus is growing in epidemic proportions and has become one of the most critical public health concerns.Cardiovascular complications associated with diabetes are the leading cause of morbidity and mortality.The cardiovascular diseases that accompany diabetes include angina,myocardial infarction,stroke,peripheral artery disease,and congestive heart failure.Among the various risk factors generated secondary to hyperglycemic situations,advanced glycation end products(AGEs)are one of the important targets for future diagnosis and prevention of diabetes.In the last decade,AGEs have drawn a lot of attention due to their involvement in diabetic pathophysiology.AGEs can be derived exogenously and endogenously through various pathways.These are a nonhomogeneous,chemically diverse group of compounds formed nonenzymatically by condensation between carbonyl groups of reducing sugars and free amino groups of protein,lipids,and nucleic acid.AGEs mediate their pathological effects at the cellular and extracellular levels by multiple pathways.At the cellular level,they activate signaling cascades via the receptor for AGEs and initiate a complex series of intracellular signaling resulting in reactive oxygen species generation,inflammation,cellular proliferation,and fibrosis that may possibly exacerbate the damaging effects on cardiac functions in diabetics.AGEs also cause covalent modifications and cross-linking of serum and extracellular matrix proteins;altering their structure,stability,and functions.Early diagnosis of diabetes may prevent its progression to complications and decrease its associated comorbidities.In the present review,we recapitulate the role of AGEs as a crucial mediator of hyperglycemia-mediated detrimental effects in diabetes-associated complications.Furthermore,this review presents an overview of future perspectives for new therapeutic interventions to ameliorate cardiovascular complications in diabetes.
基金Supported by the Deputyship for Research and Innovation,Ministry of Education and Qassim University,Saudi Arabia(Project No.QUIF-2-2-1-27012).
文摘Advanced glycation end products(AGEs)are a heterogeneous collection of compounds formed during industrial processing and home cooking through a sequence of nonenzymatic glycation reactions.The modern western diet is full of heat-treated foods that contribute to AGE intake.Foods high in AGEs in the contemporary diet include processed cereal products.Due to industrialization and marketing strategies,restaurant meals are modified rather than being traditionally or conventionally cooked.Fried,grilled,baked,and boiled foods have the greatest AGE levels.Higher AGE-content foods include dry nuts,roasted walnuts,sunflower seeds,fried chicken,bacon,and beef.Animal proteins and processed plant foods contain furosine,acrylamide,heterocyclic amines,and 5-hydroxymethylfurfural.Furosine(2-furoil-methyl-lysine)is an amino acid found in cooked meat products and other processed foods.High concentrations of carboxymethyl-lysine,carboxyethyl-lysine,and methylglyoxal-O are found in heat-treated nonvegetarian foods,peanut butter,and cereal items.Increased plasma levels of AGEs,which are harmful chemicals that lead to age-related diseases and physiological aging,diabetes,and autoimmune/inflammatory rheumatic diseases such as systemic lupus erythematosus and rheumatoid arthritis.AGEs in the pathophysiology of metabolic diseases have been linked to individuals with diabetes mellitus who have peripheral nerves with high amounts of AGEs and diabetes has been linked to increased myelin glycation.Insulin resistance and hyperglycemia can impact numerous human tissues and organs,leading to long-term difficulties in a number of systems and organs,including the cardiovascular system.Plasma AGE levels are linked to all-cause mortality in individuals with diabetes who have fatal or nonfatal coronary artery disease,such as ventricular dysfunction.High levels of tissue AGEs are independently associated with cardiac systolic dysfunction in diabetic patients with heart failure compared with diabetic patients without heart failure.It is widely recognized that AGEs and oxidative stress play a key role in the cardiovascular complications of diabetes because they both influence and are impacted by oxidative stress.All chronic illnesses involve protein,lipid,or nucleic acid modifications including crosslinked and nondegradable aggregates known as AGEs.Endogenous AGE formation or dietary AGE uptake can result in additional protein modifications and stimulation of several inflammatory signaling pathways.Many of these systems,however,require additional explanation because they are not entirely obvious.This review summarizes the current evidence regarding dietary sources of AGEs and metabolism-related complications associated with AGEs.
基金supported by grants from the National Natural Science Foundation of China(No.81374029,No.81073111,No.81874359)Natural Science Foundation of the Higher Education Institutions of Jiangsu Province(No.18KJD360002)+1 种基金a Project Funded by Jiangsu Agri-animal Husbandry Vocational College(No.NSF2021CB04)a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)(No.JKLPSE201604).
文摘Objective:The main characteristics of diabetic nephropathy(DN)at the early stage are abnormal angiogenesis of glomerular endothelial cells(GECs)and macrophage infiltration.Galectin-3 plays a pivotal role in the pathogenesis of DN via binding with its ligand,advanced glycation end products(AGEs).Catalpol,an iridoid glucoside extracted from Rehmannia glutinosa,has been found to ameliorate vascular inflammation,reduce endothelial permeability,and protect against endothelial damage in diabetic milieu.However,little is known about whether catalpol could exert an anti-angiogenesis and anti-inflammation effect induced by AGEs.Methods:Mouse GECs(mGECs)and RAW 264.7 macrophages were treated with different concentrations of AGEs(0,50,100,200 and 400μg/mL)for different time(0,6,12,24 and 48 h)to determine the optimal concentration of AGEs and treatment time.Cells were treated with catalpol(10μmol/L),GB1107(1μmol/L,galectin-3 inhibitor),PX-478(50μmol/L,HIF-1αinhibitor),adenovirus-green fluorescent protein(Ad-GFP)[3×10^(7)plaque-forming unit(PFU)/mL]or Ad-galectin-3-GFP(2×10^(8)PFU/mL),which was followed by incubation with 50μg/mL AGEs.The levels of galectin-3,vascular endothelial growth factor A(VEGFA)and pro-angiogenic factors angiopoietin-1(Ang-1),angiopoietin-2(Ang-2),tunica interna endothelial cell kinase-2(Tie-2)were detected by enzyme-linked immunosorbent assay(ELISA).Cell counting kit-8(CCK-8)assay was used to evaluate the proliferation of these cells.The expression levels of galectin-3,vascular endothelial growth factor receptor 1(VEGFR1),VEGFR2,and hypoxia-inducible factor-1α(HIF-1α)in mGECs and those of galectin-3 and HIF-1αin RAW 264.7 macrophages were detected by Western blotting and immunofluorescence(IF)staining.The rat DN model was established.Catalpol(100 mg/kg)or GB1107(10 mg/kg)was administered intragastrically once a day for 12 weeks.Ad-galectin-3-GFP(6×10^(7)PFU/mL,0.5 mL)or Ad-GFP(6×10^(6)PFU/mL,0.5 mL)was injected into the tail vein of rats 48 h before the sacrifice of the animals.The expression of galectin-3,VEGFR1,.VEGFR2,and HIF-1αin renal cortices was analyzed by Western blotting.The expression of galectin-3,F4/80(a macrophage biomarker),and CD34(an endothelium biomarker)in renal cortices was detected by IF staining,and collagen accumulation by Masson staining.Results:The expression levels of galectin-3 and VEGFA were significantly higher in mGECs and RAW 264.7 macrophages treated with 50μg/mL AGEs for 48 h than those in untreated cells.Catalpol and GB1107 could block the AGEs-induced proliferation of mGECs and RAW 264.7 macrophages.Over-expression of galectin-3 was found to reduce the inhibitory effect of catalpol on the proliferation of cells.Catalpol could significantly decrease the levels of Ang-1,Ang-2 and Tie-2 released by AGEs-treated mGECs,which could be reversed by over-expression of galectin-3.Catalpol could significantly inhibit AGEs-induced expression of galectin-3,HIF-1α,VEGFR1,and VEGFR2 in mGECs.The inhibitory effect of catalpol on galectin-3 in AGEs-treated mGECs was impaired by PX-478.Moreover,catalpol attenuated the AGEs-activated HIF-1α/galectin-3 pathway in RAW 264.7 macrophages,which was weakened by PX-478.Additionally,catalpol significantly inhibited the expression of galectin-3,macrophage infiltration,collagen accumulation,and angiogenesis in the kidney of diabetic rats.Over-expression of galectin-3 could antagonize these inhibitory effects of catalpol.Conclusion:Catalpol prevented the angiogenesis of mGECs and macrophage proliferation via inhibiting galectin-3.It could prevent the progression of diabetes-induced renal damage.
基金supported by National Key R&D Program of China(2021YFD2100104)griculture Research System of China(CARS-41-Z)+2 种基金Science and Technology Project of Nanjing City(202002040)Jiangsu Province Policy Guidance Program(BX2020008)Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX21_0579),China。
文摘Investigation that protein oxidation to the formation of advanced glycation end products(AGEs)after chicken myofibrillar protein glycation is limited.Models of protein oxidation induced by different concentrations of hydroxyl radicals(·OH)were developed after the chicken myofibrillar protein mild glycation(MPG).Results exhibited that levels of AGEs and surface hydrophobicity(H_(0))steadily increased with the a ddition of h ydrogen peroxide(H_(2)O_(2))concentration.However,levels of s ulfhydryl group,free amino group,and particle size gradually decreased with the H_(2)O_(2)concentration.The protein carbonyl value increased in H_(2)O_(2)concentration until 10 mmol/L.Pearson's correlation indicated that MPG structure modification(unfolding and degradation)induced by protein oxidation were significantly positively correlated with AGEs concentration(P<0.05).Finally,a mechanism was proposed to hypothesize t he effect of protein oxidation on the formation of AGEs under MPG conditions.
基金National Natural Science Foundation of China,No.81572187 and No.81871812Jiangsu Provincial Medical Talent,The Project of Invigorating Health Care through Science,Technology and Education,No.ZDRCA2016083+2 种基金Natural Science Foundation of Jiangsu Province for Young Scholars,China,No.BK20200398Entrepreneurship and Innovation Program of Jiangsu Province,China,No.1190000054and The Six Projects Sponsoring Talent Summits of Jiangsu Province,China,No.LGY2017099。
文摘Tendinopathy is a challenging complication observed in patients with diabetes mellitus.Tendinopathy usually leads to chronic pain,limited joint motion,and even ruptured tendons.Imaging and histological analyses have revealed pathological changes in various tendons of patients with diabetes,including disorganized arrangement of collagen fibers,microtears,calcium nodules,and advanced glycation end product(AGE)deposition.Tendon-derived stem/progenitor cells(TSPCs)were found to maintain hemostasis and to participate in the reversal of tendinopathy.We also discovered the aberrant osteochondrogenesis of TSPCs in vitro.However,the relationship between AGEs and TSPCs in diabetic tendinopathy and the underlying mechanism remain unclear.In this review,we summarize the current findings in this field and hypothesize that AGEs could alter the properties of tendons in patients with diabetes by regulating the proliferation and differentiation of TSPCs in vivo.
基金Supported by the Founding Proyectos de Impulso a la Investigación to Hernandez-Nazara ZH from Universidad de Guadalajara,Mexico,No.PIN 2020-I.
文摘Obesity and type 2 diabetes mellitus(T2DM)are chronic pathologies with a high incidence worldwide.They share some pathological mechanisms,including hyperinsulinemia,the production and release of hormones,and hyperglycemia.The above,over time,affects other systems of the human body by causing tissue hypoxia,low-grade inflammation,and oxidative stress,which lay the pathophysiological groundwork for cancer.The leading causes of death globally are T2DM and cancer.Other main alterations of this pathological triad include the accumulation of advanced glycation end products and the release of endogenous alarmins due to cell death(i.e.,damage-associated molecular patterns)such as the intracellular proteins high-mobility group box protein 1 and protein S100 that bind to the receptor for advanced glycation products(RAGE)-a multiligand receptor involved in inflammatory and metabolic and neoplastic processes.This review analyzes the latest advanced reports on the role of RAGE in the development of obesity,T2DM,and cancer,with an aim to understand the intracellular signaling mechanisms linked with cancer initiation.This review also explores inflammation,oxidative stress,hypoxia,cellular senescence,RAGE ligands,tumor microenvironment changes,and the“cancer hallmarks”of the leading tumors associated with T2DM.The assimilation of this information could aid in the development of diagnostic and therapeutic approaches to lower the morbidity and mortality associated with these diseases.
基金Supported by The National Natural Science Foundation of China,No.82070455Natural Science Foundation of Jiangsu Province,No.BK20201225Medical Innovation Team Project of Jiangsu Province,No.CXTDA2017010。
文摘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.
基金financially supported by grants from the National Natural Science Foundation of China (82170873,81871095)the National Natural Science Foundation of China (81974503)the Tsinghua University Spring Breeze Fund (20211080005)。
文摘Maillard reaction(MR)is a non-enzymatic browning reaction commonly seen in food processing,which occurs between reducing sugars and compounds with amino groups.Despite certain advantages based on Maillard reaction products(MRPs)found in some food for health and storage application have appeared,however,the MR occurring in human physiological environment can produce advanced glycation end products(AGEs)by non-enzymatic modification of macromolecules such as proteins,lipids and nucleic acid,which could change the structure and functional activity of the molecules themselves.In this review,we take AGEs as our main object,on the one hand,discuss physiologic aging,that is,age-dependent covalent cross-linking and modification of proteins such as collagen that occur in eyes and skin containing connective tissue.On the other hand,pathological aging associated with autoimmune and inflammatory diseases,neurodegenerative diseases,diabetes and diabetic nephropathy,cardiovascular diseases and bone degenerative diseases have been mainly proposed.Based on the series of adverse effects of accelerated aging and disease pathologies caused by MRPs,the possible harm caused by some MR can be slowed down or inhibited by artificial drug intervention,dietary pattern and lifestyle control.It also stimulates people's curiosity to continue to explore the potential link between the MR and human aging and health,which should be paid more attention to for the development of life sciences.
文摘BACKGROUND Type 2 diabetes mellitus(T2DM)is a metabolic disease of impaired glucose utilization.Uncontrolled high sugar levels lead to advanced glycation end products(AGEs),which affects several metabolic pathways by its receptor of advanced glycation end products(RAGE)and causes diabetic complication.MiRNAs are small RNA molecules which regulate genes linked to diabetes and affect AGEs pathogenesis,and target tissues,influencing health and disease processes.AIM To explore miRNA roles in T2DM's metabolic pathways for potential therapeutic and diagnostic advancements in diabetes complications.METHODS We systematically searched the electronic database PubMed using keywords.We included free,full-length research articles that evaluate the role of miRNAs in T2DM and its complications,focusing on genetic and molecular disease mechanisms.After assessing the full-length papers of the shortlisted articles,we included 12 research articles.RESULTS Several types of miRNAs are linked in metabolic pathways which are affected by AGE/RAGE axis in T2DM and its complications.miR-96-5p,miR-7-5p,miR-132,has_circ_0071106,miR-143,miR-21,miR-145-5p,and more are associated with various aspects of T2DM,including disease risk,diagnostic markers,complications,and gene regulation.CONCLUSION Targeting the AGE/RAGE axis,with a focus on miRNA regulation,holds promise for managing T2DM and its complications.MiRNAs have therapeutic potential as they can influence the metabolic pathways affected by AGEs and RAGE,potentially reducing inflammation,oxidative stress,and vascular complications.Additionally,miRNAs may serve as early diagnostic biomarkers for T2DM.Further research in this area may lead to innovative therapeutic strategies for diabetes and its associated complications.
文摘This study investigated the effect of advanced glycation end products(AGEs) on differentiation of na ve CD4+T cells and the role of the receptor of AGEs(RAGE) and peroxisome proliferator-activated receptors(PPARs) activity in the process in order to gain insight into the mechanism of immunological disorders in diabetes. AGEs were prepared by the reaction of bovine serum albumin(BSA) with glucose. Human na ve CD4+T cells, enriched from blood of healthy adult volunteers with negative selection assay, were cultured in vitro and treated with various agents including AGEs, BSA, high glucose, PGJ2 and PD68235 for indicated time. In short hairpin(sh) RNA knock-down experiment, na ve CD4+T cells were transduced with media containing shRNA-lentivirus generated from lentiviral packaging cell line, Lent-XTM293 T cells. Surface and intracellular cytokine stainings were used for examination of CD4+T cell phenotypes, and real-time PCR and Western blotting for detection of transcription factor mRNA and protein expression, respectively. The suppressive function of regulatory T(Treg) cells was determined by a [3H]-thymidine incorporation assay. The results showed that AGEs induced higher pro-inflammatory Th1/Th17 cells differentiated from na ve CD4+T cells than the controls, whereas did not affect anti-inflammatory Treg cells. However, AGEs eliminated suppressive function of Treg cells. In addition, AGEs increased RAGE mRNA expression in na ve CD4+T cells, and RAGE knock-down by shRNA eliminated the effect of AGEs on the differentiation of CD4+T cells and the reduction of suppressive function of Treg cells. Furthermore, AGEs inhibited the mRNA expression of PPARγ, not PPARα; PPARγ agonist, PGJ2, inhibited the effect of AGEs on na ve CD4+T cell differentiation and reversed the AGE-reduced suppressive function of Treg cells; on the other hand, PPARγ antagonist, PD68235, attenuated the blocking effect of RAGE shRNA on the role of AGEs. It was concluded that AGEs may promote CD4+T cells development toward pro-inflammatory state, which is associated with increased RAGE mRNA expression and reduced PPARγ activity. +
基金supported by the grant from Shaanxi Technology Committee of China,No.2013JM4001the China Scholarship Council(CSC)
文摘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.
文摘Objective To investigate the effects of hepatocyte growth factor(HGF)on vascular endothelial cells apoptosis induced by advanced glycation end products(AGEs)and its possible mechanism. Methods Human umbilical vein endothelial cells(HUVECs)were cultured in vitro and intervened by different concentrations of AGEs and HGF.The cell inhibitory rates of each group with different culture time(12, 24, 48, and 72 hours)were measured by methyl thiazolyl tetrazolium(MTT)assay. The early stage apoptosis was detected by flow cytometry with Annexin V-FITC/PI double staining, morphology of cell apoptosis was observed by hoechst 33258 fluorescence staining, and the expression of apoptosis-associated genes Bax and Bcl-2 were determined by Western blotting.The activity of caspase-3 was detected by enzyme-linked immunosorbent assay (ELISA).Results Morphological observation indicated that high concentration of AGEs induced characteristic apoptotic changes in HUVECs.Within a certain concentration range, HUVECs apoptosis inducing rates by AGEs were in both dose- and time-dependent manners.HGF significantly inhibited the apoptosis of HUVECs induced by AGEs (P< 0.05).AGEs significantly promoted expression of Bax protein, but not Bcl-2.Whereas HGF significantly promoted the expression of Bcl-2(P<0.01)and decreased the activity of caspase-3(P<0.05)without affecting Bax level.Conclusions AGEs can induce the apoptosis of endothelial cells in vitro.HGF may effectively attenuate AGEs-induced endothelial cells apoptosis through upregulating Bcl-2 gene expression and inhibiting caspase-3 activation.
文摘Advanced glycation end products lead to cell apoptosis, and cause cell death by increasing endoplasmic reticulum stress. Advanced glycation end products alone may also directly cause damage to tissues and cells, but the precise mechanism remains unknown. This study used primary cultures of rat cerebral cortex neurons, and treated cells with different concentrations of glycation end products (50, 100, 200, 400 mg/L), and with an antibody for the receptor of advanced glycation end products before and after treatment with advanced glycation end products. The results showed that with increasing concentrations of glycation end products, free radical content increased in neurons, and the number of apoptotic cells increased in a dose-dependent manner. Before and after treatment of advanced glycation end products, the addition of the antibody against advanced glycation end-products markedly reduced hydroxyl free radicals, malondialdehyde levels, and inhibited cell apoptosis. This result indicated that the antibody for receptor of advanced glycation end-products in neurons from the rat cerebral cortex can reduce glycation end product-induced oxidative stress damage by suppressing glycation end product receptors. Overall, our study confirms that the advanced glycation end products-advanced glycation end products receptor pathway may be the main signaling pathway leading to neuronal damage.
文摘AIMTo investigate the association of receptor for advanced glycation end products (RAGE) G82S and vascular endothelial growth factor (VEGF) -634 G/C gene polymorphisms with diabetic retinopathy (DR).METHODSOur cross-sectional study included 61 diabetic patients, 12 of them had proliferative diabetic retinopathy (PDR), 15 had non proliferative diabetic retinopathy (NPDR), 34 had no diabetic retinopathy (NDR) and 61 healthy controls. Participants were tested for RAGE G82S and VEGF -634 G/C polymorphisms by polymerase chain reaction-restriction fragment length polymorphism.RESULTSWe found a significant association between VEGF -634 G/C polymorphism and PDR as PDR patients had increased incidence of VEGF -634 CC genotype compared to NDR patients [odds ratio for CC vs (GC+GG)=6.5, 95% CI=1.5-27.8, P=0.021]. Also VEGF -634 CC genotype and C allele were significantly higher in the PDR than in NPDR patients, which is a novel finding in our study (P=0.024, 0.009 respectively). The mean triglycerides level was significantly higher in diabetic patients with CC genotype (P=0.01) as compared to patients with other genotypes. All cases and control subjects were of the same heterozygous RAGE 82G/S genotype.CONCLUSIONPatients carrying VEGF -634 C polymorphism have a higher risk of PDR development, so VEGF -634 G/C polymorphism could be used as a predictive marker for PDR in diabetic patients. We could not find a significant association between RAGE G82S polymorphism and DR.
基金supported by grants from National Natural Sciences Foundation of China (No. 30370657, No.30871172)New Century Excellent Talents Grant (No. NCET004–0712)
文摘The role of protein kinase C (PKC) activation in advanced glycation end products (AGEs)-induced epithelial-mesenchymal transition in renal proximal tubular epithelial cells was investigated. HKC cells were divided into three groups: normal group, AGE-BSA group (100 mg/L AGE-BSA) and AGE-BSA+PKC inhibitor (10 μmol/L chelerythrine chloride) group. PKC activity was measured by PKC assay kit. The expression of Vimentin, and phosphorylated β-catenin was detected by using Western blotting, and the content of TGF-β1 was examined by ELISA method. The intracellular disposition of Vimentin was observed by fluorescence microscopy. As compared with normal group, PKC activity was increased significantly in AGE-BSA group. The expression of Vimentin, phosphorylated β-catenin, and TGF-β1 was enhanced significantly in AGE-BSA group. The expression of Vimentin, phosphorylated β-catenin, and TGF-β1 was significantly blocked by chelerythrine chloride. High expression of Vimentin, phosphorylated β-catenin, and TGF-β1 induced by AGE-BSA may be mediated via the activation of PKC signal transduction pathway.
基金funded by Hubei Science and Technology Plan Key Project(G2019ABA100)。
文摘Tea as the most consumed beverage in the world has received enormous attention for its promoting health benefits.The deleterious effect ofα-dicarbonyls and AGEs formed in Maillard reaction is also a longterm challenge.The connection between the two topics was the main aim of this review,to address and update the antiglycation effect and mechanism of tea and tea polyphenols.By analyzing recent publications,we have covered across chemistry models,cell lines and animal studies.Tea polyphenols,particularly catechins,showed outstanding antiglycation effect by trappingα-dicarbonyl compounds and impeding AGEs formation.Reduction of carbonyl stress brought alleviation to aging,diabetes,and collagen related diseases or complications through regulation of RAGE expression and subsequent MAPK and TGF-βpathway.Therefore,tea polyphenols can serve as promising natural candidates in the treatment and/or prevention of nephropathy,retinopathy,hepatopathy,hyperglycemia and obesity among others,by their potent antiglycation effect.Further studies need to address on aspects like exact mechanisms,solution of detection obstacles,balance of practical usage and harmful effects such as potential flavor damage and toxicity in food,to gain a comprehensive understanding of antiglycation activities of tea polyphenols and its actual application.
文摘BACKGROUND The established cardiovascular risk factors cannot explain the overall risk of coronary artery disease(CAD),especially in women.Therefore,there is a growing need for the assessment of novel biomarkers to identify women at risk.The receptor for advanced glycation end products(RAGE)and its interaction with the advanced glycation end product(AGE)ligand have been associated with atherogenesis.The soluble fraction of RAGE(sRAGE)antagonizes RAGE signaling and exerts an antiatherogenic effect.AIM The study aim was to explore the association between plasma levels of sRAGE and CAD in nondiabetic postmenopausal women.METHODS This case-control study included 110 nondiabetic postmenopausal women who were enrolled in two groups.Group I included 55 angiographically proven CAD subjects with>50%stenosis in at least one of the major coronary arteries and Group II included 55 healthy control women who did not have CAD or had<50%stenosis of the coronary arteries.Stenosis was confirmed by invasive angiography.Plasma sRAGE was determined by an enzyme-linked immunosorbent assay.RESULTS We observed significantly lower plasma sRAGE concentrations in subjects with CAD vs healthy controls(P<0.05).Univariate and multivariate logistic regression analysis also revealed a significant correlation between plasma sRAGE levels and CAD(P=0.01).Multivariate odds ratios for CAD revealed that subjects with sRAGE concentrations below 225 pg/mL(lowest quartile)had a 6-fold increase in CAD prevalence independent of other risk factors.CONCLUSION Our findings indicated that low sRAGE levels were independently associated with CAD in nondiabetic postmenopausal women.Risk assessment of CAD in postmenopausal women can be improved by including sRAGE along with other risk factors.
文摘Objective: To study the adverse effects of advanced glycation end products(AGEs) on chondrocytes and the role of autophagy in this process. Methods: Chondrocytes were harvested from the human articular cartilage tissues in surgery. AGEs were administered during chondrocytes culture. The rapamycin was used to induce autophagy. The cell viability was determined by 3-[4,5-dimethylthiazol2-yl]-2,5-diphenyl tetrazolium bromide(MTT) assay.The expression of tumor necrosis factor-α(TNF-α) and nuclear factor-κ B(NF-κ B) was detected by quantitative real-time polymerase chain reaction. The reactive oxygen species(ROS) production and apoptosis of the chondrocytes were determined by fluorescent probe and flow cytometer, respectively. Results: The chondrocytes viability was significantly reduced after 12 h incubation with AGEs(P<0.01)). In contrast, rapamycin pretreatment increased the chondrocytes viability through autophagy. AGEs increased TNF-α and NF-κ B mRNA expression of chondrocytes and autophagy receded or proceeded the change. AGEs increased intracellular ROS accumulation and autophagy reversed the change. AGEs accelerated chondrocytes apoptosis and autophagy suspended apoptosis. Conclusions: Accumulation of AGEs may have an adverse role for chondrocytes by increasing TNF-α and NF-κB expression, ROS accumulation and apoptosis; meanwhile, autophagy ameliorates the AGEsinduced adverse effects.