High glucose reduces Nrf2-dependent cRAGE release and enhances inflammasome-dependent IL-1βproduction in monocytes:the modulatory effects of EGCG

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.

Effect of Bogie Cavity End Wall Inclination on Flow Field and Aerodynamic Noise in the Bogie Region of High-Speed Trains

Combining the detached eddy simulation(DES)method and Ffowcs Williams-Hawkings(FW-H)equation,the effect of bogie cavity end wall inclination on the flow field and aerodynamic noise in the bogie region is numerically studied.First,the simulation is conducted based on a simplified cavity-bogie model,including five cases with different inclination angles of the front and rear walls of the cavity.By comparing and analyzing the flow field and acoustic results of the five cases,the influence of the regularity and mechanism of the bogie cavity end wall inclination on the flow field and the aerodynamic noise of the bogie region are revealed.Then,the noise reduction strategy determined by the results of the simplified cavity-bogie model is applied to a three-car marshaling train model to verify its effectiveness when applied to the real train.The results reveal that the forward inclination of the cavity front wall enlarges the influence area of shear vortex structures formed at the leading edge of the cavity and intensifies the interaction between the vortex structures and the front wheelset,frontmotor,and front gearbox,resulting in the increase of the aerodynamic noise generated by the bogie itself.The backward inclination of the cavity rear wall is conducive to guiding the vortex structures flow out of the cavity and weakening the interaction between the shear vortex structures and the cavity rear wall,leading to the reduction of the aerodynamic noise generated by the bogie cavity.Inclining the rear end wall of the foremost bogie cavity of the head car is a feasible aerodynamic noise reduction measure for high-speed trains.

End-of-Pregnancy Monitoring at CHUMEFJE through the Functional Investigation Centre (FIC) in 2022

Introduction: The end of pregnancy is a high-risk period for both mother and foetus. Rigorous monitoring can prevent complications before delivery. Materials and Method: We conducted a descriptive cross-sectional observational study. It took place in the delivery room of the Teacher hospital Mother and Child of Jeanne Ebori Fondation from the 01 October 2020 to 01 October 2021. All patients followed at the Functional Investigation Centre (FIC) of the CHUMEFJE and who gave birth in that same hospital were included. Data were collected on the basis of pregnancy diaries, the fic register and delivery room registers. They were analysed using SPSS Statistical Software. Results: During the period of our study, 4086 parturients arrived in the delivery room. Of these, 150 were followed up at the FIC, giving a prevalence of 3.7%. The majority of parturients (48%) had only one prenatal contact. 6 (4%) patients underwent pelvic scans, and 4 (2.6%) presented with a narrowed pelvis. A vaginal delivery was performed in 80% of cases, and of the caesarean sections, 9 (30%) could be scheduled. The maternal prognosis was marred by one post-partum complication of hypertension, and newborns with poor adaptation to life outside the womb accounted for 3.3% of cases. Conclusion: The Functional Investigation Centre makes it possible to detect anomalies at the end of pregnancy with a view to better planning of delivery.

Advanced glycation end products:Key mediator and therapeutic target of cardiovascular complications in diabetes

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.

End-group modulation of phenazine based non-fullerene acceptors for efficient organic solar cells with high open-circuit voltage

Phenazine-based non-fullerene acceptors(NFAs)have demonstrated great potential in improving the power conversion efficiency(PCE)of organic solar cells(OSCs).Halogenation is known to be an effective strategy for increasing optical absorption,refining energy levels,and improving molecular packing in organic semiconductors.Herein,a series of NFAs(Pz IC-4H,Pz IC-4F,Pz IC-4Cl,Pz IC-2Br)with phenazine as the central core and with/without halogen-substituted(dicyanomethylidene)-indan-1-one(IC)as the electron-accepting end group were synthesized,and the effect of end group matched phenazine central unit on the photovoltaic performance was systematically studied.Synergetic photophysical and morphological analyses revealed that the PM6:Pz IC-4F blend involves efficient exciton dissociation,higher charge collection and transfer rates,better crystallinity,and optimal phase separation.Therefore,OSCs based on PM6:Pz IC-4F as the active layer exhibited a PCE of 16.48%with an open circuit voltage(Voc)and energy loss of 0.880 V and 0.53 e V,respectively.Accordingly,this work demonstrated a promising approach by designing phenazine-based NFAs for achieving high-performance OSCs.

Comparison of engineering failures and seismic responses of 500 kV transformer-bushing systems in the 2022 Luding earthquake

Cemented and mechanically clamped types of end fittings(fitting-C and fitting-M)are commonly used in transformer bushings.During the Luding Ms 6.8 earthquake that occurred in China on September 5,2022,all transformer bushings with the two types of end fittings in a 500 kV substation were damaged.Post-earthquake field investigations were conducted,and the failures of the two types of bushings were compared.Two elementary simulation models of the transformer-bushing systems were developed to simulate the engineering failures,and further compute their seismic responses for comparison.The results indicate that the hitch lugs of the connection flange are structurally harmful to seismic resistance.Fitting-M can decrease the bending stiffness of the bushing due to the flexible sealing rubber gasket.Since it provides a more flexible connection that dissipates energy,the peak accelerations and relative displacements at the top of the bushing are significantly lower than those of the bushing with fitting-C.Compared with fitting-C,fitting-M transfers the high-stress areas from the connection flange to the root of the porcelain,so the latter becomes the most vulnerable component.Fitting-M increases the failure risk of the low-strength porcelain,indicating the unsuitability of applying it in high-intensity fortification regions.

Enhancing efficiency and stability of organic solar cells through a simplified four-step synthesis of fully non-fused ring electron acceptor

Design and synthesis of superior cost-effective non-fullerene acceptors(NFAs)are still big challenges for facilitating the commercialization of organic solar cells(OSCs),yet to be realized.Herein,two medium bandgap fully non-fused ring electron acceptors(NFREAs,medium bandgap,i,e.,1,3-1,8 eV),namely PTR-2Cl and PTR-4Cl are synthesized with only four steps by using intramolecular noncovalent interaction central core,structured alkyl side chain orientation linking units and flanking with different electron-withdrawing end group.Among them,PTR-4C1 exhibits increased average electrostatic potential(ESP)difference with polymer donor,enhanced crystallinity and compactπ-πstacking compared with the control molecule PTR-2CI.As a result,the PTR-4Cl-based OSC achieved an impressive power conversion efficiency(PCE)of 14.72%,with a much higher open-circuit voltage(V_(OC))of 0.953 V and significantly improved fill factor(FF)of 0.758,demonstrating one of the best acceptor material in the top-performing fully NFREA-based OSCs with both high PCE and V_(OC).Notably,PTR-4Cl-based cells maintain a good T_80lifetime of its initial PCE after over 936 h under a continuous thermal annealing treatment and over1300 h T_(80)lifetime without encapsulation.This work provides a cost-effective design strategy for NFREAs on obtaining high V_(OC),efficient exciton dissociation,and ordered molecular packing and thus high-efficiency and stable OSCs.

Emerging roles of microRNAs as diagnostics and potential therapeutic interest in type 2 diabetes mellitus

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.

Regulatory role of peroxynitrite in advanced glycation end products mediated diabetic cardiovascular complications

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.

Prognostic value of neutrophil-to-lymphocyte ratio in end-stage liver disease:A meta-analysis

BACKGROUND The neutrophil-to-lymphocyte ratio(NLR)is commonly utilized as a prognostic indicator in end-stage liver disease(ESLD),encompassing conditions like liver failure and decompensated cirrhosis.Nevertheless,some studies have contested the prognostic value of NLR in ESLD.AIM To investigate the ability of NLR to predict ESLD.METHODS Databases,such as Embase,PubMed,Web of Science,Cochrane Library,China National Knowledge Infrastructure,Weipu,and Wanfang,were comprehensively searched to identify studies published before October 2022 assessing the prognostic ability of NLR to predict mortality in patients with ESLD.Effect sizes were calculated using comprehensive meta-analysis software and SATAT 15.1.RESULTS A total of thirty studies involving patients with end-stage liver disease(ESLD)were included in the evaluation.Among the pooled results of eight studies,it was observed that the Neutrophil-to-Lymphocyte Ratio(NLR)was significantly higher in non-survivors compared to survivors(random-effects model:standardized mean difference=1.02,95%confidence interval=0.67-1.37).Additionally,twenty-seven studies examined the associations between NLR and mortality in ESLD patients,reporting either hazard ratios(HR)or odds ratios(OR).The combined findings indicated a link between NLR and ESLD mortality(randomeffects model;univariate HR=1.07,95%CI=1.05-1.09;multivariate HR=1.07,95%CI=1.07-1.09;univariate OR=1.29,95%CI=1.18-1.39;multivariate OR=1.29,95%CI=1.09-1.49).Furthermore,subgroup and meta-regression analyses revealed regional variations in the impact of NLR on ESLD mortality,with Asian studies demonstrating a more pronounced effect.CONCLUSION Increased NLR in patients with ESLD is associated with a higher risk of mortality,particularly in Asian patients.NLR is a useful prognostic biomarker in patients with ESLD.

The effect of protein oxidation on the formation of advanced glycation end products after chicken myofibrillar protein glycation

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.

The “Dead Universe” Theory: Natural Separation of Galaxies Driven by the Remnants of a Supermassive Dead Universe

This article explores the dead universe theory as a novel interpretation for the origin and evolution of the universe, suggesting that our cosmos may have originated from the remnants of a preceding universe. This perspective challenges the conventional Big Bang theory, particularly concerning dark matter, the expansion of the universe, and the interpretation of phenomena such as gravitational waves.

On the Problem of All Equal Positive Odd Number Solutions of the Dissemination of the Ends' Guess

The thesis is concerned with the problem of the dissemination of the Ends’ guess and offers the formula of all equal positive odd number solutions.

The Alienated Plot in The End of the Road

The End of the Road is John Barth's second novel, and it is the first novel that brought abortion to the focus of public attention, which proves to be a huge success. This paper intends to study the alienation in The End of the Road based on the alienation as a literary style and the alienation embodied in the literary context. Through the analysis of the alienated plot, the paper aims to emphasize the internal cause for the end of the different character's road.

Epidemiology and outcome of individuals with intraductal papillary neoplasms of the bile duct

BACKGROUND Intraductal papillary neoplasm of the bile duct(IPNB)is a rare distinct subtype of precursor lesions of biliary carcinoma.IPNB is considered to originate from luminal biliary epithelial cells,typically displays mucin-hypersecretion or a papillary growth pattern,and results in cystic dilatation[1].IPNB develops anywhere in the intrahepatic and extrahepatic biliary tracts,and can occur in various pathological stages from low-grade dysplasia to invasive carcinoma.IPNBs have similar phenotypic changes in the occurrence and development of all subtypes,and the prognosis is significantly better than that of traditional(nonpapillary)cholangiocarcinoma.AIM To evaluate the clinicopathological features of IPNB to provide evidence-based guidance for treatment.METHODS Invasive IPNB,invasive intraductal papillary mucinous neoplasm of the pancreas(IPMN),and traditional cholangiocarcinoma data for affected individuals from 1975 to 2016 were obtained from the Surveillance,Epidemiology,and End Results(SEER)database.Annual percentage changes(APCs)in the incidence and incidence-based(IB)mortality were calculated.We identified the independent predictors of overall survival(OS)and cancer-specific survival(CSS)in indivi duals with invasive IPNB.RESULTS The incidence and IB mortality of invasive IPNB showed sustained decreases,with an APC of-4.5%(95%CI:-5.1%to-3.8%)and-3.3%(95%CI:-4.1%to-2.6%)(P<0.001),respectively.Similar decreases in incidence and IB mortality were seen for invasive IPMN but not for traditional cholangiocarcinoma.Both OS and CSS for invasive IPNB were better than for invasive IPMN and traditional cholangiocarcinoma.A total of 1635 individuals with invasive IPNB were included in our prognosis analysis.The most common tumor sites were the pancreaticobiliary ampulla(47.9%)and perihilar tract(36.7%),but the mucin-related subtype of invasive IPNB was the main type,intrahepatically(approximately 90%).In the univariate and multivariate Cox regression analysis,age,tumor site,grade and stage,subtype,surgery,and chemotherapy were associated with OS and CSS(P<0.05).CONCLUSION Incidence and IB mortality of invasive IPNB trended steadily downward.The heterogeneity of IPNB comprises site and the tumor’s mucin-producing status.

Discovery of Radiolarian Fossils from the Aiketik Group at the Western End of the South Tianshan Mountains of Chinaand Its Implications

The Aiketik Group, distributed at the western end of the South TianshanMountains, China, is an important lithostratigraphic unit involved in the South Tianshan orogen. Itis separated from the adjacent rocks by faults. Generally, the geologists ascribed it to the UpperCarboniferous according to Pseudostaffella sp., Profusulinella sp. and Fusulinella sp. found fromthe limestone and sandy limestone of Aiketik. Our radiolarian fossils were obtained from the chertsamples collected from the Haladaok section located at the upper Tuoshihan River. The fossils mainlyinclude Albaillella undulata Deflandre, Albaillella paradoxa Deflandre, Albaillella sp. aff. A.paradoxa Deflandre, Albaillella sp. cf. A. deflandrei Gourmelon, Albaillella sp., Albaillellaexcelsa Ishiga, Kito and Imoto (?), Belowea variabilis (Ormiston et Lane), Callella cf. C.parvispinosa Won, Entactinia cf. E. tortispina Ormiston et Lane, Entactinia aff. E. tortispinaOrmiston et Lane, Entactinia variospina Won, Entactinia sp., Eostylodictya rota (Won),Latentifistula impella (Ormistone et Lane) (?), Latentifistula turgita Omiston et Lane,Latentifistulidae gen. et. sp. indet. and Polyentactinia cf. aranea Gourmelon. Among them,Albaillella excelsa Ishiga, Kito and Imoto (?) is a Late Permian species with some elementsuncertain as there is only one poorly-preserved fossil of this species found so far. And tworadiolarian assemblages can be identified from the other fossils. One is the early EarlyCarboniferous assemblage represented by Albaillella undulata Deflandre, Albaillella paradoxa andAlbaillella sp. cf. A. deflandrei Gourmelon. And the other is the late Early Carboniferousassemblage represented by Eostylodictya rota (Won). This is the first discovery of radiolarianfossils in the Aiketik Group, also the first discovery of Late Permian radiolarian fossils in theSouth Tianshan Mountains. Meanwhile, this is the current westernmost sampling site of radiolarianfossils in the South Tianshan Mountains.

Bone marrow derived stem cells for the treatment of end-stage liver disease

End-stage disease due to liver cirrhosis is an important cause of death worldwide. Cirrhosis results from progressive, extensive fibrosis and impaired hepatocyte regeneration. The only curative treatment is liver transplantation, but due to the several limitations of this procedure, the interest in alternative therapeutic strategies is increasing. In particular, the potential of bone marrow stem cell(BMSC) therapy in cirrhosis has been explored in different trials. In this article, we evaluate the results of 18 prospective clinical trials, and we provide a descriptive overview of recent advances in the research on hepatic regenerative medicine. The main message from the currently available data in the literature is that BMSC therapy is extremely promising in the context of liver cirrhosis. However, its application should be further explored in randomized, controlled trials with large cohorts and long follow-ups.

Parametric Analysis of the End Face Engagement Worm Gear

A novel specific type of worm drive, so-called end face engagement worm gear（EFEWD）, is originally presented to minimize or overcome the gear backlash. Different factors, including the three different types, contact curves, tooth profile, lubrication angle and the induced normal curvature are taken into account to investigate the meshing characteristics and create the profile of a novel specific type of worm drive through mathematical models and theoretical analysis. The tooth of the worm wheel is very specific with the sine-shaped tooth which is located at the alveolus of the worm and the tooth profile of a worm is generated by the meshing movement of the worm wheel with the sine-shaped tooth, but just the end face of the worm（with three different typical meshing types） is adapted to meshing, and therefore an extraordinary manufacturing methods is used to generate the profile of the end face engagement worm. The research results indicates that the bearing contacts of the generated conjugate hourglass worm gear set are in line contacts, with certain advantages of no-backlash, high precision and high operating efficiency over other gears and gear systems besides the end face engagement worm gear drive may improve bearing contact, reduce the level of transmission errors and lessen the sensitivity to errors of alignment. Also, the end face engagement worm can be easily made with superior meshing and lubrication performance compared with the conventional techniques. In particular, the meshing and lubrication performance of the end face engagement worm gear by using the end face to meshing can be increased over 10% and 7%, respectively. This investigate is expect to provide a new insight on the design of the future no-backlash worm drive for industry.

Advanced glycation end-product expression is upregulated in the gastrointestinal tract of type 2 diabetic rats

AIM:To investigate changes in advanced glycation end products(AGEs) and their receptor(RAGE) expression in the gastrointestinal(GI) tract in type 2 diabetic rats.METHODS:Eight inherited type 2 diabetic rats GotoKakizak(GK) and ten age-matched normal rats were used in the study.From 18 wk of age,the body weight and blood glucose were measured every week and 2 wk respectively.When the rats reached 32 wk,twocentimeter segments of esophagus,duodenum,jejunum,ileum,and colon were excised and the wet weight was measured.The segments were fixed in 10% formalin,embedded in paraffin and five micron sections were cut.The layer thickness was measured in Hematoxylin and Eosin-stained slides.AGE [N epsilon-(carboxymethyl) lysine and N epsilon-(carboxyethyl)lysine] and RAGE were detected by immunohistochemistry staining and image analysis was done using Sigmascan Pro 4.0 image analysis software.RESULTS:The blood glucose concentration(mmol/L) at 18 wk age was highest in the GK group(8.88 ± 1.87 vs 6.90 ± 0.43,P < 0.001),a difference that continued to exist until the end of the experiment.The wet weight per unit length(mg/cm) increased in esophagus,jejunum and colon from the normal to the GK group(60.64 ± 9.96 vs 68.56 ± 11.69,P < 0.05 for esophagus; 87.01 ± 9.35 vs 105.29 ± 15.45,P < 0.01 for jejunum; 91.37 ± 7.25 vs 97.28 ± 10.90,P < 0.05 for colon).Histologically,the layer thickness of the GItract was higher for esophagus,jejunum and colon in the GK group [full thickness(μm):575.37 ± 69.22 vs 753.20 ± 150.41,P < 0.01 for esophagus; 813.51 ± 44.44 vs 884.81 ± 45.31,P < 0.05 for jejunum; 467.12 ± 65.92 vs 572.26 ± 93.60,P < 0.05 for colon].In esophagus,the AGE and RAGE mainly distributed in striated muscle cells and squamous epithelial cells.The AGE distribution was much stronger in the GK group compared to the normal group both in the striated muscle layer and mucosa layer(immuno-positive area/ total measuring area %:4.52 ± 0.89 vs 10.96 ± 1.34,P < 0.01 for muscle; 8.90 ± 2.62 vs 22.45 ± 1.26,P < 0.01 for mucosa).No visible difference was found for RAGE distribution between the two groups.In the intestine AGE and RAGE distributed in epithelial cells of villi and crypt.RAGE was also found in neurons in the myenteric and submucosal plexus.The intensity of AGE staining in mucosa of all segments and RAGE staining in neurons in all segments were strongest in the diabetes group.Significant difference for AGE was found in the epithelial cells of villi and crypt in duodenum(immunopositive area/total measuring area %:13.37 ± 3.51 vs 37.48 ± 8.43,P < 0.05 for villi; 0.38 ± 0.12 vs 1.87 ± 0.53,P < 0.05 for crypt) and for RAGE in neurons of all segments(e.g.,for jejunum:no staining neurons% 0 vs 0,mild 36.0 ± 5.2 vs 28.7 ± 3.5,moderate 53.2 ± 4.8 vs 55.8 ± 5.4,strong 10.7 ± 1.1 vs 15.4 ± 2.0,P < 0.05).In the colon,RAGE was primarily found in neurons in the myenteric and submucosal plexus.It was stronger in the diabetes group than in the normal group(no staining neurons% 6.2 ± 0.2 vs 0.3 ± 0.04,mild 14.9 ± 2.1 vs 17.6 ± 1.5,moderate 53.1 ± 4.6 vs 44.7 ± 4.4,strong 25.6 ± 18 vs 43.6 ± 4.0,P < 0.05).In the rectum,RAGE was primarily found in the mucosa epithelial cells.CONCLUSION:The AGE and RAGE expression was upregulated in the GI tract of GK diabetic rats and may contribute to GI dysfunction in type 2 diabetic patients.

Role of the receptor for advanced glycation end products in hepatic fibrosis

AIM： To study the role of advanced glycation end products （AGE） and their specific receptor （RAGE） in the pathogenesis of liver fibrogenesis. METHODS： In vitro RAGE expression and extracellular matrix-related gene expression in both rat and human hepatic stellate cells （HSC） were measured after stimulation with the two RAGE ligands, advanced glycation end product-bovine serum albumin （AGE- BSA） and N＇-（carboxymethyl） lysine （CML）-BSA, or with tumor necrosis factor-α （TNF-α）. In vivo RAGE expression was examined in models of hepatic fibrosis induced by bile duct ligation or thioacetamide. The effects of AGE-BSA and CML-BSA on HSC proliferation, signal transduction and profibrogenic gene expression were studied in vitro. RESULTS： In hepatic fibrosis, RAGE expression was enhanced in activated HSC, and also in endothelial cells, inflammatory cells and activated bile duct epithelia. HSC expressed RAGE which was upregulated after stimulation with AGE-BSA, CML-BSA, and TNF-α.RAGE stimulation with AGE-BSA and CML-BSA did not alter HSC proliferation, apoptosis, fibrogenic signal transduction and fibrosis- or fibrolysis-related gene expression, except for marginal upregulation of procollagen α1（ I ） mRNA by AGE-BSA. CONCLUSION： Despite upregulation of RAGE in activated HSC, RAGE stimulation by AGE does not alter their fibrogenic activation. Therefore, RAGE does not contribute directly to hepatic fibrogenesis.