Advanced glycation end products consumption and the decline of functional capacity in patients with Parkinson's disease: Cross-sectional study

Abstract Introduction Advanced Glycation End-Products (AGEs) are a diverse group of highly reactive molecules that play a vital role in the development of neurodegenerative disorders, such as Parkinson's Disease (PD), leading to a decline in functional and cognitive capacity. The objective of this study was to assess the intake and quantification of AGEs in individuals with PD and to correlate them with their functional and cognitive abilities. Methods This was a cross-sectional study involving 20 PD patients and 20 non-PD individuals as the Control group (C). The autofluorescence reader was used to evaluate skin AGEs, while food recall was used to quantify AGEs consumed for three different days. The Montreal Cognitive Assessment, Short Physical Performance Battery, and handgrip tests were used. PD patients demonstrated greater impairment in functional capacity compared to the control group. Results Dominant Handgrip (p = 0.02) and motor performance, in the sit and stand test (p = 0.01) and Short Physical Performance Battery (SPPB) (p = 0.01) were inferior in PD patients than the control group. Although PD patients tended to consume less AGEs than the control group, AGE intake was negatively correlated with handgrip strength in individuals with PD (r = -0.59; p < 0.05). Conclusion PD patients had lower strength and functional capacity, suggesting that the effects of AGEs might be exacerbated during chronic diseases like Parkinson's.

Electroacupuncture Improves Blood-Brain Barrier and Hippocampal Neuroinflammation in SAMP8 Mice by Inhibiting HMGB1/TLR4 and RAGE/NADPH Signaling Pathways / 中国结合医学杂志

OBJECTIVE@#To investigate the molecular mechanisms underlying the beneficial effect of electroacupuncture (EA) in experimental models of Alzheimer's disease (AD) in vivo.@*METHODS@#Senescence-accelerated mouse prone 8 (SAMP8) mice were used as AD models and received EA at Yingxiang (LI 20, bilateral) and Yintang (GV 29) points for 20 days. For certain experiments, SAMP8 mice were injected intravenously with human fibrin (2 mg). The Morris water maze test was used to assess cognitive and memory abilities. The changes of tight junctions of blood-brain barrier (BBB) in mice were observed by transmission electron microscope. The expressions of fibrin, amyloid- β (Aβ), and ionized calcium-binding adapter molecule 1 (IBa-1) in mouse hippocampus (CA1/CA3) were detected by reverse transcription-quantitative polymerase chain reaction (qRT-PCR), Western blot or immunohistochemical staining. The expression of fibrin in mouse plasma was detected by enzyme-linked immunosorbent assay. The expressions of tight junction proteins zonula occludens-1 and claudin-5 in hippocampus were detected by qRT-PCR and immunofluorescence staining. Apoptosis of hippocampal neurons was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining.@*RESULTS@#Fibrin was time-dependently deposited in the hippocampus of SAMP8 mice and this was inhibited by EA treatment (P<0.05 or P<0.01). Furthermore, EA treatment suppressed the accumulation of Aβ in the hippocampus of SAMP8 mice (P<0.01), which was reversed by fibrin injection (P<0.05 or P<0.01). EA improved SAMP8 mice cognitive impairment and BBB permeability (P<0.05 or P<0.01). Moreover, EA decreased reactive oxygen species levels and neuroinflammation in the hippocampus of SAMP8 mice, which was reversed by fibrin injection (P<0.05 or P<0.01). Mechanistically, EA inhibited the promoting effect of fibrin on the high mobility group box protein 1 (HMGB1)/toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE)/nicotinamide adenine dinucleotide phosphate (NADPH) signaling pathways (P<0.01).@*CONCLUSION@#EA may potentially improve cognitive impairment in AD via inhibition of fibrin/A β deposition and deactivation of the HMGB1/TLR4 and RAGE/NADPH signaling pathways.

Existence of advanced glycation / lipoxidation end-products in parenteral nutrition solutions and effects of infusion conditions on their levels

Abstract Infusion solutions must be stable from the production stage until the infusion stage. Some infusion fluids contain degradation products, known as advanced glycation end products (AGEs); however, it is unknown whether AGEs exist in parenteral nutrition solutions. We aimed to investigate this question and test the effect of infusion conditions on AGE formation in parenteral nutrition solution. Nine parenteral nutrition solutions were supplied by the pharmacy with which we collaborated. To simulate the infusion conditions, the solutions were held in a patient room with standard lighting and temperature for 24 hours. Samples were taken at the beginning (group A) and the end (24th hour, group B) of the infusion period. The degradation products were 3-deoxyglucosone, pentosidine, N-carboxymethyl lysine, and 4-hydroxynonenal, which we investigated by high-performance liquid chromatography-mass spectrometry (LC-MS) and Q-TOF LC/MS methods. Two of four degradation products, 4-hydroxynonenal and N-carboxymethyl lysine, were detected in all samples, and Group B had higher levels of both compounds compared to Group A, who showed that the quantities of these compounds increased in room conditions over time. The increase was significant for 4-hydroxynonenal (p=0.03), but not for N-carboxymethyl lysine (p=0.23). Moreover, we detected in the parenteral nutrition solutions a compound that could have been 4-hydroxy-2-butynal or furanone

Effect of Jingui Shenqiwan on Diabetic Osteoporosis in Mice via AGEs/RANKL/NF-κB Pathway Based on Theory of "Kidneys Governing Bones" / 中国实验方剂学杂志

ObjectiveTo investigate the effect of Jingui Shenqiwan on diabetic osteoporosis （DOP） in mice by regulating the advanced glycation end products （AGEs）/receptor activator of nuclear factor-κB ligand （RANKL）/nuclear factor-κB （NF-κB） signaling pathway based on the theory of "kidneys governing bones". MethodForty 6-week-old male and female skeletal-muscle-specific， dominant negative insulin-like growth factor-1 receptor （MKR） mice were selected and fed on a high-fat diet for eight weeks to establish the DOP model. The model mice were randomly divided into a model group， low- and high-dose Jingui Shenqiwan group （1.3， 2.6 g·kg-1）， and an alendronate sodium group （0.01 g·kg-1）， with 10 mice in each group. Additionally， 10 FVB/N mice of the same age were assigned to the normal group. The corresponding drugs were administered orally to each group once a day for four weeks. After the administration period， fasting blood glucose （FBG） measurement and oral glucose tolerance test （OGTT） were conducted. Kidney function and kidney index were measured. Renal tissue pathological changes were observed through hematoxylin-eosin （HE） and Masson staining. Immunohistochemistry was performed to assess the protein expression levels of AGEs， phosphorylated NF-κB （p-NF-κB）， and RANKL in renal tissues. Western blot analysis was conducted to measure the expression of proteins related to the AGEs/RANKL/NF-κB signaling pathway， osteoprotegerin （OPG）， and Runt-related transcription factor 2 （RUNX2） proteins in femoral bone tissues. ResultCompared with the normal group， mice in the model group exhibited significantly increased FBG （P<0.01）， trabecular bone degeneration， abnormal bone morphological parameters， significantly increased area under the curve （AUC） of OGTT （P<0.01）， enlarged kidney volume， significantly increased kidney function indicators and kidney index （P<0.01）， disrupted renal glomeruli and renal tubule structures， significantly increased expression of AGEs， RANKL， and p-NF-κB/NF-κB in renal tissues （P<0.05）， and significantly decreased expression of OPG and RUNX2 in femoral bone tissues （P<0.01）. Compared with the model group， mice in the Jingui Shenqiwan groups showed a significant decrease in OGTT AUC （P<0.01）. Histopathological analysis revealed alleviated structural lesions in renal glomeruli and renal tubules. Furthermore， the expression of AGEs， RANKL， and p-NF-κB/NF-κB in renal tissues was significantly reduced （P<0.05， P<0.01）， and the expression of RUNX2 and OPG in femoral bone tissues was significantly increased （P<0.05， P<0.01）. ConclusionJingui Shenqiwan can improve kidney function and downregulate the AGEs/RANKL/NF-κB signaling pathway to inhibit inflammatory reactions， thereby alleviating the symptoms of DOP in mice， demonstrating a therapeutic effect on DOP from the perspective of the kidney.

Changes of RAGE/p38MAPK/NF-κB signaling pathway in brain tissue of subchronic fluorosis rats and protective effects of Ginkgo biloba extract and RAGE antagonist / 环境与职业医学

Background Fluorine accumulates in the brain tissue after long-term excessive intake and subsequently cause nerve damage and decline of learning and memory ability. Receptor of advanced glycation end-products (RAGE)/p38 mitogen-activated protein kinase (p38MAPK)/nuclear factor kappa-B (NF-κB) signaling pathway is considered to be involved in the associated mechanism. Objective To study the changes of RAGE/ p38MAPK/ NF-κB signaling pathway in rats with subchronic fluorosis, and to explore the protective effects of extract of Ginkgo biloba 761 (EGb761) and RAGE antagonist (FPS-ZM1) on neuromemory ability. Methods Ninety male clean SD rats were divided into 9 groups with 10 rats in each group. The modeling period was 6 months. Control group (C group): free drinking tap water (fluoride content <0.5 mg·L−1), low- and high-dose fluoride groups (LF group, HF group): free drinking tap water with 10 or 50 mg·L−1 fluoride; intervention group of Ginkgo biloba extract (CE, LFE, and HFE groups): on the basis of the C group, LF group, and HF group, 100 mg·kg−1·d−1 EGb761 was given daily via intragastric administration; FPS-ZM1 intervention groups (CF, LFF, and HFF groups): 7 d before the end of modeling, 1 mg·kg−1·d−1 FPS-ZM1 was injected intraperitoneally daily on the basis of the C group, LF group, and HF group. The contents of fluoride in brain and blood of each group were detected. The learning and memory ability was tested by water maze experiment. The histopathologic changes of the hippocampus were detected by Nissl staining. The protein expression levels of RAGE and its ligand high mobility group protein B1 (HMGB1), NF-κB, p38MAPK, phospho-p38MAPK (p-p38MAPK), interleukin-6 (IL-6), and tumour necrosis factor-α (TNF-α) in brain tissue were detected by Western blotting. The mRNA expression levels of RAGE, HMGB1, and p38MAPK were detected by quantitative real-time PCR. Results Compared with the C group, the contents of blood fluoride and brain fluoride in the LF and the HF groups were increased (P<0.05). The results of the water maze experiment showed that, compared with the C group, the escape latency time of the LF group and the HF group was longer and the crossing times were reduced; compared with the HF group, the escape latency time of the HFE group and the HFF group was shortened, and the crossing times were increased (P<0.05). The Nissl staining results showed that the number of Nissl body in the HF group decreased compared with the C group; compared with the HF group, the number of Nissl body in the HFE group and the HFF group increased. The Western blotting results showed that compared with the relative protein expression levels of RAGE, HMGB1, NF-κB, p38MAPK, p-p38MAPK, IL-6, and TNF-α in the C group , the levels of above indicators in the HF group and the levels of RAGE, HMGB1, NF-κB, p-p38MAPK, and IL-6 in the LF group were up-regulated (P<0.05); compared with the HF group, the levels of above indicators in the HFE group and the HFF group were all down-regulated (P<0.05); compared with the relative protein expression levels of RAGE and HMGB1 in the LF group, the levels in the LFE group and the LFF group were all down-regulated (P<0.05). The quantitative real-time PCR results showed that compared with the C group, the mRNA expression levels of RAGE and HMGB1 in the LF group and the HF group were up-regulated; compared with the LF group, the mRNA expression levels of RAGE in the LFE group and the LFF group were down-regulated ; compared with the HF group, the mRNA expression levels of RAGE and HMGB1 in the HFE group and the HFF group were down-regulated (P<0.05). Conclusion The central nervous system injury caused by subchronic fluorosis may be related to the activation of RAGE/p38-MAPK/NF-κB signaling pathway, which can impair the learning and memory ability of rats, while EGb761 and FPS-ZM1 may have certain protective effects on the nerve injury.

Improvement effects and its mechanism of catalpol on testicular lesions in KK-Ay spontaneous diabetic mice by regulating glycolysis / 中国药房

OBJECTIVE To study the improvement effects and its mechanism of catalpol on testicular lesions in KK-Ay spontaneous diabetic mice on the basis of glycolysis process mediated by advanced glycation end products （AGEs） and their receptors （RAGE）. METHODS KK-Ay spontaneous diabetic mice fed with high-fat diet were used as diabetic model， and then randomly divided into model group， catalpol group （100 mg/kg）， aminoguanidine group （AGEs inhibitor， 100 mg/kg） and FPS- ZM1 group （RAGE inhibitor， 1 mg/kg）， and C57BL/6J mice fed in the same period were set as normal group， with 6 mice in each group. The catalpol group and aminoguanidine group mice were given relevant medicine intragastrically， normal group and model group mice were given constant volume of normal saline intragastrically， and FPS-ZM1 group mice were given relevant medicine 1 mL/g intraperitoneally， for consecutive 8 weeks. After the last administration， the body mass， fasting blood glucose， 24-hour food intake， water consumption， urine volume， testicular organ coefficient， and sperm motility of the mice were measured； pathological morphology and ultrastructural structure of testicular tissue were observed； the levels of reduced glutathione （GSH）， superoxide dismutase （SOD）， lactate dehydrogenase （LDH） and sugar metabolites in testicular tissue of mice were detected； pathway enrichment analysis was performed； the level of AGEs in serum and testicular tissue， protein expressions of RAGE， B-cell lymphoma-2 （Bcl-2） and Bcl-2-associated X protein （Bax）， and mRNA expressions of key rate-limiting enzymes [hexokinase （HK）， phosphofructose kinase （PFK）， pyruvate kinase （PK）， LDH] in testicular tissue were alldetected. RESULT S Catalpol could significantly improve the general symptoms， testicular organ coefficients and motility ofsperm in KK-Ay spontaneous diabetic mice （P＜0.05 or P＜0.01）. The morphology and ultrastructure of spermatogenic cells in each layer of the seminiferous tubules were all improved. The levels of GSH， SOD and LDH in testicular tissue，the levels of the metabolic product glucose fructose-1，6-diphosphate， 3-phosphate glycerate， 3-phosphate glyceraldehyde， lactic acid and pyruvate， the expressions of HK， PFK， PK and LDH mRNA were all significantly increased（P＜0.05 or P＜0.01）； the levels of AGEs in serum and testicular tissue， the expression of RAGE protein and the ratio of Bax to Bcl-2 in testicular tissue were significantly decreased（P＜0.05 or P＜0.01）. Aminoguanidine and FPS-ZM1 could significantly improve the levels of most of above indicators in mice（P＜0.05 or P＜0.01）. CONCLUSIONS Catalpol shows significant improvement effects on testicular lesions of KK-Ay spontaneous diabetic mice， and its mechanism of action was associated with upregulation of AGEs/RAGE signaling pathway- mediated glycolysis.

Efectos patogénicos de los productos finales de glicación avanzada en el proceso de envejecimiento-enfermedad

RESUMEN Los productos finales de glicación avanzada -conocidos como productos de la reacción de Maillard-, formados por glicación directa no enzimática de azúcares reductores con grupos amino libres de proteínas, provocan cambios estructurales y funcionales en las mismas, cuya producción endógena es incrementada con la edad, el estrés oxidativo, así como por factores externos, provocando envejecimiento prematuro y enfermedades degenerativas. El objetivo de la revisión fue obtener una visión actualizada de los avances en investigaciones sobre los efectos de productos finales de glicación avanzada y su interrelación con el estrés oxidativo en el proceso de envejecimiento-enfermedad. En la revisión se consideraron los principales artículos más recientes sobre el tema en las bases de datos PubMed, SciELO, ClinicalKey y LILACS. Se evidencian los efectos patogénicos de los productos finales de glicación avanzada que contribuyen al estrés oxidativo y a la inflamación, de forma especial en el envejecimiento prematuro, diabetes, enfermedad cardiovascular y en otras enfermedades neurodegenerativas, como un aspecto preocupante en el tema del envejecimiento poblacional y su enorme costo para la sociedad futura.

ABSTRACT The advanced glycation end-products-known like products of the Maillard reaction-formed by a direct non-enzymatic glycation of reducing sugars with amino groups free of proteins, cause structural and functional changes in them, whose endogenous production is incremented with age, oxidative stress, as well as by external factors, causing premature aging and degenerative diseases. The objective of the review objective was to obtain an updated view of the advances in research on the effects of the advanced glycation end products and their interrelation with the oxidative stress in the aging-disease process. In the review the authors considered the most recent leading articles on the topic published in the databases PubMed, SciELO, ClinicalKey and LILACS. The pathogenic effects of the advanced glycation end products that contribute to oxidative stress and inflammation are evidenced, especially in premature aging, diabetes, cardiovascular disease and other neurodegenerative diseases, as a worrying aspect in the issue of population aging and its enormous cost for future society.

Stingless bee propolis, metformin, and their combination alleviate diabetic cardiomyopathy

Abstract Background and aim: Stingless bee propolis, a resinous compound processed by mandibular secretion of stingless bees, is used for maintenance of hygiene and stability of beehives. Research on stingless bee propolis shows therapeutic properties attributed to polyphenols exhibiting antioxidative, antihyperglycemic and antiischemic effect. However, the cardioprotective effect of stingless bee propolis on diabetic cardiomyopathy is unknown. Methods: Adult male Sprague Dawley rats were randomised to five groups: normal group, diabetic group, diabetic given metformin (DM+M), diabetic given propolis (DM+P) and diabetic given combination therapy (DM+M+P) and treated for four weeks. Body weight, fasting blood glucose, food and water intake were taken weekly. At the end of experiment, biomarkers of oxidative damage were measured in serum and heart tissue. Antioxidants in heart tissue were quantified. Part of left ventricle of heart was processed for histological staining including Haematoxylin and Eosin (H&E) stain for myocyte size and Masson's Trichrome (MT) stain for heart fibrosis and perivascular fibrosis. Results: Propolis alleviated features of diabetic cardiomyopathy such as myocyte hypertrophy, heart fibrosis and perivascular fibrosis associated with improvement in antioxidative status. Conclusion: This study reports beneficial effect of propolis and combination with metformin in alleviating histopathological feature of diabetic cardiomyopathy by modulating antioxidants, making propolis an emerging complementary therapy.

Current status on the laboratory determination of advanced glycation end products / 中华检验医学杂志

The concentration and accumulation rate of advanced glycation end products (AGEs) in the body are highly correlated with glycometabolic disorders. Therefore, the clinical detection of AGEs is of great value for the early diagnosis and prognostic evaluation of these diseases. However, due to the complexity of its structure, the diversity of glycosylation sites, and the limitations of existing detection methods, there is still a lack of widely available detection methods in clinical practice. Starting from the structure and classification of AGEs and the value of clinical testing, this article summarizes current status of various laboratory detection methods of AGEs, and the deficiencies and challenges of these testing methods, future directions are further prospected.

Association between skin advanced glycation end products and carotid atherosclerosis in population with normal glucose regulation / 中华健康管理学杂志

Objective:To investigate the association between skin advanced glycation end products (AGEs) and carotid atherosclerosis (AS) in subjects with normal glucose regulation (NGR).Methods:This was a cross-sectional study. Data from the Health Management Center of the First Affiliated Hospital of University of Science and Technology between January 2019 to June 2019 were collected. A total of 902 NGR subjects aged 40-79 were enrolled and categorized into control group (530 cases), carotid intima-media thickness (IMT) thickening group (150 cases), and carotid atherosclerosis plaque group (222 cases) based on the carotid ultrasound results. Data as follows were collected, gender, age, blood pressure, body mass index (BMI), triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), fasting blood glucose (FPG), glycosylated hemoglobin (HbA 1c) and skin AGEs. Comparison via ANOVA analysis were carried out among the 3 groups. Logistic regression analysis was used to screen the independent influencing factors of carotid atherosclerosis plaque. Spearman correlation analysis was used to evaluate the correlation between AGEs and other parameters, and receiver operating characteristic (ROC) curve was used to evaluate the efficiency of skin AGEs in predicting carotid atherosclerosis plaque in NGR subjects. Results:Among the control group, IMT thickening group and carotid atherosclerosis plaque group, gender, age, systolic blood pressure (SBP), diastolic blood pressure (DBP), TC, LDL-C, FPG, HbA 1c, AGEs were significantly different (all P<0.05). Compared with IMT thickening group, the age, SBP and AGEs of carotid atherosclerotic plaque group were higher [55 (50, 60) vs 53 (49, 56) year; 132 (122, 141) vs 126 (115, 142) mmHg(1 mmHg=0.133 kPa); 74 (67, 81) vs 72 (67, 78) AU] (all P<0.001); compared with the control group, age, LDL-C, HbA 1c and AGEs of IMT thickening group were higher [53 (49, 56) vs 48 (45, 52) year; (2.8±0.7) vs (2.7±0.7) mmol/L; 5.4% (5.2, 5.6)% vs 5.4% (5.1, 5.6)%; 72 (67, 78) vs 70 (66, 76)] (all P<0.05). Age ( OR=1.179, 95% CI: 1.107-1.255), SBP ( OR=1.045, 95% CI: 1.013-1.077), LDL-C ( OR=2.028, 95% CI: 1.036-3.969), AGEs ( OR=1.049, 95% CI: 1.000-1.100) were independent influencing factors of carotid atherosclerotic plaque in population with normal glucose regulated (all P<0.05). AGEs was positively correlated with age, HbA 1c and carotid atherosclerosis plaque ( r=0.407, 0.092, 0.172) (all P<0.01). The area under the ROC curve of skin AGEs for identifying carotid atherosclerotic plaque in NGR population was 0.650 (95% CI 0.601-0.698), the best cutoff value was 70.5, the sensitivity was 65.8%, and the specificity was 56.9%. Conclusion:Skin AGEs level is closely associated with the occurrence of carotid atherosclerosis in NGR subjects.

Mechanism of 3-arylcoumarin derivatives inhibiting vascular calcification / 中国药科大学学报

@#To reveal the pharmacological mechanism of 3-arylcoumarin derivative 3-(4′-hydroxyphenyl)-6-hydroxycoumarin (SJ-6) against vascular calcification, advanced glycation end products (AGEs) were used to induce the calcification of human aortic vascular smooth muscle cells (HCASMCs), and calcification was identified by alizarin red staining and quantification.The effects of SJ-6 on alkaline phosphatase (ALP) activity, cell proliferation rate, calcium content, and total reactive oxygen species (ROS), superoxide dismutase (SOD), AGEs, and tetra methylethlene diamine proteinase factor-α (TNF-α), interleukin-6 (1L-6), interleukin-β (1L-β), runt-related transcription factor 2 mRNA (Runx2 mRNA), the receptor of advanced glycation endproducts (RAGE), nuclear factor kappa-B (NF-κB), napdh oxidase-1 (NoX-1), protein kinase C(PKC), protein kinase b(AKT), p38 mitogen-activated protein kinase (p38 MAPK), and smooth muscle actin-α (SMA-α) protein expression were determined.According to our results, SJ-6 significantly decreased AGEs content, ALP activity, intracellular calcium content, ROS content, Runx2 mRNA and inflammatory factors TNF-α, 1L-6 and 1L-β (P < 0.05) and increased SOD content (P < 0.01), with similar to those of the positive control drug aminoguanidine hydrochloride (AGH).Therefore, we investigated the pharmacological mechanism of compound SJ-6, which was found to significantly inhibit the expression of RAGE, NF-κB, NoX-1, PKC, Akt, p-p38 and other essential signaling proteins in the calcified cell model (P < 0.01) and increas the expression of smooth actin SMA-α (P < 0.01).SJ-6 inhibits vascular calcification by inhibiting oxidative stress and the expression of AGEs/RAGE, Akt/PKC and NF-κB signaling pathways, suggesting that it may be a novel drug for the treatment of vascular calcification.

The Value of Serum HMGB1 and sRAGE in the Diagnosis, Efficacy Monitoring and Prognosis of Newly Diagnosed Multiple Myeloma / 中国实验血液学杂志

OBJECTIVE@#To evaluate the value of high mobility group protein B1 (HMGB1) and soluble receptor for advanced glycation end products (sRAGE) in the diagnosis, efficacy monitoring and prognosis of newly diagnosed multiple myeloma (MM) patients.@*METHODS@#Fifty newly diagnosed MM patients before and after chemotherapy and 50 hematological outpatients from October 2018 to May 2020 were selected. Enzyme linked immunosorbent assay (ELISA) was used to detect the serum HMGB1 and sRAGE levels of the patients. ROC was used to further analyze the efficacy of serum HMGB1 and sRAGE levels on the diagnosis of MM. At the same time, the serum levels of HMGB1 and sRAGE before and after chemotherapy were compared, and their values in the evaluation of curative effect of MM patients were analyzed. According to the mean values of serum HMGB1 and sRAGE, all the patients were divided into different groups, the clinical characteristics and survival status of the patients were compared.@*RESULTS@#Before treatment the serum HMGB1 level of the patients in MM group was higher than that in control group, while sRAGE level was lower (t=11.363,6.127, P<0.001). The AUC of serum HMGB1 and sRAGE in the MM patients was 0.955 and 0.811, respectively. After 3 courses of chemotherapy, HMGB1 level of the patients in CR group was lower than before chemotherapy, while in PD group was higher, as well as sRAGE level of the patients in PR group (P<0.05). There were significant differences in R-ISS stage, HGB, CRP, ESR, CD56, CD117, D13S319 deletion between HMGB1 high expression group and HMGB1 low expression group (χ2=3.920, 6.522, 6.65, 4.16, 3.945, 6.65, 4.16, P<0.05), while there were significant differences in ISS stage, CRP and CD56 between sRAGE low expression group (28 cases) and sRAGE high expression group (22 cases) (χ2=4.565, 4.711, 5.547, P<0.05). Kaplan-Meier survival analysis showed that the patients in HMGB1 low expression group had better survival condition, for PFS Tlow>Thigh (χ2=9.470, P<0.05), and for OS Tlow>Thigh (χ2=7.808, P<0.05); there was no difference in the survival of sRAGE high expression group and low expression group, for PFS Tlow<Thigh (χ2=1.661, P>0.05), and for OS Tlow<Thigh (χ2=2.048, P>0.05). Cox analysis showed that LDH and HMGB1 were the factors affecting the prognosis of the patients, and both of them affected PFS (HR=2.771, 95% CI: 1.002-7.662, P=0.049; HR=6.022, 95% CI: 1.689-21.470, P=0.006), while HMGB1 also affected OS (HR=4.275, 95% CI: 1.183-15.451, P=0.027).@*CONCLUSION@#The serum HMGB1 and sRAGE have certain auxiliary value for the diagnosis and curative effect monitoring of newly diagnosed MM patients, and serum HMGB1 is expected to be an auxiliary detection index for the prognosis of MM.

Design, simulation and application of multichannel microfluidic chip for cell migration / 生物医学工程学杂志

Cell migration is defined as the directional movement of cells toward a specific chemical concentration gradient, which plays a crucial role in embryo development, wound healing and tumor metastasis. However, current research methods showed low flux and are only suitable for single-factor assessment, and it was difficult to comprehensively consider the effects of other parameters such as different concentration gradients on cell migration behavior. In this paper, a four-channel microfluidic chip was designed. Its characteristics were as follows: it relied on laminar flow and diffusion mechanisms to establish and maintain a concentration gradient; it was suitable for observation of cell migration in different concentration gradient environment under a single microscope field; four cell isolation zones (20 μm width) were integrated into the microfluidic device to calibrate the initial cell position, which ensured the accuracy of the experimental results. In particular, we used COMSOL Multiphysics software to simulate the structure of the chip, which demonstrated the necessity of designing S-shaped microchannel and horizontal pressure balance channel to maintain concentration gradient. Finally, neutrophils were incubated with advanced glycation end products (AGEs, 0, 0.2, 0.5, 1.0 μmol·L -1), which were closely related to diabetes mellitus and its complications. The migration behavior of incubated neutrophils was studied in the 100 nmol·L -1 of chemokine (N-formylmethionyl-leucyl-phenyl-alanine) concentration gradient. The results prove the reliability and practicability of the microfluidic chip.

Ferroptosis is essential for diabetic cardiomyopathy and is prevented by sulforaphane via AMPK/NRF2 pathways

Herein, we define the role of ferroptosis in the pathogenesis of diabetic cardiomyopathy (DCM) by examining the expression of key regulators of ferroptosis in mice with DCM and a new ex vivo DCM model. Advanced glycation end-products (AGEs), an important pathogenic factor of DCM, were found to induce ferroptosis in engineered cardiac tissues (ECTs), as reflected through increased levels of Ptgs2 and lipid peroxides and decreased ferritin and SLC7A11 levels. Typical morphological changes of ferroptosis in cardiomyocytes were observed using transmission electron microscopy. Inhibition of ferroptosis with ferrostatin-1 and deferoxamine prevented AGE-induced ECT remodeling and dysfunction. Ferroptosis was also evidenced in the heart of type 2 diabetic mice with DCM. Inhibition of ferroptosis by liproxstatin-1 prevented the development of diastolic dysfunction at 3 months after the onset of diabetes. Nuclear factor erythroid 2-related factor 2 (NRF2) activated by sulforaphane inhibited cardiac cell ferroptosis in both AGE-treated ECTs and hearts of DCM mice by upregulating ferritin and SLC7A11 levels. The protective effect of sulforaphane on ferroptosis was AMP-activated protein kinase (AMPK)-dependent. These findings suggest that ferroptosis plays an essential role in the pathogenesis of DCM; sulforaphane prevents ferroptosis and associated pathogenesis via AMPK-mediated NRF2 activation. This suggests a feasible therapeutic approach with sulforaphane to clinically prevent ferroptosis and DCM.

Activación inmune por productos finales de glicación avanzada

Con el objetivo de revisar los avances recientes en la biología de los productos de glica- ción avanzada y su papel en diversas patologías de alta relevancia en salud pública, se realizó una búsqueda dirigida de la bibliografía entre los años 2000 al 2021 en la base de datos PubMed (NCBI) y se usaron como palabras clave "advanced glycation end pro- ducts". Se ha demostrado que el receptor de productos de glicación avanzada induce una activación sostenida del factor de transcripción proinflamatorio NF-kB y suprime una serie de funciones autorreguladoras endógenas. Este efecto influye negativamente en una gran variedad de patologías como diabetes, autoinmunidad, neurodegeneración y enfermedades infecciosas. La acumulación tisular de productos de glicación avanzada está relacionada con procesos de inflamación crónica y disfunción celular, y constituye un blanco prometedor para el diseño de tratamientos enfocados en esta vía de señali- zación. Actualmente se realizan múltiples ensayos clínicos para determinar su utilidad como marcador de lesiones pulmonares en COVID-19.

To review recent advances in the biology of advanced glycation endproducts and its role in diverse pathologies of high relevance for public health, a survey of the literature from the years 2000 to 2021 was performed in PubMed (NCBI) using the key words "advanced glycation endproducts". It has been demonstrated that the receptor for advanced glyca- tion endproducts (RAGE) induces a sustained activation of the pro-inflammatory tran- scription factor NF-kB and suppresses a series of endogenous self-regulating functions. This affects negatively on a wide variety of pathological conditions such as diabetes, au- toimmunity, neurodegeneration and infectious disease. Tissular accumulation of AGEs is linked to chronic inflammation and cellular dysfunction and constitutes a promising target for the design of treatments focused on this signaling pathway. Multiple clinical trials are currently underway to define its usefulness as a marker of pulmonary lesions in COVID-19.

Associations of high-mobility group box 1 and receptor for advanced glycation end products with acute lung injury in patient with acute aortic dissection

SUMMARY OBJECTIVE: To investigate the associations of high-mobility group box 1 and its specific receptor, receptor for advanced glycation end products with acute lung injury in patients with acute aortic dissection. METHODS: A total of 96 acute aortic dissection patients were divided into acute aortic dissection with acute lung injury group (38 cases) and acute aortic dissection without acute lung injury group (58 cases), according to partial pressure of oxygen/fraction of inspired oxygen. In addition, 44 healthy individuals were selected for the control group. The blood samples were taken. The serum high-mobility group box 1 and receptor for advanced glycation end products levels were detected by enzyme-linked immunosorbent assay, and the partial pressure of oxygen/fraction of inspired oxygen was measured. RESULTS: 24 h after admission, the high-mobility group box 1 and receptor for advanced glycation end products levels in acute aortic dissection with acute lung injury and acute aortic dissection without acute lung injury groups were significantly higher than those in the control group, respectively (p<0.05), and each index in acute aortic dissection with acute lung injury group was significantly higher than that in acute aortic dissection without acute lung injury group (p<0.05). At each time point within 96 h after admission, compared with acute aortic dissection without acute lung injury group, in acute aortic dissection with acute lung injury group, the high-mobility group box 1 and receptor for advanced glycation end products levels were increased, respectively, and the partial pressure of oxygen/fraction of inspired oxygen was decreased. The correlation analysis showed that, in acute aortic dissection patients, the high-mobility group box 1 and receptor for advanced glycation end products levels were negatively correlated with partial pressure of oxygen/fraction of inspired oxygen, respectively (p<0.05). CONCLUSIONS: The serum high-mobility group box 1 and receptor for advanced glycation end products levels may be associated with the occurrence of acute lung injury in acute aortic dissection patients. Monitoring the high-mobility group box 1 and receptor for advanced glycation end products levels can evaluate the risk of acute aortic dissection with acute lung injury.

Advances in clinical detection of advanced glycation end products / 中华检验医学杂志

Advanced glycation end products (AGEs) have been implicated in aging and aging related diseases. Therefore, the clinical detection of AGEs is of great importance for the early prediction, intervention and long-term monitoring of above mentioned chronic diseases. There are various detection methods for assessment of AGEs, but due to the great heterogeneity and complex structure of AGEs, there is a lack of standardized detection method for AGEs so far. This review summarizes the current detection methods for AGEs and their advantages and disadvantages, aiming to highlight the future directions for the clinical detection of AGEs.

Spatial-resolved metabolomics reveals tissue-specific metabolic reprogramming in diabetic nephropathy by using mass spectrometry imaging

Detailed knowledge on tissue-specific metabolic reprogramming in diabetic nephropathy (DN) is vital for more accurate understanding the molecular pathological signature and developing novel therapeutic strategies. In the present study, a spatial-resolved metabolomics approach based on air flow-assisted desorption electrospray ionization (AFADESI) and matrix-assisted laser desorption ionization (MALDI) integrated mass spectrometry imaging (MSI) was proposed to investigate tissue-specific metabolic alterations in the kidneys of high-fat diet-fed and streptozotocin (STZ)-treated DN rats and the therapeutic effect of astragaloside IV, a potential anti-diabetic drug, against DN. As a result, a wide range of functional metabolites including sugars, amino acids, nucleotides and their derivatives, fatty acids, phospholipids, sphingolipids, glycerides, carnitine and its derivatives, vitamins, peptides, and metal ions associated with DN were identified and their unique distribution patterns in the rat kidney were visualized with high chemical specificity and high spatial resolution. These region-specific metabolic disturbances were ameliorated by repeated oral administration of astragaloside IV (100 mg/kg) for 12 weeks. This study provided more comprehensive and detailed information about the tissue-specific metabolic reprogramming and molecular pathological signature in the kidney of diabetic rats. These findings highlighted the promising potential of AFADESI and MALDI integrated MSI based metabolomics approach for application in metabolic kidney diseases.

Effect of advanced glycation end products on autophagic ability in osteoblasts / 中南大学学报(医学版)

OBJECTIVES@#Excessive production of AGEs in diabetic patients will affect the normal function of osteoblasts, and this process may be related to autophagy of osteoblasts. This study aims to explore the effect of advanced glycation end products (AGEs) on autophagic activity during osteogenic differentiation in rat bone marrow mesenchymal stem cells (BMSCs).@*METHODS@#BMSCs were isolated and cultured in vitro, treated with different concentrations (0, 50, 100, 200, and 400 mg/L) of AGEs for different time (3, 6, 12, 24, 48, and 72 h). The proliferation activity was detected by CCK-8 method. The mRNA and protein expression levels of Beclin1 and LC3 in cells were detected by real-time PCR and Western blotting, respectively.The autophagic vacuoles were observed under the transmission electron microscope. The cells were treated with autophagy promoter rapamycin or autophagy inhibitor 3MA. After 7 days of osteogenic induction, we performed alkaline phosphatase (ALP) staining and real-time PCR to detect the mRNA expression levels of osteogenesis-related genes.@*RESULTS@#In the low-concentration groups, the proliferation activity in BMSCs was increased (@*CONCLUSIONS@#Low concentration of AGEs can enhance the proliferative activity of BMSCs and promote osteogenic differentiation by accelerating autophagy. High concentration of AGEs can suppress the proliferation of BMSCs and inhibit osteogenic differentiation by reducing autophagy.

Progress in Advanced Glycation End-Products Effects on Biomechanics of Bone Tissues / 医用生物力学

Advanced glycation end-products (AGEs) are the products of non-enzymatic reactions between free amino groups of macromolecules and reducing sugars. AGEs accumulation in bone tissues changes the activity and function of bone cells by binding to their surface receptors, causing abnormalities in the process of bone remodeling. AGEs accumulation can also change the original structure and mineral deposition of bone collagen, affect the micro-mechanical properties of bone tissues, and further reduce bone strength and toughness, increase the bone fracture risk, which will lead to bone diseases and do great harm to human health. This article summarized the causes of AGEs and their detection methods, and reviewed previous studies about the effects of AGEs accumulation on bone biomechanics at micro and macro levels, so as to provide references for the early diagnosis and treatment of bone diseases in clinic.