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.

Oxidative stress and antioxidant markers in patients with alopecia areata: A comparative cross-sectional study

Background: Alopecia areata is a chronic inflammatory skin disease. Oxidative stress may contribute to the pathogenesis of this condition. Aim: To evaluate the serum oxidative stress markers and antioxidant capacity in patients with alopecia areata. Methods: This cross-sectional study was performed on 40 patients with alopecia areata and 40 healthy controls. The fasting blood sugar, C-reactive protein, lipid profile, and serum oxidative markers, including advanced glycation end products and advanced oxidation protein products, were measured in this study. Also, antioxidant enzymes, including paraoxonase-1, lecithin-cholesterol acyltransferase and serum ferric-reducing antioxidant power, were determined. Results: The serum levels of advanced glycation end products and advanced oxidation protein products were significantly higher in patients with alopecia areata, compared to the controls (P < 0.001), whereas the levels of ferric-reducing antioxidant power, paraoxonase-1 and lecithin-cholesterol acyltransferase were significantly lower in patients with alopecia areata, compared to the controls (P < 0.001). The mean fasting blood sugar level was significantly higher in patients with alopecia areata, compared to the controls. The ferric reducing antioxidant power level was significantly associated with the percentage of hair loss (P = 0.01, r = 0.4) and the serum C-reactive protein level (P = 0.03, r = –0.3) in patients with alopecia areata. Limitations: Since the current study had a cross-sectional design, no cause-effect relationship was established between alopecia areata and oxidative stress. The sample size of our study was also small. Conclusion: Based on the present results, the oxidant-antioxidant enzymatic system is impaired in alopecia areata due to the increased oxidative products and decreased antioxidant activity

Effect of Modified Erchentang on Bronchioles of Rats with Chronic Obstructive Pulmonary Disease by HMGB1/RAGE/NF-κB Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo study the effect of modified Erchentang on the expression of key molecules in the high mobility group Box 1 protein （HMGB1）/receptor for advanced glycation endproduct （RAGE）/nuclear factor-κB （NF-κB） signaling pathway in bronchioles of rats with chronic obstructive pulmonary disease （COPD）， to explore the mechanism of modified Erchentang against bronchiolar inflammation of COPD rats via HMGB1/RAGE/NF-κB signaling pathway. MethodSixty SD rats were randomly divided into normal group， model group， modified Erchentang low-， medium- and high-dose groups （5， 10， 20 g·kg-1·d-1） and ethyl pyruvate （HMGB1 inhibitor） group， with 10 in each group. The COPD rat model was prepared by cigarette smoke combined with tracheal injection of lipopolysaccharide （LPS）. After modeling， the modified Erchentang groups were given corresponding drugs （ig） and Ringer's solution （4 mL， ip）， while the EP group was treated with equal volume of normal saline （ig） and EP （0.04 g·kg-1·d-1， ip）. The normal group and the model group received equal volume of normal saline （ig） and Ringer's solution （ip） for 21 consecutive days. The contents of HMGB1， chemokine （C-X-C motif） ligand 1 （CXCL1）， CXCL2 and monocyte chemotactic protein-1 （MCP-1） in bronchoalveolar lavage fluid （BALF） were detected by enzyme-linked immunosorbent assay （ELISA）. The mRNA expressions of HMGB1， RAGE and NF-κB p65 were determined by Real-time polymerase chain reaction （Real-time PCR）， and the protein expressions of HMGB1， RAGE， p-NF-κB p65， and alpha-smooth muscle actin （α-SMA） in bronchioles tissue of rats were determined by immunohistochemistry （IHC）. ResultCompared with the conditions in the normal group， the forced vital capacity （FVC）， forced expiratory volume in the first second （FEV1） and FEV1/FVC in the model group were decreased （P<0.01） while the contents of HMGB1， CXCL1， CXCL2 and MCP-1 in BALF were increased （P<0.01）. And the model group presented higher mRNA expressions of HMGB1， RAGE and NF-κB p65 （P<0.01） and protein expressions of HMGB1， RAGE， p-NF-κB p65 and α-SMA （P<0.05， P<0.01） than the normal group. Compared with the model group， the modified Erchentang medium- and high-dose groups had increased FEV1/FVC （P<0.05， P<0.01）， lowered contents of HMGB1， CXCL1， CXCL2 and MCP-1 in BALF （P<0.05， P<0.05）， and reduced mRNA expressions of HMGB1， RAGE and NF-κB p65 （P<0.05， P<0.01） and protein expressions of HMGB1， RAGE， p-NF-κB p65 and α-SMA （P<0.05， P<0.01）. ConclusionModified Erchentang can resist bronchiolar inflammation of COPD rats. The mechanism may be related to down-regulating the mRNA expressiona of HMGB1 and RAGE， inhibiting the activity of NF-κB， and reducing the release of HMGB1， CXCL1， CXCL2 and MCP-1， thus suppressing the inflammatory injury and abnormal repair of bronchioles.

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.

Dahuang Mudantang Alleviates Intestinal Injury in Rat Model of Acute Pancreatitis by Regulating HMGB1/RAGE/NF-κB Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo explore the mechanism of Dahuang Mudantang in alleviating the intestinal injury in the rat model of acute pancreatitis via the high-mobility group box 1 （HMGB1）/receptor for advanced glycation endproduct （RAGE）/nuclear factor-κB （NF-κB） signaling pathway. MethodOne hundred and twenty SPF-grade Wistar rats received retrograde injection of 5% sodium taurocholate into the biliopancreatic duct for the modeling of intestinal injury in acute pancreatitis. The rats were randomized into blank， model， low-， medium-， and high-dose （3.5， 7， 14 g·kg-1， administrated by gavage） Dahuang Mudantang， and octreotide （1×10-5 g·kg-1， subcutaneous injection） groups （n=20）. The rats in blank and model groups received equal volume of distilled water by gavage. Drugs were administered 1 h before and every 12 h after modeling， and samples were collected 24 h after modeling. The general status of the rats was observed. The biochemical methods were employed to measure the levels of amylase （AMS） and C-reactive protein （CRP） in the serum. The enzyme-linked immunosorbent assay （ELISA） was employed to measure the levels of tumor necrosis factor （TNF）-α， interleukin （IL）-1β， and IL-6 in the colon tissue. The morphological changes of pancreatic and colon tissues were observed by hematoxylin-eosin （HE） staining. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） and Western blot were employed to measure the expression levels of HMGB1， RAGE， inhibitor of NF-κB kinase （IKK）， and NF-κB suppressor protein α（IκBα）in the colon tissue. ResultThe rats in the model group showed poor general survival， writhing response， reduced frequency of defecation， and dry stool. The symptoms of rats in the model group were mitigated in each treatment group， and the high-dose Dahuang Mudantang showed the most significant effect. Compared with the normal group， the model group had elevated AMS and CRP levels （P<0.05）， which were lowered by Dahuang Mudantang （P<0.05）， especially that at the high dose （P<0.05）. Compared with the normal group， the modeling elevated that levels of TNF-α， IL-1β， and IL-6 （P<0.05）. Such elevations were lowered by Dahuang Mudantang （P<0.05）， and the high-dose group and the octreotide group showed better performance （P<0.05）. The modeling caused necrotic， congested， and destructed pancreatic and colonic tissues， which were ameliorated by the drugs， especially high-dose Dahuang Mudantang. Compared with the normal group， the modeling up-regulated the mRNA levels of HMGB1， RAGE， IKK， IκBα， and NF-κB （P<0.05）. Compared with the model group， Dahuang Mudantang and octreotide down-regulated the mRNA levels of HMGB1， RAGE， IKK， IκBα， and NF-κB （P<0.05）， and the high-dose Dahuang Mudantang demonstrated the best performance （P<0.05）. Western blot results showed a trend consistent with the results of Real-time PCR. ConclusionDahuang Mudantang can improved the general status， reduce inflammation， and alleviate histopathological changes in the pancreatic and colon tissues in the rat model of acute pancreatitis by inhibiting the HMGB1/RAGE/NF-κB signaling pathway.

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.

Mechanism of Yitangkang in Improving Apoptosis of Skeletal Muscle Cells by Inhibiting AGE/RAGE Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo determine the mechanism of Yitangkang in correcting excessive apoptosis of skeletal muscle cells to improve insulin resistance （IR） by inhibiting the advanced glycation end product （AGE）/receptor for the advanced glycation end product （RAGE） signaling pathway. Method① In vitro experiments. Yitangkang-medicated serum was prepared. C2C12 cells were divided into a blank group， a model group， high-， medium-， and low-dose Yitangkang-medicated serum groups （40， 20， and 10 g·kg-1）， and a RAGE inhibitor group. The IR model was induced by palmitic acid in C2C12 cells except for those in the blank group. After the corresponding intervention methods were conducted，the cell viability and glucose consumption level of each group were determined. In addition，the apoptosis rate was determined using flow cytometry. The mRNA and protein expression levels of the important apoptotic proteins ［B-cell lymphoma 2 （Bcl-2）， Bcl-2-associated X protein （Bax）， p53， cysteinyl aspartate-specific protease-3 （Caspase-3）， and cysteinyl aspartate-specific protease-9 （Caspase-9）］ were determined using Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） and Western blot. ② In vivo experiments. Ninety-six eligible Wistar rats were divided into a blank group， a model group， high-，medium-，and low-dose Yitangkang groups （40， 20， and 10 g·kg-1）， and a western medicine group （pioglitazone hydrochloride，1.35 mg·kg-1）. The IR model was induced using high-glucose and high-fat feed for diabetes combined with intraperitoneal injection of low-dose streptozotocin （STZ） in animals and verified by the hyperinsulinemic-euglycemic clamp （HEC） test. After the model was determined successfully， the rats in each group were given intragastric administration of drugs as required. Terminal deoxynucleotidyl transferase dUTP nick end labeling （TUNEL） assay was performed to determine the number of positive apoptotic cells in the skeletal muscle tissues of rats in each group，while Real-time polymerase chain reaction（Real-time PCR） and Western blot were performed to determine the mRNA and protein expression levels of the important apoptotic proteins Bcl-2， Bax， p53， Caspase-3， and Caspase-9. Result① In vitro experiments. compared with the blank group， the model groups showed increased apoptosis rate of C2C12 cells and decreased cell viability and glucose consumption （P<0.01）. Compared with the model group， the Yitangkang-medicated serum groups and the RAGE inhibitor group showed decreased apoptosis rate of C2C12 cells and increased cell viability and glucose consumption （P<0.01）. Compared with the blank group， the model group showed decreased expression levels of Bcl-2 mRNA and protein in C2C12 cells and increased mRNA and protein expression levels of Bax， p53， Caspase-3， and Caspase-9 （P<0.01）. Compared with the model group， the Yitangkang-medicated serum groups and the RAGE inhibitor group showed increased expression levels of Bcl-2 mRNA and protein in C2C12 cells （P<0.01） and decreased mRNA and protein expression levels of Bax， p53， Caspase-3， and Caspase-9 （P<0.05， P<0.01）. ② In vivo experiments. The number of positive apoptotic cells in the skeletal muscle tissues of rats in the model group significantly increased as compared with that in the blank group （P<0.01）. The number of positive apoptotic cells in the skeletal muscle tissues of rats in the Yitangkang groups and the western medicine group decreased as compared with that in the model group （P<0.01）. Compared with the blank group， the model group showed decreased expression levels of Bcl-2 mRNA and protein in skeletal muscle tissues of rats and increased mRNA and protein expression levels of Bax， p53， Caspase-3， and Caspase-9 （P<0.01）. Compared with the model group， the Yitangkang groups and the western medicine group showed increased expression levels of Bcl-2 mRNA and protein in skeletal muscle tissues of rats （P<0.01） and decreased mRNA and protein expression levels of Bax， p53， Caspase-3， and Caspase-9 （P<0.05， P<0.01）. The medium-dose Yitangkang showed a similar effect as RAGE inhibitor， and the effect was equivalent to that of pioglitazone hydrochloride. ConclusionYitangkang can inhibit skeletal muscle cell apoptosis by inhibiting the AGE/RAGE signaling pathway.

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.

The mechanism of the receptors for advanced glycation end products affecting pericyte detachment from blood vessels after traumatic brain injury / 西安交通大学学报(医学版)

【Objective】 To observe the reactive change of cortical perivascular cells after craniocerebral injury and explore its mechanism. 【Methods】 The controllable cortical impact animal model was used to simulate craniocerebral injury, the expressions of cortical pericyte markers at different time points after trauma were studied by Western blotting, and the biological behavior of vascular pericytes after craniocerebral injury was determined by transmission electron microscopy. Post-traumatic high mobility group box 1 (HMGB1), receptor for advanced glycation end product (RAGE), and nuclear factor κB (NF-κB) were detected by Western blotting. The experimental animals were divided into FPS-ZM1 (a specific RAGE receptor blocker) injection group and wild-type group. Wet and dry brain weight and transmission electron microscopy were used to study the post-traumatic effects of HMGB1-RAGE on pericytes. The primary mouse brain microvascular pericytes were cultured and supplemented with HMGB1 recombinant protein; the cultured pericytes supplemented with FPS-ZM1 were used as the control to explore the effect of HMGB1-RAGE pathway on vascular pericytes in vitro. 【Results】 The expression levels of early post-traumatic cortical pericyte markers platelet-derived growth factor receptor beta (PDGFR-β) and NG2 proteoglycan (NG2) decreased (PDGFR-β, Control vs. CCI 3D P<0.05; NG2, Control vs. CCI 6H P<0.05; Control vs. CCI 1D P<0.05). We found that pericytes were detached from blood vessels, accompanied by local blood-brain barrier opening. The expression of HMGB1-RAGE-NF-κB signaling pathway was increased in the early cortex after trauma (HMGB1, Control vs. CCI 6H P<0.05, Control vs. CCI 1D P<0.05; RAGE, Control vs. CCI 6H P<0.05, Control vs. CCI 1D P<0.05, Control vs. CCI 3D P<0.05, Control vs. CCI 5D P<0.05, Control vs. CCI 7D P<0.05; NF-κB, Control vs. CCI 6H P<0.05, Control vs. CCI 1D P<0.05). After blocking the binding of RAGE with the ligand, cortical edema was reduced (CCI 6H P<0.05, CCI 1D P<0.05), and neurovascular unit damage was reduced. HMGB1 recombinant protein could increase the migration ability of cultured pericytes (Control vs. HMGB1 P<0.05, Control vs. HMGB1+FPS-ZM1 P<0.05), and could be reversed by FPS-ZM1 (HMGB1 vs. HMGB1+FPS-ZM1 P<0.05). 【Conclusion】 High-level HMGB1 after traumatic brain injury mediates pericytes’ detachment from blood vessels through RAGE on pericytes and leads to the occurrence of local cerebral edema.

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.

Relationship of advanced glycation end-products in hypertension in diabetic patients: a systematic review / Relação dos produtos finais de glicação avançada na hipertensão de pacientes com diabetes: uma revisão sistemática

Abstract Diabetes mellitus and arterial hypertension are among the five risk factors that increase mortality in the world. Both are chronic, non-communicable diseases (NCDs), that have a pathophysiological association. Advanced glycation end products (AGEs), produced by the lack of glycemic control in diabetic patients, interact with their AGE receptors (AGER) resulting in increased arterial stiffness, inflammation and endothelial changes - which increases the risk of developing hypertension and other complications. We ran a systematic review in Pubmed, SciELO, Cochrane Library and Web of Science databases using keywords and Boolean operators to optimize the search, with the objective of assessing the mechanism of non-enzymatic glycation of proteins present in patients with diabetes and its correlation with the onset of hypertension, exposing all the endothelial and cellular damage caused by AGEs. We found 719 papers, of which 99 were read in full, and 26 met the eligibility criteria and were included in the present review. AGEs should be considered one of the main cardiometabolic risk factors. Reducing the AGE-AGER interaction will result in cardiovascular protection and increased life expectancy.

Resumo Diabetes mellitus e hipertensão arterial estão entre os cinco fatores de risco que elevam a mortalidade no mundo. Ambas são doenças crônicas não transmissíveis (DCNT) que têm associação fisiopatológica. Os produtos finais de glicação avançada (AGEs), produzidos pela falta de controle glicêmico nos pacientes diabéticos, interagem com seus receptores para AGEs (RAGE) resultando no aumento da rigidez arterial e da inflamação e em alterações endoteliais, fatores que intensificam o risco do desenvolvimento da hipertensão e de demais complicações. Realizou-se uma revisão sistemática nas bases de dados Pubmed, SciELO, Cochrane Library e Web of Science utilizando descritores e operadores booleanos para otimizar a busca, com o objetivo de fornecer o mecanismo da glicação não enzimática de proteínas presente em pacientes com diabetes e sua correlação com o aparecimento da hipertensão, expondo todo o dano endotelial e celular ocasionado pelos AGEs. Foram encontrados 719 artigos, dos quais 99 foram lidos na íntegra, e 26 atenderam aos critérios de elegibilidade e foram incluídos na presente revisão. Os AGEs devem ser considerados um dos principais fatores de risco cardiometabólico. A redução da interação AGE-RAGE resultará na proteção cardiovascular e no aumento da expectativa de vida.

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.

Research progress in the role of HMGB1-RAGE signaling axis in hepatic ischemia-reperfusion injury / 国际生物医学工程杂志

Hepatic ischemia-reperfusion injury(HIRI) is a kind of liver injury caused by reperfusion after ischemic injury, which is clinically manifested by a series of deterioration phenomena such as liver function impairment, jaundice and even multi-organ failure after restoration of blood supply to the liver. HIRI seriously affects the patient's regression and prognosis. The essence of HIRI is a sterile inflammatory response. High mobility histone 1 (HMGB1) is an important intermediate mediator of HIRI and is a multiple cell type effector involved in HIRI. The receptor for glycosylated end products(RAGE) signaling axis of HMGB1 plays a key role in HIRI, but its mechanism is unclear. In this paper, the recent studies related to the pro-inflammatory mechanism of HMGB1-RAGE signaling axis in HIRI were summarized, and the relationship between HMGB1-RAGE signaling pathway and HIRI was discussed. The research progress of preventing and treating HIRI with surgical operation, ischemic preconditioning, drug and gene therapy using HMGB1-RAGE signaling axis as the target was reviewed.

Improvements on Glycation by Thermal Effects of Balneotherapy ─Ａ Pilot Study─ / 日本温泉気候物理医学会雑誌

  Objective: We investigated the effects of 5 days of spa therapy on the glycation reaction and oxidative balance defense system.  Subjects: The subjects were divided into a glucose spikes group (S group: 5 cases) and non-glucose spike group (non-S group: 6 cases), and a comparative study was conducted.  Method: The subjects stayed at the Inubosaki Onsen “Superb View Inubosaki Hotel” for 5 days and took spa baths twice a day for 20 min (balneotherapy). Before and after the baths, the degree of glycation was measured. Erythrocyte deformation by dark field microscope was classified into stages between 0 and 5, and the state of deformation and the levels of advanced glycation end products (AGEs) were measured. In addition, the oxidative stress (reactive oxygen metabolites, d-ROM), antioxidant power (biological antioxidant potential, BAP), and latent antioxidant capacity (BAP/d-ROM ratio) were also measured.  Result: The red blood cell images before balneotherapy were worse in the S group, but there was no significant difference in the AGE values. There was also no significant difference between the two groups in terms of the oxidative balance defense system. A comparison before and after balneotherapy showed that the red blood cell images significantly improved from 3 (3-3) (median (IQR)) to 2 (1-2)°in the S group. Oxidative stress also significantly improved in group S from 342 (334-362) to 314 (303-345) CARR U. In the non-S group, the AGE value improved significantly from 0.52 (0.48-0.59) to 0.5 (0.43-053) a.u. There were no significant differences in the other items.  Discussion: Changes in red blood cell images are considered to reflect changes in the early reactions of glycation, and AGEs may be evaluated as representing whole early and late reactions of glycation. In the S group, the early reaction improved, and in the non-S group, the entire glycative reaction was effective. Although the each mechanism of blood glucose to different, balneotherapy was shown to be effective in improving glycation.

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.

Diabetic nephropathy patients show hyper-responsiveness to N6-carboxymethyllysine

The aim of this study was to evaluate the impact of N6-carboxymethyllysine (CML) on NF-κB gene expression and tumor necrosis factor (TNF) production in diabetic nephropathy. This was an observational study comprised of three groups: diabetic nephropathy (n=30), type II diabetes mellitus (n=28), and healthy volunteers (n=30). Blood samples collected from the study participants were cultured for 24 h in the presence of CML or an appropriate control. After incubation, the cultures were centrifuged to separate the cells from the conditioned media. cDNA was prepared from the cell pellet and used to quantify NF-κB gene expression by quantitative real-time polymerase chain reaction (PCR). The conditioned media were used to measure TNF production by enzyme-linked immunosorbent assay (ELISA). The CML-induced fold change in NF-κB gene expression was significantly different among the study groups (P=5.4×10-5). Also, the CML-induced fold change in TNF levels was significantly different among the three groups (P=4.3×10-8). These results imply that patients with diabetic nephropathy and type II diabetes mellitus showed an elevated response to CML.

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.

Protective Mechanism of Youguiwan through AOPPs Regulating RAGE/ROS/NF-κB Axis and Wnt/β-catenin Signal in Rats with Adriamycin-induced Nephrotic Syndrome / 中国实验方剂学杂志

ObjectiveTo explore the effect of Youguiwan on the rats with adriamycin-induced nephrotic syndrome （NS） and its mechanism. MethodSD rats were randomly divided into a normal group， a model group， three Youguiwan low， medium， and high-dose groups， and a prednisone group. Rats in the model group were intravenously injected with adriamycin in the tail vein to induce the NS model. Rats in the Youguiwan low， medium， and high-dose groups were given 2.8， 5.6， 11.2 g·kg-1·d-1 of crude drugs， respectively， and rats in the prednisone group were given 6.3 mg·kg-1·d-1 of prednisone acetate. Each administration group was given continuous medicine for 6 weeks， and the normal group and model group were given an equal volume of normal saline. Bicinchoninic acid （BCA） assay was used to detect 24 h urine protein （24 h UP）. Automatic biochemical analyzer was used to detect serum urea nitrogen （BUN）， creatinine （SCr）， albumin （ALB）， total cholesterol （TC）， and triglyceride （TG） levels. Hematoxylin-eosin （HE） staining was used to observe renal tissue morphology， and kit was used to detect serum advanced oxidized protein products （AOPPs） and reactive oxygen species （ROS）. Western blot was used to detect the receptor of advanced glycation endproducts （RAGE） of renal tissue， nuclear factor-κB （NF-κB） phosphorylation levels， Wnt， and β-catenin protein expression. ResultAs compared with the normal group， 24 h UP， serum BUN， SCr， TC， TG， AOPPs， and ROS levels in the model group increased significantly （P<0.01）， whereas ALB decreased （P<0.01）. There were typical pathological injuries in the renal tissue， and the expressions of RAGE， phosphorylation（p）-NF-κB， Wnt1， and β-catenin protein were significantly increased （P<0.01）. As compared with the model group， the 24 h UP， serum BUN， SCr， TC， TG， AOPPs， and ROS levels of rats in the Youguiwan low， medium， and high-dose groups significantly reduced （P<0.01）， and ALB significantly increased （P<0.01）. The renal tissue damage was reduced， and the expressions of RAGE， p-NF-κB， Wnt1， and β-catenin protein were significantly decreased （P<0.01） in a dose-dependent manner. ConclusionYouguiwan improves the kidney injury of rats with adriamycin-induced NS. The mechanism may be related to the reduction of AOPPs level， inhibition of RAGE/ROS/NF-κB axis， and activation of Wnt/β-catenin signal.