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 T_low>T_high (χ²=9.470, P<0.05), and for OS T_low>T_high (χ²=7.808, P<0.05); there was no difference in the survival of sRAGE high expression group and low expression group, for PFS T_lowhigh (χ²=1.661, P>0.05), and for OS T_lowhigh (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.
Enzyme-Linked Immunosorbent Assay ; HMGB1 Protein/blood* ; Humans ; Multiple Myeloma/therapy* ; Prognosis ; Receptor for Advanced Glycation End Products/blood*

The objective of study was to explore the influence of high mobility group box 1 (HMGB1) on migration of cord blood CD34(+) cells and their mechanism of migration. The expressions of receptor for advanced glycation end products (RAGE), toll-like receptor-2 (TLR2) and TLR4 were detected by flow cytometry. The CD34(+) cells in umbilical cord blood (CB) were enriched by MiniMACS and were exposed to various concentration of HMGB1 (10, 50, 100, 1, 000 ng/ml), then the migration effect of HMGB1 on umbilical cord blood (UCB) CD34(+) cell count was determined by microscopy, the chemotactic index was calculated. The CD34(+) cells untreated with HMGB1 were used as control. The results indicated that the purity of the isolated CD34(+) cells was more than 98%. The HMGB1 could promote the migration of CD34(+) cells, and the migration effect of HMGB1 on CD34(+) cells in certain concentrations gradually increased along with raise of concentration, the strongest effect was observed in concentration of 100 ng/ml, there was significant difference as compared with control (p < 0.01). Anti-RAGE antibody partially inhibited the migration effect of HMGB1 on CD34(+) cells. It is concluded that the HMGB1 in certain concentration can enhance migration of CD34(+) cells, which may be mediated through RAGE.
Antigens, CD34 ; Cell Movement ; drug effects ; Cells, Cultured ; Female ; Fetal Blood ; cytology ; drug effects ; HMGB1 Protein ; pharmacology ; Humans ; Receptor for Advanced Glycation End Products ; Receptors, Immunologic ; metabolism ; Signal Transduction

OBJECTIVETo investigate the effects of Ganoderma lucidum polysaccharides (GLPs) on advanced glycation end products (AGEs) and the receptor (RAGE) of aorta pectoralis in the T2DM rats, and explore the protective mechanism of GLPs on the aorta pectoralis.

METHODSD rats were fed with high-fat diet for 4 weeks and then were injected STZ (30 mg x kg(-1)) to induce the type 2 diabetic rats. Once the T2DM models were set successfully, rats were randomly divided into normal control group, diabetes model (DM) group, berberine (30 mg x kg(-1)) group, GLPs of low (GLPs-L), middle (GLPs-M) and high-dose (GLPs-H) group (GLPs were orally given 200, 400, 800 mg x kg(-1)). After 12 weeks' treatment, the content of fasting blood glucose and AGEs in serum were detected. The expressions of AGEs and RAGE in aortas pectoralis were measured both by immunohistochemistric assays and western-blot analysis.

RESULTCompared with DM group, the content of blood glucose and AGEs in serum were significantly decreased in GLPs-H group and GLPs-M group (P < 0.01). Compared with DM group, the expressions of AGEs and RAGE in aorta pectoralis were decreased in other groups, especially in GLPs-H group (P < 0. 01).

CONCLUSIONGLPs could low blood glucose and protect aortas effectively. The mechanisms may be involved in down-regulation the expressions of AGEs and RAGE in aortal tissue.

Animals ; Aorta ; drug effects ; metabolism ; pathology ; Blood Glucose ; analysis ; Diabetes Mellitus, Type 2 ; metabolism ; pathology ; Female ; Glycation End Products, Advanced ; metabolism ; Male ; Plant Extracts ; pharmacology ; Polysaccharides ; pharmacology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Receptor for Advanced Glycation End Products ; Receptors, Immunologic ; metabolism ; Reishi ; chemistry

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.
Mice ; Humans ; Animals ; NADP/metabolism* ; Toll-Like Receptor 4 ; HMGB1 Protein/metabolism* ; Receptor for Advanced Glycation End Products/metabolism* ; Blood-Brain Barrier/metabolism* ; Neuroinflammatory Diseases ; Electroacupuncture ; Alzheimer Disease/therapy* ; Hippocampus/metabolism* ; Amyloid beta-Peptides/metabolism*

Objective To investigate the effects of simvastatin on diabetic neuropathic pain and systematic inflammation in diabetic rats and explore their molecular mechanisms.Methods Totally 24 rats were equally randomized into the normal+vehicle(NV)group,diabetic+vehicle(DV)group,and diabetic+simvastatin(DS)group using the random number table.Streptozotocin(STZ)was used to establish the rat models of diabetes.Blood glucose,body mass,paw withdrawal mechanical threshold(PWMT),and paw withdrawal thermal latency(PWTL)in each group were observed on days 7,14,21,and 28 after STZ injection.On day 28 after STZ injection,rats were sacrificed,and the lumbar spinal dorsal horn and serum were collected.Western blotting was used to detect the expression of receptor for advanced glycation end products(RAGE)and the phosphorylation levels of protein kinase B(AKT),extracellular signal-regulated kinase(ERK),p38,and c-Jun N-terminal kinase(JNK)in the spinal dorsal horn of rats in each group.Enzyme-linked immunosorbent assay was performed to determine the serum concentrations of oxidized low density lipoprotein(ox-LDL)and interleukin-1β(IL-1β).Results On days 14,21 and 28 after STZ injection,the PWMT in DV group were(8.6 ± 0.8),(7.1 ± 1.6),and(7.8 ± 0.8)g respectively,which were significantly lower than (12.0 ± 0.9)(=8.482, =0.000),(11.6 ± 1.5)(=11.309, =0.000),and(11.7 ± 1.5)g(=9.801, =0.000)in NV group.The PWMT in DS group on days 21 and 28 were(9.4 ± 1.4)(=5.780, =0.000)and(9.7 ± 0.9)g(=4.775, =0.003),respectively,which were significantly improved comparing with those of DV group.On days 7,14,21,and 28,there were no significant differences in PWTL among these three groups (all <0.05).The expression of RAGE in the spinal dorsal horn of DV group was significantly higher than those of NV group(=6.299, =0.000)and DS group(=2.891, =0.025).The phosphorylation level of AKT in the spinal dorsal horn of DV group was significantly higher than those of NV group(=8.915,=0.000)and DS group(=4.103,=0.003).The phosphorylation levels of ERK( =8.313,=0.000),p38( =2.965, =0.022),and JNK(=7.459, =0.000)in the spinal dorsal horn of DV group were significantly higher than those of NV group;the phosphorylation level of JNK in the spinal dorsal horn of DS group was significant lower than that of DV group(=3.866, =0.004);however,there were no significant differences in the phosphorylation levels of ERK(=1.987,=0.122)and p38(=1.260,=0.375)in the spinal dorsal horn between DS group and DV group.The serum concentrations of ox-LDL and IL-1β in DV group were(41.86 ± 13.40)ng/ml and(108.16 ± 25.88)pg/ml,respectively,which were significantly higher than those in NV group [(24.66 ± 7.87)ng/ml(=3.606,=0.003)and(49.32 ± 28.35)pg/ml(=5.079,=0.000)] and DS group [(18.81 ± 5.62)ng/ml (=4.833, =0.000)and(32.73 ± 11.73)pg/ml(=6.510, =0.000)].Conclusions Simvastatin can relieve the mechanical allodynia of diabetic rats possibly by inhibiting the activation of RAGE/AKT and the phosphorylation of JNK in the spinal dorsal horn.Simvastatin can also decrease the serum concentrations of ox-LDL and IL-1β in diabetic rats,which may contribute to the relief of systematic inflammation.
Animals ; Diabetes Mellitus, Experimental ; complications ; Hyperalgesia ; Inflammation ; drug therapy ; Interleukin-1beta ; blood ; Lipoproteins, LDL ; blood ; Neuralgia ; drug therapy ; Proto-Oncogene Proteins c-akt ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Receptor for Advanced Glycation End Products ; metabolism ; Simvastatin ; pharmacology

OBJECTIVETo evaluate the roles of N-terminal lectin-like domain of thrombomodulin (TM-N) and receptor for advanced glycation end products (RAGE) in acute hepatic failure using a mouse model system.

METHODSAcute hepatic failure was induced in Kunming mice by intraperitoneal injection of D-galactosamine (D-Galn at 600 mg/kg) and lipopolysaccharide (LPS at 5 mug/kg) and mice were divided into groups for injection with saline, recombinant (r)TM-N protein, or recombinant soluble (rs)RAGE protein. Unmanipulated model mice served as the negative controls. Effects on liver expression of high mobility group box-1 (HMGB1) were detected by immunohistochemistry and real time RT-PCR. Effects on serum levels of tumor necrosis factor-alpha (TNFa) and interleukin-1 beta (IL)-1b were quantified by ELISA.

RESULTSTreatment with rTM-N and rsRAGE both alleviated the acute liver damage induced by D-Galn/LPS exposure, and decreased the hepatic expression of HMGB1 as well as the serum levels of TNFa and IL-1b.

CONCLUSIONIntraperitoneal delivery of rTM-N and rsRAGE can alleviate acute liver damage by modulating the expression of necrosis- and inflammation-related factors.

Animals ; Disease Models, Animal ; Galactosamine ; adverse effects ; Interleukin-1beta ; blood ; Liver ; metabolism ; Liver Failure, Acute ; chemically induced ; prevention & control ; Mice ; Mice, Inbred Strains ; Receptor for Advanced Glycation End Products ; Receptors, Immunologic ; metabolism ; Recombinant Proteins ; pharmacology ; Thrombomodulin ; metabolism ; Tumor Necrosis Factor-alpha ; blood

The pathophysiology of diabetes is multifactorial and no single etiology is at the forefront. The proposed mechanisms of erectile dysfunction (ED) in diabetic patients includes elevated advanced glycation end-products (AGEs) and increased levels of oxygen free radicals, impaired nitric oxide (NO) synthesis, increased endothelin B receptor binding sites and ultrastructural changes, upregulated RhoA/Rho-kinase pathway, NO-dependent selective nitrergic nerve degeneration and impaired cyclic guanosine monophosphate (cGMP)-dependent kinase-1 (PKG-1). The treatment of diabetic ED is multimodal. Treatment of the underlying hyperglycemia and comorbidities is of utmost importance to prevent or halt the progression of the disease. The peripherally acting oral phosphodiesterase type 5 (PDE5) inhibitors are the mainstay of oral medical treatment of ED in diabetics. Vacuum erection devices are an additional treatment as a non-invasive treatment option. Local administration of vasoactive medication via urethral suppository or intracorporal injection can be effective with minimal side-effects. Patients with irreversible damage of the erectile mechanism are candidates for penile implantation. Future strategies in the evolution of the treatment of ED are aimed at correcting or treating the underlying mechanisms of ED. With an appropriate vector, researchers have been able to transfect diabetic animals with agents such as neurotrophic factors and nitric oxide synthase (NOS). Further studies in gene therapy are needed to fully ascertain its safety and utility in humans.
Alprostadil ; administration & dosage ; therapeutic use ; Cyclic GMP-Dependent Protein Kinases ; physiology ; Diabetes Complications ; physiopathology ; Diabetic Neuropathies ; physiopathology ; Erectile Dysfunction ; etiology ; physiopathology ; therapy ; Glycation End Products, Advanced ; physiology ; Humans ; Male ; Nitric Oxide ; physiology ; Penile Erection ; Penile Prosthesis ; Penis ; blood supply ; Phosphodiesterase Inhibitors ; therapeutic use ; Receptor, Endothelin B ; physiology ; Suppositories ; Vacuum