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1.
China Pharmacy ; (12): 1722-1726, 2024.
Article in Chinese | WPRIM | ID: wpr-1039350

ABSTRACT

OBJECTIVE To study the effects of leonurine on pancreatic injury in rats with severe acute pancreatitis (SAP), and to explore its mechanism based on the high-mobility group box 1 (HMGB1)/receptor for advanced glycation end products (RAGE) signaling pathway. METHODS SAP rat model was constructed by injecting 5% sodium taurocholate into the bile duct of the pancreas. Model rats were randomly divided into model group, low dose leonurine group (8 mg/kg), high dose leonurine group (16 mg/kg), HMGB1 overexpression group (8 μg/kg), and high dose leonurine+HMGB1 overexpression group (16 mg/kg+8 μg/kg), with 14 rats in each group. Another 14 rats were selected as the sham operation group. Rats in each group were injected with corresponding drugs or normal saline via abdominal cavity or tail vein once a day for 5 consecutive days. After the last administration, the levels of serum amylase (AMS) and lipase (LPS) were detected; the pathological injury of pancreatic tissue was observed; the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), malondialdehyde (MDA) and superoxide dismutase (SOD), mRNA and protein expressions of HMGB1 and RAGE in pancreatic tissues were detected. RESULTS Compared with model group, the structure of pancreatic tissue in rats gradually recovered in low and high dose leonurine groups; inflammatory cell infiltration gradually decreased; the pathological injury score and the levels of AMS, LPS, TNF-α, IL-6, MDA, the mRNA and protein expressions of HMGB1 and RAGE were significantly decreased, while the SOD levels were significantly increased (P<0.05). The high dose leonurine group showed more significant improvement (P<0.05); the pathological damage of pancreatic tissue in the HMGB1 overexpression group worsened, and except for a decrease in SOD levels, all other quantitative indicators increased significantly (P<0.05). Overexpression of HMGB1 could reduce the improvement effect of high dose leonurine on the above indexes in SAP rats (P<0.05). CONCLUSIONS Leonurine may alleviate pancreatic injury, inflammation and oxidative stress in pancreatic tissue of rats with SAP by inhibiting the HMGB1/RAGE signaling pathway.

2.
J. appl. oral sci ; J. appl. oral sci;32: e20230304, 2024. graf
Article in English | LILACS-Express | LILACS | ID: biblio-1534758

ABSTRACT

Abstract Objective: We aimed to investigate the regulatory effects of HMGB1/TLR4 signaling pathway on the expression of IL-10 and VEGF in human bone marrow mesenchymal stem cells. Methodology: Human JBMSCs were isolated and cultured. Then, HMGB1 was added into the JBMSCs culture medium, and the protein and mRNA expression levels of IL-10 and VEGF were assessed. Moreover, cells were pretreated with a specific TLR4 inhibitor (TAK-242), and the expression changes of IL-10 and VEGF were compared. Results: Compared with the control group, exposure to HMGB1 in human JBMSCs up-regulated TLR4, IL-10, and VEGF secretion at both protein and mRNA levels (P<0. 05). In addition, the increased expression of IL-10 and VEGF could be restrained in TAK-242 group compared with the HMGB1 group (P<0.05). Conclusions: The results indicated that HMGB1 activate TLR4 signaling pathway in Human JBMSCs, which plays a regulatory role in cytokines expression.

3.
Article in Chinese | WPRIM | ID: wpr-1028137

ABSTRACT

Objective To investigate the influences of arctigenin(ATG)on ventricular remodeling and inflammatory reaction in chronic heart failure(CHF)rats,and to analyze its potential mecha-nism.Methods A total of 79 SD rats were randomly divided into sham operation group(n=12),and the remaining rats were inflicted with abdominal aortic coarctation to establish a rat CHF model.After modeling,60 CHF rats were randomly divided into CHF group,low and high dose ATG group(ATG-L and ATG-H groups,10 and 20 mg/kg,respectively),ATG+NC group[20 mg/kg ATG+100 μl high mobility group protein B1(HMGB1)negative control plasmid],and ATG+HMGB1 group(20 mg/kg ATG+100 pl HMGB1 overexpression plasmid),with 12 rats per group.After 4 weeks of corresponding intervention,heart function,levels of B-type brain na-triuretic peptide(BNP),N-terminal B-type brain natriuretic peptide precursor(NT-proBNP)andIL-6 and TNF-α,heart mass index(HMI)and left ventricular mass index(LVMI),pathological changes of myocardial tissue,cross-sectional area of myocardial cells and myocardial collagen vol-ume fraction(CVF)and protein expression of HMGB1/Toll-like receptor 4(TLR4)/NF-κB sig-naling pathway in left ventricular myocardial tissue were measured.Results Compared with the sham operation group,myocardial tissue HMGB1(0.42±0.05 vs 0.15±0.02)and TLR4(0.70± 0.09 vs 0.21±0.04)protein levels,and phosphorylated NF-κB p65(p-NF-κB p65)/NF-κB p65(0.73±0.09 vs 0.26±0.05)protein ratio were obviously increased in the CHF group,while the left ventricular ejection fraction(LVEF)and left ventricular short-axis fractional shortening(LVFS)were obviously decreased(P<0.05).Myocardial tissue HMGB1(0.33±0.04、0.24±0.04 vs 0.42±0.05)and TLR4(0.56±0.06、0.41±0.05 vs 0.70±0.09)protein levels,and p-NF κB p65/NF-KB p65(0.61±0.08、0.49±0.06 vs 0.73±0.09)protein ratio were decreased,and the LVEF and LVFS were increased in the ATG-L group and ATG-H group than the CHF group(P<0.05).Overexpression of HMGB1 obviously attenuated the inhibitory effects of ATG on HMGB1/TLR4/NF-κB signaling pathway,ventricular remodeling,and inflammatory reaction in CHF rats(P<0.05).Conclusion ATG may suppress ventricular remodeling in CHF rats by in-hibiting HMGB1/TLR4/NF-κB signaling inflammatory pathway.

4.
Article in Chinese | WPRIM | ID: wpr-1032226

ABSTRACT

Objective @#To construct a rat model of trigeminal neuralgia ( TN) to explore the expression of high mobility group box-1 (HMGB1) in the trigeminal ganglion (TG) and the possible mechanism of HMGB1 effect on pain . @*Methods @#TN model was constructed by infraorbital nerve constriction and divided into operation group (CCI group) and Sham group , and the success of the model construction was determined through mechanical pain thresh old assessment. Real time fluorescence quantitative PCR ( RT-qPCR) and Western blot were used to detect high mobility group protein B1 (HMGB1) , Toll receptor 4 (TLR4) , and Nuclear Factor Kappa B(NF-κB) mRNA and protein expression in the ipsilateral trigeminal ganglion (TG) of the Sham and CCI rats . 50 mg/kg HMGB1 inhibi tor glycyrrhizin (GL) was inj ected intraperitoneally every day for two week s , and normal saline (NS) was used as control . The patients were divided into CCI group , CCI + NS group and CCI + GL group . HMGB1 , TLR4 , and NF- κB mRNA and protein expression in the ipsilateral trigeminal ganglion (TG) were detected by RT-qPCR and West ern blot in CCI group , CCI + NS group , and CCI + GL group . @*Results @#The mechanical threshold on the operated side of the rat continued to decrease (P < 0.05) , and mechanical pain threshold identification model was success fully constructed . After chronic compressive injury to the infraorbital nerve in rats , HMGB1 , TLR4 , and NF-κB mRNA and protein expression in TG on the operated side increased ( P < 0.05) ; After administration of HMGB1 inhibitor Glcyrrhizin , HMGB1 , TLR4 , NF-κB showed a decrease (P < 0.05) .@*Conclusion @#HMGB1 is associat ed with TN , and HMGB1 may be involved in the pathogenesis of TN through TLR4/NF-κB signaling pathway.

5.
Journal of Clinical Hepatology ; (12): 1130-1135, 2024.
Article in Chinese | WPRIM | ID: wpr-1032260

ABSTRACT

ObjectiveTo investigate the expression levels of serum high-mobility group box 1 (HMGB1), soluble CD163 (sCD163), and prostaglandin E2 (PGE2) in patients with hepatitis B virus-related chronic-on-acute liver failure (HBV-ACLF), and to evaluate the value of the three indicators used alone or in combination in predicting prognosis. MethodsA total of 76 patients with HBV-ACLF who were hospitalized in Department of Infectious Diseases, The First Affiliated Hospital of Xinxiang Medical University, from July 1, 2022 to September 30, 2023 were enrolled, and according to the 28-day prognosis, they were divided into survival group with 48 patients and death group with 28 patients. General data were collected, Model for End-Stage Liver Disease (MELD) score was calculated, and ELISA was used to measure the serum levels of HMGB1, sCD163, and PGE2. The independent-samples t test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups; the chi-square test was used for comparison of categorical data between two groups. The Spearman rank correlation test was used to analyze the correlation of HMGB1, sCD163, and PGE2 with MELD score; the receiver operating characteristic (ROC) curve was used to analyze the value of HMGB1, sCD163, and PGE2 used alone or in combination in predicting the prognosis of HBV-ACLF patients. ResultsThere were significant differences between the two groups in total bilirubin, white blood cell count, the percentage of neutrophils, procalcitonin, serum amyloid A, interleukin-6, serum sodium, and serum creatinine (all P<0.05). Compared with the survival group, the death group had significantly higher serum levels of HMGB1 (Z=-2.997, P=0.003) and sCD163 (Z=-2.972, P=0.003), a significantly higher MELD score (t=-6.997, P<0.001), and a significantly lower serum level of PGE2 (Z=-4.909, P<0.001). The Spearman rank correlation test showed that HMGB1 and sCD163 were positively correlated with MELD score (r=0.431 and 0.319, both P<0.05), while PGE2 was negatively correlated with MELD score (r=-0.412, P<0.05). The ROC curve analysis showed that HMGB1, sCD163, and PGE2 used alone had an area under the ROC curve (AUC) of 0.717, 0.716, and 0.856, respectively, while the combination of the three indicators had the highest predictive value, with an AUC of 0.930, a sensitivity of 0.778, and a specificity of 0.920. ConclusionSerum HMGB1, sCD163, and PGE2 used alone or in combination have a good reference value in predicting the prognosis of HBV-ACLF patients, and the combination of the three indicators has the highest predictive value, which holds promise for further observation and research.

6.
Chinese Pharmacological Bulletin ; (12): 248-255, 2024.
Article in Chinese | WPRIM | ID: wpr-1013619

ABSTRACT

Aim To explore the impacts of high mobility group box 1 (HMGB1) on the phenotypes, endocy-tosis and extracellular signal-regulated kinase (ERK)/ Jun N-terminal protein kinase (JNK)/P38 mitogen-ac-tivated protein kinase (MAPK) signaling pathway in indoxyl sulfate (IS) -induced dendritic cells (DCs). Methods After treatment with 30, 300 and 600 (xmol · L

7.
International Eye Science ; (12): 18-23, 2024.
Article in Chinese | WPRIM | ID: wpr-1003499

ABSTRACT

AIM: To explore the dynamic expression of high mobility group box 1(HMGB1)in scar tissues after glaucoma drainage valve implantation, and to further reveal the role and possible mechanism of HMGB1 in scarring after glaucoma surgery.METHODS: A total of 60 New Zealand white rabbits were randomly divided into control group(n=20), model group(n=20, silicone implantation under conjunctival sac)and model with drug administration group(n=20, silicone implantation under conjunctival sac combined with 5-fluorouracil injection). The conjunctival tissues were collected at 4 and 8 wk after surgery. HE staining and Masson staining were used to detect the proliferation and distribution of fibroblasts and collagen fibers in conjunctival tissues. Immunohistochemistry was utilized to detect the distribution and changes of HMGB1, transforming growth factor(TGF)-β1, Smad3 and α-smooth muscle actin(SMA)in conjunctival tissues. RT-PCR and Western blot were adopted to detect the mRNA and protein expression of HMGB1, TGF-β1, Smad3 and α-SMA in conjunctival tissues.RESULTS: HE staining and Masson staining showed that the proliferation of inflammatory cells, fibroblasts and collagen fibers in the model group was significantly higher than that in the control group at both 4 and 8 wk. Meanwhile, the proliferation of fibroblasts and collagen fibers in the model with drug administration group was significantly lower than that in the model group. Immunohistochemical staining showed that the expression of HMGB1, TGF-β1, Smad3 and α-SMA protein was observed in the conjunctival tissues of the model group both 4 and 8 wk, with brown and significantly deeper staining of the model group at 8 wk. Meanwhile, the positive staining in the model with drug administration group at both 4 and 8 wk was significantly lower than that in the model group. There was positive correlations between the number of fibroblasts stained with HE and the expression of HMGB1 in the conjunctival tissue of the model group at both 4 and 8 wk(r=0.602, 0.703, all P&#x0026;#x003C;0.05). RT-PCR and Western blot revealed that the mRNA and protein expression levels of HMGB1, TGF-β1, Smad3 and α-SMA in the model group were significantly higher than those in the control group at both 4 and 8 wk(all P&#x0026;#x003C;0.05). Meanwhile, the mRNA and protein expression levels of HMGB1, TGF-β1, Smad3 and α-SMA in the model with drug administration group were significantly lower than those in the model group(all P&#x0026;#x003C;0.05). There was positive correlations between mRNA expressions of HMGB1 and TGF-β1, Smad3 in the model group and the model with drug administration group(all P&#x0026;#x003C;0.05).CONCLUSION: The expression of HMGB1 increased at a time-dependent manner after glaucoma valve implantation. HMGB1 acts an indispensable role in the initiation and progression of scar formation after glaucoma surgery, which may be involved in the regulation of TGF-β/Smad signaling pathway.

8.
China Pharmacy ; (12): 51-56, 2024.
Article in Chinese | WPRIM | ID: wpr-1005213

ABSTRACT

OBJECTIVE To investigate the improvement effects of limonin on intestinal injury and intestinal flora disturbance in rats with ulcerative colitis (UC) and its mechanism. METHODS UC rat models were established, and 70 rats with successful modeling were randomly divided into model group, limonin low-, medium-, and high-dose groups (12.5, 25, 50 mg/kg), and sulfasalazine group (positive control group,500 mg/kg), with 14 rats in each group. Another 14 rats were selected as the control group. After modeling, each group was given the corresponding drug or equal amount of normal saline, once a day, for 2 weeks. Twenty-four hours after the last administration, the general condition of rats was observed and the body weight was measured, and colon tissue was collected for colonic mucosal damage index (CMDI) scoring; the levels of interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) in colon tissue were detected; the pathological changes of colon tissue were observed; the protein expressions of Claudin-1, Occludin, ZO-1, high mobility group protein B1 (HMGB1) and receptor for advanced glycation end products (RAGE) in colon tissue were detected; fecal 16S rRNA sequencing was used to detect the relative abundance of zhangxiaxia5287@163.com intestinal microbiota in rats. RESULTS Compared with the control group, the rats in the model group were in poor mental state, with darker fur, irritable mood, disordered arrangement of colon glands, inflammatory cell infiltration, cell necrosis and edema; CMDI score, the levels of IL-1β, IL-6 and TNF-α, protein expressions of HMGB1 and RAGE in colon tissue, the relative abundance of Proteobacteria and Bacteroidetes were significantly increased (P<0.05); body weight, the protein expressions of Claudin-1, Occludin and ZO-1 in colon tissue, the relative abundance of Firmicutes in the intestine were significantly decreased (P<0.05). Compared with the model group, general situation and pathological damage of colonic tissue in limonin groups were improved, the levels of the above indicators were significantly reversed (P<0.05), and in a dose-dependent manner (P<0.05); there was no significant difference in various indexes between sulfasalazine group and limonin high-dose group (P>0.05). CONCLUSIONS Limonin can improve intestinal injury and intestinal flora disturbance in UC model rats, the mechanism of which may be associated with the down-regulation of HMGB1/RAGE signaling pathway.

9.
China Pharmacy ; (12): 57-62, 2024.
Article in Chinese | WPRIM | ID: wpr-1005214

ABSTRACT

OBJECTIVE To study the improvement effects of poria acid on insulin resistance in rats with polycystic ovary syndrome (PCOS) and its mechanism. METHODS One hundred and twenty-six female rats were randomly separated into blank group, PCOS group, poria acid low-dose group (8.33 mg/kg), pachymic acid high-dose group (33.32 mg/kg), ethinylestradiol cyproterone group (positive control group, 0.34 mg/kg), recombinant rat high mobility group protein B1 protein (rHMGB1) group (8 μg/kg), and poria acid high dose+rHMGB1 group (33.32 mg/kg poria acid+8 μg/kg rHMGB1), with 18 rats in each group. Except for the blank group, the rats in all other groups were given Letrozole suspension intragastrically to construct the PCOS model. After successful modeling, administration was performed once a day for 4 weeks. After medication, the fasting blood glucose and fasting insulin levels, and insulin resistance index (HOMA-IR) were measured in rats; the levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone (T) in rat serum, and the levels of interleukin-1β (IL-1β) and tumor necrosis factor- α (TNF- α) in ovarian tissue were detected; ovarian coefficients of rats were calculated; the pathological changes of ovarian tissue were observed; the expressions of HMGB1, receptor for advanced glycosylation elaine_ tanghong@sina.com end product (RAGE) and phosphorylated nuclear factor κB p65 (p-NF-κB p65) proteins were determined in ovarian tissue of rats. RESULTS Compared with the blank group, the pathological injury of ovarian tissue of rats in the PCOS group was serious, the levels of fasting blood glucose and fasting insulin, HOMA-IR and ovarian coefficient were increased, the levels of serum LH and T were increased, while the levels of FSH were decreased; the levels of IL-1β and TNF-α, the expressions of HMGB1, RAGE and p-NF-κB p65 protein in ovarian tissue were increased, with statistical significance (P<0.05). Compared with the PCOS group, pathological damage of ovarian tissue was reduced in poria acid low-dose and high-dose groups and ethinylestradiol cyproterone group, and fasting blood glucose, fasting insulin levels, HOMA-IR and ovarian coefficient were decreased; serum LH and T levels were decreased, while FSH levels were increased; the levels of IL-1β and TNF-α and the expressions of HMGB1, RAGE and p-NF-κB p65 protein in ovarian tissue were decreased, with statistical significance (P<0.05). The trend of corresponding indexes in rHMGB1 group was opposite to the above (P<0.05). Compared with poria acid high-dose group, the changes of the above indexes were reversed significantly in poria acid high-dose+rHMGB1 group (P<0.05). CONCLUSIONS Poria acid may improve insulin resistance and inhibit inflammatory reaction in PCOS rats by inhibiting HMGB1/ RAGE pathway.

10.
Chinese Journal of Immunology ; (12): 491-496, 2024.
Article in Chinese | WPRIM | ID: wpr-1024751

ABSTRACT

Objective:To investigate the role of HMGB1-TLR4-NF-κB signaling pathway in cerebral ischemia-reperfusion in-jury and the effect of adenosine preconditioning on the signaling pathway.Methods:Total 80 adult male Sprague-Dawley rats weighing 220~270 g were selected from the Animal Center of Xinxiang Medical University.The rats were randomly divided into F group(sham operation group),I/R group(ischemia reperfusion group)and AP group(adenosine preconditioning group).The MCAO model of rats was established by wire embolization.Quantitative analysis of neural function in successfully modeled rats using animal behavior scor-ing method,the morphological changes of brain cells were observed by HE staining,TTC staining was used to observe cerebral infarc-tion and cerebral infarction volume was calculated;Immunohistochemical staining was used to detect HMGB1,TLR4 and NF-κB pro-tein expression levels in brain tissues of each group.The data were statistically analyzed by one-way ANOVA in SPSS26.0 software.Results:After ischemia reperfusion,the neurological function of I/R group and AP group showed different degrees of impairment,and the neurological function scores of the two groups were significantly higher than that of F group,the difference was statistically signifi-cant(P<0.05),and the neurological function of the AP group was significantly less than that of I/R group,the difference was also sta-tistically significant(P<0.05).TTC staining showed that AP group,I/R group rat cerebral infarction volume was significantly more than F group[(93.670±4.509)mm3,(123.670±7.234)mm3 vs(0.000±0.000)mm3],and AP group rats infarction volume was signifi-cantly reduced than that in I/R group,the difference had statistical significance(P<0.05).Immunohistochemistry showed that HMGB1,TLR4,NF-κB protein in F group with a small amount of expressions in rats,while significantly expressed in AP group and I/R group relatively,and the AP group of each subgroup rat HMGB1,TLR4,NF-κB protein expressions significantly lower than the amount of I/R group,the difference had statistical significance(P<0.05).Conclusion:Adenosine preconditioning can reduce the expressions of HMGB1,TLR4 and NF-κB protein,and then protect the rats with cerebral ischemia-reperfusion injury.

11.
Clinics ; Clinics;79: 100391, 2024. tab, graf
Article in English | LILACS-Express | LILACS | ID: biblio-1564337

ABSTRACT

Abstract Background The newly discovered CircUBE2D2 has been shown to abnormally upregulate and promote cancer progression in a variety of cancers. The present study explored circUBE2D2 (hsa_circ_0005728) in Ovarian Cancer (OC) progression. Methods CircUBE2D2, miR-885-5p, and HMGB1 were examined by RT-qPCR or WB. SKOV-3 cell functions (including cell viability, apoptosis, migration, and invasion) were validated using the CCK-8, flow cytometry, scratch assay, and transwell assay, respectively. The direct relationship between miR-885-5p and circUBE2D2 or HMGB1 was confirmed by a dual-luciferase reporter and RNA pull-down analysis. circUBE2D2′s role in vivo tumor xenograft experiment was further probed. Results OC tissue and cell lines had higher circUBE2D2 and HMGB1 and lower miR-885-5p. Mechanically, CircUBE2D2 shared a binding relation with miR-885-5p, while miR-885-5p can directly target HMGB1. Eliminating circUBE2D2 or miR-885-5p induction inhibited OC cell activities. However, these functions were relieved by down-regulating miR-885-5p or HMGB1 induction. Furthermore, circUBE2D2 knockout reduced tumor growth. Conclusion CircUBE2D2 regulates the expression of HMGB1 by acting as a sponge of ceRNA as miR-885-5p, thereby promoting the control of OC cell proliferation and migration and inhibiting cell apoptosis. Targeting CircUBE2D2 could serve as a new potential treatment strategy for OC.

12.
J. pediatr. (Rio J.) ; J. pediatr. (Rio J.);99(2): 187-192, Mar.-Apr. 2023. tab
Article in English | LILACS-Express | LILACS | ID: biblio-1430713

ABSTRACT

Abstract Objective: This study aimed to evaluate the role of miRNA-492 in the progression of mycoplasma pneumoniae (MP) infection in pediatric patients. Methods: Forty-six children admitted to the present study's hospital and diagnosed with mycoplasma pneumonia were recruited as the study group from March 2018 to August 2019, and 40 healthy children were selected as the control group. Results: The expression levels of miRNA-492, TNF-α, IL-6 and IL-18 in the study group were significantly higher than those in the control group (p < 0.05). There was no significant correlation between miRNA-492 and most of the immune-correlated indicators in the study group, except for IL-6, IL-18 and HMGB1. Meanwhile, overexpression of miRNA-492 increased IL-6 secretion in PMA-activated monocytes (p < 0.01). Conclusion: The present study's results suggested that miRNA-492 might play a role in the pathogenesis of mycoplasma pneumoniae pneumonia in children by regulating the secretion of immune-inflammatory factors such as IL-6 and IL-18 in the mononuclear macrophages.

13.
Organ Transplantation ; (6): 397-2023.
Article in Chinese | WPRIM | ID: wpr-972930

ABSTRACT

Objective To unravel the possible mechanism of the role of recombinant human high mobility group box 1 (rhHMGB1) protein in regulating the angiogenesis of endothelial cells. Methods Endothelial cells were divided into the control group, bone marrow mesenchymal stem cells (MSC) supernatant group and rhHMGB1 group. The proliferation and survival of endothelial cells were detected by cell counting kit(CCK)-8 assay. The relative expression levels of vascular endothelial growth factor (VEGF), Yes-associated protein (YAP), CD31 and hypoxia inducible factor (HIF)-1α proteins were determined by Western blot. The relative expression levels of VEGF, YAP, CD31 and HIF-1α messenger RNA (mRNA) were detected by real-time fluorescent quantitative polymerase chain reaction (RT-qPCR). The migration ability of endothelial cells was assessed by Transwell chamber test. The localization of YAP was detected by immunofluorescence staining. Results Compared with the control group, the migration rate of endothelial cells was increased in the rhHMGB1 group (P < 0.05), and the cell migration rate was enhanced over time. Compared with the control group, the relative expression levels of VEGF and p-YAP proteins were up-regulated in the MSC supernatant group, and the differences were statistically significant (both P < 0.05). Compared with the control group, the relative expression levels of VEGF and HIF-1α proteins, VEGF and CD31 mRNA and YAP and p-YAP proteins were up-regulated, and YAP/p-YAP ratio was increased in the rhHMGB1 group, and the differences were statistically significant (all P < 0.05). Compared with the MSC supernatant group, the relative expression levels of CD31 mRNA and YAP protein were up-regulated, and the YAP/p-YAP ratio was increased in the rhHMGB1 group, and the differences were statistically significant (all P < 0.05). Conclusions Exogenous high-concentration rhHMGB1 may promote the migration ability of endothelial cells and up-regulate the expression levels of angiogenesis-related proteins by regulating the recruitment of YAP to the nucleus.

14.
Article in Chinese | WPRIM | ID: wpr-961682

ABSTRACT

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.

15.
Article in Chinese | WPRIM | ID: wpr-989904

ABSTRACT

Objective:To investigate the effect of resveratrol on apoptosis of ovarian cancer cells and its molecular mechanism, and to find a potential new target for the treatment of ovarian cancer.Methods:Ovarian cancer SKOV-3 cells were divided into control group and resveratrol group.The survival rate of SKOV-3 cells treated with resveratrol was measured by MTT assay. 24 h after resveratrol intervention in SKOV-3 cells, Western blot was used to detect the expression of Bcl-2, Bax, Caspase-3, HMGB1, TLR4 and NF-?B. Ovarian cancer SKOV-3 cells were transfected with si-NC, si-HMGB1, Rb1+pcDNA3.1 or Rb1+pcDNA3.1-HMGB1, and the sensitivity of cells to resveratrol was detected by MTT assay. The transfected cells were treated with resveratrol and apoptosis was detected by flow cytometry.Results:Resveratrol could inhibit the growth of ovarian cancer SKOV-3 cells, and the higher the concentration of resveratrol, the more significant the inhibitory effect. The expression level of HMGB1 in control cells and resveratrol group was 1.24±0.15 and 0.86±0.11, respectively. 25μM resveratrol inhibited HMGB1 protein level ( P<0.01) . The sensitivity to resveratrol was increased after HMGB1 was downregulated, and the apoptosis of SKOV-3 cells was promoted. HMGB1 overexpression increased the resistance to resveratrol and inhibited the apoptosis of SKOV-3 cells. TLR4 expression quantity control and resveratrol cells were 0.98±0.12 and 0.63±0.08, amount of NF-?B expression were 1.21±0.14 and 0.45±0.07, 25 μM resveratrol could cut TLR4 and NF-?B protein levels. Conclusions:Resveratrol can promote apoptosis of ovarian cancer SKOV-3 cells. This mechanism may be related to the down-regulation of HMGB1/TLR4/NF-?B, which provides a basis for resveratrol treatment of ovarian cancer.

16.
Acta Pharmaceutica Sinica B ; (6): 2701-2714, 2023.
Article in English | WPRIM | ID: wpr-982859

ABSTRACT

Parkinson's disease (PD) is the most common neurodegenerative movement disease. It is featured by abnormal alpha-synuclein (α-syn) aggregation in dopaminergic neurons in the substantia nigra. Macroautophagy (autophagy) is an evolutionarily conserved cellular process for degradation of cellular contents, including protein aggregates, to maintain cellular homeostasis. Corynoxine B (Cory B), a natural alkaloid isolated from Uncaria rhynchophylla (Miq.) Jacks., has been reported to promote the clearance of α-syn in cell models by inducing autophagy. However, the molecular mechanism by which Cory B induces autophagy is not known, and the α-syn-lowering activity of Cory B has not been verified in animal models. Here, we report that Cory B enhanced the activity of Beclin 1/VPS34 complex and increased autophagy by promoting the interaction between Beclin 1 and HMGB1/2. Depletion of HMGB1/2 impaired Cory B-induced autophagy. We showed for the first time that, similar to HMGB1, HMGB2 is also required for autophagy and depletion of HMGB2 decreased autophagy levels and phosphatidylinositol 3-kinase III activity both under basal and stimulated conditions. By applying cellular thermal shift assay, surface plasmon resonance, and molecular docking, we confirmed that Cory B directly binds to HMGB1/2 near the C106 site. Furthermore, in vivo studies with a wild-type α-syn transgenic drosophila model of PD and an A53T α-syn transgenic mouse model of PD, Cory B enhanced autophagy, promoted α-syn clearance and improved behavioral abnormalities. Taken together, the results of this study reveal that Cory B enhances phosphatidylinositol 3-kinase III activity/autophagy by binding to HMGB1/2 and that this enhancement is neuroprotective against PD.

17.
Article in Chinese | WPRIM | ID: wpr-984577

ABSTRACT

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.

18.
Article in Chinese | WPRIM | ID: wpr-992205

ABSTRACT

OBJECTIVE Trigeminal pain is mostly uni-lateral orofacial,but pain sensitization often spreads to contralateral orofacial or distal body regions.Widespread trigeminal pain has more severe intensity,longer dura-tion,and wider distribution,accompanied by more serious comorbid emotional syndrome.Unfortunately,the first-line analgesics for neuropathic pain has limited effect on widespread pain along with unavoidable side effects.In-depth understanding of the pathogenesis of wide-spread trigeminal pain is urgently needed.METHODS Trigeminal pain was induced by partial transection of the infraorbital nerve(p-IONX)and evaluated by measur-ing nociceptive thresholds to mechanical or heat stimula-tion.Neuronal activity was evaluated by single-unit and patch clamp recordings.HMGB1 expression was mea-sured by immunohistochemistry.Antagonism of HMGB1 was achieved by injecting anti-HMGB1 monoclonal anti-body(mAb)intracerebrally or intraperitoneally.RESULTS P-IONX model induced not only orofacial algesia but also somatic algesia in hind paw.Spontaneous firing frequency of glutamatergic neurons in the ventral posteromedial tha-lamic nucleus(VPMGlu)as well as the amplitude and fre-quency of sEPSCs significantly increased after p-IONX.Moreover,calcium signal recording showed that VPMGlu became to be activated by the noxious mechanical stimu-lation given on the hind paw,suggesting that VPMGlu recruited somatic afferents after p-IONX.We further explored the upstream brain regions of VPMGlu by virus retrograde tracing.We found the afferents from the grac-ile nucleus/cuneate nucleus(Gr/Cu),which are involved in the conduction of somatic sensation,markedly increased.And chemogenetical inhibiting Gr/Cu-VPM circuit alleviated the widespread neuropathic pain.In addition,the expression of HMGB1 in the VPM was sig-nificantly increased after p-IONX.Local administration of anti-HMGB1 mAb in the VPM relieved widespread neuro-pathic pain in mice receiving p-IONX.CONCLUSION These results demonstrate that the remodeling of affer-ent neurons in VPM underlie the spreading of wide-spread trigeminal neuropathic pain.Highly expressed HMGB1 in VPM plays an important role in these patho-logical changes after nerve injury and systemic adminis-tration of anti-HMGB1 mAb concurrently relieves wide-spread pain.

19.
Article in Chinese | WPRIM | ID: wpr-992771

ABSTRACT

Objective:To investigate the role and underlying mechanisms of inhibiting high mobility group box-1 (HMGB1) in the expression of matrix metalloproteinase-9 (MMP-9) in spinal cord astrocytes (AS) in rats after spinal cord injury (SCI).Methods:After an SCI model was established in Sprague-Dawley (SD) rats using a modified Allen's Weight-Dropping method and ethyl pyruvate (EP) or glycyrrhizin (GL) was used to inhibit the effect of HMGB1, the rats were divided into a sham group, an SCI group, an SCI+EP (50 mg/kg) group, and an SCI+GL (100 mg/kg) group. The expression levels of glial fibrillary acid protein (GFAP) and MMP-9 in spinal cord AS were observed. After the spinal cord AS in SD rats was cultured and incubated by the oxygen-glucose deprivation/reoxygenation (OGD/R) procedure, the expression of MMP-9 protein was detected at 6 h/R 6 h, 12 h, 24 h, and 48 h after OGD. The time point with the highest expression was chosen in the subsequent experiments as an OGD/R group. HMGB1 was inhibited by HMGB1 shRNA or EP to observe the effect of HMGB1 on the expression of MMP-9 protein in AS treated with OGD/R. Then, toll-like receptor 4 (TLR4) inhibitor, TIR-domain-containing adaptor inducing interferon- β (TRIF) inhibitor, and nuclear factor-kappa B (NF- κB) inhibitor were used to investigate the effects of TLR4/TRIF/NF- κB signaling pathway during the regulation of HMGB1 on MMP-9 in vitro. Results:Western blot showed that the expression of MMP-9 protein in the spinal cord was significantly increased in rats at 1 d after SCI, and the expression of MMP-9 protein in the SCI+EP group and the SCI+GL group was significantly lower than that in the SCI group ( P<0.001). Immunofluorescence showed that GFAP and MMP-9 proteins were co-localized in the spinal cord after SCI, and the expression of GFAP and MMP-9 proteins in the SCI+EP and SCI+GL groups was significantly lower than that in the SCI group ( P<0.05). Since the expression of MMP-9 protein in the spinal cord AS cultured in vitro was significantly higher in the OGD 6h/R 12h group than that in the normal group and the OGD 6h/R 6h, 24, and 48 h groups, the OGD 6h/R 12h was taken as the OGD/R group. The MMP-9 protein expression in AS in the OGD/R+HMGB1 shRNA group and the OGD/R+EP group was significantly lower than that in the OGD/R group ( P<0.001). In the cultured AS, moreover, inhibiting TLR4, TRIF, and NF- κB reduced MMP-9 protein expression after OGD 6 h/R 12 h when compared with that in the OGD/R group ( P<0.001). Conclusions:HMGB1 inhibition may result in a reduction in MMP-9 expression both in the spinal cord AS in SCI rats and in AS after OGD/R treatment in vitro. HMGB1 may regulate MMP-9 protein expression in AS after OGD/R treatment via the TLR4/TRIF/NF- κB signal pathway.

20.
Article in Chinese | WPRIM | ID: wpr-993149

ABSTRACT

Objective:To evaluate the effects of high mobility group protein box 1 (HMGB1) on clinical prognosis of esophagus squamous cell carcinoma (ESCC) patients treated with chemoradiotherapy and the radiosensitivity of xenograft in nude mice.Methods:A total of 90 endoscopic biopsy specimens were obtained from ESCC patients treated with chemoradiotherapy. The expression level of HMGB1 was determined by immunohistochemical staining. High expression level was defined when staining was observed on ≥50% of the tumor cells. All patients were divided into the high expression group ( n=48) and low expression group ( n=42), and their survival information was retrospectively analyzed. Cell transfection was performed with the plasmid carrying human HMGB1-shRNA to knockdown HMGB1 expression in ECA109 cells and xenograft mouse models were established. The tumor volume and mass were calculated after irradiation with a dose of 15 Gy. The cell apoptosis in xenograft tissues were detected. Survival analysis was performed using Kaplan-Meier method. Univariate prognostic analysis was conducted by log-rank test. Intergroup comparison was performed by analysis of variance (ANOVA). Results:The expression level of HMGB1 was significantly associated with gross tumor volume, longest diameter of tumor, T staging and distant metastasis ( χ2=9.663, 5.625, 4.068, 7.146, all P<0.05). In the low expression group, the overall survival (OS) ( χ2=4.826, P=0.028), progression-free survival (PFS) ( χ2=4.390, P=0.036) were longer compared with that in the high expression group. Further analysis of HMGB1-high expression patients showed that the radiation dose and the combination of chemoradiotherapy did not significantly affect the OS or PFS of ESCC patients. We observed that knockdown of HMGB1 slowed the growth rate of xenograft, decreased the tumor volume and increased the apoptosis rate after irradiation. Conclusions:ESCC patients with high expression level of HMGB1 obtain poor prognosis after chemoradiotherapy, which can be enhanced by increasing the sensitivity to radiotherapy and chemotherapy. HMGB1 knockdown can effectively increase the radiosensitivity of xenograft in ESCC nude mice.

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