Tanshinone increases Hemopexin expression in lung cells and macrophages to protect against cigarette smoke-induced COPD and enhance antiviral responses.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease, while respiratory infections can elicit exacerbations in COPD patients to mediate increased mortality. Administration of Tanshinones (TS) derivatives has been demonstrated to protect against cigarette smoking (CS) and lipopolysaccharide (LPS)-induced COPD progression. However, the underlying molecular mechanisms and the roles of TS in mitigating the severity of viral-mediated exacerbations of COPD have not been elucidated. Here, we found that TS treatments significantly attenuated lung function decline, inflammatory responses and oxidative stress in CS and LPS-induced COPD mice. Subsequent RNA-seq analysis revealed significantly upregulated Hemopexin expression and enriched interferons (IFNs) signaling pathways in lung tissues of COPD mice upon TS treatments. Moreover, TS administration demonstrated Hemopexin-dependent beneficial roles in BEAS-2B lung cells and RAW264.7 macrophages, which was associated with the suppression of oxidative stress and ERK, NF-κB, and NLRP3 inflammasome signaling pathways-mediated inflammation. Furthermore, TS promoted IFN signaling and rescued impaired antiviral responses in CS and LPS-exposed lung cells that were infected by influenza virus. Notably, hemopexin over-expression in lung cells and macrophages recapitulated the pharmacological activities of TS. Taken together, these results indicate that TS administration is a promising and potential therapeutic strategy for treating COPD and preventing COPD exacerbations.

Prognostic effect of pulmonary hypertension in patients with chronic kidney disease: Univariate and multivariate analyses of factors associated with survival.

Background: Prognostic effect of pulmonary hypertension (PH) in patients with chronic kidney disease (CKD) is not fully clear yet, this study was designed to elucidate baseline characteristics of CKD patients with different severities of PH, the association between kidney indicators and PH severity, and survival factors in CKD patients with PH. Methods: We extracted clinical data from electronic medical records of all patients diagnosed with PH in CKD from Jan 2016 to Dec 2020, and those with comorbid conditions causing PH were excluded. CKD stages were defined by estimated glomerular filtration rate thresholds. PH was defined as a systolic pulmonary artery pressure (sPAP) >35 mmHg estimated using echocardiograms. Demographics, clinical data, and test results were analyzed, and all-cause mortality data were obtained. Results: A total of 137 patients were included in the study. The mean age of the participants was 60 (42.5, 67) years, the mean sPAP was 58 (51, 69.5) mmHg, and 40.9% of the patients were women. Moderate PH group had more patients undergoing dialysis and higher frequency of coronary heart disease. Moderate-severe PH group had higher parathyroid hormone levels and lower low-density lipoprotein levels. Severe PH group had better kidney function parameters and lower serum phosphorus levels. PH severity had no direct relationship with CKD stages. In the univariate analysis, age and PH severity influenced survival. Multivariate analysis also showed independent prognostic effects for age and sPAP. Kaplan-Meyer curve intuitively displayed the survival differences among CKD patients with different PH severity. Predictor values of nomogram identified from survival analyses enabled calculation of death probabilities for CKD with PH patients. Nomogram was validated by ROC analysis. Conclusions: PH begins with early-stage CKD, and PH severity is not related to CKD progression. A higher pulmonary artery pressure and an older age are associated with an increased risk of death.

Decreased low-density lipoprotein and the presence of pulmonary arterial hypertension among newly diagnosed drug-naïve patients with systemic lupus erythematosus: D-dimer as a mediator.

Pulmonary arterial hypertension (PAH) is commonly associated with systemic lupus erythematosus (SLE). The present study investigated the relationship between coagulation and changes in lipid parameters in newly-diagnosed patients with SLE in the presence of PAH and whether the coagulation parameters were mediators between lipids and PAH presence. A total of 301 subjects scheduled for new-onset drug-naïve SLE were consecutively enrolled. Baseline data for patients without PAH and with PAH were gathered and compared. Coagulation and lipid parameters were compared across patients without lipid regulating and anticoagulation medications. Multivariable logistic regression model was applied to examine potential predictors of PAH in SLE. The relationships between them were examined using Spearman's correlation analysis. The relationship between coagulation index and lipids with SLE-PAH was evaluated using mediation analysis. Female patients accounted for 88.0% of the 301 subjects, and the average age was 32 years (range, 25-45 years). A total of 40 patients (13.3%) had PAH, and the average pulmonary artery systolic pressure (sPAP) was 55.825±26.67 mmHg. Patients with PAH were older and had higher levels of fibrin/fibrinogen degradation products (FDP), D-dimer, C-reactive protein, lower levels of complement 3, complement 4 and 25-hydroxy vitamin D3 compared with the non-PAH group. Multivariable logistic regression analysis showed that age and D-dimer were independent predictor factors for PAH. Among patients without lipid regulating and anticoagulation medications, patients in the PAH group had higher levels of D-dimer and FDP, and lower low-density lipoprotein (LDL) levels compared with patients without PAH. There was also a positive relationship between sPAP and D-dimer and FDP, and a negative relationship between sPAP and total cholesterol and LDL. Mediation analysis indicated that 25.61% of the effect of low LDL on PAH presence in systemic lupus erythematosus was mediated by D-dimer. Overall, the effect of low LDL on SLE-PAH appeared to be mediated by D-dimer, which mediated 25.61% of this effect.

Tanshinone IIA protects against chronic obstructive pulmonary disease via exosome­shuttled miR­486­5p.

Chronic obstructive pulmonary disease (COPD) is one of the major causes of death worldwide today, and its related morbidity has been predicted to show an increase in subsequent years. Recent studies have shown that Danshen, a Chinese herbal medicine, is a potential drug in the treatment of inflammation­related lung diseases. COPD was induced in this study using cigarette smoke (CS) exposure plus intranasal inhalation of lipopolysaccharide to ascertain whether the main pharmacological component from Danshen, tanshinone IIA (TIIA), and its water soluble form, sodium tanshinone IIA sulfonate (STS), protect against the development of COPD. The weight, lung function, hematoxylin and eosin staining, and Masson Trichrome determinations revealed that TIIA inhalation attenuated lung dysfunction in COPD mice induced by cigarette smoke and lipopolysaccharide exposure. In addition, exosomes derived from TIIA­treated COPD mice exerted similar protective effects against COPD, suggesting that TIIA may protect against COPD through exosome­shuttled signals. miR­486­5p was found to be a key molecule in mediating the protective effects of exosomes derived from TIIA­treated COPD mice using miRNA sequencing and cellular screening. Treatment of COPD mice with an agomiR of miR­486­5p protected lung function in COPD mice, and treatment of COPD mice with an antagomir of miR­486­5p abolished the protective effects of TIIA. Moreover, luciferase activity reporter assay, RT­qPCR, and western blot analyses showed that miR­486­5p exerted protective effects against COPD via targeting phosphoinositide­3­kinase regulatory subunit 1 (PIK3R1). These results suggest that STS protects against COPD through upregulation of miR­486­5p, and that TIIA or miR­486­5p is a potential drug for the treatment of COPD.

Interleukin-17 aggravates right ventricular remodeling via activating STAT3 under both normoxia and hypoxia.

OBJECTIVE: Proinflammatory cytokine interleukin 17 (IL-17) is involved in ventricular remodeling, mainly of the left ventricle. This study was designed to explore the role of IL-17 played in the pathogenesis of right ventricular hypertrophy (RVH), aiming to provide a novel treatment target or diagnostic biomarker options for improving the care of RVH patients. METHODS: C57BL/6 mice were maintained in 10% O2 chamber or room air for four weeks. Right ventricular hypertrophy index (RVHI), RV/body weight ratio, pulmonary arteriolar remodeling determined by percent media thickness (%MT), and the cardiomyocyte diameter of RV were evaluated. Mice were treated with exogenous recombinant mouse IL-17 (rmIL-17, 1 µg per dose twice a week) for four weeks. H9c2 cardiomyocytes were cultured and treated with IL-17 (10 ng/mL) and STAT3 inhibitor (10 ng/mL) either under normoxia (21% O2, 5% CO2, 74% N2) or under hypoxia (3% O2, 5% CO2, 92% N2). Cardiomyocyte viability was assessed by Cell counting kit 8 (CCK-8) assay. The mRNA level was detected by RT-PCR, where as the protein expression was measured by Western blot, immunohistochemistry, and immunofluorescent analyses. RESULTS: In vivo experiments showed that IL-17 did not affect the pulmonary artery under normoxia, after treatment with rmIL-17, %MT was not changed, while RVHI and the RV/body weight ratio were increased, indicating that IL-17 directly induced right ventricular hypertrophy. In a time-course study, the mice were exposed to hypoxia for 0, 1, 2, 3, 4 weeks, respectively. We found that the expression of IL-17 was gradually upregulated in RV tissue in a time-dependent manner after one week of hypoxia exposure, especially at the third and fourth week. Cardiomyocyte hypertrophy and apoptosis were observed after the exposure of the mice to hypoxia for four weeks, rmIL-17 further aggravated the hypoxia-induced cardiomyocyte hypertrophy and apoptosis. The expression of p-STAT3 in the IL-17-deficient mice was lower than in the wild-type mice. In vitro, IL-17 inhibited cardiomyocyte viability and induced cardiomyocyte apoptosis via STAT3 under both normoxic and hypoxic conditions. CONCLUSIONS: These findings support a role for IL-17 as a mediator in the pathogenesis RVH, which might be considered as a potential novel anti-inflammation therapeutic strategy or diagnostic biomarker for RVH.

Severity of chronic obstructive pulmonary disease with 'exacerbator with emphysema phenotype' is associated with potential biomarkers.

OBJECTIVE: The present study was designed to investigate the biomarkers levels of fractalkine (FKN), neutrophil elastase (NE) and matrix metalloproteinase-12 (MMP-12) in chronic obstructive pulmonary disease (COPD) with 'exacerbator with emphysema phenotype' and to evaluate the associations between the biomarkers levels and the severity of disease by spirometric measurements. METHODS: A total of 84 COPD patients and 49 healthy controls were enrolled in our study. ELISA were utilised to detect the FKN, MMP-12 and NE in serum from all subjects. RESULTS: FKN (p<0.001), NE (p=0.039) and MMP-12 (p<0.001) in serum of COPD patients showed higher levels than that of healthy control subjects. Serum FKN (p<0.001), MMP-12 (p<0.001) and NE (p=0.043) levels were significantly higher in severe and very severe COPD patients than that in mild and moderate COPD patients. Circulating FKN, MMP-12 and NE expression levels were significantly elevated (p<0.001) in COPD smokers compared with COPD non-smokers. The smoke pack years were negatively correlated with FEV1%pred (r=-0.5036), FEV1/FVC ratio (r=-0.2847) (FEV, forced expiratory volume; FVC, forced vital capacity). Similarly, we observed a strong positive correlation between the smoke pack years and serum levels of FKN (r=0.4971), MMP-12 (r=0.4315) and NE (r=0.2754). FEV1%pred was strongly negatively correlated with cytokine levels of FKN (r=-0.4367), MMP-12 (r=-0.3295) and NE (r=-0.2684). Likewise, FEV1/FVC ratio was negatively correlated with mediators of inflammation levels of FKN (r=-0.3867), MMP-12 (r=-0.2941) and NE (r=-0.2153). CONCLUSION: Serum FKN, MMP-12 and NE concentrations in COPD patients are directly associated with the severity of COPD with 'exacerbator with emphysema phenotype'. This finding suggests that FKN, MMP-12 and NE might play an important role in the pathophysiology of COPD.

Increased levels of inflammatory biomarker CX3CL1 in patients with chronic obstructive pulmonary disease.

OBJECTIVE: To investigate the concentration of CX3CL1 in serum of patients with chronic obstructive pulmonary disease (COPD), and to evaluate the associations between the CX3CL1 level and systemic inflammation, small airway obstruction, and COPD assessment test (CAT) scores in COPD patients. METHODS: Enzyme-linked immunosorbent assay were utilized to detect the CX3CL1 protein in serum separately from 64 patients with COPD and 53 healthy controls. RESULTS: Compared with healthy non-smokers, healthy smokers and COPD non-smokers, serum CX3CL1 protein levels were significantly elevated in COPD smokers (258.33 ±â€¯56.27 pg/mL versus 177.32 ±â€¯43.21 pg/mL, 185.64 ±â€¯47.03 pg/mL, and 226.55 ±â€¯51.79 pg/mL, P < 0.05). Correlation analysis indicated that serum CX3CL1 in COPD smokers was negatively correlated with FEV1/FVC (justified r = -0.319, P < 0.001), FEV1/Pre (justified r = -0.476, P < 0.001), FEV3/FVC (justified r = -0.354, P < 0.001), MMEF25-75/Pre (justified r = -0.428, P < 0.001), but positively correlated with CRP (justified r = 0.331, P < 0.001) and MMP-12 (justified r = 0.352, P < 0.001). However, our results showed no significant correlation between serum CX3CL1 of COPD smokers and the diffusing capacity of the lung for carbon monoxide (DLCO) (justified r = 0.0397, P = 0.6025), but a positive correlation with COPD assessment test (CAT) scores (justified r = 0.367, P < 0.001). Finally, through multivariate linear analysis, statistical results demonstrated age (ß = -0.2694, P = 0.005), FEV1/Pred (ß = -0.2653, P = 0.003), CRP (ß = 0.1427, P = 0.0478) and MMP-12 (ß = 0.430, P < 0.001) are independent parameters associated with CX3CL1. CONCLUSION: The results demonstrated that elevated circulating CX3CL1 level is associated with the systemic inflammation, small airway obstruction, and CAT scores in COPD patients, suggesting that CX3CL1 may play crucial roles in the pathogenesis of COPD. Blocking CX3CL1 might prevent the progression of chronic obstructive pulmonary disease.

Comparative Study of Cytokine Levels in Different Respiratory Samples in Mild-to-Moderate AECOPD Patients.

BACKGROUND: Matrix metalloproteinase-12 (MMP-12) and Tissue inhibitor of metalloproteinase-4 (TIMP-4) play important roles in the pathophysiology of chronic obstructive pulmonary disease (COPD). Subjects of many previous studies were patients with severe and very severe COPD. However, there are comparatively few studies on patients with mild-to-moderate COPD. Our aim was to measure MMP-12 and TIMP-4 levels and to compare its levels in various materials in patients with mild-to-moderate acute exacerbation of chronic obstructive pulmonary disease (AECOPD). We also compared which of the two materials of these biomarkers was better correlated with disease severity and DODE index. METHODS: A total of 39 patients with AECOPD and 25 control subjects were enrolled in our study. MMP-12 and TIMP-4 in different respiratory samples were detected by ELISA. RESULTS: Expression levels of MMP-12 in bronchoalveolar lavage fluid (BALF) and exhaled breath condensate (EBC) and TIMP-4 in BALF were significantly higher in AECOPD patients than that in healthy subjects (P < 0.001). However, there was no significant difference in TIMP-4 level in EBC of AECOPD patients compared to healthy subjects (P = 0.0527). The levels of MMP-12 in BALF and EBC and TIMP-4 in BAFL of AECOPD patients were significantly correlated with FEV1% predicted (P < 0.001). However, in AECOPD patients, there was no significant correlation between TIMP-4 levels in EBC and BODE index (r = 0.4175, P = 0.0559). CONCLUSION: During mild-to-moderate AECOPD, the levels of MMP-12 and TIMP-4 in BALF were better correlated with FEV1% predicted and BODE index than that in EBC, indicating that they may be new target interventions for pharmacology to prevent and/or treat AECOPD.

Expressions of MMP-12, TIMP-4, and Neutrophil Elastase in PBMCs and Exhaled Breath Condensate in Patients with COPD and Their Relationships with Disease Severity and Acute Exacerbations.

OBJECTIVE: The purpose of this study was to compare matrix metalloproteinase-12 (MMP-12), neutrophil elastase (NE), and tissue inhibitor of metalloproteinase-4 (TIMP-4) in peripheral blood of patients with chronic obstructive pulmonary disease (COPD) and controls. At the same time, MMP-12, NE, and TIMP-4 in exhaled breath condensate (EBC) were also evaluated. METHODS: Peripheral blood and EBC samples from COPD patients and healthy controls were collected. In serum and EBC, MMP-12, NE, and TIMP-4 proteins were detected by enzyme-linked immunoassays. The mRNA expression levels of MMP-12, NE, and TIMP-4 in peripheral blood mononuclear cells (PBMCs) were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: The concentration of TIMP-4 protein in EBC was lower in patients with COPD (P < 0.001). MMP-12 (P = 0.046), NE (P = 0.027), and TIMP-4 (P = 0.005) proteins in serum of patients with COPD showed higher levels of concentration. The mRNA of MMP-12 (P = 0.0067), NE (P = 0.0058), and TIMP-4 (P = 0.0006) in PBMCs of COPD patients showed higher expression levels. Compared with stable patients, mRNA expression level of NE (P = 0.033) in PBMCs of patients with acute exacerbation of COPD was increased. There were differences in the ratio of MMP-12/TIMP-4 in PBMC (P = 0.0055), serum (P = 0.0427), and EBC (P = 0.0035) samples between COPD patients and healthy controls. The mRNA expression of MMP-12 (r = -0.3958, P = 0.0186) and NE (r = -0.3694, P = 0.0290) in COPD patients was negatively correlated with pulmonary function. However, the mRNA expression of TIMP-4 (r = 0.2871, P = 0.0945) in PBMCs was not correlated with the FEV1 of the pulmonary function. Serum MMP-12 level was positively correlated with the MMP-12 level in EBC (P = 0.0387). The level of TIMP-4 in serum was not correlated with the level in the EBC sample (P = 0.4332). CONCLUSION: The expression levels of MMP-12, NE, and TIMP-4 in PBMCs and serum were elevated in COPD patients. In PBMCs of COPD patients, the mRNA expression level of NE may predict acute exacerbation, and MMP-12 mRNA expression level may be used to reflect the severity of airflow limitation. However, to better assess their diagnostic or prognostic value, larger studies are necessary.

Inflammatory mediators in exhaled breath condensate and peripheral blood of healthy donors and stable COPD patients.

Objective: The aim of this work was to compare matrix metalloproteinase-9 and -12, tissue inhibitor of metalloproteinase-1 and -4, and neutrophil elastase in exhaled breath condensate (EBC) and peripheral blood of patients with COPD. Methods: Peripheral blood and EBC samples from COPD patients and healthy donors were collected. In serum and EBC, MMP-9, MMP-12, NE, TIMP-1, and TIMP-4 proteins were detected by ELISA. The mRNA expression levels of MMP-9, MMP-12, NE, TIMP-1, and TIMP-4 in peripheral blood mononuclear cells (PBMCs) were analyzed by qRT-PCR. Results: The protein levels of MMP-9 (p=.034) and MMP-12 (p=.041) in the EBC of COPD smokers were higher than those of COPD never-smokers. The concentrations of TIMP-1 (p=.072) and TIMP-4 (p=.084) in the EBC of COPD smokers were higher than those of COPD never-smokers; however, the difference was not statistically significant. MMP-9 (r=-0.78, p<.0001) and TIMP-1 (r=-0.71, p<.0001) levels in EBC were significantly negatively correlated with pulmonary function FEV1%pred. The protein levels of MMP-12 (r=-0.37, p=.034) and TIMP-4 (r=-0.34, p=.041) were also negatively correlated with FEV1%pred. The expression of MMP-9, MMP-12, NE, TIMP-1, and TIMP-4 in PBMCs and serum of COPD smokers were significantly higher than those of control never-smokers (p<.05). Conclusions: Exhaled MMP-9, MMP-12, TIMP-1, and TIMP-4 levels increased in stable COPD patients and were negatively correlated with FEV1%pred, which suggests the usefulness of their measurement in EBC for the monitoring of airway inflammation. However, to better assess their diagnostic or prognostic value, larger studies are necessary.

High Serum Fractalkine/CX3CL1 in Patients with Chronic Obstructive Pulmonary Disease: Relationship with Emphysema Severity and Frequent Exacerbation.

OBJECTIVE: The purpose of this study was to investigate the relationship between serum fractalkine (CX3CL1/FKN) level and the multi-slice spiral computed tomography (MSCT) emphysema index in Chinese patients with chronic obstructive pulmonary disease (COPD). METHODS: We detected chemokine CX3CL1 in serum from 95 Chinese patients with COPD by using an enzyme-linked immunosorbent assay. According to the MSCT emphysema index, the selected cases were divided into an emphysema-dominant group (n = 25) and a non-emphysema-dominant group (n = 70). RESULTS: There were significant differences in body mass index and lung function between the two groups. The serum level of CX3CL1 in the emphysema-dominant group was significantly higher than that in the non-emphysema-dominant group. Through multivariate logistic regression analysis, it was found that high serum CX3CL1 levels were independently associated with emphysema, with a relative risk of 2.617 (95% CI 1.018-6.121; P = 0.029). The percentage of frequent acute exacerbations during the first year of follow-up was significantly higher in the high-level serum CX3CL1 group (P = 0.039). After 3 years of follow-up, there was no significant difference in the CT emphysema index between the high and low serum CX3CL1 groups (P = 0.503). CONCLUSION: Our results suggest that the serum level of CX3CL1 is related to the MSCT emphysema index. Chemokine CX3CL1 might be a useful predictor for identifying frequent exacerbation and emphysema severity in patients with COPD.

Elevated Serum Level of Angiopoietin-2 as a Potential Marker for Poor Prognosis in Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is a fast-growing cancer with poor prognosis. Patients with extensive-stage SCLC are generally treated with chemotherapy. Thus, it is essential to identify a predictor of efficacy and prognosis for SCLC. Angiopoietin-2 promotes vascular remodeling and angiogenesis. Increasing evidence reveals that angiopoietin-2 is preferentially expressed in cancer cells, and elevated angiopoietin-2 expression is related to invasive and metastatic phenotypes in various cancers. However, serum angiopoietin-2 level and its prognostic potential in SCLC have not been investigated. The aim of this study was to determine the usefulness of angiopoietin-2 level as a predictor of efficacy and prognosis for SCLC. This study consisted of sixty patients with SCLC. Each patient received four cycles of cisplatin-etoposide chemotherapy, and was followed for 36 months. Serum angiopoietin-2 levels were measured by Enzyme-linked immunosorbent assays. The angiopoietin-2 levels were significantly higher in SCLC patients than those in healthy subjects (P < 0.001). The patients were divided into high-level group (32 patients, 2,923.9 ± 294.7 pg/ml) and low-level group (28 patients, 1,789.5 ± 355.1 pg/ml) according to the mean value of the angiopoietin-2 level (2,400 pg/ml). Compared with the patients in the high-level group, the patients in the low-level group showed remarkably survival advantage (P = 0.002). During chemotherapy, the patients in the low-level group showed better treatment response than the patients in the high-level group (P < 0.05). Therefore, angiopoietin-2 might be useful as a prognostic factor for SCLC and for predicting SCLC response to chemotherapy.

MiRNA-218, a new regulator of HMGB1, suppresses cell migration and invasion in non-small cell lung cancer.

MicroRNAs (miRNAs) function as negative regulators of gene expression involved in cancer metastasis. The aim of this study is to investigate the potential roles of miR-218 in non-small cell lung cancer and validate its regulation mechanism. Functional studies showed that miR-218 overexpression inhibited cell migration and invasion, but had no effect on cell viability. Enhanced green fluorescent protein reporter assay, real-time polymerase chain reaction and western blot analysis confirmed that miR-218 suppressed the expression of high mobility group box-1 (HMGB1) by directly targeting its 3'-untranslated region. Accordingly, silencing of HMGB1 accorded with the effects of miR-218 on cell migration and invasion, and overexpression of HMGB1 can restore cell migration and invasion which were reduced by miR-218. In conclusion, these findings demonstrate that miR-218 functions as a tumor suppressor in lung cancer. Furthermore, miR-218 may act as a potential therapeutic biomarker for metastatic lung cancer patients.

Inhibition of tumor angiogenesis by HMGB1 A box peptide.

High mobility group box 1 protein (HMGB1) is a highly conserved, ubiquitous non-histone nuclear protein, which participates in maintaining nucleosome structure, regulation of gene transcription, and modulating the activity of steroid hormone receptors. Substantial evidence demonstrated that HMGB1 could be secreted into the extracellular milieu, acts as a proinflammatory cytokine and mediates the downstream inflammatory responses in endotoxemia, arthritis and sepsis. Recently, several reports suggested that HMGB1 plays a key role in tumor angiogenesis through multiple mechanisms, including up-regulation of proangiogenic factors, promoting endothelial progenitor cells homing to ischemic tumor tissues and induction of endothelial cell migration and sprouting. And blockade of HMGB1 binding to the receptor for advanced glycation end products (RAGE) with anti-HMGB1 antibody, soluble RAGE or anti-RAGE neutralizing antibody has been proved to inhibit angiogenesis efficiently. Since HMGB1 A box peptide could antagonize the HMGB1 whole length protein by competitively binding to RAGE and has been considered as a HMGB1 specific antagonist, we postulate that the HMGB1 A box peptide could function as an anti-angiogenic agent to inhibit tumor angiogenesis. In our opinion, if the hypothesis proved to be practical, HMGB1 A box peptide could be widely used in clinical settings to treat malignant tumors.