Astragaloside IV promotes the pyroptosis of airway smooth muscle cells in childhood asthma by suppressing HMGB1/RAGE axis to inactivate NF-κb pathway.

Childhood asthma, a common chronic childhood disease, leads to high mortality and morbidity in the world. Airway smooth muscle cells (ASMCs) is a group of multifunctional cells that has been found to be correlated with the pathogenesis of asthma. Astragaloside IV (AS-IV) is a compound extracted from Astragalus membranaceus, which has the anti-asthmatic effect. However, the role of molecular mechanisms regulated by AS-IV in the biological processes of ASMCs in asthma remains unclear. Our current study aims to investigate the downstream molecular mechanism of AS-IV in modulating the aberrant proliferation and pyroptosis of ASMCs in asthma. At first, we determined that the viability of ASMCs could be efficiently suppressed by AS-IV treatment (200 µM). Moreover, AS-IV promoted the pyroptosis and suppressed PDGF-BB-induced aberrant proliferation. Through mechanism investigation, we confirmed that AS-IV could suppress high mobility group box 1 (HMGB1) expression and prevent it from entering the cytoplasm. Subsequently, AS-IV blocked the interaction between HMGB1 and advanced glycosylation end product-specific receptor (RAGE) to inactivate NF-κB pathway. Finally, in vivo experiments demonstrated that AS-IV treatment can alleviate the lung inflammation in asthma mice. Collectively, AS-IV alleviates asthma and suppresses the pyroptosis of AMSCs through blocking HMGB1/RAGE axis to inactivate NF-κB pathway.

Association of hypocalcemia with in-hospital mortality in critically ill patients with intracerebral hemorrhage: A retrospective cohort study.

Background and purpose: There was little evidence to study the relationship between hypocalcemia and mortality among critically ill patients with intracerebral hemorrhage (ICH) aged ≥16 years. This study aimed to determine the potential association between hypocalcemia and in-hospital and ICU mortality in patients with ICH in the United States. Methods: We analyzed 1,954 patients with ICH from the e-Intensive Care Unit Collaborative Research Database and divided them into hypocalcemia and non-hypocalcemia groups. Hypocalcemia was defined as albumin-adjusted total calcium below 8.4 mg/dl. The primary and secondary outcomes were hospital and ICU mortality, respectively. We performed multivariable regression and subgroup analyses to evaluate the association of hypocalcemia with hospital and ICU mortality. Cumulative survival rate analysis was performed using Kaplan-Meier curves with log-rank statistics. Results: We enrolled 1,954 patients with ICH who had been hospitalized in ICU for >24 h and were older than 16 years (average age, 61.8 years; men, 56.7%). We noted that 373 (19%) hospital mortality occurred, including 235 (12%) ICU mortality. In this sample, 195 patients had hypocalcemia. Multivariable logistic regression analyses showed that hypocalcemia was associated with a 67% increased risk of in-hospital and a 72% increased risk of ICU mortality. This association was consistent across subgroup analyses. Conclusions: Hypocalcemia was associated with a high risk of hospital and ICU mortality among critically ill patients with ICH. Future prospective, randomized, controlled studies are needed to confirm our results.

Combination therapy with dendritic cell-based vaccine and anti-CD69 antibody enhances antitumor efficacy in renal cell carcinoma-bearing mice.

BACKGROUND/AIM: Dendritic cell-based vaccine therapy for renal cell carcinoma is effective but requires improvement. Here we explored whether combination therapy with dendritic cell-based vaccine and anti-CD69 antibody can enhance antitumor efficacy in renal cell carcinoma-bearing mice. MATERIALS AND METHODS: Balb/c mice were challenged subcutaneously with murine renal cell carcinoma (Renca) cells. On day 3 after tumor cell inoculation, tumor-bearing mice either were left untreated or were treated with Renca tumor lysate-pulsed dendritic cells (i.e. dendritic cell-based vaccine), anti-CD69 antibody, or a combination of Renca tumor lysate-pulsed dendritic cells with anti-CD69 antibody. The mice were sacrificed on day 28. Tumor volume was measured for analysis of antitumor efficacy. Spleens were excised to evaluate antitumor immunological responses by measuring the proliferation and activation of T cells, which have the capacity to recognize and destroy tumor cells. RESULTS: Combination treatment with Renca tumor lysate-pulsed dendritic cells and anti-CD69 antibody resulted in significant decreases in tumor volume and significant increases in T-cell proliferation and activity, compared with no treatment or either treatment alone. CONCLUSION: These findings indicate that anti-CD69 antibody can potentiate antitumor efficacy of dendritic cell-based vaccine. The augmented therapeutic efficacy conferred by the combination therapy may be associated with increased T-cell proliferation and activity.

Anti-CD27 Antibody Potentiates Antitumor Effect of Dendritic Cell-Based Vaccine in Prostate Cancer-Bearing Mice.

In the current study, we investigated whether anti-CD27 monoclonal antibody can enhance the antitumor efficacy of a dendritic cell-based vaccine in prostate cancer-bearing mice. The overall therapeutic effect of a dendritic cell-based vaccine for prostate cancer remains moderate. A prostate cancer model was established by subcutaneous injection of RM-1 tumor cells into male C57BL/6 mice on day 0. After 4 days, tumor-bearing mice were treated with RM-1 tumor lysate-pulsed dendritic cells (i.e., dendritic cell-based vaccine), anti-CD27 monoclonal antibody, or a combination of RM-1 tumor lysate-pulsed dendritic cells with anti-CD27 monoclonal antibody. Mice were killed at 21 days after tumor cell implantation. Tumor size was measured for assessment of antitumor effect. Spleens were collected for analysis of antitumor immune responses. The antitumor immune responses were evaluated by measuring the proliferation and activity of T cells, which have the ability to kill tumor cells. The combination therapy with RM-1 tumor lysate-pulsed dendritic cells and anti-CD27 antibody significantly enhanced T-cell proliferation and activity, and significantly reduced tumor growth, compared with monotherapy with RM-1 tumor lysate-pulsed dendritic cells or anti-CD27 antibody. Our results suggest that combined treatment can strengthen antitumor efficacy by improving T-cell proliferation and activity.