c-MYC-mediated TRIB3/P62+ aggresomes accumulation triggers paraptosis upon the combination of everolimus and ginsenoside Rh2

The mammalian target of rapamycin (mTOR) pathway is abnormally activated in lung cancer. However, the anti-lung cancer effect of mTOR inhibitors as monotherapy is modest. Here, we identified that ginsenoside Rh2, an active component of Panax ginseng C. A. Mey., enhanced the anti-cancer effect of the mTOR inhibitor everolimus both in vitro and in vivo. Moreover, ginsenoside Rh2 alleviated the hepatic fat accumulation caused by everolimus in xenograft nude mice models. The combination of everolimus and ginsenoside Rh2 (labeled Eve-Rh2) induced caspase-independent cell death and cytoplasmic vacuolation in lung cancer cells, indicating that Eve-Rh2 prevented tumor progression by triggering paraptosis. Eve-Rh2 up-regulated the expression of c-MYC in cancer cells as well as tumor tissues. The increased c-MYC mediated the accumulation of tribbles homolog 3 (TRIB3)/P62+ aggresomes and consequently triggered paraptosis, bypassing the classical c-MYC/MAX pathway. Our study offers a potential effective and safe strategy for the treatment of lung cancer. Moreover, we have identified a new mechanism of TRIB3/P62+ aggresomes-triggered paraptosis and revealed a unique function of c-MYC.

Myricetin inhibits interferon-γ-induced programmed death ligand-1 and indoleamine 2, 3-dioxygenase 1 expression in lung cancer cells / 中国药理学与毒理学杂志

OBJECTIVE Programmed death ligand-1 (PD-L1) and indoleamine 2, 3-dioxygenase 1 (IDO1) are immune checkpoints which can be induced by interferon-γ(IFN-γ) in the tumor microenvironment, leading to immune escape of tumors. Myricetin (MY) is a flavonoid distributed in many edible and medicinal plants. The aim of this study is to clarify the effect and the mechanism of MY on inhibiting IFN-γ-induced PD-L1 and IDO1 in lung cancer cells. METHODS Expressions of PD-L1 and major histocompatibility complex-I (MHC-I) were evaluated by flow cytometry and Western blotting, and the expression of IDO1 was measured by Western blotting. qRT-PCR was used to detect their mRNA levels. The function of T cells was evaluated using a co-culture system consist of lung cancer cells and the Jurkat-PD-1 T cell line that overexpressing PD-1. Molecular docking analysis, Western blotting and immunofluorescence were used for mechanism study. RESULTS MY potently inhibited IFN-γ-induced PD-L1 and IDO1 expression in human lung cancer cells, while didn't show obvious effect on the expression of MHC-I. In addition, MY restored the survival, proliferation, CD69 expression and interleukin-2 (IL-2) secretion of Jurkat-PD-1 T cells suppressed by IFN-γ-treated lung cancer cells in the co-culture system. Mechanistically, IFN-γ up-regulated PD-L1 and IDO1 at the transcriptional level through the JAK-STAT-IRF1 axis, which was targeted and inhibited by MY. CONCLUSION Our research revealed a new insight into the anti-tumor effects of MY which inhibited IFN-γ-induced PD-L1 and IDO1 expression, supporting the potential of MY in anti-tumor immunotherapy.

Experimental study on systemic hematogenic immunoreactions activated by bacteria in simulation of natural system / 中华传染病杂志

Objective To study systemic hematogenic immunoreactions induced by bacterial infections using simulation of natural system.Methods Whole blood 0.2 mL or white blood cells 0.2 mL and plasma(or normal saline)0.3 mL were stimulated by 0.2 mL of yeast and inactivated Bacillus Calmette-Guerin(BCG,5?10~8/mL),respectively,which were incubated at 37℃for 1 h. Interleukin(IL)-8,C3,C4 and chemokine receptor Fy6 were detected by flow cytometry(FCM)and en- zyme-linked immunosorbentassay(ELISA).Results Bacteria could activate red blood cell to modulate IL-8 release from white blood cells in plasma.In nature experimental group,activation rate(37.04?34.84)of IL-8 was significantly higher than that(1.09?0.77)in isolation experimental group.In nature experimen- tal group,value increment(0.01?0.01)of complement C4 was significantly higher than that(-0.0027?0.008)of isolation experimental group(P

Pathological observation of airway inflammation after neonatal CVB3 inoculation in rats / 第二军医大学学报

Objective: To observe the effect of coxsackie virus B3 on airway tract and lung morphology, and to study the relation between CVB infection and asthma. Methods: We established CVB3 infective model: 5 d neonatal rats inhaled CVB3 by ultrasonic brume. CVB3-IgM was examined 10 d after inoculating of CVB3, and LW/BW, airway tract and lung pathological change 10 d and 30 d after inoculation of CVB3 were observed. Results: Rats from the virus group had higher D of CVB3-IgM than control's (+2s ) and had higher LW/BW 10 d after inoculation of CVB3 than control (P<0.01). Neonatal rats had acute inflammatory changes 10 d after inoculation of CVB3 and persistent changes in morphology and cytology. Conclusion: Neonatal rats virus model is established. Respiratory infection by CVB3 in neonatal rats has persistent changes in airway tract inflammatory and morphology.

Effects of probucol on the NF-κB-like activity of aortic smooth muscle cell in vitro / 第二军医大学学报

Objective：To observe the inhibitory effects of pr obucol on nuclear factor-κB （NF-κB）-like activity of vascular smooth mus cle cells(VSMCs). Methods:The effects of probucol and H2O2 on NF-κB-like activity of VSMCs were investigated by electrophoretic mobility shift assay(EMSA). Results:NF-κB activation of VSMCs could be induced by H2O2 or new born calf serum(NCS) for 72 h, the gray-measure of the protein bindings measured through computer scanning was 63.9 and 46.6 respe c tively. NF-κB activity of VSMCs stimulated by H2O2 or NCS might be prevent ed by 100 μmol/L probucol, the inhibitory rate was 37.1%, 14.8% respectively. Conclusion:probucol can inhibit NF-κB activity of VSMCs stim ulated by NCS or H2O2. These effects of probucol might help to re duce development of atheroclerosis and restenosis after percutaneous transluminal coronary angioplasty.

Pathological observation of airway inflammation after neonatal CVB3 inoculation in rats / 第二军医大学学报

Objective: To observe the effect of coxsackie virus B3 on airway tract and lung morphology, and to study the relation between CVB infection and asthma. Methods: We established CVB3 infective model: 5 d neonatal rats inhaled CVB3 by ultrasonic brume. CVB3-IgM was examined 10 d after inoculating of CVB3, and LW/BW, airway tract and lung pathological change 10 d and 30 d after inoculation of CVB3 were observed. Results: Rats from the virus group had higher D of CVB3-IgM than control's (+2s ) and had higher LW/BW 10 d after inoculation of CVB3 than control (P<0.01). Neonatal rats had acute inflammatory changes 10 d after inoculation of CVB3 and persistent changes in morphology and cytology. Conclusion: Neonatal rats virus model is established. Respiratory infection by CVB3 in neonatal rats has persistent changes in airway tract inflammatory and morphology.

Effects of probucol on the NF-κB-like activity of aortic smooth muscle cell in vitro / 第二军医大学学报

Objective：To observe the inhibitory effects of pr obucol on nuclear factor-κB （NF-κB）-like activity of vascular smooth mus cle cells(VSMCs). Methods:The effects of probucol and H2O2 on NF-κB-like activity of VSMCs were investigated by electrophoretic mobility shift assay(EMSA). Results:NF-κB activation of VSMCs could be induced by H2O2 or new born calf serum(NCS) for 72 h, the gray-measure of the protein bindings measured through computer scanning was 63.9 and 46.6 respe c tively. NF-κB activity of VSMCs stimulated by H2O2 or NCS might be prevent ed by 100 μmol/L probucol, the inhibitory rate was 37.1%, 14.8% respectively. Conclusion:probucol can inhibit NF-κB activity of VSMCs stim ulated by NCS or H2O2. These effects of probucol might help to re duce development of atheroclerosis and restenosis after percutaneous transluminal coronary angioplasty.