Search

Zixiao Zhang,1,* Congli Fu,1,2,* Jiaxin Liu,1 Xiaoyan Sai,1 Chu Qin,1 Tingting Di,1 Yue Yang,1 Yan Wu,1 Tao Bian1 1Department of Respiratory Medicine, Wuxi People’s Hospital Affiliated to Nanjing, Medical University, Wuxi, Jiangsu, 214023, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tao Bian; Yan WuDepartment of Respiratory Medicine, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, 214023, People’s Republic of ChinaEmail btaophd@sina.com; wuyanyangting@163.comBackground: Nuclear factor E2-related factor 2 (Nrf2) is involved in oxidative stress and lung inflammation and regulates the etiology of chronic obstructive pulmonary disease (COPD). Ferroptosis is characterized by the accumulation of lipid reactive oxygen species (ROS) via ferrous ion-dependent Fenton reactions and is involved in COPD. However, the role of Nrf2 in ferroptosis and its epigenetic regulation in the pathogenesis of COPD remain unclear.Methods: Ferroptosis was detected by 4-HNE, MDA, C11BODIPY, DCFH-DA, Peals’ staining and CCK-8 assays. qPCR and Western blotting were performed to examine the Nrf2 levels in peripheral lung tissues, primary epithelial cells collected from patients with COPD and subjects with normal pulmonary function (never-smoker [control-NS]; smoker [control-S]), and cigarette smoke extract (CSE)-treated human bronchial epithelial (HBE) cells. ELISA was used to quantify IL-8 and IL-1β levels. Methylation of the Nrf2 promoter was analyzed by bisulfite sequencing and pyrosequencing.Results: Ferroptosis was involved in COPD and glutathione peroxidase 4 (GPX4) expression was downregulated in the COPD group. Reactive oxygen species (ROS), lipid peroxides and MDA were increased, but GPX4 and SOD were exhausted in CSE-treated HBE cells. The production of IL-1β and IL-8 was promoted in HBE cells in response to CSE but could be reversed by the ferroptosis inhibitor fer-1. The Nrf2 level was significantly decreased in the COPD group compared with the control-S and control-NS groups. Increased Nrf2 expression enhanced GPX4 and SOD levels and inhibited ferroptosis and proinflammatory cytokines in the supernatant. Inhibition of GPX4 reversed the effect of Nrf2 overexpression and promoted ferroptosis. Two specific CpG sites within the Nrf2 promoter were hypermethylated in the COPD group. Similarly, CSE-treated HBE cells exhibited hypermethylation of the Nrf2 gene.Conclusion: Nrf2 expression was downregulated in the lungs of COPD patients due to hypermethylation of the Nrf2 promoter, inhibiting Nrf2/GPX4 and ferroptosis, which is related to the initiation and progression of COPD. Targeting Nrf2/GPX4 may inhibit ferroptosis, which could provide strategies to delay or treat COPD.Keywords: COPD, Nrf2, ferroptosis, GPX4, DNA methylation, oxidative stress, inflammation

Additional file 1: S-Fig. 1. Effect of PFHxS exposure on reference genes (GAPDH) for the RT-qPCR. Bar graphs show levels of cycle threshold (Ct) values. (n = 6/group, one-way ANOVA). S-Fig. 2. Levels of T4 in the control and PFHxS mice. Bar graphs show levels of T4. (n = 6/group, Student���s t-test).

OBJECTIVE To observe the effects of Fuxin decoction in rats with heart failure induced by doxorubicin injections. METHODS We employed a doxorubicin-induced heart failure model to investigate the effect of Fuxin decoction. Rats were orally administered with Fuxin decoction from 10 to 40 mg/kg. Organization structure changes were assessed by histology, circulating levels of oxidative stress-related biomarkers and inflammatory cytokines were detected via enzyme-linked immunosorbent assay. RESULTS Administration of Fuxin decoction improved the growth retardation in doxorubicin hydrochloride injection rats. Cardiac involvement was alleviated by Fuxin decoction, as well as changes of congestion systemic circulation in this rat models. Furthermore, Fuxin decoction regulates immune responses and suppresses oxidation reaction in doxorubicin hydrochloride-induced rats. CONCLUSION Fuxin decoction might be an interesting candidate for congestive heart failure.

Matrine, is a bioactive compound isolated from Sophora flavescens (Ku shen), an herb used in Chinese traditional medicine that possesses wide-reaching pharmacological action. Psoriasis is a chronic relapsing inflammatory disorder with an incompletely understood pathophysiology, and dendritic cells (DCs) play a central role in the disease. This study aimed to explore DCs related potential mechanisms based on the effect of matrine on imiquimod (IMQ)-induced psoriasiform dermatitis in BALB/c mice and DCs simulated by resiquimod. Mice with IMQ-induced psoriasiform cutaneous lesions were treated with matrine [12.5, 25 or 50 mg/(kg·d), for 6 days]. Morphology, histological changes, keratinocyte proliferation and differentiation, inflammatory cell infiltration, protein expression levels of myeloid differentiation factor 88 (MyD88), and mRNA expression levels of inflammatory factors [interleukin (IL)-12, IL-23, and IL-1β] in lesional skin were assessed. The application of matrine decreased the proliferation of IMQ-induced keratinocytes. The treatment attenuated the infiltration of PCNA(+) and CD3(+) cells in the lesions. Matrine reduced the expression of the MyD88 protein and the inflammatory factors’ mRNA in lesional skin, but also in BMDCs (bone marrow derived dendritic cells). These results indicated that matrine suppressed expression of the inflammatory factors by decreasing the expression of the MyD88 protein on the surface of BMDCs, finally alleviating psoriasiform skin lesions. Therefore, the findings suggest that matrine might be a potential candidate for treating psoriasis.

Purpose: To investigate the effect of β, β-dimethylacryloyl alkannin, a main component of Lithospermum erythrorhizon, on activated dendritic cells (DCs) in a psoriasis mouse model. Methods: BALB/c mice were used to establish the animal model for psoriasis-like skin lesion; alkannin at 10 mg/kg (high), 5 mg/kg (medium), 2.5 mg/kg (low), respectively, were intragastrically administered. Psoriasis area and severity index (PASI) was used to evaluate the skin lesions. Histological changes, the thickness of epidermis, and the quantity of interleukin (IL)-23 in skin lesion were measured. In in vitro experiments, mononuclear cells in peripheral blood from healthy people were isolated, and monocytes were obtained. DCs with a mature state in differentiation and function were obtained through in vitro induction with several cytokines, and identified by flow cytometry. The influence of DCs on proliferation of allogenic lymphocytes was analyzed. The influence of alkannin on messenger ribonucleic acid (mRNA) expression of pro-inflammatory factors by mature DCs was evaluated using reverse transcriptase polymerase chain reaction. Results: Mice treated with alkannin at varying concentration showed obvious remission in psoriasis-like skin lesion compared to control group, with decreased PASI score, obviously reduced vertical thickness of epidermis. Besides, alkannin treatment decreased the expression of IL-23 in skin lesion. Alkannin (12.5 μg/mL) suppressed the ability of DCs to stimulate the proliferation of allogenic lymphocytes, and suppressed the expression and secretion of IL-6, IL-12 p40, IL-23, IL-1β, tumor necrosis factor-α mRNA and proteins, respectively. Conclusions: β, β-dimethylacryloyl alkannin could suppress the function of activated DCs in imiquimod-induced psoriasis mouse model.