Molecular mechanism of interleukin-17A regulating airway epithelial cell ferroptosis based on allergic asthma airway inflammation.

Interleukin-17A (IL-17A) levels are elevated in patients with asthma. Ferroptosis has been identified as the non-apoptotic cell death type associated with asthma. Data regarding the relation of ferroptosis with asthma and the effect of IL-17A on modulating ferroptosis in asthma remain largely unclear. The present work focused on investigating the role of IL-17A in allergic asthma-related ferroptosis and its associated molecular mechanisms using public datasets, clinical samples, human bronchial epithelial cells, and an allergic asthma mouse model. We found that IL-17A was significantly upregulated within serum in asthma cases. Adding IL-17A significantly increased ferroptosis within human bronchial epithelial cells (BEAS-2B). In ovalbumin (OVA)-induced allergic asthmatic mice, IL-17A regulated and activated lipid peroxidation induced ferroptosis, whereas IL-17A knockdown effectively inhibited ferroptosis in vivo by protection of airway epithelial cells via the xCT-GSH-GPX4 antioxidant system and reduced airway inflammation. Mouse mRNA sequencing results indicated that the tumor necrosis factor (TNF) pathway was the differential KEGG pathway in the OVA group compared to healthy controls and the OVA group compared to the IL-17A knockout OVA group. We further used N-acetylcysteine (TNF inhibitor) to inhibit the TNF signaling pathway, which was found to protect BEAS-2B cells from IL-17A induced lipid peroxidation and ferroptosis damage. Our findings reveal a novel mechanism for the suppression of ferroptosis in airway epithelial cells, which may represent a new strategy for the use of IL-17A inhibitors against allergic asthma.

Anlotinib prove to be a potential therapy for the treatment of pulmonary fibrosis complicated with lung adenocarcinoma.

Pulmonary fibrosis is a chronic interstitial fibrosis lung disease with high mortality, which is often complicated with lung cancer. The incidence of IPF complicated with lung cancer is getting higher and higher. At present, there is no consensus on the management and treatment of pulmonary fibrosis patients with lung cancer. There is an urgent need to develop preclinical drug evaluation methods for IPF with lung cancer and potential therapeutic drugs for IPF with lung cancer. The pathogenic mechanism of IPF is similar to that of lung cancer, and the multi-effect drugs with anticancer and anti-fibrosis will have potential value in the treatment of IPF complicated with lung cancer. In this study, we established an animal model of IPF complicated with lung cancer in situ to evaluate the therapeutic effect of the antiangiogenic drug anlotinib. The pharmacodynamic results in vivo showed that anlotinib could significantly improve the lung function of IPF-LC mice, reduce the content of collagen in lung tissue, increase the survival rate of mice, and inhibit the growth of lung tumor in mice. The results of Western blot and immunohistochemical analysis of lung tissue showed that anlotinib significantly inhibited the expression of fibrosis marker protein α-SMA, Collagen I and Fibronectin and tumor proliferation marker protein PCNA in mouse lung tissue, and down-regulated the content of serum tumor marker CEA. Through transcriptome analysis, we found that anlotinib regulates MAPK signal pathway, PARP signal pathway and coagulation cascade signal pathway in lung cancer and pulmonary fibrosis, which all play an important role in lung cancer and pulmonary fibrosis. In addition, there is crosstalk between the signal pathway participated by the target of anlotinib and MAPK, JAK/STAT and mTOR signal pathway. In summary, anlotinib will be a candidate for IPF-LC treatment.

Flavokawain A suppresses the vasculogenic mimicry of HCC by inhibiting CXCL12 mediated EMT.

BACKGROUND: Hepatocellular carcinoma has high ability of vascular invasion and metastasis. Vasculogenic mimicry (VM) is closely related to the metastasis and recurrence of hepatocellular carcinoma (HCC). According to previous research, Chloranthus henryi has anti-tumor effect, but its molecular mechanism in the treatment of HCC has not yet been stated. PURPOSE: In our study, we aimed to investigate the effect of the extract of Chloranthus henryi in HCC and its target and molecular mechanism. We hoped to explore potential drugs for HCC treatment. STUDY DESIGN/METHODS: In this study, we isolated a chalcone compound from Chloranthus henryi, compound 4, identified as flavokawain A (FKA). We determined the anti-HCC effect of FKA by MTT and identified the target of FKA by molecular docking and CETSA. Hepatoma cells proliferation, migration, invasion, and VM formation were examined using EDU, wound healing, transwell, vasculogenic mimicry, and IF. WB, RT-PCR, and cell transfection were used to explore the mechanism of FKA on hepatoma cells. Tissue section staining is mainly used to demonstrate the effect of FKA on HCC in vivo. RESULTS: We confirmed that FKA can directly interact with CXCL12 and HCC proliferation, migration, invasion, and VM formation were all inhibited through reversing the EMT progress in vitro and in vivo through the PI3K/Akt/NF-κB signaling pathway. Additionally, by overexpressing and knocking down CXCL12, we got the same results. CONCLUSION: FKA attenuated proliferation, invasion and metastatic and reversed EMT in HCC via PI3K/Akt/HIF-1α/NF-κB/Twist1 pathway by targeting CXCL12. This study proposed that FKA may be a candidate drug and prospective strategy for HCC therapy.

Exogenous Thymosin Beta 4 Suppresses IPF-Lung Cancer in Mice: Possibly Associated with Its Inhibitory Effect on the JAK2/STAT3 Signaling Pathway.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung disease of unknown etiology. At present, the mortality rate of the deadly disease is still very high, while the existing treatments only delay the progression of the disease and improve the quality of life of patients. Lung cancer (LC) is the most fatal disease in the world. In recent years, IPF has been considered to be an independent risk factor for the development of LC. The incidence of lung cancer is increased in the patients with IPF and the mortality is also significantly increased in the patients inflicted with the two diseases. In this study, we evaluated an animal model of pulmonary fibrosis complicated with LC by implanting LC cells orthotopically into the lungs of mice several days after bleomycin induction of the pulmonary fibrosis in the same mice. In vivo studies with the model showed that exogenous recombinant human thymosin beta 4 (exo-rhTß4) alleviated the impairment of lung function and severity of damage of the alveolar structure by the pulmonary fibrosis and inhibited the proliferation of LC tumor growth. In addition, in vitro studies showed that exo-rhTß4 inhibited the proliferation and migration of A549 and Mlg cells. Furthermore, our results also showed that rhTß4 could effectively inhibit the JAK2-STAT3 signaling pathway and this might exert an anti-IPF-LC effect. The establishment of the IPF-LC animal model will be helpful for the development of drugs for the treatment of IPF-LC. Exogenous rhTß4 can be potentially used for the treatment of IPF and LC.

Vorapaxar proven to be a promising candidate for pulmonary fibrosis by intervening in the PAR1/JAK2/STAT1/3 signaling pathway-an experimental in vitro and vivo study.

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease, and its 5-year mortality rate is even higher than the mortality rate of some cancers. Fibrosis can cause irreversible damage to lung structure and function. Treatment options for IPF remain limited, and there is an urgent need to develop effective therapeutic drugs. Protease activated receptor-1 (PAR-1) is a G-protein-coupled receptor and is considered a potential target for the treatment of fibrotic diseases. Vorapaxar is a clinically approved PAR-1 antagonist for cardiovascular protection. The purpose of this study was to explore the potential effect and mechanism of Vorapaxar on pulmonary fibrosis in vivo and in vitro. In the experimental animal model, Vorapaxar can effectively alleviate bleomycin (BLM)-induced pulmonary fibrosis. Treatment with 2.5, 5 or 10 mg/kg Vorapaxar once a day reduced the degree of fibrosis in a dose-dependent manner. The expression of fibronectin, collagen and α smooth muscle actin decreased significantly at the messenger RNA (mRNA) and protein levels in treated mice. In vitro, our results showed that Vorapaxar could inhibit the activation of fibroblasts induced by thrombin in a dose-dependent manner. In terms of mechanism, Vorapaxar inhibits the signal transduction of JAK2/STAT1/3 by inhibiting the activation of protease activated receptor 1, which reduces the expression of HSP90ß and the interaction between HSP90ß and transforming growth factor-ß (TGFß) receptor II and inhibits the TGFß/Smad signaling pathway. In conclusion, Vorapaxar inhibits the activation of pulmonary fibroblasts induced by thrombin by targeting protease activated receptor 1 and alleviates BLM-induced pulmonary fibrosis in mice.

[Research Progress on Pathogenic Mechanism and Potential Therapeutic Drugs of 
Idiopathic Pulmonary Fibrosis Complicated with Non-small Cell Lung Cancer].

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrous interstitial lung disease of unknown etiology. IPF is also considered to be among the independent risk factors for lung cancer, increasing the risk of lung cancer by 7% and 20%. The incidence of IPF complicated with lung cancer, especially non-small cell lung cancer (NSCLC), is increasing gradually, but there is no consensus on unified management and treatment. IPF and NSCLC have similar pathological features. Both appear in the surrounding area of the lung. In pathients with IPF complicated with NSCLC, NSCLC often develops from the honeycomb region of IPF, but the mechanism of NSCLC induced by IPF remains unclear. In addition, IPF and NSCLC have similar genetic, molecular and cellular processes and common signal transduction pathways. The universal signal pathways targeting IPF and NSCLC will become potential therapeutic drugs for IPF complicated with NSCLC. This article examines the main molecular mechanisms involved in IPF and NSCLC and the research progress of drugs under development targeting these signal pathways.
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Myricetin reverses epithelial-endothelial transition and inhibits vasculogenic mimicry and angiogenesis of hepatocellular carcinoma by directly targeting PAR1.

Most antiangiogenic inhibitors targeting endothelium-dependent vessels cannot inhibit tumor growth but promote tumor invasion and metastasis in some patients. Vasculogenic mimicry (VM) employs mechanisms that differ from those used to construct endothelium-dependent vessels. Inhibiting VM may be a novel antiangiogenic strategy against alternative tumor vascularization. In this paper, myricetin was selected from among several flavonoid compounds as an effective PAR1 antagonist. In two different hepatocellular carcinoma (HCC) cell lines high-expressed PAR1, myricetin inhibited cell migration, invasion and VM formation and reversed the expression of epithelial-endothelial transition (EET) markers by inhibiting PAR1 activation. Knockout of PAR1 inhibited HCC cell invasion and metastasis and weakened the inhibitory effect of myricetin on HCC cells. The migration, invasion and tube formation ability of PLC-PRF-5 cells were enhanced after PAR1 overexpression, and the inhibitory effect of myricetin was enhanced. A docking assay revealed that myricetin binds to Leu258 and Thr261 in the PAR1 activity pocket. Mutation of Leu258 and Thr261 inhibited the antitumor effect of myricetin in vitro and in vivo. In summary, myricetin reverses PAR1-mediated EET and inhibits HCC cell invasion, metastasis, VM formation and angiogenesis by targeting PAR1, and Leu258 and Thr261 of PAR1 participate in VM and angiogenesis in HCC tissues.

[Development of mobile monitor for risk factor control on chronic disease].

In order to improve the control rate of risk factors of chronic disease, it is developed a status control method of risk factor and its mobile monitor. The monitor uses 32 bit RISC microprocessor of S3C2410X as a controller based on ARM920T core, and MC35i cellular engine GSM/GPRS supported by SIEMENS as the communication unit. The proving tests show that the physical activity, diet, smoking and alcohol of the controlled people can be controlled using the status control method, and the monitor plays a key role in the method. The conclusion is that status control method and mobile monitor can become an alternation method and technology for the risk factor control of chronic disease.