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.

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.

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.

Allergen immunotherapy combined with Notch pathway inhibitors improves HDM-induced allergic airway inflammation and inhibits ILC2 activation.

Introduction: Group 2 innate lymphoid cells (ILC2s) play a crucial role in house dust mite (HDM)-induced allergic inflammation, and allergen immunotherapy (AIT) holds promise for treating the disease by reducing the frequency of ILC2s. Despite significant progress in AIT for allergic diseases, there remains a need to improve the control of allergic symptoms. Methods: We investigated the synergistic effect of the Notch signaling pathway and subcutaneous immunotherapy (SCIT) in treating allergic airway inflammation in mice and their impact on the ratio of ILC2s in lung tissues. This was achieved by establishing the HDM-induced airway allergic disorders (HAAD) model and SCIT model. Additionally, we conducted in vitro investigations into the effect of the Notch signaling pathway on the secretory function of activated ILC2s using fluorescence-activated cell sorting. Furthermore, we explored the coactivation of the Notch signaling pathway with SCIT in vitro by sorting ILC2s from the lung tissues of mice after SCIT modeling. Results: Previously, our group demonstrated that Notch signaling pathway inhibitors can reduce allergic airway inflammation in mice. Notch signaling induces lineage plasticity of mature ILC2s. In this study, we showed that AIT alleviates allergic airway inflammation and suppresses the frequency of ILC2s induced by HDM. Interestingly, AIT combined with a γ-secretase inhibitor (GSI), an inhibitor of the Notch signaling pathway, significantly inhibited the frequency of ILC2s, reduced airway inflammation, and suppressed Th2-type responses in a mouse model. Furthermore, lung ILC2s from HDM-challenged mice with or without AIT were treated with GSI in vitro, and we found that GSI dramatically reduced the secretion of type 2 inflammatory factors in ILC2s. Discussion: These findings suggest that Notch signaling pathway inhibitors can be used as adjuvant therapy for AIT and may hold potential treatment value in the cooperative control of allergic airway inflammation during early AIT.

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.

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.

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.

[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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MnO2-based materials for supercapacitor electrodes: challenges, strategies and prospects.

Manganese dioxide (MnO2) has always been the ideal electrode material for supercapacitors due to its non-toxic nature and high theoretical capacity (1370 F g-1). Over the past few years, significant progress has been made in the development of high performance MnO2-based electrode materials. This review summarizes recent research progress in experimental, simulation and theoretical studies for the modification of MnO2-based electrode materials from different perspectives of morphology engineering, defect engineering and heterojunction engineering. Several main approaches to achieve enhanced electrochemical performance are summarized, respectively increasing the effective active site, intrinsic conductivity and structural stability. On this basis, the future problems and research directions of electrode materials are further envisaged, which provide theoretical guidance for the adequate design and synthesis of MnO2-based electrode materials for use in supercapacitors.

Both Baicalein and Gallocatechin Gallate Effectively Inhibit SARS-CoV-2 Replication by Targeting Mpro and Sepsis in Mice.

The emergence of severe acute syndrome coronavirus 2 (SARS-CoV-2) in December 2019 has led to the global COVID-19 pandemic. Although the symptoms of most COVID-19 patients are mild or self-curable, most of severe patients have sepsis caused by cytokine storms, which greatly increases the case fatality rate. Moreover, there is no effective drug that can limit the novel coronavirus thus far, so it is more needed to develop antiviral drugs for the SARS-CoV-2. In our research, we employed the techniques of molecular docking to screen 35 flavonoid compounds among which 29 compounds have Z-scores lower than - 6. Then, ( -)-gallocatechin gallate, ( +)-gallocatechin and baicalein were identified to have potent inhibitory activity against SARS-CoV-2 Mpro with IC50 values of 5.774 ± 0.805 µM, 13.14 ± 2.081 µM and 5.158 ± 0.928 µM respectively by FRET assay. Molecular docking results also showed that ( -)-gallocatechin gallate, ( +)-gallocatechin and baicalein can non-covalently bind to Mpro through π-π stacking and hydrogen bonds in the Cys145 catalytic site. We further evaluated the effect of ( -)-gallocatechin gallate and baicalein on cytokine storms using a mouse model of sepsis. ( -)-Gallocatechin gallate and baicalein significantly reduced sepsis of mouse models on weight, murine sepsis score, and survival rate and reduced the inflammatory factor levels, such as TNF-α, IL-1α, IL-4, and IL-10. Overall, ( -)-gallocatechin gallate and baicalein show certain potential of treatment against COVID-19.

[Some perspectives of management in the use of medical devices].

The improper selection, management or use of medical devices may lead to a disproportionate rise in the cost of healthcare, which has concerned many countries. Some perspectives of management in the use of medical device have been widely discussed in 1st global forum on medical devices held by the World Health Organization on Thailand in 2010. This paper presents some main perspectives about this.

Myricetin Inhibits SARS-CoV-2 Viral Replication by Targeting Mpro and Ameliorates Pulmonary Inflammation.

The coronavirus disease 2019 (COVID-19) has spread widely around the world and has seriously affected the human health of tens of millions of people. In view of lacking anti-virus drugs target to SARS-CoV-2, there is an urgent need to develop effective new drugs. In this study, we reported our discovery of SARS-CoV-2 Mpro inhibitors. We selected 15 natural compounds, including 7 flavonoids, 3 coumarins, 2 terpenoids, one henolic, one aldehyde and one steroid compound for molecular docking and enzymatic screening. Myricetin were identified to have potent inhibit activity with IC50 3.684 ± 0.076 µM in the enzyme assay. The binding pose of Myricetin with SARS-CoV-2 Mpro was identified using molecular docking method. In the binding pocket of SARS-CoV-2 Mpro, the chromone ring of Myricetin interacts with His41 through π-π stacking, and the 3'-, 4'- and 7-hydroxyl of Myricetin interact with Phe140, Glu166and Asp187 through hydrogen bonds. Significantly, our results showed that Myricetin has potent effect on bleomycin-induced pulmonary inflammation by inhibiting the infiltration of inflammatory cells and the secretion of inflammatory cytokines IL-6, IL-1α, TNF-α and IFN-γ. Overall, Myricetin may be a potential drug for anti-virus and symptomatic treatment of COVID-19.

Effect of dihydromyricetin on SARS-CoV-2 viral replication and pulmonary inflammation and fibrosis.

BACKGROUND: COVID-19 (Coronavirus Disease-2019) has spread widely around the world and impacted human health for millions. The lack of effective targeted drugs and vaccines forces scientific world to search for new effective antiviral therapeutic drugs. It has reported that flavonoids have potential inhibitory activity on SARS-CoV-2 Mpro and anti-inflammatory properties. Dihydromyricetin, as a flavonol, also has antiviral and anti-inflammatory potential. However, the inhibition of dihydromyricetin on SARS-CoV-2 Mpro and the protective effect of dihydromyricetin on pulmonary inflammation and fibrosis have not been proved and explained. PURPOSE: The coronavirus main protease (Mpro) is essential for SARS-CoV-2 replication and to be recognized as an attractive drug target, we expect to find the inhibitor of Mpro. Novel coronavirus infection can cause severe inflammation and even sequelae of pulmonary fibrosis in critically ill patients. We hope to find a drug that can not only inhibit virus replication but also alleviate inflammation and pulmonary fibrosis in patients. METHODS: FRET-based enzymatic assay was used to evaluate the inhibit activity of dihydromyricetin on SARS-CoV-2 Mpro. Molecular docking was used to identify the binding pose of dihydromyricetin with SARS-CoV-2 Mpro. The protective effects of dihydromyricetin against BLM-induced pulmonary inflammation and fibrosis were investigated in C57BL6 mice. BALF and lung tissue were collected for inflammation cells count, ELISA, masson and HE staining, western blotting and immunohistochemistry to analyze the effects of dihydromyricetin on pulmonary inflammation and fibrosis. MTT, western blotting, reverse transcription-polymerase chain reaction (RT-PCR) and wound healing were used to analyze the effects of dihydromyricetin on lung fibrosis mechanisms in Mlg cells. RESULTS: In this study, we found that dihydromyricetin is a potent inhibitor targeting the SARS-CoV-2 Mpro with a half-maximum inhibitory concentration (IC50) of 1.716 ± 0.419 µM, using molecular docking and the FRET-based enzymatic assay. The binding pose of dihydromyricetin with SARS-CoV-2 Mpro was identified using molecular docking method. In the binding pocket of SARS-CoV-2 Mpro, the dihydrochromone ring of dihydromyricetin interact with the imidazole side chain of His163 through π-π stacking. The 1-oxygen of dihydromyricetin forms a hydrogen bond with the backbone nitrogen of Glu166. The 3-, 7-, 3'- and 4'-hydroxyl of dihydromyricetin interact with Gln189, Leu141, Arg188 and Thr190 through hydrogen bonds. Moreover, our results showed that dihydromyricetin can significantly alleviate BLM-induced pulmonary inflammation by inhibiting the infiltration of inflammation cells and the secretion of inflammation factors in the early process and also ameliorate pulmonary fibrosis by improving pulmonary function and down-regulate the expression of α-SMA and fibronectin in vivo. Our results also showed that dihydromyricetin inhibits the migration and activation of myofibroblasts and extracellular matrix production via transforming growth factor (TGF)-ß1/Smad signaling pathways. CONCLUSION: Dihydromyricetin is an effective inhibitor for SARS-CoV-2 Mpro and it prevents BLM-induced pulmonary inflammation and fibrosis in mice. Dihydromyricetin will be a potential medicine for the treatment of COVID-19 and its sequelae.

[Research on a novel method for the evaluation of left ventricular diastolic function].

The methods for evaluating left ventricular diastolic function completely and simply are lacking in our country at present. To solve this problem, we presents in this paper a novel method, which is developed according to certain algorithms and mathematic models and is carried out by a MATLAB program. This method mainly obtains dP/dt loops, and calculates four important indices, including left ventricular end-diastolic pressure (LVEDP), Maximal decrease in velocity of left ventricular pressure (--(dP/dt)max), Time constant of ventricular isovolumic relaxation (tau) and Chamber stiffness (Kd), according to the changes of left ventricular pressure. The results obtained from the experiment of isolated rat hearts during ischemia/reperfusion have demonstrated the usefulness and validity of this method. Therefore, with the use of tau and Kd as indicators, this is a sensitive and effective method for evaluating the left ventricular diastolic function, and it can be applied to early detection of left ventricular diastolic dysfunction.

[Status and challenges of medical metrology in China].

In recent years, more and more new medical devices appears, among them there are many measurement instruments related to consistency and stability of value, and safety to device. Presently China is facing the health policy reforms and medical quantity management system establishment. The primary duty of the clinical engineering is to ensure security and validity of medical devices, and preventing maintenance included of measurement and safety is important measure for the duty. The paper overviews the status in medical metrology and challenge for health policy reform in China, and gives some suggestions to resolve medical metrology.

[Combination products: a new model of medical devices].

A combination product is a new model of the medical product that incorporates at least two of the regulated component categories of device, drug, or biological product into one product. It has become a new hot point within the development of devices and drugs, and has brought about a new opportunity for device and drug industries and a new challenge for administration too. In the paper, the properties of combination products are summed up and the impact on device and drug industries are discussed.

[Non-equilibrium properties of drug permeation through stratum corneum in vitro].

AIM: To illustrate the non-equilibrium properties of drug permeation through stratum corneum (SC) to provide theory and method for transdermal drug delivery. METHODS: The system of side-by-side permeation chambers in vitro was isolated, thus conditions for equilibrium state were decided. And a network thermodynamic model was established. Non-equilibrium and leakage experiments were completed with which tinidazole was pattern drug. RESULTS: The properties of non-equilibrium including: long term to reach equilibrium state; delay-start of the permeation; uncertainty of initial drug permeable flux. The properties of leakage including: degression of drug permeable flux; changeability of permeation time constant. CONCLUSION: The permeation cell is believed to be a non-linear and time variable system.

[Method and apparatus for blood flow detection based on detention catheter].

The methods for measurement of blood flow contain dilution, electro-magnetism, nuclear magnetic resonance, Doppler etc. The dilution, which includes heat dilution, 131Xe, etc., can not display the moving blood flow in real-time. The expenses of nuclear magnetic resonance expenses are very high. Electromagnetism must be used in the surgical operation. And ultrasound Doppler can not record other parameters of hemodynamics synchronously. This paper brings up a kind of blood flow measuring method with simple operating rules, dependable performance, and low cost to meet the needs in hemodynamic studies. The differential pressure between stay and fluxion points of the tube is produced in proportion to the square of velocity while fluid flows through the tube. We not only measure blood pressure or transfer drug using the detention catheter with double chamber, but also detect the differential pressure related within blood flow. The result of detecting cerebral blood flow (CBF) in clinical setting shows this method can record the diagram of dynamic blood flow and is a valid was of detecting blood flow for hemodynamic studies.