An insight into the causal relationship between sarcopenia-related traits and venous thromboembolism: A mendelian randomization study.

BACKGROUND: As a geriatric syndrome, sarcopenia has a high prevalence in the old population and represents an impaired state of health with adverse health outcomes. A strong clinical interest in its relationship with venous thromboembolism (VTE), which is a complex trait disease with a heterogeneous annual incidence rate in different countries, has emerged. The relationship between sarcopenia and venous thromboembolism has been reported in observational studies but the causality from sarcopenia to VTE remained unclarified. We aimed to assess the causal effect of sarcopenia on the risk of VTE with the two-sample Mendelian randomization (MR) method. METHODS: Two sets of single-nucleotide polymorphisms (SNPs), derived from two published genome-wide association study (GWAS) meta-analyses and genetically indexing muscle weakness and lean muscle mass separately, were pooled into inverse variance weighted (IVW), weighted median and MR-Egger analyses. RESULTS: No evidence was found for the causal effect of genetically predicted muscle weakness (IVW: OR = 0.90, 95% CI = 0.76-1.06, p = 0.217), whole body lean mass (IVW: OR = 1.01, 95% CI = 0.87-1.17, p = 0.881) and appendicular lean mass (IVW: OR = 1.13, 95% CI = 0.82-1.57, p = 0.445) on the risk of VTE. However, both genetically predicted whole-body lean mass and appendicular lean mass can causally influence diabetes mellitus (IVW of whole-body lean mass: OR = 0.87, 95% CI = 0.78-0.96, p = 0.008; IVW of appendicular lean mass: OR = 0.71, 95% CI = 0.54-0.94, p = 0.014) and hypertension (IVW of whole-body lean mass: OR = 0.92, 95% CI = 0.87-0.98, p = 0.007; IVW of appendicular lean mass: OR = 0.84, 95% CI = 0.73-0.96, p = 0.013). CONCLUSIONS: Genetically predicted sarcopenia does not causally influence VTE directly, but it might still have an indirect effect on VTE incidence via diabetes mellitus and hypertension.

Retracted: Obestatin Plays Beneficial Role in Cardiomyocyte Injury Induced by Ischemia-Reperfusion In Vivo and In Vitro.

The Editors of Medical Science Monitor wish to inform you that the above manuscript has been retracted from publication due to concerns with the credibility and originality of the study, the manuscript content, and the Figure images. Reference: Qin Zhang, Xin-wei Dong, Jia-ying Xia, Ke-ying Xu, Zhe-rong Xu. Obestatin Plays Beneficial Role in Cardiomyocyte Injury Induced by Ischemia-Reperfusion In Vivo and In Vitro. Med Sci Monit, 2017; 23: 2127-2136. DOI: 10.12659/MSM.901361.

Self-assembled c-oriented Ni(OH)2 films for enhanced electrocatalytic activity towards the urea oxidation reaction.

This study investigates the electrocatalytic properties of the transparent c-oriented Ni(OH)2 films self-assembled from colloidal 2D Ni(OH)2 nanosheets for urea oxidation. The synthesis process yields highly uniform close-packed superlattices with a dominant c-axis orientation. The self-assembled c-oriented Ni(OH)2 films exhibit advantageous electrocatalytic performance in urea oxidation, presenting significantly lower overpotentials and higher current densities compared to randomly distributed Ni(OH)2 particles. In-depth in situ impedance analysis and Raman spectroscopy demonstrate that the c-oriented Ni(OH)2 films possess a higher propensity for a Ni valence transition from +2 to +3 during the urea oxidation process. This finding provides crucial insights into the catalytic behavior and electronic transformations of c-oriented Ni(OH)2 films, shedding light on their superior electrocatalytic activity for urea oxidation. Overall, this study advances our understanding of urea electrooxidation mechanisms and contributes to the design of efficient urea electrocatalysts.

Fe3C nanoclusters integrated with Fe single-atom planted in nitrogen doped carbon derived from truncated hexahedron zeolitic imidazolate framework for the efficient transfer hydrogenation of halogenated nitrobenzenes.

The control of morphology, structure and composition of metal-organic frameworks derived metal-nitrogen doped porous carbon (M-N-C) with high precision and accuracy is essential for the catalytic performance. While single-atom or small-sized nanometer catalysts show notable effects in catalysis, one catalyst combining the advantages of single-atom and nanometer catalysts may cultivate more benefits. Herein, we designed and successfully fabricated a series of Fe-doped ZIF-x with different morphologies (cube→truncated hexahedron→truncated octahedron) in one pot by simply adjusting the adding amount of vitamin C. After high-temperature calcination, Fe3C integrated with Fe single-atom planted in N-doped carbon (FeSA/FeNC-N-C-x) with various morphology, structure and composition could be acquired. Among them, FeSA/FeNC-N-C-0.75 exhibited the best catalytic performance for the transfer hydrogenation of halogenated nitrobenzenes with N2H4·H2O under room temperature. Acid-leaching tests, poisoning experiments, and the density functional theory calculations showed that Fe3C integrated with Fe single-atom had a better catalytic effect than the separated Fe3C or Fe single-atom.

Identification of key surfactant in municipal solid waste leachate foaming and its influence mechanism.

Serious foaming problems and the excessive consumption of defoamer have undoubtedly become one of the most critical problems that hinder municipal solid waste (MSW) leachate treatment efficiency and industry development. Since there is limited research penetrating the foaming mechanism and identification of the key surfactants, current defoaming and surfactant removal techniques lack pertinence and orientation. In this study, a foaming characterization device was developed and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC/MS/MS) was optimized to accurately identify the key surfactants affecting leachate foaming and offer a glimpse into their interaction mechanisms. This study collected leachate samples from 9 typical landfills and waste-to-energy facilities of various waste compositions, climatic conditions, ages, and geographical locations. The foaming problem of leachate was mainly centered on raw leachate and nanofiltration membrane concentrate (NFC). Fresh leachate performed with relatively low foaming capacity and foam stability, associated with low surfactant concentration. The pH value of the system was positively correlated with the concentration of anionic surfactants, indicating significant impacts on surfactant release in MSW. Since the distribution characteristics of linear alkylbenzene sulfonate (LAS) in leachate were consistent with the variety of foaming performances, LAS proved to be an indispensable surfactant in the leachate involved in this study, and its content proportion escalated to 92.87% in aged leachate.

SPK1/S1P axis confers gastrointestinal stromal tumors (GISTs) resistance of imatinib.

BACKGROUND: Imatinib mesylate (IM) is highly effective in the treatment of gastrointestinal stromal tumors (GISTs). However, the most of GISTs patients develop secondary drug resistance after 1-3 years of IM treatment. The aim of this study was to explore the IM-resistance mechanism via the multi-scope combined with plasma concentration of IM, genetic polymorphisms and plasma sensitive metabolites. METHODS: This study included a total of 40 GISTs patients who had been regularly treated and not treated with IM. The plasma samples were divided into three experiments, containing therapeutic drug monitoring (TDM), OCT1 genetic polymorphisms and non-targeted metabolomics. According to the data of above three experiments, the IM-resistant cell line, GIST-T1/IMR cells, was constructed for verification the IM-resistance mechanism. RESULTS: The results of non-targeted metabolomics analysis suggested that the sphingophospholipid metabolic pathway including the SPK1/S1P axis was inferred in IM-insensitive patients with GISTs. A GIST cell line (GIST-T1) was immediately induced as an IM resistance cell model (GIST-T1/IMR) and we found that blocking the signal pathway of SPK1/S1P in the GIST-T1/IMR could sensitize treatment of IM and reverse the IM-resistance. CONCLUSIONS: Our findings suggest that IM secondary resistance is associated with the elevation of S1P, and blockage the signaling pathway of SPK1/S1P warrants evaluation as a potential therapeutic strategy in IM-resistant GISTs. The design of this study from blood management, group information collection, IM plasma concentration with different elements, identification of sphingolipid metabolism and lastly verification the function of SPK1/S1P in the IM-resistance GISTs cells.

Corrigendum: Diplatin, a Novel and Low-Toxicity Anti-Lung Cancer Platinum Complex, Activation of Cell Death in Tumors via a ROS/JNK/p53-Dependent Pathway, and a Low Rate of Acquired Treatment Resistance.

[This corrects the article DOI: 10.3389/fphar.2019.00982.].

Toxicity from a single injection of human umbilical cord mesenchymal stem cells into rat ovaries.

Intraovarian injection of human umbilical cord mesenchymal stem cells (hUC-MSCs) has been applied and with promising therapeutic effects, but its toxicity and safety remain uncertain. This study evaluated the toxic effects and the affected target organs after a single injection of hUC-MSCs into bilateral rat ovaries. Sixty Sprague-Dawley rats were randomly divided into four groups and intraovarian injected with three different doses of hUC-MSC suspension. Toxicity-related manifestations occurred over the following 14 days postinjection. On day (D)5 and D15, we assessed the clinical pathology; immunotoxicity, including the cytokine IFN-γ, TNF-α, IL-4, and IL-6 levels; the immune organs, and the organ weights. On D5, inflammatory cells mainly infiltrated the ovaries of the low- and medium-dose groups, whereas inflammatory cells infiltrated the oviduct in the medium- and high-dose groups. On D15, inflammatory cells infiltrated the corpus luteal cysts, ovarian sacs and oviducts in each group. Body weights; organ weights; immunotoxicity; clinical pathology and histopathological examinations of the immune organs did not significantly differ among the groups. No obvious hUC-MSC-related clinical symptoms were observed except in the rats that died. The high-dose group exhibited significantly higher mortality than did the control and low-dose groups. Deaths in the high-dose group, who received approximately 50 times the standard clinical dose, were related to the intraovarian hUC-MSC injection. The maximum tolerated dose was approximately ten times the standard clinical dose. The ovary and oviduct may be the target organs for this toxicity. This report provides dosage references and guidance for clinical applications of intraovarian hUC-MSC injections.

Insights into Adsorption of Humic Substances on Graphitic Carbon Nitride.

Graphitic carbon nitride (CN) has been widely used in environmental pollution remediation. However, the adsorption of organic compounds on CNs, which has practical significance for the environmental application of CNs, is poorly understood. For the first time, this study systematically investigated the adsorption behaviors and mechanisms of humic substances (HSs), i.e., humic acid (HA) and fulvic acid (FA), on CNs derived from four typical precursors. Intriguingly, CN derived from urea (CN-U) showed a great capacity for HS adsorption due to its porous structure and large surface area, with maximum adsorption amounts of 73.24 and 51.62 mgC/g for HA and FA, respectively. The formation, influencing factors, and relative contributions of multiple interactions to HS adsorption on CNs were thoroughly elucidated. HS adsorption on CNs was mainly mediated by electrostatic interactions, π-π interactions, and H-bonding. The dominance of electrostatic interactions resulted in HS adsorption being highly dependent on pH and ionic strength. HS components with high aromaticity and high molecular weight were preferentially adsorbed due to π-π interactions. These multiple interactions were largely affected by amino groups and tri-s-triazine units of CNs, as well as the moieties of aromatic rings and oxygen-containing groups of HSs.

Inorganic-Organic Hybrid Molecular Materials: From Multiferroic to Magnetoelectric.

Inorganic-organic hybrid molecular multiferroic and magnetoelectric materials, similar to multiferroic oxide compounds, have recently attracted increasing attention because they exhibit diverse architectures, a flexible framework, fascinating physics, and potential magnetoelectric functionalities in novel multifunctional devices such as energy transformation devices, sensors, and information storage systems. Herein, the classification of multiferroicity and magnetoelectricity is briefly outlined and then the recent advances in the multiferroicity and magnetoelectricity of inorganic-organic hybrid molecular materials, particularly magnetoelectricity and the relevant magnetoelectric mechanisms and their categories are summarized. In addition, a personal perspective and an outlook are provided.

Room-Temperature Magnetoelectric Coupling in Electronic Ferroelectric Film based on [(n-C3H7)4N][FeIIIFeII(dto)3] (dto = C2O2S2).

Great importance has been attached to magnetoelectric coupling in multiferroic thin films owing to their extremely practical use in a new generation of devices. Here, a film of [(n-C3H7)4N][FeIIIFeII(dto)3] (1; dto = C2O2S2) was fabricated using a simple stamping process. As was revealed by our experimental results, in-plane ferroelectricity over a wide temperature range from 50 to 300 K was induced by electron hopping between FeII and FeIII sites. This mechanism was further confirmed by the ferroelectric observation of the compound [(n-C3H7)4N][FeIIIZnII(dto)3] (2; dto = C2O2S2), in which FeII ions were replaced by nonmagnetic metal ZnII ions, resulting in no obvious ferroelectric polarization. However, both ferroelectricity and magnetism are related to the magnetic Fe ions, implying a strong magnetoelectric coupling in 1. Through piezoresponse force microscopy (PFM), the observation of magnetoelectric coupling was achieved by manipulating ferroelectric domains under an in-plane magnetic field. The present work not only provides new insight into the design of molecular-based electronic ferroelectric/magnetoelectric materials but also paves the way for practical applications in a new generation of electronic devices.

Enhanced darkening effect from the interaction of MnO2 and oxygen on the component evolution of amino-phenolic humic-like substances.

Humification is greatly enhanced by metallic oxides in nature, and the related products are critical to various environmental processes. However, little is known about the interaction between metallic oxides and oxygen in promoting the oxidative polymerization of small organic molecules during the humification process. The synthesis of humic-like acids (HLAs) with MnO2 was performed in the presence and absence of oxygen, and the influence of oxygen and MnO2 on the composition evolution of amino-phenolic HLAs was illustrated. The results of ultraviolet-visible (UV-Vis) spectra of reaction mixtures associated with two-dimensional correlation spectroscopy (2D-COS) combined with the XPS spectra of N 1s content changes in HLAs demonstrated that MnO2 induced pyrrole-type nitrogen formation and enhanced darkening. Furthermore, MnO2 mainly acted as a catalyst, and oxygen activated the regeneration of MnO2 by oxidizing free manganese ions, thus substantially promoting the formation and accumulation of HLAs, whereas it decreased the reaction rate of HLAs formation. Moreover, carbon dioxide release was found during the process of the formation of fulvic-like acids (FLAs), and the reaction was oxygen-independent. Additionally, the formation and transformation of products without MnO2 do not obey kinetics equations, whereas the darkening reaction with MnO2 followed the pseudo-second-order and pseudo-zero-order kinetics equations. These findings provide new insights into the behaviours and fate of the oxygen-mediated humification process and related reaction products.

Factors Influencing the Steady-State Plasma Concentration of Imatinib Mesylate in Patients With Gastrointestinal Stromal Tumors and Chronic Myeloid Leukemia.

Imatinib mesylate (IM) is the standard treatment for advanced, metastatic gastrointestinal stromal tumors (GISTs) and chronic myeloid leukemia (CML) with a fixed daily standard dosage via the oral route. Interindividual and intraindividual variability in plasma concentrations have been closely linked to the efficacy of IM therapy. Therefore, this review identifies and describes the key factors influencing the plasma concentration of IM in patients with GISTs and CML. We used the following keywords to search the PubMed, EMBASE, Ovid, Wangfang, and CNKI databases to identify published reports: IM, plasma concentration, GISTs, CML, drug combination/interaction, pathology, and genotype/genetic polymorphism, either alone or in combination. This literature review revealed that only 10 countries have reported the mean concentrations of IM in GISTs or CML patients and the clinical outcomes in different ethnic groups and populations. There were totally 24 different gene polymorphisms, which were examined for any potential influence on the steady-state plasma concentration of IM. As a result, some genotype locus made discrepant conclusion. Herein, the more sample capacity, multicenter, long-term study was worthy to carry out. Eleven reports were enumerated on clinical drug interactions with IM, while there is not sufficient information on the pharmacokinetic parameters altered by drug combinations with IM that could help in investigating the actual drug interactions. The drug interaction with IM should be paid more attention in the future research.

Research Progress of Chloroquine and Hydroxychloroquine on the COVID-19 and Their Potential Risks in Clinic Use.

In December 2019, a severe outbreak of a novel coronavirus (COVID-19) occurred in the whole world, posing a great threat to people's health. With the outbreak and development of the epidemic, how to improve the cure rate, find effective drugs against this virus, has been the most urgent problem. Chloroquine (CQ) was verified effective against COVID-19 in vitro. As CQ's analogue, hydroxychloroquine (HCQ) was also reminded as a potential candidate for treating COVID-19. This review summarizes the latest clinical trials of CQ and HCQ against COVID-19 and its therapeutic regimen in China aiming to share their current usage to the whole world and provide insight into its appropriate future use in the treatment of COVID-19. Through searching the CNKI and Wangfang databases in Chinese language and PubMed, EMBASE, and Ovid databases in English language to identify published reports with the keywords including "coronavirus/COVID, chloroquine, hyroxychloroquine" in alone or combined, we found out the potential preclinical or clinical evidence for using CQ and HCQ against COVID-19. Consequently, we also searched the website of Chinese Clinical Trial Registry (http://www.chictr.org.cn/) till the day on 27th, June, 2020. This review found that there are 23 programs aimed to treat the different phases under COVID-19 pipeline in clinic with CQ and HCQ, totally. The inclusion criteria, exclusion criteria and therapeutic regimen were all shared to consult. Among them, seven have been canceled due to lack of patients or other objective factors. There are two trials have completed, which the potential relationship between usage and adverse reactions was discussed emphatically. Through literature research, we suggested that paid close attention to retinal toxicity and ophthalmologic adverse symptom of CQ and HCQ. And the outcome of HCQ in clinic shows better than CQ especially in protective effect with low dosage.

Diplatin, a Novel and Low-Toxicity Anti-Lung Cancer Platinum Complex, Activation of Cell Death in Tumors via a ROS/JNK/p53-Dependent Pathway, and a Low Rate of Acquired Treatment Resistance.

Background: Platinum-based drugs prevail as the main treatment of lung cancer; this is caused by their relative effectiveness despite known side effects, such as neurotoxicity. The risk reward of the treatment and side effects is confronted when dosage is considered and when resistance to treatment develops. Development of new compounds that improve effectiveness and safety profiles addresses this ongoing need in clinical practice. Objectives: The novel water-soluble platinum complex, diplatin, was synthesized, and its antitumor potency and toxicology profile were evaluated in murine xenograft tumor models and in lung cancer cell lines. Methods: The effects of diplatin, cisplatin (DDP), and carboplatin (CBP) on the viability of nine lung tumor cell lines and one normal human lung epithelial cell line were evaluated using the MTT assay. Therapeutic index was calculated as LD50/ED50 to identify and compare the ideal therapeutic windows of the above compounds. Diplatin's antitumor effects were assessed in lung xenograft tumors of nude mice; molecular mechanisms of therapeutic effects were identified. Results: Diplatin had desirable IC50 compared to CBP in a variety of cultured tumor cells, notably lung tumor cells. In the mouse xenograft lung tumor, diplatin led to a substantially improved therapeutic index when compared to the effects of DDP and CBP. Importantly, diplatin inhibited the growth of DDP-resistant lung tumor cells. Diplatin's mode of action was characterized to be through cell cycle arrest in the G2/M phase and induction of lung tumor apoptosis via ROS/JNK/p53-mediated pathways. Conclusion: Diplatin was observed to have antitumor effects in mice with both greater potency and safety compared with DDP and CBP. These observations indicate that diplatin is promising as a potential treatment in future clinical applications.

Inhibition of Rac1 activity alleviates PM2.5-induced pulmonary inflammation via the AKT signaling pathway.

PM2.5 is the main particulate air pollutant that is capable of inducing airway injury. Previous studies have indicated that Rac1 is involved in cigarette smoke-induced lung inflammation and lipopolysaccharide-mediated pulmonary injury. However, the contribution of Rac1 activity to PM2.5-induced lung inflammation remains largely unclear. Here, we investigated the regulation of Rac1 in PM2.5-induced inflammation in mouse airways and human bronchial epithelial cells (16HBE). The lungs of mice exposed to PM2.5 showed increased IL-1ß expression and an accumulation of inflammatory cells, thereby indicating high Rac1 activity. The exposure of 16HBE cells to PM2.5 resulted in elevated Rac1 levels, as well as an increased release of IL-1ß. Particularly, the selective inhibition of Rac1 ameliorated the IL-1ß release and inflammation in model lungs. Histological assessment showed that treatment with a Rac1 inhibitor, NSC23766, reduced the infiltration of neutrophils and macrophages into the airway lumen. Moreover, the selective inhibition or knockdown of Rac1 decreased IL-1ß release in 16HBE cells induced by PM2.5, which correlated with PM2.5-induced Rac1-regulated AKT signaling. Our data suggest an important role for Rac1 in the pathological alterations associated with PM2.5-mediated lung inflammation. Rac1 may be a promising therapeutic target for the treatment of the inflammatory diseases induced by PM2.5 inhalation.

Anti-allergic activities of 5,7-dimethoxy-3,4'-dihydroxyflavone via inhalation in rat allergic models.

Various studies have shown that flavones have several pharmacological activities including anti-allergy activities. However, the bioavailability of oral flavones is very low, and whether inhaled administration can improve efficacy in respiratory disease models is unclear. In the present study, the anti-allergic activities of inhaling 5,7-dimethoxy-3,4'-dihydroxyflavone (MHF), a synthetic flavonoid, was investigated by comparison with disodium cromoglycate (DSCG) and nedocromil sodium (NS) in rat allergic models. In an anti-DNP-IgE-induced asthmatic model, inhaled MHF dose-dependently inhibited the increase in airway resistance after antigen challenge. In an ovalbumin (OVA)-induced asthmatic model, inhaled MHF showed significant suppression of airway hyperresponsiveness; a decrease in eosinophil and neutrophil counts, IL-4, IL-5 and leukotriene D4 in bronchoalveolar lavage fluid; a reduction in total IgE and OVA-specific IgE levels in serum; and suppression of eosinophil infiltration in lung tissue after antigen challenge. The efficacy of inhaled MHF was comparable to that of NS and DSCG. In conclusion, based on these findings, the report for the first time that that inhaled MHF may be a potential drug for the treatment of allergic asthma.

Construction of Magnetoelectric Composites with a Large Room-Temperature Magnetoelectric Response through Molecular-Ionic Ferroelectrics.

Magnetoelectric materials with a large magnetoelectric response, a low operating magnetic (or electric) field, and a room-temperature (or higher) operating temperature are of key importance for practical applications. However, such materials are extremely rare because a large magnetoelectric response often requires strong coupling between spins and electric dipoles. Herein, an example of a magnetoelectric composite is prepared by using a room-temperature multiaxial molecular-ionic ferroelectric, tetramethylammonium tetrachlorogallate(III) (1). Investigation of the magnetoelectric effect of the magnetoelectric laminate composite indicates that its room-temperature magnetoelectric voltage coefficient (αME ) is as high as 186 mV cm-1 Oe-1 at HDC = 275 Oe and at the HAC frequency of ≈39 kHz, providing a valid approach for the preparation of magnetoelectric materials and adding a new member to the magnetoelectric material family.

Akt/PKB signaling regulates cigarette smoke-induced pulmonary epithelial-mesenchymal transition.

OBJECTIVES: Cigarette smoke (CS) is a major risk factor for the development of lung cancer and chronic obstructive pulmonary disease (COPD). Epithelial-mesenchymal transition (EMT) is found in invasive or metastatic phenotypes in lung cancer and COPD. MK-2206, a pan Akt inhibitor, has failed in clinical trials for solid tumors when administered alone at tolerated doses, but it has been shown to have synergistic effects when applied with certain molecular targeted agents. In this study, we investigated the working mechanism of MK-2206 in CS-induced pulmonary EMT both in vivo and in vitro. MATERIALS AND METHODS: The expression of Akt, epithelial-mesenchymal transition (EMT) markers and signaling proteins were analyzed by immunohistochemistry, real-time PCR and Western blot in cigarette smoke extract (CSE)-treated pulmonary epithelia and CS-treated lung tissues in mice. RESULTS AND CONCLUSION: We demonstrated that exposure of the epithelium to CSE and exposure of the mice to CS can induce EMT by activating the Akt signaling pathway. Intragastric application of MK-2206 at a low dose (50 mg/kg) reversed the changes of the key indicators of EMT in the lungs of CS-exposed mice, including TGF-ß1, α-SMA, vimentin, MMP-9, MMP-2, S100A4, collagen deposition, and E-cadherin. MK-2206 at a non-cytotoxic concentration (0.5 µM) or Akt knockdown consistently reversed the changes of the key indicators of EMT in the pulmonary epithelia. Moreover, we found that the effects of Akt inhibition or knockdown on the CS/CSE-induced EMT acted via the TGF-ß1/Akt/Smad/mTOR and Akt/P38 MAPK pathways. Taken together, our data offer a novel perspective on the molecular mechanism of Akt for CS-induced EMT. This finding may enhance the understanding of the mechanism behind the synergistic use of a low dose of MK-2206 to achieve antitumor efficacy with reduced adverse reactions in patients with lung cancer and COPD.

Salvianolic acid B improves airway hyperresponsiveness by inhibiting MUC5AC overproduction associated with Erk1/2/P38 signaling.

Salvianolic acid B (SalB) is one of the main water-soluble composites from Chinese medicine Dansen (Radix miltiorrhiza). It is used for clinical treatment of various diseases including cardiovascular, lung, Liver, renal and cancers. However, the effects of SalB to allergy induced airway mucin hypersecretion, inflammation and hyperresponsiveness (AHR) remains not clear. Overproduction of airway MUC5AC is a central effector of inflammation that is strongly associated with AHR in asthmatic attack. In this study, we investigated the anti-asthmatic activity and mechanism of SalB in a murine model and human epithelial cells by monitoring changes in mucin expression and secretion, airway inflammation, AHR, and signaling pathways. SalB was administered by intragastric administration (i.g) daily for a week, starting at 21 days after sensitization of ovalbumin (OVA). All examinations were performed 24h after the last antigen challenge. We found that treatments with SalB significantly inhibited increase in the tracheobronchial secretion, glycosaminoglycan levels, interleukin (IL)-13, IL-4, and IL-5 cytokines mRNA and protein expression, and decrease in mucociliary clearance in lung tissues. Histological results demonstrated that SalB attenuated OVA-induced eosinophil infiltration, airway goblet cell hyperplasia, and MUC5AC and MUC5B mRNA and protein expression in lung tissues. SalB exhibited protective effects against AHR in OVA-challenged animals. In vitro, SalB significantly inhibited IL-13-induced MUC5AC and MUC5B mRNA and protein expression in human epithelial cells. These effects were blocked by SalB by downregulating the Erk1/2 and P38 signaling pathways. Taken together, these data indicate that treatment with SalB may improve AHR by inhibiting MUC5AC overproduction.