IL20Rb aggravates pulmonary fibrosis through enhancing bone marrow derived profibrotic macrophage activation.

Idiopathic pulmonary fibrosis (IPF) is one of the most fatal chronic interstitial lung diseases with unknown pathogenesis, current treatments cannot truly reverse the progression of the disease. Pulmonary macrophages, especially bone marrow derived pro-fibrotic macrophages, secrete multiple kinds of profibrotic mediators (SPP1, CD206, CD163, IL-10, CCL18…), thus further promote myofibroblast activation and fibrosis procession. IL20Rb is a cell-surface receptor that belongs to IL-20 family. The role of IL20Rb in macrophage activation and pulmonary fibrosis remains unclear. In this study, we established a bleomycin-induced pulmonary fibrosis model, used IL4/13-inducing THP1 cells to induce profibrotic macrophage (M2-like phenotype) polarization models. We found that IL20Rb is upregulated in the progression of pulmonary fibrosis, and its absence can alleviate the progression of pulmonary fibrosis. In addition, we demonstrated that IL20Rb promote the activation of bone marrow derived profibrotic macrophages by regulating the Jak2/Stat3 and Pi3k/Akt signaling pathways. In terms of therapeutic strategy, we used IL20Rb neutralizing antibodies for animal administration, which was found to alleviate the progression of IPF. Our results suggest that IL20Rb plays a profibrotic role by promoting profibrotic macrophage polarization, and IL20Rb may become a potential therapeutic target for IPF. Neutralizing antibodies against IL20Rb may become a potential drug for the clinical treatment of IPF.

Dapagliflozin promotes browning of white adipose tissue through the FGFR1-LKB1-AMPK signaling pathway.

BACKGROUND: Obesity is associated with a wide variety of metabolic disorders that impose significant burdens on patients and society. The "browning" phenomenon in white adipose tissue (WAT) has emerged as a promising therapeutic strategy to combat metabolic disturbances. However, though the anti-diabetic drug dapagliflozin (DAPA) is thought to promote "browning," the specific mechanism of this was previously unclear. METHODS: In this study, C57BL/6 J male mice were used to establish an obesity model by high-fat diet feeding, and 3T3-L1 cells were used to induce mature adipocytes and to explore the role and mechanism of DAPA in "browning" through a combination of in vitro and in vivo experiments. RESULTS: The results show that DAPA promotes WAT "browning" and improves metabolic disorders. Furthermore, we discovered that DAPA activated "browning" through the fibroblast growth factor receptors 1-liver kinase B1-adenosine monophosphate-activated protein kinase signaling pathway. CONCLUSION: These findings provide a rational basis for the use of DAPA in treating obesity by promoting the browning of white adipose tissue.

Induced Resistance Mechanism of Bacillus velezensis S3-1 Against Pepper Wilt.

In recent years, pepper wilt has emerged as a pivotal constraint on pepper yield augmentation. Bacillus velezensis S3-1, with a wide array of hosts, can be used as both a biocontrol agent and biofertilizer. Nonetheless, the precise mechanisms underpinning its employment in combating pepper wilt remain cloaked in ambiguity. In our study, we found that B. velezensis S3-1 could significantly inhibit Fusarium sp. F1T that caused pepper wilt. S3-1 could effectively inhibit both the growth and germination of F1T conidia, leading to a reduction in the spore germination percentage from 83.2 to 37.1% in vitro experiments. Additionally, leaf detachment experiments revealed that the volatile compounds produced by S3-1 could inhibit the spread of pepper leaf spot area. Moreover, we observed a significant decrease in the content of malondialdehyde (MDA) in pepper treated with S3-1, along with a significant increase in the content of soluble protein, polyphenol oxidase (PPO), peroxidase (POD), and phenylalanine ammonia-lyase (PAL) in pepper. Furthermore, RT-PCR analysis showed that the expression of the defense genes CaPR 1 and CaPIN II in pepper after treatment with S3-1 was significantly upregulated, suggesting that S3-1 had the potential to induce systemic resistance in pepper, thereby enhancing its disease resistance. Hence, our findings suggest that S3-1 can be a promising biocontrol agent for managing pepper wilt in modern agriculture.

Promotion mechanism of self-transmissible degradative plasmid transfer in maize rhizosphere and its application in naphthalene degradation in soil.

Rhizospheres can promote self-transmissible plasmid transfer, however, the corresponding mechanism has not received much attention. Plant-microbe remediation is an effective way to promote pollutant biodegradation; however, some pollutants, such as naphthalene, are harmful to plants and result in inefficient plant-microbe remediation. In this study, transfer of a TOL-like plasmid, a self-transmissible plasmid loaded with genetic determinants for pollutant degradation, among different bacteria was examined in bulk and rhizosphere soils as well as addition of maize root exudate and its artificial root exudate (ARE). The results showed that the numbers of transconjugants and recipients as well as bacterial metabolic activities, such as xylE mRNA expression levels and catechol 2,3-dioxygenase (C23O) activities of bacteria, remained high in rhizosphere soils, when compared with bulk soils. The number of transconjugants and bacterial metabolic activities increased with the increasing exudate and ARE concentrations, whereas the populations of donor and recipient bacteria were substantially unaltered at all concentrations. All the experiments consistently showed that a certain number of bacteria is required for self-transmissible plasmid transfer, and that the increased plasmid transfer might predominantly be owing to bacterial metabolic activity stimulated by root exudates and ARE. Furthermore, ARE addition increased naphthalene degradation by transconjugants in both culture medium and soil. Thus, the combined action of a wide variety of components in ARE might contribute to the increased plasmid transfer and naphthalene degradation. These findings suggest that ARE could be an effectively alternative for plant-microbe remediation of pollutants in environments where plants cannot survive.

Deglycosylated Azithromycin Attenuates Bleomycin-Induced Pulmonary Fibrosis via the TGF-ß1 Signaling Pathway.

Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening lung disease characterized by the proliferation of myofibroblasts and deposition of extracellular matrix that results in irreversible distortion of the lung structure and the formation of focal fibrosis. The molecular mechanism of IPF is not fully understood, and there is no satisfactory treatment. However, most studies suggest that abnormal activation of transforming growth factor-ß1 (TGF-ß1) can promote fibroblast activation and epithelial to mesenchymal transition (EMT) to induce pulmonary fibrosis. Deglycosylated azithromycin (Deg-AZM) is a compound we previously obtained by removing glycosyls from azithromycin; it was demonstrated to exert little or no antibacterial effects. Here, we discovered a new function of Deg-AZM in pulmonary fibrosis. In vivo experiments showed that Deg-AZM could significantly reduce bleomycin-induced pulmonary fibrosis and restore respiratory function. Further study revealed the anti-inflammatory and antioxidant effects of Deg-AZM in vivo. In vitro experiments showed that Deg-AZM inhibited TGF-ß1 signaling, weakened the activation and differentiation of lung fibroblasts, and inhibited TGF-ß1-induced EMT in alveolar epithelial cells. In conclusion, our findings show that Deg-AZM exerts antifibrotic effects by inhibiting TGF-ß1-induced myofibroblast activation and EMT.

Fedratinib Attenuates Bleomycin-Induced Pulmonary Fibrosis via the JAK2/STAT3 and TGF-ß1 Signaling Pathway.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease with multiple causes, characterized by excessive myofibrocyte aggregation and extracellular matrix deposition. Related studies have shown that transforming growth factor-ß1 (TGF-ß1) is a key cytokine causing fibrosis, promoting abnormal epithelial-mesenchymal communication and fibroblast-to-myofibroblast transition. Fedratinib (Fed) is a marketed drug for the treatment of primary and secondary myelofibrosis, targeting selective JAK2 tyrosine kinase inhibitors. However, its role in pulmonary fibrosis remains unclear. In this study, we investigated the potential effects and mechanisms of Fed on pulmonary fibrosis in vitro and in vivo. In vitro studies have shown that Fed attenuates TGF-ß1- and IL-6-induced myofibroblast activation and inflammatory response by regulating the JAK2/STAT3 signaling pathway. In vivo studies have shown that Fed can reduce bleomycin-induced inflammation and collagen deposition and improve lung function. In conclusion, Fed inhibited inflammation and fibrosis processes induced by TGF-ß1 and IL-6 by targeting the JAK2 receptor.

Real-Time Analysis of the Stability of Oil-In-Water Pickering Emulsion by Electrochemical Impedance Spectroscopy.

In this paper, electrical impedance spectroscopy (EIS) was applied to investigate the stability of oil-in-water (O/W) Pickering emulsions prepared with negatively charged silica nanoparticles in combination with a trace amount of redox switchable fluorescent molecules, ferrocene azine (FcA). Electrical impedance values of emulsions obtained at different emulsification speeds were estimated according to the frequency response data with frequencies ranging from 1 MHz to 1 Hz. The equivalent circuit model of toluene-in-water emulsion was established by the resistor (RO/W) and capacitor (CO/W) in parallel connection. Nyquist diagrams for the emulsions prepared by toluene and water were characterized by the formation of one semi-circle. The droplet size distribution is one of the important factors that affect the stability of the emulsion, except for the volume fraction of water and oil, the size of stabilizing particles, etc. The average particle size of the emulsion droplets decreased as the emulsification speed increased, indicating the higher stability of the emulsion. It was found that the fitted impedance value RO/W of the emulsion decreased with decreasing particle size prepared at different emulsification speeds and storage time by performing real-time EIS detection techniques. The results suggested that EIS could be used to characterize the stability of a toluene-in-water emulsion stabilized by FcA modified silica nanoparticles. Moreover, based on the good electrochemical activity of the FcA molecule, the stability of the Pickering emulsion can be modulated by adding oxidant and reductant and detected by EIS in real-time.

[Research Advances in Structural Characteristics,Identification Methods,and Functions of Telocytes].

Telocytes are novel interstitial cells with a specific structure:the body has an elliptical shape or a triangle shape,with slender and thin protrusions that connect with other cells to form a complex 3D network.This article summarizes the structural characteristics and identification Methods of Telocytes and demonstrates their potential functions as a new target for disease prevention and treatment.

Redox-Responsive Pickering Emulsions Based on Silica Nanoparticles and Electrochemical Active Fluorescent Molecules.

In this paper, we report a novel redox-responsive water-in-oil Pickering emulsion stabilized by negatively charged silica nanoparticles in combination with a trace amount of redox switchable fluorescent molecule ferrocene azine (FcA), in which ferrocene serves as a redox-sensitive group and anthryl unit serves as a fluorescence emission center. By alternately adding oxidants and reducing agents at a moderate condition, the amphiphilicity of silica nanoparticles changes because of the adsorption of Fc+A and the desorption of FcA on the silica surface. On the one hand, the stability of emulsions can be transformed between stable and unstable at ambient temperature via redox trigger and the regulation process can be cycled at least three times. On the other hand, the fluorescent intensity of the FcA molecule can be regulated by redox stimuli; thus, the change in fluorescent behavior of the emulsion droplets is observed upon redox cycles, which makes it useful in the fluorescent label of stimuli-responsive Pickering emulsions. This work provides a deep understanding of the regulation mechanism of Pickering emulsions upon redox stimuli and opens the new way for in situ fluorescent label of stimulus-responsive Pickering emulsions without introducing additional fluorescent molecules.

Suppressors of cytokine signaling (SOCS) and type 2 diabetes.

The suppressors of cytokine signaling (SOCS) proteins are originally identified as negative regulators of cytokine-activated Janus kinase/signal transducers and activators of transcription signaling pathway, but increasing evidence reveals that SOCS proteins play an important role in the development of type 2 diabetes involving regulation of the insulin signaling and pancreatic ß-cell function, and that SOCS are promising to be the targets for the treatment of type 2 diabetes. In this review, we focus on the emerging role for SOCS and the potential drugs targeting SOCS for type 2 diabetes.

Tacrolimus alleviates pulmonary fibrosis progression through inhibiting the activation and interaction of ILC2 and monocytes.

Idiopathic pulmonary fibrosis (IPF) is a heterogeneous group of lung diseases with different etiologies and characterized by progressive fibrosis. This disease usually causes pulmonary structural remodeling and decreased pulmonary function. The median survival of IPF patients is 2-5 years. Predominantly accumulation of type II innate immune cells accelerates fibrosis progression by secreting multiple pro-fibrotic cytokines. Group 2 innate lymphoid cells (ILC2) and monocytes/macrophages play key roles in innate immunity and aggravate the formation of pro-fibrotic environment. As a potent immunosuppressant, tacrolimus has shown efficacy in alleviating the progression of pulmonary fibrosis. In this study, we found that tacrolimus is capable of suppressing ILC2 activation, monocyte differentiation and the interaction of these two cells. This effect further reduced activation of monocyte-derived macrophages (Mo-M), thus resulting in a decline of myofibroblast activation and collagen deposition. The combination of tacrolimus and nintedanib was more effective than either drug alone. This study will reveal the specific process of tacrolimus alleviating pulmonary fibrosis by regulating type II immunity, and explore the potential feasibility of tacrolimus combined with nintedanib in the treatment of pulmonary fibrosis. This project will provide new ideas for clinical optimization of anti-pulmonary fibrosis drug strategies.

Favipiravir ameliorates bleomycin-induced pulmonary fibrosis by reprogramming M1/M2 macrophage polarization.

Corona Virus Disease 2019 (COVID-19) is an infectious disease that seriously endangers human life and health. The pathological anatomy results of patients who died of the COVID-19 showed that there was an excessive inflammatory response in the lungs. It is also known that most of the COVID-19 infected patients will cause different degrees of lung damage after infection, and may have pulmonary fibrosis remaining after cure. Macrophages are a type of immune cell population with pluripotency and plasticity. In the early and late stages of infection, the dynamic changes of the balance and function of M1/M2 alveolar macrophages have a significant impact on the inflammatory response of the lungs. In the early stage of pulmonary fibrosis inflammation, the increase in the proportion of M1 type is beneficial to clear pathogenic microorganisms and promote the progress of inflammation; in the later stage of fibrosis, the increase in the number of M2 type macrophages can inhibit the inflammatory response and promote the degradation of fibrosis. As a potential treatment drug for new coronavirus pneumonia, favipiravir is in the process of continuously carried out relevant clinical trials. This study aims to discuss whether the antiviral drug favipiravir can suppress inflammation and immune response by regulating the M1/M2 type of macrophages, thereby alleviating fibrosis. We established a bleomycin-induced pulmonary fibrosis model, using IL-4/13 and LPS/IFN-γ cell stimulating factor to induce macrophage M1 and M2 polarization models, respectively. Our study shows that favipiravir exerts anti-fibrotic effects mainly by reprogramming M1/M2 macrophages polarization, that is, enhancing the expression of anti-fibrotic M1 type, reducing the expression of M2 type pro-fibrotic factors and reprogramming it to anti-fibrotic phenotype. Aspects of pharmacological mechanisms, favipiravir inhibits the activation of JAK2-STAT6 and JAK2-PI3K-AKT signaling by targeting JAK2 protein, thereby inhibiting pro-fibrotic M2 macrophages polarization and M2-induced myofibroblast activation. In summary, favipiravir can reduce the progression of pulmonary fibrosis, we hope to provide a certain reference for the treatment of pulmonary fibrosis.

Withaferin A: A potential selective glucocorticoid receptor modulator with anti-inflammatory effect.

Glucocorticoids have been widely applied to various clinical treatment, however some serious side effects may occur during the treatment. It is widely known that glucocorticoids produce a marked effect through binding to glucocorticoid receptor (GR). As withaferin A can provide multiple health benefits, this work aims to confirm withaferin A as a potential selective GR modulator with anti-inflammatory effect. Fluorescence polarization assay confirmed that withaferin A could steadily bind to GR with an IC50 value of 203.80 ± 0.36 µM. Meanwhile, glucocorticoid receptor translocation of withaferin A was measured by nuclear fractionation assay. Dual luciferase reporter assay showed that withaferin A did not activate GR transcription. Furthermore, withaferin A decreased the GR-related protein expression with less side effects. The result of molecular docking showed that hydrogen-bonding and hydrophobic interactions contributed to the binding of withaferin A with GR. In addition, the GR-withaferin A complex maintained a stable binding throughout the dynamics simulation process. Enzyme-linked immunosorbent assay showed that withaferin A inhibited the production of cytokines, confirming its anti-inflammatory effect. These findings indicate that withaferin A is a potential selective GR modulator and this work may provide a research basis for developing dietary supplements and nutraceuticals against inflammation.

Environmental endocrine disruptors and pregnane X receptor action: A review.

The pregnane X receptor (PXR) is a kind of orphan nuclear receptor activated by a series of ligands. Environmental endocrine disruptors (EEDs) are a wide class of molecules present in the environment that are suspected to have adverse effects on the endocrine system by interfering with the synthesis, transport, degradation, or action of endogenous hormones. Since EEDs may modulate human/rodent PXR, this review aims to summarize EEDs as PXR modulators, including agonists and antagonists. The modular structure of PXR is also described, interestingly, the pharmacology of PXR have been confirmed to vary among different species. Furthermore, PXR play a key role in the regulation of endocrine function. Endocrine disruption of EEDs via PXR and its related pathways are systematically summarized. In brief, this review may provide a way to understand the roles of EEDs in interaction with the nuclear receptors (such as PXR) and the related pathways.

In vitro and in silico assessment of endocrine disrupting effects of food contaminants through pregnane X receptor.

As a promiscuous xenobiotic receptor, pregnane X receptor (PXR) has been confirmed to participate in numerous physiological process. In addition to the conventional estrogen/androgen receptor, PXR also serves as an alternative target for environmental chemical contaminants. In this work, the PXR-mediated endocrine disrupting effects of typical food contaminants were explored. Firstly, the time-resolved fluorescence resonance energy transfer assays confirmed the PXR binding affinities of 2,2',4,4',5,5'-hexachlorobiphenyl, bis(2-ethylhexyl) phthalate, dibutyl phthalate, chlorpyrifos, bisphenol A, and zearalenone, with IC50 values ranging from 1.88 to 4284.00 nM. Then their PXR agonist activities were assessed by PXR-mediated CYP3A4 reporter gene assays. Subsequently, the regulation of gene expressions of PXR and its targets CYP3A4, UGT1A1, and MDR1 by these compounds was further investigated. Intriguingly, all the tested compounds interfered with these gene expressions, confirming their endocrine disrupting effects via PXR-mediated signaling. The compound-PXR-LBD binding interactions were explored by molecular docking and molecular dynamics simulations to unravel the structural basis of their PXR binding capacities. The weak intermolecular interactions are key players in stabilizing these compound-PXR-LBD complexes. During the simulation process, 2,2',4,4',5,5'-hexachlorobiphenyl remained stable while the other 5 compounds underwent relatively severe disturbances. In conclusion, these food contaminants might exhibit endocrine disrupting effects via PXR.

Lenalidomide attenuates post-inflammation pulmonary fibrosis through blocking NF-κB signaling pathway.

Idiopathic pulmonary fibrosis (IPF) is a pathological consequence of interstitial pulmonary diseases, and is characterized by the persistence of fibroblasts and excessive deposition of extracellular matrix (ECM). The etiology of IPF is multifactorial. Although the role of inflammation in fibrogenesis is controversial, it is still recognized as an important component and epiphenomenon of IPF. Stimulus increase production of pro-inflammatory cytokines and activation of NF-κB, which will further promote inflammation response and myofibroblast transition. Lenalidomide is an immunomodulatory drug. Previous studies have revealed its anti-tumor effects through regulating immune response. Here we investigate the effect of lenalidomide on post-inflammation fibrosis. In vitro study revealed that lenalidomide inhibited NF-κB signaling in LPS-induced macrophage, and further attenuated macrophage-induced myofibroblast activation. Meanwhile, lenalidomide could inhibit TGF-ß1-induced myofibroblast activation through suppressing TGF-ß1 downstream MAPK signaling. In vivo study showed that lenalidomide inhibited pro-inflammatory cytokines TNF-α and IL-6 while enhanced anti-fibrotic cytokines IFN-γ and IL-10 in bleomycin-induced inflammation model, and attenuated pulmonary fibrosis and collagen deposition in the following fibrosis stage. In conclusion, our results demonstrate that lenalidomide possesses potential anti-fibrotic effects through suppressing NF-κB signaling.

PKM2 promotes pulmonary fibrosis by stabilizing TGF-ß1 receptor I and enhancing TGF-ß1 signaling.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease, and the molecular mechanisms remain poorly understood. Our findings demonstrated that pyruvate kinase M2 (PKM2) promoted fibrosis progression by directly interacting with Smad7 and reinforcing transforming growth factor-ß1 (TGF-ß1) signaling. Total PKM2 expression and the portion of the tetrameric form elevated in lungs and fibroblasts were derived from mice with bleomycin (BLM)-induced pulmonary fibrosis. Pkm2 deletion markedly alleviated BLM-induced fibrosis progression, myofibroblast differentiation, and TGF-ß1 signaling activation. Further study showed that PKM2 tetramer enhanced TGF-ß1 signaling by directly binding with Smad7 on its MH2 domain, and thus interfered with the interaction between Smad7 and TGF-ß type I receptor (TßR1), decreased TßR1 ubiquitination, and stabilized TßR1. Pharmacologically enhanced PKM2 tetramer by TEPP-46 promoted BLM-induced pulmonary fibrosis, while tetramer disruption by compound 3k alleviated fibrosis progression. Our results demonstrate how PKM2 regulates TGF-ß1 signaling and is a key factor in fibrosis progression.

Tacrolimus ameliorates bleomycin-induced pulmonary fibrosis by inhibiting M2 macrophage polarization via JAK2/STAT3 signaling.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease of unknown cause and characterized by excessive proliferation of fibroblasts and the irregular remodeling of extracellular matrix (ECM), which ultimately cause the severe distortion of the alveolar architecture. The median survival of IPF patients is 2-5 years. IPF patients are predominantly infiltrated by M2 macrophages during the course of disease development and progression. Predominantly accumulation of M2 macrophages accelerates fibrosis progression by secreting multiple cytokines that promote fibroblast to myofibroblast transition. In the process of M2 macrophage polarization, JAK2/STAT3 signaling plays a key role, thus, targeting activated macrophages to inhibit the pro-fibrotic phenotype is considered as an approach to the potential treatment of IPF. Tacrolimus is a macrolide antibiotic that as a specific inhibitor of T-lymphocyte function and has been used widely as an immunosuppressant in human organ transplantation. In this study we explored the potential effect and mechanism of tacrolimus on pulmonary fibrosis in vivo and vitro. Here, we found that tacrolimus is capable of suppressing M2 macrophages polarization by inhibiting pro-fibrotic factors secreted by M2 macrophages. This effect further alleviates M2-induced myofibroblast activation, thus resulting in a decline of collagen deposition, pro-fibrotic cytokines secretion, recovering of lung function, ultimately relieving the progression of fibrosis in vivo. Mechanistically, we found that tacrolimus can inhibit the activation of JAK2/STAT3 signaling by targeting JAK2. Our findings indicate a potential anti-fibrotic effect of tacrolimus by regulating macrophage polarization and might be meaningful in clinical settings.

Betulinic acid attenuated bleomycin-induced pulmonary fibrosis by effectively intervening Wnt/ß-catenin signaling.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal and progressive fibrotic lung disease lacking a validated and effective therapy. Aberrant activation of the Wnt/ß-catenin signaling cascade plays the key role in the pathogenesis of IPF. Betulinic acid is a natural pentacyclic triterpenoid molecule that has excellent antitumor and antiviral activities. HYPOTHESIS: We hypothesized that BA has an anti-pulmonary fibrosis effect mediated by the suppression of the Wnt/ß-catenin pathway. Study design Pulmonary fibrosis markers were detected in vitro and in vivo to confirm the antifibrotic effect of BA. The Wnt/ß-catenin pathway-related proteins were overexpressed to determine the effect of BA on Wnt signaling. METHODS AND RESULTS: BA dose-dependently inhibited Wnt3a-induced fibroblast activation in vitro. Moreover, BA decreased Wnt3a- and LiCl-induced transcriptional activity, as assessed by the TOPFlash assay in fibroblasts, and repressed the expression of the Wnt target genes cyclin D1, axin 2, and S100A4. Further investigation indicated that BA restrained the nuclear accumulation of ß-catenin, mainly by increasing the phospho-ß-catenin ratio (S33/S37/T41 and S45), inhibited the phosphorylation of DVL2 and LRP, and decreased the levels of Wnt3a and LRP6. In agreement with the results of the in vitro assays, the in vivo experiments indicated that BA significantly decreased bleomycin-induced pulmonary fibrosis in mice and suppressed myofibroblast activation by inhibiting Wnt/ß-catenin signaling. CONCLUSION: BA may directly interfere with the Wnt/ß-catenin pathway to subsequently repress myofibroblast activation and pulmonary fibrosis.

Clevudine attenuates bleomycin-induced early pulmonary fibrosis via regulating M2 macrophage polarization.

Pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease. It is a growing clinical problem which can result in breathlessness or respiratory failure and has an average life expectancy of 3 years from diagnosis. Predominantly accumulation of M2 macrophages accelerates fibrosis progression by secreting multiple cytokines that promote fibroblast to myofibroblast transition and aberrant wound healing of epithelial cells. Targeting activated macrophages to inhibit the pro-fibrotic phenotype is considered as an approach for the potential treatment of PF. Clevudine is s a purine nucleoside analogue which in an oral formulation is approved for treatment of patients with hepatitis B virus (HBV). Here, we found that clevudine is capable of suppressing pro-fibrotic phenotype (i.e., CD206, Arg1 and YM1) of M2 macrophages while enhancing anti-fibrotic phenotype (i.e., CD86, IL-6 and IL-10) by inhibiting PI3K/Akt signaling pathway. This effect further alleviates M2-induced myofibroblast activation and epithelial-to-mesenchymal transition (EMT), thus resulting in a decline of collagen deposition, pro-fibrotic cytokines secretion, with a concomitant recover ofpulmonary functions in vivo. Less infiltration of M2 macrophages between α-SMA + cells was also found in clevudine treated mice. Our findings indicate a potential anti-fibrotic effect of clevudine by regulating macrophage polarization and might be meaningful in clinical settings.