Selpercatinib attenuates bleomycin-induced pulmonary fibrosis by inhibiting the TGF-ß1 signaling pathway.

IPF is a chronic, progressive, interstitial lung disease with high mortality. Current drugs have limited efficacy in curbing disease progression and improving quality of life. Selpercatinib, a highly selective inhibitor of receptor tyrosine kinase RET (rearranged during transfection), was approved in 2020 for the treatment of a variety of solid tumors with RET mutations. In this study, the action and mechanism of Selpercatinib in pulmonary fibrosis were evaluated in vivo and in vitro. In vivo experiments demonstrated that Selpercatinib significantly ameliorated bleomycin (BLM)-induced pulmonary fibrosis in mice. In vitro, Selpercatinib inhibited the proliferation, migration, activation and extracellular matrix deposition of fibroblasts by inhibiting TGF-ß1/Smad and TGF-ß1/non-Smad pathway, and suppressed epithelial-mesenchymal transition (EMT) like process of lung epithelial cells via inhibiting TGF-ß1/Smad pathway. The results of in vivo pharmacological tests corroborated the results obtained from the in vitro experiments. Further studies revealed that Selpercatinib inhibited abnormal phenotypes of lung fibroblasts and epithelial cells in part by regulating its target RET. In short, Selpercatinib inhibited the activation of fibroblasts and EMT-like process of lung epithelial cells by inhibiting TGF-ß1/Smad and TGF-ß1/non-Smad pathways, thus alleviating BLM-induced pulmonary fibrosis in mice.

Evaluation of nintedanib efficacy: Attenuating the lens fibrosis in vitro and vivo.

PURPOSE: Organ fibrosis is a huge challenge in clinic. There are no drugs for fibrotic cataracts treatments in clinic. Nintedanib is approved by the FDA for pulmonary fibrosis treatments. This study aims to investigate the efficacy and mechanism of nintedanib on fibrotic cataracts. METHODS: Drug efficacy was validated through TGFß2-induced cell models and injury-induced anterior subcapsular cataract (ASC) mice. A slit lamp and the eosin staining technique were applied to access the degree of capsular fibrosis. The CCK-8 assay was used to evaluate the toxicity and anti-proliferation ability of the drug. The cell migration was determined by wound healing assay and transwell assay. The anti-epithelial mesenchymal transition (EMT) and anti-fibrosis efficacy were evaluated by qRT-PCR, immunoblot, and immunofluorescence. The inhibition of nintedanib to signaling pathways was certified by immunoblot. RESULTS: Nintedanib inhibited the migration and proliferation of TGFß2-induced cell models. Nintedanib can also repress the EMT and fibrosis of the lens epithelial cells. The intracameral injection of nintedanib can also allay the anterior subcapsular opacification in ASC mice. The TGFß2/ Smad and non-Smad signaling pathways can be blocked by nintedanib in vitro and in vivo. CONCLUSION: Nintedanib alleviates fibrotic cataracts by suppressing the TGFß2/ Smad and non-Smad signaling pathways. Nintedanib is a potential drug for lens fibrosis.

The efficacy and safety of mini-open (air/water medium) endoscopy-assisted anterior cervical discectomy and fusion for the treatment of cervical spondylotic myelopathy.

PURPOSE: To compare the clinical efficacy of mini-open (air/water medium) endoscopy-assisted anterior cervical discectomy and fusion (MOEA-ACDF) and anterior cervical decompression and fusion (ACDF) for cervical spondylotic myelopathy (CSM). METHODS: This study retrospectively analysed the clinical data of CSM patients who received surgical treatment from January 1, 2020, to December 31, 2022. Patients were divided into two groups according to the surgical method: the MOEA-ACDF group and the ACDF group. The preoperative and postoperative imaging results at one week and the last follow-up examination were compared between the two groups. The Japanese Orthopaedic Association (JOA) score, visual analogue scale (VAS) score and neck disability index (NDI) score were used to evaluate the clinical outcomes preoperatively, one week postoperatively and at the last follow-up examination. The minimum follow-up duration was 12 months. RESULTS: A total of 131 CSM patients who underwent surgery at our institution were included, including 61 patients in the MOEA-ACDF group and 70 patients in the ACDF group. In the MOEA-ACDF group, the postoperative C2-C7 Cobb angle and HAVB were significantly greater than the preoperative values (P < 0.05). In the ACDF group, the postoperative C2-C7 Cobb angle was also significantly greater than the preoperative value, and the C2-C7 ROM and HAVB significantly decreased (P < 0.05). The postoperative neurological function of the patients in both groups improved, and the postoperative VAS score and NDI score significantly decreased. Compared with ACDF, MOEA-ACDF is associated with a significantly larger postoperative C2-C7 Cobb angle and significantly better C2-C7 ROM and HAVB, as well as better clinical efficacy (P < 0.05). CONCLUSIONS: MOEA-ACDF combines endoscopic systems with ACDF technology to treat CSM, but its clinical efficacy is not inferior to that of ACDF in the short- to intermediate-term. It can effectively and safely restore the cervical intervertebral height, physiological curvature, and range of motion.

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.

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.

Inhibition of miR-29a-3p Alleviates Apoptosis of Lens Epithelial Cells via Upregulation of CAND1.

PURPOSE: Accumulated evidence has shown that microRNAs (miRNAs) are closely related to the pathogenesis and progression of senile cataracts. Here we investigate the effect of miR-29a-3p in cataractogenesis and determined the potential molecular mechanism involved. METHODS: In this study, we constructed a selenite cataract model in rats and obtained the miRNAs related to cataracts by whole transcriptome sequencing. To investigate the effect and mechanism of miR-29a-3p on cataracts, we performed several in vivo and in vitro experiments, including CCK8 assay, flow cytometry, luciferase reporter assay, Edu assay, and western blot analysis. RESULT: Sequencing data showed downregulation of miR-29a-3p in rats with selenite cataracts. Down-regulation of miR-29a-3p could promote lens epithelial cells (SRA01/04) proliferation and inhibit cell apoptosis, and miR-29a-3p silence could inhibit the development of cataracts. Additionally, CAND1 was a direct target gene for miR-29a-3p. CONCLUSION: These data demonstrate that miR-29a-3p inhibits apoptosis of lens epithelial cells by regulating CAND1, which may be a potential target for senile cataracts.

Axitinib attenuates the progression of liver fibrosis by restoring mitochondrial function.

Liver fibrosis can progress to cirrhosis and hepatocellular carcinoma, which may eventually lead to liver failure and even death. No direct anti-fibrosis drugs are available at present. Axitinib is a new generation of potent multitarget tyrosine kinase receptor inhibitors, but its role in liver fibrosis remains unclear. In this study, a CCl4-induced hepatic fibrosis mouse model and a TGF-ß1-induced hepatic stellate cell model were used to explore the effect and mechanism of axitinib on hepatic fibrosis. Results confirmed that axitinib could alleviate the pathological damage of liver tissue induced by CCl4 and inhibit the production of glutamic-oxalacetic transaminase and glutamic-pyruvic transaminase. It also inhibited collagen and hydroxyproline deposition and the protein expression of Col-1 and α-SMA in CCl4-induced liver fibrosis. In addition, axitinib inhibited the expression of CTGF and α-SMA in TGF-ß1-induced hepatic stellate cells. Further studies showed that axitinib inhibited mitochondrial damage and reduced oxidative stress and NLRP3 maturation. The use of rotenone and antimycin A confirmed that axitinib could restore the activity of mitochondrial complexes I and III, thereby inhibiting the maturation of NLRP3. In summary, axitinib inhibits the activation of HSCs by enhancing the activity of mitochondrial complexes I and III, thereby alleviating the progression of liver fibrosis. This study reveals the strong potential of axitinib in the treatment of liver fibrosis.

FOXO3 regulates Smad3 and Smad7 through SPON1 circular RNA to inhibit idiopathic pulmonary fibrosis.

Forkhead box protein O3 (FOXO3) has good inhibition ability toward fibroblast activation and extracellular matrix, especially for the treatment of idiopathic pulmonary fibrosis. How FOXO3 regulates pulmonary fibrosis remains unclear. In this study, we reported that FOXO3 had binding sequences with F-spondin 1 (SPON1) promoter, which can activate its transcription and selectively promote the expression of SPON1 circRNA (circSPON1) but not mRNA expression. We further demonstrated that circSPON1 was involved in the extracellular matrix deposition of HFL1. In the cytoplasm, circSPON1 directly interacted with TGF-ß1-induced Smad3 and inhibited the activation of fibroblasts by inhibiting nuclear translocation. Moreover, circSPON1 bound to miR-942-5p and miR-520f-3p that interfered with Smad7 mRNA and promoted Smad7 expression. This study revealed the mechanism of FOXO3-regulated circSPON1 in the development of pulmonary fibrosis. Potential therapeutic targets and new insights into the diagnosis and treatment of idiopathic pulmonary fibrosis based on circRNA were also provided.

Antifibrotic mechanism of avitinib in bleomycin-induced pulmonary fibrosis in mice.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by alveolar epithelial cell injury and lung fibroblast overactivation. At present, only two drugs are approved by the FDA for the treatment of IPF, including the synthetic pyridinone drug, pirfenidone, and the tyrosine kinase inhibitor, nintedanib. Avitinib (AVB) is a novel oral and potent third-generation tyrosine kinase inhibitor for treating non-small cell lung cancer (NSCLC). However, the role of avitinib in pulmonary fibrosis has not yet been established. In the present study, we used in vivo and in vitro models to evaluate the role of avitinib in pulmonary fibrosis. In vivo experiments first verified that avitinib significantly alleviated bleomycin-induced pulmonary fibrosis in mice. Further in vitro molecular studies indicated that avitinib inhibited myofibroblast activation, migration and extracellular matrix (ECM) production in NIH-3T3 cells, mainly by inhibiting the TGF-ß1/Smad3 signalling pathways. The cellular experiments also indicated that avitinib improved alveolar epithelial cell injury in A549 cells. In conclusion, the present findings demonstrated that avitinib attenuates bleomycin-induced pulmonary fibrosis in mice by inhibiting alveolar epithelial cell injury and myofibroblast activation.

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.

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.

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.

Duvelisib attenuates bleomycin-induced pulmonary fibrosis via inhibiting the PI3K/Akt/mTOR signalling pathway.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease that seriously threatens the health of patients. The pathogenesis of IPF is still unclear, and there is a lack of effective therapeutic drugs. Myofibroblasts are the main effector cells of IPF, leading to excessive deposition of extracellular matrix (ECM) and promoting the progression of fibrosis. Inhibiting the excessive activation and relieving autophagy blockage of myofibroblasts is the key to treat IPF. PI3K/Akt/mTOR pathway plays a key regulatory role in promoting fibroblast activation and autophagy inhibition in lung fibrosis. Duvelisib is a PI3K inhibitor that can simultaneously inhibit the activities of PI3K-δ and PI3K-γ, and is mainly used for the treatment of relapsed/refractory chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma tumour (SLL). In this study, we aimed to examine the effects of Duvelisib on pulmonary fibrosis. We used a mouse model of bleomycin-induced pulmonary fibrosis to evaluate the effects of Duvelisib on pulmonary fibrosis in vivo and further explored the potential pharmacological mechanisms of Duvelisib in lung fibroblasts in vitro. The in vivo experiments showed that Duvelisib significantly alleviated bleomycin-induced collagen deposition and improved pulmonary function. In vitro and in vivo pharmacological experiments showed that Duvelisib dose-dependently suppressed lung fibroblast activation and improved autophagy inhibition by inhibiting the phosphorylation of PI3K, Akt and mTOR. Our results indicate that Duvelisib can alleviate the severity of pulmonary fibrosis and provide potential drugs for the treatment of pulmonary fibrosis.

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.

Erratum: Lentinan-functionalized Selenium Nanoparticles target Tumor Cell Mitochondria via TLR4/TRAF3/MFN1 pathway: Erratum.

[This corrects the article DOI: 10.7150/thno.46467.].

Zanubrutinib attenuates bleomycin-induced pulmonary fibrosis by inhibiting the TGF-ß1 signaling pathway.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal interstitial lung disease with high mortality and limited treatment. Only two drugs are currently approved for the treatment of IPF, but both have limitations and neither drug could prolong survival time of patients. The etiology of IPF is unclear, but there is growing evidence that B cells and B cell receptor signaling play important roles in the pathogenesis of IPF. Zanubrutinib is a small molecule inhibitor of Bruton's tyrosine kinase (BTK), which is a key enzyme downstream of B cell receptor signaling pathway, has approved for the treatment of mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). While its role in pulmonary fibrosis remains unknown. In this study, we explored the potential effect and mechanisms of zanubrutinib on pulmonary fibrosis in vivo and in vitro. METHODS: In the in vivo experiments, different doses of zanubrutinib were administered in a mouse model of bleomycin-induced pulmonary fibrosis, and pathological manifestations and lung function indices were evaluated. In vitro experiments were performed using TGF-ß1-stimulated fibroblasts to evaluate the effect of zanubrutinib on the activation and autophagy phenotype of fibroblasts and to explore the underlying signaling pathway mechanism. RESULTS: In vivo experiments demonstrated that zanubrutinib effectively attenuated bleomycin (BLM)-induced pulmonary fibrosis in mice. An in vitro mechanistic study indicated that zanubrutinib suppresses collagen deposition and myofibroblast activation by inhibiting the TGF-ß1/Smad pathway and induces autophagy through the TGF-ß1/mTOR pathway. CONCLUSIONS: Zanubrutinib alleviated bleomycin-induced lung fibrosis in mice by inhibiting the TGF-ß1 signaling pathway.