Coronavirus disease 2019 (COVID-19) remains a major public health concern, and vaccine unavailability, hesitancy, or failure underscore the need for discovery of efficacious antiviral drug therapies. Numerous approved drugs target protein kinases associated with viral life cycle and symptoms of infection. Repurposing of kinase inhibitors is appealing as they have been vetted for safety and are more accessible for COVID-19 treatment. However, an understanding of drug mechanism is needed to improve our understanding of the factors involved in pathogenesis. We tested the in vitro activity of three kinase inhibitors against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including inhibitors of AXL kinase, a host cell factor that contributes to successful SARS-CoV-2 infection. Using multiple cell-based assays and approaches, gilteritinib, nintedanib, and imatinib were thoroughly evaluated for activity against SARS-CoV-2 variants. Each drug exhibited antiviral activity, but with stark differences in potency, suggesting differences in host dependency for kinase targets. Importantly, for gilteritinib, the amount of compound needed to achieve 90% infection inhibition, at least in part involving blockade of spike protein-mediated viral entry and at concentrations not inducing phospholipidosis (PLD), approached a clinically achievable concentration. Knockout of AXL, a target of gilteritinib and nintedanib, impaired SARS-CoV-2 variant infectivity, supporting a role for AXL in SARS-CoV-2 infection and supporting further investigation of drug-mediated AXL inhibition as a COVID-19 treatment. This study supports further evaluation of AXL-targeting kinase inhibitors as potential antiviral agents and treatments for COVID-19. Additional mechanistic studies are needed to determine underlying differences in virus response. 相似文献
AIM: To investigate the effects of nintedanib thermo-sensitive hydrogel (NTH) on neovascularization and related markers in corneal alkali burns of Wistar rats. METHODS: NTH was prepared by grinding, and its phase-transition temperature was determined. Thirty specific-pathogen-free Wistar rats served as a model of corneal alkali burn in the right eye were randomly divided into 3 groups (n=10, each): model group treated with 0.9% saline once a day, NTH group with 0.2% nintedanib b.i.d, and dexamethasone (DEX) group with DEX ointment once a day. The left eye of rats served as the controls. The corneal transparency was observed under a slit-lamp microscope, and the area of neovascularization was calculated. On day 7, the rats were sacrificed, and the cornea was removed and embedded with paraffin, then stained with hematoxylin-eosin, and the expression of VEGFR-2 and CD31 in the corneal tissues of each group was detected by immunofluorescence. RESULTS: The phase-transition temperature of nintedanib obtained by grinding was 37°C after adding artificial tears. The results of the alkali burn model indicated that the growth rate of neovascularization in the NTH group was slower than that in the model group, and the neovascularization area was significantly smaller than that in the model group (P<0.05). Moreover. CD31 and VEGFR-2 expression levels in the NTH group were significantly lower than those in the model group. CONCLUSION: NTH becomes colloidal at body temperature, which is beneficial for releasing the drug slowly and can significantly inhibit the neovascularization of corneal induced by alkali burn in rats. 相似文献
AIM: To evaluate the potential efficacy and mechanisms of nintedanib in corneal neovascularization (NV) in rabbit models.
METHODS: Corneal NV was induced using 1 mol/L NaOH. Rabbits (n=21) were randomized to 3 groups: Group 1 were treated with 0.9% NaCl, Group 2 with Avastin (5 mg/mL), and Group 3 with nintedanib (1 mg/mL). All treatments started 1d after alkaline burns and were topically performed 3 times a day for 2wk. Photographs were taken on a slit lamp microscope on day 7 and 14. The NV area, the length of the vascularization and angiogenesis index (AI) were used to evaluate the corneal NV. On day 14, the immunohistochemical (IHC) studies of the cornea were examined. Western blot was performed to test the expression levels of vascular endothelial growth factor (VEGF), Akt, p-Akt, P38, p-P38, MMP-2 and MMP-9.
RESULTS: The corneal NV area, vessel length and AI in Group 3 were significantly lower than Group 2, with both being lower than Group 1. IHC staining showed that VEGF was significantly overexpressed in the epithelium and stroma of cornea following alkaline burns. In contrast, the level of VEGF was significantly suppressed in both Group 2 and Group 3. Western blot results further confirmed that, compared with Group 1, Group 3 had significantly reduced expressions of VEGF, Akt, p-Akt, p-P38, MMP-2, and MMP-9 in corneal tissues. Trends of lower levels of MMP-2, AKT, and p-AKT in Group 3 than Group 2 were identified.
CONCLUSION: Nintedanib and Avastin can effectively inhibit corneal NV, with P38 MAPK and AKT signaling pathways being possibly involved. Nintedanib seems more effective than Avastin and has the potential to be a novel therapy for preventing corneal NV. 相似文献
Introduction: Interstitial lung disease (ILD) is the most serious complication of systemic sclerosis (SSc). There is no accepted guidance as to which clinical, radiological or physiological thresholds should prompt initiation or changes in treatment. Furthermore, some patients with extensive disease remain stable without the need for intervention whilst others with limited disease at the outset, experience a precipitous decline.
Areas covered: In this article, evidence for the integration of a number of disease-specific and patient-related domains are discussed and proposed. Introduction and maintenance of therapy requires a nuanced understanding of these factors and is crucial when weighing up the risks and benefits of immunomodulation. The evidence for the existing treatment modalities is discussed and the future directions for management of patients with SSc-ILD, which may include antifibrotic or biologic therapy, are explored.
Expert commentary: In the management of SSc-ILD, a multidisciplinary team approach which integrates physiology and radiology with the patient at the centre of the process is crucial for effective management and provision of the best outcomes. 相似文献
The fibrotic tumor microenvironment is a pivotal therapeutic target. Nintedanib, a clinically approved multikinase antifibrotic inhibitor, is effective against lung adenocarcinoma (ADC) but not squamous cell carcinoma (SCC). Previous studies have implicated the secretome of tumor-associated fibroblasts (TAFs) in the selective effects of nintedanib in ADC, but the driving factor(s) remained unidentified. Here we examined the role of tissue inhibitor of metalloproteinase-1 (TIMP-1), a tumor-promoting cytokine overproduced in ADC-TAFs. To this aim, we combined genetic approaches with in vitro and in vivo preclinical models based on patient-derived TAFs. Nintedanib reduced TIMP-1 production more efficiently in ADC-TAFs than SCC-TAFs through a SMAD3-dependent mechanism. Cell culture experiments indicated that silencing TIMP1 in ADC-TAFs abolished the therapeutic effects of nintedanib on cancer cell growth and invasion, which were otherwise enhanced by the TAF secretome. Consistently, co-injecting ADC cells with TIMP1-knockdown ADC-TAFs into immunocompromised mice elicited a less effective reduction of tumor growth and invasion under nintedanib treatment compared to tumors bearing unmodified fibroblasts. Our results unveil a key mechanism underlying the selective mode of action of nintedanib in ADC based on the excessive production of TIMP-1 in ADC-TAFs. We further pinpoint reduced SMAD3 expression and consequent limited TIMP-1 production in SCC-TAFs as key for the resistance of SCC to nintedanib. These observations strongly support the emerging role of TIMP-1 as a critical regulator of therapy response in solid tumors. 相似文献
AIM: To investigate whether nintedanib can inhibit pterygium cells through the fibroblast growth factor receptor 2 (FGFR2)/extracellular-signal-regulated kinase (ERK) pathway.
METHODS: Human primary pterygium cells were cultured in vitro. After treatment with nintedanib, the cell morphology was observed under microscopy, the morphological changes of the nucleus were observed after DAPI staining, apoptosis was analyzed by Annexin-V FITC/PI double staining, and the changes of apoptosis-associated proteins were detected by Western blot. The binding ability of nintedanib to FGFR2 was predicted by molecular docking. Finally, by silencing FGFR2, we explored whether nintedanib inhibited FGFR2/ERK pathway.
RESULTS: The results showed that nintedanib inhibited the growth of pterygium cells and caused nuclear pyknosis. The results of Annexin-VFITC/PI double staining showed that nintedanib was able to induce early and late apoptosis of pterygium cells, significantly increasing the expression of apoptosis-associated proteins Bax and cleaved-Caspase3 (P<0.05), and reducing the expression of Bcl-2 (P<0.05). In addition, nintedanib significantly inhibited ERK1/2 phosphorylation through FGFR2 (P<0.05). After silencing the expression of FGFR2, there was no significant difference in the inhibition of ERK1/2 phosphorylation by nintedanib (P>0.05).
CONCLUSION: Nintedanib induces apoptosis of pterygium cells by inhibiting FGFR2/ERK pathway. 相似文献