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Lungs can undergo facultative regeneration, but handicapped regeneration often leads to fibrosis. How microenvironmental cues coordinate lung regeneration via modulating cell death remains unknown. Here, we reveal that the neurotransmitter dopamine modifies the endothelial niche to suppress ferroptosis, promoting lung regeneration over fibrosis. A chemoproteomic approach shows that dopamine blocks ferroptosis in endothelial cells (ECs) via dopaminylating triosephosphate isomerase 1 (TPI1). Suppressing TPI1 dopaminylation in ECs triggers ferroptotic angiocrine signaling to aberrantly activate fibroblasts, leading to a transition from lung regeneration to fibrosis. Mechanistically, dopaminylation of glutamine (Q) 65 residue in TPI1 directionally enhances TPI1's activity to convert dihydroxyacetone phosphate (DHAP) to glyceraldehyde 3-phosphate (GAP), directing ether phospholipid synthesis to glucose metabolism in regenerating lung ECs. This metabolic shift attenuates lipid peroxidation and blocks ferroptosis. Restoring TPI1 Q65 dopaminylation in an injured endothelial niche overturns ferroptosis to normalize pro-regenerative angiocrine function and alleviate lung fibrosis. Overall, dopaminylation of TPI1 balances lipid/glucose metabolism and suppresses pro-fibrotic ferroptosis in regenerating lungs.
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Células Endoteliais , Ferroptose , Pulmão , Animais , Camundongos , Pulmão/metabolismo , Pulmão/patologia , Humanos , Células Endoteliais/metabolismo , Regeneração , Triose-Fosfato Isomerase/metabolismo , Camundongos Endogâmicos C57BL , Transdução de Sinais , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , MasculinoRESUMO
The FGFR signaling pathway is integral to cellular activities, including proliferation, differentiation, and survival. Dysregulation of this pathway is implicated in numerous human cancers, positioning FGFR as a prominent therapeutic target. Here, we conduct a comprehensive review of the function, signaling pathways and abnormal alterations of FGFR, as well as its role in tumorigenesis and development. Additionally, we provide an in-depth analysis of pivotal phase 2 and 3 clinical trials evaluating the performance and safety of FGFR inhibitors in oncology, thereby shedding light on the current state of clinical research in this field. Then, we highlight four drugs that have been approved for marketing by the FDA, offering insights into their molecular mechanisms and clinical achievements. Our discussion encompasses the intricate landscape of FGFR-driven tumorigenesis, current techniques for pinpointing FGFR anomalies, and clinical experiences with FGFR inhibitor regimens. Furthermore, we discuss the inherent challenges of targeting the FGFR pathway, encompassing resistance mechanisms such as activation by gatekeeper mutations, alternative pathways, and potential adverse reactions. By synthesizing the current evidence, we underscore the potential of FGFR-centric therapies to enhance patient prognosis, while emphasizing the imperative need for continued research to surmount resistance and optimize treatment modalities.
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Neoplasias , Receptores de Fatores de Crescimento de Fibroblastos , Transdução de Sinais , Humanos , Neoplasias/tratamento farmacológico , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Terapia de Alvo Molecular/métodos , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , AnimaisRESUMO
Pulmonary fibrosis (PF) is a serious and progressive fibrotic interstitial lung disease that is possibly life-threatening and that is characterized by fibroblast accumulation and collagen deposition. Nintedanib and pirfenidone are currently the only two FDA-approved oral medicines for PF. Some drugs such as antihelminthic drug niclosamide (Ncl) have shown promising therapeutic potentials for PF treatment. Unfortunately, poor aqueous solubility problems obstruct clinical application of these drugs. Herein, we prepared Ncl-encapsulated lipid nanoparticles (Ncl-Lips) for pulmonary fibrosis therapy. A mouse model of pulmonary fibrosis induced by bleomycin (BLM) was generated to assess the effects of Ncl-Lips and the mechanisms of reversing fibrosis in vivo. Moreover, cell models treated with transforming growth factor ß1 (TGFß1) were used to investigate the mechanism through which Ncl-Lips inhibit fibrosis in vitro. These findings demonstrated that Ncl-Lips could alleviate fibrosis, consequently reversing the changes in the levels of the associated marker. Moreover, the results of the tissue distribution experiment showed that Ncl-Lips had aggregated in the lung. Additionally, Ncl-Lips improved the immune microenvironment in pulmonary fibrosis induced by BLM. Furthermore, Ncl-Lips suppressed the TGFß1-induced activation of fibroblasts and epithelial-mesenchymal transition (EMT) in epithelial cells. Based on these results, we demonstrated that Ncl-Lips is an efficient strategy for reversing pulmonary fibrosis via drug-delivery.
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PARP-1 is a crucial factor in repairing DNA single strand damage and maintaining genomic stability. However, the use of PARP-1 inhibitors is limited to combination with chemotherapy or radiotherapy, or as a single agent for indications carrying HRR defects. The ubiquitin-proteasome system processes the majority of cellular proteins and is the principal manner by which cells regulate protein homeostasis. Proteasome inhibitors can cooperate with PARP-1 inhibitors to inhibit DNA homologous recombination repair function. In this study, we designed and synthesized the first dual PARP-1 and proteasome inhibitor based on Olaparib and Ixazomib. Both compounds 42d and 42i exhibited excellent proliferation inhibition and dual-target synergistic effects on cells that were insensitive to PARP-1 inhibitors. Further mechanistic evaluations revealed that 42d and 42i could inhibit homologous recombination repair function by down-regulating the expression of BRCA1 and RAD51. Additionally, 42i induced more significant apoptosis and showed better inhibitory effect on cell proliferation in clonal formation experiments in breast cancer cells than 42d. In summary, our study presented a new class of dual PARP-1/proteasome inhibitors with significant synergistic effects for the treatment of breast cancer.
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Neoplasias da Mama , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Feminino , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Proteassoma/farmacologia , Neoplasias da Mama/tratamento farmacológico , Complexo de Endopeptidases do Proteassoma , Linhagem Celular Tumoral , DNA , Ftalazinas/farmacologia , Ftalazinas/uso terapêuticoRESUMO
Solute carrier family 31 member 1 (SLC31A1) encodes a protein that functions as a homotrimer for the uptake of dietary copper. As a vital member of the cuproptosis gene family, it plays an essential role in both normal tissues and tumors. In this study, we analyzed SLC31A1 across human cancer types to gain a better understanding of SLC31A1's role in cancer development. We searched for information using online databases to analyze, systematically and comprehensively, the role of SLC31A1 in tumors. Amongst nine cancer types, the expression of SLC31A1 was significantly different between tumors and normal tissues. According to further analysis, pancreatic cancer had the highest mutation rate of the SLC31A1 gene, and the methylation levels of the gene were significantly reduced in seven tumors. The expression of SLC31A1 is also linked to the infiltration of tumors by immune cells, the expression of immune checkpoint genes, and immunotherapy markers (TMB and MSI), suggesting that SLC31A1 may be of particular relevance in immunotherapy. This thorough analysis of SLC31A1 across different types of cancer gives us a clear and comprehensive insight into its role in causing cancer on a systemic level.
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Rho-associated coiled-coil-containing kinases (ROCKs), serine/threonine protein kinases, were initially identified as downstream targets of the small GTP-binding protein Rho. Pulmonary fibrosis (PF) is a lethal disease with limited therapeutic options and a particularly poor prognosis. Interestingly, ROCK activation has been demonstrated in PF patients and in animal PF models, making it a promising target for PF treatment. Many ROCK inhibitors have been discovered, and four of these have been approved for clinical use; however, no ROCK inhibitors are approved for the treatment of PF patients. In this article, we describe ROCK signaling pathways and the structure-activity relationship, potency, selectivity, binding modes, pharmacokinetics (PKs), biological functions, and recently reported inhibitors of ROCKs in the context of PF. We will also focus our attention on the challenges to be addressed when targeting ROCKs and discuss the strategy of ROCK inhibitor use in the treatment of PF.
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Fibrose Pulmonar , Animais , Fibrose Pulmonar/tratamento farmacológico , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Quinases Associadas a rho , Relação Estrutura-AtividadeRESUMO
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized with high mortality, unknown etiology, and lack of effective treatment. Many evidences validate that inhibiting the activation of STAT3 is an attractive therapeutic strategy for IPF. Herein, based on our previous findings that nifuroxazide (NIF) could effectively attenuate pulmonary fibrosis by inhibiting STAT3 activation, a series of diarylacylhydrazones derivatives have been designed and synthesized. Among them, compounds 44 and 52 could inhibit TGF-ß1-induced abnormal activation of NIH-3T3 and A549 cells, as well as migration and EMT of A549 cells. In a bleomycin-induced mouse pulmonary fibrosis model, the oral administration of 44 and 52 (bioavailability F = 31.75% and 42.08%) improved mouse lung function and slowed the progression of IPF. Moreover, 52 could reverse the pulmonary fibrosis in treatment model. Collectively, this work shows 44 and 52 could be a potential lead compound for the treatment of IPF, and it is worthy of further study.
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Fibrose Pulmonar Idiopática , Animais , Camundongos , Humanos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/tratamento farmacológico , Células A549 , Bleomicina/farmacologia , Disponibilidade Biológica , Administração Oral , Modelos Animais de DoençasRESUMO
BACKGROUND AND AIMS: Liver fibrosis is an excessive wound-healing response governed by activated hepatic stellate cells (HSCs). To date, there is no drug available for liver fibrosis. Although ferulic acid (FA) has multiple pharmacological functions, its anti-hepatic fibrosis activity is weak. Based on the activity modification of the FA structure, we synthesized a series of phenylacrylic derivatives and found a superior compound, FA11. In this study, we investigated its antifibrotic effect and mechanism. METHODS: Activated HSC and CCl4 -induced mouse liver fibrosis were established and followed by FA11 treatment. Cell viability was measured by CCK-8 assay. Apoptosis and cell cycle analysis were conducted by flow cytometry. Western blot and Real-time qPCR were used to examine the expression of fibrotic and M1/M2-type macrophages markers. Degree of liver fibrosis was shown by histological staining. RESULTS: In vitro, FA11 inhibited TGF-ß1-induced LX-2 proliferation and led to apoptosis and cycle arrest. Furthermore, elevation of fibrotic markers in TGF-ß1-induced LX-2 and primary activated HSC was reversed by FA11. In vivo, FA11 administration alleviated collagen deposition and blocked HSC activation and epithelial-mesenchymal transition (EMT). Additionally, FA11 reduced macrophage infiltration in fibrotic liver and prevented macrophage polarization to a profibrotic phenotype. Meanwhile, the systemic toxicity of CCl4 was also ameliorated by FA11. Mechanistically, FA11 reversed the phosphorylation of canonical and noncanonical TGF-ß1 signalling, as well as FGFR1 signalling. CONCLUSIONS: We reported an oral phenylacrylic acid derivative, FA11, which showed excellent antifibrotic activity and was expected to be an anti-hepatic fibrosis candidate.
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Células Estreladas do Fígado , Fator de Crescimento Transformador beta1 , Camundongos , Animais , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Células Estreladas do Fígado/metabolismo , Cirrose Hepática/patologia , Transdução de Sinais , Fígado/patologia , Tetracloreto de Carbono/efeitos adversos , Tetracloreto de Carbono/metabolismoRESUMO
Identifying the major sources and critical periods of P loss from agricultural fields provides important guidance for reducing P loss. A rice-oilseed rape rotation with no P fertilization (NP, control), medium P fertilization (MP, 90 kg P2O5 ha-1 season-1), and high P fertilization (HP, 180 kg P2O5 ha-1 season-1) was conducted from 2019 to 2021 in the middle Yangtze River Basin. Runoff and leaching P losses were measured simultaneously using runoff event monitoring and a percolation device. Applying P fertilizer increased the P concentration in the field ponding water and percolation water of the rice-oilseed rape rotation. During the rice growing season, total P (TP), dissolved P (DP), and particulate P (PP) concentrations in the field ponding water and percolation water peaked 1 day after P was applied, and then decreased rapidly. After 10 days of fertilization, P concentration in the field ponding water of the MP treatment decreased to a minimum and stabilized, while the HP treatment extended this period to 20 days. The highest P concentration in percolation water was observed at the first sampling during the oilseed rape season, and then it continued to decrease. Inputting P fertilizer increased P loss by 55.0-109.9% compared to the NP treatment, with annual P losses of 0.89-1.10 kg P ha-1, of which runoff loss accounted for 61.7-62.9%. Fertilization and precipitation resulted in varied P loss within and between seasons. Runoff from heavy precipitation during the rice season was the main source of P loss, while PP accounted for 54.7-77.6% of runoff P loss. The strong utilization of soil P by rice resulted in a lower demand for exogenous P fertilizer than oilseed rape. Excessive P input increased the soil P surplus and vertical migration. Therefore, reducing rice season P fertilizer inputs to achieve annual P balance in rice-oilseed rape rotation can effectively reduce soil P surplus and loss while ensuring crop P demand, and the initial 10 d after fertilization in the rice season was a critical period for reducing P runoff loss.
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Brassica napus , Oryza , Fósforo , Fosfatos , Agricultura/métodos , Fertilizantes/análise , Solo , Nitrogênio/análiseRESUMO
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease of unknown aetiology with limited treatment options. Currently, only two drugs, nintedanib and pirfenidone, are approved for the clinical treatment of IPF, but their efficacies are not satisfactory. Previous studies have shown that STAT3 might be a promising therapeutic target for IPF. Here, we designed several series of compounds and finally synthesized a total of 48 novel compounds as potential STAT3 inhibitors. Notably, compound 10K was the most promising compound with excellent inhibitory activity against STAT3 phosphorylation. Subsequently, the anti-pulmonary fibrosis effect of 10K was further investigated by TGF-ß1-stimulated in vitro cell assay and bleomycin (BLM)-induced pulmonary fibrosis animal models. Specifically, compound 10K inhibited the TGF-ß1 induced fibrotic response and blocked the epithelial-mesenchymal transition (EMT) of A549 cells, and its inhibitory effect was significantly better than that of Stattic. In addition, after oral administration of 10K, the symptoms of IPF in the lung tissue in the prevention and treatment mouse models were significantly reversed, and the efficacy was comparable to that of nintedanib. Moreover, 10K improved BLM-induced imbalance of immune microenvironment in lung tissue. Taken together, these results suggest that 10K could be a potential STAT3 inhibitor for the treatment of IPF.
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Fibrose Pulmonar Idiopática , Fator de Crescimento Transformador beta1 , Animais , Camundongos , Bleomicina/farmacologia , Transição Epitelial-Mesenquimal , Fibrose , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/tratamento farmacológico , Pulmão/patologiaRESUMO
INTRODUCTION: Idiopathic pulmonary fibrosis (IPF), a life-threatening interstitial lung disease, is characterized by excessive activation and proliferation of fibroblasts and epithelial-mesenchymal transition (EMT) of alveolar epithelial cells (AEC) accompanied by a large amount of extracellular matrix aggregation. There are no therapies to reverse pulmonary fibrosis, and nintedanib and pirfenidone could only slow down the decline of lung function of IPF patients and delay their survival time. Niclosamide (Ncl) is an antihelminthic drug approved by FDA, which has been reported to have pleiotropic pharmacological activities in recent years, but it's almost complete insolubility in water limits its clinical application. OBJECTIVES: To improve the water solubility of Ncl, explore its ability to reverse BLM-induced pulmonary fibrosis and its specific mechanism of action. METHODS: The Niclosamide-loaded nanoparticles (Ncl-NPs) were formed by emulsification solvent evaporation method. A mouse model induced by bleomycin (BLM) was established to evaluate its effects and mechanisms of inhibiting and reversing fibrosis in vivo. The cell models treated by transforming growth factor-ß1 (TGF-ß1) were used to examine the mechanism of Ncl-NPs inhibiting fibrosis in vitro. Flow cytometry, IHC, IL-4-induced macrophage model and co-culture system were used to assess the effect of Ncl-NPs on M2 polarization of macrophages. RESULTS: The Ncl-NPs improved the poor water solubility of Ncl. The lower dose of Ncl-NPs (2.5 mg/kg) showed the same effect of reversing established pulmonary fibrosis as free Ncl (5 mg/kg). Mechanistic studies revealed that Ncl-NPs blocked TGF-ß/Smad and signaling transducer and activator of transcription 3 (Stat3) signaling pathways and inhibited the M2 polarization of macrophages. Additionally, H&E staining of the tissues initially showed the safety of Ncl-NPs. CONCLUSION: These results indicate Ncl-NPs may serve as a new idea for the treatment of pulmonary fibrosis.
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Fibrose Pulmonar Idiopática , Doenças Pulmonares Intersticiais , Camundongos , Animais , Niclosamida/efeitos adversos , Niclosamida/metabolismo , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/metabolismo , Doenças Pulmonares Intersticiais/metabolismo , Matriz Extracelular/metabolismo , Células Epiteliais AlveolaresRESUMO
Rosa sterilis is a new variety of Rosa roxburghii Tratt, and is rich in bioactive substances, but its role in pulmonary fibrosis has not been elucidated. The purpose of this study was to investigate the potential components of Rosa sterili juice (RSJ) and its anti-pulmonary fibrosis effects. We employed HPLC-Q-Exactive Orbitrap-MS, HPLC, and ICP-MS to analyze the composition of RSJ, and carried out free radical scavenging assays to determine its antioxidant activity. Then, the anti-pulmonary fibrosis effect of RSJ was evaluated using the bleomycin-induced mice model and the TGF-ß1-induced cell model. A total of 49 components were identified in RSJ, and the vitamin C content was 11.29 ± 0.05 mg mL-1. Catechin was the most abundant phenol, and potassium was the highest mineral element in RSJ. Attractively, we found that RSJ alleviated bleomycin-induced inflammation infiltration and tissue injury, and inhibited TGF-ß1-induced epithelial-mesenchymal transition and fibroblast differentiation through the Smad2/3 signaling pathway. In conclusion, we discovered a new health-protective activity of Rosa sterilis, and the high levels of polyphenols, flavonoids, and vitamin C may be the basic anti-fibrosis substances.
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Preparações de Plantas , Fibrose Pulmonar , Rosa , Animais , Camundongos , Ácido Ascórbico/análise , Ácido Ascórbico/uso terapêutico , Bleomicina , Transição Epitelial-Mesenquimal , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/terapia , Rosa/química , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Preparações de Plantas/química , Preparações de Plantas/uso terapêutico , Catequina/análise , Catequina/uso terapêutico , Polifenóis/análise , Polifenóis/uso terapêutico , Flavonoides/química , Flavonoides/uso terapêuticoRESUMO
Liver fibrosis is characterized by the excessive deposition of extracellular matrix components and results from chronic liver injury. At present, there is no approved drug for the treatment of liver fibrosis by the Food and Drug Administration. Here, we have reported a series of novel compounds with phenacrylanilide scaffolds that potently inhibit the transfer growth factor ß1 (TGF-ß1)-induced activation of LX-2, a hepatic stellate cell (HSC) line. Among them, compound 42 suppressed TGF-ß1-induced upregulation of fibrotic markers (α-SMA and fibronectin) and showed excellent safety in vitro. Furthermore, in a carbon tetrachloride (CCl4) -induced liver fibrosis model, 42 at a dose of 30 mg/kg/day through oral administration for 3 weeks effectively improved liver function, restored damaged liver structures, and reduced collagen deposition, with a greater effect than Tranilast. In addition, epithelial-mesenchymal transition (EMT) is inhibited by compound 42 in the process of fibrosis. Meanwhile, the imbalanced immune microenvironment could also be effectively reversed. More interestingly, compound 42 prolongs the survival of CCl4 mice and ameliorates CCl4-induced injury to spleen, kidney, lung and heart. Altogether, these results suggest that 42 could be a potential drug candidate for the treatment of liver fibrosis.
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Tetracloreto de Carbono , Fibronectinas , Animais , Tetracloreto de Carbono/metabolismo , Fibronectinas/metabolismo , Fibronectinas/farmacologia , Fibronectinas/uso terapêutico , Fibrose , Células Estreladas do Fígado , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Camundongos , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Fibrosis is characterized by the excessive extracellular matrix deposition due to dysregulated wound and connective tissue repair response. Multiple organs can develop fibrosis, including the liver, kidney, heart, and lung. Fibrosis such as liver cirrhosis, idiopathic pulmonary fibrosis, and cystic fibrosis caused substantial disease burden. Persistent abnormal activation of myofibroblasts mediated by various signals, such as transforming growth factor, platelet-derived growth factor, and fibroblast growh factor, has been recongized as a major event in the occurrence and progression of fibrosis. Although the mechanisms driving organ-specific fibrosis have not been fully elucidated, drugs targeting these identified aberrant signals have achieved potent anti-fibrotic efficacy in clinical trials. In this review, we briefly introduce the aetiology and epidemiology of several fibrosis diseases, including liver fibrosis, kidney fibrosis, cardiac fibrosis, and pulmonary fibrosis. Then, we summarise the abnormal cells (epithelial cells, endothelial cells, immune cells, and fibroblasts) and their interactions in fibrosis. In addition, we also focus on the aberrant signaling pathways and therapeutic targets that regulate myofibroblast activation, extracellular matrix cross-linking, metabolism, and inflammation in fibrosis. Finally, we discuss the anti-fibrotic drugs based on their targets and clinical trials. This review provides reference for further research on fibrosis mechanism, drug development, and clinical trials.
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Células Endoteliais , Fibrose Pulmonar Idiopática , Células Endoteliais/metabolismo , Fibroblastos/metabolismo , Fibrose , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/metabolismo , Cirrose Hepática , Miofibroblastos/metabolismo , Miofibroblastos/patologiaRESUMO
Gastric cancer is the second most lethal cancer across the world. With the progress in therapeutic approaches, the 5-year survival rate of early gastric cancer can reach > 95%. However, the prognosis and survival time of advanced gastric cancer is still somber. Therefore, more effective targeted therapies for gastric cancer treatment are urgently needed. FGFR, VEGFR and other receptor tyrosine kinases have recently been suggested as potential targets for gastric cancer treatment. We herein report the discovery of pyrrolo[2,3-d]pyrimidin/pyrazolo[3,4-d]pyrimidin-4-amine derivatives as a new class of FGFRs-dominant multi-target receptor tyrosine kinase inhibitors. SAR assessment identified the most active compounds 8f and 8k, which showed excellent inhibitory activity against a variety of receptor tyrosine kinases. Moreover, 8f and 8k displayed excellent potency in the SNU-16 gastric cancer cell line. Furthermore, 8f and 8k could inhibit FGFR1 phosphorylation and downstream signaling pathways as well as induce cell apoptosis. In vivo, 8f and 8k suppress tumor growth in the SNU-16 xenograft model without inducing obvious toxicity. These findings raise the possibility that compounds 8f and 8k might serve as potential agents for the treatment of gastric cancer.
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Antineoplásicos , Neoplasias Gástricas , Aminas/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases , Neoplasias Gástricas/tratamento farmacológico , Relação Estrutura-Atividade , Tirosina/farmacologiaRESUMO
Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal, and chronic lung disease, lacking a validated and effective therapy. Blueberry has demonstrated multiple pharmacological activities including anti-inflammatory, antioxidant, and anticancer. Therefore, the objective of this study was to investigate whether blueberry juice (BBJ) could ameliorate IPF. Experiments in vitro revealed that BBJ could significantly reduce the expressions of TGF-ß1 modulated fibrotic protein, which were involved in the cascade of fibrosis in NIH/3T3 cells and human pulmonary fibroblasts. In addition, for rat primary lung fibroblasts (RPLFs), BBJ promoted the cell apoptosis along with reducing the expressions of α-SMA, vimentin, and collagen I, while increasing the E-cadherin level. Furthermore, BBJ could reverse epithelial-mesenchymal transition (EMT) phenotypic changes and inhibit cell migration, along with inducing the upregulation of E-cadherin in A549 cells. Compared with the vehicle group, BBJ treatment alleviated fibrotic pathological changes and collagen deposition in both bleomycin-induced prevention and treatment pulmonary fibrosis models. In fibrotic lung tissues, BBJ remarkably suppressed the expressions of collagen I, α-SMA, and vimentin and improved E-cadherin, which may be related to its inhibition of the TGF-ß1/Smad pathway and anti-inflammation efficacy. Taken together, these findings comprehensively proved that BBJ could effectively prevent and attenuate idiopathic pulmonary fibrosis via suppressing EMT and the TGF-ß1/Smad signaling pathway.
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BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a serious interstitial lung disease with a complex pathogenesis and high mortality. The development of new drugs is time-consuming and laborious; therefore, research on the new use of old drugs can save time and clinical costs and even avoid serious side effects. Nifuroxazide (NIF) was originally used to treat diarrhoea, but more recently, it has been found to have additional pharmacological effects, such as anti-tumour effects and inhibition of inflammatory diseases related to diabetic nephropathy. However, there are no reports regarding its role in pulmonary fibrosis. METHODS: The therapeutic effect of NIF on pulmonary fibrosis in vivo was measured by ELISA, hydroxyproline content, H&E and Masson staining, immunohistochemistry (IHC) and western blot. Immune cell content in lung tissue was also analysed by flow cytometry. NIF cytotoxicity was evaluated in NIH/3T3 cells, human pulmonary fibroblasts (HPFs), A549 cells and rat primary lung fibroblasts (RPLFs) using the MTT assay. Finally, an in vitro cell model created by transforming growth factor-ß1 (TGF-ß1) stimulation was assessed using different experiments (immunofluorescence, western blot and wound migration assay) to evaluate the effects of NIF on the activation of NIH/3T3 and HPF cells and the epithelial-mesenchymal transition (EMT) and migration of A549 cells. RESULTS: In vivo, intraperitoneal injection of NIF relieved and reversed pulmonary fibrosis caused by bleomycin (BLM) bronchial instillation. In addition, NIF inhibited the expression of a variety of cellular inflammatory factors and immune cells. Furthermore, NIF suppressed the activation of fibroblasts and EMT of epithelial cells induced by TGF-ß1. Most importantly, we used an analytical docking experiment and thermal shift assay to further verify that NIF functions in conjunction with signal transducer and activator of transcription 3 (Stat3). Moreover, NIF inhibited the TGF-ß/Smad pathway in vitro and decreased the expression of phosphorylated Stat3 in vitro and in vivo. CONCLUSION: Taken together, we conclude that NIF inhibits and reverses pulmonary fibrosis, and these results support NIF as a viable therapeutic option for IPF treatment.