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1.
Oxid Med Cell Longev ; 2021: 7385160, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34457118

RESUMO

Obesity is considered as a risk factor of osteoarthritis (OA), but the precise relationship is still poorly understood. Leptin, one of the most relevant factors secreted by adipose tissues, plays an important role in the pathogenesis of OA. Our aim was to investigate the regulation and molecular mechanism of the leptin signaling pathway in obesity-related OA. SD rats were fed with a high-fat diet (HFD) for 5, 15, and 27 weeks. The levels of leptin in serum increased from W5, while in the synovial fluid increased from W15. The histological evaluation showed that the pathological changes of OA occurred at 27 weeks rather than 5 or 15 weeks. We also found that leptin induced CD14/TLR4 activation by the JAK2-STAT3 signaling pathway to promote OA. Moreover, silencing SOCS3 enhanced leptin-induced JAK2-STAT3-CD14/TLR4 activation in rat primary chondrocytes. Our findings indicated that leptin may be one of the initiating factors of obesity-related OA. TLR4 is at least partially regulated by leptin through the JAK2-STAT3-CD14 pathway. Meanwhile, SOCS3 acting as a negative feedback inhibitor of leptin signaling presented a potential therapeutic prospect for obesity-related OA. Our study provided new evidence suggesting the key role of leptin in mediating obesity-related OA process and its underlying mechanisms.


Assuntos
Regulação da Expressão Gênica , Janus Quinase 2/metabolismo , Leptina/metabolismo , Obesidade/complicações , Osteoartrite/patologia , Fator de Transcrição STAT3/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Janus Quinase 2/genética , Masculino , Osteoartrite/etiologia , Osteoartrite/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/genética , Receptor 4 Toll-Like/genética
2.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281163

RESUMO

Erythropoietin (EPO) acts on multiple tissues through its receptor EPOR, a member of a cytokine class I receptor superfamily with pleiotropic effects. The interaction of EPO and EPOR triggers the activation of several signaling pathways that induce erythropoiesis, including JAK2/STAT5, PI3K/AKT, and MAPK. The canonical EPOR/JAK2/STAT5 pathway is a known regulator of differentiation, proliferation, and cell survival of erythroid progenitors. In addition, its role in the protection of other cells, including cancer cells, is under intense investigation. The involvement of EPOR/JAK2/STAT5 in other processes such as mRNA splicing, cytoskeleton reorganization, and cell metabolism has been recently described. The transcriptomics, proteomics, and epigenetic studies reviewed in this article provide a detailed understanding of EPO signalization. Advances in this area of research may be useful for improving the efficacy of EPO therapy in hematologic disorders, as well as in cancer treatment.


Assuntos
Eritropoetina/metabolismo , Fator de Transcrição STAT5/metabolismo , Fator de Transcrição STAT5/fisiologia , Animais , Diferenciação Celular/efeitos dos fármacos , Epigenômica/métodos , Eritropoese/efeitos dos fármacos , Eritropoetina/fisiologia , Humanos , Janus Quinase 2/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteômica/métodos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores da Eritropoetina/metabolismo , Receptores da Eritropoetina/fisiologia , Fator de Transcrição STAT5/genética , Transdução de Sinais/efeitos dos fármacos , Transativadores/metabolismo , Transcriptoma/genética
3.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206393

RESUMO

BACKGROUND: Chronic inflammation has been recognized in neoplastic disorders, including myeloproliferative neoplasm (MPN), as an important regulator of angiogenesis. AIMS: We investigated the influence of vascular endothelial growth factor (VEGF) and pro-inflammatory interleukin-6 (IL-6) on the expression of angiogenic factors, as well as inflammation-related signaling in mononuclear cells (MNC) of patients with MPN and JAK2V617F positive human erythroleukemic (HEL) cells. RESULTS: We found that IL-6 did not change the expression of angiogenic factors in the MNC of patients with MPN and HEL cells. However, IL-6 and the JAK1/2 inhibitor Ruxolitinib significantly increased angiogenic factors-endothelial nitric oxide synthase (eNOS), VEGF, and hypoxia-inducible factor-1 alpha (HIF-1α)-in patients with polycythemia vera (PV). Furthermore, VEGF significantly increased the expression of HIF-1α and eNOS genes, the latter inversely regulated by PI3K and mTOR signaling in the MNC of primary myelofibrosis (PMF). VEGF and inhibitors of inflammatory JAK1/2, PI3K, and mTOR signaling reduced the eNOS protein expression in HEL cells. VEGF also decreased the expression of eNOS and HIF-1α proteins in the MNC of PMF. In contrast, VEGF increased eNOS and HIF-1α protein expression in the MNC of patients with PV, which was mediated by the inflammatory signaling. VEGF increased the level of IL-6 immunopositive MNC of MPN. In summary, VEGF conversely regulated gene and protein expression of angiogenic factors in the MNC of PMF, while VEGF increased angiogenic factor expression in PV mediated by the inflammation-related signaling. CONCLUSION: The angiogenic VEGF induction of IL-6 supports chronic inflammation that, through positive feedback, further promotes angiogenesis with concomitant JAK1/2 inhibition.


Assuntos
Transtornos Mieloproliferativos/etiologia , Transtornos Mieloproliferativos/metabolismo , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Biomarcadores , Medula Óssea/metabolismo , Medula Óssea/patologia , Linhagem Celular Tumoral , Citocinas/metabolismo , Regulação da Expressão Gênica , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Mutação , Transtornos Mieloproliferativos/patologia
4.
Nat Commun ; 12(1): 4441, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34290255

RESUMO

BRD4, a Bromodomain and Extraterminal (BET) protein family member, is a promising anti-cancer drug target. However, resistance to BET inhibitors targeting BRD4 is common in solid tumors. Here, we show that cancer-associated fibroblast (CAF)-activated stromal signaling, interleukin-6/8-JAK2, induces BRD4 phosphorylation at tyrosine 97/98 in colorectal cancer, resulting in BRD4 stabilization due to interaction with the deubiquitinase UCHL3. BRD4 phosphorylation at tyrosine 97/98 also displays increased binding to chromatin but reduced binding to BET inhibitors, resulting in resistance to BET inhibitors. We further show that BRD4 phosphorylation promotes interaction with STAT3 to induce chromatin remodeling through concurrent binding to enhancers and super-enhancers, supporting a tumor-promoting transcriptional program. Inhibition of IL6/IL8-JAK2 signaling abolishes BRD4 phosphorylation and sensitizes BET inhibitors in vitro and in vivo. Our study reveals a stromal mechanism for BRD4 activation and BET inhibitor resistance, which provides a rationale for developing strategies to treat CRC more effectively.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Montagem e Desmontagem da Cromatina , Neoplasias Colorretais/metabolismo , Resistencia a Medicamentos Antineoplásicos , Fatores de Transcrição/metabolismo , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Fibroblastos Associados a Câncer/metabolismo , Proteínas de Ciclo Celular/antagonistas & inibidores , Cromatina/metabolismo , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Janus Quinase 2/metabolismo , Fosforilação , Domínios Proteicos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Fatores de Transcrição/antagonistas & inibidores , Microambiente Tumoral , Ubiquitina Tiolesterase/metabolismo
5.
Int J Mol Sci ; 22(14)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34299194

RESUMO

A heterogeneous genetic subtype of B-cell precursor acute lymphoblastic leukemia is driven by constitutive kinase-activation, including patients with JAK2 fusions. In our study, we model the impact of a novel JAK2 fusion protein on hematopoietic development in human induced pluripotent stem cells (hiPSCs). We insert the RUNX1-JAK2 fusion into one endogenous RUNX1 allele through employing in trans paired nicking genome editing. Tagging of the fusion with a degron facilitates protein depletion using the heterobifunctional compound dTAG-13. Throughout in vitro hematopoietic differentiation, the expression of RUNX1-JAK2 is driven by endogenous RUNX1 regulatory elements at physiological levels. Functional analysis reveals that RUNX1-JAK2 knock-in cell lines yield fewer hematopoietic progenitors, due to RUNX1 haploinsufficiency. Nevertheless, these progenitors further differentiate toward myeloid lineages to a similar extent as wild-type cells. The expression of the RUNX1-JAK2 fusion protein only elicits subtle effects on myeloid differentiation, and is unable to transform early hematopoietic progenitors. However, phosphoprotein and transcriptome analyses reveal that RUNX1-JAK2 constitutively activates JAK-STAT signaling in differentiating hiPSCs and at the same time upregulates MYC targets-confirming the interaction between these pathways. This proof-of-principle study indicates that conditional expression of oncogenic fusion proteins in combination with hematopoietic differentiation of hiPSCs may be applicable to leukemia-relevant disease modeling.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Janus Quinase 2/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição STAT/metabolismo , Diferenciação Celular , Células Cultivadas , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Perfilação da Expressão Gênica/métodos , Células-Tronco Hematopoéticas/citologia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Janus Quinase 2/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Transdução de Sinais
6.
Nat Commun ; 12(1): 3651, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34131122

RESUMO

Extracellular cytokines are enriched in the tumor microenvironment and regulate various important properties of cancers, including autophagy. However, the precise molecular mechanisms underlying the link between autophagy and extracellular cytokines remain to be elucidated. In the present study, we demonstrate that IL-6 activates autophagy through the IL-6/JAK2/BECN1 pathway and promotes chemotherapy resistance in colorectal cancer (CRC). Mechanistically, IL-6 triggers the interaction between JAK2 and BECN1, where JAK2 phosphorylates BECN1 at Y333. We demonstrate that BECN1 Y333 phosphorylation is crucial for BECN1 activation and IL-6-induced autophagy by regulating PI3KC3 complex formation. Furthermore, we investigate BECN1 Y333 phosphorylation as a predictive marker for poor CRC prognosis and chemotherapy resistance. Combination treatment with autophagy inhibitors or pharmacological agents targeting the IL-6/JAK2/BECN1 signaling pathway may represent a potential strategy for CRC cancer therapy.


Assuntos
Autofagia/fisiologia , Proteína Beclina-1/metabolismo , Tratamento Farmacológico , Interleucina-6/metabolismo , Autofagia/efeitos dos fármacos , Proteínas Relacionadas à Autofagia/metabolismo , Proteína Beclina-1/química , Proteína Beclina-1/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-6/farmacologia , Janus Quinase 2/química , Janus Quinase 2/metabolismo , Fosforilação , Domínios e Motivos de Interação entre Proteínas , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos
7.
Aging (Albany NY) ; 13(12): 16667-16683, 2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34165442

RESUMO

IL-6 is reported to be the main upstream activator, instead of the downstream target of JAK2/STAT3. This study is intended to explore the correlation of IL-6 and JAK2/STAT3 signaling pathway with clinicopathological features and prognosis in nasopharyngeal carcinoma (NPC). First, NPC tissues and normal nasopharyngeal epithelial tissues were obtained from 117 NPC patients. Next, we detected expression levels of IL-6 in serum and those of STAT3, p-STAT3, JAK2, p-JAK2 and CyclinD1 in tissues. A follow-up was conducted in all the patients and the survival was analyzed. To verify the correlation of IL-6 and JAK2/STAT3 pathway, CNE-1 and SUNE1 NPC cells were interpreted with IL-6 and JAK2/STAT3 signaling pathway inhibitor AG490 to detect cell viability, migration and invasion. We observed thatIL-6 increased in serum of NPC patients. The expressions of IL-6, STAT3, p-STAT3, JAK2, p-JAK2 and CyclinD1 in NPC tissues were higher and correlated with TNM stage and lymph node metastasis (LNM). Survival rates were reduced in patients with positive expressions of IL-6, STAT3, p-STAT3, JAK2, p-JAK2 and CyclinD1. LNM and positive expressions of IL-6 and p-STAT3 were risk factors for poor prognosis of NPC. Besides, recombinant human IL-6 promoted cell proliferation, invasion and migration while AG490 inhibited cell proliferation, invasion and migration in CNE-1 and SUNE1 NPC cells. The results demonstrated that increased IL-6 expression and the activated JAK2/STAT3 signaling pathway had effects on prognosis and reduced the survival time in NPC patients, which provide a potential target for the treatment of NPC.


Assuntos
Interleucina-6/metabolismo , Janus Quinase 2/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Adolescente , Adulto , Idoso , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Ciclina D1/genética , Ciclina D1/metabolismo , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-6/genética , Janus Quinase 2/genética , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Invasividade Neoplásica , Fosforilação , Prognóstico , Modelos de Riscos Proporcionais , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Risco , Fator de Transcrição STAT3/genética , Análise de Sobrevida , Regulação para Cima/genética , Adulto Jovem
8.
Toxicol Lett ; 349: 84-91, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34153408

RESUMO

AIM: Smoking has been considered as a risk factor of chronic pancreatitis (CP), but the potential mechanism is still unknown. The major pathological feature of CP is pancreatic fibrosis, whose major functional cells are pancreatic stellate cells (PSCs). Nicotine is the major component of cigarette smoke, our recent study suggested that nicotine has the potential to facilitate pancreatic fibrosis in CP. This study was aimed to analyze the function and mechanism of nicotine on PSCs and pancreatic fibrosis in rats. MATERIALS AND METHODS: In vivo, a rat CP model was induced by intraperitoneal injection of 20 % L-arginine hydrochloride (200 mg/100 g) at 1 h intervals twice per week, nicotine was injected subcutaneously at a dose of 1 mg/kg body weight per day. After four weeks, the pancreatic tissue was collected for H&E, Masson and immunohistochemical staining. In vitro, primary rPSCs were isolated from rats and treated with nicotine (0.1 µM and 1 µM). The proliferation、apoptosis、α-SMA expression、extracellular matrix (ECM) metabolism and α7nAChR-mediated JAK2/STAT3 signaling pathway of rPSCs were detected by CCK-8 assay、flow cytometry、real-time Q-PCR and western blotting analysis. The α7nAChR antagonist α-bungarotoxin (α-BTX) was used to perform inhibition experiments. KEY FINDINGS: Nicotine increased pancreatic damage, collagen deposition and activation of PSCs in the CP rat model. In rPSCs, the proliferation, α-SMA expression and ECM formation were significantly promoted by nicotine in a dose-dependent manner. Meanwhile, the apoptosis of rPSCs was significantly reduced after nicotine treatment. Moreover, nicotine also activated the α7nAChR-mediated JAK2/STAT3 signaling pathway in rPSCs. These effects of nicotine on rPSCs were blocked by α-BTX. SIGNIFICANCE: Our finding in this research suggests that nicotine facilitates pancreatic fibrosis by promoting activation of pancreatic stellate cells via α7nAChR-mediated JAK2/STAT3 signaling pathway in rats, partly revealing the mechanism of smoking on chronic pancreatitis.


Assuntos
Janus Quinase 2/metabolismo , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Células Estreladas do Pâncreas/efeitos dos fármacos , Pancreatite Crônica/induzido quimicamente , Fator de Transcrição STAT3/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Fibrose , Masculino , Células Estreladas do Pâncreas/enzimologia , Células Estreladas do Pâncreas/patologia , Pancreatite Crônica/enzimologia , Pancreatite Crônica/patologia , Ratos Wistar , Transdução de Sinais , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
9.
Chem Biodivers ; 18(6): e2100139, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33973702

RESUMO

Shengxuening (SXN) is a Chinese patent medicine with main ingredients (including chlorophyll derivatives and sodium iron chlorophyllin) extracted from silkworm excrement. SXN exhibited efficacy in clinical trials of renal anemia and iron deficiency anemia; however, the specific mechanisms remain unclear. This study found that SXN increased the number of peripheral blood cells and improved the bone marrow morphology in myelosuppressed mouse model, reversed the reduction in body weight and spleen indices, and increased the serum levels of erythropoietin and granulocyte-macrophage colony-stimulating factor. Quantitative real-time PCR array and Western blot analysis showed the enhanced expression of stem cell factor (SCF), JAK2, and STAT3 in the liver. These results suggested that SXN promoted the recovery of hemopoietic function in myelosuppressed models by increasing the secretion of hematopoietic factors and activating the JAK2/STAT3 pathway. Therefore, this medicine may be applied as therapeutic pharmaceutical drug to mitigate myelosuppression.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Janus Quinase 2/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Bombyx , Células Cultivadas , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Humanos , Janus Quinase 2/genética , Células K562 , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Estrutura Molecular , Fator de Transcrição STAT3/genética , Transdução de Sinais/efeitos dos fármacos
10.
Phytomedicine ; 86: 153565, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33945919

RESUMO

BACKGROUND: Allergic rhinitis (AR) is an inflammatory, immunoglobulin E (IgE)-mediated disease characterized by the typical symptoms of sneezing, rhinorrhea, nasal itching, and congestion. Higenamine (HG) is a plant-based alkaloid, possesses a wide range of activities, including vascular and tracheal relaxation, antioxidative, antiapoptotic, anti-inflammatory, and immunomodulatory activities. So far, the effect and the underlying mechanism of HG on AR have not been studied. HYPOTHESIS/PURPOSE: The purpose of this study was to evaluate the effects of HG on AR and investigate its underlying mechanism. METHODS: The effects of HG on AR were evaluated in an ovalbumin-induced AR mouse model. Network pharmacology-based methods such as target prediction, protein-protein interaction (PPI) network analysis, pathway analysis, and molecular docking were used to identify the likely HG targets. Finally, we validated the mechanism of action of HG through its effects on these targets in human nasal epithelial cells (HNEpCs). RESULTS: Oral administration of 30, 60, and 120 mg/kg HG significantly alleviated rubbing and sneezing in AR mice and attenuated histopathological changes in the lung and nasal tissues. Additionally, HG reduced the levels of IgE, histamine, and IL-4 in the serum of AR mice, and regulated imbalance in Th1/Th2 cells. Using network pharmacology-based methods, we identified 29 HG targets related to AR. These targets are mainly involved in the PD-L1, relaxin, estrogen, HIF-1, Th1 and Th2 cell differentiation, T cell receptor, and the Th17 cell differentiation signaling pathways. Molecular docking showed that HG may well be suited to the receptor binding pockets of key target AKT1, EGFR, c-Jun, NOS2, and JAK2. In HNEpCs, HG inhibited the histamine-induced mRNA expression and secretion of interleukin (IL)-6, and IL-8, as well as the expression of MUC5AC and the phosphorylation of NF-κB. Moreover, HG affected the changes of AKT1, EGFR, c-Jun, iNOS, and JAK2 induced by histamine. CONCLUSION: Overall, our results suggest that HG may alleviate AR by activating AKT1 and suppressing the EGFR/JAK2/c-JUN signaling. HG, therefore, has great potential as a therapeutic agent for the treatment of AR.


Assuntos
Alcaloides/farmacologia , Janus Quinase 2/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Rinite Alérgica/tratamento farmacológico , Tetra-Hidroisoquinolinas/farmacologia , Alcaloides/uso terapêutico , Animais , Receptores ErbB/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Tetra-Hidroisoquinolinas/uso terapêutico
11.
Phytomedicine ; 87: 153552, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33994251

RESUMO

BACKGROUND: The naturally occurring flavonol fisetin (3,3',4',7-tetrahydroxyflavone), widely dispersed in fruits, vegetables and nuts, has been reported to exert anti-inflammatory, antioxidant and anti-angiogenic effects. Our previous study indicated fisetin ameliorated inflammation and apoptosis in septic kidneys. However, the potential nephroprotective effect of fisetin in hyperuricemic mice remains unknown. PURPOSE: The current study was designed to investigate the effect of fisetin on hyperuricemic nephropathy (HN) and explore the underlying mechanisms. METHODS: The HN was induced in mice by mixing of potassium oxonate (2400 mg/kg) and adenine (160 mg/kg) in male C57BL/6J mice. Fisetin (50 or 100 mg/kg) was orally administrated either simultaneously with the establishment of HN or after HN was induced. As a positive control, allopurinol of 10 mg/kg was included. Uric acid levels in the serum and urine as well as renal function parameters were measured. Renal histological changes were measured by periodic acid-Schiff (PAS) and Masson's trichrome stainings. The expression of gene/protein in relation to inflammation, fibrosis, and uric acid excretion in the kidneys of HN mice or uric acid-treated mouse tubular epithelial (TCMK-1) cells were measured by RNA-seq, RT-PCR, western blot and immunohistochemical analysis. RESULTS: Treatment with fisetin, regardless of administration regimen, dose-dependently attenuated hyperuricemia-induced kidney injury as indicated by the improved renal function, preserved tissue architecture, and decreased urinary albumin-to-creatinine ratio. Additionally, fisetin lowered uricemia by modulating the expression of kidney urate transporters including urate transporter 1(URAT1), organic anion transporter 1 (OAT1), organic anion transporter 3 (OAT3) and ATP binding cassette subfamily G member 2 (ABCG2). Moreover, hyperuricemia-induced secretions of proinflammatory factors including tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and monocyte chemoattractant protein-1(MCP-1) in HN mice and uric acid-stimulated TCMK-1 cells were mitigated by fisetin treatment. Meanwhile, fisetin attenuated kidney fibrosis in HN mice with restored expressions of alpha-smooth muscle actin (α-SMA), collagen I and fibronectin. Mechanistically, fisetin regulated the aberrant activation of signal transducer and activator of transcription-3 (STAT3) signaling and transforming growth factor-ß (TGF-ß) signaling in the HN kidneys and uric acid-stimulated TCMK-1 cells. CONCLUSION: Fisetin lowered uricemia, suppressed renal inflammatory response, and improved kidney fibrosis to protect against hyperuricemic nephropathy via modulation of STAT3 and TGF-ß signaling pathways. The results highlighted that fisetin might represent a potential therapeutic strategy against hyperuricemic nephropathy.


Assuntos
Flavonóis/farmacologia , Hiperuricemia/tratamento farmacológico , Interleucina-6/metabolismo , Nefropatias/tratamento farmacológico , Fator de Crescimento Transformador beta/metabolismo , Administração Oral , Animais , Fibrose , Flavonóis/administração & dosagem , Flavonóis/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperuricemia/patologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Nefropatias/sangue , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/genética , Ácido Úrico/sangue , Ácido Úrico/urina
12.
Phytomedicine ; 87: 153574, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34006448

RESUMO

BACKGROUND: Leelamine (LEE) is a lipophilic diterpene amine phytochemical, which can be naturally extracted from pine's bark trees. It has been extensively studied recently for its promising chemopreventive and anti-cancer effects against various cancers such as that of prostate and breast. HYPOTHESIS: We examined the potential impact of LEE in affecting the activation of signal transducer and activator of transcription 3 (STAT3) and promoting apoptosis in human multiple myeloma (MM) cells. METHODS: We evaluated the effect of LEE on STAT3 signaling pathway in MM cells by using Western blot analysis and reverse transcription polymerase chain reaction (RT-PCR). Thereafter, apoptosis was evaluated using cell cycle analysis and Annexin V assay. RESULTS: We noted that LEE could attenuate the phosphorylation of STAT3 and other up-stream signaling molecules such as JAK1, JAK2, and Src activation in U266 and MM.1S cells. It also diminished STAT3 translocation into the nucleus and enhanced the expression of protein-tyrosine phosphatase epsilon (PTPε). Additionally, LEE caused cell cycle arrest and synergistically augmented the apoptotic actions of bortezomib against MM cells. CONCLUSIONS: Our data indicates that LEE could block STAT3 signaling cascade linked to tumorigenesis and can be used in combination with approved anti-cancer agents in attenuating MM growth and survival.


Assuntos
Abietanos/farmacologia , Janus Quinase 1/metabolismo , Janus Quinase 2/metabolismo , Mieloma Múltiplo/metabolismo , Fator de Transcrição STAT3/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Janus Quinase 1/genética , Janus Quinase 2/genética , Mieloma Múltiplo/tratamento farmacológico , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
13.
Chem Biol Interact ; 344: 109529, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34029542

RESUMO

Ganoderic acid A (GAA), one of the major triterpenoid components extracted from Ganoderma mushroom has been shown to possess numerous important pharmacological activities. The present study was aimed to investigate the mechanisms of GAA on carbon tetrachloride (CCl4)-induced kidney inflammation, fibrosis and oxidative stress in mice. The male mice were treated with 25 and 50 mg/mg GAA after stimulated with CCl4. Our results showed that GAA improved renal damage by decreasing the serum levels of creatinine, urea, uric acid and alleviating kidney fibrosis. GAA ameliorated CCl4-induced indices of inflammation. GAA suppressed oxidative stress by regulating the glutathione antioxidant system and the thioredoxin antioxidant system. GAA increased the activations of thioredoxin reductase (TrxR), Trx, GSH, SOD, GPx. Furthermore, GAA supplementation inhibited the JAK and STAT3 pathway. GAA inhibited the activations of RhoA, ROCK, NF-κB, TGF-ß and Smad3. Thus, this study demonstrated that GAA possesses immune-protective properties through regulating the Trx/TrxR, JAK2/STAT3 and RhoA/ROCK pathways.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Fibrose/tratamento farmacológico , Ácidos Heptanoicos/uso terapêutico , Nefropatias/tratamento farmacológico , Lanosterol/análogos & derivados , Transdução de Sinais/efeitos dos fármacos , Animais , Tetracloreto de Carbono , Fibrose/induzido quimicamente , Fibrose/patologia , Janus Quinase 2/metabolismo , Nefropatias/induzido quimicamente , Nefropatias/patologia , Lanosterol/uso terapêutico , Masculino , Camundongos Endogâmicos ICR , Estresse Oxidativo/efeitos dos fármacos , Proteína Smad3/metabolismo , Tiorredoxina Dissulfeto Redutase/metabolismo , Tiorredoxinas/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Quinases Associadas a rho/metabolismo
14.
Biochem Biophys Res Commun ; 556: 16-22, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-33836343

RESUMO

Evidence suggests constipation precedes motor dysfunction and is the most common gastrointestinal symptom in Parkinson's disease (PD). 5-HT4 receptor (5-HT4R) agonist prucalopride has been approved to treat chronic constipation. Here, we reported intraperitoneal injection of prucalopride for 7 days increased dopamine and decreased dopamine turnover. Prucalopride administration improved motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-induced PD mouse models. Prucalopride treatment also ameliorated intestinal barrier impairment and increased IL-6 release in PD model mice. However, prucalopride treatment exerted no impact on JAK2/STAT3 pathway, suggesting that prucalopride may stimulate IL-6 via JAK2/STAT3-independent pathway. In conclusion, prucalopride exerted beneficial effects in MPTP-induced Parkinson's disease mice by attenuating the loss of dopamine, improving motor dysfunction and intestinal barrier.


Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Benzofuranos/farmacologia , Benzofuranos/uso terapêutico , Mucosa Intestinal/efeitos dos fármacos , Destreza Motora/efeitos dos fármacos , Doença de Parkinson/prevenção & controle , Doença de Parkinson/fisiopatologia , Animais , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Dopamina/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Interleucina-6/metabolismo , Mucosa Intestinal/metabolismo , Janus Quinase 2/metabolismo , Intoxicação por MPTP/tratamento farmacológico , Intoxicação por MPTP/fisiopatologia , Intoxicação por MPTP/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neostriado/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson Secundária/fisiopatologia , Doença de Parkinson Secundária/prevenção & controle , Fator de Transcrição STAT3/metabolismo
15.
Clin Immunol ; 227: 108728, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33878452

RESUMO

OBJECTIVE: To investigate the relationship between lncRNA PVT1(PVT1) level and PD-L1 expression and their functions in cisplatin resistant epithelial ovarian cancer (CREOC). METHODS: PVT1 and PD-L1 in ovarian cancer tissues were detected and analyzed. The cells proliferation, apoptosis, invasion abilities and potential mechanism were detected by cell functional experiments and western-blot assay, respectively. RESULTS: The average expressions of PVT1 and PD-L1 in CREOC tissues were significantly higher. The expression of PVT1 is positively associated with PD-L1 in CREOC. Higher expressions of PVT1 and PD-L1 indicated more malignant clinical behavior and shorter PFS and OS. Knockdown of PVT1 inhibited the proliferation and invasion and promote apoptosis for A2780cis cells, which may be related to decrease the expression of PD-L1 via repressing JAK2/STAT3 pathway. CONCLUSIONS: The synergistic therapeutic strategy using LncRNA PVT1-targeted therapy and immune checkpoint blockade of PD-L1 warrant study further for ovarian cancer patients with cisplatin resistant recurrence.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antígeno B7-H1/genética , Carcinoma Epitelial do Ovário/genética , Inibidores de Checkpoint Imunológico/farmacologia , Janus Quinase 2/efeitos dos fármacos , Neoplasias Ovarianas/genética , RNA Longo não Codificante/genética , Fator de Transcrição STAT3/efeitos dos fármacos , Adulto , Idoso , Antineoplásicos , Apoptose/efeitos dos fármacos , Apoptose/genética , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/metabolismo , Estudos de Casos e Controles , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Cisplatino , Resistencia a Medicamentos Antineoplásicos , Feminino , Técnicas de Silenciamento de Genes , Humanos , Janus Quinase 2/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Intervalo Livre de Progressão , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Fator de Transcrição STAT3/metabolismo
16.
Life Sci ; 277: 119501, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33862108

RESUMO

AIMS: The present study evaluated the functions of Piperlongumine (PL) in osteosarcoma (OS) cell growth and metastasis both in vitro and in vivo. MAIN METHODS: MTT assay was conducted to test the cytotoxic effects of PL on the human osteoblasts line HFOB1.19 and the human normal chondrocyte line C28/I2T. FITC-Annexin V and propidium iodide (PI) were used to examine cell apoptosis. The migration, invasion and relative epithelial-mesenchymal transition were examined by Transwell assay and Western blotting. Reverse transcription-quantitative PCR (RT-qPCR) was performed to analyze the cytokine signaling 3 (SOCS3) mRNA expression. TargetScan database was used to predict the target of SOCS3. The binding association between miR-30d-5p and SOCS3 in U2OS and MG63 cells was evaluated by the dual-luciferase reporter assay. A xenograft model was constructed to evaluate the effect of PL on OS cell growth in vivo. KEY FINDINGS: The results revealed that PL inhibited the growth, migration, invasion, epithelial-mesenchymal transition, and promoted the apoptosis of OS cells dose-dependently. In addition, PL upregulated the protein levels of suppressor of SOCS3, while it inactivated the JAK2/STAT3 pathway, which was accompanied by a decreased level of microRNA (miR)-30d-5p. Furthermore, SOCS3was confirmed as a novel target of miR-30d-5p. Overexpression of miR-30d-5p not only led to decreased expression of SOCS3, but also dampened the antitumor effect of PL on OS. SIGNIFICANCE: The present data demonstrated that PL inhibited the progression of OS via downregulation of the SOCS3-mediated JAK2/STAT3 pathway by inhibiting miR-30d-5p.


Assuntos
Dioxolanos/farmacologia , MicroRNAs/genética , Osteossarcoma/metabolismo , Animais , Apoptose/genética , Movimento Celular/genética , Proliferação de Células/genética , Dioxolanos/metabolismo , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Janus Quinase 2/metabolismo , Camundongos , Camundongos Nus , MicroRNAs/metabolismo , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/genética , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo
17.
Jpn J Clin Oncol ; 51(7): 1176-1178, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33912910

RESUMO

Extramammary Paget's disease is a rare malignant tumor of the skin that occurs primarily in the genitocrural region. Although the prognosis of extramammary Paget's disease with distant metastasis is poor, an effective therapy has not been established. Because Janus kinase 2 has attracted attention as a therapeutic target in several cancers, we investigated the expression of the Janus kinase 2 protein and the relationship between its level of expression and clinical significance in 53 patients with extramammary Paget's disease in our hospital. Immunohistochemistry showed that most extramammary Paget's disease tissues were positive for Janus kinase 2 (50/53, 94.3%), and the immunostaining intensity of Janus kinase 2 was correlated with the degree of invasiveness, lymph node metastasis and distant metastasis. Based on these findings, Janus kinase 2 may be a promising therapeutic target in extramammary Paget's disease.


Assuntos
Janus Quinase 2/metabolismo , Doença de Paget Extramamária/metabolismo , Neoplasias Cutâneas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Doença de Paget Extramamária/mortalidade , Doença de Paget Extramamária/patologia , Prognóstico , Pele/metabolismo , Pele/patologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia
18.
Cell Death Dis ; 12(4): 341, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33795649

RESUMO

The JAK2/STAT pathway is hyperactivated in many cancers, and such hyperactivation is associated with a poor clinical prognosis and drug resistance. The mechanism regulating JAK2 activity is complex. Although translocation of JAK2 between nucleus and cytoplasm is an important regulatory mechanism, how JAK2 translocation is regulated and what is the physiological function of this translocation remain largely unknown. Here, we found that protease SENP1 directly interacts with and deSUMOylates JAK2, and the deSUMOylation of JAK2 leads to its accumulation at cytoplasm, where JAK2 is activated. Significantly, this novel SENP1/JAK2 axis is activated in platinum-resistant ovarian cancer in a manner dependent on a transcription factor RUNX2 and activated RUNX2/SENP1/JAK2 is critical for platinum-resistance in ovarian cancer. To explore the application of anti-SENP1/JAK2 for treatment of platinum-resistant ovarian cancer, we found SENP1 deficiency or treatment by SENP1 inhibitor Momordin Ic significantly overcomes platinum-resistance of ovarian cancer. Thus, this study not only identifies a novel mechanism regulating JAK2 activity, but also provides with a potential approach to treat platinum-resistant ovarian cancer by targeting SENP1/JAK2 pathway.


Assuntos
Cisteína Endopeptidases/metabolismo , Resistência a Medicamentos/efeitos dos fármacos , Janus Quinase 2/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Platina/farmacologia , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , Feminino , Humanos , Neoplasias Ovarianas/metabolismo , Transdução de Sinais/efeitos dos fármacos
19.
J Immunol ; 206(8): 1752-1764, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33811103

RESUMO

Macrophages play an important role in the pathogenesis of systemic lupus erythematosus-associated diffuse alveolar hemorrhage (DAH). The immunomodulation of macrophage responses might be a potential approach for the prevention and treatment of DAH. Erythropoietin (EPO) could regulate macrophage bioactivities by binding to the EPO receptor expressing on macrophages. This study assessed the effects of EPO on DAH protection using an immune-mediated DAH murine model with macrophages as the major contributor. A DAH murine model was established in female C57BL/6 mice by an i.p. injection of pristane. We found that EPO administration alleviates DAH by reducing pulmonary macrophages recruitment and promoting phenotype switch toward M2 macrophages in vivo. EPO drove macrophages to the anti-inflammatory phenotype in the primary murine bone marrow-derived macrophages and macrophages cell line RAW 264.7 with LPS, IFN-γ, and IL-4 in vitro. Moreover, EPO treatment increases the expression of EPOR and decreases the expression of miR-494-3p, resulting in increased phosphorylation of JAK2 and STAT3. In conclusion, EPO can be a potential therapeutic agent in DAH by reducing cell apoptosis and regulating macrophage polarization through the EPOR/JAK2/STAT3 axis. Further studies are also needed to validate the direct target of miR-494-3p in regulating JAK2/STAT3 signaling transduction.


Assuntos
Eritropoetina/metabolismo , Hemorragia/imunologia , Pneumopatias/imunologia , Macrófagos Alveolares/imunologia , Alvéolos Pulmonares/patologia , Animais , Diferenciação Celular , Modelos Animais de Doenças , Feminino , Humanos , Janus Quinase 2/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Receptores da Eritropoetina/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Terpenos
20.
Eur J Med Chem ; 218: 113394, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33813153

RESUMO

Herein, we describe the design, synthesis, and structure-activity relationships of a series of imidazopyrrolopyridines derivatives that selectively inhibit Janus kinase 2 (JAK2). These screening cascades revealed that 6k was a preferred compound, with IC50 values of 10 nM for JAK2. Moreover, 6k was a selective JAK2 inhibitor with 19-fold, >30-fold and >30-fold selectivity over JAK1, JAK3 and TYK2 respectively. In cytokine-stimulated cell-based assays, 6k exhibited a higher JAK2 selectivity over JAK1 isoforms. Indeed, at a dose of 20 mg/kg compound 6k, pSTAT3 and pSTAT5 expression was reduced to levels comparable to those of control animals untreated with GM-CSF. Additionally, 6k showed a relatively good bioavailability (F = 38%), a suitable half-life time (T1/2 = 1.9 h), a satisfactory metabolic stability, suggesting that 6k might be a promising inhibitor of JAK2 for further development research for the treatment of MPNs.


Assuntos
Descoberta de Drogas , Imidazóis/farmacologia , Janus Quinase 2/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Imidazóis/síntese química , Imidazóis/química , Janus Quinase 2/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridinas/síntese química , Piridinas/química , Pirróis/síntese química , Pirróis/química , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
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