RESUMO
Okadaic acid (OA) is a marine biotoxin that is produced by algae and accumulates in filter-feeding shellfish, through which it enters the human food chain, leading to diarrheic shellfish poisoning (DSP) after ingestion. Furthermore, additional effects of OA have been observed, such as cytotoxicity. Additionally, a strong downregulation of the expression of xenobiotic-metabolizing enzymes in the liver can be observed. The underlying mechanisms of this, however, remain to be examined. In this study, we investigated a possible underlying mechanism of the downregulation of cytochrome P450 (CYP) enzymes and the nuclear receptors pregnane X receptor (PXR) and retinoid-X-receptor alpha (RXRα) by OA through NF-κB and subsequent JAK/STAT activation in human HepaRG hepatocarcinoma cells. Our data suggest an activation of NF-κB signaling and subsequent expression and release of interleukins, which then activate JAK-dependent signaling and thus STAT3. Moreover, using the NF-κB inhibitors JSH-23 and Methysticin and the JAK inhibitors Decernotinib and Tofacitinib, we were also able to demonstrate a connection between OA-induced NF-κB and JAK signaling and the downregulation of CYP enzymes. Overall, we provide clear evidence that the effect of OA on the expression of CYP enzymes in HepaRG cells is regulated through NF-κB and subsequent JAK signaling.
Assuntos
Neoplasias Hepáticas , NF-kappa B , Humanos , Sistema Enzimático do Citocromo P-450/metabolismo , NF-kappa B/metabolismo , Ácido Okadáico , Transdução de Sinais , Xenobióticos , Janus Quinases/efeitos dos fármacos , Fatores de Transcrição STAT/efeitos dos fármacosRESUMO
PURPOSE: The constitutive activation of STAT3 through receptor tyrosine kinases triggered breast cancer cell growth and invasion-metastasis. Atiprimod impacts anti-proliferative, anti-carcinogenic effects in hepatocellular carcinoma, lymphoma, multiple myeloma via hindering the biological activity of STAT3. Dose-dependent atiprimod evokes first autophagy as a survival mechanism and then apoptosis due to prolonged ER stress in pituitary adenoma cells. The therapeutic efficiency and mechanistic action of atiprimod in breast cancer cells have not been investigated yet. Thus, we aimed to modulate the pivotal role of ER stress in atiprimod-triggered apoptosis in MDA-MB-231 and MDA-MB-468 breast cancer cells. RESULTS: Dose- and time-dependent atiprimod treatment inhibits cell viability and colony formation in MDA-MB-468 and MDA-MB-231 breast cancer cells. A moderate dose of atiprimod (2 µM) inhibited STAT3 phosphorylation at Tyr705 residue and also suppressed the total expression level of p65. In addition, nuclear localization of STAT1, 3, and NF-κB was prevented by atiprimod exposure in MDA-MB-231 and MDA-MB-468 cells. Atiprimod evokes PERK, BiP, ATF-4, CHOP upregulation, and PERK (Thr980), eIF2α (Ser51) phosphorylation's. However, atiprimod suppressed IRE1α-mediated Atg-3, 5, 7, 12 protein expressions and no alteration was observed on Beclin-1, p62 expression levels. PERK/eIF2α/ATF4/CHOP axis pivotal role in atiprimod-mediated G1/S arrest and apoptosis via Bak, Bax, Bim, and PUMA upregulation in MDA-MB-468 cells. Moreover, atiprimod renders MDA-MB-231 more vulnerable to type I programmed cell death by plasmid-mediated increased STAT3 expression. CONCLUSION: Atiprimod induced prolonged ER stress-mediated apoptosis via both activating PERK/eIF2α/ATF4/CHOP axis and suppressing STAT3/NF-κB transcription factors nuclear migration in TBNC cells.
Assuntos
Neoplasias da Mama/metabolismo , Fator de Transcrição STAT3/metabolismo , Compostos de Espiro/farmacologia , Fator 4 Ativador da Transcrição/metabolismo , Apoptose/fisiologia , Autofagia/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/genética , Estresse do Retículo Endoplasmático/fisiologia , Fator de Iniciação 2 em Eucariotos/metabolismo , Feminino , Humanos , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição STAT/efeitos dos fármacos , Fatores de Transcrição STAT/metabolismo , Fator de Transcrição STAT3/efeitos dos fármacos , Compostos de Espiro/metabolismo , Fator de Transcrição CHOP/metabolismo , eIF-2 Quinase/metabolismoRESUMO
Psoriasis is a chronic, inflammatory autoimmune disease mediated by T cells, and characterized with abnormal proliferation and differentiation of keratinocytes, and inflammatory infiltration. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway has been identified to play essential roles in mediating various of biological processes, and is closely related to autoimmune diseases. Dendritic cells (DCs) are important antigen presenting cells and play an important regulatory role in T cells. The proliferation, differentiation and function of DCs are regulated by JAK and FMS-like tyrosine kinase 3 (FLT3) signal pathways. Flonoltinib maleate (FM), a high selectivity dual JAK2/FLT3 inhibitor with IC50 values of 0.8 nM and 15 nM for JAK2 and FLT3, respectively, was developed by our laboratory. Moreover, FM was a potent JAK2 inhibitor with 863-fold and 696-fold selectivity over JAK1 and JAK3, respectively. In this study, the anti-psoriasis activity of FM was evaluated both in vitro and in vivo. FM effectively inhibited the proliferation of HaCaT, the inflammatory keratinocyte induced by M5 and markedly suppressed the generation and differentiation of DCs from bone marrow (BM), and inhibited the expression of FLT3 in DCs in vitro. FM effectively inhibited the ear thickening and improved the pathological changes of the ear in interleukin (IL)-23-induced psoriasis-like acanthosis mouse model. Further in keratin 14-vascular endothelial growth factor (K14-VEGF) transgenic homozygous mice model, FM could obviously improve the psoriatic symptom and pathological changes, significantly inhibit the generations of Th1 and Th17 cells in the spleen, and the accumulations of DCs in the ears. FM could also significantly reduce the expression of various inflammatory factors both in C57BL/6 and K14-VEGF mice ears, and the serum of K14-VEGF mice. Mechanism revealed that FM effectively suppressed the phosphorylation of JAK2, STAT3 and STAT5 in inflammatory keratinocytes and the mice ears of C57BL/6 and K14-VEGF, as well as the phosphorylation of FLT3 in K14-VEGF mice ears. In conclusion, FM plays an excellent anti-psoriasis activity, including inhibiting keratinocyte proliferation and regulating inflammatory response through inhibiting JAK2 and FLT3 signaling pathway.
Assuntos
Janus Quinase 2/antagonistas & inibidores , Psoríase/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Células da Medula Óssea/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Orelha Externa/efeitos dos fármacos , Humanos , Queratinócitos/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibidores de Proteínas Quinases/farmacologia , Fatores de Transcrição STAT/efeitos dos fármacos , Fatores de Transcrição STAT/genéticaRESUMO
Research over decades has enabled us in developing a better understanding of the multifaceted and heterogeneous nature of cancer. High-throughput technologies have helped the researchers in unraveling of the underlying mechanisms which centrally regulate cancer onset, metastasis and drug resistance. Our rapidly expanding knowledge about signal transduction cascade has added another layer of complexity to already complicated nature of cancer. Deregulation of cell signaling pathways played a linchpin role in carcinogenesis and metastasis. Cucurbitacins have gained tremendous attention because of their remarkable pharmacological properties and considerable ability to mechanistically modulate myriad of cell signaling pathways in different cancers. In this review, we have attempted to provide a mechanistic and comprehensive analysis of regulation of oncogenic pathways by cucurbitacins in different cancers. We have partitioned this review into separate sections for exclusive analysis of each signaling pathway and critical assessment of the knowledge gaps. In this review, we will summarize most recent and landmark developments related to regulation of Wnt/ß-catenin, JAK/STAT, mTOR, VEGFR, EGFR and Hippo pathway by cucurbitacins. Moreover, we will also address how cucurbitacins regulate DNA damage repair pathway and TRAIL-driven signaling in various cancers. However, there are still outstanding questions related to regulation of SHH/GLI, TGF/SMAD and Notch-driven pathway by cucurbitacins in different cancers. Future studies must converge on the analysis of full-fledge potential of cucurbitacins by in-depth analysis of these pathways and how these pathways can be therapeutically targeted by cucurbitacins.
Assuntos
Cucurbitacinas/farmacologia , Neoplasias , Compostos Fitoquímicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Humanos , Janus Quinases/efeitos dos fármacos , RNA não Traduzido/efeitos dos fármacos , Fatores de Transcrição STAT/efeitos dos fármacos , Ligante Indutor de Apoptose Relacionado a TNF/efeitos dos fármacos , Serina-Treonina Quinases TOR/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacosRESUMO
There has always been a keen interest of basic and clinical researchers to search for cancer therapeutics having minimum off-target effects and maximum anticancer activities. In accordance with this approach, there has been an explosion in the field of natural products research in the past few decades because of extra-ordinary list of natural extracts and their biologically and pharmacologically active constituents having significant medicinal properties. Apparently, luteolin-mediated anticancer effects have been investigated in different cancers but there is superfluousness of superficial data. Generalized scientific evidence encompassing apoptosis, DNA damage and anti-inflammatory effects has been reported extensively. However, how luteolin modulates deregulated oncogenic pathways in different cancers has not been comprehensively uncovered. In this review we have attempted to focus on cutting-edge research which has unveiled remarkable abilities of luteolin to modulate deregulated oncogenic pathways in different cancers. We have partitioned the review into various sections to separately discuss advancements in therapeutic targeting of oncogenic protein networks. We have provided detailed mechanistic insights related to JAK-STAT signaling and summarized how luteolin inhibited STAT proteins to inhibit STAT-driven gene network. We have also individually analyzed Wnt/ß-catenin and NOTCH pathway and how luteolin effectively targeted these pathways. Mapping of the signaling landscape has revealed that NOTCH pathway can be targeted therapeutically. NOTCH pathway was noted to be targeted by luteolin. We have also conceptually analyzed how luteolin restored TRAIL-induced apoptosis in resistant cancers. Luteolin induced an increase in pro-apoptotic proteins and efficiently inhibited anti-apoptotic proteins to induce apoptosis. Luteolin mediated regulation of non-coding RNAs is an exciting and emerging facet. Excitingly, there is sequential and systematic accumulation of clues which have started to shed light on intricate regulation of microRNAs by luteolin in different cancers. Collectively, sophisticated information will enable us to develop a refined understanding of the multi-layered regulation of signaling pathways and non-coding RNAs by luteolin in different cancers.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Luteolina/farmacologia , MicroRNAs/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Marcação de Genes , Humanos , Luteolina/uso terapêutico , Receptores Notch/efeitos dos fármacos , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/efeitos dos fármacos , Fatores de Transcrição STAT/efeitos dos fármacos , Serina-Treonina Quinases TOR/efeitos dos fármacosRESUMO
Pharmacological modulation of the Janus kinase (JAK) family has achieved clinically meaningful therapeutic outcomes for the treatment of inflammatory and hematopoietic diseases. Several JAK1 selective compounds are being investigated clinically to determine their anti-inflammatory potential. We used recombinant enzymes and primary human lymphocytes to assess the JAK1 specificity of itacitinib (INCB039110) and study inhibition of signal transducers and activators of transcription (STAT) signaling. Rodent models of arthritis and inflammatory bowel disease were subsequently explored to elucidate the efficacy of orally administered itacitinib on inflammatory pathogenesis. Itacitinib is a potent and selective JAK1 inhibitor when profiled against the other JAK family members. Upon oral administration in rodents, itacitinib achieved dose-dependent pharmacokinetic exposures that highly correlated with STAT3 pharmacodynamic pathway inhibition. Itacitinib ameliorated symptoms and pathology of established experimentally-induced arthritis in a dose-dependent manner. Furthermore, itacitinib effectively delayed disease onset, reduced symptom severity, and accelerated recovery in three distinct mouse models of inflammatory bowel disease. Low dose itacitinib administered via cannula directly into the colon was highly efficacious in TNBS-induced colitis but with minimal systemic drug exposure, suggesting localized JAK1 inhibition is sufficient for disease amelioration. Itacitinib treatment in an acute graft-versus-host disease (GvHD) model rapidly reduced inflammatory markers within lymphocytes and target tissue, resulting in a marked improvement in disease symptoms. This is the first manuscript describing itacitinib as a potent and selective JAK1 inhibitor with anti-inflammatory activity across multiple preclinical disease models. These data support the scientific rationale for ongoing clinical trials studying itacitinib in select GvHD patient populations.
Assuntos
Azetidinas/farmacologia , Inflamação/tratamento farmacológico , Ácidos Isonicotínicos/farmacologia , Janus Quinase 1/antagonistas & inibidores , Animais , Artrite Experimental/tratamento farmacológico , Azetidinas/farmacocinética , Azetidinas/uso terapêutico , Quimiocina CCL2/efeitos dos fármacos , Colite/induzido quimicamente , Colite/tratamento farmacológico , Relação Dose-Resposta a Droga , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Ácidos Isonicotínicos/farmacocinética , Ácidos Isonicotínicos/uso terapêutico , Linfócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Cultura Primária de Células , Ratos , Ratos Endogâmicos Lew , Fatores de Transcrição STAT/efeitos dos fármacos , Fator de Transcrição STAT3/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/efeitos dos fármacosRESUMO
Anti-CD38 monoclonal antibody (MoAb) treatments including daratumumab (DARA) are effective therapies for both newly diagnosed and relapsed multiple myeloma (MM). In this study, we examined the soluble factors that modulate CD38 expression and are associated with sensitivity to DARA-mediated antibody-dependent cellular cytotoxicity (ADCC) in the bone marrow (BM) microenvironment. Importantly, primary BM stromal cell (BMSC) culture supernatant (BMSC-sup) and interleukin-6 (IL-6) downregulated CD38 expression and reduced DARA-mediated ADCC. Both cytokine profiling of the BMSC-sup and genome-scale clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) knockout screening in MM cell lines identified and validated the JAK-STAT3 signaling pathway mediating CD38 downregulation, whereas the JAK-STAT1 pathway mediated CD38 upregulation. STAT3 knockdown abrogated BMSC-sup- and IL-6-induced CD38 downregulation on MM cell lines. We also confirmed that STAT3 and CD38 is negatively correlated in primary MM cells. To assess potential clinical relevance, pharmacological inhibition of the JAK-STAT pathway on BMSC-sup-induced CD38 downregulation was further examined. JAK inhibitor ruxolitinib inhibited STAT3 phosphorylation in MM cell lines, upregulated CD38 expression in MM cell lines and primary patient MM cells, and augmented DARA-mediated ADCC against MM cell lines. Taken together, our results suggest that CD38 expression on MM cells in the BM microenvironment is regulated by both STAT1 (positively) and STAT3 (negatively), and that inhibition of the JAK-STAT3 pathway represents a novel therapeutic option to enhance CD38 expression and anti-CD38 MoAb-mediated MM cytotoxicity.
Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Janus Quinases/metabolismo , Glicoproteínas de Membrana/metabolismo , Mieloma Múltiplo/metabolismo , Fatores de Transcrição STAT/metabolismo , Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Medula Óssea/metabolismo , Medula Óssea/patologia , Humanos , Janus Quinases/efeitos dos fármacos , Mieloma Múltiplo/patologia , Nitrilas , Pirazóis/farmacologia , Pirimidinas , Fatores de Transcrição STAT/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologiaRESUMO
BACKGROUND: Kidney ischemia-reperfusion injury is a common pathophysiological phenomenon in the clinic. A large number of studies have found that the tyrosine protein kinase/signal transducer and activator of transcription (JAK/STAT) pathway is involved in the development of a variety of kidney diseases and renal protection associated with multiple drugs. Edaravone (EDA) is an effective free radical scavenger that has been used clinically for the treatment of postischemic neuronal injury. This study aimed to identify whether EDA improved kidney function in rats with ischemia-reperfusion injury by regulating the JAK/STAT pathway and clarify the underlying mechanism. METHODS: Histomorphological analysis was used to assess pathological kidney injury, and mitochondrial damage was observed by transmission electron microscopy. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining was performed to detect tubular epithelial cell apoptosis. The expression of JAK2, P-JAK2, STAT3, P-STAT3, STAT1, P-STAT1, BAX and Bcl-2 was assessed by western blotting. Mitochondrial function in the kidney was assessed by mitochondrial membrane potential (ΔΨm) measurement. RESULTS: The results showed that EDA inhibited the expression of p-JAK2, p-STAT3 and p-STAT1, accompanied by downregulation of the expression of Bax and caspase-3, and significantly ameliorated kidney damage caused by ischemia-reperfusion injury (IRI). Furthermore, the JC-1 dye assay showed that edaravone attenuated ischemia-reperfusion-induced loss of kidney ΔΨm. CONCLUSION: Our findings indicate that EDA protects against kidney damage caused by ischemia-reperfusion through JAK/STAT signaling, inhibiting apoptosis and improving mitochondrial injury.
Assuntos
Edaravone , Sequestradores de Radicais Livres , Traumatismo por Reperfusão , Animais , Apoptose , Edaravone/farmacologia , Sequestradores de Radicais Livres/farmacologia , Janus Quinases/efeitos dos fármacos , Masculino , Mitocôndrias , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Fatores de Transcrição STAT/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
Chronic inflammation, such as that present in rheumatoid arthritis (RA) and psoriatic arthritis (PsA), leads to aberrations in bone remodeling, which is mediated by several signaling pathways, including the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. In this light, pro-inflammatory cytokines are now clearly implicated in these processes as they can perturb normal bone remodeling through their action on osteoclasts and osteoblasts at both intra- and extra-articular skeletal sites. As a selective inhibitor of JAK1 and JAK3, tofacitinib has the potential to play a role in the management of rheumatic diseases such as RA and PsA. Preclinical studies have demonstrated that tofacitinib can inhibit disturbed osteoclastogenesis in RA, which suggests that targeting the JAK-STAT pathway may help limit bone erosion. Evidence from clinical trials with tofacitinib in RA and PsA is encouraging, as tofacitinib treatment has been shown to decrease articular bone erosion. In this review, the authors summarize current knowledge on the relationship between the immune system and the skeleton before examining the involvement of JAK-STAT signaling in bone homeostasis as well as the available preclinical and clinical evidence on the benefits of tofacitinib on prevention of bone involvement in RA and PsA.Key Points⢠Chronic inflammation in rheumatoid arthritis (RA) and psoriatic arthritis (PsA) leads to disturbances in bone remodeling⢠Bone remodeling is mediated by several signaling pathways, including the JAK-STAT pathway⢠Tofacitinib, a selective inhibitor of JAK1 and JAK3, is active in RA and PsA and may help limit systemic bone loss through inhibiting disturbed osteoclastogenesis⢠Clinical trials show that tofacitinib reduces articular bone erosion.
Assuntos
Artrite Psoriásica/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Remodelação Óssea/efeitos dos fármacos , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Osso e Ossos/efeitos dos fármacos , Humanos , Sistema Imunitário/efeitos dos fármacos , Janus Quinases/antagonistas & inibidores , Fatores de Transcrição STAT/efeitos dos fármacos , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Kidney ischemia-reperfusion injury is a common pathophysiological phenomenon in the clinic. A large number of studies have found that the tyrosine protein kinase/signal transducer and activator of transcription (JAK/STAT) pathway is involved in the development of a variety of kidney diseases and renal protection associated with multiple drugs. Edaravone (EDA) is an effective free radical scavenger that has been used clinically for the treatment of postischemic neuronal injury. This study aimed to identify whether EDA improved kidney function in rats with ischemia-reperfusion injury by regulating the JAK/STAT pathway and clarify the underlying mechanism. METHODS: Histomorphological analysis was used to assess pathological kidney injury, and mitochondrial damage was observed by transmission electron microscopy. Terminal deoxynucleotidyl transferase-mediated dUTP nick endlabeling (TUNEL) staining was performed to detect tubular epithelial cell apoptosis. The expression of JAK2, P-JAK2, STAT3, P-STAT3, STAT1, P-STAT1, BAX and Bcl-2 was assessed by western blotting. Mitochondrial function in the kidney was assessed by mitochondrial membrane potential (ΔψM) measurement. RESULTS: The results showed that EDA inhibited the expression of p-JAK2, p-STAT3 and p-STAT1, accompanied by downregulation of the expression of Bax and caspase-3, and significantly ameliorated kidney damage caused by ischemia-reperfusion injury (IRI). Furthermore, the JC-1 dye assay showed that edaravone attenuated ischemia-reperfusion-induced loss of kidney (ΔψM). CONCLUSION: Our findings indicate that EDA protects against kidney damage caused by ischemia-reperfusion through JAK/STAT signaling, inhibiting apoptosis and improving mitochondrial injury.
Assuntos
Animais , Masculino , Ratos , Traumatismo por Reperfusão/tratamento farmacológico , Sequestradores de Radicais Livres/farmacologia , Edaravone/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ratos Sprague-Dawley , Apoptose , Fatores de Transcrição STAT/efeitos dos fármacos , Janus Quinases/efeitos dos fármacos , MitocôndriasRESUMO
Allogeneic mesenchymal stem cells (MSCs) exhibit immunoregulatory function in human autoimmune diseases such as systemic lupus erythematosus (SLE), but the underlying mechanisms remain incompletely understood. Here we show that the number of peripheral tolerogenic CD1c+ dendritic cells (DCs) and the levels of serum FLT3L are significantly decreased in SLE patients especially with lupus nephritis, compared to healthy controls. Transplantation of allogeneic umbilical cord-derived MSCs (UC-MSCs) significantly up-regulates peripheral blood CD1c+DCs and serum FLT3L. Mechanistically, UC-MSCs express FLT3L that binds to FLT3 on CD1c+DCs to promote the proliferation and inhibit the apoptosis of tolerogenic CD1c+DCs. Conversely, reduction of FLT3L with small interfering RNA in MSCs abolishes the up-regulation of tolerogenic CD1c+DCs in lupus patients treated with MSCs. Interferon-γ induces FLT3L expression in UC-MSCs through JAK/STAT signaling pathway. Thus, allogeneic MSCs might suppress inflammation in lupus through up-regulating tolerogenic DCs.
Assuntos
Antígenos CD1/imunologia , Células Dendríticas/imunologia , Glicoproteínas/imunologia , Tolerância Imunológica/imunologia , Lúpus Eritematoso Sistêmico/terapia , Proteínas de Membrana/imunologia , Transplante de Células-Tronco Mesenquimais , Adulto , Antígenos CD1/metabolismo , Estudos de Casos e Controles , Células Dendríticas/metabolismo , Feminino , Glicoproteínas/metabolismo , Humanos , Interferon gama/farmacologia , Janus Quinases/efeitos dos fármacos , Janus Quinases/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/terapia , Masculino , Proteínas de Membrana/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Pessoa de Meia-Idade , Fatores de Transcrição STAT/efeitos dos fármacos , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transplante Homólogo , Adulto JovemRESUMO
OBJECTIVE: The aim of this study was to explore the role of lncRNA ZNF667-AS1 in the recovery of spinal cord injury (SCI), and to investigate its underlying mechanism. MATERIALS AND METHODS: Mice were randomly assigned to the SCI group, the sham group and the lncRNA ZNF667-AS1 group, with 10 mice in each group. With Infinite Horizon device at a dose of 80 Kdyn, mice in the SCI group and the lncRNA ZNF667-AS1 group experienced SCI by an acute hit on the C5 spinous process. Before animal procedures, mice in the lncRNA ZNF667-AS1 group were additionally injected with overexpression lentivirus of lncRNA ZNF667-AS1. On the contrary, mice in the sham group only received laminectomy. After successful construction of the SCI model in mice, grip strength was accessed. LncRNA ZNF667-AS1 expression in spinal cord tissues before and after SCI was detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR), respectively. Meanwhile, the protein expression levels of relative genes in Janus Kinase-signal transducer and activator of transcription (JAK-STAT) pathway were detected by Western blot. RESULTS: Grip strength of forelimb in the SCI group recovered significantly slower than that of the sham group. With the prolongation of SCI, the expression of lncRNA ZNF667-AS1 was gradually decreased. However, the expression levels of JAK2, STAT3 and iNOS were upregulated in a time-dependent manner. In addition, mice in the lncRNA ZNF667-AS1 group presented remarkable grip strength recovery of forelimb after SCI. CONCLUSIONS: LncRNA ZNF667-AS expression is gradually downregulated after SCI. Meanwhile, it inhibits the inflammatory response and promotes SCI recovery via suppressing the JAK-STAT pathway.
Assuntos
Inflamação/tratamento farmacológico , Janus Quinases/efeitos dos fármacos , RNA Longo não Codificante/uso terapêutico , Fatores de Transcrição STAT/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Feminino , Vetores Genéticos , Força da Mão , Inflamação/etiologia , Janus Quinase 2/biossíntese , Janus Quinase 2/genética , Lentivirus/genética , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo II/genética , RNA Longo não Codificante/genética , Recuperação de Função Fisiológica , Fator de Transcrição STAT3/biossíntese , Fator de Transcrição STAT3/genética , Transdução de Sinais/efeitos dos fármacos , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/fisiopatologiaRESUMO
BACKGROUND: Curcumin, a primary active ingredient extracted from the Curcuma longa, has been recently identified as a potential anti-tumor agent in multiple kinds of cancers. However, the effect of curcumin on retinoblastoma (Rb) is still unclear. Therefore, we attempted to reveal the functional impacts and the underlying mechanisms of curcumin in Rb cells. METHODS: Two Rb cell lines SO-Rb50 and Y79 were pre-treated with various doses of curcumin, and then cell proliferation, apoptosis, migration, and invasion were assessed, respectively. Further, regulatory effects of curcumin on miR-99a expression, as well as the activation of JAK/STAT pathway were studied. RESULTS: Data showed that curcumin significantly inhibited the viability, colony formation capacity, migration and invasion, while induced apoptosis of SO-Rb50 and Y79 cells. Up-regulation of miR-99a was observed in curcumin-treated cells. Curcumin suppressed the phosphorylation levels of JAK1, STAT1, and STAT3, while curcumin did not inhibit the activation of JAK/STAT pathway when miR-99a was knocked down. CONCLUSION: Curcumin inhibited proliferation, migration, invasion, but promoted apoptosis of Rb cells. The anti-tumor activities of curcumin on Rb cells appeared to be via up-regulation of miR-99a, and thereby inhibition of JAK/STAT pathway.
Assuntos
Antineoplásicos/farmacologia , Curcumina/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias da Retina/patologia , Retinoblastoma/patologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Janus Quinases/efeitos dos fármacos , Janus Quinases/metabolismo , MicroRNAs/efeitos dos fármacos , MicroRNAs/metabolismo , Fatores de Transcrição STAT/efeitos dos fármacos , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Convergent evidence demonstrates that immune dysfunction (e.g. chronic low-grade inflammatory activation) plays an important role in the development and progression of mood disorders. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway is a pleiotropic cellular cascade that transduces numerous signals, including signals from the release of cytokines and growth factors. The JAK/STAT signaling pathway is involved in mediating several functions of the central nervous system, including neurogenesis, synaptic plasticity, gliogenesis, and microglial activation, all of which have been implicated in the pathophysiology of mood disorders. In addition, the antidepressant actions of current treatments have been shown to be mediated by JAK/STAT-dependent mechanisms. To date, two JAK inhibitors (JAKinibs) have been approved by the U.S. Food and Drug Administration and are primarily indicated for the treatment of inflammatory conditions such as rheumatoid arthritis. Indirect evidence from studies in populations with inflammatory conditions indicates that JAKinibs significantly improve measures of mood and quality of life. There is also direct evidence from studies in populations with depressive disorders, suggesting that JAK/STAT pathways may be involved in the pathophysiology of depression and that the inhibition of specific JAK/STAT pathways (i.e. via JAKinibs) may be a promising novel treatment for depressive disorders.
Assuntos
Janus Quinases/metabolismo , Transtornos do Humor/terapia , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/fisiologia , Animais , Citocinas/metabolismo , Humanos , Transtornos do Humor/fisiopatologia , Qualidade de Vida , Fatores de Transcrição STAT/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
Cerebral ischemia/reperfusion injury (I/R injury) can cause neuronal deficits even death. Recent studies demonstrated that resveratrol (RSV) exerts neuroprotective effects in ischemia and several signaling pathways were involved in the process. However, it is still possible that other signaling pathway participates in the neuronal protective process. Our study examines the possible mechanism underlying RSV treatment. We randomly divided rats into four groups: the sham group, I/R group, I/R group, I/R+RSV group, I/R+vehicle group. Locomotive and cognitive behavior were utilized by open-field and closed-field test and Morris water maze test. Neuronal cell loss was measured by hematoxylin-eosin (HE) staining for hippocampus. Western blot was applied to measure the level of p-JAK, p-ERK, p-STAT and p-JNK. The results indicated that RSV could alleviate cognitive impairment, reduce neuronal loss, downregulate p-JAK, p-ERK, p-STAT and p-JNK expression and inflammatory cytokines. In summary, resveratrol protects hippocampal neurons against cerebral ischemia-reperfusion injury via modulating JAK/ERK/STAT signaling pathway in rats.
Assuntos
Isquemia Encefálica/fisiopatologia , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Resveratrol/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Janus Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/fisiopatologia , Fatores de Transcrição STAT/efeitos dos fármacosRESUMO
BACKGROUND AND OBJECTIVE: Mangiferin is a natural polyphenol compound with anti-inflammatory properties. However, there have been few reports on the effect of mangiferin on periodontitis. Here, we investigated the anti-inflammatory effects of this compound on experimental periodontitis and the underlying mechanisms. MATERIAL AND METHODS: Mice were inoculated with Porphyromonas gingivalis to induce periodontitis, and treated with mangiferin orally (50 mg/kg bodyweight, once a day) for 8 wk. Then, the alveolar bone loss was examined using a scanning electronic microscope. Expression of tumor necrosis factor-α (TNF-α) and the phosphorylation levels of nuclear factor-κB (NF-κB) and Janus kinase 1-signal transducer and activator of adhesion (JAK1-STAT) pathways in the gingival epithelium were detected using western blot analysis and immunohistochemical staining. RESULTS: The results showed that mice with periodontitis exhibited greater alveolar bone loss, stronger expression of TNF-α and higher phosphorylation levels of NF-κB and JAK1-STAT1/3 pathways in gingival epithelia, compared with control mice with no periodontitis. Moreover, treatment with mangiferin could significantly inhibit alveolar bone loss, TNF-α production and phosphorylation of NF-κB and JAK1-STAT1/3 pathways in gingival epithelia. CONCLUSION: Mangiferin has anti-inflammatory effects on periodontitis, which is associated with its ability to down-regulate the phosphorylation of NF-κB and JAK1-STAT1/3 pathways in gingival epithelia.
Assuntos
Anti-Inflamatórios/farmacologia , Janus Quinase 1/antagonistas & inibidores , NF-kappa B/metabolismo , Periodontite/tratamento farmacológico , Porphyromonas gingivalis/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Xantonas/farmacologia , Perda do Osso Alveolar/patologia , Animais , Anti-Inflamatórios/uso terapêutico , Western Blotting , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Varredura , NF-kappa B/efeitos dos fármacos , Periodontite/microbiologia , Fosforilação/efeitos dos fármacos , Porphyromonas gingivalis/metabolismo , Fatores de Transcrição STAT/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Xantonas/uso terapêuticoRESUMO
BACKGROUND: Psoriatic arthritis (PsA) is a chronic inflammatory disease, characterised by synovitis and destruction of articular cartilage/bone. Janus-kinase and signal transducer and activator of transcription (JAK-STAT) signalling pathway is implicated in the pathogenesis of PsA. OBJECTIVES: To examine the effect of tofacitinib (JAK inhibitor) on proinflammatory mechanisms in PsA. METHODS: Primary PsA synovial fibroblasts (PsAFLS) and ex vivo PsA synovial explants were cultured with tofacitinib (1 µM). PhosphoSTAT3 (pSTAT3), phosphoSTAT1 (pSTAT1), suppressor of cytokine signaling-3 (SOCS3), protein inhibitor of activated Stat3 (PIAS3) and nuclear factor kappa B cells (NFκBp65) were quantified by western blot. The effect of tofacitinib on PsAFLS migration, invasion, Matrigel network formation and matrix metallopeptidase (MMP)2/9 was quantified by invasion/migration assays and zymography. Interleukin (IL)-6, IL-8, IFN-gamma-inducible protein 10 (IP-10) monocyte chemoattractant protein (MCP)-1, IL-17, IL-10, MMP3 and tissue inhibitor of metalloproteinases 3 (TIMP3) were assessed by ELISA. RESULTS: Tofacitinib significantly decreased pSTAT3, pSTAT1, NFκBp65 and induced SOCS3 and PIAS3 expression in PsAFLS and synovial explant cultures (p<0.05). Functionally, PsAFLS invasion, network formation and migration were inhibited by tofacitinib (all p<0.05). In PsA explant, tofacitinib significantly decreased spontaneous secretion of IL-6, IL-8, MCP-1, MMP9/MMP2, MMP3 (all p<0.05) and decreased the MMP3/TIMP3 ratio (p<0.05), with no effect observed for IP-10 or IL-10. CONCLUSIONS: This study further supports JAK-STAT inhibition as a therapeutic target for the treatment of PsA.
Assuntos
Artrite Psoriásica/metabolismo , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Fatores de Transcrição STAT/efeitos dos fármacos , Sinovite/metabolismo , Adulto , Artrite Psoriásica/patologia , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Janus Quinase 3/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismo , Sinovite/patologia , Técnicas de Cultura de TecidosRESUMO
BACKGROUND: JAK/STAT signal pathway plays an important role in the inflammation process of acute lung injury (ALI). This study aimed to investigate the correlation between recombinant human brain natriuretic peptide (rhBNP) and the JAK/STAT signaling pathway and to explore the protective mechanism of rhBNP against trauma-induced ALI. METHODS: The arterial partial pressure in oxygen, lung wet-dry weight ratios, protein content in bronchoalveolar lavage fluid, the histopathologic of the lung, as well as the protein expressions of STAT1, JAK2, and STAT3 were detected. RESULTS: Sprague-Dawley rats were randomly divided into five groups: a control group, a sham-operated group, an ALI group, an ALI + rhBNP group, and an ALI + AG490 group. At 4 hours, 12 hours, 1 day, 3 days, and 7 days after injury, injured lung specimens were harvested. rhBNP pretreatment significantly ameliorated hypoxemia and histopathologic changes and alleviated pulmonary edema in trauma-induced ALI rats. rhBNP pretreatment reduced the phosphorylated protein and total protein level of STAT1. Similarly to JAK-specific inhibitor AG490, rhBNP was shown to significantly inhibit the phosphorylation of JAK2 and STAT3 in rats with trauma-induced ALI. CONCLUSION: Our experimental findings indicated that rhBNP can protect rats against trauma-induced ALI and that its underlying mechanism may be related to the inhibition of JAK/STAT signaling pathway activation.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Janus Quinase 1/efeitos dos fármacos , Peptídeo Natriurético Encefálico/uso terapêutico , Fatores de Transcrição STAT/efeitos dos fármacos , Ferimentos e Lesões/complicações , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Animais , Western Blotting , Líquido da Lavagem Broncoalveolar/química , Modelos Animais de Doenças , Imuno-Histoquímica , Janus Quinase 1/metabolismo , Masculino , Natriuréticos/uso terapêutico , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Interleukin-27 (IL-27) is a multifunctional cytokine with both pro-inflammatory and immunoregulatory functions. At present, the role of IL-27 in pulmonary fibrosis remains unknown. METHODS: In this study, we observed the expression of IL-27/IL-27R in a mouse model of bleomycin (BLM)-induced pulmonary fibrosis. We verified the role of IL-27 using hematoxylin and eosin as well as Masson's staining methods and measuring the content of hydroxyproline as well as collagen I and III. We assessed the differentiation of T lymphocytes in the spleen and measured the concentration of cytokines in bronchoalveolar lavage fluid (BALF) and the expression level of relevant proteins in the JAK/STAT and TGF-ß/Smad signaling pathways in lung tissue. RESULTS: Increased IL-27 expression in BLM-induced pulmonary fibrosis was noted. IL-27 treatment may alleviate pulmonary fibrosis and increase the survival of mice. IL-27 inhibited the development of CD4(+) IL-17(+), CD4(+) IL-4(+) T, and CD4(+) Foxp3(+) cells and the secretion of IL-17, IL-4, IL-6, and TGF-ß. IL-27 induced the production of CD4(+) IL-10(+) and CD4(+) INF-γ(+) T cells. IL-27 decreased the levels of phosphorylated STAT1, STAT3, STAT5, Smad1, and Smad3 but increased the level of SOCS3. CONCLUSIONS: This study demonstrates that IL-27 potentially attenuates BLM-induced pulmonary fibrosis by regulating Th17 differentiation and cytokine secretion.
Assuntos
Diferenciação Celular/imunologia , Citocinas/imunologia , Interleucinas/genética , Pulmão/imunologia , Fibrose Pulmonar/imunologia , Receptores de Citocinas/genética , Células Th17/imunologia , Animais , Antibióticos Antineoplásicos/toxicidade , Bleomicina/toxicidade , Western Blotting , Líquido da Lavagem Broncoalveolar/imunologia , Diferenciação Celular/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Interleucinas/imunologia , Interleucinas/farmacologia , Janus Quinases/efeitos dos fármacos , Janus Quinases/imunologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Citocinas/imunologia , Receptores de Interleucina , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição STAT/efeitos dos fármacos , Fatores de Transcrição STAT/imunologia , Transdução de Sinais , Proteínas Smad/efeitos dos fármacos , Proteínas Smad/imunologia , Baço/citologia , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/efeitos dos fármacos , Proteínas Supressoras da Sinalização de Citocina/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Células Th17/efeitos dos fármacos , Fator de Crescimento Transformador beta/efeitos dos fármacos , Fator de Crescimento Transformador beta/imunologiaRESUMO
OBJECTIVE: Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated. METHODS: A randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10â mg twice daily or placebo for 28â days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699). RESULTS: Tofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (p<0.05) and chemokines CCL2, CXCL10 and CXCL13 (p<0.05). No overall changes were observed in synovial inflammation score or the presence of T cells, B cells or macrophages. Changes in synovial phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 strongly correlated with 4-month clinical responses (p<0.002). Tofacitinib significantly decreased plasma CXCL10 (p<0.005) at Day 28 compared with placebo. CONCLUSIONS: Tofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response. TRIAL REGISTRATION NUMBER: NCT00976599.