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1.
Int J Med Sci ; 21(6): 1176-1186, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38774752

RESUMO

Background: To uncover the potential significance of JAK-STAT-SOCS1 axis in penile cancer, our study was the pioneer in exploring the altered expression processes of JAK-STAT-SOCS1 axis in tumorigenesis, malignant progression and lymphatic metastasis of penile cancer. Methods: In current study, the comprehensive analysis of JAK-STAT-SOCS1 axis in penile cancer was analyzed via multiple analysis approaches based on GSE196978 data, single-cell data (6 cancer samples) and bulk RNA data (7 cancer samples and 7 metastasis lymph nodes). Results: Our study observed an altered molecular expression of JAK-STAT-SOCS1 axis during three different stages of penile cancer, from tumorigenesis to malignant progression to lymphatic metastasis. STAT4 was an important dominant molecule in penile cancer, which mediated the immunosuppressive tumor microenvironment by driving the apoptosis of cytotoxic T cell and was also a valuable biomarker of immune checkpoint inhibitor treatment response. Conclusions: Our findings revealed that the complexity of JAK-STAT-SOCS1 axis and the predominant role of STAT4 in penile cancer, which can mediate tumorigenesis, malignant progression, and lymphatic metastasis. This insight provided valuable information for developing precise treatment strategies for patients with penile cancer.


Assuntos
Progressão da Doença , Janus Quinases , Metástase Linfática , Neoplasias Penianas , Fator de Transcrição STAT4 , Proteína 1 Supressora da Sinalização de Citocina , Humanos , Masculino , Neoplasias Penianas/patologia , Neoplasias Penianas/genética , Neoplasias Penianas/metabolismo , Proteína 1 Supressora da Sinalização de Citocina/genética , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Metástase Linfática/patologia , Metástase Linfática/genética , Janus Quinases/metabolismo , Fator de Transcrição STAT4/metabolismo , Fator de Transcrição STAT4/genética , Regulação Neoplásica da Expressão Gênica , Carcinogênese/genética , Carcinogênese/patologia , Transdução de Sinais , Microambiente Tumoral/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia
2.
Bull Exp Biol Med ; 176(5): 576-580, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38724808

RESUMO

We performed a comparative in vitro study of the involvement of NF-κB, PI3K, cAMP, ERK1/2, p38, JAKs, STAT3, JNK, and p53-dependent intracellular signaling in the functioning of neural stem cells (NSC) under the influence of basic fibroblast growth factor (FGF) and FGF receptor agonist, diterpene alkaloid songorine. The significant differences in FGFR-mediated intracellular signaling in NSC were revealed for these ligands. In both cases, stimulation of progenitor cell proliferation occurs with the participation of NF-κB, PI3K, ERK1/2, JAKs, and STAT3, while JNK and p53, on the contrary, inhibit cell cycle progression. However, under the influence of songorin, cAMP- and p38-mediated cascades are additionally involved in the transmission of the NSC division-activating signal. In addition, unlike FGF, the alkaloid stimulates progenitor cell differentiation by activating ERK1/2, p38, JNK, p53, and STAT3.


Assuntos
Diferenciação Celular , Proliferação de Células , Diterpenos , Células-Tronco Neurais , Receptores de Fatores de Crescimento de Fibroblastos , Fator de Transcrição STAT3 , Transdução de Sinais , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/citologia , Animais , Fator de Transcrição STAT3/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/agonistas , Transdução de Sinais/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diterpenos/farmacologia , Diferenciação Celular/efeitos dos fármacos , NF-kappa B/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Fator 2 de Crescimento de Fibroblastos/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/agonistas , Fosfatidilinositol 3-Quinases/metabolismo , Alcaloides/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Janus Quinases/metabolismo , AMP Cíclico/metabolismo , Células Cultivadas , Ratos
3.
Int J Mol Sci ; 25(9)2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38731900

RESUMO

Psoriasis is a highly prevalent dermatological disease associated with an increased systemic inflammatory response. In addition, joint involvement is also present in around 20% of patients. Therefore, treatment modalities used in this condition should be simultaneously effective at improving skin manifestations, reducing inflammation, and addressing psoriatic arthritis when present. Twenty years ago, the introduction of biologic treatments for psoriasis was a turning point in the management of this condition, offering an effective and reasonably safe option for patients whose disease could not be adequately controlled with conventional therapies. At the moment, Janus Kinase inhibitors (JAKis) are a new class of promising molecules in the management of psoriasis. They are orally administered and can show benefits in patients who failed biologic therapy. We conducted a scoping review in order to identify randomized-controlled trials that investigated different JAKis in patients with plaque psoriasis and psoriatic arthritis, with an emphasis on molecules that have been approved by the European Medicines Agency and the Food and Drug Administration. The added value of this study is that it collected information about JAKis approved for two different indications, plaque psoriasis and psoriatic arthritis, in order to provide an integrated understanding of the range of effects that JAKis have on the whole spectrum of psoriasis manifestations.


Assuntos
Inibidores de Janus Quinases , Janus Quinases , Psoríase , Fatores de Transcrição STAT , Transdução de Sinais , Humanos , Psoríase/tratamento farmacológico , Psoríase/metabolismo , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/farmacologia , Janus Quinases/metabolismo , Janus Quinases/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição STAT/metabolismo , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/metabolismo
4.
Cardiovasc Toxicol ; 24(6): 576-586, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38691302

RESUMO

Hypertension is a pathological state of the metabolic syndrome that increases the risk of cardiovascular disease. Managing hypertension is challenging, and we aimed to identify the pathogenic factors and discern therapeutic targets for metabolic hypertension (MHR). An MHR rat model was established with the combined treatment of a high-sugar, high-fat diet and ethanol. Histopathological observations were performed using hematoxylin-eosin and Sirius Red staining. Transcriptome sequencing was performed to screen differentially expressed genes. The role of ubiquitin-specific protease 18 (USP18) in the proliferation, apoptosis, and oxidative stress of HUVECs was explored using Cell Counting Kit-8, flow cytometry, and enzyme-linked immunosorbent assays. Moreover, USP18 downstream signaling pathways in MHR were screened, and the effects of USP18 on these signaling pathways were investigated by western blotting. In the MHR model, total cholesterol and low-density lipoprotein levels increased, while high-density lipoprotein levels decreased. Moreover, high vessel thickness and percentage of collagen were noted along with increased malondialdehyde, decreased superoxide dismutase and catalase levels. The staining results showed that the MHR model exhibited an irregular aortic intima and disordered smooth muscle cells. There were 78 differentially expressed genes in the MHR model, and seven hub genes, including USP18, were identified. USP18 overexpression facilitated proliferation and reduced apoptosis and oxidative stress in HUVECs treated with Ang in vitro. In addition, the JAK/STAT pathway was identified as a USP18 downstream signaling pathway, and USP18 overexpression inhibited the expression of JAK/STAT pathway-related proteins. Conclusively, USP18 restrained MHR progression by promoting cell proliferation, reversing apoptosis and oxidative stress, and suppressing the JAK/STAT pathway.


Assuntos
Apoptose , Proliferação de Células , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana , Hipertensão , Janus Quinases , Síndrome Metabólica , Estresse Oxidativo , Transdução de Sinais , Ubiquitina Tiolesterase , Animais , Humanos , Masculino , Ratos , Apoptose/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Progressão da Doença , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/enzimologia , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Hipertensão/patologia , Hipertensão/enzimologia , Janus Quinases/metabolismo , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Síndrome Metabólica/enzimologia , Músculo Liso Vascular/patologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/enzimologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Fatores de Transcrição STAT/metabolismo , Ubiquitina Tiolesterase/metabolismo , Ubiquitina Tiolesterase/genética , Remodelação Vascular/efeitos dos fármacos
5.
Am J Reprod Immunol ; 91(5): e13863, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38796740

RESUMO

PROBLEM: Hypertensive disorders of pregnancy (HDP) are a common pregnancy disease. NANOG and Cyclin-dependent kinase 1 (CDK1) are essential for regulating the function of cell proliferation and apoptosis. However, the mechanism of action in HDP is yet unclear. METHOD: The microarray dataset GSE6573 was downloaded from the GEO database. Emt-related gene set was downloaded from Epithelial-Mesenchymal Transition gene database 2.0 were screened differentially expressed genes by bioinformatics analysis. Pathway Commons and Scansite 4.0 databases were used to predict the interaction between proteins. Placental tissue samples were collected from HDP patients and patients with uneventful pregnancies. RT-qPCR, Western blot and immunohistochemistry were used to detect the expression of NANOG, CDK1, MMP-2, MMP-9, EMT markers and the JAK/STAT3 pathway proteins. Transfection NANOG overexpression/knockdown, and CDK1 knockdown into the human chorionic trophoblast cells (HTR-8/Svneo). CCK-8, Transwell and Wound-healing assay were used to evaluate cell proliferation, invasion and migration. CO-IP and GST pull-down assays were used to confirm the protein interaction. RESULTS: A total obtained seven EMT-related differentially expressed genes, wherein NANOG, NODAL and LIN28A had protein interaction. In the HDP patients' tissue found that NANOG and CDK1 had lower expression. NANOG overexpression promoted HTR-8/Svneo proliferation, migration and EMT, while NANOG knockdown had the opposite effect. Further a protein interaction between STAT3 and CDK1 with NANOG. NANOG overexpression downregulated the JAK/STAT3 pathway to promote HTR-8/Svneo proliferation, migration and EMT, which was reversed by CDK1 knockdown. CONCLUSIONS: NANOG downregulated the JAK/STAT3 pathway to promote trophoblast cell proliferation, migration and EMT through protein interaction with CDK1.


Assuntos
Proteína Quinase CDC2 , Movimento Celular , Transição Epitelial-Mesenquimal , Janus Quinases , Proteína Homeobox Nanog , Fator de Transcrição STAT3 , Transdução de Sinais , Trofoblastos , Humanos , Feminino , Fator de Transcrição STAT3/metabolismo , Transição Epitelial-Mesenquimal/genética , Trofoblastos/metabolismo , Gravidez , Proteína Quinase CDC2/metabolismo , Proteína Quinase CDC2/genética , Proteína Homeobox Nanog/metabolismo , Proteína Homeobox Nanog/genética , Janus Quinases/metabolismo , Hipertensão Induzida pela Gravidez/metabolismo , Hipertensão Induzida pela Gravidez/patologia , Hipertensão Induzida pela Gravidez/genética , Adulto , Proliferação de Células , Linhagem Celular
6.
J Am Chem Soc ; 146(19): 13317-13325, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38700457

RESUMO

We describe the synthesis and biological testing of ruthenium-bipyridine ruxolitinib (RuBiRuxo), a photoreleasable form of ruxolitinib, a JAK inhibitor used as an antitumoral agent in cutaneous T-cell lymphomas (CTCL). This novel caged compound is synthesized efficiently, is stable in aqueous solution at room temperature, and is photoreleased rapidly by visible light. Irradiation of RuBiRuxo reduces cell proliferation and induces apoptosis in a light- and time-dependent manner in a CTCL cell line. This effect is specific and is mediated by a decreased phosphorylation of STAT proteins. Our results demonstrate the potential of ruthenium-based photocompounds and light-based therapeutic approaches for the potential treatment of cutaneous lymphomas and other pathologies.


Assuntos
Antineoplásicos , Apoptose , Proliferação de Células , Nitrilas , Pirazóis , Pirimidinas , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Nitrilas/química , Nitrilas/farmacologia , Nitrilas/síntese química , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/síntese química , Apoptose/efeitos dos fármacos , Pirazóis/farmacologia , Pirazóis/química , Pirazóis/síntese química , Linhagem Celular Tumoral , Inibidores de Janus Quinases/farmacologia , Inibidores de Janus Quinases/química , Inibidores de Janus Quinases/síntese química , Rutênio/química , Rutênio/farmacologia , Luz , Estrutura Molecular , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo
7.
Yakugaku Zasshi ; 144(5): 489-496, 2024.
Artigo em Japonês | MEDLINE | ID: mdl-38692922

RESUMO

The tumor necrosis factor receptor (TNFR)-associated factor (TRAF) family of molecules are intracellular adaptors that regulate cellular signaling through members of the TNFR and Toll-like receptor superfamily. Mammals have seven TRAF molecules numbered sequentially from TRAF1 to TRAF7. Although TRAF5 was identified as a potential regulator of TNFR superfamily members, the in vivo function of TRAF5 has not yet been fully elucidated. We identified an unconventional role of TRAF5 in interleukin-6 (IL-6) receptor signaling involving CD4+ T cells. Moreover, TRAF5 binds to the signal-transducing glycoprotein 130 (gp130) receptor for IL-6 and inhibits the activity of the janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway. In addition, Traf5-deficient CD4+ T cells exhibit significantly enhanced IL-6-driven differentiation of T helper 17 (Th17) cells, which exacerbates neuroinflammation in experimental autoimmune encephalomyelitis. Furthermore, TRAF5 demonstrates a similar activity to gp130 for IL-27, another cytokine of the IL-6 family. Additionally, Traf5-deficient CD4+ T cells display significantly increased IL-27-mediated differentiation of Th1 cells, which increases footpad swelling in delayed-type hypersensitivity response. Thus, TRAF5 functions as a negative regulator of gp130 in CD4+ T cells. This review aimed to explain how TRAF5 controls the differentiation of CD4+ T cells and discuss how the expression of TRAF5 in T cells and other cell types can influence the development and progression of autoimmune and inflammatory diseases.


Assuntos
Linfócitos T CD4-Positivos , Encefalomielite Autoimune Experimental , Transdução de Sinais , Fator 5 Associado a Receptor de TNF , Humanos , Animais , Fator 5 Associado a Receptor de TNF/genética , Fator 5 Associado a Receptor de TNF/metabolismo , Fator 5 Associado a Receptor de TNF/fisiologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/etiologia , Encefalomielite Autoimune Experimental/metabolismo , Receptor gp130 de Citocina/fisiologia , Receptor gp130 de Citocina/metabolismo , Células Th17/imunologia , Interleucina-6/metabolismo , Interleucina-6/fisiologia , Diferenciação Celular , Receptores de Interleucina-6/fisiologia , Receptores de Interleucina-6/metabolismo , Janus Quinases/metabolismo , Janus Quinases/fisiologia , Fatores de Transcrição STAT/fisiologia , Fatores de Transcrição STAT/metabolismo , Camundongos
8.
Front Immunol ; 15: 1385473, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38720890

RESUMO

Interferons (IFNs) are a family of cytokines that activate the JAK-STAT signaling pathway to induce an antiviral state in cells. Interleukin 27 (IL-27) is a member of the IL-6 and/or IL-12 family that elicits both pro- and anti-inflammatory responses. Recent studies have reported that IL-27 also induces a robust antiviral response against diverse viruses, both in vitro and in vivo, suggesting that IFNs and IL-27 share many similarities at the functional level. However, it is still unknown how similar or different IFN- and IL-27-dependent signaling pathways are. To address this question, we conducted a comparative analysis of the transcriptomic profiles of human monocyte-derived macrophages (MDMs) exposed to IL-27 and those exposed to recombinant human IFN-α, IFN-γ, and IFN-λ. We utilized bioinformatics approaches to identify common differentially expressed genes between the different transcriptomes. To verify the accuracy of this approach, we used RT-qPCR, ELISA, flow cytometry, and microarrays data. We found that IFNs and IL-27 induce transcriptional changes in several genes, including those involved in JAK-STAT signaling, and induce shared pro-inflammatory and antiviral pathways in MDMs, leading to the common and unique expression of inflammatory factors and IFN-stimulated genes (ISGs)Importantly, the ability of IL-27 to induce those responses is independent of IFN induction and cellular lineage. Additionally, functional analysis demonstrated that like IFNs, IL-27-mediated response reduced chikungunya and dengue viruses replication in MDMs. In summary, IL-27 exhibits properties similar to those of all three types of human IFN, including the ability to stimulate a protective antiviral response. Given this similarity, we propose that IL-27 could be classified as a distinct type of IFN, possibly categorized as IFN-pi (IFN-π), the type V IFN (IFN-V).


Assuntos
Vírus Chikungunya , Vírus da Dengue , Dengue , Interferons , Janus Quinases , Macrófagos , Fatores de Transcrição STAT , Transdução de Sinais , Replicação Viral , Humanos , Vírus Chikungunya/fisiologia , Vírus Chikungunya/imunologia , Vírus da Dengue/fisiologia , Vírus da Dengue/imunologia , Janus Quinases/metabolismo , Replicação Viral/efeitos dos fármacos , Fatores de Transcrição STAT/metabolismo , Macrófagos/imunologia , Macrófagos/virologia , Macrófagos/metabolismo , Interferons/metabolismo , Dengue/imunologia , Dengue/virologia , Febre de Chikungunya/imunologia , Febre de Chikungunya/virologia , Interleucina-27/metabolismo , Interleucinas/metabolismo , Interleucinas/farmacologia , Interleucinas/imunologia , Transcriptoma , Células Cultivadas
9.
Cells ; 13(9)2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38727296

RESUMO

Derangement of the epidermal barrier lipids and dysregulated immune responses are key pathogenic features of atopic dermatitis (AD). The Th2-type cytokines interleukin IL-4 and IL-13 play a prominent role in AD by activating the Janus Kinase/Signal Transduction and Activator of Transcription (JAK/STAT) intracellular signaling axis. This study aimed to investigate the role of JAK/STAT in the lipid perturbations induced by Th2 signaling in 3D epidermal equivalents. Tofacitinib, a low-molecular-mass JAK inhibitor, was used to screen for JAK/STAT-mediated deregulation of lipid metabolism. Th2 cytokines decreased the expression of elongases 1, 3, and 4 and serine-palmitoyl-transferase and increased that of sphingolipid delta(4)-desaturase and carbonic anhydrase 2. Th2 cytokines inhibited the synthesis of palmitoleic acid and caused depletion of triglycerides, in association with altered phosphatidylcholine profiles and fatty acid (FA) metabolism. Overall, the ceramide profiles were minimally affected. Except for most sphingolipids and very-long-chain FAs, the effects of Th2 on lipid pathways were reversed by co-treatment with tofacitinib. An increase in the mRNA levels of CPT1A and ACAT1, reduced by tofacitinib, suggests that Th2 cytokines promote FA beta-oxidation. In conclusion, pharmacological inhibition of JAK/STAT activation prevents the lipid disruption caused by the halted homeostasis of FA metabolism.


Assuntos
Citocinas , Janus Quinases , Metabolismo dos Lipídeos , Fatores de Transcrição STAT , Células Th2 , Humanos , Células Th2/metabolismo , Células Th2/efeitos dos fármacos , Fatores de Transcrição STAT/metabolismo , Janus Quinases/metabolismo , Citocinas/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Epiderme/metabolismo , Epiderme/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Piperidinas/farmacologia , Pirimidinas/farmacologia , Inibidores de Janus Quinases/farmacologia , Interleucina-4/metabolismo , Ácidos Graxos/metabolismo
10.
Front Immunol ; 15: 1385190, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38711523

RESUMO

The discovery of Suppressor of Cytokine Signaling 1 (SOCS1) in 1997 marked a significant milestone in understanding the regulation of Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling pathways. Subsequent research deciphered its cellular functions, and recent insights into SOCS1 deficiencies in humans underscored its critical role in immune regulation. In humans, SOCS-haploinsufficiency (SOCS1-HI) presents a diverse clinical spectrum, encompassing autoimmune diseases, infection susceptibility, and cancer. Variability in disease manifestation, even within families sharing the same genetic variant, raises questions about clinical penetrance and the need for individualized treatments. Current therapeutic strategies include JAK inhibition, with promising results in controlling inflammation in SOCS1-HI patients. Hematopoietic stem cell transplantation and gene therapy emerge as promising avenues for curative treatments. The evolving landscape of SOCS1 research, emphasizes the need for a nuanced understanding of genetic variants and their functional consequences.


Assuntos
Transdução de Sinais , Proteína 1 Supressora da Sinalização de Citocina , Humanos , Proteína 1 Supressora da Sinalização de Citocina/genética , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Animais , Janus Quinases/metabolismo , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/terapia , Haploinsuficiência , Fatores de Transcrição STAT/metabolismo , Fatores de Transcrição STAT/genética , Terapia Genética
11.
Nature ; 629(8012): 688-696, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38658752

RESUMO

Although cancer initiation and progression are generally associated with the accumulation of somatic mutations1,2, substantial epigenomic alterations underlie many aspects of tumorigenesis and cancer susceptibility3-6, suggesting that genetic mechanisms might not be the only drivers of malignant transformation7. However, whether purely non-genetic mechanisms are sufficient to initiate tumorigenesis irrespective of mutations has been unknown. Here, we show that a transient perturbation of transcriptional silencing mediated by Polycomb group proteins is sufficient to induce an irreversible switch to a cancer cell fate in Drosophila. This is linked to the irreversible derepression of genes that can drive tumorigenesis, including members of the JAK-STAT signalling pathway and zfh1, the fly homologue of the ZEB1 oncogene, whose aberrant activation is required for Polycomb perturbation-induced tumorigenesis. These data show that a reversible depletion of Polycomb proteins can induce cancer in the absence of driver mutations, suggesting that tumours can emerge through epigenetic dysregulation leading to inheritance of altered cell fates.


Assuntos
Proteínas de Drosophila , Drosophila melanogaster , Epigênese Genética , Janus Quinases , Neoplasias , Proteínas do Grupo Polycomb , Fatores de Transcrição STAT , Animais , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Proteínas do Grupo Polycomb/metabolismo , Proteínas do Grupo Polycomb/genética , Neoplasias/genética , Neoplasias/patologia , Fatores de Transcrição STAT/metabolismo , Fatores de Transcrição STAT/genética , Janus Quinases/metabolismo , Janus Quinases/genética , Feminino , Carcinogênese/genética , Masculino , Transdução de Sinais/genética , Inativação Gênica , Transformação Celular Neoplásica/genética , Linhagem da Célula/genética , Regulação Neoplásica da Expressão Gênica
12.
Inflamm Res ; 73(6): 897-913, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38625657

RESUMO

OBJECTIVES AND DESIGN: As an interferon-inducible protein, Viperin has broad-spectrum antiviral effects and regulation of host immune responses. We aim to investigate how Viperin regulates interferon-γ (IFN-γ) production in macrophages to control Mycobacterium tuberculosis (Mtb) infection. METHODS: We use Viperin deficient bone-marrow-derived macrophage (BMDM) to investigate the effects and machines of Viperin on Mtb infection. RESULTS: Viperin inhibited IFN-γ production in macrophages and in the lung of mice to promote Mtb survival. Further insight into the mechanisms of Viperin-mediated regulation of IFN-γ production revealed the role of TANK-binding kinase 1 (TBK1), the TAK1-dependent inhibition of NF-kappa B kinase-epsilon (IKKε), and interferon regulatory factor 3 (IRF3). Inhibition of the TBK1-IKKε-IRF3 axis restored IFN-γ production reduced by Viperin knockout in BMDM and suppressed intracellular Mtb survival. Moreover, Viperin deficiency activated the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, which promoted IFN-γ production and inhibited Mtb infection in BMDM. Additionally, a combination of the anti-TB drug INH treatment in the absence of Viperin resulted in further IFN-γ production and anti-TB effect. CONCLUSIONS: This study highlights the involvement of TBK1-IKKε-IRF3 axis and JAK-STAT signaling pathways in Viperin-suppressed IFN-γ production in Mtb infected macrophages, and identifies a novel mechanism of Viperin on negatively regulating host immune response to Mtb infection.


Assuntos
Fator Regulador 3 de Interferon , Interferon gama , Macrófagos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis , Proteínas Serina-Treonina Quinases , Proteínas , Transdução de Sinais , Animais , Interferon gama/metabolismo , Interferon gama/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Mycobacterium tuberculosis/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Camundongos , Proteínas/genética , Proteínas/metabolismo , Quinase I-kappa B/metabolismo , Janus Quinases/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Camundongos Knockout , Tuberculose/imunologia , Pulmão/imunologia , Pulmão/microbiologia , Proteína Viperina
13.
Arch Biochem Biophys ; 756: 110002, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38636689

RESUMO

BACKGROUND: Phospholipid scramblase 1 (PLSCR1) is a calcium-dependent endofacial plasma-membrane protein that plays an essential role in multiple human cancers. However, little is known about its role in glioma. This study aimed to investigate PLSCR1 function in glioma, and elucidate its underlying molecular mechanisms. METHODS: PLSCR1 expression in human glioma cell lines (U87MG, U251, LN229, A172 and T98G) and human astrocytes was detected by western blot and qRT-PCR. PLSCR1 was silenced using si-PLSCR1-1 and si-PLSCR1-2 in LN229 and U251 cells. PLSCR1 was overexpressed using the pcDNA-PLSCR1 plasmid in T98G cells. Colony formation, 5-ethynyl-2'-deoxyuridine, flow cytometry and transwell assays were employed for measuring cell proliferation, apoptosis and mobility after PLSCR1 knockdown or overexpression. PLSCR1 function in glycolysis in glioma cells was determined through measuring the extracellular acidification rate, oxygen consumption rate, glucose consumption and lactate production. Besides, immunohistochemistry, western blot and qRT-PCR were utilized to assess mRNA and protein expression. Besides, the effect of PLSCR1 silencing on subcutaneous tumor was also monitored. RESULTS: PLSCR1 expression was upregulated in glioma. The downregulation of PLSCR1 repressed the proliferation, mobility, epithelial-to-mesenchymal transition (EMT) and glycolysis; however, it facilitated apoptosis in glioma cells. Whereas, PLSCR1 upregulation had the opposite effect. Moreover, PLSCR1 promoted the activation of the IL-6/JAK/STAT3 pathway in glioma cells. Besides, IL-6 treatment significantly reversed the function of PLSCR1 silencing on cell proliferation, mobility, EMT, apoptosis and glycolysis. In a nude mouse tumor model, silencing PLSCR1 suppressed tumor growth via inactivating IL-6/JAK/STAT3 signaling. CONCLUSION: Our results indicated that PLSCR1 could facilitate proliferation, mobility, EMT and glycolysis, but repress apoptosis through activating IL-6/JAK/STAT3 signaling in glioma. Therefore, PLSCR1 may function as a potential therapeutic target for glioma.


Assuntos
Proliferação de Células , Glioma , Interleucina-6 , Proteínas de Transferência de Fosfolipídeos , Fator de Transcrição STAT3 , Transdução de Sinais , Humanos , Glioma/metabolismo , Glioma/patologia , Glioma/genética , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Proteínas de Transferência de Fosfolipídeos/metabolismo , Proteínas de Transferência de Fosfolipídeos/genética , Linhagem Celular Tumoral , Animais , Interleucina-6/metabolismo , Camundongos , Camundongos Nus , Janus Quinases/metabolismo , Apoptose , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Glicólise , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Camundongos Endogâmicos BALB C , Movimento Celular
14.
Am J Physiol Renal Physiol ; 326(6): F931-F941, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38634132

RESUMO

Coronavirus disease 2019 (COVID-19) induces respiratory dysfunction as well as kidney injury. Although the kidney is considered a target organ of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and affected by the COVID-19-induced cytokine storm, the mechanisms of renal reaction in SARS-CoV-2 infection are unknown. In this study, a murine COVID-19 model was induced by nasal infection with mouse-adapted SARS-CoV-2 (MA10). MA10 infection induced body weight loss along with lung inflammation in mice 4 days after infection. Serum creatinine levels and the urinary albumin/creatinine ratio increased on day 4 after MA10 infection. Measurement of the urinary neutrophil gelatinase-associated lipocalin/creatinine ratio and hematoxylin and eosin staining revealed tubular damage in MA10-infected murine kidneys, indicating kidney injury in the murine COVID-19 model. Interferon (IFN)-γ and interleukin-6 upregulation in the sera of MA10-infected mice, along with the absence of MA10 in the kidneys, implied that the kidneys were affected by the MA10 infection-induced cytokine storm rather than by direct MA10 infection of the kidneys. RNA-sequencing analysis revealed that antiviral genes, such as the IFN/Janus kinase (JAK) pathway, were upregulated in MA10-infected kidneys. Upon administration of the JAK inhibitor baricitinib on days 1-3 after MA10 infection, an antiviral pathway was suppressed, and MA10 was detected more frequently in the kidneys. Notably, JAK inhibition upregulated the hypoxia response and exaggerated kidney injury. These results suggest that endogenous antiviral activity protects against SARS-CoV-2-induced kidney injury in the early phase of infection, providing valuable insights into the pathogenesis of COVID-19-associated nephropathy.NEW & NOTEWORTHY Patients frequently present with acute kidney injury or abnormal urinary findings after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we investigated how the kidneys respond during SARS-CoV-2 infection using a murine coronavirus disease 2019 (COVID-19) model and showed that Janus kinase-mediated endogenous antiviral activity protects against kidney injury in the early phase of SARS-CoV-2 infection. These findings provide valuable insights into the renal pathophysiology of COVID-19.


Assuntos
COVID-19 , Inibidores de Janus Quinases , Purinas , Pirazóis , SARS-CoV-2 , Sulfonamidas , Animais , COVID-19/complicações , Inibidores de Janus Quinases/farmacologia , Inibidores de Janus Quinases/uso terapêutico , Sulfonamidas/farmacologia , Camundongos , Purinas/farmacologia , Pirazóis/farmacologia , Modelos Animais de Doenças , Injúria Renal Aguda/virologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/metabolismo , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Janus Quinases/metabolismo , Janus Quinases/antagonistas & inibidores , Rim/patologia , Rim/virologia , Rim/metabolismo , Rim/efeitos dos fármacos , Tratamento Farmacológico da COVID-19 , Antivirais/farmacologia , Antivirais/uso terapêutico , Masculino , Camundongos Endogâmicos C57BL
15.
Cell Commun Signal ; 22(1): 203, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38566182

RESUMO

BACKGROUND: The metabolically demanding nature of immune response requires nutrients to be preferentially directed towards the immune system at the expense of peripheral tissues. We study the mechanisms by which this metabolic reprograming occurs using the parasitoid infection of Drosophila larvae. To overcome such an immune challenge hemocytes differentiate into lamellocytes, which encapsulate and melanize the parasitoid egg. Hemocytes acquire the energy for this process by expressing JAK/STAT ligands upd2 and upd3, which activates JAK/STAT signaling in muscles and redirects carbohydrates away from muscles in favor of immune cells. METHODS: Immune response of Drosophila larvae was induced by parasitoid wasp infestation. Carbohydrate levels, larval locomotion and gene expression of key proteins were compared between control and infected animals. Efficacy of lamellocyte production and resistance to wasp infection was observed for RNAi and mutant animals. RESULTS: Absence of upd/JAK/STAT signaling leads to an impaired immune response and increased mortality. We demonstrate how JAK/STAT signaling in muscles leads to suppression of insulin signaling through activation of ImpL2, the inhibitor of Drosophila insulin like peptides. CONCLUSIONS: Our findings reveal cross-talk between immune cells and muscles mediates a metabolic shift, redirecting carbohydrates towards immune cells. We emphasize the crucial function of muscles during immune response and show the benefits of insulin resistance as an adaptive mechanism that is necessary for survival.


Assuntos
Proteínas de Drosophila , Resistência à Insulina , Vespas , Animais , Fatores de Transcrição/metabolismo , Proteínas de Drosophila/metabolismo , Janus Quinases/metabolismo , Fatores de Transcrição STAT/metabolismo , Drosophila/genética , Músculos , Vespas/metabolismo , Larva/metabolismo , Imunidade , Carboidratos , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo
16.
Sci Rep ; 14(1): 8762, 2024 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-38627442

RESUMO

Metastatic colorectal cancer (CRC) is still in need of effective treatments. This study applies a holistic approach to propose new targets for treatment of primary and liver metastatic CRC and investigates their therapeutic potential in-vitro. An integrative analysis of primary and metastatic CRC samples was implemented for alternative target and treatment proposals. Integrated microarray samples were grouped based on a co-expression network analysis. Significant gene modules correlated with primary CRC and metastatic phenotypes were identified. Network clustering and pathway enrichments were applied to gene modules to prioritize potential targets, which were shortlisted by independent validation. Finally, drug-target interaction search led to three agents for primary and liver metastatic CRC phenotypes. Hesperadin and BAY-1217389 suppress colony formation over a 14-day period, with Hesperadin showing additional efficacy in reducing cell viability within 48 h. As both candidates target the G2/M phase proteins NEK2 or TTK, we confirmed their anti-proliferative properties by Ki-67 staining. Hesperadinin particular arrested the cell cycle at the G2/M phase. IL-29A treatment reduced migration and invasion capacities of TGF-ß induced metastatic cell lines. In addition, this anti-metastatic treatment attenuated TGF-ß dependent mesenchymal transition. Network analysis suggests IL-29A induces the JAK/STAT pathway in a preventive manner.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Indóis , Neoplasias Hepáticas , Neoplasias Retais , Sulfonamidas , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Transcriptoma , Janus Quinases/metabolismo , Transdução de Sinais , Fatores de Transcrição STAT/metabolismo , Neoplasias do Colo/genética , Neoplasias Retais/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Fator de Crescimento Transformador beta/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Regulação Neoplásica da Expressão Gênica , Quinases Relacionadas a NIMA/genética
17.
Nan Fang Yi Ke Da Xue Xue Bao ; 44(3): 541-552, 2024 Mar 20.
Artigo em Chinês | MEDLINE | ID: mdl-38597446

RESUMO

OBJECTIVE: To investigate the role of JAK1/STAT3/KHSRP axis in mediating the regulatory effect of LINC00626 on progression of esophagogastric junction adenocarcinoma. METHODS: We collected surgical tumor and adjacent tissue specimens from 64 patients with esophagogastric junction adenocarcinoma and examined the expression levels of LINC00626 and KHSRP. qRT-PCR was used to detect the expressions of LINC00626 and KHSRP in 6 esophageal adenocarcinoma cell lines (OE-19, TE-7, Bic-1, Flo-1, SK-GT-4, and BE-3) and a normal esophageal epithelial cell line (HET-1A). OE-19 and TE-7 cell lines with stable LINC00626 knockdown and FLO-1 and SK-GT-4 cells stably overexpressing LINC00626 were constructed by lentiviral transfection, and the changes in proliferation, migration and invasion of the cells were evaluated using Cell Counting Kit-8 (CCK-8) assay and Transwell migration/invasion assay. The expressions of KHSRP and JAK/STAT pathway proteins in the transfected cells were detected with Western blotting. The effects of LINC006266 knockdown and overexpression on subcutaneous tumor formation and lung metastasis of OE-19 and FLO-1 cell xenografts were tested in nude mice. RESULTS: The expression levels of LINC00626 and KHSRP were significantly increased in esophagogastric junction adenocarcinoma tissues and in esophageal adenocarcinoma cells. LINC00626 knockdown obviously inhibited the proliferation, migration and invasion of esophageal adenocarcinoma cells in vitro and decreased their tumor formation and lung metastasis abilities in nude mice, while overexpression of LINC00626 produced the opposite effects. In esophageal adenocarcinoma cells, LINC0626 knockdown significantly decreased and LINC00626 overexpression strongly enhanced the phosphorylation of JAK1 and STAT3. CONCLUSION: High LINC00626 expression promotes esophageal-gastric junction adenocarcinoma metastasis by activating the JAK1/STAT3/KHSRP signal axis.


Assuntos
Adenocarcinoma , Neoplasias Esofágicas , Janus Quinase 1 , Neoplasias Pulmonares , Proteínas de Ligação a RNA , Animais , Humanos , Camundongos , Adenocarcinoma/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Junção Esofagogástrica/metabolismo , Junção Esofagogástrica/patologia , Regulação Neoplásica da Expressão Gênica , Janus Quinases/metabolismo , Neoplasias Pulmonares/metabolismo , Camundongos Nus , Transdução de Sinais , Fatores de Transcrição STAT/metabolismo , Fator de Transcrição STAT3/metabolismo , Transativadores , RNA Longo não Codificante/genética
18.
Rev Assoc Med Bras (1992) ; 70(3): e20231167, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38656003

RESUMO

OBJECTIVE: The aim of this study was to analyze possible alterations (morphological and inflammatory) in the ocular cells of fetuses from mothers with insulin resistance exposed to saturated fatty acids through the period of pregnancy. METHODS: Wistar female rats were induced to develop insulin resistance before pregnancy. Fetuses' skulls were collected on the 20th day of intrauterine life. The rats were separated on the first day of management into two groups according to the diet applied: control group (C): diet containing soybean oil as a source of fat; and saturated fatty acid group (S): diet containing butter as a source of fat. RESULTS: Histological and immunohistochemical analyses have been conducted. The immunohistochemical analyses of interleukin 6, suppressor of cytokine signaling, 3 and signal transducer and activator of transcription 3 did not demonstrate alterations in the expression of proteins in the fetuses of mothers fed with a saturated fatty diet. Moreover, no histopathological changes were noticed between groups. CONCLUSION: The saturated fatty diet does not induce tissue changes or activate the Janus kinase/signal transducer and activator of transcription signaling pathway during eye development in the fetuses of mothers with insulin resistance.


Assuntos
Resistência à Insulina , Janus Quinases , Ratos Wistar , Transdução de Sinais , Animais , Feminino , Gravidez , Transdução de Sinais/efeitos dos fármacos , Resistência à Insulina/fisiologia , Janus Quinases/metabolismo , Ácidos Graxos/análise , Gorduras na Dieta/farmacologia , Gorduras na Dieta/efeitos adversos , Feto/efeitos dos fármacos , Imuno-Histoquímica , Fator de Transcrição STAT3/metabolismo , Interleucina-6/análise , Interleucina-6/metabolismo , Ratos , Olho/embriologia , Olho/efeitos dos fármacos
19.
J Cardiovasc Pharmacol Ther ; 29: 10742484241248046, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38656132

RESUMO

Atherosclerosis is now widely considered to be a chronic inflammatory disease, with increasing evidence suggesting that lipid alone is not the main factor contributing to its development. Rather, atherosclerotic plaques contain a significant amount of inflammatory cells, characterized by the accumulation of monocytes and lymphocytes on the vessel wall. This suggests that inflammation may play a crucial role in the occurrence and progression of atherosclerosis. As research deepens, other pathological factors have also been found to influence the development of the disease. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is a recently discovered target of inflammation that has gained attention in recent years. Numerous studies have provided evidence for the causal role of this pathway in atherosclerosis, and its downstream signaling factors play a significant role in this process. This brief review aims to explore the crucial role of the JAK/STAT pathway and its representative downstream signaling factors in the development of atherosclerosis. It provides a new theoretical basis for clinically affecting the development of atherosclerosis by interfering with the JAK/STAT signaling pathway.


Assuntos
Aterosclerose , Janus Quinases , Fatores de Transcrição STAT , Transdução de Sinais , Humanos , Aterosclerose/metabolismo , Aterosclerose/tratamento farmacológico , Fatores de Transcrição STAT/metabolismo , Janus Quinases/metabolismo , Animais , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/farmacologia , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/farmacologia , Mediadores da Inflamação/metabolismo
20.
Nan Fang Yi Ke Da Xue Xue Bao ; 44(3): 465-473, 2024 Mar 20.
Artigo em Chinês | MEDLINE | ID: mdl-38597437

RESUMO

OBJECTIVE: To explore the therapeutic mechanism of Jianpi Zishen (JPZS) granules for systemic lupus erythematosus(SLE) in light of podocyte autophagy regulation. METHODS: TCMSP, GeneCards, OMIM, and TTD databases were used to obtain the targets of JPZS granules, SLE, and podocyte autophagy. The protein-protein interaction network was constructed using Cytoscape, and the key active ingredients and targets were screened for molecular docking. In the clinical study, 46 patients with SLE were randomized into two groups to receive baseline treatment with prednisone acetate and mycophenolate mofetil (control group) and additional treatment with JPZS granules (observation group) for 12 weeks, with 10 healthy volunteers as the healthy control group. Urinary levels of nephrin and synaptopodin of the patients were detected with ELISA. Western blotting was performed to determine peripheral blood levels of p-JAK1/JAK1, p-STAT1/STAT1, LC3II/LC3I, and p62 proteins of the participants. RESULTS: Four key active ingredients and 5 core target genes (STAT1, PIK3CG, MAPK1, PRKCA, and CJA1) were obtained, and enrichment analysis identified the potentially involved signaling pathways including AGE-RAGE, JAK/STAT, EGFR, and PI3K/Akt. Molecular docking analysis showed that STAT1 was the most promising target protein with the highest binding activity, suggesting its role as an important mediator for signal transduction after JPZS granule treatment. In the 43 SLE patients available for analysis, treatment with JPZS granule significantly reduced serum levels of p-JAK1/JAK1, p-STAT1/STAT1, and LC3II/LC3I (P < 0.05 or 0.01), increased the protein level of P62 (P < 0.05), and reduced urinary levels of nephrin and synaptopodin (P < 0.05). CONCLUSION: The therapeutic effect of JPZS granules on SLE is mediated probably by coordinated actions of quercetin, kaempferol, ß-sitosterol, and isorhamnetin on their target gene STAT1 to inhibit the JAK/STAT pathway, thus suppressing autophagy and alleviating podocyte injuries in SLE.


Assuntos
Medicamentos de Ervas Chinesas , Lúpus Eritematoso Sistêmico , Podócitos , Humanos , Autofagia , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Janus Quinases/metabolismo , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/metabolismo , Simulação de Acoplamento Molecular , Farmacologia em Rede , Fosfatidilinositol 3-Quinases/metabolismo , Podócitos/metabolismo , Transdução de Sinais , Fatores de Transcrição STAT/metabolismo
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