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1.
Cytokine ; 161: 156081, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36327541

RESUMO

The tumor microenvironment consists of tumor cells, extracellular matrix, blood vessels, and non-tumor cells such as fibroblasts and immune cells. Crosstalk among components of this cellular ecosystem can transform non-malignant cells and promote tumor invasion and metastasis. Evidence is accumulating that the transcription factor STAT2, a downstream effector of type I interferon (IFN-I) signaling, can either inhibit or promote tumorigenesis depending on the unique environment presented by each type of cancer. STAT2 has long been associated with the canonical JAK/STAT pathway involved in various biological processes including reshaping of the tumor microenvironment and in antitumor immunity. This dichotomous tendency of STAT2 to both inhibit and worsen tumor formation makes the protein a curious, and yet relatively ill-defined player in many cancer pathways involving IFN-I. In this review, we discuss the role of STAT2 in contributing to either a tumorigenic or anti-tumorigenic microenvironment as well as chemoresistance.


Assuntos
Interferon Tipo I , Janus Quinases , Fator de Transcrição STAT2/metabolismo , Janus Quinases/metabolismo , Microambiente Tumoral , Ecossistema , Resistencia a Medicamentos Antineoplásicos , Transdução de Sinais , Fatores de Transcrição STAT/metabolismo , Interferon Tipo I/metabolismo , Fator de Transcrição STAT1/metabolismo
2.
Int J Pharm ; 629: 122387, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36375683

RESUMO

Vitiligo is an autoimmune disease where its current treatment strategies are lengthy in course and do not guarantee complete cure. Tofacitinib citrate (JAK inhibitor) is a potential cure of vitiligo through halting JAK-STAT pathway preventing the destruction of melanocytes. The dermato-pharmacokinetics of the prepared transethosomes (Et) and the hybridized ethosomes/nanostructured lipid carriers (Eth/NLC), namely formulations; M.E-Cr and M.E-S.M, were evaluated. In addition, in vivo studies on C57/BL6 vitiligo mouse model were conducted to confirm effectiveness of Tofacitinib citrate delivery. The results unveiled that the transethosomes (359.46 ± 11.82 nm) were suitable for dermal delivery while M.E-Cr (179.64 ± 11.16 nm), a hybrid Eth/NLC formulation, was mostly suitable for transdermal delivery. Nevertheless, another hybrid formulation, M.E-S.M (253.60 ± 14.64 nm), was apt for both dermal and transdermal delivery. The histopathology confirmed re-pigmentation of mice skin where formulations Et and M.E-S.M showed severe pigmentation compared to the control healthy and induced mice. On the other hand, M.E-Cr showed mild pigmentation. Immunohistochemical assay was performed to evaluate infiltration of CD 8+T-lymphocytes where mild infiltration was observed. However, the systemic IFN-γ was significantly reduced in case of M.E-Cr and M.E-S.M. The present work proposed potential effective formulations to improve the treatment of vitiligo with potential reduction in the total therapeutic dose, drug's side effects, and treatment costs.


Assuntos
Vitiligo , Camundongos , Animais , Vitiligo/tratamento farmacológico , Vitiligo/metabolismo , Janus Quinases/metabolismo , Janus Quinases/farmacologia , Janus Quinases/uso terapêutico , Fatores de Transcrição STAT/metabolismo , Fatores de Transcrição STAT/farmacologia , Fatores de Transcrição STAT/uso terapêutico , Transdução de Sinais , Pele/metabolismo , Lipídeos/farmacologia , Portadores de Fármacos/metabolismo
3.
SAR QSAR Environ Res ; 33(11): 833-859, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36398489

RESUMO

The Janus kinase (JAK) is a master regulator of the JAK/STAT pathway. Dysregulation of this signalling cascade causes neuroinflammation and autoimmune disorders. Therefore, JAKs have been characterized as an attractive target for developing anti-inflammatory drugs. Nowadays, designing efficient, effective, and specific targeted therapeutics without being cytotoxic has gained interest. We performed the virtual screening of natural products in combination with pharmacological analyses. Subsequently, we performed molecular dynamics simulations to study the stability of the ligand-bound complexes and ligand-induced inactive conformations. Notably, inactive kinases display remarkable conformational plasticity; however, ligand-induced molecular mechanisms of these conformations are still poorly understood. Herein, we performed a free energy landscape analysis to explore the conformational plasticity of the JAK1 kinase. Leonurine, STOCK1N-68642, STOCK1N-82656, and STOCK1N-85809 bound JAK1 exhibited a smooth transition from an active (αC-in) to a completely inactive conformation (αC-out). Ligand binding induces disorders in the αC-helix. Molecular mechanics Poisson Boltzmann surface area (MM/PBSA) calculation suggested three phytochemicals, namely STOCK1N-68642, Epicatechin, and STOCK1N-98615, have higher binding affinity compared to other ligand molecules. The ligand-induced conformational plasticity revealed by our simulations differs significantly from the available crystal structures, which might help in designing allosteric drugs.


Assuntos
Janus Quinases , Relação Quantitativa Estrutura-Atividade , Janus Quinases/química , Janus Quinases/metabolismo , Ligantes , Transdução de Sinais , Fatores de Transcrição STAT/metabolismo
4.
Leukemia ; 36(12): 2802-2816, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36229595

RESUMO

ETP-ALL (Early T cell Progenitor Acute Lymphoblastic Leukemia) represents a high-risk subtype of T cell acute lymphocytic leukemia (T-ALL). Therapeutically, ETP-ALL patients frequently relapse after conventional chemotherapy highlighting the need for alternative therapeutic approaches. Using our ZEB2Tg ETP-ALL mouse model we previously documented the potential utility of the catalytic LSD1 inhibitor (GSK2879552) for treating mouse/human ETP-ALL. However, this approach proved to be inefficient, especially in killing human LOUCY cell ETP-ALL xenografts in vivo. Here we have revealed the novel involvement of ZEB2/LSD1 complexes in repressing the intrinsic apoptosis pathway by inhibiting the expression of several pro-apoptotic proteins such as BIM (BCL2L11) as a major driver for ETP-ALL survival. Treatment with LSD1i (particularly with the steric inhibitor SP2509) restored the expression of ZEB2/LSD1 pro-apoptotic BIM (BCL2L11) target. In combination with a JAK/STAT pathway inhibitor (JAKi, Ruxolitinib) or with a direct inhibitor of the anti-apoptotic BCL2 protein (BCL2i, ABT-199) resistance of human and mouse ETP-ALL to LSD1i was reversed. This new combination approach efficiently inhibited the growth of human and mouse ETP-ALL cells in vivo by enhancing their differentiation and triggering an apoptotic response. These results set the stage for novel combination therapies to be used in clinical trials to treat ETP-ALL patients.


Assuntos
Inibidores de Janus Quinases , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Camundongos , Animais , Janus Quinases/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Proteína 11 Semelhante a Bcl-2/metabolismo , Inibidores de Janus Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Histona Desmetilases/metabolismo
5.
Life Sci Alliance ; 5(12)2022 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-36260750

RESUMO

The immunosuppressive function "licensed" by IFN-γ is a vital attribute of mesenchymal stem cells (MSCs) widely used in the treatment of inflammatory diseases. However, the mechanism and impact of metabolic reprogramming on MSC immunomodulatory plasticity remain unclear. Here, we explored the mechanism by which glucose metabolism affects the immunomodulatory reprogramming of MSCs "licensed" by IFN-γ. Our data showed that glucose metabolism regulates the immunosuppressive function of human umbilical cord MSCs (hUC-MSCs) challenged by IFN-γ through the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. Furthermore, ATP facilitated the cross talk between glucose metabolism and the JAK-STAT system, which stimulates the phosphorylation of JAK2 and STATs, as well as the expression of indoleamine 2, 3-dioxygenase and programmed cell death-1 ligand. Moreover, ATP synergistically enhanced the therapeutic efficacy of IFN-γ-primed hUC-MSCs against acute pneumonia in mice. These results indicate a novel cross talk between the immunosuppressive function, glucose metabolism, and mitochondrial oxidation and provide a novel targeting strategy to enhance the therapeutic efficacies of hUC-MSCs.


Assuntos
Dioxigenases , Células-Tronco Mesenquimais , Humanos , Camundongos , Animais , Ligantes , Células-Tronco Mesenquimais/metabolismo , Interferon gama/metabolismo , Terapia de Imunossupressão , Janus Quinases/metabolismo , Dioxigenases/metabolismo , Glucose/metabolismo , Trifosfato de Adenosina/metabolismo
6.
Biol Pharm Bull ; 45(10): 1466-1475, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36184504

RESUMO

Curculigoside (Cur) is a natural component from Curculigo orchioides Gaertn, with various bioactivities. The function of Cur in the nervous system and osteoarthritis has been reported. However, its role in osteosarcoma (OS) needs to be investigated. Hence, we focus on probing the impact of Cur on OS. In vitro, cell counting kit 8 (CCK-8), flow cytometry and Transwell assay were used to investigate the effects of Cur on OS cell proliferation, apoptosis, migration and invasion. In vivo, we developed a xenograft model to figure out the effect of Cur on tumor growth in nude mice. Western blotting (WB) was conducted to compare the levels of Cur on apoptosis-related proteins (C-caspase-3, Bax, and Bcl-2), epithelial-mesenchymal transition (EMT)-related proteins (N-cadherin, Snail, and E-cadherin) and the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and nuclear factor-κB (NF-κB) pathways in vitro and in vivo. In-vitro data testified that Cur treatment markedly hampered OS cells' growth, migration and invasion and intensified their apoptosis compared to that of the control group. In vivo, Cur treatment notably hampered the growth of OS tumors in mice. In addition, both in vitro and in vivo experiments demonstrated that the phosphorylation of JAK2, STAT3, and NF-κB were inhibited through Cur treatment. Furthermore, the inhibition of Cur in OS cells was demonstrated by up-regulating the expression of JAK/STAT and NF-κB pathways protein levels. In summary, the data suggest that Cur curbs OS growth by down-regulating the JAK/STAT and NF-κB pathways, which is an underlying therapeutic option for OS treatment.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Animais , Apoptose , Benzoatos , Neoplasias Ósseas/tratamento farmacológico , Caderinas , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Glucosídeos , Humanos , Janus Quinases/metabolismo , Janus Quinases/farmacologia , Janus Quinases/uso terapêutico , Camundongos , Camundongos Nus , NF-kappa B/metabolismo , Osteossarcoma/tratamento farmacológico , Transdução de Sinais , Sincalida/farmacologia , Sincalida/uso terapêutico , Proteína X Associada a bcl-2
7.
Front Immunol ; 13: 947213, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36238296

RESUMO

Immune cells fine tune their responses to infection and inflammatory cues. Here, using live-cell confocal microscopy and mathematical modelling, we investigate interferon-induced JAK-STAT signalling in innate immune macrophages. We demonstrate that transient exposure to IFN-γ stimulation induces a long-term desensitisation of STAT1 signalling and gene expression responses, revealing a dose- and time-dependent regulatory feedback that controls JAK-STAT responses upon re-exposure to stimulus. We show that IFN-α/ß1 elicit different level of desensitisation from IFN-γ, where cells refractory to IFN-α/ß1 are sensitive to IFN-γ, but not vice versa. We experimentally demonstrate that the underlying feedback mechanism involves regulation of STAT1 phosphorylation but is independent of new mRNA synthesis and cognate receptor expression. A new feedback model of the protein tyrosine phosphatase activity recapitulates experimental data and demonstrates JAK-STAT network's ability to decode relative changes of dose, timing, and type of temporal interferon stimulation. These findings reveal that STAT desensitisation renders cells with signalling memory of type I and II interferon stimulation, which in the future may improve administration of interferon therapy.


Assuntos
Interferon-alfa , Proteínas Tirosina Quinases , Antivirais , Retroalimentação , Interferon-alfa/metabolismo , Janus Quinases/metabolismo , Proteínas Tirosina Fosfatases/metabolismo , Proteínas Tirosina Quinases/metabolismo , RNA Mensageiro , Fatores de Transcrição STAT/metabolismo , Transcrição Genética
8.
PLoS One ; 17(10): e0276010, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36240188

RESUMO

Salmonella is an intracellular pathogen causing significant morbidity and mortality. Its ability to grow inside macrophages is important to virulence, and is dependent on the activation state of the macrophages. Classically activated M1 macrophages are non-permissive for Salmonella growth, while alternatively activated M2 macrophages are permissive for Salmonella growth. Here we showed that endotoxin-primed macrophages (MEP), such as those associated with sepsis, showed similar levels of Salmonella resistance to M1 macrophages after 2 hr of intracellular infection, but at the 4 hr and 24 hr time points were susceptible like M2 macrophages. To understand this mechanistically, transcriptomic sequencing, RNA-Seq, was performed. This showed that M1 and MEP macrophages that had not been exposed to Salmonella, demonstrated a process termed here as primed activation, in expressing relatively higher levels of particular anti-infective genes and pathways, including the JAK-STAT (Janus kinase-signal transducer and activator of transcription) pathway. In contrast, in M2 macrophages these genes and pathways were largely expressed only in response to infection. Conversely, in response to infection, M1 macrophages, but not MEP macrophages, modulated additional genes known to be associated with susceptibility to Salmonella infection, possibly contributing to the differences in resistance at later time points. Application of the JAK inhibitor Ruxolitinib before infection reduced resistance in M1 macrophages, supporting the importance of early JAK-STAT signalling in M1 resistance to Salmonella.


Assuntos
Inibidores de Janus Quinases , Transcriptoma , Tolerância à Endotoxina , Endotoxinas/metabolismo , Inibidores de Janus Quinases/metabolismo , Inibidores de Janus Quinases/farmacologia , Janus Quinases/metabolismo , Ativação de Macrófagos/genética , Macrófagos/metabolismo , Salmonella/genética , Salmonella/metabolismo
9.
Cell ; 185(21): 3857-3876, 2022 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-36240739

RESUMO

The discovery of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway arose from investigations of how cells respond to interferons (IFNs), revealing a paradigm in cell signaling conserved from slime molds to mammals. These discoveries revealed mechanisms underlying rapid gene expression mediated by a wide variety of extracellular polypeptides including cytokines, interleukins, and related factors. This knowledge has provided numerous insights into human disease, from immune deficiencies to cancer, and was rapidly translated to new drugs for autoimmune, allergic, and infectious diseases, including COVID-19. Despite these advances, major challenges and opportunities remain.


Assuntos
COVID-19 , Janus Quinases , Animais , Citocinas/metabolismo , Humanos , Interferons/metabolismo , Janus Quinases/metabolismo , Mamíferos/metabolismo , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais
10.
Int J Mol Sci ; 23(19)2022 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-36233087

RESUMO

Systemic lupus erythematosus (SLE) is a chronic, multifactorial autoimmune disease with complex pathogenesis characterized by the imbalance of pro-inflammatory and anti-inflammatory cytokines. Janus kinases (JAKs), intracellular non-receptor tyrosine kinases, are essential for signal pathways of many cytokines. The JAK signal transducers and activators of transcription (STAT) pathways consist of four JAK kinases and seven STATs family members. The dysregulation of JAK-STAT pathways represents an important process in the pathogenesis of SLE. Thus, the use of therapies that target specific signaling pathways would be a challenge in SLE. It is well known that JAK inhibitors have real potential for the treatment of rheumatic diseases, but their efficacy in the treatment of SLE remains to be determined. JAK inhibitors are currently being investigated in phase II and III trials and are considered to become the next stage in SLE therapy. In this review, we report the current data regarding the efficacy of JAK inhibitors in SLE. The development of clinically useful kinase inhibitors might improve upon traditional therapeutic strategies.


Assuntos
Inibidores de Janus Quinases , Lúpus Eritematoso Sistêmico , Anti-Inflamatórios/uso terapêutico , Citocinas/metabolismo , Humanos , Inibidores de Janus Quinases/farmacologia , Inibidores de Janus Quinases/uso terapêutico , Janus Quinases/metabolismo , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Fatores de Transcrição STAT/metabolismo , Tirosina
11.
Immunity ; 55(10): 1761-1763, 2022 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-36223725

RESUMO

Lineage plasticity is a critical mechanism of therapeutic resistance in cancer. In a recent issue of Science, Chan and colleagues demonstrate that early lineage plasticity in prostate cancer is driven by JAK-STAT inflammatory cytokine signaling.


Assuntos
Citocinas , Neoplasias da Próstata , Citocinas/metabolismo , Humanos , Janus Quinases/metabolismo , Masculino , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais
12.
Oxid Med Cell Longev ; 2022: 7838583, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36193062

RESUMO

The permeability of glioblastoma, as well as its escaping the immune system, makes them one of the most deadly human malignancies. By avoiding programmed cell death (apoptosis), unlimited cell growth and metastatic ability could dramatically affect the immune system. Genetic mutations, epigenetic changes, and overexpression of oncogenes can cause this process. On the other hand, the blood-brain barrier (BBB) and intratumor heterogeneity are important factors causing resistance to therapy. Several signaling pathways have been identified in this field, including the Janus tyrosine kinase (JAK) converter and signal transducer and activator of transcription (STAT) activator pathways, which are closely related. In addition, the JAK/STAT signaling pathway contributes to a wide array of tumorigenesis functions, including replication, anti-apoptosis, angiogenesis, and immune suppression. Introducing this pathway as the main tumorigenesis and treatment resistance center can give a better understanding of how it operates. In light of this, it is an important goal in treating many disorders, particularly cancer. The inhibition of this signaling pathway is being considered an approach to the treatment of glioblastoma. The use of natural products alternatively to conventional therapies is another area of research interest among researchers. Some natural products that originate from plants or natural sources can interfere with JAK/STAT signaling in human malignant cells, also by stopping the progression and phosphorylation of JAK/STAT, inducing apoptosis, and stopping the cell cycle. Natural products are a viable alternative to conventional chemotherapy because of their cost-effectiveness, wide availability, and almost no side effects.


Assuntos
Produtos Biológicos , Glioblastoma , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Carcinogênese , Glioblastoma/tratamento farmacológico , Humanos , Janus Quinases/metabolismo , Fatores de Transcrição STAT/genética , Transdução de Sinais
13.
Theranostics ; 12(16): 7051-7066, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36276640

RESUMO

Rationale: The mitogen-activated protein kinase pathway (MAPK) is one of the major cancer-driving pathways found in non-small cell lung cancer (NSCLC) patients. ERK inhibitors (ERKi) have been shown to be effective in NSCLC patients with MAPK pathway mutations. However, like other MAPK inhibitors, ERKi rarely confers complete and durable responses. The mechanism of tumor relapse after ERKi treatment is yet defined. Methods: To best study the mechanism of tumor relapse after ERK inhibitor treatment in NSCLC patients, we treated various NSCLC cell lines and patient-derived xenograft (PDX) with ERK inhibitors and evaluated the enrichment of cancer stem cell (CSC) population. We then performed a Next-generation sequencing (NGS) to identify potential pathways that are responsible for the CSC enrichment. Further, the involvement of specific pathways was examined using molecular and cellular methods. Finally, we investigated the therapeutic benefits of ERKi treatment combined with JAK/STAT pathway inhibitor using cellular and xenograft NSCLC models. Results: We found that ERKi treatment expands the CSC population in NSCLC cells through enhanced epithelial-to-mesenchymal transition (EMT)-mediated cancer cell dedifferentiation. Mechanistically, ERK inactivation induces EMT via pSTAT3-mediated upregulation of Slug, in which, upregulation of miR-204 and downregulation of SPDEF, a transcription repressor of Slug, are involved. Finally, the JAK/STAT pathway inhibitor Ruxolitinib blocks the ERK inactivation-induced EMT and CSC expansion, as well as the tumor progression in xenograft models after ERKi treatment. Conclusions: This study revealed a potential tumor relapse mechanism of NSCLC after ERK inhibition through the unintended activation of the EMT program, ascertained the pSTAT-miR-204-SPDEF-Slug axis, and provided a promising combination inhibitor approach to prevent tumor relapse in patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , MicroRNAs , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Janus Quinases/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Transdução de Sinais , Fatores de Transcrição STAT/metabolismo , Recidiva Local de Neoplasia/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Fatores de Transcrição/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , MicroRNAs/farmacologia , Regulação Neoplásica da Expressão Gênica
14.
Oncoimmunology ; 11(1): 2127271, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36185806

RESUMO

Janus kinase Tyk2 is implicated in cancer immune surveillance, but its role in solid tumors is not well defined. We used Tyk2 knockout mice (Tyk2Δ/Δ) and mice with conditional deletion of Tyk2 in hematopoietic (Tyk2ΔHem) or intestinal epithelial cells (Tyk2ΔIEC) to assess their cell type-specific functions in chemically induced colorectal cancer. All Tyk2-deficient mouse models showed a higher tumor burden after AOM-DSS treatment compared to their corresponding wild-type controls (Tyk2+/+ and Tyk2fl/fl), demonstrating tumor-suppressive functions of Tyk2 in immune cells and epithelial cancer cells. However, specific deletion of Tyk2 in hematopoietic cells or in intestinal epithelial cells was insufficient to accelerate tumor progression, while deletion in both compartments promoted carcinoma formation. RNA-seq and proteomics revealed that tumors of Tyk2Δ/Δ and Tyk2ΔIEC mice were immunoedited in different ways with downregulated and upregulated IFNγ signatures, respectively. Accordingly, the IFNγ-regulated immune checkpoint Ido1 was downregulated in Tyk2Δ/Δ and upregulated in Tyk2ΔIEC tumors, although both showed reduced CD8+ T cell infiltration. These data suggest that Tyk2Δ/Δ tumors are Ido1-independent and poorly immunoedited while Tyk2ΔIEC tumors require Ido1 for immune evasion. Our study shows that Tyk2 prevents Ido1 expression in CRC cells and promotes CRC immune surveillance in the tumor stroma. Both of these Tyk2-dependent mechanisms must work together to prevent CRC progression.


Assuntos
Colite , Neoplasias Colorretais , Animais , Colite/induzido quimicamente , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Janus Quinases/metabolismo , Camundongos , Camundongos Knockout
15.
Bioorg Chem ; 129: 106181, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36302332

RESUMO

In recent years, the development of dual target drugs has become a research hotspot in cancer treatment and the reasonable design of the drugs is critical. The nonclearable linked pharmacophore mode is one of the commonly used strategies for designing dual target drugs, it can connect the pharmacophores of two synergistic target inhibitors into one molecule through the linker, which greatly improves the utilization of drugs. Epigenetic modifications as a potential treatment for multiple diseases have always been a subject of great concern, and Histone deacetylases (HDAC) plays an important role. Janus Kinase (JAK) is a family of intracellular non-receptor tyrosine kinases that transduce cytokine-mediated signals through the JAK-signal transducers and the activators of transcription (STAT) pathway. Studies showed the combination of HDAC and JAK inhibitors exhibited synergistic effects in breast cancer treatment [1]. In addition, the pharmacophore models of the aforementioned two inhibitors indicate similar essential features. Further investigation on recent years' progress in the field demonstrated the nonclearable linked pharmacophore mode, using different length carbon chains as linkers to connect the pharmacophores of the two inhibitors, is the main strategy to design HDAC/JAK dual-target inhibitors which has been verified to be effective in biological activity tests. This review takes recent years' HDAC/JAK dual target inhibitors' development details as an example to summarize the general ideas behind the scene. We wish to provide the readers a theoretical basis for the development of more efficient dual-target or multi-target drugs in future.


Assuntos
Inibidores de Janus Quinases , Neoplasias , Histona Desacetilases/metabolismo , Inibidores de Janus Quinases/farmacologia , Inibidores de Janus Quinases/uso terapêutico , Pirimidinas/farmacologia , Janus Quinases/metabolismo , Janus Quinases/farmacologia , Transdução de Sinais , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo
16.
Med Oncol ; 39(12): 255, 2022 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-36224441

RESUMO

The precise mechanism of action of Janus Kinases (JAK)/Signal Transducer and activator of Transcription (STAT) signaling in human papillomavirus (HPV)-associated cervical cancer (CaCx) is poorly defined. The present study dissected the underlying components of JAK/STAT signaling in HPV-positive cervical neoplasms. Whole transcriptome profile of CaCx cohort from TCGA database revealed elevated STAT3 and its impact on CaCx patients' survival. Using the RT2 Profiler PCR Array, we analyzed 84 genes of interest associated with JAK/STAT signaling in mRNA derived from HPV-negative and HPV-positive cervical lesions which revealed 21 differentially expressed genes (DEGs). Analyses of DEGs using the Database for Annotation, Visualization and Integrated Discovery tool indicated maximum genes enriched in immune response and negative regulation of apoptotic process. Protein-protein network analysis indicated IL4, STAT5A, STAT4, and JAK3 to be the key genes in the interaction network. Further, 7 key DEGs (IL4R, IRF1, EGFR, OAS1, PIAS1, STAT4, and STAT5A) were validated in TCGA cohort using R2 platform. These genes were differentially expressed among HPV-positive cervical tissues and their correlation with STAT3 was established. EGFR and IL4R showed a comparatively strong correlation with STAT3 that supports their involvement in pathogenesis of CaCx. Finally, the Kaplan-Meier analysis established the prognostic association of the key DEGs, in CaCx cohort. The STAT3 and associated key genes discovered from our study establish a strong pathogenic role of JAK/STAT3 pathway in HPV-mediated cervical carcinogenesis.


Assuntos
Alphapapillomavirus , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Alphapapillomavirus/genética , Alphapapillomavirus/metabolismo , Carcinogênese , Receptores ErbB/metabolismo , Feminino , Humanos , Interleucina-4 , Janus Quinases/genética , Janus Quinases/metabolismo , Papillomaviridae/genética , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/genética , RNA Mensageiro , Transdução de Sinais/genética , Neoplasias do Colo do Útero/genética
17.
Ann Hematol ; 101(12): 2665-2677, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36266510

RESUMO

It has been postulated that the changes in the molecular characteristics of the malignant clone(s) and the abnormal activation of JAK-STAT signaling are responsible for myeloproliferative neoplasm progression to more advanced disease phases and the immune escape of the malignant clone. The continuous JAK-STAT pathway activation leads to enhanced activity of the promoter of CD274 coding programmed death-1 receptor ligand (PD-L1), increased PD-L1 level, and the immune escape of MPN cells. The aim of study was to evaluate the PDL1 mRNA and JAK2 mRNA level in molecularly defined essential thrombocythaemia (ET) patients (pts) during disease progression to post-ET- myelofibrosis (post-ET-MF). The study group consisted of 162 ET pts, including 30 pts diagnosed with post-ET-MF. The JAK2V617F, CALR, and MPL mutations were found in 59.3%, 19.1%, and 1.2% of pts, respectively. No copy-number alternations of the JAK2, PDL1, and PDCDL1G2 (PDL2) genes were found. The level of PD-L1 was significantly higher in the JAK2V617F than in the JAK2WT, CALR mutation-positive, and triple-negative pts. The PD-L1 mRNA level was weakly correlated with both the JAK2V617F variant allele frequency (VAF), and with the JAK2V617F allele mRNA level. The total JAK2 level in post-ET-MF pts was lower than in ET pts, despite the lack of differences in the JAK2V617F VAF. In addition, the PD-L1 level was lower in post-ET-MF. A detailed analysis has shown that the decrease in JAK2 and PDL1 mRNA levels depended on the bone marrow fibrosis grade. The PDL1 expression showed no differences in relation to the genotype of the JAK2 haplotypeGGCC_46/1, hemoglobin concentration, hematocrit value, leukocyte, and platelet counts. The observed drop of the total JAK2 and PDL1 levels during the ET progression to the post-ET-MF may reflect the changes in the JAK2V617F positive clone proliferative potential and the PD-L1 level-related immunosuppressive effect. The above-mentioned hypothesis is supported by The Cancer Genome Atlas (TCGA) data, confirming a strong positive association between CD274 (encoding PD-L1), CXCR3 (encoding CXCR3), and CSF1 (encoding M-CSF) expression levels, and recently published results documenting a drop in the CXCR3 level and circulating M-CSF in patients with post-ET-MF.


Assuntos
Transtornos Mieloproliferativos , Mielofibrose Primária , Trombocitemia Essencial , Humanos , Trombocitemia Essencial/genética , Trombocitemia Essencial/patologia , Fator Estimulador de Colônias de Macrófagos/genética , Fator Estimulador de Colônias de Macrófagos/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Janus Quinases/metabolismo , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Mielofibrose Primária/genética , Mielofibrose Primária/patologia , Mutação , RNA Mensageiro/genética , Calreticulina/genética , Calreticulina/metabolismo
18.
Molecules ; 27(19)2022 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-36234859

RESUMO

New Ni (II) and Cu (II) complexes with pyridoxal-semicarbazone were synthesized and their structures were solved by X-ray crystallography. This analysis showed the bis-ligand octahedral structure of [Ni(PLSC-H)2]·H2O and the dimer octahedral structure of [Cu(PLSC)(SO4)(H2O)]2·2H2O. Hirshfeld surface analysis was employed to determine the most important intermolecular interactions in the crystallographic structures. The structures of both complexes were further examined using density functional theory and natural bond orbital analysis. The photocatalytic decomposition of methylene blue in the presence of both compounds was investigated. Both compounds were active toward E. coli and S. aureus, with a minimum inhibition concentration similar to that of chloramphenicol. The obtained complexes led to the formation of free radical species, as was demonstrated in an experiment with dichlorofluorescein-diacetate. It is postulated that this is the mechanistic pathway of the antibacterial and photocatalytic activities. Cyclic voltammograms of the compounds showed the peaks of the reduction of metal ions. A molecular docking study showed that the Ni(II) complex exhibited promising activity towards Janus kinase (JAK), as a potential therapy for inflammatory diseases, cancers, and immunologic disorders.


Assuntos
Complexos de Coordenação , Semicarbazonas , Antibacterianos/farmacologia , Cloranfenicol , Complexos de Coordenação/química , Cristalografia por Raios X , Escherichia coli/metabolismo , Janus Quinases/metabolismo , Ligantes , Azul de Metileno , Simulação de Acoplamento Molecular , Estrutura Molecular , Piridoxal , Staphylococcus aureus/metabolismo , Níquel , Cobre
19.
Tissue Cell ; 79: 101954, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36270072

RESUMO

BACKGROUND: To explore the regulatory effect of serine/arginine repetitive matrix 1 (SRRM1) on hepatocellular carcinoma (HCC) and its potential pathway. METHODS: SRRM1 level in the tissue was tested by western blot and immunohistochemistry. Cells proliferation, apoptosis, migration, and invasion were tested by EdU, flow cytometry, wound healing assay, and Transwell, respectively. The potential mechanism of SRRM1 was explored through GSEA enrichment analysis and GeneMANIA protein-protein interaction (PPI) network. Co-immunoprecipitation assay was used to detect PPI. Levels of Bcl-2, Bax, Cleaved caspase 3, E-cadherin, N-cadherin, Vimentin, p-JAK2, JAK2, p-STAT3, and STAT3 were tested by Western blot. SRRM1 was highly expressed in HCC tissues, and was related to the survival and prognosis of patients. RESULTS: SRRM1 is significantly upregulated in HCC tumour tissues and correlated with progression of HCC. Overexpression of SRRM1 accelerated the proliferation, migration and invasion of HCC cells, and inhibited cell apoptosis, but low expression of SRRM1 had the opposite effect. SRRM1 positively correlated with the expression of IL6ST (GP130) and activated the JAK/STAT signaling pathways. SRRM1 affected the level of key molecules p-JAK2, JAK2, p-STAT3, and STAT3 in the JAK/STAT pathway. CONCLUSION: SRRM1 played a significant role in the proliferation, migration, invasion and apoptosis of HCC, and promoted cancer by regulating the JAK/STAT signaling pathway.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Janus Quinases/metabolismo , Janus Quinases/farmacologia , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Transdução de Sinais , Fatores de Transcrição STAT/metabolismo , Fatores de Transcrição STAT/farmacologia , Proliferação de Células/genética , Apoptose/genética , Movimento Celular/genética , MicroRNAs/metabolismo , Proteínas de Ligação a RNA , Proteínas Associadas à Matriz Nuclear/metabolismo , Proteínas Associadas à Matriz Nuclear/farmacologia , Antígenos Nucleares/metabolismo , Antígenos Nucleares/farmacologia
20.
Int J Mol Sci ; 23(17)2022 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-36077241

RESUMO

CXCR7 and CXCR4 are G protein-coupled receptors (GPCRs) that can be stimulated by CXCL12 in various human cancers. CXCR7/4-CXCL12 binding can initiate activation of multiple pathways including JAK/STAT and manganese superoxide dismutase (MnSOD) signaling, and initiate epithelial-mesenchymal transition (EMT) process. It is established that cancer cell invasion and migration are caused because of these events. In particular, the EMT process is an important process that can determine the prognosis for cancer. Since the antitumor effect of leelamine (LEE) has been reported in various previous studies, here, we have evaluated the influence of LEE on the CXCR7/4 signaling axis and EMT processes. We first found that LEE suppressed expression of CXCR7 and CXCR4 both at the protein and mRNA levels, and showed inhibitory effects on these chemokines even after stimulation by CXCL12 ligand. In addition, LEE also reduced the level of MnSOD and inhibited the EMT process to attenuate the invasion and migration of breast cancer cells. In addition, phosphorylation of the JAK/STAT pathway, which acts down-stream of these chemokines, was also abrogated by LEE. It was also confirmed that LEE can induce an imbalance of GSH/GSSG and increases ROS, thereby resulting in antitumor activity. Thus, we establish that targeting CXCR7/4 in breast cancer cells can not only inhibit the invasion and migration of cancer cells but also can affect JAK/STAT, EMT process, and production of ROS. Overall, the findings suggest that LEE can function as a novel agent affecting the breast cancer.


Assuntos
Neoplasias da Mama , Receptores CXCR , Abietanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Quimiocina CXCL12/farmacologia , Transição Epitelial-Mesenquimal , Feminino , Humanos , Janus Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores CXCR/genética , Receptores CXCR/metabolismo , Receptores CXCR4/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais
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