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1.
Int Rev Cell Mol Biol ; 385: 101-155, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38663958

RESUMEN

Most adult human cancers are solid tumors prevailing in vital organs and lead to mortality all over the globe. Genetic and epigenetic alterations in cancer genes or genes of associated signaling pathways impart the most common characteristic of malignancy, that is, uncontrolled proliferation. Unless the mechanism of action of these cells signaling pathways (involved in cell proliferation, apoptosis, metastasis, and the maintenance of the stemness of cancer stem cells and cancer microenvironment) and their physiologic alteration are extensively studied, it is challenging to understand tumorigenesis as well as develop new treatments and precision medicines. Targeted therapy is one of the most promising strategies for treating various cancers. However, cancer is an evolving disease, and most patients develop resistance to these drugs by acquired mutations or mediation of microenvironmental factors or due to tumor heterogeneity. Researchers are striving to develop novel therapeutic options like combinatorial approaches targeting multiple responsible pathways effectively. Thus, in-depth knowledge of cell signaling and its components remains a critical topic of cancer research. This chapter summarized various extensively studied pathways in solid cancer and how they are targeted for therapeutic strategies.


Asunto(s)
Neoplasias , Transducción de Señal , Humanos , Neoplasias/patología , Neoplasias/metabolismo , Neoplasias/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Animales , Terapia Molecular Dirigida , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico
2.
J Exp Clin Cancer Res ; 43(1): 85, 2024 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-38500204

RESUMEN

Anaplastic thyroid cancer (ATC) is the most aggressive thyroid cancer. Despite advances in tissue culture techniques, a robust model for ATC spheroid culture is yet to be developed. In this study, we created an efficient and cost-effective 3D tumor spheroids culture system from human ATC cells and existing cell lines that better mimic patient tumors and that can enhance our understanding of in vivo treatment response. We found that patient-derived ATC cells and cell lines can readily form spheroids in culture with a unique morphology, size, and cytoskeletal organization. We observed both cohesive (dense and solid structures) and discohesive (irregularly shaped structures) spheroids within the same culture condition across different cell lines. BRAFWT ATC spheroids grew in a cohesive pattern, while BRAFV600E-mutant ATC spheroids had a discohesive organization. In the patient-derived BRAFV600E-mutant ATC spheroids, we observed both growth patterns, but mostly the discohesive type. Histologically, ATC spheroids had a similar morphology to the patient's tumor through H&E staining and proliferation marker staining. Moreover, RNA sequencing analysis revealed that the gene expression profile of tumor cells derived from the spheroids closely matched parental patient tumor-derived cells in comparison to monolayer cultures. In addition, treatment response to combined BRAF and MEK inhibition in BRAFV600E-mutant ATC spheroids exhibited a similar sensitivity to the patient clinical response. Our study provides a robust and novel ex vivo spheroid model system that can be used in both established ATC cell lines and patient-derived tumor samples to better understand the biology of ATC and to test therapeutics.


Asunto(s)
Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Humanos , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Neoplasias de la Tiroides/patología , Línea Celular Tumoral
3.
Nat Rev Cancer ; 23(12): 805-824, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37857840

RESUMEN

Adrenocortical carcinoma is a rare malignancy with an annual worldwide incidence of 1-2 cases per 1 million and a 5-year survival rate of <60%. Although adrenocortical carcinoma is rare, such rare cancers account for approximately one third of patients diagnosed with cancer annually. In the past decade, there have been considerable advances in understanding the molecular basis of adrenocortical carcinoma. The genetic events associated with adrenocortical carcinoma in adults are distinct from those of paediatric cases, which are often associated with germline or somatic TP53 mutations and have a better prognosis. In adult primary adrenocortical carcinoma, the main somatic genetic alterations occur in genes that encode proteins involved in the WNT-ß-catenin pathway, cell cycle and p53 apoptosis pathway, chromatin remodelling and telomere maintenance pathway, cAMP-protein kinase A (PKA) pathway or DNA transcription and RNA translation pathways. Recently, integrated molecular studies of adrenocortical carcinomas, which have characterized somatic mutations and the methylome as well as gene and microRNA expression profiles, have led to a molecular classification of these tumours that can predict prognosis and have helped to identify new therapeutic targets. In this Review, we summarize these recent translational research advances in adrenocortical carcinoma, which it is hoped could lead to improved patient diagnosis, treatment and outcome.


Asunto(s)
Neoplasias de la Corteza Suprarrenal , Carcinoma Corticosuprarrenal , Adulto , Humanos , Niño , Carcinoma Corticosuprarrenal/genética , Carcinoma Corticosuprarrenal/terapia , Carcinoma Corticosuprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/terapia , Neoplasias de la Corteza Suprarrenal/diagnóstico , Investigación Biomédica Traslacional , Vía de Señalización Wnt , Factores de Transcripción
4.
Thyroid ; 33(10): 1201-1214, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37675898

RESUMEN

Background: Anaplastic thyroid cancer (ATC) is uniformly lethal. BRAFV600E mutation is present in 45% of patients with ATC. Targeted therapy with combined BRAF and MEK inhibition in BRAFV600E-mutant ATC can be effective, but acquired resistance is common because this combination targets the same pathway. Drug matrix screening, in BRAFV600E ATC cells, of highly active compounds in combination with BRAF inhibition showed multitargeting tyrosine kinase inhibitors (MTKIs) had the highest synergistic/additive activity. Thus, we hypothesized that the combination of BRAFV600E inhibition and an MTKI is more effective than a single drug or combined BRAF and MEK inhibition in BRAFV600E-mutant ATC. We evaluated the effect of BRAFV600E inhibitors in combination with the MTKI axitinib and its mechanism(s) of action. Methods: We evaluated the effects of BRAFV600E inhibitors and axitinib alone and in combination in in vitro and in vivo models of BRAFV600E-mutant and wild-type ATC. Results: The combination of axitinib and BRAFV600E inhibitors (dabrafenib and PLX4720) showed an additive effect on inhibiting cell proliferation based on the Chou-Talalay algorithm in BRAFV600E-mutant ATC cell lines. This combination also significantly inhibited cell invasion and migration (p < 0.001) compared with the control. Dabrafenib and PLX4720 arrested ATC cells in the G0/G1 phase. Axitinib arrested ATC cells in the G2/M phase by decreasing phosphorylation of aurora kinase B (Thr232) and histone H3 (Ser10) proteins and by upregulating the c-JUN signaling pathway. The combination of BRAF inhibition and axitinib significantly inhibited tumor growth and was associated with improved survival in an orthotopic ATC model. Conclusions: The novel combination of axitinib and BRAFV600E inhibition enhanced anticancer activity in in vitro and in vivo models of BRAFV600E-mutant ATC. This combination may have clinical utility in BRAFV600E-mutant ATC that is refractory to current standard therapy, namely combined BRAF and MEK inhibition.


Asunto(s)
Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Humanos , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Carcinoma Anaplásico de Tiroides/genética , Carcinoma Anaplásico de Tiroides/patología , Axitinib/farmacología , Axitinib/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Quinasas de Proteína Quinasa Activadas por Mitógenos/uso terapéutico , Mutación , Línea Celular Tumoral
5.
Surgery ; 169(2): 298-301, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33023754

RESUMEN

BACKGROUND: Genetic testing for germline pheochromocytoma and paraganglioma susceptibility genes is associated with improved patient management. However, data are currently sparse on the probability of a positive testing result based on an individual's clinical presentation. This study evaluates clinical characteristics for association with testing positive for known pheochromocytoma and paraganglioma susceptibility genes. METHODS: This retrospective analysis examined 111 patients with a diagnosis of pheochromocytoma and paraganglioma who underwent genetic testing. Logistic regression and receiver operating characteristic analyses were performed to identify factors associated with a positive genetic testing result. Probabilities were then calculated for combinations of significant factors to determine the likelihood of a positive test result in each group. RESULTS: Of 32 patients with a family history of pheochromocytoma and paraganglioma, 31 (97%) had a germline mutation detected. Of 79 patients without a family history, 24 (30%) had a pathogenic germline mutation detected. In multivariate analysis, a positive family history, aged ≤47 years, and tumor size ≤2.9 cm were independent factors associated with a positive genetic testing result. Patients meeting all 3 criteria had a 100% probability compared with 13% in those without any of the criteria. In addition to a positive family history, having either aged ≤47 years or tumor size ≤2.9 cm resulted in a 90% and 100% probability of a positive result, respectively. In the absence of a family history, the probability in patients who were aged ≤47 years and had a tumor size ≤2.9 cm was 60%. CONCLUSION: In addition to a family history of pheochromocytoma and paraganglioma, aged ≤47 years, and tumor size ≤2.9 cm are associated with a higher probability of testing positive for a pheochromocytoma and paraganglioma susceptibility gene mutation. Patients meeting all 3 criteria have a 100% probability of a positive genetic testing result.


Asunto(s)
Neoplasias de las Glándulas Suprarrenales/diagnóstico , Biomarcadores de Tumor/genética , Pruebas Genéticas/estadística & datos numéricos , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , Adolescente , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/patología , Neoplasias de las Glándulas Suprarrenales/cirugía , Glándulas Suprarrenales/patología , Glándulas Suprarrenales/cirugía , Adrenalectomía , Adulto , Factores de Edad , Análisis Mutacional de ADN/estadística & datos numéricos , Femenino , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Humanos , Modelos Logísticos , Masculino , Anamnesis/estadística & datos numéricos , Persona de Mediana Edad , Oportunidad Relativa , Paraganglioma/genética , Paraganglioma/patología , Paraganglioma/cirugía , Feocromocitoma/genética , Feocromocitoma/patología , Feocromocitoma/cirugía , Periodo Preoperatorio , Curva ROC , Estudios Retrospectivos , Carga Tumoral , Adulto Joven
6.
J Clin Med ; 9(5)2020 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-32413990

RESUMEN

The aim of this study is to determine the accuracy of adrenal vein sampling (AVS) with and without adrenocorticotropic hormone (ACTH) stimulation to distinguish between unilateral and bilateral primary hyperaldosteronism (PA). Retrospective analysis of a prospective database from a referral center between 1984 and 2009, 76 patients had simultaneous cannulation of bilateral adrenal veins and AVS with and without ACTH stimulation. All patients had adrenalectomies. The selectivity index (SI, cut-off value ≥2) was used for confirmation of successful cannulation of the adrenal vein. The lateralization index (LI, cut-off value >2 and >4) was used for distinguishing between unilateral and bilateral PA. The SI ratio was higher with ACTH stimulation compared to without for the right adrenal vein (p = 0.027). The LI >2 ratio was higher with ACTH stimulation compared to without (p = 0.007). For the LI >4 ratio, there was no difference between with and without ACTH stimulation (p = 0.239). However, for a LI >4, 7 patients (9.2%) were not lateralized with ACTH stimulation, but they did lateralize without ACTH stimulation. AVS with ACTH stimulation is associated with a higher SI ratio compared to AVS without ACTH stimulation. However, when using LI >4 for AVS, samples without ACTH stimulation should also be included to detect a subset of patients with unilateral disease that are not detected with ACTH stimulation.

7.
Clin Cancer Res ; 26(8): 2022-2036, 2020 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-31937621

RESUMEN

PURPOSE: Most aggressive thyroid cancers are commonly associated with a BRAF V600E mutation. Preclinical and clinical data in BRAF V600E cancers suggest that combined BRAF and MEK inhibitor treatment results in a response, but resistance is common. One mechanism of acquired resistance is through persistent activation of tyrosine kinase (TK) signaling by alternate pathways. We hypothesized that combination therapy with BRAF and multitargeting TK inhibitors (MTKI) might be more effective in BRAF V600E thyroid cancer than in single-agent or BRAF and MEK inhibitors. EXPERIMENTAL DESIGN: The combined drug activity was analyzed to predict any synergistic effect using high-throughput screening (HTS) of active drugs. We performed follow-up in vitro and in vivo studies to validate and determine the mechanism of action of synergistic drugs. RESULTS: The MTKI ponatinib and the BRAF inhibitor PLX4720 showed synergistic activity by HTS. This combination significantly inhibited proliferation, colony formation, invasion, and migration in BRAF V600E thyroid cancer cell lines and downregulated pERK/MEK and c-JUN signaling pathways, and increased apoptosis. PLX4720-resistant BRAF V600E cells became sensitized to the combination treatment, with decreased proliferation at lower PLX4720 concentrations. In an orthotopic thyroid cancer mouse model, combination therapy significantly reduced tumor growth (P < 0.05), decreased the number of metastases (P < 0.05), and increased survival (P < 0.05) compared with monotherapy and vehicle control. CONCLUSIONS: Combination treatment with ponatinib and PLX4720 exhibited significant synergistic anticancer activity in preclinical models of BRAF V600E thyroid cancer, in addition to overcoming PLX4720 resistance. Our results suggest this combination should be tested in clinical trials.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Evaluación Preclínica de Medicamentos/métodos , Sinergismo Farmacológico , Mutación , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Neoplasias de la Tiroides/tratamiento farmacológico , Animales , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Imidazoles/administración & dosificación , Indoles/administración & dosificación , Ratones , Ratones Endogámicos NOD , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Piridazinas/administración & dosificación , Sulfonamidas/administración & dosificación , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/patología , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Gastroenterology ; 158(5): 1433-1449.e27, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31786131

RESUMEN

BACKGROUND & AIMS: Prolactin (PRL) signaling is up-regulated in hormone-responsive cancers. The PRL receptor (PRLR) is a class I cytokine receptor that signals via the Janus kinase (JAK)-signal transducer and activator of transcription and mitogen-activated protein kinase pathways to regulate cell proliferation, migration, stem cell features, and apoptosis. Patients with pancreatic ductal adenocarcinoma (PDAC) have high plasma levels of PRL. We investigated whether PRLR signaling contributes to the growth of pancreatic tumors in mice. METHODS: We used immunohistochemical analyses to compare levels of PRL and PRLR in multitumor tissue microarrays. We used structure-based virtual screening and fragment-based drug discovery to identify compounds likely to bind PRLR and interfere with its signaling. Human pancreatic cell lines (AsPC-1, BxPC-3, Panc-1, and MiaPaCa-2), with or without knockdown of PRLR (clustered regularly interspaced short palindromic repeats or small hairpin RNA), were incubated with PRL or penfluridol and analyzed in proliferation and spheroid formation. C57BL/6 mice were given injections of UNKC-6141 cells, with or without knockdown of PRLR, into pancreas, and tumor development was monitored for 4 weeks, with some mice receiving penfluridol treatment for 21 days. Human pancreatic tumor tissues were implanted into interscapular fat pads of NSG mice, and mice were given injections of penfluridol daily for 28 days. Nude mice were given injections of Panc-1 cells, xenograft tumors were grown for 2 weeks, and mice were then given intraperitoneal penfluridol for 35 days. Tumors were collected from mice and analyzed by histology, immunohistochemistry, and immunoblots. RESULTS: Levels of PRLR were increased in PDAC compared with nontumor pancreatic tissues. Incubation of pancreatic cell lines with PRL activated signaling via JAK2-signal transducer and activator of transcription 3 and extracellular signal-regulated kinase, as well as formation of pancospheres and cell migration; these activities were not observed in cells with PRLR knockdown. Pancreatic cancer cells with PRLR knockdown formed significantly smaller tumors in mice. We identified several diphenylbutylpiperidine-class antipsychotic drugs as agents that decreased PRL-induced JAK2 signaling; incubation of pancreatic cancer cells with these compounds reduced their proliferation and formation of panco spheres. Injections of 1 of these compounds, penfluridol, slowed the growth of xenograft tumors in the different mouse models, reducing proliferation and inducing autophagy of the tumor cells. CONCLUSIONS: Levels of PRLR are increased in PDAC, and exposure to PRL increases proliferation and migration of pancreatic cancer cells. Antipsychotic drugs, such as penfluridol, block PRL signaling in pancreatic cancer cells to reduce their proliferation, induce autophagy, and slow the growth of xenograft tumors in mice. These drugs might be tested in patients with PDAC.


Asunto(s)
Antipsicóticos/farmacología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Penfluridol/farmacología , Prolactina/metabolismo , Receptores de Prolactina/antagonistas & inhibidores , Animales , Antipsicóticos/uso terapéutico , Autofagia/efectos de los fármacos , Carcinoma Ductal Pancreático/sangre , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Descubrimiento de Drogas , Técnicas de Silenciamiento del Gen , Humanos , Inyecciones Intraperitoneales , Janus Quinasa 2/metabolismo , Masculino , Ratones , Páncreas/patología , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/patología , Penfluridol/uso terapéutico , Prolactina/sangre , Receptores de Prolactina/genética , Receptores de Prolactina/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Esferoides Celulares , Análisis de Matrices Tisulares , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Gastroenterology ; 157(6): 1646-1659.e11, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31442435

RESUMEN

BACKGROUND & AIMS: The histone lysine demethylase 3A (KDM3A) demethylates H3K9me1 and H3K9Me2 to increase gene transcription and is upregulated in tumors, including pancreatic tumors. We investigated its activities in pancreatic cancer cell lines and its regulation of the gene encoding doublecortin calmodulin-like kinase 1 (DCLK1), a marker of cancer stem cells. METHODS: We knocked down KDM3A in MiaPaCa-2 and S2-007 pancreatic cancer cell lines and overexpressed KDM3A in HPNE cells (human noncancerous pancreatic ductal cell line); we evaluated cell migration, invasion, and spheroid formation under hypoxic and normoxic conditions. Nude mice were given orthotopic injections of S2-007 cells, with or without (control) knockdown of KDM3A, and HPNE cells, with or without (control) overexpression of KDM3A; tumor growth was assessed. We analyzed pancreatic tumor tissues from mice and pancreatic cancer cell lines by immunohistochemistry and immunoblotting. We performed RNA-sequencing analysis of MiaPaCa-2 and S2-007 cells with knockdown of KDM3A and evaluated localization of DCLK1 and KDM3A by immunofluorescence. We analyzed the cancer genome atlas for levels of KDM3A and DCLK1 messenger RNA in human pancreatic ductal adenocarcinoma (PDAC) tissues and association with patient survival time. RESULTS: Levels of KDM3A were increased in human pancreatic tumor tissues and cell lines, compared with adjacent nontumor pancreatic tissues, such as islet and acinar cells. Knockdown of KDM3A in S2-007 cells significantly reduced colony formation, invasion, migration, and spheroid formation, compared with control cells, and slowed growth of orthotopic tumors in mice. We identified KDM3A-binding sites in the DCLK1 promoter; S2-007 cells with knockdown of KDM3A had reduced levels of DCLK1. HPNE cells that overexpressed KDM3A formed foci and spheres in culture and formed tumors and metastases in mice, whereas control HPNE cells did not. Hypoxia induced sphere formation and increased levels of KDM3A in S2-007 cells and in HPNE cells that overexpressed DCLK1, but not control HPNE cells. Levels of KDM3A and DCLK1 messenger RNA were higher in human PDAC than nontumor pancreatic tissues and correlated with shorter survival times of patients. CONCLUSIONS: We found human PDAC samples and pancreatic cancer cell lines to overexpress KDM3A. KDM3A increases expression of DCLK1, and levels of both proteins are increased in human PDAC samples. Knockdown of KDM3A in pancreatic cancer cell lines reduced their invasive and sphere-forming activities in culture and formation of orthotopic tumors in mice. Hypoxia increased expression of KDM3A in pancreatic cancer cells. Strategies to disrupt this pathway might be developed for treatment of pancreatic cancer.


Asunto(s)
Carcinogénesis/genética , Carcinoma Ductal Pancreático/genética , Regulación Neoplásica de la Expresión Génica , Péptidos y Proteínas de Señalización Intracelular/genética , Histona Demetilasas con Dominio de Jumonji/metabolismo , Neoplasias Pancreáticas/genética , Proteínas Serina-Treonina Quinasas/genética , Animales , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Metilación de ADN , Conjuntos de Datos como Asunto , Quinasas Similares a Doblecortina , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Histona Demetilasas con Dominio de Jumonji/genética , Masculino , Ratones , Persona de Mediana Edad , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Regiones Promotoras Genéticas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Análisis de Supervivencia , Regulación hacia Arriba , Ensayos Antitumor por Modelo de Xenoinjerto
10.
Oncotarget ; 10(16): 1554-1571, 2019 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-30899425

RESUMEN

Super-enhancers (SEs) are unique areas of the genome which drive high-level of transcription and play a pivotal role in the cell physiology. Previous studies have established several important genes in cancer as SE-driven oncogenes. It is likely that oncogenes may hack the resident tissue regenerative program and interfere with SE-driven repair networks, leading to the specific pancreatic ductal adenocarcinoma (PDAC) phenotype. Here, we used ChIP-Seq to identify the presence of SE in PDAC cell lines. Differential H3K27AC marks were identified at enhancer regions of genes including c-MYC, MED1, OCT-4, NANOG, and SOX2 that can act as SE in non-cancerous, cancerous and metastatic PDAC cell lines. GZ17-6.02 affects acetylation of the genes, reduces transcription of major transcription factors, sonic hedgehog pathway proteins, and stem cell markers. In accordance with the decrease in Oct-4 expression, ChIP-Seq revealed a significant decrease in the occupancy of OCT-4 in the entire genome after GZ17-6.02 treatment suggesting the possible inhibitory effect of GZ17-6.02 on PDAC. Hence, SE genes are associated with PDAC and targeting their regulation with GZ17-6.02 offers a novel approach for treatment.

11.
Indian J Exp Biol ; 53(2): 82-92, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25757238

RESUMEN

Toll-like receptors (TLR) are a family of pattern recognition receptors identifying pathogen associated molecular patterns (PAMPs). They play a critical role in the innate immune response during the initial interaction between the infecting microorganism and phagocytic cells. Here, we verified the presence of TLR-2 in spleen, lymph node and thymus of Swiss albino mice and their modulation after infection with Staphylococcus aureus and Lipopolysaccharide (LPS) challenge. It was seen that TLR-2 gene transcribed to its respective mRNA on S. aureus infection, in thymus, spleen and lymph node of mice but their levels and mode of expression varied. When challenged with LPS no prominent changes in the expression of TLR-2 receptor was observed but its expression increased gradually with time in the thymus, spleen and lymph node of S. aureus infected mice. TLR-2 expression was also found enhanced in infected splenic macrophages. By studying the serum cytokine profile the functionality of the receptor was measured. The results indicate the presence of TLR-2 in thymus, spleen and lymph node of Swiss albino strain of mice and that they are modulated by S. aureus.


Asunto(s)
Lipopolisacáridos/inmunología , Ganglios Linfáticos/inmunología , Bazo/inmunología , Infecciones Estafilocócicas/inmunología , Staphylococcus aureus/inmunología , Timo/inmunología , Receptor Toll-Like 2/inmunología , Animales , Antibacterianos/farmacología , Western Blotting , Citocinas/sangre , Citocinas/inmunología , Expresión Génica/efectos de los fármacos , Expresión Génica/inmunología , Interacciones Huésped-Patógeno/inmunología , Lipopolisacáridos/farmacología , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/microbiología , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/microbiología , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Bazo/metabolismo , Bazo/microbiología , Infecciones Estafilocócicas/sangre , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/fisiología , Timo/metabolismo , Timo/microbiología , Factores de Tiempo , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/metabolismo
12.
J Immunol Res ; 2015: 137981, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25759837

RESUMEN

Expression of innate immune receptors varies among organs and species and within different strains among the same species; thus, periodic classification of different pattern recognition receptors in the available strains is necessary to initiate different therapeutic approaches to combat inflammation. On characterization of TLR-4 in spleen and thymus of Swiss albino mice--with no reports of TLR-4 expression--induced with endotoxemia, it was found that the mode of expression varied among the organs at both mRNA and protein level in a time-dependent manner. Their functionality was verified by measuring proinflammatory and anti-inflammatory cytokines. In the in vitro study using isolated macrophages and lymphocytes from the same organs, the expression of TLR-4 after a shorter period of LPS stimulation was verified. The results substantiated the potent role of macrophage on LPS challenge compared to lymphocytes. The diverse pattern of TLR-4 expression on different cell population indicated their distinct functional activity in LPS-endotoxemia. It may be hypothesized that the expression patterns of TLR-4 could be different based on the anatomical localization and the varying bacterial milieu or bacterial endotoxin encountered in each anatomical location. Thus, blocking TLR-4 or administering IL-6 or IL-10 might impart protection against endotoxemia in the clinical field.


Asunto(s)
Endotoxemia/inmunología , Endotoxemia/metabolismo , Inmunomodulación , Bazo/inmunología , Bazo/metabolismo , Timo/inmunología , Timo/metabolismo , Receptor Toll-Like 4/metabolismo , Animales , Proteína C-Reactiva , Medios de Cultivo Condicionados/metabolismo , Citocinas/sangre , Modelos Animales de Enfermedad , Endotoxemia/genética , Endotoxemia/patología , Expresión Génica , Mediadores de Inflamación/sangre , Lipopolisacáridos/inmunología , Linfocitos/inmunología , Linfocitos/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones , ARN Mensajero/genética , ARN Mensajero/metabolismo , Bazo/patología , Timo/patología , Receptor Toll-Like 4/genética
13.
Immunobiology ; 220(7): 910-23, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25698349

RESUMEN

Staphylococcus aureus induced septic arthritis has emerged as a potent disabling and life threatening disease; hence combating this malady has become an imperative need of medical science. Role of TLR-2 in innate recognition of S. aureus and activation of inflammatory cascade by the interplay of some proinflammatory cytokines, resulting in joint inflammation has been established. Variation in the reports suggesting both functional dependency and independency of TLR-2 on its heterodimeric partner TLR-6 in response to ligands exists, thus this study was postulated to observe the expression pattern of TLR-6 in synovial tissue and lymphoid organs after inducing septic arthritis by S. aureus in Swiss albino mouse model and the instigated cytokine profile could affirm its plausible role in SA. The functional relation of TLR-2 and 6 was verified by simulating an in vitro study design on synovial mononuclear cells, blocking TLR-2 and 6, and it was found that they are required to co-express for generating cytokine, NO and H2O2 on infection. IFN-γ, IL-6 and IL-17 were identified to play a distinguished role in SA from their secretion pattern in both in vivo and in vitro study. IFN-γ and IL-6 remained high throughout the infection possibly by the shift of response from Th1 to Th2 and Th17 and contribute in various converging pathways of inflammation. IL-17 increased with the onset of the disease but reduced on the late period. Hence IFN-γ, IL-6, IL-17 along with TLR-6 can be a potent target for therapeutic approach because of their significant contribution in SA.


Asunto(s)
Artritis Infecciosa/inmunología , Interleucina-17/inmunología , Staphylococcus aureus/inmunología , Receptor Toll-Like 2/inmunología , Receptor Toll-Like 6/inmunología , Animales , Artritis Infecciosa/microbiología , Peróxido de Hidrógeno/metabolismo , Inflamación/inmunología , Inflamación/microbiología , Interferón gamma/sangre , Interferón gamma/inmunología , Interleucina-10/sangre , Interleucina-6/sangre , Interleucina-6/inmunología , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Macrófagos/inmunología , Masculino , Ratones , Óxido Nítrico/metabolismo , Bazo/citología , Bazo/inmunología , Bazo/microbiología , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/microbiología , Membrana Sinovial/citología , Membrana Sinovial/inmunología , Membrana Sinovial/microbiología , Células TH1/inmunología , Células Th17/inmunología , Células Th2/inmunología , Factor de Necrosis Tumoral alfa/sangre
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