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1.
Int J Mol Sci ; 25(11)2024 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-38892407

RESUMEN

Breast cancer is influenced by factors such as diet, a sedentary lifestyle, obesity, and postmenopausal status, which are all linked to prolonged hormonal and inflammatory exposure. Physical activity offers protection against breast cancer by modulating hormones, immune responses, and oxidative defenses. This study aimed to assess how a prolonged high-fat diet (HFD) affects the effectiveness of physical activity in preventing and managing mammary tumorigenesis. Ovariectomised C57BL/6 mice were provided with an enriched environment to induce spontaneous physical activity while being fed HFD. After 44 days (short-term, ST HFD) or 88 days (long-term, LT HFD), syngenic EO771 cells were implanted into mammary glands, and tumour growth was monitored until sacrifice. Despite similar physical activity and food intake, the LT HFD group exhibited higher visceral adipose tissue mass and reduced skeletal muscle mass. In the tumour microenvironment, the LT HFD group showed decreased NK cells and TCD8+ cells, with a trend toward increased T regulatory cells, leading to a collapse of the T8/Treg ratio. Additionally, the LT HFD group displayed decreased tumour triglyceride content and altered enzyme activities indicative of oxidative stress. Prolonged exposure to HFD was associated with tumour growth despite elevated physical activity, promoting a tolerogenic tumour microenvironment. Future studies should explore inter-organ exchanges between tumour and tissues.


Asunto(s)
Dieta Alta en Grasa , Ratones Endogámicos C57BL , Condicionamiento Físico Animal , Microambiente Tumoral , Animales , Dieta Alta en Grasa/efectos adversos , Femenino , Ratones , Estrés Oxidativo , Carcinogénesis , Neoplasias Mamarias Experimentales/patología , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/prevención & control , Línea Celular Tumoral , Neoplasias Mamarias Animales/patología , Neoplasias Mamarias Animales/metabolismo , Neoplasias Mamarias Animales/prevención & control , Grasa Intraabdominal/metabolismo , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo
2.
Allergy ; 78(3): 714-730, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36181709

RESUMEN

BACKGROUND: Group 2 innate lymphoid cells (ILC2s) play a critical role in asthma pathogenesis. Non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) is associated with reduced signaling via EP2, a receptor for prostaglandin E2 (PGE2 ). However, the respective roles for the PGE2 receptors EP2 and EP4 (both share same downstream signaling) in the regulation of lung ILC2 responses has yet been deciphered. METHODS: The roles of PGE2 receptors EP2 and EP4 on ILC2-mediated lung inflammation were investigated using genetically modified mouse lines and pharmacological approaches in IL-33-induced lung allergy model. The effects of PGE2 receptors and downstream signals on ILC2 metabolic activation and effector function were examined using in vitro cell cultures. RESULTS: Deficiency of EP2 rather than EP4 augments IL-33-induced mouse lung ILC2 responses and eosinophilic inflammation in vivo. In contrast, exogenous agonism of EP4 and EP2 or inhibition of phosphodiesterase markedly restricts IL-33-induced lung ILC2 responses. Mechanistically, PGE2 directly suppresses IL-33-dependent ILC2 activation through the EP2/EP4-cAMP pathway, which downregulates STAT5 and MYC pathway gene expression and ILC2 energy metabolism. Blocking glycolysis diminishes IL-33-dependent ILC2 responses in mice where endogenous PG synthesis or EP2 signaling is blocked but not in mice with intact PGE2 -EP2 signaling. CONCLUSION: We have defined a mechanism for optimal suppression of mouse lung ILC2 responses by endogenous PGE2 -EP2 signaling which underpins the clinical findings of defective EP2 signaling in patients with NERD. Our findings also indicate that exogenously targeting the PGE2 -EP4-cAMP and energy metabolic pathways may provide novel opportunities for treating the ILC2-initiated lung inflammation in asthma and NERD.


Asunto(s)
Asma , Inmunidad Innata , Ratones , Animales , Interleucina-33/metabolismo , Subtipo EP4 de Receptores de Prostaglandina E/genética , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Subtipo EP2 de Receptores de Prostaglandina E/genética , Subtipo EP2 de Receptores de Prostaglandina E/metabolismo , Linfocitos/metabolismo , Dinoprostona/metabolismo , Pulmón/metabolismo
3.
Immunology ; 164(4): 777-791, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34529833

RESUMEN

Regulatory T (Treg) cells are essential for control of inflammatory processes by suppressing effector T-cell functions. The actions of PGE2 on the development and function of Treg cells, particularly under inflammatory conditions, are debated. In this study, we employed pharmacological and genetic approaches to examine whether PGE2  had a direct action on T cells to modulate de novo differentiation of Treg cells. We found that TGF-ß-induced Foxp3 expression and iTreg cell differentiation in vitro is markedly inhibited by PGE2 , which was mediated by the receptors EP2 and EP4. Mechanistically, PGE2 -EP2/EP4 signalling interrupts TGF-ß signalling during iTreg differentiation. Moreover, EP4 deficiency in T cells impaired iTreg cell differentiation in vivo. Thus, our results demonstrate that PGE2 negatively regulates iTreg cell differentiation through a direct action on T cells, highlighting the potential for selectively targeting the PGE2 -EP2/EP4 pathway to control T cell-mediated inflammation.


Asunto(s)
Dinoprostona/metabolismo , Subtipo EP2 de Receptores de Prostaglandina E/metabolismo , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Transducción de Señal , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Dinoprostona/farmacología , Perfilación de la Expresión Génica , Humanos , Inmunofenotipificación , Ratones , Ratones Transgénicos , Transducción de Señal/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/efectos de los fármacos
4.
Sci Adv ; 7(7)2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33579710

RESUMEN

The gut microbiota fundamentally regulates intestinal homeostasis and disease partially through mechanisms that involve modulation of regulatory T cells (Tregs), yet how the microbiota-Treg cross-talk is physiologically controlled is incompletely defined. Here, we report that prostaglandin E2 (PGE2), a well-known mediator of inflammation, inhibits mucosal Tregs in a manner depending on the gut microbiota. PGE2 through its receptor EP4 diminishes Treg-favorable commensal microbiota. Transfer of the gut microbiota that was modified by PGE2-EP4 signaling modulates mucosal Treg responses and exacerbates intestinal inflammation. Mechanistically, PGE2-modified microbiota regulates intestinal mononuclear phagocytes and type I interferon signaling. Depletion of mononuclear phagocytes or deficiency of type I interferon receptor diminishes PGE2-dependent Treg inhibition. Together, our findings provide emergent evidence that PGE2-mediated disruption of microbiota-Treg communication fosters intestinal inflammation.


Asunto(s)
Microbioma Gastrointestinal , Linfocitos T Reguladores , Dinoprostona/farmacología , Humanos , Inflamación , Subtipo EP2 de Receptores de Prostaglandina E
5.
Cancers (Basel) ; 14(1)2021 Dec 23.
Artículo en Inglés | MEDLINE | ID: mdl-35008220

RESUMEN

Our goal was to evaluate the effect of spontaneous physical activity on tumour immunity during aging. Elderly (n = 10/group, 33 weeks) ovariectomized C57BL/6J mice fed a hyperlipidic diet were housed in standard (SE) or enriched (EE) environments. After 4 weeks, orthotopic implantation of syngeneic mammary cancer EO771 cells was performed to explore the immune phenotyping in the immune organs and the tumours, as well as the cytokines in the tumour and the plasma. EE lowered circulating myostatin, IL-6 and slowed down tumour growth. Spleen and inguinal lymph node weights reduced in relation to SE. Within the tumours, EE induced a lower content of lymphoid cells with a decrease in Th2, Treg and MDCS; and, conversely, a greater quantity of Tc and TAMs. While no change in tumour NKs cells occurred, granzyme A and B expression increased as did that of perforin 1. Spontaneous physical activity in obese conditions slowed tumour growth by decreasing low-grade inflammation, modulating immune recruitment and efficacy within the tumour.

6.
Pharmacol Rev ; 72(4): 910-968, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32962984

RESUMEN

Prostaglandins are derived from arachidonic acid metabolism through cyclooxygenase activities. Among prostaglandins (PGs), prostacyclin (PGI2) and PGE2 are strongly involved in the regulation of homeostasis and main physiologic functions. In addition, the synthesis of these two prostaglandins is significantly increased during inflammation. PGI2 and PGE2 exert their biologic actions by binding to their respective receptors, namely prostacyclin receptor (IP) and prostaglandin E2 receptor (EP) 1-4, which belong to the family of G-protein-coupled receptors. IP and EP1-4 receptors are widely distributed in the body and thus play various physiologic and pathophysiologic roles. In this review, we discuss the recent advances in studies using pharmacological approaches, genetically modified animals, and genome-wide association studies regarding the roles of IP and EP1-4 receptors in the immune, cardiovascular, nervous, gastrointestinal, respiratory, genitourinary, and musculoskeletal systems. In particular, we highlight similarities and differences between human and rodents in terms of the specific roles of IP and EP1-4 receptors and their downstream signaling pathways, functions, and activities for each biologic system. We also highlight the potential novel therapeutic benefit of targeting IP and EP1-4 receptors in several diseases based on the scientific advances, animal models, and human studies. SIGNIFICANCE STATEMENT: In this review, we present an update of the pathophysiologic role of the prostacyclin receptor, prostaglandin E2 receptor (EP) 1, EP2, EP3, and EP4 receptors when activated by the two main prostaglandins, namely prostacyclin and prostaglandin E2, produced during inflammatory conditions in human and rodents. In addition, this comparison of the published results in each tissue and/or pathology should facilitate the choice of the most appropriate model for the future studies.


Asunto(s)
Receptores de Prostaglandina E/metabolismo , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Dinoprostona/inmunología , Dinoprostona/metabolismo , Epoprostenol/inmunología , Epoprostenol/metabolismo , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Ratones , Polimorfismo de Nucleótido Simple , Multimerización de Proteína , Ratas , Receptores de Prostaglandina E/química , Receptores de Prostaglandina E/genética , Receptores de Prostaglandina E/inmunología , Especificidad de la Especie
7.
Bioessays ; 42(9): e1900116, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32643186

RESUMEN

This study shows that double thymidine block treatment efficiently arrests the EO771 cells in the S-phase without altering cell growth or survival. A long-term analysis of cell behavior, using 5(6)-carboxyfluorescein diacetate N-succinimidyl ester (CFSE) staining, show synchronization to be stable and consistent over time. The EO771 cell line is a medullary breast-adenocarcinoma cell line isolated from a spontaneous murine mammary tumor, and can be used to generate murine tumor implantation models. Different biological (serum or amino acid deprivation), physical (elutriation, mitotic shake-off), or chemical (colchicine, nocodazole, thymidine) treatments are widely used for cell synchronization. Of the different methods tested, the double thymidine block is the most efficient for synchronization of murine EO771 cells if a large quantity of highly synchronized cells is recommended to study functional and biochemical events occurring in specific points of cell cycle progression.


Asunto(s)
Ciclo Celular , Animales , División Celular , Línea Celular , Ratones , Fase S , Timidina
8.
Br J Pharmacol ; 177(21): 4899-4920, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32700336

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the novel coronavirus disease 2019 (COVID-19), a highly pathogenic and sometimes fatal respiratory disease responsible for the current 2020 global pandemic. Presently, there remains no effective vaccine or efficient treatment strategies against COVID-19. Non-steroidal anti-inflammatory drugs (NSAIDs) are medicines very widely used to alleviate fever, pain, and inflammation (common symptoms of COVID-19 patients) through effectively blocking production of prostaglandins (PGs) via inhibition of cyclooxyganase enzymes. PGs can exert either proinflammatory or anti-inflammatory effects depending on the inflammatory scenario. In this review, we survey the potential roles that NSAIDs and PGs may play during SARS-CoV-2 infection and the development and progression of COVID-19. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.


Asunto(s)
Betacoronavirus/aislamiento & purificación , Infecciones por Coronavirus/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacología , COVID-19 , Infecciones por Coronavirus/virología , Progresión de la Enfermedad , Humanos , Inflamación/tratamiento farmacológico , Inflamación/virología , Pandemias , Neumonía Viral/virología , Prostaglandinas/administración & dosificación , Prostaglandinas/farmacología , SARS-CoV-2 , Tratamiento Farmacológico de COVID-19
9.
Sci Rep ; 10(1): 8794, 2020 05 29.
Artículo en Inglés | MEDLINE | ID: mdl-32472095

RESUMEN

Accumulative evidence links breast cancer development to excess weight and obesity. During obesity, dysregulations of adipose tissue induce an increase in pro-inflammatory adipokine secretions, such as leptin and oestrogen secretions. Furthermore, a raise in oxidative stress, along with a decrease in antioxidant capacity, induces and maintains chronic inflammation, which creates a permissive environment for cancer development. Physical activity is recommended as a non-pharmacological therapy in both obese and cancer situations. Physical activity is associated with a moderation of acute inflammation, higher antioxidant defences and adipokine regulation, linked to a decrease of tumour-cell proliferation. However, the biological mechanisms underlying the relationship between oxidative stress, low-grade inflammation, carcinogenesis, obesity and physical activity are poorly understood. Our study is based on old, ovariectomised mice (C57BL/6J mice, 33 weeks old), fed with a high fat diet which increases adipose tissue favouring overweight and obesity, and housed in either an enriched environment, promoting physical activity and social interactions, or a standard environment constituting close to sedentary conditions. Our model of mammary carcinogenesis allowed for the exploration of tissue secretions and signalling pathway activation as well as the oxidative status in tumours to clarify the mechanisms involved in a multiple factorial analysis of the data set. The multiple factorial analysis demonstrated that the most important variables linked to moderate, spontaneous physical activity were the increase in growth factor (epithelial growth factor (EGF), hepatocyte growth factor (HGF)) and the activation of the signalling pathways (STAT3, c-jun n-terminal kinases (JNK), EKR1/2, nuclear factor-kappa B (NF-κB)) in the gastrocnemius (G). In inguinal adipose tissue, the NF-κB inflammation pathway was activated, increasing the IL-6 content. The adiponectin plasma (P) level increased and presented an inverse correlation with tumour oxidative status. Altogether, these results demonstrated that spontaneous physical activity in obesity conditions could slow down tumour growth through crosstalk between muscle, adipose tissue and tumour. A spontaneous moderate physical activity was able to modify the inter-organ exchange in a paracrine manner. The different tissues changed their signalling pathways and adipokine/cytokine secretions, such as adiponectin and leptin, resulting in a decrease in anti-oxidative response and inflammation in the tumour environment. This model showed that moderate, spontaneous physical activity suppresses tumour growth via a dialogue between the organs close to the tumour.


Asunto(s)
Biomarcadores/sangre , Neoplasias de la Mama/rehabilitación , Terapia por Ejercicio/métodos , Obesidad/rehabilitación , Adiponectina/sangre , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Factor de Crecimiento de Hepatocito/sangre , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Trasplante de Neoplasias , Obesidad/inducido químicamente , Obesidad/metabolismo , Ovariectomía , Transducción de Señal , Microambiente Tumoral
10.
PLoS One ; 11(6): e0157767, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27315244

RESUMEN

The Ikaros transcription factor is a tumor suppressor that is also important for lymphocyte development. How post-translational modifications influence Ikaros function remains partially understood. We show that Ikaros undergoes sumoylation in developing T cells that correspond to mono-, bi- or poly-sumoylation by SUMO1 and/or SUMO2/3 on three lysine residues (K58, K240 and K425). Sumoylation occurs in the nucleus and requires DNA binding by Ikaros. Sumoylated Ikaros is less effective than unsumoylated forms at inhibiting the expansion of murine leukemic cells, and Ikaros sumoylation is abundant in human B-cell acute lymphoblastic leukemic cells, but not in healthy peripheral blood leukocytes. Our results suggest that sumoylation may be important in modulating the tumor suppressor function of Ikaros.


Asunto(s)
Proteínas de Unión al ADN/genética , Factor de Transcripción Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Transcripción Genética , Animales , Linfocitos B/patología , Línea Celular Tumoral , Proteínas de Unión al ADN/biosíntesis , Regulación Neoplásica de la Expresión Génica , Humanos , Factor de Transcripción Ikaros/biosíntesis , Linfocitos/patología , Ratones , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Procesamiento Proteico-Postraduccional/genética , Proteína SUMO-1/genética , Sumoilación/genética , Proteínas Supresoras de Tumor
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