Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 31
Filtrar
Más filtros

Banco de datos
Tipo del documento
Intervalo de año de publicación
1.
Reprod Biol Endocrinol ; 22(1): 21, 2024 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-38341605

RESUMEN

Biomarker identification could help in deciphering endometriosis pathophysiology in addition to their use in the development of non invasive diagnostic and prognostic approaches, that are essential to greatly improve patient care. Despite extensive efforts, no single potential biomarker or combination has been clinically validated for endometriosis.Many studies have investigated endometriosis-associated biological markers in specific tissues, but an integrative approach across tissues is lacking. The aim of this review is to propose a comprehensive overview of identified biomarkers based on tissue or biological compartment, while taking into account endometriosis phenotypes (superficial, ovarian or deep, or rASRM stages), menstrual cycle phases, treatments and symptoms.We searched PubMed and Embase databases for articles matching the following criteria: 'endometriosis' present in the title and the associated term 'biomarkers' found as Medical Subject Headings (MeSH) terms or in all fields. We restricted to publications in English and on human populations. Relevant articles published between 01 January 2005 (when endometriosis phenotypes start to be described in papers) and 01 September 2022 were critically analysed and discussed.Four hundred forty seven articles on endometriosis biomarkers that included a control group without endometriosis and provided specific information on endometriosis phenotypes are included in this review. Presence of information or adjustment controlling for menstrual cycle phase, symptoms and treatments is highlighted, and the results are further summarized by biological compartment. The 9 biological compartments studied for endometriosis biomarker research are in order of frequency: peripheral blood, eutopic endometrium, peritoneal fluid, ovaries, urine, menstrual blood, saliva, feces and cervical mucus. Adjustments of results on disease phenotypes, cycle phases, treatments and symptoms are present in 70%, 29%, 3% and 6% of selected articles, respectively. A total of 1107 biomarkers were identified in these biological compartments. Of these, 74 were found in several biological compartments by at least two independent research teams and only 4 (TNF-a, MMP-9, TIMP-1 and miR-451) are detected in at least 3 tissues with cohorts of 30 women or more.Integrative analysis is a crucial step to highlight potential pitfalls behind the lack of success in the search for clinically relevant endometriosis biomarkers, and to illuminate the physiopathology of this disease.


Asunto(s)
Endometriosis , Humanos , Femenino , Endometriosis/patología , Biomarcadores , Endometrio/patología , Pronóstico
2.
Proc Natl Acad Sci U S A ; 116(24): 11894-11899, 2019 06 11.
Artículo en Inglés | MEDLINE | ID: mdl-31142643

RESUMEN

Endometriosis is characterized by the presence of ectopic endometrial cells outside the uterine cavity. Thyroid autoimmunity has been associated with endometriosis. This work investigated the potential pathophysiological link between endometriosis and thyroid disorders. Transcripts and proteins involved in thyroid metabolism are dysregulated in eutopic and ectopic endometrium of endometriotic patients, leading to resistance of ectopic endometrium to triiodothyronine (T3) action and local accumulation of thyroxine (T4). Thyroid-stimulating hormone (TSH) acts as a proliferative and prooxidative hormone on all endometria of endometriosis patients and controls, whereas T3 and T4 act to specifically increase ectopic endometrial cell proliferation and reactive oxygen species (ROS) production. Mouse studies confirmed the data gained in vitro since endometriotic implants were found to be bigger when thyroid hormones increased. A retrospective analysis of endometriosis patients with or without a thyroid disorder revealed an increased chronic pelvic pain and disease score in endometriotic patients with a thyroid disorder.


Asunto(s)
Endometriosis/metabolismo , Glándula Tiroides/metabolismo , Hormonas Tiroideas/metabolismo , Animales , Proliferación Celular/fisiología , Endometrio/metabolismo , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Especies Reactivas de Oxígeno/metabolismo , Estudios Retrospectivos , Tirotropina/metabolismo , Tiroxina/metabolismo , Triyodotironina/metabolismo
3.
Hum Reprod ; 34(3): 479-490, 2019 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-30753458

RESUMEN

STUDY QUESTION: Is endometriosis associated with aberrant sialylation patterns and what is the potential impact of such anomalies on cell migratory properties? SUMMARY ANSWER: The reduced α-2,6 sialylation patterns in the peritoneal fluid of endometriosis-affected women and in stromal and epithelial cells from endometriotic lesions could be associated with enhanced cell migration. WHAT IS KNOWN ALREADY: Endometriosis is considered to be a benign disease although, like cancer, it has the characteristic of being an invasive disease with cells that have an enhanced capacity to migrate. Aberrant sialylation has been reported in various malignancies and it has been linked to tumour invasion and metastasis. STUDY DESIGN, SIZE, DURATION: We conducted a prospective laboratory study in a tertiary-care university hospital. We investigated non-pregnant patients who were <42 years of age (n = 273) when they underwent surgery for a benign gynaecological condition. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study population consisted of 102 women with histologically proven endometriosis and 71 endometriosis-free controls, who underwent a complete surgical exploration of the abdominopelvic cavity. Peritoneal fluids were collected during the surgical procedures, and endometrial and endometriotic biopsies were performed on all of the patients to generate stromal and epithelial primary cell cultures. The expression of α-2,6-sialyltransferase (ST6GALNAC1) was studied in eutopic and ectopic endometria of endometriosis patients and in eutopic endometria of controls by reverse transcription followed by quantitative real-time polymerase chain reaction (RT-qPCR). The α-2,6 sialylation levels were measured by ELISA in the peritoneal fluids of patients and controls and by western-blot in primary endometrial and endometriotic cell cultures using Sambucus nigra agglutinin (SNA), an α-2,6 sialic acid-binding lectin. A transwell migration assay after incubation of the cells with neuraminidase was also performed to evaluate the impact of desialylation on eutopic endometrial stromal cell migration. MAIN RESULTS AND THE ROLE OF CHANCE: ST6GALNAC1 gene expression was significantly lower in endometriotic lesions compared to that in eutopic endometrium of endometriosis-affected patients and healthy endometrium (16-fold for both; P < 0.01). We observed a significant reduction in SNA levels in the peritoneal fluids of endometriosis-affected women compared to control women (median optic density (OD), 0.257; range, 0.215-0.279 versus median OD, 0.278; range 0.238-0.285; P < 0.01), as well as in stromal (mean OD, 705 907; standard error of the mean (SEM), 141 549 versus mean OD, 1.16 × 106; SEM, 107,271; P < 0.05) and epithelial (mean OD, 485 706; SEM, 179 681 versus mean OD, 1.25 × 106; SEM, 232 120; P < 0.05) ectopic endometriotic cells compared to control eutopic cells, indicating reduced α-2,6 sialylation. Finally, in the transwell migration assay, the eutopic endometrial cells of endometriosis patients migrated significantly more into the lower chamber after incubation with neuraminidase, indicating enhanced migration by these cells after desialylation. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Our control group involved patients operated for benign gynaecological conditions (e.g. tubal infertility, uterine fibroids or ovarian cysts) which may also be associated with altered sialylation patterns. WIDER IMPLICATIONS OF THE FINDINGS: The hyposialylation pattern of endometriotic cells appeared to be associated with enhanced migratory abilities, which might contribute to the establishment of early endometriotic implants. Further research is needed to confirm these findings, as this could lead to new potential therapeutic targets for this complex disorder. STUDY FUNDING AND COMPETING INTEREST(S): No external funding was received and there are no conflicts of interest.


Asunto(s)
Movimiento Celular , Endometriosis/metabolismo , Endometriosis/fisiopatología , Sialiltransferasas/metabolismo , Adulto , Líquido Ascítico/metabolismo , Endometrio/metabolismo , Células Epiteliales/metabolismo , Femenino , Humanos , Infertilidad Femenina/metabolismo , Leiomioma/metabolismo , Quistes Ováricos/metabolismo , Estudios Prospectivos , Reacción en Cadena en Tiempo Real de la Polimerasa , Células del Estroma/metabolismo , Centros de Atención Terciaria
4.
Hum Mol Genet ; 21(9): 1968-78, 2012 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-22246292

RESUMEN

SERPINA3 (Serpin peptidase inhibitor clade A member 3), also known as a1-antichymotrypsin, is a serine protease inhibitor involved in a wide range of biological processes. Recently, it has been shown to be up-regulated in human placental diseases in association with a hypomethylation of the 5' region of the gene. In the present study, we show that the promoter of SERPINA3 is transcriptionally activated by three transcription factors (TFs) (SP1, MZF1 and ZBTB7B), the level of induction being dependent on the rs1884082 single nucleotide polymorphism (SNP) located inside the promoter, the T allele being consistently induced to a higher level than the G, with or without added TFs. When the promoter was methylated, the response to ZBTB7B was allele specific (the G allele was strongly induced, while the T allele was strongly down-regulated). We propose an adaptive model to explain the interest of such a regulation for placental function and homeostasis. Overexpression of SERPINA3 in JEG-3 cells, a trophoblast cell model, decreased cell adhesion to the extracellular matrix and to neighboring cells, but protects them from apoptosis, suggesting a way by which this factor could be deleterious at high doses. In addition, we show in different human populations that the T allele appears to predispose to Intra Uterine Growth Restriction (IUGR), while a G allele at a second SNP located in the second exon (rs4634) increases the risk of preeclampsia. Our results provide mechanistic views inside the involvement of SERPINA3 in placental diseases, through its regulation by a combination of epigenetic, genetic and TF-mediated regulations.


Asunto(s)
Enfermedades Placentarias/genética , Serpinas/genética , Alelos , Apoptosis , Secuencia de Bases , Estudios de Casos y Controles , Adhesión Celular , Línea Celular , Metilación de ADN , Proteínas de Unión al ADN/metabolismo , Epigénesis Genética , Femenino , Retardo del Crecimiento Fetal/genética , Retardo del Crecimiento Fetal/metabolismo , Regulación de la Expresión Génica , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Hipoxia/genética , Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Modelos Biológicos , Enfermedades Placentarias/metabolismo , Polimorfismo de Nucleótido Simple , Preeclampsia/genética , Preeclampsia/metabolismo , Embarazo , Regiones Promotoras Genéticas , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factor de Transcripción Sp1/metabolismo , Factores de Transcripción/metabolismo , Activación Transcripcional , Trofoblastos/citología , Trofoblastos/metabolismo , Dedos de Zinc
5.
Reprod Sci ; 31(6): 1617-1625, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38418666

RESUMEN

An anonymous online survey in French was used to assess if endometriosis patients would be as ready as unaffected women to donate their menstrual blood for biological research on endometriosis and evaluate potential barriers to such donation. It was distributed in September 2022 by social media and two mailing lists, including a French patient organization. The questionnaire assessed participant age and brief medical history (hormonal contraception, endometriosis diagnosis, type of endometriosis), menstrual experience (menstrual blood abundance, dysmenorrhea), and whether participants would donate menstrual blood. Women who self-declared with an established endometriosis diagnosis versus no endometriosis were compared. Seven hundred seventy-eight women answered the survey. Among women with menstruation (n = 568), 78% are willing to donate menstrual blood for research. Importantly, this proportion was higher in women who declared having an established endometriosis diagnosis (83%, n = 299) compared to self-declared unaffected women (68%, n = 134, p < 0.001). The previous use of a menstrual cup and dysmenorrhea were significantly associated with the willingness to donate menstrual blood, while the use of hormonal contraception was significantly associated with an unwillingness to donate. Only the previous use of the menstrual cup had a predictive value for menstrual blood donation. No significant relationship was observed between menstrual blood donation and age, heavy menstrual bleeding and in endometriosis patients, endometriosis subtypes. In conclusion, women affected or not by endometriosis are largely willing to donate their menstrual blood for research on endometriosis, dysmenorrhea is not a barrier for donation, and women who use a menstrual cup are the more likely to donate.


Asunto(s)
Endometriosis , Menstruación , Humanos , Femenino , Endometriosis/diagnóstico , Endometriosis/psicología , Endometriosis/sangre , Adulto , Estudios Transversales , Menstruación/psicología , Encuestas y Cuestionarios , Donantes de Sangre/psicología , Adulto Joven , Persona de Mediana Edad , Investigación Biomédica , Donación de Sangre
6.
Int Immunopharmacol ; 136: 112344, 2024 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-38833846

RESUMEN

Systemic sclerosis (SSc) is a devastating autoimmune illness with a wide range of clinical symptoms, including vascular abnormalities, inflammation, and persistent and progressive fibrosis. The disease's complicated pathophysiology makes it difficult to develop effective therapies, necessitating research into novel therapeutic options. Molecular hybridization is a strategy that can be used to develop new drugs that act on two or multiple targets and represents an interesting option to be explored for the treatment of complex diseases. We aimed to evaluate the effects of a hybrid mutual prodrug of ibuprofen and acetaminophen (IBPA) in peripheral blood mononuclear cells (PBMC) isolated from SSc patients, and in an in vivo model of SSc induced in BALB/c mice by intradermal injections of hypochlorous acid (HOCl) for 6 weeks. The mice were treated at the same time with daily intraperitoneal injections of IBPA (40 mg/kg). Pulmonary and skin fibrosis as well as immune responses were evaluated. IBPA significantly decreased the release of cytokines in PBMC culture supernatants from SSc patients after stimulation with phytohemagglutinin-M (IL-2, IL-4, IL-6, IL-10, IL-13, IL-17A, TNF and IFN-γ).In HOCl-induced SSc, IBPA treatment prevented dermal and pulmonary fibrosis, in addition to reducing CD4 + T and B cells activation and reversing the M2 polarization of macrophages in spleen cells, and inhibiting IFN-γ secretion in splenocyte cultures. These results show the anti-inflammatory and antifibrotic effects of IBPA in SSc and highlight the therapeutic potential of this mutual prodrug, providing support for future studies.


Asunto(s)
Acetaminofén , Citocinas , Modelos Animales de Enfermedad , Fibrosis , Ibuprofeno , Leucocitos Mononucleares , Ratones Endogámicos BALB C , Profármacos , Esclerodermia Sistémica , Animales , Humanos , Profármacos/uso terapéutico , Profármacos/farmacología , Acetaminofén/farmacología , Femenino , Esclerodermia Sistémica/tratamiento farmacológico , Esclerodermia Sistémica/inmunología , Esclerodermia Sistémica/patología , Ibuprofeno/uso terapéutico , Ibuprofeno/farmacología , Citocinas/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Fibrosis/tratamiento farmacológico , Ratones , Masculino , Persona de Mediana Edad , Inflamación/tratamiento farmacológico , Células Cultivadas , Piel/efectos de los fármacos , Piel/patología , Piel/inmunología , Ácido Hipocloroso , Adulto
7.
Proc Biol Sci ; 280(1768): 20131532, 2013 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-23926155

RESUMEN

Digit length ratios, especially the second-to-fourth digit ratio (2D : 4D), are associated with various pathological and behavioural conditions in many species including humans and are dependent upon prenatal androgen to oestrogen balance. It is unknown whether digit ratios are modified by environmental exposure to ubiquitous endocrine disruptors. We studied the effect on adult male Wistar rat digit ratios of a gestational exposure to the oestrogenic and antiandrogenic compounds bisphenol A (BPA), genistein and vinclozolin, in low doses, and in combination with investigating in parallel a possible sexual dimorphism of this trait. We also investigated the effects on the male progeny not exposed during gestation. X-rays were taken of the left and right forepaws, and 2D-5D proximal to distal phalanx distances were measured by a standardized procedure based on semi-automatic image analysis. We provide evidence that there is a sexual dimorphism of digit ratios in the Wistar rat, and we found that BPA alone or in combination with genistein and vinclozolin significantly feminized digit ratios in male rats. Intriguingly, significant feminization of digit ratios was also found in the unexposed male progeny of males that had been exposed to compound mixtures. In conclusion, prenatal environmental levels of endocrine-active substances permanently disrupt digit ratios. Digit ratio measurement in adults is thus a promising biomarker of prenatal exposure to low-dose endocrine disruptors in rodents, with potential implications for future studies in humans.


Asunto(s)
Compuestos de Bencidrilo/toxicidad , Estrógenos no Esteroides/toxicidad , Extremidades/embriología , Fenoles/toxicidad , Caracteres Sexuales , Animales , Desarrollo Embrionario/efectos de los fármacos , Exposición a Riesgos Ambientales , Extremidades/anatomía & histología , Femenino , Masculino , Ratas , Ratas Wistar
8.
Cell Cycle ; 22(5): 542-564, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36123968

RESUMEN

Self-sustained quiescence (SSQ) has been characterized as a stable but reversible non-proliferative cellular state that limits the cloning of cultured cancer cells. By developing refined clonogenic assays, we showed here that cancer cells in SSQ can be selected with anticancer agents and that culture at low cell density induced SSQ in pancreas and prostate adenocarcinoma cells. Pre-culture of cells in 3D or their pretreatment with pharmacological inhibitors of mechanistic target of rapamycin (mTOR) synergize with low cell density for induction of SSQ in a Beclin-1-dependent manner. Dissociated pancreatic adenocarcinoma (PAAD) cells rendered defective for SSQ by down-regulating Beclin-1 expression exhibit higher tumor growth rate when injected subcutaneously into mice. Conversely, dissociated PAAD cells in SSQ promote the formation of small indolent tumors that eventually transitioned to a rapid growth phase. Ex vivo clonogenic assays showed that up to 40% of clonogenic cancer cells enzymatically dissociated from resected fast-growing tumors could enter SSQ, suggesting that SSQ could significantly impact the proliferation of cancer cells that are naturally dispersed from tumors. Remarkably, the kinetics of clinical metastatic recurrence in 124 patients with pancreatic adenocarcinoma included in the TGCA-PAAD project could be predicted from Beclin-1 and Cyclin-A2 mRNA levels in their primary tumor, Cyclin A2 mRNA being a marker of both cell proliferation and mTOR complex 1 activity. Overall, our data show that SSQ is likely to promote the late development of clinical metastases and suggest that identifying new agents targeting cancer cells in SSQ could help improve patient survival.


Asunto(s)
Adenocarcinoma , Neoplasias Pancreáticas , Masculino , Animales , Ratones , Adenocarcinoma/patología , Beclina-1/genética , Neoplasias Pancreáticas/patología , Serina-Treonina Quinasas TOR/metabolismo , Sirolimus , Proliferación Celular , ARN Mensajero , Línea Celular Tumoral , Neoplasias Pancreáticas
9.
Endosc Int Open ; 11(2): E149-E156, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36741340

RESUMEN

Background and study aims Esophageal stricture is the most frequent adverse event after endoscopic resection for early esophageal neoplasia. Currently available treatments for the prevention of esophageal stricture are poorly effective and associated with major adverse events. Our aim was to identify transcripts specifically overexpressed or repressed in patients who have developed a post-endoscopic esophageal stricture, as potential targets for stricture prevention. Patients and methods We conducted a prospective single-center study in a tertiary endoscopy center. Patients scheduled for an endoscopic resection and considered at risk of esophageal stricture were offered inclusion in the study. The healthy mucosa and resection bed were biopsied on Days 0, 14, and 90. A transcriptomic analysis by microarray was performed, and the differences in transcriptomic profile compared between patients with and without esophageal strictures. Results Eight patients, four with esophageal stricture and four without, were analyzed. The mean ± SD circumferential extension of the mucosal defect was 85 ±â€Š11 %. The transcriptomic analysis in the resection bed at day 14 found an activation of the interleukin (IL)-1 group (Z score = 2.159, P  = 0.0137), while interferon-gamma (INFγ) and NUPR1 were inhibited (Z score = -2.375, P  = 0.0022 and Z score = -2.333, P  = 0.00131) in the stricture group. None of the activated or inhibited transcripts were still significantly so in any of the groups on Day 90. Conclusions Our data suggest that IL-1 inhibition or INFγ supplementation could constitute promising targets for post-endoscopic esophageal stricture prevention.

10.
JCI Insight ; 8(1)2023 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-36413406

RESUMEN

Carbohydrate response element-binding protein (ChREBP) is a carbohydrate-sensing transcription factor that regulates both adaptive and maladaptive genomic responses in coordination of systemic fuel homeostasis. Genetic variants in the ChREBP locus associate with diverse metabolic traits in humans, including circulating lipids. To identify novel ChREBP-regulated hepatokines that contribute to its systemic metabolic effects, we integrated ChREBP ChIP-Seq analysis in mouse liver with human genetic and genomic data for lipid traits and identified hepatocyte growth factor activator (HGFAC) as a promising ChREBP-regulated candidate in mice and humans. HGFAC is a protease that activates the pleiotropic hormone hepatocyte growth factor. We demonstrate that HGFAC-KO mice had phenotypes concordant with putative loss-of-function variants in human HGFAC. Moreover, in gain- and loss-of-function genetic mouse models, we demonstrate that HGFAC enhanced lipid and glucose homeostasis, which may be mediated in part through actions to activate hepatic PPARγ activity. Together, our studies show that ChREBP mediated an adaptive response to overnutrition via activation of HGFAC in the liver to preserve glucose and lipid homeostasis.


Asunto(s)
Glucosa , Factores de Transcripción , Animales , Humanos , Ratones , Glucosa/metabolismo , Homeostasis , Lípidos , Factores de Transcripción/metabolismo
11.
J Leukoc Biol ; 111(5): 1009-1020, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-34533228

RESUMEN

Trained immunity is a new concept illustrating that innate immune cells are able to undergo a long-term metabolic and epigenetic reprogramming after infection or vaccination, thus displaying either a pro- or an anti-inflammatory phenotype during a sequential unrelated challenge. Innate immune cells such as natural killer (NK) cells and macrophages constitute a large part of the decidual leukocyte population at the maternal-fetal interface, playing an important role in placental development and as such in fetal growth and development. In this study, we hypothesized that training the innate immune cells before pregnancy could have an impact on pregnancy. To test this hypothesis, we used CBA/J x DBA/2 mouse model to investigate pregnancy outcomes and leukocyte population at the maternal-fetal interface. Although we were not able to show a beneficial effect of LPS-tolerogenic training on fetal resorption, Bacillus Calmette-Guérin (BCG) training, known to prime innate immune cells to be proinflammatory, led to fetal growth restriction, without aggravating the fetal resorption rate. We also found that BCG training led to less NK cells and macrophages at the maternal-fetal interface at the early stage of placentation (E9.5), associated with a down-regulation of Ccr3 and Lif mRNA expression. This induced altered leucocyte population profile can be an explanation for the subsequent fetal growth restriction. These data suggest that preconceptional infections-induced trained immunity could influence pregnancy outcomes.


Asunto(s)
Vacuna BCG , Mycobacterium bovis , Animales , Femenino , Retardo del Crecimiento Fetal , Reabsorción del Feto , Humanos , Inmunidad Innata , Ratones , Ratones Endogámicos CBA , Ratones Endogámicos DBA , Placenta , Embarazo
12.
Nat Commun ; 13(1): 4423, 2022 07 30.
Artículo en Inglés | MEDLINE | ID: mdl-35908073

RESUMEN

Preservation and expansion of ß-cell mass is a therapeutic goal for diabetes. Here we show that the hyperactive isoform of carbohydrate response-element binding protein (ChREBPß) is a nuclear effector of hyperglycemic stress occurring in ß-cells in response to prolonged glucose exposure, high-fat diet, and diabetes. We show that transient positive feedback induction of ChREBPß is necessary for adaptive ß-cell expansion in response to metabolic challenges. Conversely, chronic excessive ß-cell-specific overexpression of ChREBPß results in loss of ß-cell identity, apoptosis, loss of ß-cell mass, and diabetes. Furthermore, ß-cell "glucolipotoxicity" can be prevented by deletion of ChREBPß. Moreover, ChREBPß-mediated cell death is mitigated by overexpression of the alternate CHREBP gene product, ChREBPα, or by activation of the antioxidant Nrf2 pathway in rodent and human ß-cells. We conclude that ChREBPß, whether adaptive or maladaptive, is an important determinant of ß-cell fate and a potential target for the preservation of ß-cell mass in diabetes.


Asunto(s)
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Células Secretoras de Insulina , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Retroalimentación , Glucosa/metabolismo , Humanos , Células Secretoras de Insulina/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo
13.
Front Immunol ; 12: 670776, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34413847

RESUMEN

Despite significant therapeutic advances, graft-versus-host disease (GvHD) remains the main life-threatening complication following allogeneic hematopoietic stem cell transplantation. The pathogenesis of GvHD is dominated by a dysregulated allogeneic immune response that drives fibrosis and autoimmunity in chronic forms. A multitude of cell therapy approaches, including infusion of myeloid cells, has been proposed to prevent GvHD through tolerance induction but yielded variable results. Myeloid cells like macrophages can be reprogrammed to develop adaptive-like features following antigenic challenge to reinforce or inhibit a subsequent immune response; a phenomenon termed 'trained immunity'. Here we report that, whereas LPSlow-trained macrophages elicit a suppressor effect on allogeneic T cell proliferation and function in vitro in an IL-10-dependent manner, Bacille Calmette et Guérin (BCG)-trained macrophages exert an opposite effect. In a murine model of sclerodermatous chronic GvHD, LPSlow-trained macrophages attenuate clinical signs of GvHD with significant effects on T cell phenotype and function, autoantibodies production, and tissue fibrosis. Furthermore, infusion of LPSlow-macrophages significantly improves survival in mice with acute GvHD. Importantly, we also provide evidence that LPSlow-macrophages do not accelerate A20-lymphoma tumor growth, which is significantly reduced upon transfer of BCG-macrophages. Collectively, these data indicate that macrophages can be trained to significantly inhibit in vitro and in vivo allo-reactive T cell proliferation without exhibiting pro-tumoral effect, thereby opening the way to promising clinical applications.


Asunto(s)
Enfermedad Injerto contra Huésped/inmunología , Trasplante de Células Madre Hematopoyéticas , Linfoma/inmunología , Macrófagos/inmunología , Linfocitos T/inmunología , Animales , Carcinogénesis , Proliferación Celular , Células Cultivadas , Reprogramación Celular , Femenino , Tolerancia Inmunológica , Interleucina-10/metabolismo , Lipopolisacáridos/metabolismo , Macrófagos/trasplante , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Trasplante Homólogo
14.
Nutrients ; 13(10)2021 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-34684643

RESUMEN

The metabolic syndrome (MetS), defined as the co-occurrence of disorders including obesity, dyslipidemia, insulin resistance, and hepatic steatosis, has become increasingly prevalent in the world over recent decades. Dietary and other environmental factors interacting with genetic predisposition are likely contributors to this epidemic. Among the involved dietary factors, excessive fructose consumption may be a key contributor. When fructose is consumed in large amounts, it can quickly produce many of the features of MetS both in humans and mice. The mechanisms by which fructose contributes to metabolic disease and its potential interactions with genetic factors in these processes remain uncertain. Here, we generated a small F2 genetic cohort of male mice derived from crossing fructose-sensitive and -resistant mouse strains to investigate the interrelationships between fructose-induced metabolic phenotypes and to identify hepatic transcriptional pathways that associate with these phenotypes. Our analysis indicates that the hepatic transcriptional pathways associated with fructose-induced hypertriglyceridemia and hyperinsulinemia are distinct from those that associate with fructose-mediated changes in body weight and liver triglyceride. These results suggest that multiple independent mechanisms and pathways may contribute to different aspects of fructose-induced metabolic disease.


Asunto(s)
Fructosa/efectos adversos , Hiperinsulinismo/complicaciones , Hipertrigliceridemia/complicaciones , Hígado/metabolismo , Análisis de Sistemas , Triglicéridos/metabolismo , Animales , Estudios de Cohortes , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Haplotipos , Hiperinsulinismo/sangre , Hipertrigliceridemia/sangre , Insulina/sangre , Masculino , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Mutación Missense/genética , Fenotipo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Triglicéridos/sangre
15.
Cell Rep ; 33(5): 108325, 2020 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-33147452

RESUMEN

Endometriosis is a frequent, chronic, inflammatory gynecological disease characterized by the presence of ectopic endometrial tissue causing pain and infertility. Macrophages have a central role in lesion establishment and maintenance by driving chronic inflammation and tissue remodeling. Macrophages can be reprogrammed to acquire memory-like characteristics after antigenic challenge to reinforce or inhibit a subsequent immune response, a phenomenon termed "trained immunity." Here, whereas bacille Calmette-Guérin (BCG) training enhances the lesion growth in a mice model of endometriosis, tolerization with repeated low doses of lipopolysaccharide (LPSlow) or adoptive transfer of LPSlow-tolerized macrophages elicits a suppressor effect. LPSlow-tolerized human macrophages mitigate the fibro-inflammatory phenotype of endometriotic cells in an interleukin-10 (IL-10)-dependent manner. A history of severe Gram-negative infection is associated with reduced infertility duration and alleviated symptoms, in contrast to patients with Gram-positive infection history. Thus, the manipulation of innate immune memory may be effective in dampening hyper-inflammatory conditions, opening the way to promising therapeutic approaches.


Asunto(s)
Endometriosis/inmunología , Endometriosis/patología , Memoria Inmunológica , Macrófagos Peritoneales/inmunología , Traslado Adoptivo , Animales , Técnicas de Cocultivo , Citocinas/biosíntesis , Endometriosis/microbiología , Femenino , Infecciones por Bacterias Gramnegativas/complicaciones , Humanos , Tolerancia Inmunológica , Lipopolisacáridos , Ratones , Fenotipo
16.
iScience ; 23(5): 101086, 2020 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-32371375

RESUMEN

STOX1 is a transcription factor involved in preeclampsia and Alzheimer disease. We show that the knock-down of the gene induces rather mild effect on gene expression in trophoblast cell lines (BeWo). We identified binding sites of STOX1 shared by the two major isoforms, STOX1A and STOX1B. Profiling gene expression of cells overexpressing either STOX1A or STOX1B, we identified genes downregulated by both isoforms, with a STOX1 binding site in their promoters. Among those, STOX1-induced Annexin A1 downregulation led to abolished membrane repair in BeWo cells. By contrast, overexpression of STOX1A or B has opposite effects on trophoblast fusion (acceleration and inhibition, respectively) accompanied by syncytin genes deregulation. Also, STOX1A overexpression led to abnormal regulation of oxidative and nitrosative stress. In sum, our work shows that STOX1 isoform imbalance is a cause of gene expression deregulation in the trophoblast, possibly leading to placental dysfunction and preeclampsia.

17.
Redox Biol ; 25: 101122, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30737171

RESUMEN

Systemic sclerosis is an autoimmune disorder characterized by inflammation and a progressive fibrosis affecting the skin and visceral organs. Over the last two decades, it became clear that oxidative stress plays a key role in its pathogenesis. In this review, we highlighted the role of ROS in the various pathological components of systemic sclerosis, namely the inflammatory, the autoimmune and the fibrotic processes. We also discussed how these pathological processes can induce ROS overproduction, thus maintaining a vicious circle. Finally, we summarized the therapeutic approaches targeting oxidative stress tested in systemic sclerosis, in cells, animal models and patients.


Asunto(s)
Autoinmunidad , Inflamación/patología , Estrés Oxidativo , Esclerodermia Sistémica/etiología , Esclerodermia Sistémica/patología , Animales , Fibrosis , Humanos , Especies Reactivas de Oxígeno/metabolismo
18.
Nat Commun ; 10(1): 5670, 2019 12 11.
Artículo en Inglés | MEDLINE | ID: mdl-31827093

RESUMEN

Chronic inflammation and fibrosis can result from inappropriately activated immune responses that are mediated by macrophages. Macrophages can acquire memory-like characteristics in response to antigen exposure. Here, we show the effect of BCG or low-dose LPS stimulation on macrophage phenotype, cytokine production, chromatin and metabolic modifications. Low-dose LPS training alleviates fibrosis and inflammation in a mouse model of systemic sclerosis (SSc), whereas BCG-training exacerbates disease in this model. Adoptive transfer of low-dose LPS-trained or BCG-trained macrophages also has beneficial or harmful effects, respectively. Furthermore, coculture with low-dose LPS trained macrophages reduces the fibro-inflammatory profile of fibroblasts from mice and patients with SSc, indicating that trained immunity might be a phenomenon that can be targeted to treat SSc and other autoimmune and inflammatory fibrotic disorders.


Asunto(s)
Fibrosis/inmunología , Macrófagos/inmunología , Esclerodermia Sistémica/inmunología , Traslado Adoptivo , Animales , Citocinas/genética , Citocinas/inmunología , Femenino , Fibrosis/genética , Fibrosis/terapia , Humanos , Inmunidad , Ratones , Ratones Endogámicos BALB C , Esclerodermia Sistémica/genética , Esclerodermia Sistémica/terapia
19.
Cell Death Discov ; 5: 94, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31098302

RESUMEN

Aspirin (acetyl-salicylic acid) is one of the most ancient drugs of the human pharmacopeia. Nonetheless, its action at low doses is not well understood at the molecular level. One of the applications of low-dose aspirin treatment is the prevention of preeclampsia (PE) in patients at risk. Foeto-placental overexpression of the STOX1A transcription factor in mice triggers PE symptoms. Transcriptomic analysis of the placentas, showed that aspirin massively down-regulates genes of the coagulation and complement cascade, as well as genes involved in lipid transport. The genes modified by aspirin treatment are not the ones that are modified by STOX1 overexpression, suggesting that aspirin could act downstream, symptomatically on the preeclamptic disease. Bioinformatics analysis of the promoters of the deregulated genes showed that they are strongly enriched in HNF transcription factors-binding sites, in accordance with existing literature showing their roles as regulators of coagulation. Two of these transcription factors, Hnf1ß and Hnf4α are found down-regulated by aspirin treatment. In parallel, we show that in human patient placentas, aspirin-induced deregulations of genes of the coagulation cascade are also observed. Finally, the expression of Hnf1ß target sequences (Kif12, F2, Hnf4α promoters and a synthetic concatemer of the Hnf1ß-binding site) were investigated by transfection in trophoblast cell models, with or without aspirin treatment and with or without STOX1A overexpression. In this model we observed that STOX1A and aspirin tended to synergize in the down-regulation of Hnf1ß target genes in trophoblasts.

20.
Reprod Sci ; 26(2): 198-206, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30518300

RESUMEN

BACKGROUND: Adenomyosis (ADE) is an enigmatic uterine disorder. Several types have been previously described: diffuse adenomyosis (DIF-ADE), focal adenomyosis (FOC-ADE), and association of focal and diffuse lesions (FOC/DIF-ADE). Abnormal immune phenomena have been described that may provide an understanding of the pathophysiology of adenomyosis. However, the immune imbalance in adenomyosis is however still poorly understood. OBJECTIVE: To compare serum cytokine profiles for the various adenomyosis phenotypes in adenomyosis versus disease-free women. MATERIALS AND METHODS: This cohort study included 80 women. Based on the magnetic resonance imaging (MRI) findings, the women were allocated to the ADE group (n = 60) and the control group (n = 20). The ADE group was further subdivided according to the phenotype: DIF-ADE, FOC-ADE, and FOC/DIF-ADE. For all of the women, serum cytokine levels were assayed by multiplex immunoassay. RESULTS: Serum levels of interleukin (IL) 23 (237.77 pg/mL ± 70.97 in the ADE-group versus 1855.04 ± 1411.33 in the control group, P = .019), IL25 (31.98 ± 8.54 vs 222.08 ± 170.90, respectively, P = .006), IL31 (10.13 ± 3.83 vs 91.51 ± 71.21, respectively, P = .034), IL33 (3.77 ± 1.23 vs 17.86 ± 11.49, respectively, P = .016), and IL17F (16.29 ± 2.35 vs 30.12 ± 8.29, respectively, P = .042) were significantly lower in the women with adenomyosis when compared to the controls In the FOC/DIF-ADE group, the serum levels of IL23, IL31, IL25, and IL33 were significantly lower when compared to the control group. CONCLUSION: Serum levels of IL23, IL31, IL25, and IL33 were lower in women exhibiting adenomyosis forms with associated diffuse and focal lesions when compared with controls. The pathogenesis of adenomyosis may be associated with an immunotolerant process that is more pronounced in associated FOC/DIF-ADE.


Asunto(s)
Adenomiosis/sangre , Citocinas/sangre , Endometrio/diagnóstico por imagen , Miometrio/diagnóstico por imagen , Adenomiosis/diagnóstico por imagen , Adulto , Femenino , Humanos , Imagen por Resonancia Magnética , Fenotipo , Adulto Joven
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA