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1.
Int J Gynaecol Obstet ; 165(3): 1040-1046, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38108543

RESUMEN

OBJECTIVE: To evaluate whether acute histologic chorioamnionitis (HCA) diagnosed in the placenta may be associated with an increased occurrence of bronchopulmonary dysplasia (BPD) or death among extremely low gestational age neonates (ELGAN). METHODS: This Italian single-center case-control retrospective study involved ELGAN admitted to the neonatal intensive care unit between January 2019 and June 2022. Infants born from pregnant women with acute and severe HCA, identified as stage ≥2 and grade 2 HCA, (HCA-infants) were compared with infants of pregnant women without chorioamnionitis or with stage 1, grade 1 chorioamnionitis (no-HCA-infants). RESULTS: Among 101 eligible ELGAN, 63 infants had complete clinical and histologic data relevant to the study: thirty infants were included in the HCA-infants group and 33 in the no-HCA-infants group. Neonatal and maternal demographic and clinical characteristics were similar between the two groups. Infants born from mothers with acute and severe HCA had significantly higher occurrence of composite BPD or death (18 [60%] vs. 9 [27%]; P = 0.012), as well as higher incidence of severe forms of BPD (6 [30%] vs. 2 [6%]; P = 0.045). In multiple logistic regression analysis, after adjustment for confounding covariates, HCA was an independent risk factor for BPD or death (OR, 4.49; 95% CI: 1.47-13.71). CONCLUSIONS: This is the first study showing that in utero exposure to acute and severe HCA is an independent risk factor for the occurrence of composite BPD or death among ELGAN.


Asunto(s)
Displasia Broncopulmonar , Corioamnionitis , Humanos , Femenino , Displasia Broncopulmonar/epidemiología , Displasia Broncopulmonar/mortalidad , Corioamnionitis/epidemiología , Estudios Retrospectivos , Embarazo , Recién Nacido , Estudios de Casos y Controles , Adulto , Italia/epidemiología , Recien Nacido Extremadamente Prematuro , Masculino , Unidades de Cuidado Intensivo Neonatal , Factores de Riesgo , Edad Gestacional , Mortalidad Infantil
2.
Sci Rep ; 12(1): 4016, 2022 03 07.
Artículo en Inglés | MEDLINE | ID: mdl-35256767

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuronal disorder characterized by neuronal degeneration and currently no effective cure is available to stop or delay the disease from progression. Transplantation of murine glial-restricted precursors (mGRPs) is an attractive strategy to modulate ALS development and advancements such as the use of immune modulators could potentially extend graft survival and function. Using a well-established ALS transgenic mouse model (SOD1G93A), we tested mGRPs in combination with the immune modulators synthetic PreImplantation Factor (sPIF), Tacrolimus (Tac), and Costimulatory Blockade (CB). We report that transplantation of mGRPs into the cisterna magna did not result in increased mice survival. The addition of immunomodulatory regimes again did not increase mice lifespan but improved motor functions and sPIF was superior compared to other immune modulators. Immune modulators did not affect mGRPs engraftment significantly but reduced pro-inflammatory cytokine production. Finally, sPIF and CB reduced the number of microglial cells and prevented neuronal number loss. Given the safety profile and a neuroprotective potential of sPIF, we envision its clinical application in near future.


Asunto(s)
Esclerosis Amiotrófica Lateral , Trastornos Motores , Neuroglía , Péptidos , Trasplante de Células Madre , Esclerosis Amiotrófica Lateral/genética , Animales , Modelos Animales de Enfermedad , Inflamación , Ratones , Ratones Transgénicos , Trastornos Motores/tratamiento farmacológico , Trastornos Motores/terapia , Neuroglía/citología , Neuroglía/trasplante , Péptidos/farmacología , Células Madre/citología
3.
Cells ; 10(7)2021 07 16.
Artículo en Inglés | MEDLINE | ID: mdl-34359973

RESUMEN

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease, causing motor neuron and skeletal muscle loss and death. One of the promising therapeutic approaches is stem cell graft application into the brain; however, an immune reaction against it creates serious limitations. This study aimed to research the efficiency of glial restricted progenitors (GRPs) grafted into murine CNS (central nervous system) in healthy models and the SOD1G93A ALS disease model. The cellular grafts were administered in semiallogenic and allogeneic settings. To investigate the models of immune reaction against grafted GRPs, we applied three immunosuppressive/immunomodulatory regimens: preimplantation factor (PiF); Tacrolimus; and CTLA-4, MR1 co-stimulatory blockade. We tracked the cells with bioluminescence imaging (BLI) in vivo to study their survival. The immune response character was evaluated with brain tissue assays and multiplex ELISA in serum and cerebrospinal fluid (CSF). The application of immunosuppressive drugs is disputable when considering cellular transplants into the immune-privileged site/brain. However, our data revealed that semiallogenic GRP graft might survive inside murine CNS without the necessity to apply any immunomodulation or immunosuppression, whereas, in the situation of allogeneic mouse setting, the combination of CTLA-4, MR1 blockade can be considered as the best immunosuppressive option.


Asunto(s)
Sistema Nervioso Central/efectos de los fármacos , Terapia de Inmunosupresión , Inmunosupresores/uso terapéutico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Células Madre , Animales , Sistema Nervioso Central/inmunología , Modelos Animales de Enfermedad , Tolerancia Inmunológica/efectos de los fármacos , Terapia de Inmunosupresión/métodos , Ratones , Enfermedades Neurodegenerativas/inmunología , Trasplante de Células Madre/métodos , Células Madre/inmunología
4.
Reprod Biol Endocrinol ; 19(1): 96, 2021 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-34176510

RESUMEN

BACKGROUND: Successful human embryo implantation requires the differentiation of endometrial stromal cells (ESCs) into decidual cells during a process called decidualization. ESCs express specific markers of decidualization, including prolactin, insulin-like growth factor-binding protein-1 (IGFBP-1), and connexin-43. Decidual cells also control of trophoblast invasion by secreting various factors, such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases. Preimplantation factor (PIF) is a recently identified, embryo-derived peptide with activities at the fetal-maternal interface. It creates a favorable pro-inflammatory environment in human endometrium and directly controls placental development by increasing the human trophoblastic cells' ability to invade the endometrium. We hypothesized that PIF's effects on the endometrium counteract its pro-invasive effects. METHODS: We tested sPIF effect on the expression of three decidualization markers by RT-qPCR and/or immunochemiluminescence assay. We examined sPIF effect on human ESC migration by performing an in vitro wound healing assay. We analyzed sPIF effect on endometrial control of human trophoblast invasion by performing a zymography and an invasion assay. RESULTS: Firstly, we found that a synthetic analog of PIF (sPIF) significantly upregulates the mRNA expression of IGFBP-1 and connexin-43, and prolactin secretion in ESCs - suggesting a pro-differentiation effect. Secondly, we showed that the HTR-8/SVneo trophoblastic cell line's invasive ability was low in the presence of conditioned media from ESCs cultured with sPIF. Thirdly, this PIF's anti-invasive action was associated with a specifically decrease in MMP-9 activity. CONCLUSION: Taken as a whole, our results suggest that PIF accentuates the decidualization process and the production of endometrial factors that limit trophoblast invasion. By controlling both trophoblast and endometrial cells, PIF therefore appears to be a pivotal player in the human embryo implantation process.


Asunto(s)
Decidua/citología , Decidua/efectos de los fármacos , Endometrio/citología , Endometrio/efectos de los fármacos , Proteínas Gestacionales/administración & dosificación , Trofoblastos/efectos de los fármacos , Adulto , Movimiento Celular/efectos de los fármacos , Movimiento Celular/fisiología , Células Cultivadas , Decidua/fisiología , Endometrio/fisiología , Femenino , Humanos , Células del Estroma/efectos de los fármacos , Células del Estroma/fisiología , Trofoblastos/fisiología
5.
PLoS One ; 15(6): e0232493, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32511256

RESUMEN

Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality and spontaneous PTB is a major contributor. The preceding inflammation/infection contributes not only to spontaneous PTB but is associated with neonatal morbidities including impaired brain development. Therefore, control of exaggerated immune response during pregnancy is an attractive strategy. A potential candidate is synthetic PreImplantation Factor (sPIF) as sPIF prevents inflammatory induced fetal loss and has neuroprotective properties. Here, we tested maternal sPIF prophylaxis in pregnant mice subjected to a lipopolysaccharides (LPS) insult, which results in PTB. Additionally, we evaluated sPIF effects in placental and microglial cell lines. Maternal sPIF application reduced the LPS induced PTB rate significantly. Consequently, sPIF reduced microglial activation (Iba-1 positive cells) and preserved neuronal migration (Cux-2 positive cells) in fetal brains. In fetal brain lysates sPIF decreased IL-6 and INFγ concentrations. In-vitro, sPIF reduced Iba1 and TNFα expression in microglial cells and reduced the expression of pro-apoptotic (Bad and Bax) and inflammatory (IL-6 and NLRP4) genes in placental cell lines. Together, maternal sPIF prophylaxis prevents PTB in part by controlling exaggerated immune response. Given the sPIF`FDA Fast Track approval in non-pregnant subjects, we envision sPIF therapy in pregnancy.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Inflamación/terapia , Péptidos/farmacología , Complicaciones del Embarazo/tratamiento farmacológico , Nacimiento Prematuro/prevención & control , Animales , Encéfalo/efectos de los fármacos , Encéfalo/embriología , Encéfalo/inmunología , Línea Celular , Modelos Animales de Enfermedad , Femenino , Inflamación/inmunología , Lipopolisacáridos , Ratones , Microglía/efectos de los fármacos , Microglía/inmunología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Embarazo , Complicaciones del Embarazo/inmunología , Nacimiento Prematuro/inmunología
6.
Int J Biol Markers ; 35(2): 82-90, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32389051

RESUMEN

BACKGROUND: The PreImplantation Factor (PIF)-a peptide secreted by viable embryos-exerts autotrophic protective effects, promotes endometrial receptivity and controls trophoblast invasion. Synthetic PIF (sPIF) has both immune-protective and regenerative properties, and reduces oxidative stress and protein misfolding. PIF is detected by immunohistochemistry (IHC) in hyperplastic endometriotic lesions and advanced uterine cancer. sPIF reduces graft-versus-host disease while maintaining a graft-versus-leukemia effect. METHODS: PIF detection in prostate cancer was assessed in 50 human prostate samples following radical prostatectomy using tumor-microarray-based IHC correlating PIF immune staining with Gleason score (GS) and cancer aggressiveness. RESULTS: PIF was detected in moderate-to-high risk prostate cancer (GS 4+3 and beyond, prognostic groups 3 to 5). In prostate cancer (GS (WHO Grade Group (GG)5), PIF was detected in 50% of cases; in prostate cancer (GS 4+4 GG4), PIF was observed in 62.5% of cases; in prostate cancer (GS 4+3 GG3), PIF immunostaining was observed in 57.1% of cases. In prostate cancer, (GS 3+4 GG2) and (GS 3+3 GG1) cases where PIF staining was negative to weak, membranous staining was observed in 20% of cases (staining pattern considered negative). High-grade prostate intraepithelial neoplasia PIF positive stain in 28.57% of cases (6 of 21) was observed. In contrast, PIF was not detected in normal prostate glands. Importantly, sPIF added to the PC3 cell line alone or combined with prostate cancer fibroblast feeder-cells did not affect proliferation. Only when peripheral blood mononuclear cells were added to the culture, a minor increase in cell proliferation was noted, reflecting local proliferation control. CONCLUSIONS: Collectively, PIF assessment could be a valuable, simple-to-use immunohistochemical biomarker to evaluate aggressiveness/prognosis in specimens from prostate cancer patients.


Asunto(s)
Inmunohistoquímica/métodos , Péptidos/metabolismo , Prostatectomía/métodos , Neoplasias de la Próstata/inmunología , Animales , Línea Celular Tumoral , Proliferación Celular , Humanos , Masculino , Ratones
7.
Sci Rep ; 9(1): 12876, 2019 10 02.
Artículo en Inglés | MEDLINE | ID: mdl-31578341

RESUMEN

An autoimmune response against myelin protein is considered one of the key pathogenic processes that initiates multiple sclerosis (MS). The currently available MS disease modifying therapies have demonstrated to reduce the frequency of inflammatory attacks. However, they appear limited in preventing disease progression and neurodegeneration. Hence, novel therapeutic approaches targeting both inflammation and neuroregeneration are urgently needed. A new pregnancy derived synthetic peptide, synthetic PreImplantation Factor (sPIF), crosses the blood-brain barrier and prevents neuro-inflammation. We report that sPIF reduces paralysis and de-myelination of the brain in a clinically-relevant experimental autoimmune encephalomyelitis mice model. These effects, at least in part, are due to post-translational modifications, which involve cyclic AMP dependent protein kinase (PKA), calcium-dependent protein kinase (PKC), and immune regulation. In terms of potential MS treatment, sPIF was successfully tested in neurodegenerative animal models of perinatal brain injury and experimental autoimmune encephalitis. Importantly, sPIF received a FDA Fast Track Approval for first in human trial in autommuninty (completed).


Asunto(s)
Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Parálisis , Péptidos , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Animales , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Femenino , Ratones , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Parálisis/tratamiento farmacológico , Parálisis/metabolismo , Parálisis/patología , Péptidos/farmacocinética , Péptidos/farmacología
8.
Vet Med Sci ; 4(4): 351-356, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30273998

RESUMEN

Persistent mating-induced endometritis (PMIE) is a significant cause of mare infertility hence its treatment would advance the management of susceptible mares. Preimplantation factor (PIF) is secreted by viable embryos, including human, mouse and cattle, and is essential for maternal immune-tolerance without immune-suppression by modulating inflammation. This preliminary study aimed to test whether PIF exerts inflammatory-modulating properties upon equine endometrium challenged with Escherichia coli-derived lipopolysaccharide (LPS) using endometrial explant culture. Follicular (n = 3), luteal (n = 4), anoestrous (n = 4) and transitional (n = 4) stage endometrial explants were established and cultured in triplicate in either serum-free medium alone (control) or medium with; 50 or 100 nmol/L synthetic PIF (sPIF); 3 µg/mL LPS; LPS and 50 or 100 nmol/L sPIF; or scrambled PIF (PIFscr; same amino acid composition arranged in a different order). Media samples were collected at 24 and 72 h, representing acute and chronic inflammatory response. Radioimmunoassay determined Prostaglandin F2α (PGF2α ) as an inflammatory marker. The only significant observation was the abrogation of PGF2α response to LPS challenge by 100 nmol/L PIF for follicular stage tissue, 24 h after treatment. Further studies are therefore, warranted to realise PIF potential in managing PMIE.


Asunto(s)
Endometrio/efectos de los fármacos , Caballos , Inflamación/veterinaria , Proteínas Gestacionales/metabolismo , Animales , Dinoprost/metabolismo , Femenino , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Técnicas de Cultivo de Tejidos
9.
J Assist Reprod Genet ; 35(1): 81-89, 2018 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-29128910

RESUMEN

PURPOSE: Allogeneic ovarian transplantation may be an alternative in the future to oocyte donation in women with premature ovarian failure. The objectives of this study were to (a) evaluate allotransplantation feasibility for restoration of ovarian function and (b) assess efficacy of synthetic preimplantation factor (PIF) monotherapy as sole immune-acceptance regimen. METHODS: This is an experimental animal study using non-human primates (Papio anubis). Allogeneic orthotopic ovarian tissue transplantation was performed in two female olive baboons. PIF was administered as a monotherapy to prevent immune rejection and achieve transplant maintenance and function. Subjects underwent bilateral oophorectomy followed by cross-transplantation of prepared ovarian cortex. Postoperatively, subjects were monitored for clinical and biochemical signs of graft rejection and return of function. Weekly blood samples were obtained to monitor graft acceptance and endocrine function restoration. RESULTS: Postoperatively, there were no clinical signs of rejection. Laboratory parameters (alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine) did not indicate organ rejection at any stage of the experiment. Initially, significant loss of follicles was noticed after grafting and serum follicle-stimulating hormone (FSH) and E2 levels were consistent with ovarian failure. Seven months after transplantation, one animal exhibited recurrence of ovarian endocrine function (perineal swelling, E2 rise, FSH decrease, and return of menstruation). CONCLUSIONS: Organ rejection after allogeneic ovarian transplantation was prevented using PIF as monotherapy for the first time and no side effects were recorded. The study suggests the clinical feasibility of ovarian allotransplantation to obtain ovarian function.


Asunto(s)
Factores Inmunológicos/uso terapéutico , Ovario/trasplante , Péptidos/uso terapéutico , Insuficiencia Ovárica Primaria/terapia , Animales , Estudios de Factibilidad , Femenino , Rechazo de Injerto/prevención & control , Ovariectomía/veterinaria , Ovario/efectos de los fármacos , Ovario/fisiología , Papio anubis , Insuficiencia Ovárica Primaria/rehabilitación , Acondicionamiento Pretrasplante/métodos , Acondicionamiento Pretrasplante/veterinaria , Trasplante Homólogo
10.
Horm Metab Res ; 50(2): 168-174, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29065432

RESUMEN

The main treatment algorithm for adrenal insufficiency is hormonal replacement, however, inadequate hormone substitution often leads to severe side effects. Adrenal cell transplantation could be a more effective alternative but would require life-long immune suppressive therapy. PreImplantation Factor (PIF) is an endogenous peptide secreted by viable human embryos that leads to maternal tolerance without immunosuppression. PIF could be effective for xenogeneic cell transplantation such as of bovine adrenocortical cells (BAC), which are used for bioartificial adrenal gland development that may more effectively restore complex adrenal functions. We report here that PIF exerts a dual regulatory effect on BAC by targeting mostly hyper-activated cells to specifically reduce adrenocorticotropic hormone (ACTH)-stimulated cortisol secretion. Reverse transcription real time PCR analysis revealed that PIF modulates the expression of two genes in the cortisol synthesis pathway, Steroidogenic Factor 1 (SF1), an activator of steroidogenesis, and the downstream steroidogenic enzyme Cytochrome P450 17A1 (CYP17A1). PIF increased basal expression of SF1 and CYP17A1 regardless of the activation level of the adrenocortical cells. In contrast, following ACTH stimulation, PIF reduced SF1 expression and induced expression of the immune suppressing anti-inflammatory cytokine IL10 only in the hyper-activated cells, suggesting both a protective and immune tolerant function. In conclusion, PIF regulates stress-induced adrenal steroidogenesis and immune tolerance in BAC, supporting a potential clinical application to reduce rejection by the host's immune response following xenotransplantation.


Asunto(s)
Glándulas Suprarrenales/trasplante , Antiinflamatorios/metabolismo , Órganos Bioartificiales , Citocinas/metabolismo , Péptidos/farmacología , Esteroides/biosíntesis , Glándulas Suprarrenales/metabolismo , Hormona Adrenocorticotrópica/farmacología , Secuencia de Aminoácidos , Animales , Vías Biosintéticas/efectos de los fármacos , Vías Biosintéticas/genética , Bovinos , Regulación de la Expresión Génica/efectos de los fármacos , Hidrocortisona/biosíntesis , Interleucina-10/metabolismo , Péptidos/química
11.
Cell Physiol Biochem ; 43(6): 2277-2296, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29073617

RESUMEN

BACKGROUND/AIMS: Pregnancy success requires mandatory maternal tolerance of the semi/ allogeneic embryo involving embryo-derived signals. Expression levels of PreImplantation Factor (PIF), a novel peptide secreted by viable embryos, correlate with embryo development, and its early detection in circulation correlates with a favourable pregnancy outcome. PIF enhances endometrial receptivity to promote embryo implantation. Via the p53 pathway, it increases trophoblast invasion, improving cell survival / immune privilege. PIF also reduces spontaneous and LPS-induced foetal death in immune naïve murine model. We examined PIF effect on gene expression of human leukocyte antigen (HLA-G, -E -F and -C) and the influence of PIF on local progesterone activity in JEG-3 choriocarcinoma cells. METHODS: PIF and progesterone (P4) effects on JEG-3 cells surface and intracellular HLA molecules was tested using monoclonal antibodies, flow cytometry, and Western blotting. PIF and IL17 effects on P4 and cytokines secretion was determined by ELISA. PIF and P4 effects on JEG-3 cells proteome was examined using 2D gel staining followed by spot analysis, mass spectrometry and bioinformatic analysis. RESULTS: In cytotrophoblastic JEG-3 cells PIF increased intracellular expression of HLA-G, HLA-F, HLA-E and HLA-C and surface expression of HLA-G, HLA-E and HLA-C in dose and time dependent manner. In case of HLA-E, -F results were confirmed also by Western blot. Proteome analysis confirmed an increase in HLA-G, pro-tolerance FOXP3+ regulatory T cells (Tregs), coagulation factors and complement regulator. In contrast, PIF reduced PRDX2 and HSP70s to negate oxidative stress and protein misfolding. PIF enhanced local progesterone activity, increasing steroid secretion and the receptor protein. It also promoted the secretion of the Th1/Th2 cytokines (IL-10, IL-1ß, IL-8, GM-CSF and TGF-ß1), resulting in improved maternal signalling. CONCLUSION: PIF can generate a pro-tolerance milieu by enhancing the expression of HLA molecules and by amplifying endogenous progesterone activity. A Fast-Track clinical trial for autoimmune disease has been satisfactorily completed. The acquired data warrants PIF use for the treatment of early pregnancy disorders.


Asunto(s)
Expresión Génica/efectos de los fármacos , Antígenos HLA-C/metabolismo , Antígenos HLA-G/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Proteínas Gestacionales/farmacología , Progesterona/farmacología , Línea Celular Tumoral , Coriocarcinoma/metabolismo , Coriocarcinoma/patología , Análisis por Conglomerados , Citocinas/análisis , Electroforesis en Gel Bidimensional , Ensayo de Inmunoadsorción Enzimática , Femenino , Antígenos HLA-C/genética , Antígenos HLA-G/genética , Proteínas HSP70 de Choque Térmico/metabolismo , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Interleucina-17/farmacología , Péptidos/análisis , Peroxirredoxinas/metabolismo , Embarazo , Proteínas Gestacionales/genética , Proteínas Gestacionales/metabolismo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patología , Antígenos HLA-E
12.
PLoS One ; 12(9): e0184399, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28902871

RESUMEN

Endometriosis is a chronic inflammatory condition characterised by the growth of endometrial epithelial and stromal cells outside the uterine cavity. In addition to Sampson's theory of retrograde menstruation, endometriosis pathogenesis is facilitated by a privileged inflammatory microenvironment, with T regulatory FoxP3+ expressing T cells (Tregs) being a significant factor. PreImplantation Factor (PIF) is a peptide essential for pregnancy recognition and development. An immune modulatory function of the synthetic PIF analog (sPIF) has been successfully confirmed in multiple animal models. We report that PIF is expressed in the epithelial ectopic cells in close proximity to FoxP3+ stromal cells. We provide evidence that PIF interacts with FoxP3+ cells and modulates cell viability, dependent on cell source and presence of inflammatory mediators. Our finding represent a novel PIF-based mechanism in endometriosis that has potential for novel therapeutics.


Asunto(s)
Endometriosis/inmunología , Endometrio/inmunología , Endometrio/metabolismo , Inmunidad Innata/genética , Proteínas Gestacionales/fisiología , Células Cultivadas , Coristoma/genética , Coristoma/metabolismo , Coristoma/patología , Endometriosis/genética , Endometriosis/patología , Endometrio/patología , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunidad Innata/efectos de los fármacos , Enfermedades del Ovario/genética , Enfermedades del Ovario/inmunología , Enfermedades del Ovario/patología , Enfermedades Peritoneales/genética , Enfermedades Peritoneales/inmunología , Enfermedades Peritoneales/patología , Embarazo , Complicaciones del Embarazo/genética , Complicaciones del Embarazo/inmunología , Complicaciones del Embarazo/patología , Proteínas Gestacionales/genética , Proteínas Gestacionales/metabolismo , Proteínas Gestacionales/farmacología , Células del Estroma/efectos de los fármacos , Células del Estroma/metabolismo , Células del Estroma/patología , Transcriptoma/efectos de los fármacos
13.
Oncotarget ; 8(13): 21834-21851, 2017 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-28423529

RESUMEN

Neurologic disease diagnosis and treatment is challenging. Multiple Sclerosis (MS) is a demyelinating autoimmune disease with few clinical forms and uncertain etiology. Current studies suggest that it is likely caused by infection(s) triggering a systemic immune response resulting in antigen/non-antigen-related autoimmune response in central nervous system (CNS). New therapeutic approaches are needed. Secreted by viable embryos, PreImplantation Factor (PIF) possesses a local and systemic immunity regulatory role. Synthetic PIF (PIF) duplicates endogenous peptide's protective effect in pre-clinical autoimmune and transplantation models. PIF protects against brain hypoxia-ischemia by directly targeting microglia and neurons. In chronic experimental autoimmune encephalitis (EAE) model PIF reverses paralysis while promoting neural repair. Herein we report that PIF directly promotes brain re-myelination and reverses paralysis in relapsing remitting EAE MS model. PIF crosses the blood-brain barrier targeting microglia. Systemically, PIF decreases pro-inflammatory IL23/IL17 cytokines, while preserving CNS-specific T-cell repertoire. Global brain gene analysis revealed that PIF regulates critical Na+/K+/Ca++ ions, amino acid and glucose transport genes expression. Further, PIF modulates oxidative stress, DNA methylation, cell cycle regulation, and protein ubiquitination while regulating multiple genes. In cultured astrocytes, PIF promotes BDNF-myelin synthesis promoter and SLC2A1 (glucose transport) while reducing deleterious E2F5, and HSP90ab1 (oxidative stress) genes expression. In cultured microglia, PIF increases anti-inflammatory IL10 while reducing pro-inflammatory IFNγ expression. Collectively, PIF promotes brain re-myelination and neuroprotection in relapsing remitting EAE MS model. Coupled with ongoing, Fast-Track FDA approved clinical trial, NCT#02239562 (immune disorder), current data supports PIF's translation for neurodegenerative disorders therapy.


Asunto(s)
Encéfalo/efectos de los fármacos , Encefalomielitis Autoinmune Experimental/patología , Vaina de Mielina/efectos de los fármacos , Péptidos/farmacología , Animales , Femenino , Perfilación de la Expresión Génica , Inflamación/patología , Ratones , Esclerosis Múltiple Recurrente-Remitente , Infecciones por Mycobacterium no Tuberculosas/complicaciones , Mycobacterium smegmatis , Reacción en Cadena en Tiempo Real de la Polimerasa , Transcriptoma
14.
Oncotarget ; 8(20): 32419-32432, 2017 05 16.
Artículo en Inglés | MEDLINE | ID: mdl-28423690

RESUMEN

Recurrent pregnancy loss (RPL) affects 2-3% of couples. Despite a detailed work-up, the etiology is frequently undefined, leading to non-targeted therapy. Viable embryos and placentae express PreImplantation Factor (PIF). Maternal circulating PIF regulates systemic immunity and reduces circulating natural killer cells cytotoxicity in RPL patients. PIF promotes singly cultured embryos' development while anti-PIF antibody abrogates it. RPL serum induced embryo toxicity is negated by PIF. We report that PIF rescues delayed embryo development caused by <3 kDa RPL serum fraction likely by reducing reactive oxygen species (ROS). We reveal that protein disulfide isomerase/thioredoxin (PDI/TRX) is a prime PIF target in the embryo, rendering it an important ROS scavenger. The 16F16-PDI/TRX inhibitor drastically reduced blastocyst development while exogenous PIF increased >2 fold the number of embryos reaching the blastocyst stage. Mechanistically, PDI-inhibitor preferentially binds covalently to oxidized PDI over its reduced form where PIF avidly binds. PIF by targeting PDI/TRX at a distinct site limits the inhibitor's pro-oxidative effects. The >3kDa RPL serum increased embryo demise by three-fold, an effect negated by PIF. However, embryo toxicity was not associated with the presence of putative anti-PIF antibodies. Collectively, PIF protects cultured embryos both against ROS, and higher molecular weight toxins. Using PIF for optimizing in vitro fertilization embryos development and reducing RPL is warranted.


Asunto(s)
Aborto Habitual/terapia , Estrés Oxidativo/efectos de los fármacos , Péptidos/farmacología , Aborto Habitual/metabolismo , Aborto Habitual/prevención & control , Animales , Bovinos , Desarrollo Embrionario/efectos de los fármacos , Femenino , Humanos , Ratones , Péptidos/metabolismo , Embarazo , Proteínas Gestacionales/metabolismo
15.
Pediatr Endocrinol Rev ; 15(2): 147-158, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-29292626

RESUMEN

The earliest stages of pregnancy are marked by countless changes in the maternal environment. A specific coordination of activity is required for a successful pregnancy, starting early in the menstrual cycle. Early establishment of maternal-fetal crosstalk is critical for the progression of pregnancy. Many factors, both maternal and fetal derived, play specific and important roles immediately following fertilization, through implantation and beyond. Here we present a review of some of the key factors involved with a focus on PreImplantation Factor (PIF), a small peptide secreted only by competent embryos, which carries an important role required for pregnancy progression.


Asunto(s)
Endocrinología , Femenino , Humanos , Péptidos , Embarazo
16.
Cell Death Dis ; 7(12): e2504, 2016 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-27906186

RESUMEN

From the earliest stages of gestation, embryonic-maternal interaction has a key role in a successful pregnancy. Various factors present during gestation may significantly influence this type of juxta/paracrine interaction. PreImplantation Factor (PIF) is a recently identified factor with activity at the fetomaternal interface. PIF is secreted by viable embryos and directly controls placental development by increasing the invasive capacity of human extravillous trophoblasts (EVTs). To further specify PIF's role in the human placenta, we analyzed the genome-wide expression profile of the EVT in the presence of a synthetic PIF analog (sPIF). We found that sPIF exposure altered several pathways related to p53 signaling, survival and the immune response. Functional assays revealed that sPIF acts through the p53 pathway to reduce both early and late trophoblast apoptosis. More precisely, sPIF (i) decreases the phosphorylation of p53 at Ser-15, (ii) enhances the B-cell lymphoma-2 (BCL2) expression and (iii) reduces the BCL2-associated X protein (BAX) and BCL2 homologous antagonist killer (BAK) mRNA expression levels. Furthermore, invalidation experiments of TP53 allowed us to demonstrate that PIF's effects on placental apoptosis seemed to be essentially mediated by this gene. We have clearly shown that p53 and sPIF pathways could interact in human trophoblast and thus promotes cell survival. Furthermore, sPIF was found to regulate a gene network related to immune tolerance in the EVT, which emphasizes the beneficial effect of this peptide on the human placenta. Finally, the PIF protein levels in placentas from pregnancies affected by preeclampsia or intra-uterine growth restriction were significantly lower than in gestational age-matched control placentas. Taken as a whole, our results suggest that sPIF protects the EVT's functional status through a variety of mechanisms. Clinical application of sPIF in the treatment of disorders of early pregnancy can be envisioned.


Asunto(s)
Apoptosis , Proteínas Gestacionales/metabolismo , Transducción de Señal , Trofoblastos/citología , Trofoblastos/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Femenino , Retardo del Crecimiento Fetal/genética , Retardo del Crecimiento Fetal/patología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Redes Reguladoras de Genes/efectos de los fármacos , Silenciador del Gen/efectos de los fármacos , Humanos , Péptidos/farmacología , Placenta/efectos de los fármacos , Placenta/metabolismo , Placenta/patología , Preeclampsia/genética , Preeclampsia/patología , Embarazo , Mapas de Interacción de Proteínas/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , Transcriptoma/efectos de los fármacos , Transcriptoma/genética , Trofoblastos/efectos de los fármacos , Proteína p53 Supresora de Tumor/genética
17.
Oncotarget ; 7(37): 58975-58994, 2016 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-27449294

RESUMEN

Acute Radiation Syndrome (ARS) may lead to cancer and death and has few effective countermeasures. Efficacy of synthetic PIF treatment was demonstrated in preclinical autoimmune and transplantation models. PIF protected against inflammation and mortality following lethal irradiation in allogeneic bone marrow transplant (BMT) model. Herein, we demonstrate that PIF imparts comprehensive local and systemic protection against lethal and sub-lethal ARS in murine models. PIF treatment 2 h after lethal irradiation led to 100% survival and global hematopoietic recovery at 2 weeks after therapy. At 24 h after irradiation PIF restored hematopoiesis in a semi-allogeneic BMT model. PIF-preconditioning provided improved long-term engraftment. The direct effect of PIF on bone marrow cells was also demonstrated in vitro: PIF promoted pre-B cell differentiation and increased immunoregulatory properties of BM-derived mesenchymal stromal cells. PIF treatment also improved hematopoietic recovery and reduced systemic inflammatory cytokine production after sub-lethal radiation exposure. Here, PIF also prevented colonic crypt and basal membrane damage coupled with reduced nitric oxide synthetase (iNOS) and increased (B7h1) expression. Global upper GI gene pathway analysis revealed PIF's involvement in protein-RNA interactions, mitochondrial oxidative pathways, and responses to cellular stress. Some effects may be attributed to PIF's influence on macrophage differentiation and function. PIF demonstrated a regulatory effect on irradiated macrophages and on classically activated M1 macrophages, reducing inflammatory gene expression (iNOS, Cox2), promoting protective (Arg1) gene expression and inducing pro-tolerance cytokine secretion. Notably, synthetic PIF is stable for long-term field use. Overall, clinical investigation of PIF for comprehensive ARS protection is warranted.


Asunto(s)
Síndrome de Radiación Aguda/prevención & control , Trasplante de Médula Ósea , Proteoglicanos/uso terapéutico , Protectores contra Radiación/uso terapéutico , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Supervivencia de Injerto , Hematopoyesis/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Embarazo , Acondicionamiento Pretrasplante , Trasplante Homólogo , Irradiación Corporal Total
18.
Thromb Haemost ; 115(5): 1010-24, 2016 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-26842698

RESUMEN

PreImplantation factor (PIF) is a 15-amino acid peptide endogenously secreted by viable embryos, regulating/enabling maternal (host) acceptance/tolerance to the "invading" embryo (allograft) all-while preserving maternal immunity to fight infections. Such attributes make PIF a potential therapeutic agent for chronic inflammatory diseases. We investigated whether PIF's immunomodulatory properties prevent progression of atherosclerosis in the hyper-cholesterolaemic ApoE-deficient murine model. Male, high-fat diet fed, ApoE-deficient (ApoE-/-) mice were administered either PBS, scrambled PIF (0.3-3 mg/kg) or PIF (0.3-3 mg/kg) for seven weeks. After treatment, PIF (3 mg/kg)-treated ApoE-/- mice displayed significantly reduced atherosclerosis lesion burden in the aortic sinus and aortic arch, without any effect on lipid profile. PIF also caused a significant reduction in infiltration of macrophages, decreased expression of pro-inflammatory adhesion molecules, cytokines and chemokines in the plaque, and reduced circulating IFN-γ levels. PIF preferentially binds to monocytes/neutrophils. In vitro, PIF attenuated monocyte migration (MCP-1-induced chemotaxis assay) and in vivo in LPS peritonitis model. Also PIF prevented leukocyte extravasation (peritonitis thioglycollate-induced model), demonstrating that PIF exerts its effect in part by modulation of monocyte function. Inhibition of the potassium channel KCNAB3 (Kv1.3) and of the insulin degrading enzyme (IDE) was demonstrated as potential mechanism of PIF's immunomodulatory effects. In conclusion, PIF regulates/lowers inflammation and prevents atherosclerosis development without affecting circulating lipids. Overall our findings establish PIF as a strong immunomodulatory drug candidate for atherosclerosis therapy.


Asunto(s)
Aterosclerosis/prevención & control , Factores Inmunológicos/farmacología , Péptidos/farmacología , Animales , Apolipoproteínas E/deficiencia , Aterosclerosis/patología , Aterosclerosis/fisiopatología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Línea Celular , Dieta Alta en Grasa/efectos adversos , Humanos , Mediadores de Inflamación/metabolismo , Insulisina/antagonistas & inhibidores , Insulisina/genética , Canal de Potasio Kv1.3/antagonistas & inhibidores , Canal de Potasio Kv1.3/genética , Lípidos/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/efectos de los fármacos , Placa Aterosclerótica/prevención & control , ARN Interferente Pequeño/genética
19.
Immunobiology ; 220(7): 865-75, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25766203

RESUMEN

PreImplantation Factor (PIF(9&15)) secreted by viable embryos exerts an essential transplant acceptance and immune regulatory role in pregnancy. Synthetic PIF replicates endogenous PIF's effect in pregnant and non-pregnant immune disorder models. PIF binds macrophages to regulate CD3/CD28-induced T-cell response. We present evidence that PIF regulates the co-stimulatory T-cell receptor, CD2, which binds to and is activated by phytohemagglutinin (PHA), a potent mitogen, confirming PIF's ability to systemically respond to diverse immune stimulants. PIF's effect on PHA-activated PBMC (male and non-pregnant females) proliferation and cytokine secretion was tested, showing that both PIF(9&15) block PHA-induced PBMC proliferation and promote anti-inflammatory IL10 secretion, while reducing pro-inflammatory IFNγ secretion. Thus favoring a T(H)2 cytokine bias. Surface plasmon resonance spectroscopy, immunocytochemistry and Flex station experiments reveal that PIF effect is direct. PIF targets intracellular targets but does not affect early Ca(2+) mobilization. By promoting the CD2 receptor in activated T-cells and through inhibition of co-ligand CD58 expression, PIF regulates antigen-presenting cell (APC)-T-cell interactions required for PHA action. Structure-based design demonstrated that PIF15 offers improved target specificity as compared to PIF9. Collectively, PIF directly regulates mitogen-induced PBMC activation. Results support PIF translation for therapy of immune disorders.


Asunto(s)
Calcio/metabolismo , Leucocitos Mononucleares/inmunología , Péptidos/farmacología , Fitohemaglutininas/metabolismo , Proteínas Gestacionales/inmunología , Células Presentadoras de Antígenos/inmunología , Antígenos CD2/metabolismo , Antígenos CD28/metabolismo , Complejo CD3/metabolismo , Antígenos CD58/biosíntesis , Canales de Calcio/metabolismo , Femenino , Humanos , Interferón gamma/metabolismo , Interleucina-10/biosíntesis , Activación de Linfocitos/inmunología , Macrófagos/inmunología , Masculino , Simulación de Dinámica Molecular , Embarazo , Resonancia por Plasmón de Superficie , Células TH1/inmunología , Células Th2/inmunología
20.
Proc Natl Acad Sci U S A ; 111(38): 13882-7, 2014 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-25205808

RESUMEN

Dysfunction and loss of neurons are the major characteristics of CNS disorders that include stroke, multiple sclerosis, and Alzheimer's disease. Activation of the Toll-like receptor 7 by extracellular microRNA let-7, a highly expressed microRNA in the CNS, induces neuronal cell death. Let-7 released from injured neurons and immune cells acts on neighboring cells, exacerbating CNS damage. Here we show that a synthetic peptide analogous to the mammalian PreImplantation factor (PIF) secreted by developing embryos and which is present in the maternal circulation during pregnancy inhibits the biogenesis of let-7 in both neuronal and immune cells of the mouse. The synthetic peptide, sPIF, destabilizes KH-type splicing regulatory protein (KSRP), a key microRNA-processing protein, in a Toll-like receptor 4 (TLR4)-dependent manner, leading to decreased production of let-7. Furthermore, s.c. administration of sPIF into neonatal rats following hypoxic-ischemic brain injury robustly rescued cortical volume and number of neurons and decreased the detrimental glial response, as is consistent with diminished levels of KSRP and let-7 in sPIF-treated brains. Our results reveal a previously unexpected mechanism of action of PIF and underscore the potential clinical utility of sPIF in treating hypoxic-ischemic brain damage. The newly identified PIF/TLR4/KSRP/let-7 regulatory axis also may operate during embryo implantation and development.


Asunto(s)
Blastocisto/metabolismo , Implantación del Embrión/fisiología , MicroARNs/metabolismo , Péptidos/metabolismo , Animales , Blastocisto/citología , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Femenino , Ratones , MicroARNs/genética , Péptidos/genética , Embarazo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Ratas , Ratas Wistar , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Transactivadores/genética , Transactivadores/metabolismo
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