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PROBLEM: Antiphospholipid syndrome (APS) is characterized by the clinical manifestation of vascular thrombosis (VT) or pregnancy morbidity (PM) and antiphospholipid antibodies (aPL) that can modify the nitric oxide production. Low-dose aspirin is used in the prevention and treatment of diverse alterations of pregnancy. One of the mechanisms of action of aspirin is to induce the production of aspirin-triggered-lipoxins (ATL). The aim of this study was to evaluate the modulatory effect of ATL over the activation of endothelial nitric oxide synthase (eNOS) and nitrosative stress biomarkers induced by aPL. METHODS: We used polyclonal IgG and sera from women with aPL and PM/VT or VT only, and from women with PM only and positive for non-criteria aPL (SN-OAPS). In these sera, biomarkers of nitrosative stress (nitrites and nitrotyrosine) were measured. The protein expression of nitrotyrosine and the phosphorylation of eNOS (at Ser1177) were estimated in human umbilical vein endothelial cells (HUVECs) stimulated with polyclonal IgG with or without ATL. RESULTS: Women with SN-OAPS showed increased circulating levels of nitrites and nitrotyrosine. Likewise, polyclonal IgG from either SN-OAPS or VT patients stimulated nitrotyrosine expression in HUVECs. ATL decreased the nitrotyrosine expression induced by polyclonal IgG from the SN-OAPS group. ATL also recovered the reduced eNOS phosphorylation at Ser1177 in HUVECs stimulated with polyclonal IgG from women with PM/VT or SN-OAPS. CONCLUSIONS: Increased nitrosative stress present in serum of women with SN-OAPS is associated with IgG-mediated impaired endothelial NO synthesis in endothelial cells. ATL prevent these cellular changes.
Assuntos
Síndrome Antifosfolipídica , Lipoxinas , Gravidez , Humanos , Feminino , Aspirina/farmacologia , Aspirina/uso terapêutico , Lipoxinas/farmacologia , Óxido Nítrico Sintase Tipo III , Estresse Nitrosativo , Nitritos , Células Endoteliais da Veia Umbilical Humana , Imunoglobulina GRESUMO
The microbiome -defined as the microbiota (bacteria, archaea, lower and higher eukaryotes), their genomes, and the surrounding environmental conditions- has a well-described range of physiological functions. Thus, an imbalance of the microbiota composition -dysbiosis- has been associated with pregnancy complications or adverse fetal outcomes. Although there is controversy about the existence or absence of a microbiome in the placenta and fetus during healthy pregnancy, it is known that gut microbiota can produce bioactive metabolites that can enter the maternal circulation and may be actively or passively transferred through the placenta. Furthermore, the evidence suggests that such metabolites have some effect on the fetus. Since the microbiome can influence the epigenome, and modifications of the epigenome could be responsible for fetal programming, it can be experimentally supported that the maternal microbiome and its metabolites could be involved in fetal programming. The developmental origin of health and disease (DOHaD) approach looks to understand how exposure to environmental factors during periods of high plasticity in the early stages of life (e.g., gestational period) influences the program for disease risk in the progeny. Therefore, according to the DOHaD approach, the influence of maternal microbiota in disease development must be explored. Here, we described some of the diseases of adulthood that could be related to alterations in the maternal microbiota. In summary, this review aims to highlight the influence of maternal microbiota on both fetal development and postnatal life, suggesting that dysbiosis on this microbiota could be related to adulthood morbidity.
Assuntos
Microbioma Gastrointestinal , Microbiota , Gravidez , Feminino , Humanos , Disbiose/microbiologia , Placenta/microbiologia , Desenvolvimento FetalRESUMO
Resumen Introducción: la mentalidad machista es un fenómeno persistente en Latinoamérica. Sin embargo, no se tienen claros los factores que la generan, por ello, se realizó el estudio para analizar la mentalidad machista en función de factores como los estilos parentales y la vulnerabilidad social. Método: la muestra estuvo constituida por 389 (M.edad = 35.87, DE = 10.13) cuidadores primarios de niños, niñas y adolescentes de 4-16 años (M.edad= 9.33, DE = 4.66, femenino = 196) de diferentes regiones de Perú y Argentina. Se utilizaron (a) la subescala de Machismo de la Evaluación Multifásica de las Culturas (MACC-SF), (b) la Adaptación Española del Cuestionario de Crianza Parental y (c) una ficha sociodemográfica ad hoc, aplicadas través de las redes sociales mediante un formulario. Resultados: en ambas muestras, los niveles de machismo son relativamente bajos, aunque la muestra argentina presentó menores niveles y hábitos más positivos de crianza, en comparación con Perú. A su vez, se encontró asociación negativa entre machismo y estilos parentales, con mayor intensidad en las dimensiones; satisfacción con la crianza y disciplina. Finalmente, el machismo se asoció de forma negativa con la vulnerabilidad social y los estilos de crianza. Conclusión: las creencias machistas estarían asociadas con menor nivel socioeconómico y estilos de crianza más autoritarios, los que también se rigen por sus tradiciones y a un conservadurismo del legado cultural, en comparación a culturas más flexibles y democráticas.
Abstract Introduction: the macho mentality is a phenomenon that persists in the Latin American population; however, the factors that generate it are not clear. Therefore, the study is carried out with the objective of analyzing the macho mentality, based on factors such as parental styles and social vulnerability; and comparing according to country of origin: Argentina and Peru, respectively. Method: the sample consisted of 389 (M.age = 35.87, SD = 10.13) primary caregivers of children and adolescents from 4 to 16 (M.age = 9.33, SD = 4.66, feminine = 196) years of age from different regions of Peru and Argentina. The instruments used were the Machismo subscale of the Multiphasic Evaluation of Cultures (MACC-SF), the Spanish Adaptation of the Parental Upbringing Questionnaire, and an ad-hoc sociodemographic record, which were all applied through social networks using a Google® form. Results: in both samples, the levels of machismo are relatively low, although the Argentine sample presented lower levels of machismo and more positive parenting habits compared to that of Peru. In turn, a negative association was found between machismo and parenting styles, with greater intensity in the dimensions: satisfaction with parenting and discipline. Finally, machismo was negatively associated with social vulnerability and parenting styles. Conclusions: macho beliefs would be associated with a lower socioeconomic level and more authoritarian and inflexible parenting styles, which are also governed by their traditions and a cultural legacy of conservatism in comparison to more flexible and democratic cultures.
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Antiphospholipid syndrome (APS) is an autoimmune disease characterized by thrombosis and pregnancy morbidity (PM) obstetric events together with persistent high titers of circulating antiphospholipid antibodies (aPL). Several mechanisms that explain the development of thrombosis and PM in APS include the association of aPL with alterations in the coagulation cascade and inflammatory events. Other mechanisms disturbing cellular homeostases, such as mitochondrial dysfunction, autophagy, and cell proliferation, have been described in other autoimmune diseases. Therefore, the objective of this study was to investigate the impact of aPL from different patient populations on endothelial cell mitochondrial function, activation of the mammalian target of rapamycin (mTOR) and autophagy pathways, and cellular growth. Using an in vitro model, human umbilical vein endothelial cells (HUVECs) were treated with polyclonal immunoglobulin G (IgG) purified from the serum of women with both PM and vascular thrombosis (PM/VT), with VT only (VT), or with PM and non-criteria aPL (seronegative-obstetric APS, SN-OAPS). We included IgG from women with PM without aPL (PM/aPL-) and healthy women with previous uncomplicated pregnancies (normal human serum, NHS) as control groups. Mitochondrial function, mTOR activation, autophagy, and cell proliferation were evaluated by Western blotting, flow cytometry, and functional assays. IgG from women with PM/VT increased HUVEC mitochondrial hyperpolarization and activation of the mTOR and autophagic pathways, while IgG from patients with VT induced endothelial autophagy and cell proliferation in the absence of elevated mTOR activity or mitochondrial dysfunction. IgG from the SN-OAPS patient group had no effect on any of these HUVEC responses. In conclusion, aPL from women with PM and vascular events induce cellular stress evidenced by mitochondrial hyperpolarization and increased activation of the mTOR and autophagic pathways which may play a role in the pathogenesis of obstetric APS.
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Although crotoxin B (CB) is a well-established catalytically active secretory phospholipase A2 group IIA (sPLA2-IIA) myotoxin, we investigated its potential stimulatory effect on myogenesis with the involvement of prostaglandins (PGs) produced by cyclooxygenase (COX)-1 and -2 pathways. Myoblast C2C12 were cultured in proliferation or commitment protocols and incubated with CB followed by lumiracoxib (selective COX-2 inhibitor) or valeryl salicylate (selective COX-1 inhibitor) and subjected to analysis of PG release, cell proliferation and activation of myogenic regulatory factors (MRFs). Our data showed that CB in non-cytotoxic concentrations induces an increase of COX-2 protein expression and stimulates the activity of both COX isoforms to produce PGE2, PGD2 and 15d-PGJ2. CB induced an increase in the proliferation of C2C12 myoblast cells dependent on PGs from both COX-1 and COX-2 pathways. In addition, CB stimulated the activity of Pax7, MyoD, Myf5 and myogenin in proliferated cells. Otherwise, CB increased myogenin activity but not MyoD in committed cells. Our findings evidence the role of COX-1- and COX-2-derived PGs in modulating CB-induced activation of MRFs. This study contributes to the knowledge that CB promote early myogenic events via regulatory mechanisms on PG-dependent COX pathways, showing new concepts about the effect of sPLA2-IIA in skeletal muscle repair.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Crotoxina/farmacologia , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Fosfolipases A2 do Grupo II/farmacologia , Proteínas de Membrana/metabolismo , Desenvolvimento Muscular/efeitos dos fármacos , Mioblastos Esqueléticos/efeitos dos fármacos , Neurotoxinas/farmacologia , Prostaglandinas/metabolismo , Animais , Linhagem Celular , Camundongos , Proteína MyoD/metabolismo , Mioblastos Esqueléticos/enzimologia , Fator Regulador Miogênico 5/metabolismo , Miogenina/metabolismo , Fator de Transcrição PAX7/metabolismo , Transdução de SinaisRESUMO
In this study, we investigated the effects and mechanisms of the pro-inflammatory cytokines IL-1ß and TNF-α on the proliferation and commitment phases of myoblast differentiation. C2C12 mouse myoblast cells were cultured to reach a proliferated or committed status and were incubated with these cytokines for the evaluation of cell proliferation, cyclooxygenase 2 (COX-2) expression, release of prostaglandins (PGs) and myokines, and activation of myogenic regulatory factors (MRFs). We found that inhibition of the IL-6 receptor reduced IL-1ß- and TNF-α-induced cell proliferation, and that the IL-1ß effect also involved COX-2-derived PGs. Both cytokines modulated the release of the myokines myostatin, irisin, osteonectin, and IL-15. TNF-α and IL-6 reduced the activity of Pax7 in proliferated cells and reduced MyoD and myogenin activity at both proliferative and commitment stages. Otherwise, IL-1ß increased myogenin activity only in committed cells. Our data reveal a key role of IL-6 and COX-2-derived PGs in IL-1ß and TNF-α-induced myoblast proliferation and support the link between TNF-α and IL-6 and the activation of MRFs. We concluded that IL-1ß and TNF-α induce similar effects at the initial stages of muscle regeneration but found critical differences between their effects with the progression of the process, bringing new insights into inflammatory signalling in skeletal muscle regeneration.
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Proliferação de Células/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Interleucina-1beta/farmacologia , Interleucina-6/metabolismo , Mioblastos/metabolismo , Prostaglandinas/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Inibidores de Ciclo-Oxigenase 2/farmacologia , Diclofenaco/análogos & derivados , Diclofenaco/farmacologia , Camundongos , Desenvolvimento Muscular/efeitos dos fármacos , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Receptores de Interleucina-6/antagonistas & inibidores , Regeneração/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
The placenta works as a selective barrier, protecting the fetus from potential infections that may affect the maternal organism during pregnancy. In this review, we will discuss several challenging infections that are common within Latin American countries and that may affect the maternal-fetal interface and pose risks to fetal development. Specifically, we will focus on emerging infectious diseases including the arboviruses, malaria, leishmaniasis, and the bacterial foodborne disease caused by Shiga toxin-producing Escherichia coli. We will also highlight some topics of interest currently being studied by research groups that comprise an international effort aimed at filling the knowledge gaps in this field. These topics address the relationship between exposure to microorganisms and placental abnormalities, congenital anomalies, and complications of pregnancy. ABBREVIATIONS: ADE: antibody-dependent enhancement; CCL2: monocyte chemoattractant protein-1; CCL3: macrophage inflammatory protein-1 α; CCL5: chemokine (C-C motif) ligand 5; CHIKV: chikungunya virus; DCL: diffuse cutaneous leishmaniasis; DENV: dengue virus; Gb3: glycolipid globotriaosylceramyde; HIF: hypoxia-inducible factor; HUS: hemolytic uremic syndrome; IFN: interferon; Ig: immunoglobulins; IL: interleukin; IUGR: intrauterine growth restriction; LCL: localized cutaneous leishmaniasis; LPS: lipopolysaccharid; MCL: mucocutaneous leishmaniasis; NO: nitric oxide; PCR: polymerase chain reaction; PGF: placental growth factor; PM: placental malaria; RIVATREM: Red Iberoamericana de Alteraciones Vasculares em transtornos del Embarazo; sVEGFR: soluble vascular endothelial growth factor receptor; STEC: shiga toxin-producing Escherichia coli; stx: shiga toxin protein; TNF: tumor necrosis factor; TOAS: T cell original antigenic sin; Var2CSA: variant surface antigen 2-CSA; VEGF: vascular endothelial growth factor; VL: visceral leishmaniasis; WHO: world health organization; YFV: yellow fever virus; ZIKV: Zika virus.
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Doenças Placentárias/etiologia , Placenta/patologia , Complicações Infecciosas na Gravidez/patologia , Infecções por Escherichia coli/complicações , Infecções por Escherichia coli/microbiologia , Feminino , Humanos , América Latina , Leishmaniose/complicações , Malária/complicações , Doenças Placentárias/patologia , Gravidez , Complicações Infecciosas na Gravidez/microbiologia , Complicações Infecciosas na Gravidez/virologia , Saúde Pública , Escherichia coli Shiga Toxigênica , Doenças Vasculares/complicações , Viroses/complicaçõesRESUMO
PROBLEM: Oxidative stress and inflammation are key events leading to pre-eclampsia, involved in several maternal deaths. Low doses of acetylsalicylic acid (ASA) are used in the prevention and treatment of pre-eclampsia. The synthesis of aspirin-triggered lipoxin (ATL) by cyclooxygenase-2 acetylation is an alternative mechanism of ASA, which could explain the effectiveness of ASA treatments. The aim of this study was to evaluate the role of ASA, salicylates, and ATL in the modulation of the oxidative and inflammatory responses induced by plasma from women with pre-eclampsia. METHOD OF STUDY: Plasma from 14 women with pre-eclampsia and 17 normotensive pregnant women was probed for inducing oxidative and inflammatory responses on endothelial cells and U937 promonocytes. The role of ATL, ASA, and salicylic acid (SA) on these events was evaluated. RESULTS: Plasma from women with pre-eclampsia induced TBARS and nitrotyrosine production on endothelial and U937 cells. Pre-treatment with both ATL and ASA decreased the TBARS production, while ATL decreased the nitrotyrosine. Pre-eclamptic plasma augmented the translocation of NF-kB on U937 cells, which decreased by a high dose of ASA and SA. Finally, the pre-eclamptic plasma increased the adhesion of leukocytes-PMN and monocytes-to endothelium, and we were able to determine a state of resolution of inflammation, since ATL decreased the PMN adhesion, and conversely, it increased the monocytes adhesion to endothelium. CONCLUSION: Together, these results suggest that ATL could explain the beneficial actions of ASA and support further research on mechanisms, real efficacy, and rational use of ASA in pre-eclampsia.
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Aspirina/uso terapêutico , Lipoxinas/sangue , Estresse Oxidativo/efeitos dos fármacos , Pré-Eclâmpsia/sangue , Ácido Salicílico/sangue , Acetilação , Adolescente , Adulto , Aspirina/sangue , Aspirina/farmacologia , Adesão Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/sangue , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/sangue , Lipoxinas/biossíntese , Lipoxinas/farmacologia , NF-kappa B/metabolismo , Neutrófilos/efeitos dos fármacos , Pré-Eclâmpsia/tratamento farmacológico , Pré-Eclâmpsia/prevenção & controle , Gravidez , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Ácido Salicílico/farmacologia , Substâncias Reativas com Ácido Tiobarbitúrico/análise , Tirosina/análogos & derivados , Tirosina/biossíntese , Células U937 , Adulto JovemRESUMO
Introducción:El síndrome antifosfolipídico (SAF) es una enfermedad autoinmune caracterizada por la presencia persistente de anticuerpos antifosfolípidos (aAFL) y manifestaciones clínicas de trombosis y/o morbilidad gestacional que se asocian con estrés nitrosativo/ oxidativo y disminución de la capacidad antioxidante, alterando el desarrollo gestacional. Objetivo: Evaluar algunos biomarcadores de estrés nitrosativo/oxidativo del suero de mujeres con diferentes manifestaciones clínicas del SAF y sus efectos en células endoteliales. Métodos: Se incluyeron sueros de 48 mujeres divididas en dos grupos con y sin aAFL. Se evaluó la concentración de nitritos, la capacidad antioxidante y la actividad de la enzima paraoxonasa
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Síndrome Antifosfolipídica , Estresse Nitrosativo , Estresse OxidativoRESUMO
Introducción y Objetivo: Los anticuerpos antifosfolípidos (aAFL) se pueden unir a las células trofoblásticas o a las endoteliales, alterando la remodelación vascular y consecuentemente la placentación normal. El objetivo fue evaluar el efecto del suero de pacientes con síndrome antifosfolipídico (SAF) obstétrico en la interacción endotelio-trofoblasto utilizando un modelo in vitro tridimensional de remodelación vascular. Métodos: Las pacientes con aAFL fueron clasificadas en dos grupos: morbilidad gestacional y trombosis (MG/TV, n=7) y morbilidad gestacional sola (MG, n=8). Como control, se incluyeron mujeres sin aAFL con MG (MG/ aAFL-, n=10), y mujeres sanas (SHN, n=7). Células endoteliales HUVEC fueron cultivadas en Matrigel™ hasta formar estructuras tubulares (angiogénesis) y luego se adicionaron células trofoblásticas HTR8; estas células invaden las estructuras tubulares de las células endoteliales mejorando su estabilidad. Se evaluó el efecto de 10% del suero de las mujeres del estudio sobre esta interacción.