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During pregnancy, apoptosis is a physiological event critical in the remodeling and aging of the placenta. Increasing evidence has pointed towards the relevance of hypoxia as modulator of trophoblast cell death. Previous reports have shown that leptin, a placental cytokine, promotes cell survival in both cell culture and placental explant models. The aim of this work is to establish the role of leptin in apoptosis under hypoxic condition in trophoblast cells. In this study, we evaluated the effect of cobalt chloride, a hypoxia mimicking agent that stabilizes the expression of hypoxia inducible factor-1 alpha (HIF-1α), on Swan-71 and human placental explants. Hypoxia chamber was also used to generate 2% oxygen. Apoptosis was determined by the presence of apoptotic nucleus, fragmentation of DNA and Caspase-3 and PARP-1 cleavage. The pro-apoptotic proteins BAX, BID, BAD and BAK and the anti-apoptotic effectors BCL-2, BCL-xL and MCL-1 were also analyzed. We found that HIF-1α stabilization increased the appearance of apoptotic nucleus, fragmentation of DNA, and Caspase-3 and PARP-1 cleavage. Hypoxia mimicking conditions enhanced the expression of pro-apoptotic effectors BAX, BID, BAD and BAK. HIF-1α stabilization also downregulated the level of BCL-2, BCL-xL and MCL-1. All these apoptotic parameters changes were reversed with leptin treatment. Moreover, we showed that leptin action on apoptosis modulation involves PI3K and MAPK signaling pathways. Obtained data demonstrate that HIF-1α stabilization induces apoptosis in human placenta and leptin counteracts this effect, reinforcing its role as a survival cytokine.
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The burden of cardiovascular disease is particularly high among individuals with diabetes, even when LDL cholesterol is normal or within the therapeutic target. Despite this, cholesterol accumulates in their arteries, in part, due to persistent atherogenic dyslipidaemia characterized by elevated triglycerides, remnant cholesterol, smaller LDL particles and reduced HDL cholesterol. The causal link between dyslipidaemia and atherosclerosis in T2DM is complex, and our contention is that a deeper understanding of lipoprotein composition and functionality, the vehicle that delivers cholesterol to the artery, will provide insight for improving our understanding of the hidden cardiovascular risk of diabetes. This narrative review covers three levels of complexity in lipoprotein characterization: 1-the information provided by routine clinical biochemistry, 2-advanced nuclear magnetic resonance (NMR)-based lipoprotein profiling and 3-the identification of minor components or physical properties of lipoproteins that can help explain arterial accumulation in individuals with normal LDLc levels, which is typically the case in individuals with T2DM. This document highlights the importance of incorporating these three layers of lipoprotein-related information into population-based studies on ASCVD in T2DM. Such an attempt should inevitably run in parallel with biotechnological solutions that allow large-scale determination of these sets of methodologically diverse parameters.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Factores de Riesgo de Enfermedad Cardiaca , Lipoproteínas , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Lipoproteínas/metabolismo , Lipoproteínas/sangre , Enfermedades Cardiovasculares/etiología , Dislipidemias , Espectroscopía de Resonancia Magnética , Aterosclerosis , LDL-Colesterol/metabolismo , LDL-Colesterol/sangre , HDL-Colesterol/metabolismo , Triglicéridos/metabolismoRESUMEN
The dental implant surface plays a crucial role in osseointegration. The topography and physicochemical properties will affect the cellular functions. In this research, four distinct titanium surfaces have been studied: machined acting (MACH), acid etched (AE), grit blasting (GBLAST), and a combination of grit blasting and subsequent acid etching (GBLAST + AE). Human amniotic mesenchymal (hAMSCs) and epithelial stem cells (hAECs) isolated from the amniotic membrane have attractive stem-cell properties. They were cultured on titanium surfaces to analyze their impact on biological behavior. The surface roughness, microhardness, wettability, and surface energy were analyzed using interferometric microscopy, Vickers indentation, and drop-sessile techniques. The GBLAST and GBLAST + AE surfaces showed higher roughness, reduced hydrophilicity, and lower surface energy with significant differences. Increased microhardness values for GBLAST and GBLAST + AE implants were attributed to surface compression. Cell viability was higher for hAMSCs, particularly on GBLAST and GBLAST + AE surfaces. Alkaline phosphatase activity enhanced in hAMSCs cultured on GBLAST and GBLAST + AE surfaces, while hAECs showed no mineralization signals. Osteogenic gene expression was upregulated in hAMSCs on GBLAST surfaces. Moreover, α2 and ß1 integrin expression enhanced in hAMSCs, suggesting a surface-integrin interaction. Consequently, hAMSCs would tend toward osteoblastic differentiation on grit-blasted surfaces conducive to osseointegration, a phenomenon not observed in hAECs.
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Amnios , Implantes Dentales , Propiedades de Superficie , Titanio , Humanos , Titanio/química , Amnios/citología , Amnios/metabolismo , Osteogénesis , Diferenciación Celular , Células Cultivadas , Oseointegración , Células Madre/citología , Células Madre/metabolismo , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Supervivencia Celular , Fosfatasa Alcalina/metabolismoRESUMEN
Cancer is a complex disease that, despite advances in treatment and the greater understanding of the tumor biology until today, continues to be a prevalent and lethal disease. Chemotherapy, radiotherapy, and surgery are the conventional treatments, which have increased the survival for cancer patients. However, the complexity of this disease together with the persistent problems due to tumor progression and recurrence, drug resistance, or side effects of therapy make it necessary to explore new strategies that address the challenges to obtain a positive response. One important point is that tumor cells can interact with the microenvironment, promoting proliferation, dissemination, and immune evasion. Therefore, immunotherapy has emerged as a novel therapy based on the modulation of the immune system for combating cancer, as reflected in the promising results both in preclinical studies and clinical trials obtained. In order to enhance the immune response, the combination of immunotherapy with nanoparticles has been conducted, improving the access of immune cells to the tumor, antigen presentation, as well as the induction of persistent immune responses. Therefore, nanomedicine holds an enormous potential to enhance the efficacy of cancer immunotherapy. Here, we review the most recent advances in specific molecular and cellular immunotherapy and in nano-immunotherapy against cancer in the light of the latest published preclinical studies and clinical trials.
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Inmunoterapia , Neoplasias , Humanos , Neoplasias/terapia , Presentación de Antígeno , Evasión Inmune , Nanomedicina , Microambiente TumoralRESUMEN
Diabetes mellitus (DM) is a highly prevalent disease worldwide, estimated to affect 1 in every 11 adults; among them, 90-95% of cases are type 2 diabetes mellitus. This is partly attributed to the surge in the prevalence of obesity, which has reached epidemic proportions since 2008. In these patients, cardiovascular (CV) risk stands as the primary cause of morbidity and mortality, placing a substantial burden on healthcare systems due to the potential for macrovascular and microvascular complications. In this context, leptin, an adipocyte-derived hormone, plays a fundamental role. This hormone is essential for regulating the cellular metabolism and energy balance, controlling inflammatory responses, and maintaining CV system homeostasis. Thus, leptin resistance not only contributes to weight gain but may also lead to increased cardiac inflammation, greater fibrosis, hypertension, and impairment of the cardiac metabolism. Understanding the relationship between leptin resistance and CV risk in obese individuals with type 2 DM (T2DM) could improve the management and prevention of this complication. Therefore, in this narrative review, we will discuss the evidence linking leptin with the presence, severity, and/or prognosis of obesity and T2DM regarding CV disease, aiming to shed light on the potential implications for better management and preventive strategies.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Leptina , Obesidad , Adulto , Humanos , Enfermedades Cardiovasculares/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Leptina/metabolismo , Obesidad/metabolismoRESUMEN
Obesity is frequently accompanied by non-alcoholic fatty liver disease (NAFLD). These two diseases are associated with altered lipid metabolism, in which reverse cholesterol transport (LXRα/ABCA1/ABCG1) and leptin response (leptin receptor (Ob-Rb)/Sam68) are involved. The two pathways were evaluated in peripheral blood mononuclear cells (PBMCs) from 86 patients with morbid obesity (MO) before and six months after Roux-en-Y gastric bypass (RYGB) and 38 non-obese subjects. In the LXRα pathway, LXRα, ABCA1, and ABCG1 mRNA expressions were decreased in MO compared to non-obese subjects (p < 0.001, respectively). Ob-Rb was decreased (p < 0.001), whereas Sam68 was increased (p < 0.001) in MO. RYGB did not change mRNA gene expressions. In the MO group, the LXRα pathway (LXRα/ABCA1/ABCG1) negatively correlated with obesity-related variables (weight, body mass index, and hip), inflammation (C-reactive protein), and liver function (alanine-aminotransferase, alkaline phosphatase, and fatty liver index), and positively with serum albumin. In the Ob-R pathway, Ob-Rb and Sam68 negatively correlated with alanine-aminotransferase and positively with albumin. The alteration of LXRα and Ob-R pathways may play an important role in NAFLD development in MO. It is possible that MO patients may require more than 6 months following RYBGB to normalize gene expression related to reverse cholesterol transport or leptin responsiveness.
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Transportador 1 de Casete de Unión a ATP , Colesterol , Leucocitos Mononucleares , Receptores X del Hígado , Hígado , Obesidad Mórbida , Receptores de Leptina , Humanos , Obesidad Mórbida/metabolismo , Obesidad Mórbida/cirugía , Obesidad Mórbida/genética , Masculino , Leucocitos Mononucleares/metabolismo , Femenino , Receptores de Leptina/genética , Receptores de Leptina/metabolismo , Adulto , Colesterol/metabolismo , Receptores X del Hígado/metabolismo , Receptores X del Hígado/genética , Transportador 1 de Casete de Unión a ATP/genética , Transportador 1 de Casete de Unión a ATP/metabolismo , Persona de Mediana Edad , Hígado/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/genética , Transducción de Señal , Transporte Biológico , Regulación de la Expresión Génica , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genéticaRESUMEN
Breast cancer (BC) continues to be the most diagnosed tumor in women and a very heterogeneous disease both inter- and intratumoral, mainly given by the variety of molecular profiles with different biological and clinical characteristics. Despite the advancements in early detection and therapeutic strategies, the survival rate is low in patients who develop metastatic disease. Therefore, it is mandatory to explore new approaches to achieve better responses. In this regard, immunotherapy arose as a promising alternative to conventional treatments due to its ability to modulate the immune system, which may play a dual role in this disease since the relationship between the immune system and BC cells depends on several factors: the tumor histology and size, as well as the involvement of lymph nodes, immune cells, and molecules that are part of the tumor microenvironment. Particularly, myeloid-derived suppressor cell (MDSC) expansion is one of the major immunosuppressive mechanisms used by breast tumors since it has been associated with worse clinical stage, metastatic burden, and poor efficacy of immunotherapies. This review focuses on the new immunotherapies in BC in the last five years. Additionally, the role of MDSC as a therapeutic target in breast cancer will be described.
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Neoplasias de la Mama , Células Supresoras de Origen Mieloide , Neoplasias , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias/terapia , Inmunoterapia , Microambiente TumoralRESUMEN
BACKGROUND: Viscoelastic tests (rotational thromboelastometry, ROTEM®), together with the implementation of a specific algorithm for coagulation management in cardiac surgery, enable perioperative coagulopathy to be better controlled. METHODS: Retrospective cohort study including 675 patients who underwent cardiac surgery with cardiopulmonary bypass. The incidence of allogeneic blood transfusions and clinical postoperative complications were analyzed before and after ROTEM® implementation. RESULTS: Following viscoelastic testing and the implementation of a specific algorithm for coagulation management, the incidence of any allogeneic blood transfusion decreased (41.4% vs 31.9%, p = .026) during the perioperative period. In the group monitored with ROTEM®, decreased incidence of transfusion was observed for packed red blood cells (31.3% vs 19.8%, p = .002), fresh frozen plasma (9.8% vs 3.8%, p = .008), prothrombin complex concentrate administration (0.9% vs 0.3%, p = .599) and activated recombinant factor VII (0.3% vs 0.0%, p = .603). Increased incidence was observed for platelet transfusion (4.8% vs 6.8%, p = .530) and fibrinogen concentrate (0.9% vs 3.5%, p = .066), tranexamic acid (0.0% vs 0.6%, p = .370) and protamine administration (0.6% vs 0.9%, p = .908). Similar results were observed in the postoperative period, but with a decreased incidence of platelet transfusion (4.8% vs 3.8%, p = .813). In addition, statistically significant reductions were detected in the incidence of postoperative bleeding (9.5% vs 5.3%, p = .037), surgical reexploration (6.0% vs 2.9%, p = .035), and length of Intensive Care Unit (ICU) stay (6.0 days vs 5.3 days, p = .026). CONCLUSIONS: The monitoring of hemostasis by ROTEM® in cardiac surgery, was associated with decreased incidence of allogeneic blood transfusion, clinical hematologic postoperative complications and lengths of ICU stay.
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Procedimientos Quirúrgicos Cardíacos , Tromboelastografía , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Humanos , Evaluación de Resultado en la Atención de Salud , Hemorragia Posoperatoria/prevención & control , Estudios Retrospectivos , Tromboelastografía/métodosRESUMEN
Leptin is a non-glycosylated 16 kDa protein synthesized mainly in adipose cells. The main function of leptin is to regulate energy homeostasis and weight control in a central manner. There is increasing evidence that leptin also has systemic effects, acting as a link between innate and acquired immune responses. The expression of leptin and its receptor in human dental pulp and periradicular tissues have already been described, as well as several stimulatory effects of leptin protein expression in dental and periodontal tissues. The aim of this paper was to review and to compile the reported scientific literature on the role and effects of leptin in the dental pulp and periapical tissues. Twelve articles accomplished the inclusion criteria, and a comprehensive narrative review was carried out. Review of the available scientific literature concluded that leptin has the following effects on pulpal and periapical physiology: 1) Stimulates odontogenic differentiation of dental pulp stem cells (DPSCs), 2) Increases the expression of dentin sialophosphoprotein (DSPP) and dentin matrix protein-1 (DMP-1), odontoblastic proteins involved in odontoblastic differentiation and dentin mineralization, 3) Stimulates vascular endothelial growth factor (VEGF) expression in human dental pulp tissue and primary cultured cells of human dental pulp (hDPCs), 4) Stimulates angiogenesis in rat dental pulp cells, and 5) Induces the expression of interleucinas 6 and 8 in human periodontal ligament cells (hPDLCs). There is evidence which suggests that leptin is implicated in the dentin mineralization process and in pulpal and periapical inflammatory and reparative responses.
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Pulpa Dental/metabolismo , Leptina/metabolismo , Ligamento Periodontal/metabolismo , Animales , Diferenciación Celular/fisiología , Humanos , Odontogénesis/fisiologíaRESUMEN
Asthma and obesity are considered as highly prevalent diseases with a great impact on public health. Obesity has been demonstrated to be an aggravating factor in the pathogenesis of asthma. Adipose tissue secretes proinflammatory cytokines and mediators, including leptin, which may promote the development and severity of asthma in obese patients. This study is a systematic review and a meta-analysis based on the relationship between leptin and asthma during obesity. MEDLINE, Cochrane, EMBASE and CINAHL databases were used. Data heterogeneity was analyzed using Cochran's Q and treatment effect with the DerSimonian and Laird method. Random effect analyses were carried out to test data sensitivity. Asymmetry was estimated using Begg's and Egger's tests. All studies showed significant differences in leptin levels. The effect of the measures (p < 0.001), data sensitivity (p < 0.05) and data asymmetry were statistically significant, as well as tBegg's test (p = 0.010) and Egge's test (p < 0.001). Despite the existing limiting factors, the results of this study support the relevant role of leptin in the pathophysiology of asthma in obese subjects. Nevertheless, further studies are needed to obtain better insight in the relationship between leptin and asthma in obesity.
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Asma , Leptina , Obesidad , Humanos , Tejido Adiposo/patología , Asma/complicaciones , Asma/patología , Citocinas , Obesidad/complicaciones , Obesidad/patologíaRESUMEN
Obesity is a growing worldwide health problem, affecting many people due to excessive saturated fat consumption, lack of exercise, or a sedentary lifestyle. Leptin is an adipokine secreted by adipose tissue that increases in obesity and has central actions not only at the hypothalamic level but also in other regions and nuclei of the central nervous system (CNS) such as the cerebral cortex and hippocampus. These regions express the long form of leptin receptor LepRb, which is the unique leptin receptor capable of transmitting complete leptin signaling, and are the first regions to be affected by chronic neurocognitive deficits, such as mild cognitive impairment (MCI) and Alzheimer's Disease (AD). In this review, we discuss different leptin resistance mechanisms that could be implicated in increasing the risk of developing AD, as leptin resistance is frequently associated with obesity, which is a chronic low-grade inflammatory state, and obesity is considered a risk factor for AD. Key players of leptin resistance are SOCS3, PTP1B, and TCPTP whose signalling is related to inflammation and could be worsened in AD. However, some data are controversial, and it is necessary to further investigate the underlying mechanisms of the AD-causing pathological processes and how altered leptin signalling affects such processes.
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Enfermedad de Alzheimer , Leptina , Enfermedad de Alzheimer/complicaciones , Humanos , Obesidad/complicaciones , Receptores de Leptina , Factores de RiesgoRESUMEN
Obesity, which is considered a pandemic due to its high prevalence, is a risk factor for many types of cancers, including lymphoma, through a variety of mechanisms by promoting an inflammatory state. Specifically, over the last few decades, obesity has been suggested not only to increase the risk of lymphoma but also to be associated with poor clinical outcomes and worse responses to different treatments for those diseases. Within the extensive range of proinflammatory mediators that adipose tissue releases, leptin has been demonstrated to be a key adipokine due to its pleotropic effects in many physiological systems and diseases. In this sense, different studies have analyzed leptin levels and leptin/leptin receptor expressions as a probable bridge between obesity and lymphomas. Since both obesity and lymphomas are prevalent pathophysiological conditions worldwide and their incidences have increased over the last few years, here we review the possible role of leptin as a promising proinflammatory mediator promoting lymphomas.
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Leptina , Linfoma , Humanos , Leptina/metabolismo , Obesidad/complicaciones , Obesidad/metabolismo , Tejido Adiposo/metabolismo , Adipoquinas/metabolismo , Linfoma/metabolismo , Receptores de Leptina/metabolismoRESUMEN
BACKGROUND: Early identification of patients with COVID-19 who may develop critical illness is of great importance. METHODS: In this study a retrospective cohort of 264 COVID-19 cases admitted at Macarena University was used for development and internal validation of a risk score to predict the occurrence of critical illness in hospitalized patients with COVID-19. Backward stepwise logistic regression was used to derive the model, including clinical and laboratory variables predictive of critical illness. Internal validation of the final model used bootstrapped samples and the model scoring derived from the coefficients. External validation was performed in a cohort of 154 cases admitted at Valme and Virgen del Rocio University Hospital. RESULTS: A total of 62 (23.5%) patients developed a critical illness during their hospitalization stay, 21 (8.0%) patients needed invasive ventilation, 34 (12.9%) were admitted at the ICU and the overall mortality was of 14.8% (39 cases). 5 variables were included in the final model: age >59.5 years (OR: 3.11;95%CI 1.39-6.97), abnormal CRP results (OR: 5.76;95%CI 2.32-14.30), abnormal lymphocytes count (OR: 3.252;95%CI 1.56-6.77), abnormal CK results (OR: 3.38;95%CI 1.59-7.20) and abnormal creatinine (OR: 3.30;95%CI 1.42-7.68). The AUC of this model was 0.850 with sensitivity of 65% and specificity of 87% and the IDI and NRI were 0.1744 and 0.2785, respectively. The validation indicated a good discrimination for the external population. CONCLUSIONS: Biomarkers add prognostic information in COVID-19 patients. Our risk-score provides an easy to use tool to identify patients who are likely to develop critical illness during their hospital stay.
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Biomarcadores/sangre , COVID-19/etiología , Adulto , Anciano , Anciano de 80 o más Años , Proteína C-Reactiva/análisis , COVID-19/mortalidad , COVID-19/terapia , Creatina Quinasa/sangre , Creatinina/sangre , Enfermedad Crítica , Femenino , Hospitalización , Humanos , Laboratorios , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Respiración Artificial , Estudios Retrospectivos , Medición de Riesgo , Sensibilidad y Especificidad , Adulto JovenRESUMEN
Pregnancy success requires a proper fetal maternal interaction at the establishment of implantation. Leptin has been described as a multitasking cytokine in pregnancy, particularly in the placenta, where it acts as an autocrine hormone. The expression of leptin in normal trophoblastic cells is regulated by different endogenous signals. We have previously reported that 17ß-estradiol upregulates placental leptin expression through genomic and non-genomic mechanisms. To improve the knowledge of estrogen receptor mechanisms in regulating leptin gene expression, we examined transcription nuclear factor kappa B (NFκB) effect on estradiol leptin induction in human BeWo cell line and human term placental explants. We demonstrated that estradiol induction effect on leptin expression is blocked by the inhibition of NFκB signaling. We also found that the overexpression of p65 subunit, the active form of NFκB, induces leptin expression. Moreover, downregulation of estrogen receptor alpha (ERα), through a specific siRNA, abolished NFκB effect on leptin expression. We also demonstrated that ERα enhanced NFκB signaling pathway activation in trophoblastic cells. Estradiol treatment significantly increased p65 expression and phosphorylation of the inhibitory protein κB alpha (IκBα). A reporter plasmid containing NFκB elements was also induced in response to estradiol stimulation. Localization experiments revealed that estradiol treatment induced nuclear localization of overexpressed p65. Moreover, the overexpression of ERα produced a complete displacement of p65 protein to the nucleus. Finally, immunoprecipitation experiments showed the presence of a complex containing ERα and NFκB. All these evidences suggest a cooperative behavior between ERα and NFκB transcription factors to induce leptin transcription.
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Coriocarcinoma/patología , Estrógenos/farmacología , Leptina/metabolismo , FN-kappa B/metabolismo , Placenta/metabolismo , Neoplasias Uterinas/patología , Núcleo Celular , Coriocarcinoma/genética , Coriocarcinoma/metabolismo , Femenino , Humanos , Leptina/genética , FN-kappa B/genética , Fosforilación , Placenta/efectos de los fármacos , Embarazo , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Neoplasias Uterinas/genética , Neoplasias Uterinas/metabolismoRESUMEN
Inflammation is an essential immune response for the maintenance of tissue homeostasis. In a general sense, acute and chronic inflammation are different types of adaptive response that are called into action when other homeostatic mechanisms are insufficient. Although considerable progress has been made in understanding the cellular and molecular events that are involved in the acute inflammatory response to infection and tissue injury, the causes and mechanisms of systemic chronic inflammation are much less known. The pathogenic capacity of this type of inflammation is puzzling and represents a common link of the multifactorial diseases, such as cardiovascular diseases and type 2 diabetes. In recent years, interest has been raised by the discovery of novel mediators of inflammation, such as microRNAs and adipokines, with different effects on target tissues. In the present review, we discuss the data emerged from research of leptin in obesity as an inflammatory mediator sustaining multifactorial diseases and how this knowledge could be instrumental in the design of leptin-based manipulation strategies to help restoration of abnormal immune responses. On the other direction, chronic inflammation, either from autoimmune or infectious diseases, or impaired microbiota (dysbiosis) may impair the leptin response inducing resistance to the weight control, and therefore it may be a cause of obesity. Thus, we are reviewing the published data regarding the role of leptin in inflammation, and the other way around, the role of inflammation on the development of leptin resistance and obesity.
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Enfermedades Autoinmunes/inmunología , Enfermedades Transmisibles/inmunología , Leptina/metabolismo , Obesidad/inmunología , Inmunidad Adaptativa , Animales , Humanos , Inmunidad Innata , Leptina/genéticaRESUMEN
Development of the human placenta is critical for a successful pregnancy. The placenta allows the exchange of oxygen and carbon dioxide and is crucial to manage acid-base balance within a narrow pH. It is known that low pH levels are a risk of apoptosis in several tissues. However, there has been little discussion about the effect of acidic stress in the placenta. Leptin is produced by the placenta with a trophic autocrine effect. Previous results of our group have demonstrated that leptin prevents apoptosis of trophoblast cells under different stress conditions such as serum deprivation and hyperthermia. The purpose of the present work is to evaluate acidic stress consequences in trophoblast explant survival and to determine leptin action in these conditions. For this objective, term human trophoblast explants were cultured at physiological pH (pH 7.4) and at acidic pH (pH 6.8) in the presence or absence of leptin. Western blot assays were performed to study the abundance of active caspase-3 and the p89 fragment of PARP-1. Pro-apoptotic and pro-survival members of Bcl-2 family, as Bax, t-Bid, and Bcl-2, were studied. Moreover, p53 pathway was also evaluated including Mdm-2, the main p53 regulator. Active caspase-3 and cleaved PARP-1 abundances were increased at low extracellular pH. Moreover, t-Bid levels were also augmented as well as p53 expression and phosphorylation on S46. Leptin treatment prevents the consequences of acidosis, decreasing p53 expression and increasing Mdm-2 expression. In summary, this work demonstrated for first time that low pH induces apoptosis of human trophoblast explants involving apoptotic intrinsic pathway, and leptin impairs this effect.
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Ácidos/toxicidad , Apoptosis/efectos de los fármacos , Citoprotección/efectos de los fármacos , Leptina/farmacología , Placenta/citología , Estrés Fisiológico/efectos de los fármacos , Adulto , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/metabolismo , Femenino , Humanos , Concentración de Iones de Hidrógeno , Modelos Biológicos , Fosforilación/efectos de los fármacos , Embarazo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Trofoblastos/citología , Proteína p53 Supresora de Tumor/metabolismo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Leptin is now considered an important signalling molecule of the reproductive system, as it regulates the production of gonadotrophins, the blastocyst formation and implantation, the normal placentation, as well as the foeto-placental communication. Leptin is a peptide hormone secreted mainly by adipose tissue, and the placenta is the second leptin-producing tissue in humans. Placental leptin is an important cytokine which regulates placental functions in an autocrine or paracrine manner. Leptin seems to play a crucial role during the first stages of pregnancy as it modulates critical processes such as proliferation, protein synthesis, invasion and apoptosis in placental cells. Furthermore, deregulation of leptin levels has been correlated with the pathogenesis of various disorders associated with reproduction and gestation, including polycystic ovary syndrome, recurrent miscarriage, gestational diabetes mellitus, pre-eclampsia and intrauterine growth restriction. Due to the relevant incidence of the mentioned diseases and the importance of leptin, we decided to review the latest information available about leptin action in normal and pathological pregnancies to support the idea of leptin as an important factor and/or predictor of diverse disorders associated with reproduction and pregnancy.
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Leptina/metabolismo , Complicaciones del Embarazo/metabolismo , Tejido Adiposo/metabolismo , Femenino , Humanos , Factores Inmunológicos/metabolismo , Placenta/embriología , Placenta/metabolismo , Embarazo , ReproducciónRESUMEN
Leptin is a homeostatic regulator in the placenta where it promotes proliferation, protein synthesis and the expression of tolerogenic maternal response molecules such as HLA-G. Leptin also exerts an anti-apoptotic action in placenta controlling the expression of p53 master cell cycle regulator under different stress conditions. On the other hand, leptin is an integrative target of different placental stimuli. The expression of leptin in placenta is regulated by hCG, insulin, steroids, hypoxia and many other growth hormones, suggesting that it might have an important endocrine function in the trophoblastic cells. The leptin expression is induced involving the cAMP/PKA or cAMP/Epac pathways which have profound actions upon human trophoblast function. The activation of PI3K and MAPK pathways also participates in the leptin expression. Estrogens play a central role during pregnancy, particularly 17ß-estradiol upregulates the leptin expression in placental cells through genomic and non-genomic actions. The leptin promoter analysis reveals specific elements that are active in placental cells. The transcription factors CREB, AP1, Sp1, NFκB and the coactivator CBP are involved in the placental leptin expression. Moreover, placental leptin promoter is a target of epigenetic marks such as DNA methylation and histone acetylation that regulates not only the leptin expression in placenta during pregnancy but also determines the predisposition of acquiring adult metabolism diseases. Taken together, all these results allow a better understanding of leptin function and regulatory mechanisms of leptin expression in human placental trophoblasts, and support the importance of leptin during pregnancy and in programming adult health.
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Leptina/metabolismo , Placenta/fisiología , Animales , Femenino , Humanos , Placenta/citología , Embarazo , Transducción de SeñalRESUMEN
BACKGROUND: The use of a glucose challenge test as the universal screening for gestational diabetes is common in many countries. This test represents significant costs for laboratories and inconveniences for the patients, who have to wait for one hour and, very often, feel discomfort and nausea. In this work we propose the use of fasting glycemia, in a population with low prevalence of gestational diabetes as a pre-screening test that would avoid the oral glucose overload in those pregnant women with low risk of gestational diabetes. METHODS: The study was done with the fasting glucose levels of 6,573 pregnant women who underwent a two steps strategy to screen for gestational diabetes, a first step consisting of a 50 g glucose challenge test, followed when glycemia ≥ 140 mg/dL by a 100 g Oral Glucose Tolerance Test, based on recommendations made by National Diabetes Data Group. RESULTS: The ROC curve for fasting glucose was calculated, and we obtained an AUC = 0.633 (0.569 - 0.696). The sensitivity, specificity, and predictive values were established for different thresholds. CONCLUSIONS: We proposed that women with fasting glycemia ≤ 62 mg/dL, (S = 91.3%, NPV = 98.79% and LR- = 0.87) are in low risk of suffering gestational diabetes, which means that 10% of our population would not undergo the glucose challenge test.
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Glucemia/metabolismo , Diabetes Gestacional/sangre , Ayuno/sangre , Tamizaje Masivo/métodos , Adulto , Diabetes Gestacional/diagnóstico , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Embarazo , Curva ROC , Estudios RetrospectivosRESUMEN
Aquaporins are integral membrane proteins that have permeability functions in many tissues. Aquaporin 9 may transport not only water but also small molecules, such as glycerol, monocarboxylates, purines and pyrimidines. Aquaporin 9 is expressed in syncytiotrophoblast of human term placenta, and it may contribute to the embryonic/fetal growth and survival. We have previously found that Aquaporin 9 expression levels seem to be increased in placenta from gestational diabetes. Since leptin plasma levels and leptin expression are increased in placenta from gestational diabetes, we aimed to study the possible role of leptin on Aquaporin 9 expression in human placenta in vitro. The present work shows that leptin produces a dose-dependent increase of Aquaporin 9 expression, resulting in an increase in Aquaporin-9 protein in human trophoblast explants.