Newborns of Mothers with Venous Disease during Pregnancy Show Increased Levels of Lipid Peroxidation and Markers of Oxidative Stress and Hypoxia in the Umbilical Cord

The study (FIS-PI18/00912) was supported by the Instituto de Salud Carlos III (grant no. Estatal de I + D + I 2013–2016) and co-financed by the European Development Regional Fund “A way to achieve Europe” and B2017/BMD-3804 MITIC-CM (Comunidad de Madrid), and Halekulani S.L.Chronic venous disease (CVD) encompasses a set of disorders of the venous system that have a high prevalence in Western societies and are associated with significant sociohealth costs. Pregnancy is a period in which different hormonal and haemodynamic changes occur that lead to significant changes in the cardiovascular system, increasing the risk of developing venous problems, especially during the third trimester of gestation. In turn, CVD involves a series of local and systemic alterations that can have negative repercussions in pregnancy. In this context, the role of oxidative stress in the pathophysiology of this condition has been shown to significantly affect other vascular structures during pregnancy, such as the placenta. However, the effects of oxidative stress on the umbilical cord in women with CVD have not yet been fully elucidated. Thus, the objective of this study was to analyse the gene and protein expression of the enzymes NOX-1, NOX-2 and iNOS, which are involved in the production of reactive oxygen and nitrogen species, respectively. Similarly, the presence of hypoxia-inducible factor 1-alpha (HIF-1α) in the umbilical cord in women with CVD was compared to that of pregnant control women, and the levels of the lipid peroxidation marker malonyldialdehyde (MDA) in cord tissue and blood was also analysed. Our results support a significant increase in the enzymes NOX-1, NOX-2 and iNOS and HIF-1α and MDA in the umbilical cord tissue and blood of women with CVD. For the first time, our work demonstrates an increase in oxidative stress and cellular damage in the umbilical cords of pregnant women who develop this condition, deepening the understanding of the consequences of CVD during pregnancy.Depto. de Salud Pública y Materno - InfantilFac. de MedicinaTRUEUnión EuropeaComunidad de MadridInstituto de Salud Carlos IIIHalekulanipu

Understanding HAT1: A Comprehensive Review of Noncanonical Roles and Connection with Disease

Histone acetylation plays a vital role in organizing chromatin, regulating gene expression and controlling the cell cycle. The first histone acetyltransferase to be identified was histone acetyltransferase 1 (HAT1), but it remains one of the least understood acetyltransferases. HAT1 catalyzes the acetylation of newly synthesized H4 and, to a lesser extent, H2A in the cytoplasm. However, 20 min after assembly, histones lose acetylation marks. Moreover, new noncanonical functions have been described for HAT1, revealing its complexity and complicating the understanding of its functions. Recently discovered roles include facilitating the translocation of the H3H4 dimer into the nucleus, increasing the stability of the DNA replication fork, replication-coupled chromatin assembly, coordination of histone production, DNA damage repair, telomeric silencing, epigenetic regulation of nuclear lamina-associated heterochromatin, regulation of the NF-kappa B response, succinyl transferase activity and mitochondrial protein acetylation. In addition, the functions and expression levels of HAT1 have been linked to many diseases, such as many types of cancer, viral infections (hepatitis B virus, human immunodeficiency virus and viperin synthesis) and inflammatory diseases (chronic obstructive pulmonary disease, atherosclerosis and ischemic stroke). The collective data reveal that HAT1 is a promising therapeutic target, and novel therapeutic approaches, such as RNA interference and the use of aptamers, bisubstrate inhibitors and small-molecule inhibitors, are being evaluated at the preclinical level

Women with psychotic episodes during pregnancy show increased markers of placental damage with Tenney-Parker changes

y. Psychosis is a hazardous and functionally disruptive psychiatric condition which may affect women in pregnancy, entailing negative consequences for maternofetal well-being. The precise pathophysiological basis and consequences of a psychotic episode in pregnancy remain to be further elucidated. The placenta is a pivotal tissue with many functions in the gestational period, critically influencing the fate and development of pregnancy. Although detrimental alterations have been observed in women undergoing severe psychiatric disorders in pregnancy, there are little studies evaluating the consequences of suffering from a psychotic episode in the placental tissue In this work, we have evaluated the histopathological consequences of a first episode of psychosis in pregnancy (FE-PW; N=22) and compare them with healthy pregnant women (HC-PW; N=20) by using histological, immunohistochemical and gene expression techniques. Our results define that the placental tissue of FE-PW display an increase in the number of placental villi, bridges, syncytial knots and syncytial knots/villi. Besides, we have also observed an enhanced gene and protein expression in FE-PW of the hypoxic marker HIF-1α, together with the apoptotic markers BAX and Bcl-2. To our knowledge, this is the first study demonstrating significant histopathological changes in the placenta of women suffering a new-onset psychotic episode in pregnancy. Further studies should be aimed at deepening the knowledge about the pernicious effects of psychosis in the maternofetal tissues, as well as the potential implications of these alterations

The Use of Prebiotics from Pregnancy and Its Complications: Health for Mother and Offspring—A Narrative Review

Pregnancy involves a metabolic reprogramming that includes changes in the gut microbiota composition in women. Evidence shows that maternal dysbiosis is linked to neonatal dysbiosis, and this factor can determine health status in adulthood. Although there is little literature available on this topic, high heterogeneity is a limitation when examining nutritional interventions. Information has been gathered to contrast the benefits of prebiotic usage, specifically in pregnancy, in its possible complications and in newborns’ gut microbiota development. The objective pursued in this brief narrative review is to provide a clear summary of relevant content when searching with regard to the use of prebiotics in pregnancy, the effects in prenatal and postnatal periods, and to help in clinical decision-making in pregnancy management and lactation. A search has found that the nutritional status of the pregnant mother is key for the earliest microbial colonization in newborns, and thus intervention programs from pregnancy could assure better outcomes in both the mother and offspring. In this sense, prebiotics (administered to mothers who breastfeed or provided in formula milk) are feasible and cost-effective elements that can prevent allergies, colic, and other maladies in newborn

Reframing the link between metabolism and NLRP3 inflammasome: therapeutic opportunities

Inflammasomes are multiprotein signaling platforms in the cytosol that senses exogenous and endogenous danger signals and respond with the maturation and secretion of IL-1β and IL-18 and pyroptosis to induce inflammation and protect the host. The inflammasome best studied is the Nucleotide-binding oligomerization domain, leucine-rich repeat-containing family pyrin domain containing 3 (NLRP3) inflammasome. It is activated in a two-step process: the priming and the activation, leading to sensor NLRP3 oligomerization and recruitment of both adaptor ASC and executioner pro-caspase 1, which is activated by cleavage. Moreover, NLRP3 inflammasome activation is regulated by posttranslational modifications, including ubiquitination/deubiquitination, phosphorylation/dephosphorylation, acetylation/deacetylation, SUMOylation and nitrosylation, and interaction with NLPR3 protein binding partners. Moreover, the connection between it and metabolism is receiving increasing attention in this field. In this review, we present the structure, functions, activation, and regulation of NLRP3, with special emphasis on regulation by mitochondrial dysfunction-mtROS production and metabolic signals, i.e., metabolites as well as enzymes. By understanding the regulation of NLRP3 inflammasome activation, specific inhibitors can be rationally designed for the treatment and prevention of various immune- or metabolic-based diseases. Lastly, we review current NLRP3 inflammasome inhibitors and their mechanism of action

Chronic Venous Disease in Pregnant Women Causes an Increase in ILK in the Placental Villi Associated with a Decrease in E-Cadherin

Chronic venous disease (CVD) is a multifactorial vascular disorder frequently manifested in lower limbs in the form of varicose veins (VVs). Women are a vulnerable population for suffering from CVD, especially during pregnancy, when a plethora of changes occur in their cardiovascular system. Previous studies have indicated a worrisome association between CVD in pregnancy with the placental structure and function. Findings include an altered cellular behavior and extracellular matrix (ECM) composition. Integrin-linked kinase (ILK) is a critical molecule involved in multiple physiological and pathological conditions, and together with cadherins, is essential to mediate cell to ECM and cell to cell interplay, respectively. Thus, the aim of this study was to evaluate the implication of ILK and a set of cadherins (e-cadherin, cadherin-6 and cadherin-17) in placentas of women with CVD in order to unravel the possible pathophysiological role of these components. Gene expression (RT-qPCR) and protein expression (immunohistochemistry) studies were performed. Our results show a significant increase in the gene and protein expression of ILK, cadherin-6 and cadherin-17 and a decrease of e-cadherin in the placenta of women with CVD. Overall, this work shows that an abnormal expression of ILK, e-cadherin, cadherin-6 and cadherin-17 may be implicated in the pathological changes occurring in the placental tissue. Further studies should be conducted to determine the possible associations of these changes with maternal and fetal well-being

Estudio de la expresión de EGFL7 (Epidermal growth factor-like domain-containing protein 7) en la pared venosa de pacientes con enfermedad venosa crónica

La enfermedad venosa crónica (EVC) se trata de una amplia variedad de anomalías del sistema venoso de gran prevalencia en nuestra sociedad. Frecuentemente, se manifiesta en las extremidades inferiores en forma de vena varicosa (VV), cursando como una situación de hipertensión venosa ambulatoria que se agrava conforme progresa la enfermedad. Cada vez más estudios evidencian la importancia de los cambios moleculares y de la matriz extracelular en la fisiopatogenia de la EVC. EGFL-7 (Epidermal growth factor-like domain-containing protein 7) es un componente de gran importancia en el desarrollo y patología del sistema vascular, aunque su papel en la EVC todavía no ha sido esclarecido. Así, el objetivo del presente trabajo es analizar la expresión génica y proteica de EGFL7 en la pared venosa de pacientes con EVC (n=35) y sanos (n=27), mediante la realización de RT-qPCR e immunohistoquímica, respectivamente. Nuestros resultados muestran como existe una disminución en la expresión de EGFL-7 en pacientes con EVC en comparación con las venas de individuos sanos. En su conjunto, nuestro trabajo apoya el papel de EGFL7 en la pérdida de la homeostasis vascular asociada a la EVC. Futuros estudios son necesarios para profundizar en las implicaciones de estos cambios en el tejido venoso patológico, así como el desarrollo de posibles estrategias dirigidas a esta diana.Chronic venous disease (CVD) is a wide variety of anomalies of the venous system that are highly prevalent in our society. Frequently, it manifests in the lower extremities in the form of varicose veins(VV), presenting as a situation of ambulatory venous hypertension that worsens as the disease progresses. More and more studies show the importance of molecular changes and of the extracellular matrix in the pathophysiology of CVD. EGFL-7 (Epidermal growth factor-like domain-containing protein 7) is a component of great importance in the development and pathology of the vascular system, although its role in CVD has not yet been clarified. Thus, the objective of this study is to analyze the gene and proteinexpression of EGFL7 in the venous wall of patients with CVD (n=35) and healthy patients (n=27), by performing RT-qPCR and immunohistochemistry, respectively. Our results show how there is a decrease in the expression of EGFL-7 in patients with CVD compared to the veins of healthy individuals. As a whole, our work supports the role of EGFL7 in the loss of vascular homeostasis associated with CVD. Future studies are necessary to delve into the implications of these changes in the pathological venous tissue, as well as the development of possible strategies aimed at this target

An Updated Review of SARS-CoV-2 Vaccines and the Importance of Effective Vaccination Programs in Pandemic Times

first_pagesettingsOrder Article Reprints Open AccessReview An Updated Review of SARS-CoV-2 Vaccines and the Importance of Effective Vaccination Programs in Pandemic Times by Cielo García-Montero 1ORCID,Oscar Fraile-Martínez 1,Coral Bravo 2,3,4,Diego Torres-Carranza 5,Lara Sanchez-Trujillo 1,6ORCID,Ana M. Gómez-Lahoz 1,Luis G. Guijarro 7,Natalio García-Honduvilla 1,8,Angel Asúnsolo 8,9ORCID,Julia Bujan 1,8ORCID,Jorge Monserrat 1,8ORCID,Encarnación Serrano 10,Melchor Álvarez-Mon 1,8,11,Juan A De León-Luis 3,4,5,*ORCID,Miguel A. Álvarez-Mon 1,8,12ORCID andMiguel A. Ortega 1,8,13ORCID 1 Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain 2 Department of Public and Maternal and Child Health, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain 3 Department of Obstetrics and Gynecology, University Hospital Gregorio Marañón, 28009 Madrid, Spain 4 Health Research Institute Gregorio Marañón, 28009 Madrid, Spain 5 First of May Health Centre, Health Area I, Rivas Vaciamadrid, 28521 Madrid, Spain 6 Service of Pediatric, Hospital Universitario Principe de Asturias, 28801 Alcalá de Henares, Spain 7 Unit of Biochemistry and Molecular Biology (CIBEREHD), Department of System Biology, University of Alcalá, 28801 Alcalá de Henares, Spain 8 Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain 9 Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain 10 Los fresnos of Health Centre, Health Area III, Torrejon de Ardoz, 28850 Madrid, Spain add Show full affiliation list * Author to whom correspondence should be addressed. Vaccines 2021, 9(5), 433; https://doi.org/10.3390/vaccines9050433 Received: 9 April 2021 / Revised: 21 April 2021 / Accepted: 22 April 2021 / Published: 27 April 2021 (This article belongs to the Special Issue Unraveling SARS-CoV-2 Pathogenesis: Development of Vaccines and Therapeutics for COVID-19) Download Browse Figures Versions Notes Abstract Since the worldwide COVID-19 pandemic was declared a year ago, the search for vaccines has become the top priority in order to restore normalcy after 2.5 million deaths worldwide, overloaded sanitary systems, and a huge economic burden. Vaccine development has represented a step towards the desired herd immunity in a short period of time, owing to a high level of investment, the focus of researchers, and the urge for the authorization of the faster administration of vaccines. Nevertheless, this objective may only be achieved by pursuing effective strategies and policies in various countries worldwide. In the present review, some aspects involved in accomplishing a successful vaccination program are addressed, in addition to the importance of vaccination in a pandemic in the face of unwillingness, conspiracy theories, or a lack of information among the public. Moreover, we provide some updated points related to the landscape of the clinical development of vaccine candidates, specifically, the top five vaccines that are already being assessed in Phase IV clinical trials (BNT162b2, mRNA-1273, AZD1222, Ad26.COV2.S, and CoronaVac)

Patients with Invasive Lobular Carcinoma Show a Significant Increase in IRS-4 Expression Compared to Infiltrative Ductal Carcinoma—A Histopathological Study

Background and Objectives: Breast cancer (BC) is the first diagnosed type of cancer and the second leading cause of cancer-related mortality in women. In addition, despite the improvement in treatment and survival in these patients, the global prevalence and incidence of this cancer are rising, and its mortality may be different according to the histological subtype. Invasive lobular carcinoma (ILC) is less common but entails a poorer prognosis than infiltrative ductal carcinoma (IDC), exhibiting a different clinical and histopathological profile. Deepening study on the molecular profile of both types of cancer may be of great aid to understand the carcinogenesis and progression of BC. In this sense, the aim of the present study was to explore the histological expression of Insulin receptor substrate 4 (IRS-4), cyclooxygenase 2 (COX-2), Cyclin D1 and retinoblastoma protein 1 (Rb1) in patients with ILC and IDC. Patients and Methods: Thus, breast tissue samples from 45 patients with ILC and from 45 subjects with IDC were analyzed in our study. Results: Interestingly, we observed that IRS-4, COX-2, Rb1 and Cyclin D1 were overexpressed in patients with ILC in comparison to IDC. Conclusions: These results may indicate a differential molecular profile between both types of tumors, which may explain the clinical differences among ILC and IDC. Further studies are warranted in order to shed light onto the molecular and translational implications of these components, also aiding to develop a possible targeted therapy to improve the clinical management of these patients

Modification of the Polymer of a Bone Cement with Biodegradable Microspheres of PLGA and Loading with Daptomycin and Vancomycin Improve the Response to Bone Tissue Infection

Chronic infections are one of the most serious adverse outcomes of prosthetic surgery. Prosthetic revision surgery using a bone cement loaded with antibiotics between the two stages of the surgery is commonly performed. However, this method often fails to reach the minimum inhibitory concentration and promotes antibiotic resistance, thus emphasizing the need for improving the current available therapies. Materials and methods: In this study, we performed a study of the in vivo response of a polymer-based construct of poly (lactic-co-glycolic acid) (PLGA) in the solid phase of Palacos R® in combination with vancomycin, daptomycin, and/or linezolid. To test its effectiveness, we applied an in vivo model, using both histological and immunohistochemical analyses to study the bone tissue. Results: The presence of PLGA in the combination of vancomycin with daptomycin showed the most promising results regarding the preservation of bone cytoarchitecture and S. aureus elimination. Conversely, the combination of vancomycin plus linezolid was associated with a loss of bone cytoarchitecture, probably related to an increased macrophage response and inefficient antimicrobial activity. Conclusions: The modification of Palacos R® bone cement with PLGA microspheres and its doping with the antibiotic daptomycin in combination with vancomycin improve the tissue response to bone infection