Dysfunctional Immune Response in Acute-on-Chronic Liver Failure: It Takes Two to Tango

Acute-on-chronic liver failure (ACLF) is characterized by the acute decompensation of cirrhosis associated with organ failure and high short-term mortality. The key event in the pathogenesis is a dysfunctional immune response arising from exacerbation of the two main immunological alterations already present in cirrhosis: systemic inflammation and immune cell paralysis. High-grade systemic inflammation due to predominant activation and dysregulation of the innate immune response leads to the massive release of cytokines. Recognition of acutely increased pathogen and damage-associated molecular patterns by specific receptors underlies its pathogenesis and contributes to tissue damage and organ failure. In addition, an inappropriate compensatory anti-inflammatory response over the course of ACLF, along with the exhaustion and dysfunction of both the innate and adaptive immune systems, leads to functional immune cell paralysis. This entails a high risk of infection and contributes to a poor prognosis. Therapeutic approaches seeking to counteract the immune alterations present in ACLF are currently under investigation

Increased expression of cytokines, soluble cytokine receptors, soluble apoptosis ligand and apoptosis in dengue

AbstractSeveral studies have been performed to determine biomarkers that define the risk factors to developing severe forms of dengue. In this study, the levels of TNF-α, IL-6, IL-1, IL-17, soluble interleukin-1 receptor like 1 protein (sST2), soluble TNF-related apoptosis-inducing ligand (sTRAIL), IL-12 and soluble receptors for TNF (sTNF-RI and sTNF-RII) were determined by ELISA in dengue patients and monocyte/macrophage cultures. Dengue was classified as dengue without warning symptoms (DNWS), with warning symptoms (DWWS) and severe dengue (SD). High values of IL-6, sTNFRI, sTNFRII and sST2 were observed in DWWS and/or SD and IL-12 and sTRAIL in DNWS. TNF-α and IL-17 were increased not associated to the disease severity. High production of TNF-α, IL-1β, IL-12, IL-17, sST2 and sTRAIL and apoptosis expression were observed in dengue monocyte/macrophage cultures. This study shows that beneficial or deleterious biomarkers can be present in dengue regardless the disease severity and that monocytes may be in part the source of studied molecules

Histopathological study of JNK in venous wall of patients with chronic venous insufficiency related to osteogenesis process

Chronic venous insufficiency (CVI) is one of the most common vascular pathologies worldwide. One of the risk factors for the development of CVI is aging, which is why it is related to senile changes. The main trigger of the changes that occur in the venous walls in CVI is blood flow reflux, which produces increased hydrostatic pressure, leading to valve incompetence. The cellular response is one of the fundamental processes in vascular diseases, causing the activation of cell signalling pathways such as c-Jun N-terminal kinase (JNK). Metabolic changes and calcifications occur in vascular pathology as a result of pathophysiological processes. The aim of this study was to determine the expression of JNK in venous disease and its relationship with the role played by the molecules involved in the osteogenic processes in venous tissue calcification. This was a cross-sectional study that analyzed the greater saphenous vein wall in 110 patients with (R) and without venous reflux (NR), classified according to age. Histopathological techniques were used and protein expression was analysed using immunohistochemistry techniques for JNK and markers of osteogenesis (RUNX2, osteocalcin (OCN), osteopontin (OPN)). Significantly increased JNK, RUNX2, OCN, OPN and pigment epithelium-derived factor (PEDF) protein expression and the presence of osseous metaplasia and amorphous calcification were observed in younger patients (<50 years) with venous reflux. This study shows for the first time the existence of an osteogenesis process related to the expression of JNK in the venous wall.This study (FIS-PI18/00912) was supported by the Instituto de Salud Carlos III (Plan Estatal de I+D+i 2013-2016) and cofinanced by the European Development Regional Fund ‘‘A way to achieve Europe’’ (ERDF) and B2017/BMD-3804 MITIC-C

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

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

Monocyte populations as markers of response to adalimumab plus MTX in rheumatoid arthritis

INTRODUCTION: The treatment of rheumatoid arthritis (RA) patients with anti-tumor necrosis factor alpha (TNFα) biological drugs has dramatically improved the prognosis of these patients. However, a third of the treated patients do not respond to this therapy. Thus, the search for biomarkers of clinical response to these agents is currently highly active. Our aim is to analyze the number and distribution of circulating monocytes, and of their CD14(+high)CD16(-), CD14(+high)CD16(+ )and CD14(+low)CD16(+ )subsets in methotrexate (MTX) non-responder patients with RA, and to determine their value in predicting the clinical response to adalimumab plus MTX treatment. METHODS: This prospective work investigated the number of circulating monocytes, and of their CD14(+high)CD16(-), CD14(+high)CD16(+ )and CD14(+low)CD16(+ )subsets, in 35 MTX non-responder patients with RA before and after three and six months of anti-TNFα treatment using multiparametric flow cytometry. The number of circulating monocytes in an age- and sex-matched healthy population was monitored as a control. RESULTS: Non-responder patients with RA show an increased number of monocytes and of their CD14(+high)CD16(-), CD14(+high)CD16(+ )and CD14(+low)CD16(+ )subsets after three months of adalimumab plus MTX treatment that remained significantly increased at six months. In contrast, significant normalization of the numbers of circulating monocytes was found in responders at three months of adalimumab plus MTX treatment that lasts up to six months. CX3CR1 expression is increased in monocytes in non-responders. At three months of anti-TNFα treatment the number of circulating monocytes and their subsets was associated with at least 80% sensitivity, 84% specificity and an 86% positive predictive value (PPV) in terms of discriminating between eventual early responders and non-responders. CONCLUSIONS: The absolute number of circulating monocytes and of their CD14(+high)CD16(-), CD14(+high)CD16(+ )and CD14(+low)CD16(+ )subsets at three months of adalimumab plus MTX treatment, have a predictive value (with high specificity and sensitivity) in terms of the clinical response after six months of anti-TNFα treatment in patients with RA

Statins Inhibit HIV-1 Infection by Down-regulating Rho Activity

Human immunodeficiency virus (HIV)-1 infectivity requires actin-dependent clustering of host lipid raft–associated receptors, a process that might be linked to Rho guanosine triphosphatase (GTPase) activation. Rho GTPase activity can be negatively regulated by statins, a family of drugs used to treat hypercholesterolemia in man. Statins mediate inhibition of Rho GTPases by impeding prenylation of small G proteins through blockade of 3-hydroxy-3-methylglutaryl coenzyme A reductase. We show that statins decreased viral load and increased CD4+ cell counts in acute infection models and in chronically HIV-1–infected patients. Viral entry and exit was reduced in statin-treated cells, and inhibition was blocked by the addition of l-mevalonate or of geranylgeranylpyrophosphate, but not by cholesterol. Cell treatment with a geranylgeranyl transferase inhibitor, but not a farnesyl transferase inhibitor, specifically inhibited entry of HIV-1–pseudotyped viruses. Statins blocked Rho-A activation induced by HIV-1 binding to target cells, and expression of the dominant negative mutant RhoN19 inhibited HIV-1 envelope fusion with target cell membranes, reducing cell infection rates. We suggest that statins have direct anti–HIV-1 effects by targeting Rho

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