Interferon-β decreases LPS-induced neutrophil recruitment to cardiac fibroblasts

Introduction: Cardiac fibroblasts (CF) are crucial cells in damaged heart tissues, expressing TLR4, IFN-receptor and responding to lipopolysaccharide (LPS) and interferon-β (IFN-β) respectively. While CF interact with immune cells; however, their relationship with neutrophils remains understudied. Additionally, theimpact of LPS and IFN-β on CF-neutrophil interaction is poorly understood.Methods: Isolated CF from adult rats were treated with LPS, with or without IFN-β. This study examined IL-8 secretion, ICAM-1 and VCAM-1 expression, and neutrophil recruitment, as well as their effects on MMPs activity.Results: LPS triggered increased IL-8 expression and secretion, along with elevated ICAM-1 and VCAM-1 expression, all of which were blocked by TAK-242. Pre-treatment with IFN-β countered these LPS effects. LPS treated CF showed higher neutrophil recruitment (migration and adhesion) compared to unstimulated CF, an effect prevented by IFN-β. Ruxolitinib blocked these IFN-β anti-inflammatory effects, implicating JAK signaling. Analysis of culture medium zymograms from CF alone, and CF-neutrophils interaction, revealed that MMP2 was mainly originated from CF, while MMP9 could come from neutrophils. LPS and IFN-β boosted MMP2 secretion by CF. MMP9 activity in CF was low, and LPS or IFN-β had no significant impact. Pre-treating CF with LPS, IFN-β, or both before co-culture with neutrophils increased MMP2. Neutrophil co-culture increased MMP9 activity, with IFN-β pre-treatment reducing MMP9 compared to unstimulated CF.Conclusion: In CF, LPS induces the secretion of IL-8 favoring neutrophils recruitment and these effects were blocked by IFN-. The results highlight that CF-neutrophil interaction appears to influence the extracellular matrix through MMPs activity modulation

Resolvin E1 attenuates doxorubicin-induced cardiac fibroblast senescence: A key role for IL-1β

Cardiac fibroblasts (CFs) undergo senescence in reaction to different stressors, leading to a poor prognosis of cardiac disease. Doxorubicin (Doxo) is an antineoplastic drug with strong cardiotoxic effects, which induces IL-1β secretion and thus, triggers a potent pro-inflammatory response. Doxo induces CFs senescence; however, the mechanisms are not fully understood. Different pharmacological strategies have been used to eliminate senescent cells by inducing their apoptosis or modifying their secretome. However, Resolvin E1 (RvE1), a lipid derivative resolutive mediator with potent anti-inflammatory effects has not been used before to prevent CFs senescence. CFs were isolated from adult male C57BL/6J mice and subsequently stimulated with Doxo, in the presence or absence of RvE1. Senescence-associated β-galactosidase activity (SA-β-gal), γ-H2A.X, p53, p21, and senescence-associated secretory phenotype (SASP) were evaluated. The involvement of the NLRP3 inflammasome/interleukin-1 receptor (IL-1R) signaling pathway on CFs senescence was studied using an NLRP3 inhibitor (MCC950) and an endogenous IL-1R antagonist (IR1A). Doxo is able to trigger CFs senescence, as evidenced by an increase of γ-H2A.X, p53, p21, and SA-β-gal, and changes in the SASP profile. These Doxo effects were prevented by RvE1. Doxo triggers IL-1β secretion, which was dependent on NLRP3 activation. Doxo-induced CFs senescence was partially blocked by MCC950 and IR1A. In addition, IL-1β also triggered CFs senescence, as evidenced by the increase of γ-H2A.X, p53, p21, SA-β-gal activity, and SASP. All these effects were also prevented by RvE1 treatment. Conclusion: These data show the anti-senescent role of RvE1 in Doxo-induced CFs senescence, which could be mediated by reducing IL-1β secretion.This study was supported by PID2020-115590RB-100/AEI/ 10.13039/501100011033 and FONDECYT 1210627 to C.P., C.F.S.F., and G.D.A., respectively. L.S. and J.A.E.C. are the recipients of FPI Universidad Autonoma ´ de Madrid (SFPI/2020-00053) and Beca Doctorado Nacional Ano ˜ 2017 ANID (21170233) fellowships, respectivel

A resilience indicator for Eco-Industrial Parks

An Eco-Industrial Park (EIP) is a community of businesses that seeks to reduce the global impact by sharing material. The connections among the industrial participants within this park improve the environmental performance of the industrial network. However, the connectivity also propagates failures. This risk is an important point of criticism and a barrier to industrial plants when evaluate their integration to an EIP. This paper proposes an indicator to follow the resilience of an EIP so as to improve the security of the whole system, considering the dynamic of the participants to endure a disruptive event. This metric could be used by decision-makers in order to include the resilience in the design phase of an EIP. Solving these security problems would expand the set of experiences of cleaner production, facilitating the integration of industrial processes. The proposed resilience indicator is based on two main characteristics of an industrial network: the number of connections among participants, and the capacity of each flow to change its magnitude when a participant suddenly stops sharing flows within the park. A network is separated in independent layers to quantify its flexibility when substituting flows. Each layer includes a single shared material. The resilience of a multi-layer park is then calculated as a weighted summation. This indicator is applied over two illustrative cases to study: Kalundborg, in Denmark; and Ulsan, in South Korea. These applications show consistent results when compared with reality. Although the proposed resilience indicator has been developed for material networks, it can be adapted to heat integration networks. In this case, special attention should be payed to physical constraints as minimal temperature gradients

In vitro Characterization of Anti-SARS-CoV-2 Intravenous Immunoglobulins (IVIg) Produced From Plasma of Donors Immunized With the BNT162b2 Vaccine and Its Comparison With a Similar Formulation Produced From Plasma of COVID-19 Convalescent Donors

Despite vaccines are the main strategy to control the ongoing global COVID-19 pandemic, their effectiveness could not be enough for individuals with immunosuppression. In these cases, as well as in patients with moderate/severe COVID-19, passive immunization with anti-SARS-CoV-2 immunoglobulins could be a therapeutic alternative. We used caprylic acid precipitation to prepare a pilot-scale batch of anti-SARS-CoV-2 intravenous immunoglobulins (IVIg) from plasma of donors immunized with the BNT162b2 (Pfizer-BioNTech) anti-COVID-19 vaccine (VP-IVIg) and compared their in vitro efficacy and safety with those of a similar formulation produced from plasma of COVID-19 convalescent donors (CP-IVIg). Both formulations showed immunological, physicochemical, biochemical, and microbiological characteristics that meet the specifications of IVIg formulations. Moreover, the concentration of anti-RBD and ACE2-RBD neutralizing antibodies was higher in VP-IVIg than in CP-IVIg. In concordance, plaque reduction neutralization tests showed inhibitory concentrations of 0.03–0.09 g/L in VP-IVIg and of 0.06–0.13 in CP-IVIg. Thus, VP-IVIg has in vitro efficacy and safety profiles that justify their evaluation as therapeutic alternative for Rojas-Jiménez et al. Anti-SARS-CoV-2 IVIg clinical cases of COVID-19. Precipitation with caprylic acid could be a simple, feasible, and affordable alternative to produce formulations of anti-SARS-CoV-2 IVIg to be used therapeutically or prophylactically to confront the COVID-19 pandemic in middle and low-income countries.Universidad de Costa Rica/[741-C0-198]/UCR/Costa RicaBanco Centroamericano de Integración Económica/[DI- 87/2020]/BCIE/Costa RicaMinisterio de Ciencia, Innovación, Tecnología y Telecomunicaciones de Costa Rica/[FV-0001- 20]/MICITT/Costa RicaGerman academic exchange services/[57592642]/DAAD/AlemaniaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto Clodomiro Picado (ICP)UCR::Vicerrectoría de Docencia::Salud::Facultad de MicrobiologíaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Centro de Investigación en Enfermedades Tropicales (CIET

Mecanismos bioquímicos de acción de las endotelinas en la barrera hematoencefálica

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 7-7-199

Synthesis and biological evaluation of novel thiazolyl-coumarin derivatives as potent histone deacetylase inhibitors with antifibrotic activity

New histone deacetylases (HDAC) inhibitors with low toxicity to non-cancerous cells, are a prevalent issue at present because these enzymes are actively involved in fibrotic diseases. We designed and synthesized a novel series of thiazolyl-coumarins, substituted at position 6 (R = H, Br, OCH3), linked to classic zinc binding groups, such as hydroxamic and carboxylic acid moieties and alternative zinc binding groups such as disulfide and catechol. Their in vitro inhibitory activities against HDACs were evaluated. Disulfide and hydroxamic acid derivatives were the most potent ones. Assays with neonatal rat cardiac fibroblasts demonstrated low cytotoxic effects for all compounds. Regarding the parameters associated to cardiac fibrosis development, the compounds showed antiproliferative effects, and triggered a strong decrease on the expression levels of both α-SMA and procollagen I. In conclusion, the new thiazolyl-coumarin derivatives inhibit HDAC activity and decr

Antioxidant effects of 1,4-dihydropyridine and niitroso aryl derivatives on the Fe+3/ascorbate-stimulated lipid peroxidation in rat brain slices

Lipid peroxidation in rat brain slices was induced by Fe+3/ascorbate.Brain lipid peroxidation, as measured by malondialdehyde formation, was inhibited by all the tested nitro aryl 1,4-dihydropyridine derivatives over a wide range of concentrations. The time-course antioxidant effects of the most representative agents were assessed. On the basis of both time-course and IC50 experiments the tentative order of antioxidant activity on rat brain slices could be: nicardipine>nisoldipine>(R,S/S,R)-furnidipine>(R,R/S,S)-furnidipine>nitrendipine>nimodipine>nifedipine.1,4-Dihydropyridine derivatives that lack of a nitro group in the molecule (isradipine, amlodipine) also inhibited lipid peroxidation in rat brain slices but at higher concentrations than that of nitro-substituted derivatives.All the tested nitroso aryl derivatives [2,6-dimethyl-4-(2-nitrosophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester (NTP), nitrosotoluene, nitrosobenzene] were more potent inhibitors of lipid peroxidation

Role of FoxO3a as a negative regulator of the cardiac myofibroblast conversion induced by TGF-β1

Cardiac fibroblasts (CFs) are necessary to maintain extracellular matrix (ECM) homeostasis in the heart. Normally, CFs are quiescent and secrete small amounts of ECM components, whereas, in pathological conditions, they differentiate into more active cells called cardiac myofibroblasts (CMF). CMF conversion is characteristic of cardiac fibrotic diseases, such as heart failure and diabetic cardiomyopathy. TGF-beta 1 is a key protein involved in CMF conversion. SMADs are nuclear factor proteins activated by TGF-beta 1 that need other proteins, such as forkhead box type O (FoxO) family members, to promote CMF conversion. FoxO1, a member of this family protein, is necessary for TGF-beta 1-induced CMF conversion, whereas the role of FoxO3a, another FoxO family member, is unknown. FoxO3a plays an important role in many fibrotic processes in the kidney and lung. However, the participation of FoxO3a in the conversion of CFs into CMF is not clear. In this paper, we demonstrate that TGF-beta 1 decreases the activation and expression of FoxO3a in CFs. FoxO3a regulation by TGF-ss 1 requires activated SMAD3, ERK1/2 and Akt. Furthermore, we show that FoxO1 is crucial in the FoxO3a regulation induced by TGF-beta 1, as shown by overexpressed FoxO1 enhancing and silenced FoxO1 suppressing the effects of TGF-beta 1 on FoxO3a. Finally, the regulation of TGF-beta 1-induced CMF conversion was enhanced by FoxO3a silencing and suppressed by inhibited FoxO3a degradation. Considering these collective findings, we suggest that FoxO3a acts as a negative regulator of the CMF conversion that is induced by TGF-beta 1.Consejo Nacional de Ciencia y Tecnologia (CONACyT) Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT) FONDECYT 11160531 FONDECYT 11160281 FONDECYT 1170425 Vicerrectoria de Investigacion y Desarrollo, Universidad de Chile UI-15/1

Cardiac fibroblasts as sentinel cells in cardiac tissue: Receptors, signaling pathways and cellular functions

Artículo de publicación ISICardiac fibroblasts (CF) not only modulate extracellular matrix (ECM) proteins homeostasis, but also respond to chemical and mechanical signals. CF express a variety of receptors through which they modulate the proliferation/cell death, autophagy, adhesion, migration, turnover of ECM, expression of cytokines, chemokines, growth factors and differentiation into cardiac myofibroblasts (CMF). Differentiation of CF to CMF involves changes in the expression levels of various receptors, as well as, changes in cell phenotype and their associated functions. CF and CMF express the beta 2-adrenergic receptor, and its stimulation activates PKA and EPAC proteins, which differentially modulate the CF and CMF functions mentioned above. CF and CMF also express different levels of Angiotensin 11 receptors, in particular, AT1R activation increases collagen synthesis and cell proliferation, but its overexpression activates apoptosis. CF and CMF express different levels of B1 and B2 kinin receptors, whose stimulation by their respective agonists activates common signaling transduction pathways that decrease the synthesis and secretion of collagen through nitric oxide and prostacyclin I2 secretion. Besides these classical functions, CF can also participate in the inflammatory response of cardiac repair, through the expression of receptors commonly associated to immune cells such as Toll like receptor 4, NLRP3 and interferon receptor. The activation by their respective agonists modulates the cellular functions already described and the release of cytokines and chemokines. Thus, CF and CMF act as sentinel cells responding to a plethora of stimulus, modifying their own behavior, and that of neighboring cells. (c) 2015 Elsevier Ltd. All rights reserved