UCP2 deficiency helps to restrict the pathogenesis of experimental cutaneous and visceral leishmaniosis in mice

10 p.-4 fig.3 tab.BACKGROUND: Uncoupling protein 2 (UCP2) is a mitochondrial transporter that has been shown to lower the production of reactive oxygen species (ROS). Intracellular pathogens such as Leishmania upregulate UCP2 and thereby suppress ROS production in infected host tissues, allowing the multiplication of parasites within murine phagocytes. This makes host UCP2 and ROS production potential targets in the development of antileishmanial therapies. Here we explore how UCP2 affects the outcome of cutaneous leishmaniosis (CL) and visceral leishmaniosis (VL) in wild-type (WT) C57BL/6 mice and in C57BL/6 mice lacking the UCP2 gene (UCP2KO). METHODOLOGY AND FINDINGS: To investigate the effects of host UCP2 deficiency on Leishmania infection, we evaluated parasite loads and cytokine production in target organs. Parasite loads were significantly lower in infected UCP2KO mice than in infected WT mice. We also found that UCP2KO mice produced significantly more interferon-¿ (IFN-¿), IL-17 and IL-13 than WT mice (P<0.05), suggesting that UCP2KO mice are resistant to Leishmania infection. CONCLUSIONS: In this way, UCP2KO mice were better able than their WT counterparts to overcome L. major and L. infantum infections. These findings suggest that upregulating host ROS levels, perhaps by inhibiting UPC2, may be an effective approach to preventing leishmaniosis.This research was supported in part by grants AGL2010-17394, ISCIII PI09-01928 and Consolider-Ingenio 2010 (CSD2007-00020) from the Spanish Ministry of Education and Science (MEC). MMGB and JC were supported by a ‘‘Ramo´n y Cajal’’ contract and a ‘‘Juan de la Cierva’’ (JCI-2009-04069) contract,respectively, from the Ministry of Economy and Competitiveness (formerly MEC). Funding from the grant RICET RD 06/0021/0006 is also gratefully acknowledged.Peer reviewe

Influence of Pd/AC catalytic properties on the continuous production of hydrogen from formic acid

Formic acid (FA) is a promising liquid organic hydrogen carrier for safe and efficient hydrogen handling. FA dehydrogenation occurs under near-ambient conditions using palladium/activated carbon (Pd/AC) catalysts, but aspects like high Pd loading grand gradual catalyst deactivation remain key challenges. This study investigates how the physicochemical properties of Nanoparticles and support characteristics influence the continuous process performance including FA conversion, evolved gas flow rate, total hydrogen production, and catalyst durability. Pd catalysts were prepared via wet impregnation using various pre-cursors, powdered supports, and Pd loadings and evaluated in a fixed-bed reactor. The findings reveal that Pd/AC catalysts prepared with PdCl2 precursor and nano powdered AC are the most efficient. Strong electrostatic interactions between negatively charged PdCl42− species and the positively charged AC surface during impregnation enhance nanoparticle support interactions, resulting in small (∼2 nm), highly dispersed Pd nanoparticles with a high Pd2+/Pd 0 atomic surface ratio. Metal dispersion is the dominant factor influencing hydrogen production, surpassing the effects of both particle size and electronic state. Higher Pd loadings also increased catalyst durability, reducing regeneration frequency. This study provides valuable insights into the rational design of Pd/AC catalysts, paving the way for efficient FA utilization as a hydrogen carrierThe authors thank the financial support by the Government of Spain through the projects PID2021-125427OB-I00 and TED2021-130312B-I00 (MCIU/AEI/FEDER, UE). The authors thank the “Servicio Interdepartamental de Investigación” (Sidi) of the Universidad Autónoma de Madrid (UAM), and in particular Luis Larumbe from FTIR lab and Josué Friedrich from TXRF lab, the “Centro Nacional de Microscopía Electrónica” (ICTS-CNME) of the Universidad Complutense de Madrid (UCM), especially to Esteban Urones and the “Servicios Centrales de Apoyo a la Investigación”(SCAI), in particular María Dolores Marqués from Solidos Porosos La

Dysregulation of the EphrinB2−EphB4 ratio in pediatric cerebral arteriovenous malformations is associated with endothelial cell dysfunction in vitro and functions as a novel noninvasive biomarker in patients

We investigated (1) EphrinB2 and EphB4 receptor expression in cerebral AVMs, (2) the impact of an altered EphrinB2:EphB4 ratio on brain endothelial cell function and (3) potential translational applications of these data. The following parameters were compared between AVM endothelial cells (AVMECs) and human brain microvascular endothelial cells (HBMVECs): quantified EphrinB2 and EphB4 expression, angiogenic potential, and responses to manipulation of the EphrinB2:EphB4 ratio via pharmacologic stimulation/inhibition. To investigate the clinical relevance of these in vitro data, Ephrin expression was assessed in AVM tissue (by immunohistochemistry) and urine (by ELISA) from pediatric patients with AVM (n = 30), other cerebrovascular disease (n = 14) and control patients (n = 29), and the data were subjected to univariate and multivariate statistical analyses. Compared to HBMVECs, AVMECs demonstrated increased invasion (p = 0.04) and migration (p = 0.08), impaired tube formation (p = 0.06) and increased EphrinB2:EphB4 ratios. Altering the EphrinB2:EphB4 ratio (by increasing EphrinB2 or blocking EphB4) in HBMVECs increased invasion (p = 0.03 and p  25.7 pg/μg), AVMs were detected with high accuracy (80% vs. controls) and were distinguished from other cerebrovascular disease (75% accuracy). Post-treatment urinary EphrinB2 levels normalized in an index patient. In summary, AVMECs have an EphrinB2:EphB4 ratio that is increased compared to that of normal HBMVECs. Changing this ratio in HBMVECs induces AVMEC-like behavior. EphrinB2 is clinically relevant, and its levels are increased in AVM tissue and patient urine. This work suggests that dysregulation of the EphrinB2:EphB4 signaling cascade and increases in EphrinB2 may play a role in AVM development, with potential utility as a diagnostic and therapeutic target

Characterization of a third generation lentiviral vector pseudotyped with Nipah virus envelope proteins for endothelial cell transduction

Lentiviruses are becoming progressively more popular as gene therapy vectors due to their ability to integrate into quiescent cells and recent clinical trial successes. Directing these vectors to specific cell types and limiting off-target transduction in vivo remains a challenge. Replacing the viral envelope proteins responsible for cellular binding, or pseudotyping, remains a common method to improve lentiviral targeting. Here, we describe the development of a high titer, 3(rd) generation lentiviral vector pseudotyped with Nipah virus fusion protein (NiV-F) and attachment protein (NiV-G). Critical to high titers was truncation of the cytoplasmic domains of both NiV-F and NiV-G. As known targets of wild-type Nipah virus, primary endothelial cells are shown to be effectively transduced by the Nipah pseudotype. In contrast, human CD34+ hematopoietic progenitors were not significantly transduced. Additionally, the Nipah pseudotype has increased stability in human serum compared to VSV pseudotyped lentivirus. These findings suggest that the use of Nipah virus envelope proteins in 3(rd) generation lentiviral vectors would be a valuable tool for gene delivery targeted to endothelial cells

DNA damage-induced ephrin-B2 reverse signalling promotes chemoresistance and drives EMT in colorectal carcinoma harboring mutant p53

Mutation in the TP53 gene positively correlates with increased incidence of chemoresistance in different cancers. In this study, we investigated the mechanism of chemoresistance and epithelial-to-mesenchymal transition (EMT) in colorectal cancer involving the gain-of-function (GOF) mutant p53/ephrin-B2 signaling axis. Bioinformatic analysis of the NCI-60 data set and subsequent hub prediction identified EFNB2 as a possible GOF mutant p53 target gene, responsible for chemoresistance. We show that the mutant p53-NF-Y complex transcriptionally upregulates EFNB2 expression in response to DNA damage. Moreover, the acetylated form of mutant p53 protein is recruited on the EFNB2 promoter and positively regulates its expression in conjunction with coactivator p300. In vitro cell line and in vivo nude mice data show that EFNB2 silencing restores chemosensitivity in mutant p53-harboring tumors. In addition, we observed high expression of EFNB2 in patients having neoadjuvant non-responder colorectal carcinoma compared with those having responder version of the disease. In the course of deciphering the drug resistance mechanism, we also show that ephrin-B2 reverse signaling induces ABCG2 expression after drug treatment that involves JNK-c-Jun signaling in mutant p53 cells. Moreover, 5-fluorouracil-induced ephrin-B2 reverse signaling promotes tumorigenesis through the Src-ERK pathway, and drives EMT via the Src-FAK pathway. We thus conclude that targeting ephrin-B2 might enhance the therapeutic potential of DNA-damaging chemotherapeutic agents in mutant p53-bearing human tumor