Cigarette smoke induces pulmonary arterial dysfunction through an imbalance in the redox status of the soluble guanylyl cyclase

Chronic obstructive pulmonary disease (COPD), whose main risk factor is cigarette smoking (CS), is one of the most common diseases globally. Some COPD patients also develop pulmonary hypertension (PH), a severe complication that leads to premature death. Evidence suggests reactive oxygen species (ROS) involvement in COPD and PH, especially regarding pulmonary artery smooth muscle cells (PASMC) dysfunction. However, the effects of CS-driven oxidative stress on the pulmonary vasculature are not completely understood. Herein we provide evidence on the effects of CS extract (CSE) exposure on PASMC regarding ROS production, antioxidant response and its consequences on vascular tone dysregulation. Our results indicate that CSE exposure promotes mitochondrial fission, mitochondrial membrane depolarization and increased mitochondrial superoxide levels. However, this superoxide increase did not parallel a counterbalancing antioxidant response in human pulmonary artery (PA) cells. Interestingly, the mitochondrial superoxide scavenger mitoTEMPO reduced mitochondrial fission and membrane potential depolarization caused by CSE. As we have previously shown, CSE reduces PA vasoconstriction and vasodilation. In this respect, mitoTEMPO prevented the impaired nitric oxide-mediated vasodilation, while vasoconstriction remained reduced. Finally, we observed a CSE-driven downregulation of the Cyb5R3 enzyme, which prevents soluble guanylyl cyclase oxidation in PASMC. This might explain the CSE-mediated decrease in PA vasodilation. These results provide evidence that there might be a connection between mitochondrial ROS and altered vasodilation responses in PH secondary to COPD, and strongly support the potential of antioxidant strategies specifically targeting mitochondria as a new therapy for these diseasesThe Spanish Ministerio de Ciencia e Innovacion, ´ Programa Retos en Investigacion ´ (grant number PID2019-104406RB-100) to MJC provided the financial support for the conduct of the research included in this manuscript. Garantia Juvenil program from Comunidad de Madrid contributed with the research assistant contract to M-R,

From full-scale biofilters to bioreactors: Engineering biological metaldehyde removal

Polar, low molecular weight pesticides such as metaldehyde are challenging and costly to remove from drinking water using conventional treatment methods. Although biological treatments can be effective at treating micropollutants, through biodegradation and sorption processes, only some operational biofilters have shown the ability to remove metaldehyde. As sorption plays a minor role for such polar organic micropollutants, biodegradation is therefore likely to be the main removal pathway. In this work, the biodegradation of metaldehyde was monitored, and assessed, in an operational slow sand filter. Long-term data showed that metaldehyde degradation improved when inlet concentrations increased. A comparison of inactive and active sand batch reactors showed that metaldehyde removal happened mainly through biodegradation and that the removal rates were greater after the biofilm was acclimated through exposure to high metaldehyde concentrations. This suggested that metaldehyde removal was reliant on enrichment and that the process could be engineered to decrease treatment times (from days to hours). Through-flow experiments using fluidised bed reactors, showed the same behaviour following metaldehyde acclimation. A 40% increase in metaldehyde removal was observed in acclimated compared with non-acclimated columns. This increase was sustained for >40 days, achieving an average of 80% removal and compliance (−1) for >20 days. An initial microbial analysis of the acclimated and non-acclimated biofilm from the same filter materials, showed that the microbial community in acclimated sand was significantly different. This work presents a novel conceptual template for a faster, chemical free, low cost, biological treatment of metaldehyde and other polar pollutants in drinking water. In addition, this is the first study to report kinetics of metaldehyde degradation in an active microbial biofilm at a WTW

Drug-clay nanohybrids as sustained delivery systems

Biocompatible 2-dimensional layered compounds such as clays and layered double hydroxides (anionic clays) have been explored and utilized in drug delivery system for therapeutic application because they can safely encapsulate drug molecules via intercalation reaction. Therefore, various kinds of drug molecules and bio-functional molecules with cationic or anionic charge have been incorporated into clay delivery carriers, giving rise to the heterostructured layered nanohybrids with chemo-therapeutic and gene-therapeutic functions. Recently, such inorganic delivery systems have received growing attention because their inertness and low toxicity gives rise to safety and stability in bio-systems. Furthermore, the hybridization of drug with clays offers the fascinating features such as controlled and sustained release, improved water-solubility, and even protective and targeted delivery. Unique release behaviors of drugs from the drug clay nanohybrids are originated from molecular level incorporation, and strong interaction between drug and inorganic layers including electrostatic and hydrogen bonding interactions. In the present review, various drug clay nanohybrids will be introduced, and their recent development will be highlighted in the viewpoint of oral administration drugs with controlled and sustained release.This work was supported by the National Research Foundation of Korea (NRF) grant, funded by the Korea Government (MSIP) ( 2005-0049412 and 2013R1A1A2062239 ).Scopu

Downregulation of thioredoxin-1-dependent CD95 S-nitrosation by Sorafenib reduces liver cáncer

Hepatocellular carcinoma (HCC) represents 80% of the primary hepatic neoplasms. It is the sixth most frequent neoplasm, the fourth cause of cancer-related death, and 7% of registered malignancies. Sorafenib is the first line molecular targeted therapy for patients in advanced stage of HCC. The present study shows that Sorafenib exerts free radical scavenging properties associated with the downregulation of nuclear factor E2-related factor 2 (Nrf2)-regulated thioredoxin 1 (Trx1) expression in liver cancer cells. The experimental downregulation and/or overexpression strategies showed that Trx1 induced activation of nitric oxide synthase (NOS) type 3 (NOS3) and S-nitrosation (SNO) of CD95 receptor leading to an increase of caspase-8 activity and cell proliferation, as well as reduction of caspase-3 activity in liver cancer cells. In addition, Sorafenib transiently increased mRNA expression and activity of S-nitrosoglutathione reductase (GSNOR) in HepG2 cells. Different experimental models of hepatocarcinogenesis based on the subcutaneous implantation of HepG2 cells in nude mice, as well as the induction of HCC by diethylnitrosamine (DEN) confirmed the relevance of Trx1 downregulation during the proapoptotic and antiproliferative properties induced by Sorafenib. In conclusion, the induction of apoptosis and antiproliferative properties by Sorafenib were related to Trx1 downregulation that appeared to play a relevant role on SNO of NOS3 and CD95 in HepG2 cells. The transient increase of GSNOR might also participate in the deactivation of CD95-dependent proliferative signaling in liver cancer cells

Downregulation of thioredoxin-1-dependent CD95 S-nitrosation by Sorafenib reduces liver cancer

Hepatocellular carcinoma (HCC) represents 80% of the primary hepatic neoplasms. It is the sixth most frequent neoplasm, the fourth cause of cancer-related death, and 7% of registered malignancies. Sorafenib is the first line molecular targeted therapy for patients in advanced stage of HCC. The present study shows that Sorafenib exerts free radical scavenging properties associated with the downregulation of nuclear factor E2-related factor 2 (Nrf2)-regulated thioredoxin 1 (Trx1) expression in liver cancer cells. The experimental downregulation and/or overexpression strategies showed that Trx1 induced activation of nitric oxide synthase (NOS) type 3 (NOS3) and S-nitrosation (SNO) of CD95 receptor leading to an increase of caspase-8 activity and cell proliferation, as well as reduction of caspase-3 activity in liver cancer cells. In addition, Sorafenib transiently increased mRNA expression and activity of S-nitrosoglutathione reductase (GSNOR) in HepG2 cells. Different experimental models of hepatocarcinogenesis based on the subcutaneous implantation of HepG2 cells in nude mice, as well as the induction of HCC by diethylnitrosamine (DEN) confirmed the relevance of Trx1 downregulation during the proapoptotic and antiproliferative properties induced by Sorafenib. In conclusion, the induction of apoptosis and antiproliferative properties by Sorafenib were related to Trx1 downregulation that appeared to play a relevant role on SNO of NOS3 and CD95 in HepG2 cells. The transient increase of GSNOR might also participate in the deactivation of CD95-dependent proliferative signaling in liver cancer cells.This study was funded by Institute of Health Carlos III (ISCIII) (PI13/00021, PI15/00107, PI16/00090 and PI19/01266), Spanish Ministry of Economy and Competitiveness (SAF2015-71208-R, BFU2016-8006-P, PGC2018-094276-B-I00 and RED2018-102576-T), Andalusian Ministry of Economy, Innovation, Science and Employment (BIO-216 and CTS-6264) and Andalusian Ministry of Equality, Health and Social Policies (PI-00025-2013 and PI-0198-2016). P de la C–O was supported by FPU predoctoral fellowship (FPU17/00026) from Ministry of Education, Culture and Sports. We thank the Biomedical Research Network Center for Cardiovascular Diseases (CIBERCV), and the Biomedical Research Network Center for Liver and Digestive Diseases (CIBERehd) founded by the ISCIII and co-financed by European Development Regional Fund “A way to achieve Europe” ERDF for their financial support.Ye

Downregulation of thioredoxin-1-dependent CD95 S-nitrosation by Sorafenib reduces liver cancer

Hepatocellular carcinoma (HCC) represents 80% of the primary hepatic neoplasms. It is the sixth most frequent neoplasm, the fourth cause of cancer-related death, and 7% of registered malignancies. Sorafenib is the first line molecular targeted therapy for patients in advanced stage of HCC. The present study shows that Sorafenib exerts free radical scavenging properties associated with the downregulation of nuclear factor E2-related factor 2 (Nrf2)-regulated thioredoxin 1 (Trx1) expression in liver cancer cells. The experimental downregulation and/or overexpression strategies showed that Trx1 induced activation of nitric oxide synthase (NOS) type 3 (NOS3) and S-nitrosation (SNO) of CD95 receptor leading to an increase of caspase-8 activity and cell proliferation, as well as reduction of caspase-3 activity in liver cancer cells. In addition, Sorafenib transiently increased mRNA expression and activity of S-nitrosoglutathione reductase (GSNOR) in HepG2 cells. Different experimental models of hepatocarcinogenesis based on the subcutaneous implantation of HepG2 cells in nude mice, as well as the induction of HCC by diethylnitrosamine (DEN) confirmed the relevance of Trx1 downregulation during the proapoptotic and antiproliferative properties induced by Sorafenib. In conclusion, the induction of apoptosis and antiproliferative properties by Sorafenib were related to Trx1 downregulation that appeared to play a relevant role on SNO of NOS3 and CD95 in HepG2 cells. The transient increase of GSNOR might also participate in the deactivation of CD95-dependent proliferative signaling in liver cancer cells.This study was funded by Institute of Health Carlos III (ISCIII) (PI13/00021, PI15/00107, PI16/00090 and PI19/01266), Spanish Ministry of Economy and Competitiveness (SAF2015-71208-R, BFU2016-8006-P, PGC2018-094276-B-I00 and RED2018-102576-T), Andalusian Ministry of Economy, Innovation, Science and Employment (BIO-216 and CTS-6264) and Andalusian Ministry of Equality, Health and Social Policies (PI-00025-2013 and PI-0198-2016). P de la C–O was supported by FPU predoctoral fellowship (FPU17/00026) from Ministry of Education, Culture and Sports. We thank the Biomedical Research Network Center for Cardiovascular Diseases (CIBERCV), and the Biomedical Research Network Center for Liver and Digestive Diseases (CIBERehd) founded by the ISCIII and co-financed by European Development Regional Fund “A way to achieve Europe” ERDF for their financial support

Na+ controls hypoxic signalling by the mitochondrial respiratory chain

All metazoans depend on O2 delivery and consumption by the mitochondrial oxidative phosphorylation (OXPHOS) system to produce energy. A decrease in O2 availability (hypoxia) leads to profound metabolic rewiring. In addition, OXPHOS uses O2 to produce reactive oxygen species (ROS) that can drive cell adaptations through redox signalling, but also trigger cell damage1–4, and both phenomena occur in hypoxia4–8. However, the precise mechanism by which acute hypoxia triggers mitochondrial ROS production is still unknown. Ca2+ is one of the best known examples of an ion acting as a second messenger9, yet the role ascribed to Na+ is to serve as a mere mediator of membrane potential and collaborating in ion transport10. Here we show that Na+ acts as a second messenger regulating OXPHOS function and ROS production by modulating fluidity of the inner mitochondrial membrane (IMM). We found that a conformational shift in mitochondrial complex I during acute hypoxia11 drives the acidification of the matrix and solubilization of calcium phosphate precipitates. The concomitant increase in matrix free-Ca2+ activates the mitochondrial Na+/Ca2+ exchanger (NCLX), which imports Na+ into the matrix. Na+ interacts with phospholipids reducing IMM fluidity and mobility of free ubiquinone between complex II and complex III, but not inside supercomplexes. As a consequence, superoxide is produced at complex III, generating a redox signal. Inhibition of mitochondrial Na+ import through NCLX is sufficient to block this pathway, preventing adaptation to hypoxia. These results reveal that Na+ import into the mitochondrial matrix controls OXPHOS function and redox signalling through an unexpected interaction with phospholipids, with profound consequences in cellular metabolism