Cardioprotective effect of the mitochondrial unfolded protein response during chronic pressure overload

Background The mitochondrial unfolded protein response (UPRmt) is activated when misfolded proteins accumulate within mitochondria and leads to increased expression of mitochondrial chaperones and proteases to maintain protein quality and mitochondrial function. Cardiac mitochondria are essential for contractile function and regulation of cell viability, while mitochondrial dysfunction characterizes heart failure. The role of the UPRmt in the heart is unclear. Objectives The purpose of this study was to: 1) identify conditions that activate the UPRmt in the heart; and 2) study the relationship among the UPRmt, mitochondrial function, and cardiac contractile function. Methods Cultured cardiac myocytes were subjected to different stresses in vitro. Mice were subjected to chronic pressure overload. Tissues and blood biomarkers were studied in patients with aortic stenosis. Results Diverse neurohumoral or mitochondrial stresses transiently induced the UPRmt in cultured cardiomyocytes. The UPRmt was also induced in the hearts of mice subjected to chronic hemodynamic overload. Boosting the UPRmt with nicotinamide riboside (which augments NAD+ pools) in cardiomyocytes in vitro or hearts in vivo significantly mitigated the reductions in mitochondrial oxygen consumption induced by these stresses. In mice subjected to pressure overload, nicotinamide riboside reduced cardiomyocyte death and contractile dysfunction. Myocardial tissue from patients with aortic stenosis also showed evidence of UPRmt activation, which correlated with reduced tissue cardiomyocyte death and fibrosis and lower plasma levels of biomarkers of cardiac damage (high-sensitivity troponin T) and dysfunction (N-terminal pro–B-type natriuretic peptide). Conclusions These results identify the induction of the UPRmt in the mammalian (including human) heart exposed to pathological stresses. Enhancement of the UPRmt ameliorates mitochondrial and contractile dysfunction, suggesting that it may serve an important protective role in the stressed heart

Targets, mechanisms and cytotoxicity of half-sandwich Ir(III) complexes are modulated by structural modifications on the benzazole ancillary ligand

Cancers are driven by multiple genetic mutations but evolve to evade treatments targeting specific mutations. Nonetheless, cancers cannot evade a treatment that targets mitochondria, which are essential for tumor progression. Iridium complexes have shown anticancer properties, but they lack specificity for their intracellular targets, leading to undesirable side effects. Herein we present a systematic study on structure-activity relationships of eight arylbenzazole-based Iridium(III) complexes of type [IrCl(Cp*)], that have revealed the role of each atom of the ancillary ligand in the physical chemistry properties, cytotoxicity and mechanism of biological action. Neutral complexes, especially those bearing phenylbenzimidazole (HL1 and HL2), restrict the binding to DNA and albumin. One of them, complex 1[C,NH-Cl], is the most selective one, does not bind DNA, targets exclusively the mitochondria, disturbs the mitochondria membrane permeability inducing proton leak and increases ROS levels, triggering the molecular machinery of regulated cell death. In mice with orthotopic lung tumors, the administration of complex 1[C,NH-Cl] reduced the tumor burden. Cancers are more vulnerable than normal tissues to a treatment that harnesses mitochondrial dysfunction. Thus, complex 1[C,NH-Cl] characterization opens the way to the development of new compounds to exploit this vulnerability

Atlas de las praderas marinas de España

Knowledge of the distribution and extent of seagrass habitats is currently the basis of management and conservation policies of the coastal zones in most European countries. This basic information is being requested through European directives for the establishment of monitoring programmes and the implementation of specific actions to preserve the marine environment. In addition, this information is crucial for the quantification of the ecological importance usually attributed to seagrass habitats due to, for instance, their involvement in biogeochemical cycles, marine biodiversity and quality of coastal waters or global carbon budgets. The seagrass atlas of Spain represents a huge collective effort performed by 84 authors across 30 Spanish institutions largely involved in the scientific research, management and conservation of seagrass habitats during the last three decades. They have contributed to the availability of the most precise and realistic seagrass maps for each region of the Spanish coast which have been integrated in a GIS to obtain the distribution and area of each seagrass species. Most of this information has independently originated at a regional level by regional governments, universities and public research organisations, which explain the elevated heterogeneity in criteria, scales, methods and objectives of the available information. On this basis, seagrass habitats in Spain occupy a total surface of 1,541,63 km2, 89% of which is concentrated in the Mediterranean regions; the rest is present in sheltered estuarine areas of the Atlantic peninsular regions and in the open coastal waters of the Canary Islands, which represents 50% of the Atlantic meadows. Of this surface, 71.5% corresponds to Posidonia oceanica, 19.5% to Cymodocea nodosa, 3.1% to Zostera noltii (=Nanozostera noltii), 0.3% to Zostera marina and 1.2% to Halophila decipiens. Species distribution maps are presented (including Ruppia spp.), together with maps of the main impacts and pressures that has affected or threatened their conservation status, as well as the management tools established for their protection and conservation. Despite this considerable effort, and the fact that Spain has mapped wide shelf areas, the information available is still incomplete and with weak precision in many regions, which will require an investment of major effort in the near future to complete the whole picture and respond to demands of EU directives.Versión del edito

The MEST score provides earlier risk prediction in lgA nephropathy

Item does not contain fulltextThe Oxford Classification of IgA nephropathy (IgAN) includes the following four histologic components: mesangial (M) and endocapillary (E) hypercellularity, segmental sclerosis (S) and interstitial fibrosis/tubular atrophy (T). These combine to form the MEST score and are independently associated with renal outcome. Current prediction and risk stratification in IgAN requires clinical data over 2 years of follow-up. Using modern prediction tools, we examined whether combining MEST with cross-sectional clinical data at biopsy provides earlier risk prediction in IgAN than current best methods that use 2 years of follow-up data. We used a cohort of 901 adults with IgAN from the Oxford derivation and North American validation studies and the VALIGA study followed for a median of 5.6 years to analyze the primary outcome (50% decrease in eGFR or ESRD) using Cox regression models. Covariates of clinical data at biopsy (eGFR, proteinuria, MAP) with or without MEST, and then 2-year clinical data alone (2-year average of proteinuria/MAP, eGFR at biopsy) were considered. There was significant improvement in prediction by adding MEST to clinical data at biopsy. The combination predicted the outcome as well as the 2-year clinical data alone, with comparable calibration curves. This effect did not change in subgroups treated or not with RAS blockade or immunosuppression. Thus, combining the MEST score with cross-sectional clinical data at biopsy provides earlier risk prediction in IgAN than our current best methods

The MEST score provides earlier risk prediction in IgA nephropathy

The Oxford Classification of IgA nephropathy (IgAN) includes the following four histologic components: mesangial (M) and endocapillary (E) hypercellularity, segmental sclerosis (S) and interstitial fibrosis/tubular atrophy (T). These combine to form the MEST score and are independently associated with renal outcome. Current prediction and risk stratification in IgAN requires clinical data over 2 years of follow-up. Using modern prediction tools, we examined whether combining MEST with cross-sectional clinical data at biopsy provides earlier risk prediction in IgAN than current best methods that use 2 years of follow-up data. We used a cohort of 901 adults with IgAN from the Oxford derivation and North American validation studies and the VALIGA study followed for a median of 5.6 years to analyze the primary outcome (50% decrease in eGFR or ESRD) using Cox regression models. Covariates of clinical data at biopsy (eGFR, proteinuria, MAP) with or without MEST, and then 2-year clinical data alone (2-year average of proteinuria/MAP, eGFR at biopsy) were considered. There was significant improvement in prediction by adding MEST to clinical data at biopsy. The combination predicted the outcome as well as the 2-year clinical data alone, with comparable calibration curves. This effect did not change in subgroups treated or not with RAS blockade or immunosuppression. Thus, combining the MEST score with cross-sectional clinical data at biopsy provides earlier risk prediction in IgAN than our current best methods

Recombinant <i>Fasciola hepatica</i> fatty acid binding protein (Fh15) as a novel anti-inflammatory biotherapeutic in an acute gram-negative non-human primate sepsis model

AbstractDue to their phylogenetic proximity to human, non-human primates (NHP) are considered an adequate choice for basic and pre-clinical model of sepsis. Gram-negative bacteria are the primary causative of sepsis. During infection bacteria continuously release the potent toxin lipopolysaccharide (LPS) into the bloodstream, which triggers an uncontrolled systemic inflammatory response leading to death. Our previous research has demonstrated in vitro and in vivo using a mouse model of septic shock that Fh15, a recombinant variant of the Fasciola hepatica fatty acid binding protein, acts as an antagonist of TLR4 suppressing the LPS-induced pro-inflammatory cytokine storm. The present study aimed to demonstrate that Fh15 suppress the cytokine storm and other inflammatory markers during the early phase of an endotoxemia induced in rhesus macaques by i.v. infusion with lethal doses of live E. coli. Fh15 was administrated as isotonic infusion 30 min prior to the bacterial infusion. Among the novel findings reported in this communication, I) Fh15 significantly prevented bacteremia, suppressed LPS levels in plasma and the production of C-reactive protein and procalcitonin, which are key signature of inflammation and bacterial infection, respectively, II) notably reduced the production of pro-inflammatory cytokines, and III) increased innate immune cell populations in blood, which suggest a role in promoting a prolonged steady state in rhesus macaques even in the presence of inflammatory stimuli. This is the first report demonstrating that a F. hepatica-derived molecule possesses potential as anti-inflammatory drug against endotoxemia in an NHP-model.TweetThis is the first communication demonstrating that a F. hepatica-derived molecule possesses potential as anti-inflammatory drug against endotoxemia in an NHP-model.ImportanceSepsis caused by Gram-negative bacteria affect 1.7 million adults annually in the United States and is one of the most important causes of death at intensive care units. Although the effective use of antibiotics has resulted in improved prognosis of sepsis, the pathological and deathly effects has been attributed to the persistent inflammatory cascade. There is a present need to develop anti-inflammatory agents that can suppress or neutralize the inflammatory responses and prevent the lethal consequences of sepsis. We demonstrated herein that a small molecule of 14.5kDa can suppress the bacteremia, endotoxemia and many other inflammatory markers in a rhesus macaque model. These results reinforce the notion that Fh15 constitute an excellent candidate for drug development against sepsis.</jats:sec