Cardioprotective medications are still unmet clinical needs. We have previously identified several cardioprotective microRNAs (termed ProtectomiRs), the mRNA targets of which may reveal new drug ...targets for cardioprotection. Here we aimed to identify key molecular targets of ProtectomiRs and confirm their association with cardioprotection in a translational pig model of acute myocardial infarction (AMI). By using a network theoretical approach, we identified 882 potential target genes of 18 previously identified protectomiRs. The Rictor gene was the most central and it was ranked first in the protectomiR-target mRNA molecular network with the highest node degree of 5. Therefore, Rictor and its targeting microRNAs were further validated in heart samples obtained from a translational pig model of AMI and cardioprotection induced by pre- or postconditioning. Three out of five Rictor-targeting pig homologue of rat ProtectomiRs showed significant upregulation in postconditioned but not in preconditioned pig hearts. Rictor was downregulated at the mRNA and protein level in ischemic postconditioning but not in ischemic preconditioning. This is the first demonstration that Rictor is the central molecular target of ProtectomiRs and that decreased Rictor expression may regulate ischemic postconditioning-, but not preconditioning-induced acute cardioprotection. We conclude that Rictor is a potential novel drug target for acute cardioprotection.
The macrophage is a major phagocytic cell type, and its impaired function is a primary cause of immune paralysis, organ injury, and death in sepsis. An incomplete understanding of the endogenous ...molecules that regulate macrophage bactericidal activity is a major barrier for developing effective therapies for sepsis. Using an in vitro killing assay, we report here that the endogenous purine ATP augments the killing of sepsis-causing bacteria by macrophages through P2X4 receptors (P2X4Rs). Using newly developed transgenic mice expressing a bioluminescent ATP probe on the cell surface, we found that extracellular ATP levels increase during sepsis, indicating that ATP may contribute to bacterial killing in vivo. Studies with P2X4R-deficient mice subjected to sepsis confirm the role of extracellular ATP acting on P2X4Rs in killing bacteria and protecting against organ injury and death. Results with adoptive transfer of macrophages, myeloid-specific P2X4R-deficient mice, and P2rx4 tdTomato reporter mice indicate that macrophages are essential for the antibacterial, antiinflammatory, and organ protective effects of P2X4Rs in sepsis. Pharmacological targeting of P2X4Rs with the allosteric activator ivermectin protects against bacterial dissemination and mortality in sepsis. We propose that P2X4Rs represent a promising target for drug development to control bacterial growth in sepsis and other infections.
Hepatorenal syndrome (HRS) is a life-threatening complication of end-stage liver disease characterized by the rapid decline of kidney function. Herein, we explored the therapeutic potential of ...targeting the cannabinoid-2 receptor (CB2-R) utilizing a commonly used mouse model of liver fibrosis and hepatorenal syndrome (HRS), induced by bile duct ligation (BDL).
Gene expression analysis, histological evaluation, determination of serum levels of renal injury-biomarkers were used to characterize the BDL-induced organ injury; laser speckle analysis to measure microcirculation in the kidneys.
We found that liver injury triggered marked inflammation and oxidative stress in the kidneys of BDL-operated mice. We detected pronounced histopathological alterations with tubular injury paralleled with increased inflammation, oxidative/nitrative stress and fibrotic remodeling both in hepatic and renal tissues as well as endothelial activation and markedly impaired renal microcirculation. This was accompanied by increased CB2-R expression in both the liver and the kidney tissues of diseased animals. A selective CB2-R agonist, HU-910, markedly decreased numerous markers of inflammation, oxidative stress and fibrosis both in the liver and in the kidneys. HU-910 also attenuated markers of kidney injury and improved the impaired renal microcirculation in BDL-operated mice.
Our results suggest that oxidative stress, inflammation and microvascular dysfunction are key events in the pathogenesis of BDL-associated renal failure. Furthermore, we demonstrate that targeting the CB2-R by selective agonists may represent a promising new avenue to treat HRS by attenuating tissue and vascular inflammation, oxidative stress, fibrosis and consequent microcirculatory dysfunction in the kidneys.
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•Bile duct ligation (BDL) causes hepatorenal syndrome (HRS).•Oxidative damage/inflammation drives liver and kidney injury following BDL.•Cannabinoid-2 receptor (CB2-R) activation attenuates hepatic damage in BDL.•CB2-R activation mitigates the renal inflammation and oxidative damage in BDL.•CB2-R activation attenuates renal microcirculatory dysfunction in BDL.
Our ability to understand and simulate the reactions catalyzed by iron depends strongly on our ability to predict the relative energetics of spin states. In this work, we studied the electronic ...structures of Fe
ion, gaseous FeO and 14 iron complexes using Kohn-Sham density functional theory with particular focus on determining the ground spin state of these species as well as the magnitudes of relevant spin-state energy splittings. The 14 iron complexes investigated in this work have hexacoordinate geometries of which seven are Fe(ii), five are Fe(iii) and two are Fe(iv) complexes. These are calculated using 20 exchange-correlation functionals. In particular, we use a local spin density approximation (LSDA) - GVWN5, four generalized gradient approximations (GGAs) - BLYP, PBE, OPBE and OLYP, two non-separable gradient approximations (NGAs) - GAM and N12, two meta-GGAs - M06-L and M11-L, a meta-NGA - MN15-L, five hybrid GGAs - B3LYP, B3LYP*, PBE0, B97-3 and SOGGA11-X, four hybrid meta-GGAs - M06, PW6B95, MPW1B95 and M08-SO and a hybrid meta-NGA - MN15. The density functional results are compared to reference data, which include experimental results as well as the results of diffusion Monte Carlo (DMC) calculations and ligand field theory estimates from the literature. For the Fe
ion, all functionals except M11-L correctly predict the ground spin state to be quintet. However, quantitatively, most of the functionals are not close to the experimentally determined spin-state splitting energies. For FeO all functionals predict quintet to be the ground spin state. For the 14 iron complexes, the hybrid functionals B3LYP, MPW1B95 and MN15 correctly predict the ground spin state of 13 out of 14 complexes and PW6B95 gets all the 14 complexes right. The local functionals, OPBE, OLYP and M06-L, predict the correct ground spin state for 12 out of 14 complexes. Two of the tested functionals are not recommended to be used for this type of study, in particular M08-SO and M11-L, because M08-SO systematically overstabilizes the high spin state, and M11-L systematically overstabilizes the low spin state.
Feeding rats with high-fat diet (HFD) with a single streptozotocin (STZ) injection induced obesity, slightly elevated fasting blood glucose and impaired glucose and insulin tolerance, and caused ...cardiac hypertrophy and mild diastolic dysfunction as published before by Koncsos et al. in 2016. Here we aimed to explore the renal consequences in the same groups of rats. Male Long-Evans rats were fed normal chow (CON; n = 9) or HFD containing 40% lard and were administered STZ at 20 mg/kg (i.p.) at week four (prediabetic rats, PRED, n = 9). At week 21 blood and urine samples were taken and kidney and liver samples were collected for histology, immunohistochemistry and for analysis of gene expression. HFD and STZ increased body weight and visceral adiposity and plasma leptin concentration. Despite hyperleptinemia, plasma C-reactive protein concentration decreased in PRED rats. Immunohistochemistry revealed elevated collagen IV protein expression in the glomeruli, and
mRNA expression increased, while
mRNA expression decreased in both the renal cortex and medulla in PRED vs. CON rats. Kidney histology, urinary protein excretion, plasma creatinine, glomerular Feret diameter, desmin protein expression, and cortical and medullary mRNA expression of
and
were similar in CON and PRED rats. Reduced
phosphorylation of the autophagy regulator
was the first sign of liver damage, while plasma lipid and liver enzyme concentrations were similar. In conclusion, glomerular collagen deposition and increased lipocalin-2 expression were the early signs of kidney injury, while most biomarkers of inflammation, oxidative stress and fibrosis were negative in the kidneys of obese, prediabetic rats with mild heart and liver injury.
The external genital appendages of Noctuidae represent correlated–coevolved elements of a complex structure. The pathways of changes are delimited by some constraints, and they are parallelly evolved ...in different phyletic lines. Asymmetrical male external genitalia were found in Hadenini, in Polia and its closely related genera, but also in Anarta (s. l.). In Poliina, the asymmetry of the genital capsule is mostly expressed in the Holarctic Polia nebulosa species group, forming the basal split within Polia (s. str.). Higher species diversity, as a consequence of asymmetry connected with the split of functions between the right and left sides, was observed in Polia (s. str.) and in Anarta (s. l.). The highest level of expansivity was observed in the Holarctic Anarta, where some species are migrating and becoming invasive ones, while a bulk of species populates the steppic and mountainous habitats of North America and Central Asia. Parallelly, while some genera/subgenera of the subtribe Poliina are oligotypic and/or consist of strictly localised species, the sensu stricto Polia species with asymmetrical genital capsules are widely distributed. The diversification of the Hadulina phylogenetic line should have been initiated by the Messinian aridisation crisis. The core area of diversification of Poliina was connected with the Sino-Himalayan region, followed by expansion into the Holarctic boreo-nemoral zone.
Background and Aims
Hepatic cardiomyopathy, a special type of heart failure, develops in up to 50% of patients with cirrhosis and is a major determinant of survival. However, there is no reliable ...model of hepatic cardiomyopathy in mice. We aimed to characterize the detailed hemodynamics of mice with bile duct ligation (BDL)–induced liver fibrosis, by monitoring echocardiography and intracardiac pressure–volume relationships and myocardial structural alterations. Treatment of mice with a selective cannabinoid‐2 receptor (CB2‐R) agonist, known to attenuate inflammation and fibrosis, was used to explore the impact of liver inflammation and fibrosis on cardiac function.
Approach and Results
BDL induced massive inflammation (increased leukocyte infiltration, inflammatory cytokines, and chemokines), oxidative stress, microvascular dysfunction, and fibrosis in the liver. These pathological changes were accompanied by impaired diastolic, systolic, and macrovascular functions; cardiac inflammation (increased macrophage inflammatory protein 1, interleukin‐1, P‐selectin, cluster of differentiation 45–positive cells); and oxidative stress (increased malondialdehyde, 3‐nitrotyrosine, and nicotinamide adenine dinucleotide phosphate oxidases). CB2‐R up‐regulation was observed in both livers and hearts of mice exposed to BDL. CB2‐R activation markedly improved hepatic inflammation, impaired microcirculation, and fibrosis. CB2‐R activation also decreased serum tumor necrosis factor‐alpha levels and improved cardiac dysfunction, myocardial inflammation, and oxidative stress, underlining the importance of inflammatory mediators in the pathology of hepatic cardiomyopathy.
Conclusions
We propose BDL‐induced cardiomyopathy in mice as a model for hepatic/cirrhotic cardiomyopathy. This cardiomyopathy, similar to cirrhotic cardiomyopathy in humans, is characterized by systemic hypotension and impaired macrovascular and microvascular function accompanied by both systolic and diastolic dysfunction. Our results indicate that the liver–heart inflammatory axis has a pivotal pathophysiological role in the development of hepatic cardiomyopathy. Thus, controlling liver and/or myocardial inflammation (e.g., with selective CB2‐R agonists) may delay or prevent the development of cardiomyopathy in severe liver disease.
Since 2011, the volume of passenger air transport grew nearly 7.5%/year, while freight air transport grew 3.6%/year regarding to the performed kilometers. The expansion of the aviation sector ...resulted increasing fuel consumption, too. The growing usage of fossil-based jet fuel results significant particle and carbon dioxide emissions, which causes remarkable environment pollution. This emission can only be reduced with using alternative jet fuels, especially those are originated from natural/waste fatty acid/-ester triglyceride sources. The aim of the experimental work was to compare industrially applied sulfide-state catalysts containing different transition metals from the aspect of catalytic conversion of mixtures of waste coconut oil and unrefined kerosene to produce jet fuel at various process parameters (temperature = 280-360 °C, liquid hourly space velocity = 1.0-3.0 h
−1
, pressure = 30 bar, hydrogen/hydrocarbon volume ratio = 600 Nm
3
/m
3
) in a continuous down-flow tubular reactor system. The obtained products contributes to decrease in particle and carbon dioxide emission of aircrafts due to their lower aromatic content. The smoke point of the products obtained at favorable process parameters was higher than 30 mm, while the requirement in ASTM D 1655 standard is minimum 25 mm.
Background and Purpose
Immune checkpoint inhibitors (ICI), such as anti‐PD‐1 monoclonal antibodies, have revolutionized cancer therapy by enhancing the cytotoxic effects of T‐cells against tumours. ...However, enhanced T‐cell activity also may cause myocarditis and cardiotoxicity. Our understanding of the mechanisms of ICI‐induced cardiotoxicity is limited. Here, we aimed to investigate the effect of PD‐1 inhibition on cardiac function and explore the molecular mechanisms of ICI‐induced cardiotoxicity.
Experimental Approach
C57BL6/J and BALB/c mice were treated with isotype control or anti‐PD‐1 antibody.
Echocardiography was used to assess cardiac function. Cardiac transcriptomic changes were investigated by bulk RNA sequencing. Inflammatory changes were assessed by qRT‐PCR and immunohistochemistry in heart, thymus, and spleen of the animals. In follow‐up experiments, anti‐CD4 and anti‐IL‐17A antibodies were used along with PD‐1 blockade in C57BL/6J mice.
Key Results
Anti‐PD‐1 treatment led to cardiac dysfunction and left ventricular dilation in C57BL/6J mice, with increased nitrosative stress. Only mild inflammation was observed in the heart. However, PD‐1 inhibition resulted in enhanced thymic inflammatory signalling, where Il17a increased most prominently. In BALB/c mice, cardiac dysfunction was not evident, and thymic inflammatory activation was more balanced. Inhibition of IL‐17A prevented anti‐PD‐1‐induced cardiac dysfunction in C57BL6/J mice. Comparing myocardial transcriptomic changes in C57BL/6J and BALB/c mice, differentially regulated genes (Dmd, Ass1, Chrm2, Nfkbia, Stat3, Gsk3b, Cxcl9, Fxyd2, and Ldb3) were revealed, related to cardiac structure, signalling, and inflammation.
Conclusions
PD‐1 blockade induces cardiac dysfunction in mice with increased IL‐17 signalling in the thymus. Pharmacological inhibition of IL‐17A treatment prevents ICI‐induced cardiac dysfunction.
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