Importance of chronic fibroproliferative diseases (FDs) including pulmonary fibrosis, chronic kidney diseases, inflammatory bowel disease, and cardiovascular or liver fibrosis is rapidly increasing ...and they have become a major public health problem. According to some estimates about 45% of all deaths are attributed to FDs in the developed world. Independently of their etiology the common hallmark of FDs is chronic inflammation. Infiltrating immune cells, endothelial, epithelial, and other resident cells of the injured organ release an orchestra of inflammatory mediators, which stimulate the proliferation and excessive extracellular matrix (ECM) production of myofibroblasts, the effector cells of organ fibrosis. Abnormal amount of ECM disturbs the original organ architecture leading to the decline of function. Although our knowledge is rapidly expanding, we still have neither a diagnostic tool to detect nor a drug to specifically target fibrosis. Therefore, there is an urgent need for the more comprehensive understanding of the pathomechanism of fibrosis and development of novel diagnostic and therapeutic strategies. In the present review we provide an overview of the common key mediators of organ fibrosis highlighting the role of interleukin-10 (IL-10) cytokine family members (IL-10, IL-19, IL-20, IL-22, IL-24, and IL-26), which recently came into focus as tissue remodeling-related inflammatory cytokines.
Perception of inanimate objects as animate based on motion cues alone seems to be present in phylogenetically distant species, from birth (humans and chicks). However, we do not know whether the ...species' social and ecological environment has an influence on this phenomenon. Dogs serve as a unique species to investigate whether selection for specific behavioural traits influences animacy perception. We tested purebred companion dogs, and assigned them into two groups based on the type of work they were originally selected for: (1) Chasers, tracking and chasing prey; (2) Retrievers, mark and remember downed game. We displayed isosceles triangles presenting a chasing pattern vs moving independently, in parallel on a screen. We hypothesised that Chasers prefer to look at chasing and Retrievers eventually focus their visual attention on the independent motion. Overall, we did not find a significant difference between groups regarding the looking duration of dogs or the frequency of their gaze alternation between the chasing and independent motions. Thus it seems that selection for specific traits does not influence the perception of animate entities within the species.
•Subsidiary and parent capitalization boosts lending; more so in and post-crisis.•Parent capitalization most important for high FX lenders and banks outside EU.•Nonperforming loan ratios (NPLs) and ...funding constraints hinder lending growth.•Policy inferences include purging banks of NPLs & enhanced regulatory coordination.•Suggests integrating parent traits into countercyclical capital buffer calculations.
We analyze the relative roles of subsidiary and parent banking group traits in driving foreign banks’ lending patterns in the Central and Eastern European (CEE) region before and during the crisis. We use a bank-level dataset on Western European banking groups and their CEE subsidiaries over the 2002–2013 period. We find that lower capital-to-asset ratios and higher non-performing loans (NPL) ratios at either the subsidiary or the parent bank level significantly lowered subsidiary lending growth before and during the crisis. The onset of the crisis not only lowered subsidiary lending growth in the CEE countries, but also has altered the relationship between balance sheet conditions and lending growth. However, we also find strong evidence that this crisis effect is significantly less pronounced for subsidiaries participating in the Vienna Initiative. Our results’ policy implications include purging banks of NPLs, enhanced regulatory coordination and the inclusion of parent bank traits in countercyclical capital buffer calculations.
Increased permeability of the epithelial and endothelial cell layers results in the onset of pathogenic mechanisms. In both cell types, cell–cell connections play a regulatory role in altering ...membrane permeability. The aim of this study was to investigate the modulating effect of anthocyanin-rich extract (AC) on TJ proteins in inflammatory Caco-2 and HUVEC monolayers. Distribution of Occludin and zonula occludens-1 (ZO-1) were investigated by immunohistochemical staining and the protein levels were measured by flow cytometry. The mRNA expression was determined by quantitative real-time PCR. The transepithelial electrical resistance (TEER) values were measured during a permeability assay on HUVEC cell culture. As a result of inflammatory induction by TNF-α, redistribution of proteins was observed in Caco-2 cell culture, which was reduced by AC treatment. In HUVEC cell culture, the decrease in protein and mRNA expression was more dominant during inflammatory induction, which was compensated for by the AC treatment. Overall, AC positively affected the expression of the examined cell-binding structures forming the membrane on both cell types.
Exercise initiates systemic adaptation to promote health and prevent various lifestyle-related chronic diseases. Emerging evidence suggests that circulating exosomes mediate some of the beneficial ...effects of exercise via the transfer of microRNAs between tissues. Yet to date, a comprehensive profile of the exosomal miRNA (exomiR) content released following short-term (0.5 year in this study) and long-term (25 + years in this study) regular bouts of exercise is still lacking. However, a better understanding of these miRNA species would assist in clarifying the role of regular exercise at the molecular level in the prevention of chronic diseases. In the present pilot studies we analyzed serum exomiR expression in healthy young, sedentary participants (
n
= 14; age: 23 ± 2 years) at baseline and following a half year-long moderate-intensity regular exercise training. We also analyzed serum exomiR expression in older, healthy trained participants (seniors,
n
= 11; age: 62 ± 6 years) who engaged in endurance activities for at least 25 years. Following the isolation and enrichment of serum exosomes using Total Exosome Isolation Reagent (TEI) their exomiR levels were determined using the amplification-free Nanostring platform. Hierarchical cluster analysis revealed that the majority of exomiRs overlap for short-term (0.5 year in this study) and long-term (25 + years in this study) regular bouts of exercise. The top 12 significantly altered exomiRs (let-7a-5p; let-7g-5p; miR-130a-3p; miR-142-3p; miR-150-5p; miR-15a-5p; miR-15b-5p; miR-199a-3p; miR-199b-3p; miR-223-3p; miR-23a-3p, and miR-451a-3p) were used for further evaluation. According to KEGG pathway analysis a large portion of the exomiRs target chronic diseases including cancer, neurodegenerative and metabolic diseases, and viral infections. Our results provide evidence that exosomal miRNA modulation is the molecular mechanism through which regular exercise prevents various chronic diseases. The possibility of using such exomiRs to target diseases is of great interest. While further validation is needed, our comprehensive exomiR study presents, for the first time, the disease-preventive molecular pattern of both short and long-term regular exercise.
Spinocerebellar ataxia (SCA) 40 is an extremely rare subtype of the phenotypically and genetically diverse autosomal dominant ataxias caused by mutations of the
gene. Most reported cases of SCA40 are ...characterized by late-onset cerebellar ataxia and variable extrapyramidal features; however, there is a report of a patient with early-onset spastic paraparesis as well. Here, we describe a novel missense
mutation (p.R203W) in the hook domain of the DAPLE protein encoded by the
gene that was identified in a female patient who developed late-onset ataxia, dysmetria and intention tremor. To explore the molecular consequences of the newly identified and previously described
mutations, we carried out in vitro functional tests. The
alleles were expressed in HEK293 cells, and the impact of the mutant DAPLE protein variants on JNK pathway activation and apoptosis was assessed. Our results revealed only a small-scale activation of the JNK pathway by mutant DAPLE proteins; however, increased JNK1 phosphorylation could not be detected. Additionally, none of the examined mutations triggered proapoptotic effect. In conclusion, we identified a novel mutation of the
gene from a patient with spinocerebellar ataxia. Our results are not in accord with previous observations and do not support the primary role of the
mutations in induction of JNK pathway activation in ataxia. Therefore, we propose that
mutations may exert their effects through different and possibly in much broader, yet unexplored, biological processes.
•Groundwater flow system hierarchy is significantly affected by decreasing recharge.•Climate change can strongly affect local ecologically-significant flow regimes.•Future conditions of wetlands ...strongly depend on their hydraulic position.•Changing penetration depths of flow systems are shown by 2D transient simulations.
Climate change can directly influence groundwater systems through modification of recharge. Affecting not only groundwater levels and flow dynamics, climate change can also modify the fragmentation and hierarchy of groundwater flow systems. In this study, the influence of climate change – impacted recharge on groundwater levels and on inter-connected groundwater flow patterns is evaluated. Special emphasis is placed on how flow system hierarchy may change, to examine possible consequences on groundwater-related shallow surface water bodies and on groundwater – surface water interaction. As a test site with no significant anthropogenic impacts, the Tihany Peninsula in Hungary was an ideal area for the study. We address the following issues: i) How might a groundwater system, including groundwater-surface water interaction, be modified by predicted climate change?, ii) Given the variable groundwater levels and flow patterns, how will the water levels and fluxes be impacted around surface water bodies?, and iii) How sensitive are groundwater-related wetlands to these changes, and will they be maintained or will they eventually disappear? In order to answer these questions, two-dimensional transient numerical simulations were performed based on site-specific measurements and climatic prediction at the Tihany Peninsula. Results show that future climate trends can cause dynamic evolution and dissipation of transient groundwater flow systems, and the characteristic flow system hierarchy can change from nested flow systems to a set of single flow cells. Preservation of associated groundwater-dependent ecosystems would be challenging under these conditions since long-term climate change could potentially have serious consequences, including wetland disappearance. Understanding these transient processes in two-dimensions can also help to set-up three-dimensional site-specific models.
In response to various inflammatory stimuli, neutrophils secrete neutrophil extracellular traps (NETs), web-like meshworks of DNA, histones and granular components forming supplementary scaffolds in ...venous and arterial thrombi. Isolated DNA and histones are known to promote thrombus formation and render fibrin clots more resistant to mechanical forces and tissue-type plasminogen activator (tPA)-induced enzymatic digestion. The present study extends our earlier observations to a physiologically more relevant environment including plasma clots and NET-forming neutrophils. A range of techniques was employed including imaging (scanning electron microscopy (SEM), confocal laser microscopy, and photoscanning of macroscopic lysis fronts), clot permeability measurements, turbidimetric lysis and enzyme inactivation assays. Addition of DNA and histones increased the median fibre diameter of plasma clots formed with 16 nM thrombin from 108 to 121 and 119 nm, respectively, and decreased their permeability constant from 6.4 to 3.1 and 3.7×10(-9) cm(2). Histones effectively protected thrombin from antithrombin-induced inactivation, while DNA inhibited plasminogen activation on the surface of plasma clots and their plasmin-induced resolution by 20 and 40 %, respectively. DNA and histones, as well as NETs secreted by phorbol-myristate-acetate-activated neutrophils, slowed down the tPA-driven lysis of plasma clots and the latter effect could be reversed by the addition of DNase (streptodornase). SEM images taken after complete digestion of fibrin in NET-containing plasma clots evidenced retained NET scaffold that was absent in DNase-treated clots. Our results show that DNA and histones alter the fibrin architecture in plasma clots, while NETs contribute to a decreased lytic susceptibility that can be overcome by DNase.
Key points
Increased activation of the renin‐angiotensin‐aldosterone system (RAAS) and elevated growth factor production are of crucial importance in the development of renal fibrosis leading to ...diabetic kidney disease.
The aim of this study was to provide evidence for the antifibrotic potential of RAAS inhibitor (RAASi) treatment and to explore the exact mechanism of this protective effect.
We found that RAASi ameliorate diabetes‐induced renal interstitial fibrosis and decrease profibrotic growth factor production.
RAASi prevents fibrosis by acting directly on proximal tubular cells, and inhibits hyperglycaemia‐induced growth factor production and thereby fibroblast activation.
These results suggest a novel therapeutic indication and potential of RAASi in the treatment of renal fibrosis.
In diabetic kidney disease (DKD) increased activation of renin‐angiotensin‐aldosterone system (RAAS) contributes to renal fibrosis. Although RAAS inhibitors (RAASi) are the gold standard therapy in DKD, the mechanism of their antifibrotic effect is not yet clarified. Here we tested the antifibrotic and renoprotective action of RAASi in a rat model of streptozotocin‐induced DKD. In vitro studies on proximal tubular cells and renal fibroblasts were also performed to further clarify the signal transduction pathways that are directly altered by hyperglycaemia. After 5 weeks of diabetes, male Wistar rats were treated for two more weeks per os with the RAASi ramipril, losartan, spironolactone or eplerenone. Proximal tubular cells were cultured in normal or high glucose (HG) medium and treated with RAASi. Platelet‐derived growth factor (PDGF) or connective tissue growth factor (CTGF/CCN2)‐induced renal fibroblasts were also treated with various RAASi. In diabetic rats, reduced renal function and interstitial fibrosis were ameliorated and elevated renal profibrotic factors (TGFβ1, PDGF, CTGF/CCN2, MMP2, TIMP1) and alpha‐smooth muscle actin (αSMA) levels were decreased by RAASi. HG increased growth factor production of HK‐2 cells, which in turn induced activation and αSMA production of fibroblasts. RAASi decreased tubular PDGF and CTGF expression and reduced production of extracellular matrix (ECM) components in fibroblasts. In proximal tubular cells, hyperglycaemia‐induced growth factor production increased renal fibroblast transformation, contributing to the development of fibrosis. RAASi, even in non‐antihypertensive doses, decreased the production of profibrotic factors and directly prevented fibroblast activation. All these findings suggest a novel therapeutic role for RAASi in the treatment of renal fibrosis.
Key points
Increased activation of the renin‐angiotensin‐aldosterone system (RAAS) and elevated growth factor production are of crucial importance in the development of renal fibrosis leading to diabetic kidney disease.
The aim of this study was to provide evidence for the antifibrotic potential of RAAS inhibitor (RAASi) treatment and to explore the exact mechanism of this protective effect.
We found that RAASi ameliorate diabetes‐induced renal interstitial fibrosis and decrease profibrotic growth factor production.
RAASi prevents fibrosis by acting directly on proximal tubular cells, and inhibits hyperglycaemia‐induced growth factor production and thereby fibroblast activation.
These results suggest a novel therapeutic indication and potential of RAASi in the treatment of renal fibrosis.
Sulfur (S) is an essential plant macronutrient and the pivotal role of sulfur compounds in plant disease resistance has become obvious in recent decades. This review attempts to recapitulate results ...on the various functions of sulfur-containing defense compounds (SDCs) in plant defense responses to pathogens. These compounds include sulfur containing amino acids such as cysteine and methionine, the tripeptide glutathione, thionins and defensins, glucosinolates and phytoalexins and, last but not least, reactive sulfur species and hydrogen sulfide. SDCs play versatile roles both in pathogen perception and initiating signal transduction pathways that are interconnected with various defense processes regulated by plant hormones (salicylic acid, jasmonic acid and ethylene) and reactive oxygen species (ROS). Importantly, ROS-mediated reversible oxidation of cysteine residues on plant proteins have profound effects on protein functions like signal transduction of plant defense responses during pathogen infections. Indeed, the multifaceted plant defense responses initiated by SDCs should provide novel tools for plant breeding to endow crops with efficient defense responses to invading pathogens.
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