IL-33/ST2 Axis in Organ Fibrosis

Interleukin 33 (IL-33) is highly expressed in barrier sites, acting via the suppression of tumorigenicity 2 receptor (ST2). IL-33/ST2 axis has long been known to play a pivotal role in immunity and cell homeostasis by promoting wound healing and tissue repair. However, it is also involved in the loss of balance between extensive inflammation and tissue regeneration lead to remodeling, the hallmark of fibrosis. The aim of the current review is to critically evaluate the available evidence regarding the role of the IL-33/ST2 axis in organ fibrosis. The role of the axis in tissue remodeling is better understood considering its crucial role reported in organ development and regeneration. Generally, the IL-33/ST2 signaling pathway has mainly anti-inflammatory/anti-proliferative effects; however, chronic tissue injury is responsible for pro-fibrogenetic responses. Regarding pulmonary fibrosis mature IL-33 enhances pro-fibrogenic type 2 cytokine production in an ST2- and macrophage-dependent manner, while full-length IL-33 is also implicated in the pulmonary fibrotic process in an ST2-independent, Th2-independent fashion. In liver fibrosis, evidence indicate that when acute and massive liver damage occurs, the release of IL-33 might act as an activator of tissue-protective mechanisms, while in cases of chronic injury IL-33 plays the role of a hepatic fibrotic factor. IL-33 signaling has also been involved in the pathogenesis of acute and chronic pancreatitis. Moreover, IL-33 could be used as an early marker for ulcer-associated activated fibroblasts and myofibroblast trans-differentiation; thus one cannot rule out its potential role in inflammatory bowel disease-associated fibrosis. Similarly, the upregulation of the IL-33/ST2 axismay contribute to tubular cell injury and fibrosis via epithelial to mesenchymal transition (EMT) of various cell types in the kidneys. Of note, IL-33 exerts a cardioprotective role via ST2 signaling, while soluble ST2 has been demonstrated as a marker of myocardial fibrosis. Finally, IL-33 is a crucial cytokine in skin pathology responsible for abnormal fibroblast proliferation, leukocyte infiltration and morphologic differentiation of human endothelial cells. Overall, emerging data support a novel contribution of the IL-33/ST2 pathway in tissue fibrosis and highlight the significant role of the Th2 pattern of immune response in the pathophysiology of organ fibrosis

Post-COVID-19 Parkinsonism and Parkinson's Disease Pathogenesis: The Exosomal Cargo Hypothesis

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer's disease, globally. Dopaminergic neuron degeneration in substantia nigra pars compacta and aggregation of misfolded alpha-synuclein are the PD hallmarks, accompanied by motor and non-motor symptoms. Several viruses have been linked to the appearance of a post-infection parkinsonian phenotype. Coronavirus disease 2019 (COVID-19), caused by emerging severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, has evolved from a novel pneumonia to a multifaceted syndrome with multiple clinical manifestations, among which neurological sequalae appear insidious and potentially long-lasting. Exosomes are extracellular nanovesicles bearing a complex cargo of active biomolecules and playing crucial roles in intercellular communication under pathophysiological conditions. Exosomes constitute a reliable route for misfolded protein transmission, contributing to PD pathogenesis and diagnosis. Herein, we summarize recent evidence suggesting that SARS-CoV-2 infection shares numerous clinical manifestations and inflammatory and molecular pathways with PD. We carry on hypothesizing that these similarities may be reflected in exosomal cargo modulated by the virus in correlation with disease severity. Travelling from the periphery to the brain, SARS-CoV-2-related exosomal cargo contains SARS-CoV-2 RNA, viral proteins, inflammatory mediators, and modified host proteins that could operate as promoters of neurodegenerative and neuroinflammatory cascades, potentially leading to a future parkinsonism and PD development

Autism or hautism? An etymological approach

The word “autism” was first used at the beginning of the 20th century by the psychiatrist Eugen Bleuler. Autism was derived from the ancient Greek word «εαυτός» (meaning self ) and the suffix «-ισμος» (-ism). This short report investigates whether the formation of the word in English was conducted using the correct rules regarding the transformation of Greek words into foreign languages. Our investigation showed that the word «εαυτός» is derived from the reflexive pronoun «έαυτού» (pronounced with rough breathing) of ancient Greek. When they are transcribed into English, the ancient Greek words with rough breathing are written with the first letter “Η” (e.g., history, hero). In those without rough breathing, the “H” is absent (e.g., anatomy). Our conclusion is that the correct form of the derived term would be the word “hautism” rather than the currently used “autism”. If written in such a way, the term would state the action of reflexion, which is the main characteristic of “autism”. © Athens Medical Society

Effect of long-term dietary supplementation with clinoptilolite on performance and selected serum biochemical values in dairy goats

Objective-To determine the effect of dietary supplementation with clinoptilolite on health and production as well as serum concentrations of fat-soluble vitamins, macroelements and trace elements, and activities of hepatic enzymes in dairy goats. Animals-72 Saanen-cross dairy goats. Procedures-G oats were randomly assigned to 1 of 2 groups. The clinoptilolite group (n = 36) received concentrate feed, of which 2.5% contained clinoptilolite; the control group (36) received unsupplemented feed. The experiment began 8 weeks before parturition and continued to the beginning of the next nonlactating period (280 days of lactation). At the day of parturition, kids were weighed. Milk yields were recorded at day 60 of lactation and thereafter at monthly intervals. Milk percentages of fat, protein, and lactose and somatic cell count (SCC) were evaluated at the same points. Blood samples were obtained at the beginning of the experiment, the day of parturition, and thereafter at monthly intervals to measure serum concentrations of fat-soluble vitamins, macroelements and trace elements, and activities of hepatic enzymes. Results-Birth weights of triplets and quadruplets were significantly higher in clinoptilolite-treated goats versus control goats. Milk fat percentage was significantly higher and SCC was significantly lower in clinoptilolite-treated goats, compared with respective values in control goats. However, no changes in serum concentrations of any variable were detected. A A Conclusions and Clinical Relevance-In the context of this experiment, clinoptilolite supplementation of concentrate feed at 2.5% improved milk fat percentage in dairy goats, without adverse effects on the serum variables evaluated. Furthermore, the reduction of SCC achieved with clinoptilolite supplementation provided some evidence of improved milk hygiene. (Am J Vet Res 2009;70:346-352

Crystalline silica activates the T-cell and the B-cell antigen receptor complexes and induces T-cell and B-cell proliferation

Silicosis is an occupational fibrotic lung disease, which is associated with an increased incidence of autoimmune diseases. The effect of crystalline silica on the immune system is thought to be mediated by the antigen presenting cells. However, the direct effect of silica on T-cells and B-cells has not been evaluated adequately. For this purpose, CD4(+)T-cells and B-cells from 10 healthy individuals were isolated and cultured with or without Min-U-Sil 5. Cell proliferation was assessed with BrdU assay. In cell proliferation experiments, tacrolimus, an inhibitor of the signal transduction derived from the activation of the T-cell or the B-cell antigen receptor (BCR) complex, was also used. The levels of phosphorylated zeta and phosphorylated Igα, indicative of the T-cell and BCR complex activation respectively, and of the transcription factor c-Myc, required for cell proliferation, were assessed by Western blotting. Crystalline silica triggered CD4(+)T-cell and B-cell proliferation, while tacrolimus significantly decreased the silica-induced proliferation in both cell types. Crystalline silica enhanced the level of phosphorylated zeta and phosphorylated Igα in CD4(+)T-cells and B-cells, respectively. In both cell types, treatment with silica increased c-Myc expression. Thus, crystalline silica may induce T-cell and B-cell proliferation by activating T-cell and BCR complexes. It is likely that the direct activation of CD4(+)T-cells and B-cells by silica crystals detected in this study circumvents many self-tolerance check-points and offers a mechanistic explanation for the crystalline silica-induced autoimmune diseases. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group

Permeability of the arachnoid and pia mater. The role of ion channels in the leptomeningeal physiology

Purpose: The purpose of this paper is to study the ionic permeability of the leptomeninges related to the effect of ouabain (sodium-potassium-ATPase inhibitor) and amiloride (epithelial sodium channel (ENaC) inhibitor) on the tissue, as well as identify the presence of ion channels. Methods: Cranial leptomeningeal samples from 26 adult sheep were isolated. Electrophysiological measurements were performed with Ussing system and transmembrane resistance values (RTM in Ω*cm2) obtained over time. Experiments were conducted with the application of ouabain 10-3 M or amiloride 10-5 M at the arachnoidal and pial sides. Immunohistochemical studies of leptomeningeal tissue were prepared with alpha-1 sodium-potassium-ATPase (ATP1A1), beta-ENaC, and delta-ENaC subunit antibodies. Results: The application of ouabain at the arachnoidal side raised the transmembrane resistance statistically significantly and thus decreased its ionic permeability. The addition of ouabain at the pial side led also to a significant but less profound increment in transmembrane resistance. The addition of amiloride at the arachnoidal or pial side did not produce any statistical significant change in the RTM from controls (p>0.05). Immunohistochemistry confirmed the presence of the ATP1A1 and beta- and delta-ENaC subunits at the leptomeninges. Conclusions: In summary, leptomeningeal tissue possesses sodium-potassium-ATPase and ENaC ion channels. The application of ouabain alters the ionic permeability of the leptomeninges thus reflecting the role of sodium-potassium-ATPase. Amiloride application did not alter the ionic permeability of leptomeninges possibly due to localization of ENaC channels towards the subarachnoid space, away from the experimental application sites. The above properties of the tissue could potentially be related to cerebrospinal fluid turnover at this interface. © 2012 Springer-Verlag

Salbutamol Modulation of Ion Transport in Sheep Parietal Pleura Is Protein Dependent

The formation of pleural effusion during pulmonary edema is an important physiological mechanism of resolution of alveolar flooding. In cases of pulmonary edema resulting from acute respiratory distress syndrome (ARDS) these effusions are exudative, having high protein load. To this end, the effect of salbutamol in the presence of protein, on the ion transport properties of the sheep parietal pleura was investigated by Ussing chamber experiments. Our results show that salbutamol increases ion transport in the presence of protein in sheep parietal pleura by stimulation of beta(2)-adrenergic receptors since this effect was completely abolished by the specific beta(2)-adrenergic blocker, ICI-118551. This finding may be of importance regarding the acceleration of the resolution of protein-rich pleural effusions occurring in cases of ARDS

The Water Permeability Reduction After Successive Hypo-Osmotic Shocks in Kidney Principal Cells is Apically Regulated

Background/Aims: Renal principal cells maintain their intracellular water and electrolyte content despite significant fluctuations of the extracellular water and salt concentrations. Their water permeability decreases rapidly (within a few seconds) after successive hypo-osmotic shocks. Our aim was to investigate the contribution of the apical and basolateral surface to this effect and the potential influence of fast reduction in AQP-2, -3 or -4 plasma membrane content. Methods: Rat principal cells of kidney collecting duct fragments underwent hypoosmotic challenge applied apically or basolaterally and the regulatory volume decrease (RVD) was measured by the calcein quenching method. The AQP -2, -3 and -4 content of the plasma membrane fraction was quantified by Western blotting. Results: The hypo-osmotic shock applied apically causes rapid swelling with high apparent water permeability and fast RVD. An identical successive shock after 15-20 sec causes significantly lower swelling rate with 3-fold reduction in apparent water permeability. This reaction is accompanied by AQP2 decrease in the plasma membrane while AQP3 and AQP4 are unaffected. The contribution of the basolateral cell surface to RVD is significantly lower than the apical. Conclusion: These results indicate that in principal cells the effective mechanism of RVD is mainly regulated by the apical cell plasma membrane. Copyright (C) 2014 S. Karger AG, Base