Aspirin and some other nonsteroidal anti-inflammatory drugs inhibit cystic fibrosis transmembrane conductance regulator protein gene expression in T-84 cells.

Cystic fibrosis (CF) is caused by mutations in the CF gene, which encodes CF transmembrane conductance regulator protein (CFTR), a transmembrane protein that acts as a cAMP-regulated chloride channel The disease is characterized by inflammation but the relationship between inflammation, abnormal transepithelial ion transport, and the clinical manifestations of CF are uncertain. The present study was undertaken to determine whether three nonsteroidal anti-inflammatory drugs (NSAIDs) (aspirin, ibuprofen, and indomethacin) modulate CFTR gene expression in T-84 cells. Treatment with NSAIDs reduced CFTR transcripts, and decreased cAMP-stimulated anion fluxes, an index of CFTR function. However, the two phenomena occurred at different concentrations of both drugs. The results indicate that NSAIDs can regulate both CFTR gene expression and the function of CFTR-related chloride transport, and suggest that NSAIDs act via multiple transduction pathways

Critical role of a sheath phosphorylation site on the assembly and function of an atypical type VI secretion system

The bacterial pathogen Francisella tularensis possesses a non-canonical type VI secretion system (T6SS) that is required for phagosomal escape in infected macrophages. KCl stimulation has been previously used to trigger assembly and secretion of the T6SS in culture. By differential proteomics, we found here that the amounts of the T6SS proteins remained unchanged upon KCl stimulation, suggesting involvement of post-translational modifications in T6SS assembly. A phosphoproteomic analysis indeed identified a unique phosphorylation site on IglB, a key component of the T6SS sheath. Substitutions of Y139 with alanine or phosphomimetics prevented T6SS formation and abolished phagosomal escape whereas substitution with phenylalanine delayed but did not abolish phagosomal escape in J774-1 macrophages. Altogether our data demonstrated that the Y139 site of IglB plays a critical role in T6SS biogenesis, suggesting that sheath phosphorylation could participate to T6SS dynamics

Lubiprostone Stimulates Duodenal Bicarbonate Secretion in Rats

Lubiprostone, a bicyclic fatty acid, is used for the treatment of chronic constipation. No published study has addressed the effect of lubiprostone on intestinal ion secretion in vivo. The aim of this study was to test the hypothesis that lubiprostone augments duodenal HCO3 − secretion (DBS). Rat proximal duodenal loops were perfused with pH 7.0 Krebs, control vehicle (medium-chain triglycerides), or lubiprostone (0.1–10 μM). We measured DBS with flow-through pH and CO2 electrodes, perfusate [Cl−] with a Cl− electrode, and water flux using a non-absorbable ferrocyanide marker. Some rats were pretreated with a potent, selective CFTR antagonist, CFTRinh-172 (1 mg/kg, ip), 1 h before experiments. Perfusion of lubiprostone concentration dependently increased DBS, whereas net Cl− output and net water output were only increased at 0.1 μM, compared with vehicle. CFTRinh-172 reduced lubiprostone (10 μM)-induced DBS increase, whereas net Cl− output was also unchanged. Nevertheless, CFTRinh-172 reduced basal net water output, which was reversed by lubiprostone. Furthermore, lubiprostone-induced DBS was inhibited by EP4 receptor antagonist, not by an EP1/2 receptor antagonist or by indomethacin pretreatment. In this first study of the effect of lubiprostone on intestinal ion secretion in vivo, lubiprostone stimulated CFTR-dependent DBS without changing net Cl− secretion. This effect supports the hypothesis that Cl− secreted by CFTR is recycled across the apical membrane by anion exchangers. Recovery of water output during CFTR inhibition suggests that lubiprostone may improve the intestinal phenotype in CF patients. Furthermore, increased DBS suggests that lubiprostone may protect the duodenum from acid-induced injury via EP4 receptor activation

Eicosanoid Release Is Increased by Membrane Destabilization and CFTR Inhibition in Calu-3 Cells

The antiinflammatory protein annexin-1 (ANXA1) and the adaptor S100A10 (p11), inhibit cytosolic phospholipase A2 (cPLA2α) by direct interaction. Since the latter is responsible for the cleavage of arachidonic acid at membrane phospholipids, all three proteins modulate eicosanoid production. We have previously shown the association of ANXA1 expression with that of CFTR, the multifactorial protein mutated in cystic fibrosis. This could in part account for the abnormal inflammatory status characteristic of this disease. We postulated that CFTR participates in the regulation of eicosanoid release by direct interaction with a complex containing ANXA1, p11 and cPLA2α. We first analyzed by plasmon surface resonance the in vitro binding of CFTR to the three proteins. A significant interaction between p11 and the NBD1 domain of CFTR was found. We observed in Calu-3 cells a rapid and partial redistribution of all four proteins in detergent resistant membranes (DRM) induced by TNF-α. This was concomitant with increased IL-8 synthesis and cPLA2α activation, ultimately resulting in eicosanoid (PGE2 and LTB4) overproduction. DRM destabilizing agent methyl-β-cyclodextrin induced further cPLA2α activation and eicosanoid release, but inhibited IL-8 synthesis. We tested in parallel the effect of short exposure of cells to CFTR inhibitors Inh172 and Gly-101. Both inhibitors induced a rapid increase in eicosanoid production. Longer exposure to Inh172 did not increase further eicosanoid release, but inhibited TNF-α-induced relocalization to DRM. These results show that (i) CFTR may form a complex with cPLA2α and ANXA1 via interaction with p11, (ii) CFTR inhibition and DRM disruption induce eicosanoid synthesis, and (iii) suggest that the putative cPLA2/ANXA1/p11/CFTR complex may participate in the modulation of the TNF-α-induced production of eicosanoids, pointing to the importance of membrane composition and CFTR function in the regulation of inflammation mediator synthesis

Toxin Mediated Diarrhea in the 21st Century: The Pathophysiology of Intestinal Ion Transport in the Course of ETEC, V. cholerae and Rotavirus Infection

An estimated 4 billion episodes of diarrhea occur each year. As a result, 2–3 million children and 0.5–1 million adults succumb to the consequences of this major healthcare concern. The majority of these deaths can be attributed to toxin mediated diarrhea by infectious agents, such as E. coli, V. cholerae or Rotavirus. Our understanding of the pathophysiological processes underlying these infectious diseases has notably improved over the last years. This review will focus on the cellular mechanism of action of the most common enterotoxins and the latest specific therapeutic approaches that have been developed to contain their lethal effects

Mutations in KEOPS-Complex Genes Cause Nephrotic Syndrome with Primary Microcephaly

Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms

Body image in depression. Comparative analysis of people with affective disorders and with symptomatology of depression in the course of personality disorders.

Celem niniejszego opracowania jest zbadanie różnic pod względem obrazu własnego ciała wśród dwóch grup klinicznych: u pacjentów z zaburzeniami afektywnymi jednobiegunowymi oraz u grupy z symptomatologią depresji w przebiegu zaburzenia osobowości, a także porównanie ich z grupą kontrolną. Dodatkowo, praca ta ma na celu zbadanie związków pomiędzy depresją, obrazem ciała a autodestrukcją pośrednią i bezpośrednią (próba samobójcza). W referowanym badaniu wzięło udział 95 osób (33 grupa kontrolna, 32 afektywna, 30 osobowościowa). Zostali oni poproszeni o wypełnienie 3 kwestionariuszy, badających: głębokość depresji (Inwentarz Depresji Becka BDI), obraz ciała (Wielowymiarowy Kwestionariusz do Badania Obrazu Ciała The MBSRQ) oraz poziom autodestrukcji pośredniej (Skala Pośredniej Autodestruktywności PAD). Informacja, czy badany podjął w swoim życiu próbę samobójczą, została podana w Arkuszu danych socjodemograficznych. Analiza statystyczna wyników ujawniła, że: 1) Osoby z grupy kontrolnej najlepiej spośród wszystkich grup oceniają obraz własnego ciała; 2) osoby z grupy afektywnej lepiej niż osoby z grupy osobowościowej oceniają obraz własnego ciała; 3) osoby z grupy kontrolnej podejmują więcej zachowań pielęgnacyjnych wobec własnego ciała niż grupa osobowościowa; 4) w przypadku grupy osobowościowej, głębsza depresja wiąże się z gorszą oceną ciała i mniejszą ilością działań pielęgnacyjnych; 5) osoby z grupy osobowościowej, które podjęły próbę samobójczą, gorzej oceniają obraz swojego ciała i podejmują mniej zachowań związanych z dbałością o wygląd zewnętrzny.The aim of the present study was to examine the differences in terms of the body image among two clinical groups: inpatients with unipolar affective disorder and in a group with symptomatology of depression in the course of personality disorders, as well as comparing them with a control group. In addition, this work was aimed to explore the relationship between depression, body image and direct and indirect self-destruction (suicide attempt). 95 people participated in the study (33 control group, 32 affective group, 30 personality group). They were asked to fill in three questionnaires, examining: the depth of depression (Beck Depression Inventory BDI), body image (The Multidimensional Body-Self Relations Questionnaire The MBSRQ) and the level of indirect self-destructiveness (Chronic Self-Destructiveness Scale PAD). Information about whether the suicide attempt was made by patient was given in the socio-demographic data. Statistical analysis revealed that: 1) the control group best evaluated the image of one's own body; 2) the affective group better than the personality group evaluated the image of one's own body; 3) the control group took more body care behaviors than the personality group; 4) in the case of the personality group, deeper depression was associated with worse body assessment and fewer bodycare activities; 5) people from the personality group who attempted suicide evaluated their body image worse and took less actions related to taking care of the external appearance

Personal resources and a sense of burden in carers of people with unipolar affective disorder.

Celem niniejszej pracy jest zbadanie związku pomiędzy zasobami osobistymi a poczuciem obciążenia u opiekunów osób z zaburzeniem afektywnym jednobiegunowym. W referowanym badaniu udział wzięło 30 osób będących opiekunami osób chorych. Zostali oni poproszeni o wypełnienie 5 kwestionariuszy, badających: poczucie obciążenia (Skala Obciążenia Opiekuna), postrzegane wsparcie społeczne (Kwestionariusz Spostrzeganego Wsparcia ISEL), odporność psychiczną (Skala Pomiaru Prężności SPP-25), własną skuteczność (Skala Uogólnionej Własnej Skuteczności GSES), koherencję (Kwestionariusz Orientacji Życiowej SOC-29). Analiza statystyczna wyników ujawniła, że: 1) mężczyźni wykazują większe poczucie zrozumiałości niż kobiety będące opiekunami osób cierpiących na depresję; 2) opiekunowie osób znajdujących się w epizodzie depresji wykazują większe poczucie obciążenia niż opiekunowie osób będących w okresie remisji.The aim of this study is to examine the relationship between personal resources and the sense of burden in caregivers of people with unipolar affective disorder. 30 people took part in the study. They were asked to fill in 5 questionnaires examining: the feeling of burden (Zarit Caregiver Burden Scale), perceived social support (Interpersonal Support Evaluation ISEL), mental resilience (Scale of Resilience SPP-25), own effectiveness (General Self-Efficacy Scale GSES), coherence (Sense of Coherence Scale SOC-29). Statistical analysis of the results revealed that: 1) men have a greater sense of understanding than women being carers of people suffering from depression; 2) caregivers of people in the episode of depression show a greater sense of burden than caregivers of people who are in the remission period

Relationship between the fecundity of mothers and daughters

Целью настоящего труда было определение зависимости между средним числом ягнят урожденных матерьми и средним числом ягнят урожденных их дочерями происходящими из трех первых окотов и более поздних окотов. Установлено, что дочери, независимо от окота матери, из которого они происходят, характеризуются в сравнении с последними высшей оплодотворимостыо. Исчисленные коэффициенты фенотипной корреляции между оплотоворимостью матерей и их дочерей были существенными или высокосущественными. Самая тесная зависимость была установлена для среднего числа ягнят приходящегося на 1 окот матери за все годы репродуктивного использования, и числом ягнят приходящимся на 1 окот дочерей за все годы репродуктивного использования, происходящих из трех первых окотов матерей (в Угруске 0,179, в Боровине - 0,151).The aim of the work was to determine the relationship between the mean number of lambs reared by mother-ewes and the mean number of lambs born by their daughters originating from three first lambings and later lambings. It has been found that daughters, irrespective of lambing type, of their mothers from which they originate, distinguish themselves with higher fecundity. The calculated coefficients of the phenotypic correlation between the fecundity of mothers and their daughters were mostly statistically significant or highly significant. The closest relationship has been found for the mean number of lambs falling for 1 lambing of the mother for all years of the reproductive utilization and the number of lambs falling for 1 lambing of daughters for all the reproductive utilization years, originating from the first lambing of their mothers (at Uhrusk 0.179, at Borowina 0.151)