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Cell Mar 2022Fungal communities (the mycobiota) are an integral part of the gut microbiota, and the disruption of their integrity contributes to local and gut-distal pathologies....
Fungal communities (the mycobiota) are an integral part of the gut microbiota, and the disruption of their integrity contributes to local and gut-distal pathologies. Yet, the mechanisms by which intestinal fungi promote homeostasis remain unclear. We characterized the mycobiota biogeography along the gastrointestinal tract and identified a subset of fungi associated with the intestinal mucosa of mice and humans. Mucosa-associated fungi (MAF) reinforced intestinal epithelial function and protected mice against intestinal injury and bacterial infection. Notably, intestinal colonization with a defined consortium of MAF promoted social behavior in mice. The gut-local effects on barrier function were dependent on IL-22 production by CD4 T helper cells, whereas the effects on social behavior were mediated through IL-17R-dependent signaling in neurons. Thus, the spatial organization of the gut mycobiota is associated with host-protective immunity and epithelial barrier function and might be a driver of the neuroimmune modulation of mouse behavior through complementary Type 17 immune mechanisms.
Topics: Animals; Fungi; Gastrointestinal Microbiome; Immunity, Mucosal; Intestinal Mucosa; Mice; Mucous Membrane; Mycobiome; Receptors, Interleukin-17; Social Behavior
PubMed: 35176228
DOI: 10.1016/j.cell.2022.01.017 -
Physiological Reviews Apr 2014Reactive oxygen species (ROS) are generated as by-products of normal cellular metabolic activities. Superoxide dismutase, glutathione peroxidase, and catalase are the... (Review)
Review
Reactive oxygen species (ROS) are generated as by-products of normal cellular metabolic activities. Superoxide dismutase, glutathione peroxidase, and catalase are the enzymes involved in protecting cells from the damaging effects of ROS. ROS are produced in response to ultraviolet radiation, cigarette smoking, alcohol, nonsteroidal anti-inflammatory drugs, ischemia-reperfusion injury, chronic infections, and inflammatory disorders. Disruption of normal cellular homeostasis by redox signaling may result in cardiovascular, neurodegenerative diseases and cancer. ROS are produced within the gastrointestinal (GI) tract, but their roles in pathophysiology and disease pathogenesis have not been well studied. Despite the protective barrier provided by the mucosa, ingested materials and microbial pathogens can induce oxidative injury and GI inflammatory responses involving the epithelium and immune/inflammatory cells. The pathogenesis of various GI diseases including peptic ulcers, gastrointestinal cancers, and inflammatory bowel disease is in part due to oxidative stress. Unraveling the signaling events initiated at the cellular level by oxidative free radicals as well as the physiological responses to such stress is important to better understand disease pathogenesis and to develop new therapies to manage a variety of conditions for which current therapies are not always sufficient.
Topics: Animals; Antioxidants; Gastric Mucosa; Gastrointestinal Diseases; Homeostasis; Humans; Intestinal Mucosa; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; Signal Transduction
PubMed: 24692350
DOI: 10.1152/physrev.00040.2012 -
Journal of the European Academy of... Sep 2021This guideline on mucous membrane pemphigoid (MMP) has been elaborated by the Task Force for Autoimmune Blistering Diseases of the European Academy of Dermatology and...
This guideline on mucous membrane pemphigoid (MMP) has been elaborated by the Task Force for Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology (EADV) with a contribution of physicians from all relevant disciplines and patient organizations. It is a S3 consensus-based guideline encompassing a systematic review of the literature until June 2019 in the MEDLINE and EMBASE databases. This first part covers methodology, the clinical definition of MMP, epidemiology, MMP subtypes, immunopathological characteristics, disease assessment and outcome scores. MMP describes a group of autoimmune skin and mucous membrane blistering diseases, characterized by a chronic course and by predominant involvement of the mucous membranes, such as the oral, ocular, nasal, nasopharyngeal, anogenital, laryngeal and oesophageal mucosa. MMP patients may present with mono- or multisite involvement. Patients' autoantibodies have been shown to be predominantly directed against BP180 (also called BPAG2, type XVII collagen), BP230, laminin 332 and type VII collagen, components of junctional adhesion complexes promoting epithelial stromal attachment in stratified epithelia. Various disease assessment scores are available, including the Mucous Membrane Pemphigoid Disease Area Index (MMPDAI), the Autoimmune Bullous Skin disorder Intensity Score (ABSIS), the 'Cicatrising Conjunctivitis Assessment Tool' and the Oral Disease Severity Score (ODSS). Patient-reported outcome measurements (PROMs), including DLQI, ABQOL and TABQOL, can be used for assessment of quality of life to evaluate the effectiveness of therapeutic interventions and monitor disease course.
Topics: Autoantibodies; Autoantigens; Dermatology; Humans; Mucous Membrane; Pemphigoid, Benign Mucous Membrane; Pemphigoid, Bullous; Quality of Life; Systematic Reviews as Topic; Venereology
PubMed: 34245180
DOI: 10.1111/jdv.17397 -
Journal of the European Academy of... Oct 2021This guideline has been initiated by the task force Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology, including physicians from all...
This guideline has been initiated by the task force Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology, including physicians from all relevant disciplines and patient organizations. It is a S3 consensus-based guideline that systematically reviewed the literature on mucous membrane pemphigoid (MMP) in the MEDLINE and EMBASE databases until June 2019, with no limitations on language. While the first part of this guideline addressed methodology, as well as epidemiology, terminology, aetiology, clinical presentation and outcome measures in MMP, the second part presents the diagnostics and management of MMP. MMP should be suspected in cases with predominant mucosal lesions. Direct immunofluorescence microscopy to detect tissue-bound IgG, IgA and/or complement C3, combined with serological testing for circulating autoantibodies are recommended. In most patients, serum autoantibodies are present only in low levels and in variable proportions, depending on the clinical sites involved. Circulating autoantibodies are determined by indirect IF assays using tissue substrates, or ELISA using different recombinant forms of the target antigens or immunoblotting using different substrates. The major target antigen in MMP is type XVII collagen (BP180), although in 10-25% of patients laminin 332 is recognized. In 25-30% of MMP patients with anti-laminin 332 reactivity, malignancies have been associated. As first-line treatment of mild/moderate MMP, dapsone, methotrexate or tetracyclines and/or topical corticosteroids are recommended. For severe MMP, dapsone and oral or intravenous cyclophosphamide and/or oral corticosteroids are recommended as first-line regimens. Additional recommendations are given, tailored to treatment of single-site MMP such as oral, ocular, laryngeal, oesophageal and genital MMP, as well as the diagnosis of ocular MMP. Treatment recommendations are limited by the complete lack of high-quality randomized controlled trials.
Topics: Autoantibodies; Autoantigens; Dermatology; Humans; Mucous Membrane; Pemphigoid, Benign Mucous Membrane; Pemphigoid, Bullous; Venereology
PubMed: 34309078
DOI: 10.1111/jdv.17395 -
Peritoneal Dialysis International :... Jul 2021A pathophysiological classification of membrane dysfunction, which provides mechanistic links to functional characteristics, should be used when prescribing...
GUIDELINE 1
A pathophysiological classification of membrane dysfunction, which provides mechanistic links to functional characteristics, should be used when prescribing individualized dialysis or when planning modality transfer (e.g. to automated peritoneal dialysis (PD) or haemodialysis) in the context of shared and informed decision-making with the person on PD, taking individual circumstances and treatment goals into account. ().
GUIDELINE 2A
It is recommended that the PSTR is determined from a 4-h peritoneal equilibration test (PET), using either 2.5%/2.27% or 4.25%/3.86% dextrose/glucose concentration and creatinine as the index solute. () This should be done early in the course dialysis treatment (between 6 weeks and 12 weeks) () and subsequently when clinically indicated. ().
GUIDELINE 2B
A faster PSTR is associated with lower survival on PD. () This risk is in part due to the lower ultrafiltration (UF) and increased net fluid reabsorption that occurs when the PSTR is above the average value. The resulting lower net UF can be avoided by shortening glucose-based exchanges, using a polyglucose solution (icodextrin), and/or prescribing higher glucose concentrations. () Compared to glucose, use of icodextrin can translate into improved fluid status and fewer episodes of fluid overload. () Use of automated PD and icodextrin may mitigate the mortality risk associated with fast PSTR. ().
GUIDELINE 3
UF This is easy to measure and a valuable screening test. Insufficient UF should be suspected when either (a) the net UF from a 4-h PET is <400 ml (3.86% glucose/4.25% dextrose) or <100 ml (2.27% glucose /2.5% dextrose), () and/or (b) the daily UF is insufficient to maintain adequate fluid status. () Besides membrane dysfunction, low UF capacity can also result from mechanical problems, leaks or increased fluid absorption across the peritoneal membrane not explained by fast PSTR.
GUIDELINE 4A
Diagnosing intrinsic membrane dysfunction (manifesting as low osmotic conductance to glucose) as a cause of UF insufficiency: When insufficient UF is suspected, the 4-h PET should be supplemented by measurement of the sodium dip at 1 h using a 3.86% glucose/4.25% dextrose exchange for diagnostic purposes. A sodium dip ≤5 mmol/L and/or a sodium sieving ratio ≤0.03 at 1 h indicates UF insufficiency. ().
GUIDELINE 4B
in the absence of residual kidney function, this is likely to necessitate the use of hypertonic glucose exchanges and possible transfer to haemodialysis. Acquired membrane injury, especially in the context of prolonged time on treatment, should prompt discussions about the risk of encapsulating peritoneal sclerosis. ().
GUIDELINE 5
measures of peritoneal protein loss, intraperitoneal pressure and more complex tests that estimate osmotic conductance and 'lymphatic' reabsorption are not recommended for routine clinical practice but remain valuable research methods. ().
GUIDELINE 6
When resource constraints prevent the use of routine tests, consideration of membrane function should still be part of the clinical management and may be inferred from the daily UF in response to the prescription. ().
Topics: Adult; Dialysis Solutions; Glucans; Glucose; Humans; Icodextrin; Peritoneal Dialysis; Peritoneum; Sodium; Ultrafiltration
PubMed: 33563110
DOI: 10.1177/0896860820982218 -
Molecules (Basel, Switzerland) Aug 2022This review is an attempt to incorporate water as a structural and thermodynamic component of biomembranes. With this purpose, the consideration of the membrane... (Review)
Review
This review is an attempt to incorporate water as a structural and thermodynamic component of biomembranes. With this purpose, the consideration of the membrane interphase as a bidimensional hydrated polar head group solution, coupled to the hydrocarbon region allows for the reconciliation of two theories on cells in dispute today: one considering the membrane as an essential part in terms of compartmentalization, and another in which lipid membranes are not necessary and cells can be treated as a colloidal system. The criterium followed is to describe the membrane state as an open, non-autonomous and responsive system using the approach of Thermodynamic of Irreversible Processes. The concept of an open/non-autonomous membrane system allows for the visualization of the interrelationship between metabolic events and membrane polymorphic changes. Therefore, the Association Induction Hypothesis (AIH) and lipid properties interplay should consider hydration in terms of free energy modulated by water activity and surface (lateral) pressure. Water in restricted regions at the lipid interphase has thermodynamic properties that explain the role of H-bonding networks in the propagation of events between membrane and cytoplasm that appears to be relevant in the context of crowded systems.
Topics: Lipid Bilayers; Lipids; Membranes; Thermodynamics; Water
PubMed: 35956945
DOI: 10.3390/molecules27154994 -
Nature Communications Nov 2022Stimulus transduction in cilia of olfactory sensory neurons is mediated by odorant receptors, Gαolf, adenylate cyclase-3, cyclic nucleotide-gated and chloride ion...
Stimulus transduction in cilia of olfactory sensory neurons is mediated by odorant receptors, Gαolf, adenylate cyclase-3, cyclic nucleotide-gated and chloride ion channels. Mechanisms regulating trafficking and localization of these proteins in the dendrite are unknown. By lectin/immunofluorescence staining and in vivo correlative light-electron microscopy (CLEM), we identify a retinitis pigmentosa-2 (RP2), ESCRT-0 and synaptophysin-containing multivesicular organelle that is not part of generic recycling/degradative/exosome pathways. The organelle's intraluminal vesicles contain the olfactory transduction proteins except for Golf subunits Gγ13 and Gβ1. Instead, Gβ1 colocalizes with RP2 on the organelle's outer membrane. The organelle accumulates in response to stimulus deprivation, while odor stimuli or adenylate cyclase activation cause outer membrane disintegration, release of intraluminal vesicles, and RP2/Gβ1 translocation to the base of olfactory cilia. Together, these findings reveal the existence of a dendritic organelle that mediates both stimulus-regulated storage of olfactory ciliary transduction proteins and membrane-delimited sorting important for G protein heterotrimerization.
Topics: Adenylyl Cyclases; Multivesicular Bodies; Olfactory Receptor Neurons; Receptors, Odorant; Smell; Cilia; Proteins; Olfactory Mucosa
PubMed: 36371422
DOI: 10.1038/s41467-022-34604-y -
Philosophical Transactions of the Royal... Dec 2022Embryonic development and growth in placental mammals proceeds with the support of exchanges of gases, nutrients and waste products between maternal tissues and... (Review)
Review
Embryonic development and growth in placental mammals proceeds with the support of exchanges of gases, nutrients and waste products between maternal tissues and offspring. Murine embryos are surrounded by several extraembryonic membranes, parietal and visceral yolk sacs, and amnion in the uterus. Notably, the parietal yolk sac is the most outer membrane, consists of three layers, trophoblasts and parietal endoderm (PaE) cells, and is separated by a thick basal lamina termed Reichert's membrane (RM). RM is composed of extracellular matrix (ECM) initially formed as the basement membrane of the trophectoderm of pre-implanted embryos and followed by the heavy deposition of ECM mainly produced in PaE cells of post-implanted embryos. In addition to the physiological roles of RM, such as gas and nutrient exchange, it also plays a crucial role in cushioning and dispersing intrauterine pressures exerted on embryos for normal egg-cylinder morphogenesis. Mechanistically, such intrauterine pressures generated by uterine smooth muscle contractions appear to be involved in the elongation of the egg-cylinder shape, along with primary axis formation, as an important biomechanical element . This review focuses on our current views of the roles of RM in properly buffering intrauterine mechanical forces for mouse egg-cylinder morphogenesis. This article is part of the theme issue 'Extraembryonic tissues: exploring concepts, definitions and functions across the animal kingdom'.
Topics: Animals; Basement Membrane; Endoderm; Female; Gases; Mammals; Mice; Placenta; Pregnancy; Waste Products; Yolk Sac
PubMed: 36252218
DOI: 10.1098/rstb.2021.0257 -
Cell and Tissue Research Jul 2017The last 5 years have witnessed tremendous advances in both light- and electron-microscopic techniques in the biomedical sciences. Application of these new cutting-edge... (Review)
Review
The last 5 years have witnessed tremendous advances in both light- and electron-microscopic techniques in the biomedical sciences. Application of these new cutting-edge methods to glomerular biology has advanced considerably and, in part, completed our endeavor to draw a detailed map of the glomerular tuft. The scope of this review is to illustrate these new insights within both the morphometry of podocyte cells and the architecture of the glomerular filtration barrier and to assess whether these findings have indeed had an impact on our biological understanding of glomerular function.
Topics: Animals; Glomerular Basement Membrane; Humans; Podocytes
PubMed: 28283912
DOI: 10.1007/s00441-017-2590-3 -
Journal of the American Society of... Nov 2021Autoantibodies binding to podocyte antigens cause idiopathic membranous glomerulonephritis (iMGN). However, it remains elusive how autoantibodies reach the subepithelial...
BACKGROUND
Autoantibodies binding to podocyte antigens cause idiopathic membranous glomerulonephritis (iMGN). However, it remains elusive how autoantibodies reach the subepithelial space because the glomerular filtration barrier (GFB) is size selective and almost impermeable for antibodies.
METHODS
Kidney biopsies from patients with iMGN, cell culture, zebrafish, and mouse models were used to investigate the role of nephronectin (NPNT) regulating microRNAs (miRs) for the GFB.
RESULTS
Glomerular endothelial cell (GEC)-derived miR-192-5p and podocyte-derived miR-378a-3p are upregulated in urine and glomeruli of patients with iMGN, whereas glomerular NPNT is reduced. Overexpression of miR-192-5p and morpholino-mediated npnt knockdown induced edema, proteinuria, and podocyte effacement similar to podocyte-derived miR-378a-3p in zebrafish. Structural changes of the glomerular basement membrane (GBM) with increased lucidity, splitting, and lamellation, especially of the lamina rara interna, similar to ultrastructural findings seen in advanced stages of iMGN, were found. IgG-size nanoparticles accumulated in lucidity areas of the lamina rara interna and lamina densa of the GBM in npnt-knockdown zebrafish models. Loss of slit diaphragm proteins and severe structural impairment of the GBM were further confirmed in podocyte-specific Npnt knockout mice. GECs downregulate podocyte NPNT by transfer of miR-192-5p-containing exosomes in a paracrine manner.
CONCLUSIONS
Podocyte NPNT is important for proper glomerular filter function and GBM structure and is regulated by GEC-derived miR-192-5p and podocyte-derived miR-378a-3p. We hypothesize that loss of NPNT in the GBM is an important part of the initial pathophysiology of iMGN and enables autoantigenicity of podocyte antigens and subepithelial immune complex deposition in iMGN.
Topics: Animals; Antigen-Antibody Complex; Autoantigens; Cells, Cultured; Coculture Techniques; Endothelial Cells; Exosomes; Extracellular Matrix Proteins; Gene Expression Regulation; Gene Targeting; Glomerular Basement Membrane; Glomerulonephritis, Membranous; Gold Sodium Thiosulfate; Humans; Kidney Glomerulus; Metal Nanoparticles; Mice; MicroRNAs; Paracrine Communication; Permeability; Podocytes; Proteinuria; Transfection; Zebrafish; Zebrafish Proteins
PubMed: 34716242
DOI: 10.1681/ASN.2020121699