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American Journal of Physiology.... Apr 2016Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with a complex pathogenesis. Diarrhea is a highly prevalent and often debilitating symptom of IBD... (Review)
Review
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with a complex pathogenesis. Diarrhea is a highly prevalent and often debilitating symptom of IBD patients that results, at least in part, from an intestinal hydroelectrolytic imbalance. Evidence suggests that reduced electrolyte absorption is more relevant than increased secretion to this disequilibrium. This systematic review analyses and integrates the current evidence on the roles of epithelial Na(+)-K(+)-ATPase (NKA), Na(+)/H(+) exchangers (NHEs), epithelial Na(+) channels (ENaC), and K(+) channels (KC) in IBD-associated diarrhea. NKA is the key driving force of the transepithelial ionic transport and its activity is decreased in IBD. In addition, the downregulation of apical NHE and ENaC and the upregulation of apical large-conductance KC all contribute to the IBD-associated diarrhea by lowering sodium absorption and/or increasing potassium secretion.
Topics: Animals; Epithelial Cells; Epithelial Sodium Channels; Gastrointestinal Absorption; Gastrointestinal Agents; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Ion Transport; Membrane Transport Modulators; Potassium Channels; Signal Transduction; Sodium-Hydrogen Exchangers; Sodium-Potassium-Exchanging ATPase
PubMed: 26744474
DOI: 10.1152/ajpgi.00369.2015 -
Frontiers in Immunology 2019The Wnt signaling pathway is a conserved pathway involved in important cellular processes such as the control of embryonic development, cellular polarity, cellular... (Review)
Review
The Wnt signaling pathway is a conserved pathway involved in important cellular processes such as the control of embryonic development, cellular polarity, cellular migration, and cell proliferation. In addition to playing a central role during embryogenesis, this pathway is also an essential part of adult homeostasis. Indeed, it controls the proliferation of epithelial cells in different organs such as intestine, lung, and kidney, and guarantees the maintenance of the mucosa in physiological conditions. The origin of this molecular pathway is the binding between Wnt ligands (belonging to a family of 19 different homologous secreted glycoproteins) and their specific membrane receptors, from the Frizzled receptor family. This specific interaction triggers the activation of the signaling cascade, which in turn activates or suppresses the expression of different genes in order to change the behavior of the cell. On the other hand, alterations of this pathway have been described in pathological conditions such as inflammation, fibrosis, and cancer. In recent years, macrophages-among other cell types-have emerged as a potential source of Wnt ligands. Due to their high plasticity, macrophages, which are central to the innate immune response, are capable of adopting different phenotypes depending on their microenvironment. In the past, two different phenotypes were described: a proinflammatory phenotype-M1 macrophages-and an anti-inflammatory phenotype-M2 macrophages-and a selective expression of Wnt ligands has been associated with said phenotypes. However, nowadays it is assumed that macrophages move through a continual spectrum of functional phenotypes. In both physiological and pathological (inflammation, fibrosis and cancer) conditions, the accumulation and polarization of macrophages conditions the future of the tissue, facilitating various scenarios, such as resolution of inflammation, activation of fibrosis, and cancer development due to the modulation of the Wnt signaling pathway, in autocrine and paracrine manner. In this work, we provide an overview of studies that have explored the role of macrophages and how they act as a source of Wnt ligands and as mediators of mucosal integrity.
Topics: Humans; Immunity, Innate; Inflammation; Ligands; Macrophages; Mucous Membrane; Neoplasms; Protein Binding; Wnt Proteins; Wnt Signaling Pathway
PubMed: 31608072
DOI: 10.3389/fimmu.2019.02297 -
Hearing Research Sep 2022It is a common belief that the mammalian cochlea achieves its exquisite sensitivity, frequency selectivity, and dynamic range through an outer hair cell-based active...
It is a common belief that the mammalian cochlea achieves its exquisite sensitivity, frequency selectivity, and dynamic range through an outer hair cell-based active process, or cochlear amplification. As a sound-induced traveling wave propagates from the cochlear base toward the apex, outer hair cells at a narrow region amplify the low level sound-induced vibration through a local feedback mechanism. This widely accepted theory has been tested by measuring sound-induced sub-nanometer vibrations within the organ of Corti in the sensitive living cochleae using heterodyne low-coherence interferometry and optical coherence tomography. The aim of this short review is to summarize experimental findings on the cochlear active process by the authors' group. Our data show that outer hair cells are able to generate substantial forces for driving the cochlear partition at all audible frequencies in vivo. The acoustically induced reticular lamina vibration is larger and more broadly tuned than the basilar membrane vibration. The reticular lamina and basilar membrane vibrate approximately in opposite directions at low frequencies and in the same direction at the best frequency. The group delay of the reticular lamina is larger than that of the basilar membrane. The magnitude and phase differences between the reticular lamina and basilar membrane vibration are physiologically vulnerable. These results contradict predictions based on the local feedback mechanism but suggest a global hydromechanical mechanism for cochlear amplification. This article is part of the Special Issue Outer hair cell Edited by Joseph Santos-Sacchi and Kumar Navaratnam.
Topics: Animals; Basilar Membrane; Cochlea; Hair Cells, Auditory, Outer; Mammals; Organ of Corti; Sound; Vibration
PubMed: 34922772
DOI: 10.1016/j.heares.2021.108407 -
International Journal of Molecular... Jun 2021In order to overcome the limitations associated with vaginal administration of drugs, e.g., the short contact time of the drug form with the mucosa or continuous carrier... (Review)
Review
In order to overcome the limitations associated with vaginal administration of drugs, e.g., the short contact time of the drug form with the mucosa or continuous carrier wash-out, the development of new carriers for gynecological use is necessary. Furthermore, high individual anatomical and physiological variability resulting in unsatisfactory therapeutic efficacy of lipophilic active substances requires application of multicompartment drug delivery systems. This manuscript provides an up-to-date comprehensive review of the literature on emulsion-based vaginal dosage forms (EVDF) including macroemulsions, microemulsions, nanoemulsions, multiple emulsions and self-emulsifying drug delivery systems. The first part of the paper discusses (i) the influence of anatomical-physiological conditions on therapeutic efficacy of drug forms after local and systemic administration, (ii) characterization of EVDF components and the manufacturing techniques of these dosage forms and (iii) methods used to evaluate the physicochemical and pharmaceutical properties of emulsion-based vaginal dosage forms. The second part of the paper presents (iv) the results of biological and in vivo studies as well as (v) clinical evaluation of EVDF safety and therapeutic efficacy across different indications.
Topics: Administration, Intravaginal; Chemical Phenomena; Drug Carriers; Drug Compounding; Drug Delivery Systems; Emulsions; Female; Humans; Microbiota; Mucous Membrane; Pharmaceutical Preparations; Theranostic Nanomedicine
PubMed: 34208652
DOI: 10.3390/ijms22126455 -
Frontiers in Immunology 2021Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse drug effect. There are multiple hypotheses to explain the development of MRONJ. Reduced... (Review)
Review
Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse drug effect. There are multiple hypotheses to explain the development of MRONJ. Reduced bone remodeling and infection or inflammation are considered central to the pathogenesis of MRONJ. In recent years, increasing evidence has shown that bisphosphonates (BPs)-mediated immunity dysfunction is associated with the pathophysiology of MRONJ. In a healthy state, mucosal immunity provides the first line of protection against pathogens and oral mucosal immune cells defense against potentially invading pathogens by mediating the generation of protective immunoinflammatory responses. In addition, the immune system takes part in the process of bone remodeling and tissue repair. However, the treatment of BPs disturbs the mucosal and osteo immune homeostasis and thus impairs the body's ability to resist infection and repair from injury, thereby adding to the development of MRONJ. Here, we present the current knowledge about immunity dysfunction to shed light on the role of local immune disorder in the development of MRONJ.
Topics: Animals; Biomarkers; Bone Density Conservation Agents; Cytokines; Diphosphonates; Disease Susceptibility; Drug-Related Side Effects and Adverse Reactions; Humans; Immunity, Mucosal; Inflammation Mediators; Jaw; Mucous Membrane; Osteogenesis; Osteonecrosis; Signal Transduction; Wound Healing
PubMed: 33717086
DOI: 10.3389/fimmu.2021.606043 -
Journal of Cell Science Aug 2014The cell cortex is a dynamic and heterogeneous structure that governs cell identity and behavior. The ERM proteins (ezrin, radixin and moesin) are major architects of...
The cell cortex is a dynamic and heterogeneous structure that governs cell identity and behavior. The ERM proteins (ezrin, radixin and moesin) are major architects of the cell cortex, and they link plasma membrane phospholipids and proteins to the underlying cortical actin cytoskeleton. Recent studies in several model systems have uncovered surprisingly dynamic and complex molecular activities of the ERM proteins and have provided new mechanistic insight into how they build and maintain cortical domains. Among many well-established and essential functions of ERM proteins, this Cell Science at a Glance article and accompanying poster will focus on the role of ERMs in organizing the cell cortex during cell division and apical morphogenesis. These examples highlight an emerging appreciation that the ERM proteins both locally alter the mechanical properties of the cell cortex, and control the spatial distribution and activity of key membrane complexes, establishing the ERM proteins as a nexus for the physical and functional organization of the cell cortex and making it clear that they are much more than scaffolds. This article is part of a Minifocus on Establishing polarity.
Topics: Animals; Basement Membrane; Cell Polarity; DNA-Binding Proteins; Epithelial Cells; GTPase-Activating Proteins; Humans; Integrins; Neoplasms; Transcription Factors
PubMed: 24951115
DOI: 10.1242/jcs.098343 -
Biochimica Et Biophysica Acta Sep 2014There are many peptides known that inhibit the entry of enveloped viruses into cells, including one peptide that is successfully being used in the clinic as a drug. In... (Review)
Review
There are many peptides known that inhibit the entry of enveloped viruses into cells, including one peptide that is successfully being used in the clinic as a drug. In this review, we discuss the discovery, antiviral activity and mechanism of action of such peptides. While peptide entry inhibitors have been discovered by a wide variety of approaches (structure-based, accidental, intentional, rational and brute force) we show here that they share a common physical chemical property: they are at least somewhat hydrophobic and/or amphipathic and have a propensity to interact with membrane interfaces. We propose that this propensity drives a shared mechanism of action for many peptide entry inhibitors, involving direct interactions with viral and cellular membranes, as well as interactions with the complex hydrophobic protein/lipid interfaces that are exposed, at least transiently, during virus-cell fusion. By interacting simultaneously with the membrane interfaces and other critical hydrophobic surfaces, we hypothesize that peptide entry inhibitors can act by changing the physical chemistry of the membranes, and the fusion protein interfaces bridging them, and by doing so interfere with the fusion of cellular and viral membranes. Based on this idea, we propose that an approach that focuses on the interfacial hydrophobicity of putative entry inhibitors could lead to the efficient discovery of novel, broad-spectrum viral entry inhibitors. This article is part of a Special Issue entitled: Interfacially Active Peptides and Proteins. Guest Editors: William C. Wimley and Kalina Hristova.
Topics: Cell Membrane; Genome, Viral; Hydrophobic and Hydrophilic Interactions; Membrane Fusion; Membranes; Peptides; Protein Conformation; Viral Envelope Proteins; Viral Fusion Proteins; Virion
PubMed: 24780375
DOI: 10.1016/j.bbamem.2014.04.015 -
International Journal of Molecular... Jun 2019Mycotoxins, which are widely found in feed ingredients and human food, can exert harmful effects on animals and pose a serious threat to human health. As the first... (Review)
Review
Mycotoxins, which are widely found in feed ingredients and human food, can exert harmful effects on animals and pose a serious threat to human health. As the first barrier against external pollutants, the intestinal mucosa is protected by a mechanical barrier, chemical barrier, immune barrier, and biological barrier. Firstly, mycotoxins can disrupt the mechanical barrier function of the intestinal mucosa, by destroying the morphology and tissue integrity of the intestinal epithelium. Secondly, mycotoxins can cause changes in the composition of mucin monosaccharides and the expression of intestinal mucin, which in turn affects mucin function. Thirdly, mycotoxins can cause damage to the intestinal mucosal immune barrier function. Finally, the microbiotas of animals closely interact with ingested mycotoxins. Based on existing research, this article reviews the effects of mycotoxins on the intestinal mucosal barrier and its mechanisms.
Topics: Animals; Humans; Immunity, Innate; Intestinal Mucosa; Mucins; Mycotoxins
PubMed: 31174254
DOI: 10.3390/ijms20112777 -
International Journal of Molecular... Jan 2022Pleural injury and subsequent loculation is characterized by acute injury, sustained inflammation and, when severe, pathologic tissue reorganization. While fibrin... (Review)
Review
Pleural injury and subsequent loculation is characterized by acute injury, sustained inflammation and, when severe, pathologic tissue reorganization. While fibrin deposition is a normal part of the injury response, disordered fibrin turnover can promote pleural loculation and, when unresolved, fibrosis of the affected area. Within this review, we present a brief discussion of the current IPFT therapies, including scuPA, for the treatment of pathologic fibrin deposition and empyema. We also discuss endogenously expressed PAI-1 and how it may affect the efficacy of IPFT therapies. We further delineate the role of pleural mesothelial cells in the progression of pleural injury and subsequent pleural remodeling resulting from matrix deposition. We also describe how pleural mesothelial cells promote pleural fibrosis as myofibroblasts via mesomesenchymal transition. Finally, we discuss novel therapeutic targets which focus on blocking and/or reversing the myofibroblast differentiation of pleural mesothelial cells for the treatment of pleural fibrosis.
Topics: Animals; Disease Progression; Drug Delivery Systems; Fibrosis; Gene Expression Regulation; Humans; Plasminogen Activator Inhibitor 1; Pleura; Recombinant Proteins; Urokinase-Type Plasminogen Activator
PubMed: 35163509
DOI: 10.3390/ijms23031587 -
Hearing Research Sep 2022Cochlear distortions afford researchers and clinicians a glimpse into the conditions and properties of inner ear signal processing mechanisms. Until recently, our... (Review)
Review
Cochlear distortions afford researchers and clinicians a glimpse into the conditions and properties of inner ear signal processing mechanisms. Until recently, our examination of these distortions has been limited to measuring the vibration of the basilar membrane or recording acoustic distortion output in the ear canal. Despite its importance, the generation mechanism of cochlear distortion remains a substantial task to understand. The ability to measure the vibration of the reticular lamina in rodent models is a recent experimental advance. Surprising mechanical properties have been revealed. These properties merit both discussion in context with our current understanding of distortion, and appraisal of the significance of new interpretations of cochlear mechanics. This review focusses on some of the recent data from our research groups and discusses the implications of these data on our understanding of vocalization processing in the periphery, and their influence upon future experimental directions. This article is part of the Special Issue Outer hair cell Edited by Joseph Santos-Sacchi and Kumar Navaratnam.
Topics: Acoustic Stimulation; Basement Membrane; Basilar Membrane; Cochlea; Hair Cells, Auditory, Outer; Vibration
PubMed: 34916081
DOI: 10.1016/j.heares.2021.108405