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Journal of Hepatology Feb 2021Many epithelia secrete bicarbonate-rich fluid to generate flow, alter viscosity, control pH and potentially protect luminal and intracellular structures from chemical... (Review)
Review
Many epithelia secrete bicarbonate-rich fluid to generate flow, alter viscosity, control pH and potentially protect luminal and intracellular structures from chemical stress. Bicarbonate is a key component of human bile and impaired biliary bicarbonate secretion is associated with liver damage. Major efforts have been undertaken to gain insight into acid-base homeostasis in cholangiocytes and more can be learned from analogous secretory epithelia. Extrahepatic examples include salivary and pancreatic duct cells, duodenocytes, airway and renal epithelial cells. The cellular machinery involved in acid-base homeostasis includes carbonic anhydrase enzymes, transporters of the solute carrier family, and intra- and extracellular pH sensors. This pH-regulatory system is orchestrated by protein-protein interactions, the establishment of an electrochemical gradient across the plasma membrane and bicarbonate sensing of the intra- and extracellular compartment. In this review, we discuss conserved principles identified in analogous secretory epithelia in the light of current knowledge on cholangiocyte physiology. We present a framework for cholangiocellular acid-base homeostasis supported by expression analysis of publicly available single-cell RNA sequencing datasets from human cholangiocytes, which provide insights into the molecular basis of pH homeostasis and dysregulation in the biliary system.
Topics: Acid-Base Equilibrium; Acid-Base Imbalance; Bicarbonates; Bile; Bile Ducts; Epithelium; Humans; Hydrogen-Ion Concentration; Secretory Pathway
PubMed: 33342564
DOI: 10.1016/j.jhep.2020.10.010 -
Food Research International (Ottawa,... Aug 2023Many healthy people suffer from milk-related gastrointestinal discomfort (GID) despite not being lactose intolerant; the mechanisms underpinning such condition are...
Many healthy people suffer from milk-related gastrointestinal discomfort (GID) despite not being lactose intolerant; the mechanisms underpinning such condition are unknown. This study aimed to explore milk protein digestion and related physiological responses (primary outcome), gut microbiome and gut permeability in 19 lactose-tolerant healthy nonhabitual milk consumers [NHMCs] reporting GID after consuming cow milk compared to 20 habitual milk consumers [HMCs] without GID. NHMCs and HMCs participated in a milk-load (250 mL) test, underwent blood sample collection at 6 time points over 6 h after milk consumption and collected urine samples and GID self-reports over 24 h. We measured the concentrations of 31 milk-derived bioactive peptides (BAPs), 20 amino acids, 4 hormones, 5 endocannabinoid system mediators, glucose and the dipeptidyl peptidase-IV (DPPIV) activity in blood and indoxyl sulfate in urine samples. Subjects also participated in a gut permeability test and delivered feces sample for gut microbiome analysis. Results showed that, compared to HMCs, milk consumption in NHMCs, along with GID, elicited a slower and lower increase in circulating BAPs, lower responses of ghrelin, insulin, and anandamide, a higher glucose response and serum DPPIV activity. The gut permeability of the two groups was similar, while the habitual diet, which was lower in dairy products and higher in the dietary-fibre-to-protein ratio in NHMCs, possibly shaped the gut microbiome; NHMCs exhibited lower abundance of Bifidobacteria, higher abundance of Prevotella and lower abundance of protease-coding genes, which may have reduced protein digestion, as evidenced by lower urinary excretion of indoxyl sulfate. In conclusion, the findings showed that a less efficient digestion of milk proteins, supported by a lower proteolytic capability of the gut microbiome, may explain GID in healthy people after milk consumption.
Topics: Animals; Cattle; Female; Humans; Milk; Milk Proteins; Proteolysis; Gastrointestinal Microbiome; Healthy Volunteers; Indican; Lactose
PubMed: 37316045
DOI: 10.1016/j.foodres.2023.112953 -
Frontiers in Endocrinology 2020Proteins to be secreted through so-called "conventional mechanisms" are characterized by the presence of an N-terminal peptide that is a leader or signal peptide, needed... (Review)
Review
Proteins to be secreted through so-called "conventional mechanisms" are characterized by the presence of an N-terminal peptide that is a leader or signal peptide, needed for access to the endoplasmic reticulum and the Golgi apparatus for further secretion. However, some relevant cytosolic proteins lack of this signal peptides and should be secreted by different unconventional or "non-canonical" processes. One form of this unconventional secretion was named secretory autophagy (SA) because it is specifically associated with the autophagy pathway. It is defined by ATG proteins that regulate the biogenesis of the autophagosome, its representative organelle. The canonical macroautophagy involves the fusion of the autophagosomes with lysosomes for content degradation, whereas the SA pathway bypasses this degradative process to allow the secretion. ATG5, as well as other factors involved in autophagy such as BCN1, are also activated as part of the secretory pathway. SA has been recognized as a new mechanism that is becoming of increasing relevance to explain the unconventional secretion of a series of cytosolic proteins that have critical biological importance. Also, SA may play a role in the release of aggregation-prone protein since it has been related to the autophagosome biogenesis machinery. SA requires the autophagic pathway and both, secretory autophagy and canonical degradative autophagy are at the same time, integrated and highly regulated processes that interact in ultimate cross-talking molecular mechanisms. The potential implications of alterations in SA, its cargos, pathways, and regulation in human diseases such as metabolic/aging pathological processes are predictable. Further research of SA as potential target of therapeutic intervention is deserved.
Topics: Animals; Autophagosomes; Autophagy; Humans; Intervertebral Disc Degeneration; Metabolic Diseases; Protein Transport; Proteins; Secretory Pathway
PubMed: 32477265
DOI: 10.3389/fendo.2020.00266 -
Neuroendocrinology 2023Identification of the molecular mechanisms governing neuroendocrine secretion and resulting intercellular communication is one of the great challenges of cell biology to... (Review)
Review
Identification of the molecular mechanisms governing neuroendocrine secretion and resulting intercellular communication is one of the great challenges of cell biology to better understand organism physiology and neurosecretion disruption-related pathologies such as hypertension, neurodegenerative, or metabolic diseases. To visualize molecule distribution and dynamics at the nanoscale, many imaging approaches have been developed and are still emerging. In this review, we provide an overview of the pioneering studies using transmission electron microscopy, atomic force microscopy, total internal reflection microscopy, and super-resolution microscopy in neuroendocrine cells to visualize molecular mechanisms driving neurosecretion processes, including exocytosis and associated fusion pores, endocytosis and associated recycling vesicles, and protein-protein or protein-lipid interactions. Furthermore, the potential and the challenges of these different advanced imaging approaches for application in the study of neuroendocrine cell biology are discussed, aiming to guide researchers to select the best approach for their specific purpose around the crucial but not yet fully understood neurosecretion process.
Topics: Exocytosis; Bodily Secretions; Diagnostic Imaging
PubMed: 34915491
DOI: 10.1159/000521457 -
Frontiers in Immunology 2021Intestinal mucus plays important roles in protecting the epithelial surfaces against pathogens, supporting the colonization with commensal bacteria, maintaining an... (Review)
Review
Intestinal mucus plays important roles in protecting the epithelial surfaces against pathogens, supporting the colonization with commensal bacteria, maintaining an appropriate environment for digestion, as well as facilitating nutrient transport from the lumen to the underlying epithelium. The mucus layer in the poultry gut is produced and preserved by mucin-secreting goblet cells that rapidly develop and mature after hatch as a response to external stimuli including environmental factors, intestinal microbiota as well as dietary factors. The ontogenetic development of goblet cells affects the mucin composition and secretion, causing an alteration in the physicochemical properties of the mucus layer. The intestinal mucus prevents the invasion of pathogens to the epithelium by its antibacterial properties (e.g. β-defensin, lysozyme, avidin and IgA) and creates a physical barrier with the ability to protect the epithelium from pathogens. Mucosal barrier is the first line of innate defense in the gastrointestinal tract. This barrier has a selective permeability that allows small particles and nutrients passing through. The structural components and functional properties of mucins have been reviewed extensively in humans and rodents, but it seems to be neglected in poultry. This review discusses the impact of age on development of goblet cells and their mucus production with relevance for the functional characteristics of mucus layer and its protective mechanism in the chicken's intestine. Dietary factors directly and indirectly (through modification of the gut bacteria and their metabolic activities) affect goblet cell proliferation and differentiation and can be used to manipulate mucosal integrity and dynamic. However, the mode of action and mechanisms behind these effects need to be studied further. As mucins resist to digestion processes, the sloughed mucins can be utilized by bacteria in the lower part of the gut and are considered as endogenous loss of protein and energy to animal. Hydrothermal processing of poultry feed may reduce this loss by reduction in mucus shedding into the lumen. Given the significance of this loss and the lack of precise data, this matter needs to be carefully investigated in the future and the nutritional strategies reducing this loss have to be defined better.
Topics: Amino Acids; Animal Feed; Animals; Bacterial Translocation; Chickens; Dietary Fats; Dietary Proteins; Edible Grain; Gastrointestinal Microbiome; Goblet Cells; Hydrogen-Ion Concentration; Intestinal Absorption; Intestinal Mucosa; Intestines; Mucins; Mucus; Nutrients; Oxidative Stress; Particle Size
PubMed: 34671361
DOI: 10.3389/fimmu.2021.745849 -
Journal of Extracellular Vesicles Sep 2022Extracellular vesicle (EV) secretion enables cell-cell communication in multicellular organisms. During development, EV secretion and the specific loading of signalling...
Extracellular vesicle (EV) secretion enables cell-cell communication in multicellular organisms. During development, EV secretion and the specific loading of signalling factors in EVs contributes to organ development and tissue differentiation. Here, we present an in vivo model to study EV secretion using the fat body and the haemolymph of the fruit fly, Drosophila melanogaster. The system makes use of tissue-specific EV labelling and is amenable to genetic modification by RNAi. This allows the unique combination of microscopic visualisation of EVs in different organs and quantitative biochemical purification to study how EVs are generated within the cells and which factors regulate their secretion in vivo. Characterisation of the system revealed that secretion of EVs from the fat body is mainly regulated by Rab11 and Rab35, highlighting the importance of recycling Rab GTPase family members for EV secretion. We furthermore discovered a so far unknown function of Rab14 along with the kinesin Klp98A in EV biogenesis and secretion.
Topics: Animals; Bodily Secretions; Drosophila Proteins; Drosophila melanogaster; Endosomes; Extracellular Vesicles; Kinesins; Signal Transduction; rab GTP-Binding Proteins
PubMed: 36103151
DOI: 10.1002/jev2.12263 -
Nutrients Oct 2023Our narrative review focuses on colostrum components, particularly those that influence the neonatal immune system of newborns. Colostrum is secreted in small volumes by... (Review)
Review
Our narrative review focuses on colostrum components, particularly those that influence the neonatal immune system of newborns. Colostrum is secreted in small volumes by the alveolar cells of the breast during the first two to five days after birth. Colostrum is poor in fat and carbohydrates, with larger protein and bioactive compounds than mature milk. It plays a crucial role in driving neonates' immunity, transferring those immunological factors which help the correct development of the neonatal immune system and support establishing a healthy gut microbiome. The newborn has an innate and adaptive immune system deficiency, with a consequent increase in infection susceptibility. In particular, neonates born prematurely have reduced immunological competencies due to an earlier break in the maternal trans-placenta transfer of bioactive components, such as maternal IgG antibodies. Moreover, during pregnancy, starting from the second trimester, maternal immune cells are conveyed to the fetus and persist in small quantities post-natal, whereby this transfer is known as microchimerism (MMc). Thus, preterm newborns are deficient in this maternal heritage, and have their own immune system under-developed, but colostrum can compensate for the lack. Early breastfeeding, which should be strongly encouraged in mothers of preterm and full-term babies, provides those immunomodulant compounds that can act as a support, allowing the newborn to face immune needs, including fronting infections and establishing tolerance. Moreover, making mothers aware that administering colostrum helps their infants in building a healthy immune system is beneficial to sustain them in the difficult post-partum period.
Topics: Pregnancy; Female; Infant, Newborn; Humans; Colostrum; Breast Feeding; Milk, Human; Lactation; Antibodies; Infant, Newborn, Diseases; Anti-Inflammatory Agents
PubMed: 37836533
DOI: 10.3390/nu15194249 -
Journal of Proteome Research Sep 2023Cerebrospinal fluid (CSF) is an essential matrix for the discovery of neurological disease biomarkers. However, the high dynamic range of protein concentrations in CSF...
Cerebrospinal fluid (CSF) is an essential matrix for the discovery of neurological disease biomarkers. However, the high dynamic range of protein concentrations in CSF hinders the detection of the least abundant protein biomarkers by untargeted mass spectrometry. It is thus beneficial to gain a deeper understanding of the secretion processes within the brain. Here, we aim to explore if and how the secretion of brain proteins to the CSF can be predicted. By combining a curated CSF proteome and the brain elevated proteome of the Human Protein Atlas, brain proteins were classified as CSF or non-CSF secreted. A machine learning model was trained on a range of sequence-based features to differentiate between CSF and non-CSF groups and effectively predict the brain origin of proteins. The classification model achieves an area under the curve of 0.89 if using high confidence CSF proteins. The most important prediction features include the subcellular localization, signal peptides, and transmembrane regions. The classifier generalized well to the larger brain detected proteome and is able to correctly predict novel CSF proteins identified by affinity proteomics. In addition to elucidating the underlying mechanisms of protein secretion, the trained classification model can support biomarker candidate selection.
Topics: Humans; Proteome; Brain; Protein Transport; Biological Transport; Biomedical Research; Cerebrospinal Fluid Proteins
PubMed: 37606934
DOI: 10.1021/acs.jproteome.3c00366 -
Cells Oct 2023Impaired iron homeostasis has been proven to be one of the critical contributors to the pathology of Parkinson's disease (PD). Ferritin is considered an intracellular...
Impaired iron homeostasis has been proven to be one of the critical contributors to the pathology of Parkinson's disease (PD). Ferritin is considered an intracellular protein responsible for storing cytosolic iron. Recent studies have found that ferritin can be secreted from cells independent of the classical endoplasmic reticulum-Golgi system. However, the precise mechanisms underlying the secretion of ferritin in the brain were not elucidated. In the present study, we demonstrated that the primary cultured astrocytes do have the ability to secrete ferritin, which is enhanced by iron treatment. Increased ferritin secretion was accompanied by increased protein expression of ferritin response to iron stimulation. Further study showed that iron-induced expression and secretion of ferritin could be inhibited by CQ or 3-MA pretreatment. In addition, the knockdown of transient receptor potential mucolipin 1 (TRPML1) antagonized iron-induced ferritin secretion, accompanied by further increased intracellular protein levels of ferritin. Further study demonstrated that ferritin colocalized with LAMP1 in iron-treated astrocytes. On the contrary, ras-associated protein 27a (Rab27a) knockdown further enhanced iron-induced ferritin secretion and decreased intracellular protein levels of ferritin. Furthermore, we also showed that the secretory autophagy protein tripartite motif containing 16 (TRIM16) and sec22b decreased in iron-treated astrocytes. These results suggested that astrocytes might secrete ferritin via TRPML1-mediated exocytosis. This provides new evidence for the mechanisms underlying the secretion of ferritin in primary cultured astrocytes under a high iron environment.
Topics: Iron; Ferritins; Astrocytes; Biological Transport; Exocytosis
PubMed: 37947597
DOI: 10.3390/cells12212519 -
Bone Research Aug 2023Proper regulation of Wnt signaling is critical for normal bone development and homeostasis. Mutations in several Wnt signaling components, which increase the activity of...
Proper regulation of Wnt signaling is critical for normal bone development and homeostasis. Mutations in several Wnt signaling components, which increase the activity of the pathway in the skeleton, cause high bone mass in human subjects and mouse models. Increased bone mass is often accompanied by severe headaches from increased intracranial pressure, which can lead to fatality and loss of vision or hearing due to the entrapment of cranial nerves. In addition, progressive forehead bossing and mandibular overgrowth occur in almost all subjects. Treatments that would provide symptomatic relief in these subjects are limited. Porcupine-mediated palmitoylation is necessary for Wnt secretion and binding to the frizzled receptor. Chemical inhibition of porcupine is a highly selective method of Wnt signaling inhibition. We treated three different mouse models of high bone mass caused by aberrant Wnt signaling, including homozygosity for loss-of-function in Sost, which models sclerosteosis, and two strains of mice carrying different point mutations in Lrp5 (equivalent to human G171V and A214V), at 3 months of age with porcupine inhibitors for 5-6 weeks. Treatment significantly reduced both trabecular and cortical bone mass in all three models. This demonstrates that porcupine inhibition is potentially therapeutic for symptomatic relief in subjects who suffer from these disorders and further establishes that the continued production of Wnts is necessary for sustaining high bone mass in these models.
Topics: Animals; Humans; Mice; Adaptor Proteins, Signal Transducing; Bodily Secretions; Disease Models, Animal; Gain of Function Mutation; Hyperostosis; Low Density Lipoprotein Receptor-Related Protein-5; Mutation
PubMed: 37612291
DOI: 10.1038/s41413-023-00278-5