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Story at-a-glance Breastfeeding for at least six months increases gut microbiome diversity in infants, reducing inflammation and supporting immune function, which contributes to lower blood pressure in early childhood A one-unit increase in gut microbiome diversity at one month of age correlates with a 1.86 mmHg decrease in systolic blood pressure by age 6, lowering long-term cardiovascular risk Formula-fed infants have a less diverse gut microbiome with more inflammatory bacteria, increasing the likelihood of gut imbalance, immune dysfunction, and higher blood pressure later in life Human milk oligosaccharides (HMOs) in breastmilk selectively feed beneficial bacteria, enhancing digestion, immune support, and disease protection, advantages formula cannot replicate Secretory immunoglobulin A (SIgA) in breastmilk strengthens gut lining integrity, prevents infections, and trains the immune system to differentiate between harmful and harmless substances
In this episode, we detail the role of immunoglobulins in gut-immune function, examining their involvement in mucosal defense, microbial regulation, and immune homeostasis within the intestines. We discuss the mechanisms of antibody production, highlighting how secretory IgA (sIgA) contributes to intestinal barrier integrity and pathogen neutralization. We also detail low secretory immunoglobulin A levels and Candida overgrowth. Lastly, we go through tools to support the gut-immune axis including oral immunoglobulin supplementation.1. Introduction - Overview of immunoglobulins, roles in gut-immune health - The gut as a constant interface with antigens, microbes, and potential pathogens - Adequate but balanced immunoglobulin levels; preventing opportunistic pathogen overgrowth 2. Immunoglobulins - Immunoglobulins (Ig) as glycoproteins, fundamental role in immune defense - Five major immunoglobulin isotypes and their distinct roles - How immunoglobulins recognize and neutralize pathogens / toxins / foreign antigens 3. Antibody Production in the Intestines - Naïve B cells originate in the bone marrow, migrate to secondary lymphoid tissues - Antigen-presenting cells (APCs) facilitate antigen processing and B cell activation - Plasma cells and mucosal immunity 4. The Intestinal Barrier and Immune Components - Layers of the gut barrier and their functions - The role of gut-associated lymphoid tissue (GALT) in immune surveillance - Immune cells within the lamina propria and their contributions to gut homeostasis 5. Secretory IgA (sIgA) and Its Role in Gut Immunity - sIgA production and transport across the intestinal epithelium - Role of sIgA in immune exclusion and pathogen neutralization 6. Factors That Can Influence sIgA Levels - Chronic stress, infections, and gut inflammation as contributors to low sIgA - Consequences of low sIgA, including increased susceptibility to pathogens - Nutrients essential for supporting optimal sIgA levels 7. Other Key Immunoglobulins in Gut Immunity - Immunoglobulin G's role in immune responses / pathogen neutralization - Immunoglobulin M's location and function as an early immune responder in mucosal defense 8. Supplemental Immunoglobulins - Oral immunoglobulin supplementation and its benefits - Bovine colostrum as a source of immunoglobulins for intestinal and immune support 9. Conclusion - Recap of immunoglobulins' role in gut-immune function - The importance of balanced IgA, IgG, and IgM levels - Strategies to support gut immunityThank you to our episode sponsor:1. Shop CYLN's full skincare line here.Get Chloe's Book Today! "75 Gut-Healing Strategies & Biohacks" Follow Chloe on Instagram @synthesisofwellnessVisit synthesisofwellness.com
In this episode, we discuss the relationship between the intestinal mucus layer and secretory immunoglobulin A (sIgA), highlighting both as key components of the gut's first line of defense against pathogens, toxins, and environmental stressors. We detail how dysbiosis and microbial overgrowths can impact sIgA levels and can disrupt mucus integrity and function, contributing to increased intestinal permeability and inflammation. We then examine several additional factors influencing sIgA production. Topics: 1. Introduction: Importance of Secretory IgA and Intestinal Mucus - Intestinal epithelial lining and its protective mucus layer - Focus on intestinal dysbiosis and sIgA 2. Anatomy of the Gastrointestinal Lining - Intestinal lumen, microbiome, mucus layer, epithelial cells, tight junctions, lamina propria, and smooth muscle - Role of goblet cells in mucus secretion and epithelial integrity 3. Role of the Protective Mucus Layer - Dual function of the mucus layer as a physical and biochemical barrier - Composition of mucus: mucins, antimicrobial peptides, immunoglobulins 4. Goblet Cells and Mucin Production - Mechanisms of mucin secretion and hydration - Variability in goblet cell density across the intestinal tract - Dysfunctions linked to conditions like IBD and IBS 5. Microbial Interactions with Mucins - Glycan structures in mucins - Roles of commensal and pathogenic bacteria in mucin degradation and mucus turnover - Importance of regulated mucus production for gut homeostasis 6. Dysbiosis and Mucus Degradation - Excessive mucin degradation leading to thinning of the mucus layer - Consequences of increased intestinal permeability and inflammation - Role of dysbiosis in disrupting the mucus layer 7. Overview of Secretory IgA - Introduction to secretory IgA (sIgA) and its role in mucosal immunity - Mechanisms of immune exclusion and pathogen neutralization 8. Production and Function of Secretory IgA - sIgA production by plasma cells in the lamina propria - Translocation of IgA through epithelial cells into the gut lumen - sIgA binding to mucins and its immunological role in the mucus layer 9. Factors Affecting Secretory IgA Levels - Possible contributing factors to low sIgA levels - Implications of low and high sIgA levels for immune defense and intestinal health 10. Interactions Between Secretory IgA and Dysbiosis - Cyclical relationship between low sIgA, dysbiosis, and infections - Examples of overgrowths, like candida, disrupting sIgA - Importance of addressing immune dysregulation to break the cycle 11. Bioindividual Root Cause Approach - Factors to consider Thank you to our episode sponsors: 1. Shop Fresh Press Farms' Peach Cider Vinegar at Sprouts locations nationwide, and check out their full collection here. 2. Check out Spectrum Sciences' Serums and The Vitamin B12 Protocol here, and use code CHLOE15 for 15% off. Get Chloe's Book Today! "75 Gut-Healing Strategies & Biohacks" Follow Chloe on Instagram @synthesisofwellness Visit synthesisofwellness.com
In this episode, we go through the gut-immune axis and mycobiome, focusing on the mechanisms underlying intestinal fungal overgrowth. We highlight the roles of the intestinal mucus layer, intestinal epithelial cells, lamina propria, and secretory immunoglobulin A (sIgA) in maintaining homeostasis and defending against fungal overgrowth. We also detail the pathogenic transition of Candida from its commensal yeast form to an invasive hyphal state, as well as the resulting disruptions to immune function. Topics 1. Introduction to the Gut-Immune Axis and Mycobiome - The gut-immune axis and mycobiome. - Exploring intestinal fungal overgrowth. 2. Overview of the Gastrointestinal Lining - Anatomy of the intestinal lining: lumen and microbiome, mucus layer, epithelial monolayer, and lamina propria. - The dual role of the mucus layer: physical and biochemical barrier. - Composition of mucus. 3. Goblet Cells and Mucus Production - Goblet cells as critical producers of mucin glycoproteins and their role in mucus barrier integrity. - Signals for mucin release, such as mechanical stress. 4. The Lamina Propria and Gut-Associated Lymphoid Tissue (GALT) - Layers beneath the epithelium - Peyer's patches, mesenteric lymph nodes, isolated lymphoid follicles, and intraepithelial lymphocytes. - Immune tolerance and defense against pathogens. 5. Peyer's Patches - Positioning of Peyer's patches. - The transition of microbial density from the small intestine to the colon and its immune implications. 6. Immune Cells in the Lamina Propria - Overview of macrophages, dendritic cells, mast cells, plasma cells, and lymphocytes. - Their role in maintaining immunological equilibrium in the gut. 7. The Mycobiome and Pathogenic Transition of Candida - Candida's transition from yeast to hyphal form. - Regulation of Candida by microbial competition and immune surveillance. - Factors promoting pathogenicity: immune suppression, lacking beneficial microbes, more. 8. Virulence Factors of Candida - Secretion of hydrolytic enzymes such as SAPs and phospholipases. - Degradation of sIgA and its consequences for immune evasion. - Adhesins that facilitate fungal binding. 9. Intestinal Barrier Disruption by Candida - Penetration of the mucus layer and epithelial barrier by Candida hyphae. - Disruption of tight junctions and the resulting increased intestinal permeability. - Inflammatory cascade triggered by fungal antigens and microbial toxins entering the lamina propria. 10. Biofilm Formation - The role of biofilms in shielding fungal cells from immune attack and antifungal treatments. 11. Small Intestinal Fungal Overgrowth (SIFO) - Intestinal dysmotility, low stomach acid, immunocompromise. - Possible symptoms of SIFO. - Discussion of the overlap between SIFO, SIBO, histamine intolerance, and other gastrointestinal conditions. - Root cause. Thank you to our episode sponsors: 1. Shop Fresh Press Farms' Peach Cider Vinegar at Sprouts locations nationwide, and check out their full collection here. 2. Check out Ulyana Organics' Tallow Wild Yam Cream and Healing Facial Oil, and use code CHLOE10 10% off your order. 3. Check out Spectrum Sciences' Serums and The Vitamin B12 Protocol here, and use code CHLOE15 for 15% off. Get Chloe's Book Today! "75 Gut-Healing Strategies & Biohacks" Follow Chloe on Instagram @synthesisofwellness Visit synthesisofwellness.com
In this episode, we dive into the interplay between the gut microbiota (their postbiotics) and the immune system. We will examine how gut microbiome-derived metabolites, such as short-chain fatty acids (SCFAs) and polyphenol metabolites, influence immune function by modulating key cellular and molecular pathways within the intestinal mucosa. Additionally, we discuss strategies for supporting butyrate production and optimizing microbiome health to foster a balanced and resilient gut-immune axis. Topics: 1. Introduction Overview of the gut-immune axis. Importance of gut microbiome-derived metabolites in supporting immune function. 2. The Intestinal Barrier Layers of the intestinal wall Focus on mucosa, specifically the epithelium and lamina propria. 3. Structure of the Intestinal Layers The intestinal lumen, mucus layer, epithelium (with tight junctions), and lamina propria. Importance of the lamina propria as a hub for immune responses and structural integrity. 4. Cellular and Structural Components of the Lamina Propria Extracellular matrix (ECM): structural support. Fibroblasts and myofibroblasts. Lymphatic vessels: immune cell transport, linking mucosal and systemic immune systems. 5. Immune Cells in the Lamina Propria T cells: immune tolerance, regulatory T cells (Tregs). B cells: Secretory immunoglobulin A (sIgA). Dendritic cells: antigen sampling and presentation. Macrophages: pathogen clearance. Mast cells 6. Role of Secretory Immunoglobulin A (sIgA) Functions as a first-line defense in the intestinal mucus layer. Neutralizes pathogens, prevents epithelial adhesion. 7. Postbiotics Overview Bioactive compounds produced by gut microbiota. Examples: short-chain fatty acids (SCFAs) 8. Short-Chain Fatty Acids (SCFAs) and Their Functions Influence on Treg cells in the lamina propria, promoting immune tolerance. Butyrate also as an energy source for epithelial cells. 9. Supporting Butyrate Production Microbiome optimization to enhance beneficial butyrate-producing microbes. Use of prebiotics: resistant starch, soluble fibers, and polyphenols. Supplementation with sodium butyrate as an additional tool. 10. Other Postbiotics Antimicrobial peptides produced by beneficial microbes. Complex carbohydrates produced by beneficial microbes and can act as prebiotics. Polyphenol metabolites: Gut microbiota biotransforms polyphenols into bioactive metabolites with increased bioavailability. 11. Specific Polyphenols Examples: resveratrol, quercetin, and ellagitannins. Effects on intestinal barrier function, inflammation, and immune cell populations. "75 Gut-Healing Strategies & Biohacks" Follow Chloe on Instagram @synthesisofwellness Follow Chloe on TikTok @chloe_c_porter Visit synthesisofwellness.com --- Support this podcast: https://podcasters.spotify.com/pod/show/chloe-porter6/support
In today's episode, we dive into the interplay between the gut and immune system, focusing specifically on the critical role of immunoglobulins in mucosal immunity. Immunoglobulins, specialized glycoproteins synthesized by B cells, serve as the frontline defenders within the gastrointestinal tract, where they neutralize pathogens and maintain immune homeostasis. We also explore the mechanisms by which these antibodies fortify the intestinal barrier and aid in preventing dysbiosis. We finish by going through tools for supporting immunoglobulins. Topics: 1. Introduction - Overview of the gut-immune axis and focus on immunoglobulins. - How low levels of immunoglobulins can contribute to dysbiosis. 2. What Are Immunoglobulins? - Immunoglobulins (Igs) are glycoproteins produced by B cells. - They play a critical role in recognizing and neutralizing pathogens. - Antigen-binding sites for specific targeting. - Essential for immune homeostasis and pathogen elimination. 3. Immunoglobulins' Role in the Gut - Protect mucosal surfaces exposed to antigens. - B cells differentiate into plasma cells, and secrete immunoglobulins into the gut lumen. 4. Layers of the Intestinal Lining - Intestinal lumen is covered by a protective mucus layer. - Mucosa consists of epithelial cells, including mucus-secreting goblet cells. - Lamina propria beneath the epithelium is rich in immune cells. - Submucosa beneath mucosa. 5. The Function of the Mucus Layer - Acts as a physical barrier against pathogens. - Functions as a biochemical barrier by housing antimicrobial peptides and immunoglobulins. - Primarily composed of mucins secreted by goblet cells. - Goblet cells release mucins in response to stimuli, forming gel-like mucus. 6. Introduction to Secretory Immunoglobulin A (sIgA) - sIgA is the most abundant immunoglobulin in mucosal secretions. - Forms a protective barrier in the mucus layer. - Plays a critical role in immune exclusion by trapping and neutralizing pathogens. - Helps maintain non-inflammatory defense at mucosal surfaces. 7. Production of Secretory IgA - Plasma cells in the lamina propria secrete IgA. - IgA binds to receptors on epithelial cells and is transported across to the gut lumen. - sIgA to neutralize pathogens effectively within the mucus layer. 8. Functions of Secretory IgA in the Gut - Binds to antigens like bacterial walls, viruses, and toxins. - Traps antigens in the mucus to prevent adherence to epithelial cells. - Provides immune exclusion, reducing pathogen access to the gut lining. - Maintains mucosal barrier integrity to prevent inflammation. 9. Impact of Low sIgA Levels - Contributes to dysbiosis by allowing pathogenic bacteria to proliferate. - Intestinal hyperpermeability. - Increased risk of intestinal inflammation and infections. 10. Comparison with Other Immunoglobulins: IgG and IgM - IgG is most abundant in blood. - IgM is produced early in immune responses. - IgM can also be secreted into the gut lumen in IgA deficiency. 11. Immunoglobulin Supplements - IgG supplements. - Colostrum: IgG to help neutralize pathogens. - Supports gut barrier integrity. 12. Supporting Immunoglobulin Levels - Colostrum - Probiotics, prebiotics - Vitamin A - Zinc 13. Conclusion - Immunoglobulins, intestinal health, and immune balance. Thanks for tuning in! "75 Gut-Healing Strategies & Biohacks" Follow Chloe on Instagram @synthesisofwellness Follow Chloe on TikTok @chloe_c_porter Visit synthesisofwellness.com --- Support this podcast: https://podcasters.spotify.com/pod/show/chloe-porter6/support
In this episode, we explore the critical role of Secretory IgA (sIgA) in maintaining intestinal health. We discuss how sIgA acts as a frontline immune defense, preventing pathogens from adhering to the gut epithelium and aiding in controlling microbial populations. Additionally, we dive into the implications of low and high sIgA levels - as indicated in a stool test, how sIgA levels relate to dysbiosis and Candida overgrowth, addressing underlying root causes, and tools for supporting healthy sIgA levels. Topics: 1. Introduction to Secretory IgA and its Functions - Overview of sIgA's role in mucosal immunity - Importance of sIgA in maintaining the gut's lining integrity - How sIgA regulates pathogenic microbes in the gut 2. Structure of the Gut Lining and Mucosal Layers - The intestinal lumen and the protective mucus layer - Layers of the intestinal wall: mucosa, submucosa, muscularis, and serosa - The epithelium within the mucosa: epithelial cells including goblet cells 3. The Mucus Layer and Its Protective Function - Composition of the mucus layer: mucins and other components - How the mucus acts as both a physical and biochemical barrier - Differences between the mucus layer in the small and large intestines 4. Secretory IgA: Location and Role in the Gut - Where sIgA is found in the mucus layer - Differences in sIgA concentration in the small vs. large intestine - Interaction between sIgA and mucins to trap pathogens 5. Production and Secretion of Secretory IgA - Plasma cells in the lamina propria and their role in sIgA production - Transport of sIgA across the gut epithelium via the polymeric immunoglobulin receptor (pIgR) - Secretory component (SC) and its role in protecting sIgA from degradation 6. Immune Functions of sIgA in the Gut - Binding and neutralizing pathogens - The process of immune exclusion - The role of sIgA in preventing pathogen adherence to epithelial cells 7. Low and High sIgA Levels and Gut Conditions - What low and high sIgA levels can indicate in a stool test - Gut conditions associated with abnormal sIgA levels (e.g., dysbiosis, Candida overgrowth, infections) - The impact of chronic stress and prolonged infections on sIgA levels 8. Root Causes for Low sIgA Levels - Addressing root causes and underlying infections - Lifestyle factors that support healthy sIgA levels - Nutrients such as Vitamin A and Zinc for supporting sIgA production 9. Probiotics & More to Support sIgA - Probiotics, prebiotics, and phages that enhance sIgA production - Individual gut health needs Thank you to our episode sponsors: 1. Check out Daily Nouri and use code CHLOE20 for 20% off your order. 2. Check out the TruAge Biological Age Test from TruMe Labs. Thanks for tuning in! Get Chloe's Book Today! "75 Gut-Healing Strategies & Biohacks" Follow Chloe on Instagram @synthesisofwellness Follow Chloe on TikTok @chloe_c_porter Visit synthesisofwellness.com to purchase products, subscribe to our mailing list, and more! --- Support this podcast: https://podcasters.spotify.com/pod/show/chloe-porter6/support
In this episode, we explore the crucial role of the protective mucus layer in maintaining intestinal lining integrity, highlighting how it shields the epithelial cells from harmful substances and supports overall digestive function. We dive into the components and functions of mucins, goblet cells, and secretory IgA, explaining their contributions to gut immunity and barrier integrity. Additionally, we discuss strategies for supporting mucus production centered around butyrate, N-acetyl glucosamine, and plant-derived mucilage. Topics: 1. Introduction: Overview of the Gastrointestinal Mucus Layer - Importance of the mucus secretions in forming a protective layer - Brief review of the gastrointestinal lining and its structure 2. The Mucosal Layer and Its Components - The mucus layer on the epithelial cells of the mucosa - Four main layers of the intestinal wall, focusing on the mucosa - Epithelium: absorptive enterocytes and mucus-secreting goblet cells - Lamina propria: connective tissue rich in immune cells, blood vessels, and lymphatics - Smooth muscle aiding in subtle movements - Submucosa: thicker connective tissue layer with blood vessels, nerves, and lymphatics 3. Dual Function of the Mucus Layer - Physical barrier preventing pathogens and toxins from reaching epithelial cells - Biochemical barrier housing antimicrobial peptides and immunoglobulins 4. Goblet Cells and Their Role in Mucin Production - Goblet cells: specialized epithelial cells producing mucins - Distribution of goblet cells from small to large intestine - Importance of goblet cells in maintaining the mucus barrier 5. Mucins: Structure and Glycosylation - Glycosylation and its role in mucus properties and host-microbiota interactions - Commensal bacteria and their interactions with mucins (e.g., Bacteroides and Akkermansia muciniphila) 6. The Importance of Controlled Mucin Degradation - Mutualistic relationship between mucin-degrading bacteria and the host - Risks of dysregulated mucin degradation, leading to dysbiosis and leaky gut 7. Secretory IgA and Its Role in Gut Immunity - Overview of secretory IgA (sIgA) and its production - sIgA's mechanism of neutralizing pathogens "without inflammation" - Immune exclusion as a defense mechanism to maintain gut barrier integrity 8. Recap: The Dynamic Nature of the Mucus Layer - Continuous renewal of the mucus layer and the role of goblet cells and plasma cells - Importance of regular mucus turnover for maintaining a healthy gut barrier 9. Supporting Gastrointestinal Mucus Production - Short-chain fatty acids (SCFAs) and their role in stimulating mucus production - Butyrate and its effects on goblet cells and epithelial repair - N-Acetyl Glucosamine (NAG) as a supplement to support mucin glycosylation 10. Supporting the Intestinal Lining After Dysbiosis or Increased Permeability - Mucilage and its role in coating and soothing mucosal surfaces - Plant-derived mucilage from slippery elm and marshmallow root - Physical protection provided by mucilage - Soothing effects on inflamed tissues and promoting smooth digestion Thank you to our episode sponsor: 1. Check out Daily Nouri and use code CHLOE20 for 20% off your order. Thanks for tuning in! Get Chloe's Book Today! "75 Gut-Healing Strategies & Biohacks" Follow Chloe on Instagram @synthesisofwellness Follow Chloe on TikTok @chloe_c_porter Visit synthesisofwellness.com to purchase products, subscribe to our mailing list, and more! --- Support this podcast: https://podcasters.spotify.com/pod/show/chloe-porter6/support
NPR's CEO is an overly pious narcissist. German politician threatens exactly what I'd say they'd threaten. Why is the Secretory of the Department of Homeland Security tied to NGOs that push unfettered immigration?
Dr. Guerra: membrane graduate biochemistry lecture notes J Cell Mol Med . 2015 Jul;19(7):1427-40 Langmuir, 2018, 34 (1), pp 530–539 Elgar, E. 1900. The Dream of Gerontius https://youtu.be/rnwmVypRY-g?si=CxF8tZrfRR-uWdhn --- Send in a voice message: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/message Support this podcast: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/support
Join Dr. Gurevich in a break down of when and how to use stool SIgA in clinical practice. The doctors discuss: - What is SIgA? - What does it tell us about your immune system? - How to analyze SIgA in clinical practice? - How lab values and set - How to interpret labs with an informed but skeptical view - What dietary and lifestyle modifications and change this marker - What supplements can impact the SIgA results Learn more about us at: Ilana Gurevich ND, FABNG, LAc, MSOM - https://www.openwellnesspdx.com Rebecca Sand ND, LAc, MSOM - https://www.drrebeccasand.com/ Ami Kapadia, MD, ABFM, ABIHM - https://www.amikapadia.com/
References J Pharm Bioallied Sci. 2019 May; 11(Suppl 2): S135–S139. J Oral Microbiol. 2017; 9(1): 1400858. J Dent Res. 2020 Jun;99(6):644-649. Mozart WA 1782. D major, K. 385. Symphony 35 (Haffner) --- Send in a voice message: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/message Support this podcast: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/support
In today's episode, Chris & Filly dive into a common “pattern” linked to body burnout - PERFECTIONISM - and how it causes adrenal fatigue & breaks down the gut. They cover: What is “perfectionism” (hint: it's not about having “high standards” but actually “lack of standards”) How perfectionism stems from NLP (neurolinguistic programming) meta-programs around self-esteem, goal-striving & stress coping The deepest root-cause of perfectionism - core wound beliefs you have about yourself How perfectionism stresses out your adrenal glands How perfectionism & stress then breaks down the gut, leading to depleted secretory IgA, leaky gut & digestive organ breakdown How to rewire your brain & nervous system from perfectionism patterns & heal your body systems Want more of this goodness? Register for our FREE 3-Day LIVE Beating Body Burnout & Perfectionism event kicking off next week! And, if you're keen to finally get to the root of your body burnout and heal your WHOLE self for lasting results, apply to secure a spot in our Ending Body Burnout Method. Doors are OPEN until 29th Aug - get in on our hugely discounted beta-prices (prices will double next time!). Show Note Links: Register for the 3-Day LIVE Beating Body Burnout & Perfectionism Challenge Apply for the Ending Body Burnout Method here Take our Ending Body Burnout Assessment here Check out how you can work with us here Disclaimer: This Ending Body Burnout Show podcast and any information, advice, opinions or statements within it do not constitute medical, health care or other professional advice, and are provided for general information purposes only. All care is taken in the preparation of the information in this Podcast. Chris & Filly Functional Medicine does not make any representations or give any warranties about its accuracy, reliability, completeness or suitability for any particular purpose. This Podcast and any information, advice, opinions or statements within it are not to be used as a substitute for professional medical, psychology, psychiatric or other mental health care or natural medicine health care. Chris & Filly Functional Medicine recommends you seek the advice of your doctor or other qualified health providers with any questions you may have regarding a medical condition. Inform your doctor of any changes you may make to your lifestyle and discuss these with your doctor. Do not disregard medical advice or delay visiting a medical professional because of something you hear in this Podcast. To the extent permissible by law Chris & Filly Functional Medicine and the Ending Body Burnout Show Podcast will not be liable for any expenses, losses, damages (including indirect or consequential damages) or costs which might be incurred as a result of the information being inaccurate or incomplete in any way and for any reason. No part of this Podcast can be reproduced, redistributed, published, copied or duplicated in any form without the prior permission of Chris & Filly Functional Medicine.
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.08.01.551382v1?rss=1 Authors: Choi, H., Liao, Y.-C., Yoon, Y. J., Grimm, J. B., Lavis, L., Singer, R. H., Lippincott-Schwartz, J. Abstract: One-third of the mammalian proteome is comprised of transmembrane and secretory proteins that are synthesized on endoplasmic reticulum (ER). Here, we investigate the spatial distribution and regulation of mRNAs encoding these membrane and secretory proteins (termed 'secretome' mRNAs) through live cell, single molecule tracking to directly monitor the position and translation states of secretome mRNAs on ER and their relationship to other organelles. Notably, translation of secretome mRNAs occurred preferentially near lysosomes on ER marked by the ER junction-associated protein, Lunapark. Knockdown of Lunapark reduced the extent of secretome mRNA translation without affecting translation of other mRNAs. Less secretome mRNA translation also occurred when lysosome function was perturbed by raising lysosomal pH or inhibiting lysosomal proteases. Secretome mRNA translation near lysosomes was enhanced during amino acid deprivation. Addition of the integrated stress response inhibitor, ISRIB, reversed the translation inhibition seen in Lunapark knockdown cells, implying an eIF2 dependency. Altogether, these findings uncover a novel coordination between ER and lysosomes, in which local release of amino acids and other factors from ER-associated lysosomes patterns and regulates translation of mRNAs encoding secretory and membrane proteins. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.30.551178v1?rss=1 Authors: Ma, C.-I. J., Brill, J. A. Abstract: Secretory granules (SGs) are crucial for normal animal physiology due to their role in regulated exocytosis of biologically active molecules. SG membranes are enriched in phosphatidylinositol 4-phosphate (PI4P) and cholesterol, and previous studies suggest lipid composition is important for SG biogenesis and function. Nonetheless, the molecular details of how lipids are regulated during SG biogenesis remain poorly understood. Here, we identify Oxysterol binding protein (Osbp) as a novel regulator of SG biogenesis in a Drosophila model. We show Osbp expression level positively correlates with SG size and that Osbp requires type II phosphatidylinositol 4-kinase (PI4KII) to increase SG size. Moreover, Osbp is needed for proper PI4KII and PI4P distribution, autophagic resolution and formation of cholesterol-rich endosomal tubules that are positive for PI4KII. Feeding larvae food supplemented with sterol leads to partial suppression of SG size and PI4P distribution defects in Osbp mutants. Our results indicate that reciprocal regulation of Osbp and PI4KII drives formation of membrane tubules that mediate SG maturation through elevating PI4P levels on SG membranes. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.19.549095v1?rss=1 Authors: Lyu, Z., Genereux, J. C. Abstract: Proximity labeling is a powerful approach for characterizing subcellular proteomes. We recently demonstrated that proximity labeling can be used to identify mistrafficking of secretory proteins, such as occurs during pre-emptive quality control (pre-QC) following endoplasmic reticulum (ER) stress. This assay depends on protein quantification by immunoblotting and densitometry, which is only semi-quantitative and suffers from poor sensitivity. Here, we integrate parallel reaction monitoring mass spectrometry to enable a more quantitative platform for ER import. PRM as opposed to densitometry improves quantification of transthyretin mistargeting while also achieving at least a ten-fold gain in sensitivity. The multiplexing of PRM also enabled us to evaluate a series of normalization approaches, revealing that normalization to auto-labeled APEX2 peroxidase is necessary to account for drug treatment-dependent changes in labeling efficiency. We apply this approach to systematically characterize the relationship between chemical ER stressors and ER pre-QC induction in HEK293T cells. Using dual-FLAG-tagged transthyretin (FLAGTTR) as a model secretory protein, we find that Brefeldin A treatment as well as ER calcium depletion cause pre-QC, while tunicamycin and dithiothreitol do not, indicating ER stress alone is not sufficient. This finding contrasts with the canonical model of pre-QC induction, and establishes the utility of our platform. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.10.548399v1?rss=1 Authors: Suda, Y., Tachikawa, H., Suda, T., Kurokawa, K., Nakano, A., Irie, K. Abstract: Gametogenesis in budding yeast involves large-scale rearrangement of membrane traffic to allow de novo formation of a membrane, called the prospore membrane (PSM). However, the mechanism underlying this event is not fully elucidated. Here, we show that the number of endoplasmic reticulum exit sites (ERES) per cell fluctuates and switches from decreasing to increasing upon the onset of PSM formation. Reduction in ERES number is accompanied by a transient stall in membrane traffic, resulting in loss of the preexisting Golgi apparatus from the cell, as well as local ERES regeneration, leading to Golgi reassembly in nascent spores. We have revealed that protein phosphatase-1 (PP-1) and its development-specific subunit, Gip1, promote ERES regeneration through Sec16 foci formation. Furthermore, a mutant with impaired ERES formation showed defects in PSM growth and spore formation. Thus, ERES regeneration in nascent spores facilitates the segregation of membrane traffic organelles, leading to PSM growth. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.27.546668v1?rss=1 Authors: Banik, P., Kamps, J., Chen, Q.-Y., Luesch, H., Winklhofer, K. F., Tatzelt, J. Abstract: Mistargeting of secretory proteins to the cytosol can induce formation of aggregation-prone conformers and subsequent proteostasis decline. We have identified a quality control pathway that redirects non-ER-imported prion protein (PrP) to proteasomal degradation in the nucleus to prevent formation of toxic aggregates in the cytosol. Upon aborted ER import, PrP sequentially interacted with VCP/p97 and importins, which kept PrP soluble and promoted its nuclear import. In the nucleus, RNA buffered aggregation of PrP to facilitate ubiquitin-dependent proteasomal degradation. Notably, the cytosolic interaction of PrP with VCP/p97 and its nuclear import were independent of ubiquitination but required the intrinsically unstructured N-terminal domain of PrP. Transient proteotoxic stress promoted the formation of self-perpetuating PrP aggregates in the cytosol, which disrupted further nuclear targeting of PrP and compromised cellular proteostasis. Our study delineates a VCP/p97-dependent nucleus-based quality control pathway of non-ER-imported secretory proteins and emphasizes the important role of the nuclear milieu for the degradation of aggregation-prone proteins. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
A new editorial paper was published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 8, entitled, “The senescence-associated secretory phenotype induces neuroendocrine transdifferentiation.” In this editorial, researchers Anda Huna, Nadine Martin and David Bernard from the Université de Lyon discuss the senescence-associated secretory phenotype (SASP). SASP, in addition to stable proliferation arrest, is one of the most remarkable characteristics of senescent cells. Indeed, these cells secrete a variety of factors including cytokines, growth factors and matrix metalloproteases among others. In response to stress, through their SASP, senescent cells are able to modify and instruct their microenvironment. “The SASP is known to have several, sometimes contradictory, effects on phenotypes, including the induction or reinforcement of senescence in neighboring cells, promotion or inhibition of stemness, modification of extracellular matrix, activation or inhibition of immune responses and induction of epithelial-mesenchymal transition and cell migration.” Although cellular senescence and its SASP can initially display some beneficial effects, for instance favoring wound healing or blocking tumor initiation, accumulation of senescent cells and their secretome during aging or chronic stresses (tobacco, obesity, alcohol among others) plays a significant role in promoting aging-associated features and pathologies, like fibrosis, steatosis, chronic inflammation or cancer. In the context of cancer, senescence initially has an antitumoral role, as it promotes proliferation arrest and favors an anti-tumoral immune surveillance in response to oncogenic stress or DNA damage accumulation. However, SASP plays a dual role in tumor initiation and progression, as it first has a tumor suppressive action by reinforcing senescence in neighboring cells and recruiting immune cells, but also plays a tumor promoting role by promoting stemness, epithelial-mesenchymal transition and cell migration and by inhibiting immune responses. “Overall our work reveals a new effect of senescent cells and their SASP in tumors and offers new insights into NED [neuroendocrine transdifferentiation] in breast and prostate cancer biology. It also provides a new vision of the contribution of senescent cells and their SASP to aging-related pathologies, which could involve NED induction in some contexts.” DOI - https://doi.org/10.18632/aging.204669 Corresponding author - David Bernard - david.bernard@lyon.unicancer.fr Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204669 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, cellular senescence, aging, cancer, NF-κB, calcium signaling About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.18.537395v1?rss=1 Authors: Castello-Serrano, I., Heberle, F. A., Diaz-Rohrer, B., Ippolito, R., Shurer, C. R., Lujan, P., Campelo, F., Levental, K. R., Levental, I. Abstract: The organelles of eukaryotic cells maintain distinct protein and lipid compositions required for their specific functions. The mechanisms by which many of these components are sorted to their specific locations remain unknown. While some motifs mediating subcellular protein localization have been identified, many membrane proteins and most membrane lipids lack known sorting determinants. A putative mechanism for sorting of membrane components is based on membrane domains known as lipid rafts, which are laterally segregated nanoscopic assemblies of specific lipids and proteins. To assess the role of such domains in the secretory pathway, we applied a robust tool for synchronized secretory protein traffic (RUSH, Retention Using Selective Hooks) to protein constructs with defined affinity for raft phases. These constructs consist solely of single-pass transmembrane domains (TMDs) and, lacking other sorting determinants, constitute probes for membrane domain-mediated trafficking. We find that while raft affinity can be sufficient for steady-state PM localization, it is not sufficient for rapid exit from the endoplasmic reticulum (ER), which is instead mediated by a short cytosolic peptide motif. In contrast, we find that Golgi exit kinetics are highly dependent on raft affinity, with raft preferring probes exiting Golgi ~2.5-fold faster than probes with minimal raft affinity. We rationalize these observations with a kinetic model of secretory trafficking, wherein Golgi export can be facilitated by protein association with raft domains. These observations support a role for raft-like membrane domains in the secretory pathway and establish an experimental paradigm for dissecting its underlying machinery. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.06.535922v1?rss=1 Authors: Tang, V. T., Abbineni, P. S., da Veiga Leprevost, F., Basrur, V., Emmer, B. T., Nesvizhskii, A., Ginsburg, D. Abstract: Most proteins secreted into the extracellular space are first recruited from the endoplasmic reticulum into coat protein complex II (COPII)-coated vesicles or tubules that facilitate their transport to the Golgi apparatus. Although several secreted proteins have been shown to be actively recruited into COPII vesicles/tubules by the cargo receptors LMAN1 and SURF4, the full cargo repertoire of these receptors is unknown. We now report mass spectrometry analysis of conditioned media and cell lysates from HuH7 cells CRISPR targeted to inactivate the LMAN1 or SURF4 gene. We found that LMAN1 has limited clients in HuH7 cells whereas SURF4 traffics a broad range of cargoes. Analysis of putative SURF4 cargoes suggests that cargo recognition is governed by complex mechanisms rather than interaction with a universal binding motif. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.03.534570v1?rss=1 Authors: Hartmann, J., Bajaj, T., Otten, J., Klengel, C., Gellner, A.-K., Junglas, E., Hafner, K., Anderzhanova, E. A., Tang, F., Missig, G., Rexrode, L., Li, K., Poehlmann, M. L., Heinz, D. E., Lardenoije, R., Dedic, N., McCullough, K. M., Prochnicki, T., Rhomberg, T., Martinelli, S., Payton, A., Robinson, A. C., Stein, V., Latz, E., Carlezon, W. A., Schmidt, M. V., Murgatroyd, C., Berretta, S., Klengel, T., Pantazopoulos, H., Ressler, K. J., Gassen, N. C. Abstract: High levels of proinflammatory cytokines induce neurotoxicity and catalyze inflammation-driven neurodegeneration, but the specific release mechanisms from microglia remain elusive. We demonstrate that secretory autophagy (SA), a non-lytic modality of autophagy for secretion of vesicular cargo, regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling. SKA2 inhibits SA-dependent IL-1b release by counteracting FKBP5 function. Hippocampal Ska2 knockdown in mice hyperactivates SA resulting in neuroinflammation, subsequent neurodegeneration and complete hippocampal atrophy within six weeks. The hyperactivation of SA increases IL-1b release, initiating an inflammatory feed-forward vicious cycle including NLRP3-inflammasome activation and Gasdermin D (GSDMD)-mediated neurotoxicity, which ultimately drives neurodegeneration. Results from protein expression and co-immunoprecipitation analyses of postmortem brains demonstrate that SA is hyperactivated in Alzheimer's disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimer's disease, providing new mechanistic insight into the biology of neuroinflammation. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.22.533752v1?rss=1 Authors: Dennis, C., Pouchin, P., Richard, G., Mirouse, V. Abstract: The basement membrane (BM) is an essential structural element of tissues, and its diversification participates in organ morphogenesis. However, the traffic routes associated with BM formation and the mechanistic modulations explaining its diversification are still poorly understood. Drosophila melanogaster follicular epithelium relies on a BM composed of oriented BM fibrils and a more homogenous matrix. Here, we determined the specific molecular identity and cell exit sites of BM protein secretory routes. First, we found that Rab10 and Rab8 define two parallel routes for BM protein secretion. When both routes were abolished, BM production was fully blocked; however, genetic interactions revealed that these two routes competed. Rab10 promoted lateral and planar-polarized secretion, whereas Rab8 promoted basal secretion, leading to the formation of BM fibrils and homogenous BM, respectively. We also found that the dystrophin-associated protein complex (DAPC) associated with Rab10 and both were present in a planar-polarized tubular compartment containing BM proteins. DAPC was essential for fibril formation and sufficient to reorient secretion towards the Rab10 route. Moreover, we identified a dual function for the exocyst complex in this context. First, the Exo70 subunit directly interacted with dystrophin to limit its planar polarization. Second, the exocyst complex was also required for the Rab8 route. Altogether, these results highlight important mechanistic aspects of BM protein secretion and illustrate how BM diversity can emerge from the spatial control of distinct traffic routes. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.19.533351v1?rss=1 Authors: Houngue, R., Sangare, L. O., Alayi, T. D., Dieng, A., Bitard-Feildel, T., Boulogne, C., Slomianny, C., Atindehou, C. M., Fanou, L. A., Hathout, Y., Saeij, J. P., Callebaut, I., Tomavo, S. Abstract: Apicomplexan parasites have specialized secretory organelles called rhoptries, micronemes, and dense granules that are essential for host infection. Here, we show that TgREMIND, a Toxoplasma gondii protein containing a membrane phospholipid interacting domain, is required for the biogenesis of rhoptries and dense granules. TgREMIND contains a Fes/CIP4 homology-Bin/Amphiphysin/Rvs (F-BAR) domain at the N-terminus, known to promote cell membrane bending, and a novel uncharacterized domain that we named REMIND for regulator of membrane interacting domain at the C-terminus. TgREMIND binds to PIP2 lipid species and both F-BAR and REMIND domains are necessary to ensure proper biological activities in vitro and in cellulo. Conditional depletion of TgREMIND results in the absence of dense granules and abnormal transparent rhoptries, leading to a severe inhibition of parasite motility, host invasion, and dissemination. Thus, our study demonstrates that TgREMIND is essential for the proper functioning of key secretory organelles required for successful infection by Toxoplasma. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.27.530122v1?rss=1 Authors: Lv, Z., Liu, Z., Liu, K., Pu, W., Li, Y., Zhao, H., Xi, Y., Vaughan, A., Gillich, A., Zhou, B. Abstract: Lung injury activates epithelial stem or progenitor cells for alveolar repair and regeneration. However, the origin and fate of injury-induced progenitors are poorly defined. Here, we report that p63-expressing progenitors emerge upon bleomycin-induced lung injury. These p63+ progenitors proliferate rapidly and differentiate into alveolar type 1 (AT1) and type 2 (AT2) cells through distinct trajectories. Dual recombinase-mediated sequential genetic lineage tracing reveals that p63+ progenitors originate from airway secretory cells and subsequently generate alveolar cells. Functionally, p63 activation is required for efficient alveolar regeneration from secretory cells. Our study identifies a secretory cell-derived p63+ progenitor that contributes to alveolar repair, indicating a potential therapeutic avenue for lung regeneration after injury. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.22.529485v1?rss=1 Authors: Panagiotou, S., Nguyen, P. M., Tan, K.-W., Mueller, A., Wendt, A., Eliasson, L., Tengholm, A., Solimena, M., Idevall-Hagren, O. Abstract: Insulin secretion is the process whereby insulin-containing granules fuse with the plasma membrane of {beta}-cells. Exocytosis is preceded by cargo loading, maturation and transport of the secretory granules; processes that require modification of both the protein and lipid composition of the granules. We recently identified phosphatidylinositol-4 phosphate (PI[4]P) dephosphorylation by INPP5F/Sac2 on the surface of insulin granules as a key step that precedes stable granule docking at the plasma membrane and that is required for normal insulin secretion. Here, we show that PI(4)P is used to target the lipid exchange protein oxysterol-binding protein (OSBP) to the granule surface where it is involved in PI(4)P/cholesterol exchange. Loss of Sac2 resulted in excess accumulation of cholesterol on insulin granules that was normalized when OSBP expression was reduced. Acute inhibition of OSBP resulted in dramatic cellular redistribution of OSBP to insulin granules where it colocalized with the ER-resident protein VAP-A at ER-granule contact sites. Stimulation of insulin secretion also resulted in translocation of OSBP to the insulin granule surface in a process that depended on Ca2+-induced acidification of the cytosol. Similar to Sac2 knockdown, inhibition of OSBP suppressed insulin secretion without affecting insulin production. In conclusion, we show that lipid exchange at ER-granule contacts sites is involved in the exocytic process, and propose that these contacts act as reaction centers with multimodal functions during insulin granule maturation. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.21.520923v1?rss=1 Authors: Greig, J., Bates, G. T., Yin, D. I., Simonetti, B., Cullen, P. J., Brodsky, F. M. Abstract: The two clathrin isoforms, CHC17 and CHC22, generate separate vesicles for intracellular transport. CHC17 mediates endocytosis and housekeeping membrane traffic in all cells. CHC22, expressed most highly in skeletal muscle, transports the glucose transporter GLUT4 from the endoplasmic-reticulum-to-Golgi intermediate compartment (ERGIC) to an intracellular GLUT4 storage compartment (GSC) from where GLUT4 is mobilized by insulin. Molecular determinants distinguishing the trafficking of CHC22 clathrin from CHC17 within the GLUT4 pathway are defined in this study. The C-terminal trimerization domain of CHC22, but not CHC17, directly binds SNX5, which also binds the ERGIC tether p115. SNX5, and the functionally redundant SNX6, are required for CHC22 localization independently of their participation in the endosomal ESCPE-1 complex. Both the SNX5-BAR domain and an isoform-specific patch on the CHC22 N-terminal domain separately mediate binding to p115, and both interactions are required for CHC22 recruitment. These indirect and direct interactions at each CHC22 terminus are required for GLUT4 traffic to the GSC, defining a dual mechanism regulating the function of CHC22 in glucose metabolism. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.01.514675v1?rss=1 Authors: Shah, V., Hou, J., Vinarsky, V., Xu, J., Lin, C. P., Rajagopal, J. Abstract: The specific functional properties of a tissue are distributed amongst its component cell types. The various cells act coherently, as an ensemble, in order to execute a properly orchestrated physiologic response. Thus, modern approaches to dissect physiologic mechanism would benefit from an ability to identify specific cell types in live tissues and image them in real time. Current techniques require the use of fluorescent genetic reporters that are not only cumbersome, but which only allow the simultaneous study of 2 or 3 cell types. We report a non-invasive imaging modality that capitalizes on the endogenous autofluorescence signatures of the metabolic cofactors NAD(P)H and FAD. By marrying morphological characteristics with autofluorescence signatures, all seven of the airway epithelial cell types can be distinguished simultaneously in real time. Furthermore, we find that this methodology for direct cell type specific identification avoid potential pitfalls with the use of ostensibly cell type-specific markers that can be altered by clinically relevant physiologic stimuli. Finally, we utilize this methodology to interrogate realtime physiology using a clinically relevant model of cholinergic stimulation and identify dynamic secretory cell associated antigen passages (SAPs) that are highly reminiscent of previously reported goblet cell associated antigen passages (GAPs) in the intestine. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.31.514578v1?rss=1 Authors: Boyer, C. K., Zhang, J., Wang, Y., Stephens, S. B. Abstract: The pancreatic islet beta-cell's preference for release of newly synthesized insulin requires careful coordination of insulin exocytosis with sufficient insulin granule production to ensure that insulin stores exceed peripheral demands for glucose homeostasis. Thus, the cellular mechanisms regulating insulin granule production are critical to maintaining beta-cell function. In this report, we utilized the synchronous protein trafficking system, RUSH, in primary beta-cells to evaluate proinsulin transit through the secretory pathway leading to insulin granule formation. We demonstrate that the trafficking, processing, and secretion of the proinsulin RUSH reporter, proCpepRUSH, are consistent with current models of insulin maturation and release. Using a rodent dietary model of hyperglycemia and beta-cell dysfunction, we show that proinsulin trafficking is impeded at the Golgi and coincides with the decreased appearance of nascent insulin granules at the plasma membrane. Ultrastructural analysis of beta-cells from diabetic leptin receptor deficient mice revealed gross morphological changes in Golgi structure, including shortened and swollen cisternae, and partial Golgi vesiculation, which are consistent with defects in secretory protein export. Collectively, this work highlights the utility of the proCpepRUSH reporter in studying proinsulin trafficking dynamics and suggests that altered Golgi export function contributes to beta-cell secretory defects in the pathogenesis of Type 2 diabetes. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
When it comes to gut health, Secretory IgA is kind of a big deal. Secretory IgA is the dominant antibody in our gut mucosal layer and acts as a “first line of defense” against pathogens. When Secretory IgA is low, it's like the bouncer at the bar is GONE - which means anyone who wants to get in, can. In fact, the lower the SIgA is, the more prone you are to acquiring infections AND the less likely you are to clear up existing infections in your gut. Inspired by recent stool test results, today Erin covers Secretory IgA and why it's so important when it comes to overall immune and gut health. She discusses where this antibody is found (not just the gut!) and reasons why it may be low or high on a lab test. In this episode Erin also highlights an important contributing factor that even functional medicine can miss: your mindset. If you're a gut geek, if you struggle with food sensitivities, if you know you have low Secretory IgA, or if you are looking for another way to improve your own immune and gut health, grab a pen because this episode is one you don't want to miss! In this episode: -The noteworthy results in Erin's latest stool test [4:30] -The dominant antibody in our mucosal secretions [8:04] -How Secretory IgA protects us from food sensitivities [10:18] -What happens when Secretory IgA is low (and what it means if it's elevated) [11:33] -Cortisol, burnout and chronic health problems [14:11] -The often overlooked aspect of healing [15:03] -Clinically proven things that increase Secretory IgA [17:18] -How our thoughts, emotions and stressors impact immunoglobulin A levels [21:21] -The entertainment, media and news we consume [22:35] -Stress, leaky gut, cortisol dysregulation and their connection to Secretory IgA [25:11] -Factors that support healthy Secretory IgA levels [27:02] -Self-compassion and releasing guilt [31:39] -Allowing yourself to access joy and pleasure [34:08] -What is “healing diet orthorexia”? [42:20] -Signs you may be entering disordered eating territory [44:02] -Why belief work is so important to health [48:16] -What to do if you can't access feeling good [51:11] FOR OUR FULL LIST OF LINKS + RESOURCES, HEAD TO: https://www.thefunktionalnutritionist.com/podcast/197-secretory-iga-gut-health-what-you-may-not-know
Thank you for joining us for our 2nd Cabral HouseCall of the weekend! I'm looking forward to sharing with you some of our community's questions that have come in over the past few weeks… Let's get started! Nycole: Hi Dr Cabral, I love the podcast and your positive energy, thank you for all your work!I have spots on my skin called CARP, confluent and reticulated papillomatosis. I have had them for 3 years, wondering where it comes from and what to do about it. I eat a mostly paleo diet and recently strictly gluten free due to celiac. Thanks! Rebecca: I'm looking for information on an elevated secretory IGa, my results were >6000 Anti-Gliiadin IgA was >500 Occult blood 77 I had a gi map test completed by a different company and I don't feel like they understood the results. I'm concerned about celiac and will start removing gluten from my diet. And get a FOBT from PCP. Just looking for more insight on the elevated IgAs Thank You so very much, I have spent a small fortune and don't feel like I got the best support or answers to my labs. The health coach said she had never seen such high IgA,s before As well I'm enrolled in the IHP 1&2 program, just signed up 2 weeks ago. Maria: Hi Dr. Cabral! I have a question in regards to vitamin D levels. I have had my levels tested 4 times over the last 9 months. I can't get my levels to budge from 30-35. I was supplementing with 5000 IU of the EquiLife drops and then bumped up to 10000 IU two months before my last test, but to no avail. I have listened to your podcast on the cofactors for vitamin D absorption many times. I use the DNS powder daily, so I'm getting all the other vitamins and minerals you mention in that podcast that are required for absorption. I had been taking my vitamin D at breakfast with my morning smoothie which contains 1-2 tablespoons of seeds. I just started taking it at lunch time instead and also started supplementing with additional K2 (MK7) at that time as well. I live in the Midwest, so sunlight vitamin D is really only possible from June-September. Not sure what else I can do to get my levels up. I am on month 1 of the CBO finisher, after completion of CBO protocol. I'm sure poor gut absorption has had something to do with it? Any other advice on how to get my levels up or why my levels haven't budged at all?! Do you have a favorite vitamin D light that you recommend? Karen: Dear Dr. Cabral, Thank you for your podcast and the easy way you get the information out about having good health. I am 62 and in the best health of my life thanks to many changes I have made. 10 years ago, I switched to a gluten free diet, the change it made in how I felt was amazing. Since then, I have been devouring books on health, and continuing to modify my diet and exercise. I am now dairy free, (a recent change) and eat very little sugar products. At 62 I am back to the weight I was when I graduated from high school! My question for you is about a condition I have on my lower lip, it has been there for about 25 years in varying degrees, and is called Actinic Cheilitis. It is a continual sloughing of skin cells on my lower lip, sometimes it is mildly painful, and is worse in the winter months. My dermatologist gave me a cream to treat it, a strong pharmaceutical that actually works by destroying the skin. I went through 1 round of this and couldn't tolerate the cream. The pain and ugliness on my lip was awful and I experienced body aches, headaches and couldn't sleep, a condition that is a rare side effect of this cream. As this is considered a pre-cancerous condition, I need to do something. I appreciate any suggestions you have. Dawn: I started the 7 day detox and after the 3rd shake, I felt nauseous? Is this normal? Should I continue on? Bettina: Hi Stephen thank you for your podcast, i only recently started listening to you. I got your rRain Barrel book and the 14 day detox. would love to have the tests done however with the $ exchange and taxes it get really expensive. can you suggest any labs in Brisbane or Gold Coast that you would recommend. looking forward to hearing from you. sincerely Bettina Thank you for tuning into this weekend's Cabral HouseCalls and be sure to check back tomorrow for our Mindset & Motivation Monday show to get your week started off right! - - - Show Notes & Resources: http://StephenCabral.com/2200 - - - Dr. Cabral's New Book, The Rain Barrel Effect https://amzn.to/2H0W7Ge - - - Join the Community & Get Your Questions Answered: http://CabralSupportGroup.com - - - Dr. Cabral's Most Popular At-Home Lab Tests: > Complete Minerals & Metals Test (Test for mineral imbalances & heavy metal toxicity) - - - > Complete Candida, Metabolic & Vitamins Test (Test for 75 biomarkers including yeast & bacterial gut overgrowth, as well as vitamin levels) - - - > Complete Stress, Mood & Metabolism Test (Discover your complete thyroid, adrenal, hormone, vitamin D & insulin levels) - - - > Complete Stress, Sleep & Hormones Test (Run your adrenal & hormone levels) - - - > Complete Food Sensitivity Test (Find out your hidden food sensitivities) - - - > Complete Omega-3 & Inflammation Test (Discover your levels of inflammation related to your omega-6 to omega-3 levels)
References Nat Cell Biol. 2019 Mar; 21(3): 397–407 J Diabetes Metab Disord. 2020 Jul 21;19(2):1797-1825 Int. J. Mol. Sci. 2014, 15, 16848-16884 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message Support this podcast: https://anchor.fm/dr-daniel-j-guerra/support
Aging-US published a Special Collection on Eye Disease which included "Effects of senescent secretory phenotype acquisition on human retinal pigment epithelial stem cells" which reported that loss of retinal pigment epithelium (RPE) cells occurs early in AMD, and their transplant has the potential to slow disease progression. Age-related MSC changes involve loss of function and acquisition of a senescence-associated secretory phenotype (SASP). These changes can contribute to the maintenance of a chronic state of low-grade inflammation in tissues and organs. Dr. Cesare Mariotti from The Università Politecnica delle Marche said, "Age-related macular degeneration (AMD) is an eye disorder affecting the elderly which can induce an irreversible loss of central visual function." Age-related macular degeneration (AMD) is one of the most serious and debilitating forms of aging-related eye disease. Smoking, cataract surgery, high BMI and cardiovascular disease are risk factors for AMD, as well as a family history of AMD. No effective treatment is available for neovascular AMD, while anti-VEGFD is the mainstay of treatment for dry AMD. Neovascular AMD and GA are characterized by RPE dysfunction; formation of large confluent drusen and hyperpigmentation seem to be the initial insult. AMD patients show a different phenotype as well as functional changes such as altered autophagy, mitochondrial dysfunction, and susceptibility to oxidative stress. A greater understanding of the molecular pathways that are involved in the various stages of AMD would contribute to the development of innovative therapies. The Mariotti Research Team concluded in their Aging-US Research Output that RPESCs can undergo replicative senescence, which affects their proliferation and differentiation ability. In addition, they acquired the SASP, which probably compounds the inflammatory RPE microenvironment during AMD development and progression. A greater understanding of the role of RPESCs in AMD pathogenesis is needed to find means to control the disease. Full Text - https://www.aging-us.com/article/101624/text Correspondence to: Cesare Mariotti email: mariottiocul@gmail.com Keywords: AMD, RPESCs, age-related diseases, senescence, inflammation About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research as well as topics beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, cancer, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR among others), and approaches to modulating these signaling pathways. To learn more about Aging-US, please visit http://www.Aging-US.com or connect with @AgingJrnl Aging-US is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact 18009220957x105 MEDIA@IMPACTJOURNALS.COM
Welcome back to our weekend Cabral HouseCall shows! This is where we answer our community's wellness, weight loss, and anti-aging questions to help people get back on track! Check out today's questions: Ruth: Hi Dr Cabral, my daughter introduced me to your podcasts and I am so glad she did. I listened to podcast 1173 on “why you need to boost your low T naturally”. I have been getting the pelleted HRT for a few years now and the day I listened to this podcast I had just gotten pelleted again. I think it will be my last one after listening to your podcast. Because I have had a total hysterectomy two years ago, I thought the pelleting would give my body what it no longer can do by itself. I also had very low libido and drive at the time I started them. I am an obese, 67-year-old female and have gained about 20 pounds since the hysterectomy. Would you recommend I stay off the HRT pelleting and try the supplements you mentioned in your podcast? Vitamin D Magnesium full spectrum Zinc picolinate I already have high cholesterol and you mentioned that HRT could lead to even raise it more!? I am currently on phase III of the cell core detox program. I do have chronic stress because I am in pain from a scope of my right knee a few years ago where the surgeon cut away some cartilage and said I need a total knee replacement because of arthritis. I am hoping to correct my nutrition and give my knee the right environment to heal itself. Is this possible? The following is in my HRT pellet: t-pellet 100 mg x 2 estradiol 12.5 mg I also take NP thyroid 90 mg 1am and ½ noon FreeTe 1 capsule daily after 1 ½ months after pellet insertion (I understand this is to draw out the extra testosterone and make it last longer) Iodine 12.5 mg 1 daily DIM one daily ADK 1 daily Thank you for any insight you can give me! Luke: Hi Dr. Cabral. Sorry for the controversial question but I need some guidance. My wife and I have just found out that she is pregnant after a very long journey in trying to conceive. During this time we have done lots of research and decided not to vaccinate or have any unnecessary medical intervention during the pregnancy and beyond. My wife and I would like to know what else we should consider doing to make sure that our baby has the best start to life. We both take the level 3 daily protocol, have done all major protocols from equilibrium nutrition in preparation to having our baby, we follow your recommended diet, we exercise and have removed all toxins from the home among other things. I believe that this is enough for us to give our baby the best start to life but is there anything else that we should consider? We know that we are up for some push back from friends and family for our decisions but we just want to make sure that we are doing what is best for our baby. Thanks in advance for your guidance with this. Sally: Hi doctor Cabral, I was wondering if you could explain what Secretory IgA is. After suffering with digestive issues (bloating, gas, etc) for a few years, I did a stool test, and my Secretory IgA came back very low. My doctor tried to explain what it is and what I can do, but I did not really understand it. I've been listening to your podcast for years, therefore I know that you have the amazing ability to explain difficult medical terms and make them more digestible (pun intended!), so I would be very grateful if you could tell me more about it. In particular, what lowers Secretory IgA and what I can do to fix it? Thank you very much! Sally David: There are multivitamins that have an AM and PM formula, or are taken separately. One reason is to control certain vitamin and mineral ratios. This is based on science that says that there are different nutrients that compete against or inhibit the absorption of other nutrients. Examples I found online were: Iron can have a negative effect on zinc absorption; Folate can mask the symptoms of B12 deficiency; Vitamin A interferes with absorption of vitamin K; and aim to take calcium and magnesium supplements at least 2 hours apart. Is this something that should be considered when evaluating a multivitamin? Does the dosage and formulation of DNS control for nutrients that compete or inhibit absorption of other nutrients? Thanks so much. Michael: Why would someone get sicker and develop new symptoms by killing pathogens? I have mold toxicity (Chaetomium), some candida and high h. pylori. Thank you for tuning into today's Cabral HouseCall and be sure to check back tomorrow where we answer more of our community's questions! - - - Show Notes & Resources: http://StephenCabral.com/2010 - - - Get Your Question Answered: http://StephenCabral.com/askcabral - - - Dr. Cabral's New Book, The Rain Barrel Effect https://amzn.to/2H0W7Ge - - - Join the Community & Get Your Questions Answered: http://CabralSupportGroup.com - - - Dr. Cabral's Most Popular At-Home Lab Tests: > Complete Minerals & Metals Test (Test for mineral imbalances & heavy metal toxicity) - - - > Complete Candida, Metabolic & Vitamins Test (Test for 75 biomarkers including yeast & bacterial gut overgrowth, as well as vitamin levels) - - - > Complete Stress, Mood & Metabolism Test (Discover your complete thyroid, adrenal, hormone, vitamin D & insulin levels) - - - > Complete Stress, Sleep & Hormones Test (Run your adrenal & hormone levels) - - - > Complete Food Sensitivity Test (Find out your hidden food sensitivities) - - - > Complete Omega-3 & Inflammation Test (Discover your levels of inflammation related to your omega-6 to omega-3 levels) - - - > View all Functional Medicine lab tests (View all Functional Medicine lab tests you can do right at home for you and your
This episode covers locations of GI secretory cells!
Non-uniform ageing is a major associative risk factor for cancer and degenerative diseases and mitochondrial dysfunction is linked to cellular senescence in association with cell cycle arrest, telomerase decline and nucleic acid/lipid/protein oxidation. Indeed, mitochondrial dysfunction comprises a distinct type of cellular senescence; mitochondrial SIRT3 or SIRT5, can induce Mitochondrial Dysfunction Associated-Senescence (MiDAS) Senescence is a chronological and pathophysiological sequenced event response that restricts mitotic division and thus aberrant proliferation of damaged, infected and/or tumor inducing cells. Because these cells are senescent and exhibit low anabolic currency to present self-produced antigen epitopes as displayed by HLA, they are not targeted by immune responses but rather, may become secretory and induce inflammation by instantiating the Senescence Associated Secretory Phenotype-SASP. Senescence presents with metabolic reprogramming, epigenetic chromatin remodeling, and the secretion of growth factors, signaling molecules, proinflammatory cytokines and chemokines, extra-cellular matrix metallo proteases, nucleotides, exosomes and ionic bursts collectively referred to as SASP. Both SASP and MiDAS can occur in the CNS during human aging thus generating a remarkably complex-contrarion dual pathophysiological phenotype leading to neurodegeneration or more rarely, certain forms of brain cancer. Authentic Biochemistry Podcast is produced by Daniel J. Guerra, PhD. Today's Date: 16 January 2021 Refs. Trends in Biochemical Sciences Volume 41 Issue 3 Pages 207-209 (March 2016) Cell Metabolism Volume 23, Issue 2, 9 February 2016, Pages 303-314 Front. Immunol., 19 March 2018 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message Support this podcast: https://anchor.fm/dr-daniel-j-guerra/support
Dr. Randy Schekman overviews the secretory pathway and reviews historical experiments that shaped our molecular understanding of this pathway. The journey begins at the endoplasmic reticulum (ER), where proteins that engage the secretory pathway get translated. The mRNA of these proteins codes for a signal sequence that serves as a “tag” to bring the mRNA-ribosome-newly-synthesized protein to the ER for continued translation and movement of the new secretory protein across the ER membrane into the interior or lumen of the organelle. Vesicles transport the recently translated proteins to the Golgi Apparatus, where they get “packaged” and sent to their final destination.
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.21.299198v1?rss=1 Authors: Kim, K.-e., Park, I., Kim, J., Kang, M.-G., Choi, W. G., Shin, H., Kim, J.-S., Rhee, H.-W., Suh, J. M. Abstract: Here we describe iSLET (in situ Secretory protein Labeling via ER-anchored TurboID) which labels secretory pathway proteins as they transit through the ER-lumen to enable dynamic tracking of tissue-specific secreted proteomes in vivo. We expressed iSLET in the mouse liver and demonstrated efficient in situ labeling of the liver-specific secreted proteome which could be tracked and identified within circulating blood plasma. iSLET is a versatile and powerful tool for studying spatiotemporal dynamics of secretory proteins, a valuable class of biomarkers and therapeutic targets. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.05.283267v1?rss=1 Authors: Lin-Moore, A. T., Oyeyemi, M. J., Hammarlund, M. Abstract: Injured axons must regenerate to restore nervous system function, and regeneration is regulated in part by external factors from non-neuronal tissues. Many of these extrinsic factors act in the immediate cellular environment of the axon to promote or restrict regeneration, but the existence of long-distance signals regulating axon regeneration has not been clear. Here we show that the Rab GTPase rab-27 inhibits regeneration of GABAergic motor neurons in C. elegans through activity in the intestine. Re-expression of RAB-27, but not the closely related RAB-3, in the intestine of rab-27 mutant animals is sufficient to rescue normal regeneration. Several additional components of an intestinal neuropeptide secretion pathway also inhibit axon regeneration, including NPDC1/cab-1, SNAP25/aex-4, and KPC3/aex-5. Together these data indicate that RAB-27-dependent neuropeptide secretion from the intestine inhibits axon regeneration, and point to distal tissues as potent extrinsic regulators of regeneration. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.10.243634v1?rss=1 Authors: Kuo, C.-C., Chiang, W.-T., Lewis, N. E. Abstract: A hallmark of amyloid disorders, such as Alzheimer's disease, is aggregation of secreted proteins. However it is largely unclear how the hundreds of secretory pathway proteins contribute to amyloid formation. We developed a systems biology framework that integrates expression data with protein-protein interaction networks to successfully estimate a tissue's fitness for producing specific secreted proteins. Using this framework, we analyzed the fitness of the secretory pathway of various brain regions and cell types for synthesizing the Alzheimer's disease-associated amyloid-precursor protein (APP). While none of the key amyloidogenic pathway components were differentially expressed in AD brain, we found the deposition of A{beta} is associated with repressed expression of the secretory pathway components proximal to APP. Concurrently, we detected systemic up-regulation of the secretory pathway components proximal to {beta}- and {gamma}-secretases in AD brains. Our analyses suggest that perturbations from 3 high confidence AD risk genes cascade through the secretory machinery support network for APP and into the endocytosis pathway. Thus, we present a model where amyloidogenesis is associated with dysregulation of dozens of secretory pathway components supporting APP, which could yield novel therapeutic targets for the treatment of AD. Copy rights belong to original authors. Visit the link for more info
Dr Guerra discusses the cancer marker gene mKI67 and its turnover linked to predisposition to euchromatin formation and the progression toward a senescent phenotype. Published 04 August 2020. --- Support this podcast: https://anchor.fm/dr-daniel-j-guerra/support
Traditional Approach: Secretory -- poisoned mucosal villi -- "the sieve" Cytotoxic -- destroyed mucosal villi -- "the shred" Osmotic -- malabsorption -- "the pull" Inflammatory -- edema, motility -- "the push" Lots of overlap, difficult to apply to clinical signs and symptoms. Bedside Approach: Fever/No Fever, Bloody/No Blood Non-bloody, febrile -- most likely viral Non-bloody, afebrile -- may be viral Bloody, febrile -- likely bacterial Non-bloody, afebrile -- full stop. Eval for Hemolytic Uremic Syndrome Workup Ask yourself -- again -- why is this not... appendicitis-torsion-intussusception-etc. Admit sick children, but most go home, so... Non-bloody, febrile -- no workup necessary; precautionary advice Non-bloody, afebrile -- be more skeptical, but generally same as above Bloody, febrile -- stool culture, follow up; do not treat empirically unless septic and admitted. Culture will dictate treat/no treat/how. Bloody, afebrile -- evaluate for hemolytic uremic syndrome, especially if under 5 years old: CBC, chemistries, UA, stool culture Evaluate Hydration Status Selected References Khan WA et al. Central Nervous System Manifestations of Childhood Shigellosis: Prevalence, Risk Factors, and Outcome. Pediatrics. 1999 Feb;103(2):E18 Lee JY et al. Diagnostic yield of stool culture and predictive factors for positive culture in patients with diarrheal illness. Medicine (Baltimore). 2017 Jul; 96(30): e7641. Nelson JD et al. Treatment of Salmonella gastroenteritis with ampicillin, amoxicillin, or placebo. Pediatrics 1980; 65:1125.
Jesus Gil, Cell Proliferation Group MRC London Institute of Medical Sciences (LMS) ImperialCollege,HammersmithHospitalCampus London, UK speaks on "Linking senescence and inflammation: the senescence-associated secretory phenotype (SASP)". This movie has been recorded at ICGEB Trieste.
Daniel and Vincent solve the case of the Woman With Anal Area Discomfort, and discuss the multiple functions of a clathrin adapter protein in formation of rhoptry and microneme secretory organelles of Toxoplasma gondii. Hosts: Vincent Racaniello and Daniel Griffin Become a patron of TWiP. Links for this episode: Journal of Microbiology and Biology Education SciComm Issue (link) TWiP 19: Enterobius vermicularis, the pinworm Multiple roles of Toxoplasma gondii clathrin adaptor AP1 protein (PLoS Path) Image credit Letters read on TWiP 133 Case Study for TWiP 133 Seen while working in remote mountain makeshift mobile clinic in Dominican Republic, on Haitian border. Traveled 3 h by pickup truck, remote mountain town, womens centers. Set up makeshift mobile clinic in this center. Mother concerned about 6 yo girl, failure to thrive compared with sister, protuberant belly, frequent abdominal discomfort, going on over 1 year. No surgeries, no meds, first time ever seeing medical person. Mother and sister are family. Three children in family. Father does timber work. Very impoverished region, living in dirt floor home, drinking untreated water from local stream, go to bathroom outside, could be contamination. Diet: carbohydrate, plantains, rice, beans. On exam: lungs clear, heart fine, belly protuberant, liver and spleen not enlarged, some edema. Mother said noticed long motile worm in girls feces. Firm belly, not painful to her. Send your case diagnosis, questions and comments to twip@microbe.tv Music by Ronald Jenkees
Tissue-specific transcripts are likely to be of importance for the corresponding organ. While attempting to define the specific transcriptome of the human lung, we identified the transcript of a yet uncharacterized protein, SFTA2. In silico analyses, biochemical methods, fluorescence imaging and animal challenge experiments were employed to characterize SFTA2. Human SFTA2 is located on Chr. 6p21.33, a disease-susceptibility locus for diffuse panbronchiolitis. RT-PCR verified the abundance of SFTA2-specific transcripts in human and mouse lung. SFTA2 is synthesized as a hydrophilic precursor releasing a 59 amino acid mature peptide after cleavage of an N-terminal secretory signal. SFTA2 has no recognizable homology to other proteins while orthologues are present in all mammals. SFTA2 is a glycosylated protein and specifically expressed in nonciliated bronchiolar epithelium and type II pneumocytes. In accordance with other hydrophilic surfactant proteins, SFTA2 did not colocalize with lamellar bodies but colocalized with golgin97 and clathrin-labelled vesicles, suggesting a classical secretory pathway for its expression and secretion. In the mouse lung, Sfta2 was significantly downregulated after induction of an inflammatory reaction by intratracheal lipopolysaccharides paralleling surfactant proteins B and C but not D. Hyperoxia, however, did not alter SFTA2 mRNA levels. We have characterized SFTA2 and present it as a novel unique secretory peptide highly expressed in the lung.
Lecture 09: Kaplan discusses the secretory pathway, with emphasis on protein targeting and translocation.
Lecture 08: Kaplan talks about how various proteins are directed to certain areas within the cell and to the plasma membrane.
Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 07/19
Besides of dental erosions, sialadenosis manifesting as bilateral swelling of parotid glands, is a typical manifestation of bulimia. Objective: The mechanism of acinar enlargement in sialadenosis is obscure, although peripheral polyneuropathy secondary to systemic disorders is assumed to be significant. This study aimed to find new aspects of pathogenesis of sialadenosis. Methods: Based on a fortuitous observation of diminished alpha-actin-positive myofilaments in myoepithelial cells in sialadenosis, 11 cases each of control and sialadenosis parotid glands were morphometrically analysed assisted by immunohistochemistry for alpha-actin, p63, cytokeratin 14 and Ki67 including double staining. Results: In sialadenosis: the acini were significantly (p
Enhanced Video PodcastAired date: 3/28/2007 3:00:00 PM Eastern Time
Enhanced Audio PodcastAired date: 3/28/2007 3:00:00 PM Eastern Time
Objective To evaluate two commercial stool tests for detection of secretory IgA antibodies against gliadin and human tissue transglutaminase for diagnosis of coeliac disease in children with symptoms.Setting Tertiary care children's hospital.Participants Coded stool samples from 20 children with newly diagnosed coeliac disease and 64 controls. Six children with coeliac disease had stool tests every two weeks for three months after starting a gluten-free diet.Main outcome measures Secretory IgA antibodies against gliadin and human tissue transglutaminase in stool samples, determined in duplicate by using recommended cut-off limits.Results Sensitivity of faecal antibodies against human tissue transglutaminase was 10% (95% confidence interval 1% to 32%), and specificity was 98% (91% to 100%). For antibodies against gliadin, sensitivity was 6% (0% to 29%) and specificity was 97% (89% to 100%). Optimisation of cut-off limits by receiver operating characteristic analysis and use of results of both tests increased sensitivity to 82%, but specificity decreased to 58%. All follow-up stool tests remained negative, except for two positive anti-gliadin results in one patient, six and 10 weeks after the gluten-free diet was started.Conclusions Neither stool test was suitable for screening for coeliac disease in children with symptoms.
Neuronal communication and endocrine signaling are fundamental for integrating the function of tissues and cells in the body. Hormones released by endocrine cells are transported to the target cells through the circulation. By contrast, transmitter release from neurons occurs at specialized intercellular junctions, the synapses. Nevertheless, the mechanisms by which signal molecules are synthesized, stored, and eventually secreted by neurons and endocrine cells are very similar. Neurons and endocrine cells have in common two different types of secretory organelles, indicating the presence of two distinct secretory pathways. The synaptic vesicles of neurons contain excitatory or inhibitory neurotransmitters, whereas the secretory granules (also referred to as dense core vesicles, because of their electron dense content) are filled with neuropeptides and amines. In endocrine cells, peptide hormones and amines predominate in secretory granules. The function and content of vesicles, which share antigens with synaptic vesicles, are unknown for most endocrine cells. However, in B cells of the pancreatic islet, these vesicles contain GABA, which may be involved in intrainsular signaling.' Exocytosis of both synaptic vesicles and secretory granules is controlled by cytoplasmic calcium. However, the precise mechanisms of the subsequent steps, such as docking of vesicles and fusion of their membranes with the plasma membrane, are still incompletely understood. This contribution summarizes recent observations that elucidate components in neurons and endocrine cells involved in exocytosis. Emphasis is put on the intracellular aspects of the release of secretory granules that recently have been analyzed in detail.
Wed, 1 Jan 1992 12:00:00 +0100 https://epub.ub.uni-muenchen.de/7360/1/Gratzl_Manfred_7360.pdf Gratzl, Manfred; Gratzl, O.; Vereczkey, C.; Langley, K.; Lahr, G.
Mon, 1 Jan 1990 12:00:00 +0100 https://epub.ub.uni-muenchen.de/9777/1/serum_contents_of_immunoreactive_pancreatic_secretory_trypsin_inhibitor_9777.pdf Ohlsson, K.; Jochum, Marianne; Nast-Kolb, Dieter; Hehlein-Fink, C.; Fink, Edwin
Mon, 1 Jan 1990 12:00:00 +0100 https://epub.ub.uni-muenchen.de/9758/1/9758.pdf Fritz, Hans; Fink, Edwin; Schomburg, Dietmar; Vasel, Birger; Hecht, Hans-Jürgen; Frank, Ronald; Blöcker, Helmut; Maywald, Friedhelm; Szardenings, Michael; Collins, John
Mon, 1 Jan 1990 12:00:00 +0100 https://epub.ub.uni-muenchen.de/9761/1/Fink_Edwin_9761.pdf Ohlsson, K.; Jochum, Marianne; Nast-Kolb, Dieter; Hehlein-Fink, Christa; Fink, Edwin
Sun, 1 Jan 1989 12:00:00 +0100 https://epub.ub.uni-muenchen.de/7964/1/7964.pdf Goebel, Frank-Detlef; Matuschke, A.; Heinrich, B.; Bogner, Johannes R.; Kochen, M. M.; Zoller, W. G.; Füeßl, H. S. dd
Fri, 1 Jan 1988 12:00:00 +0100 http://epub.ub.uni-muenchen.de/8575/ http://epub.ub.uni-muenchen.de/8575/1/8575.pdf Zimmermann, Richard; Sagstetter, Maria; Schlenstedt, Gabriel; Wiech, Hans; Kaßeckert, Brigitta; Müller, Günter Kamp, Jos A. F. op den (Hrsg.) (1988): Import of Small Secretory and Membrane Proteins into the Endoplasmic Reticulum. NATO Advanced Study Inst. on New Perspectives in the Dynamics of Assembly of Biomembranes, 24.08.-04.09.1987, Cargèse, Korsica, Frankreich. Chemie und Ph
Fri, 1 Jan 1988 12:00:00 +0100 https://epub.ub.uni-muenchen.de/7504/1/7504.pdf Gratzl, Manfred ddc:610, Medizin
Crude chromaffin secretory vesicles, obtained by differential centrifugation, were further purified on isotonic (Percoll) gradients. The chromaffin vesicle fractions recovered from the gradients contain acetylcholinesterase as well as lysosomal enzymes. With the aid of a subsequent sucrose gradient lysosomal enzymes could be removed from chromaffin vesicle fractions, but not acetylcholinesterase. This suggests that lysosomal enzymes do not pass through the chromaffin vesicles during the biogenesis of lysosomes but acetylcholinesterase does.
Purified secretory vesicles isolated from bovine neurohypophyses take up Na+ under the same circumstances where an efflux of Ca2+ takes place, suggesting a Na+/Ca2+ exchange. Potassium cannot substitute for Na+ in this process. Also, a Ca2+/Ca2+ exchange can occur. Inhibiting the latter process by Mg2+ allowed to estimate an apparent KM of 0.7 μM free Ca2+ and a maximal uptake of 1.5 nmol × mg protein−1 × min−1 Ca2+ in exchange for Na+. The vesicles did not contain plasma membrane marker (Na+/K+ ATPase) as shown by distribution analyses on the density gradients on which they were purified. Similarly, distribution studies also showed that no other ATPase activity could be detected in the purified vesicle fraction. It is concluded that a Na+/Ca2+ exchange is operating across the secretory vesicle membrane and that it is not directly dependent on ATP hydrolysis.
Abstract: Membranes of the secretory vesicles from bovine adrenal medulla were investigated for the presence of the endogenous protein phosphorylation activity. Seven phosphoprotein bands in the molecular weight range of 250,000 to 30,000 were observed by means of the sodium dodecyl sulphate electrophoresis and autoradiography. On the basis of the criteria of molecular weight, selective stimulation of the phosphorylation by cyclic AMP (as compared with cyclic GMP) and immunoprecipitation by specific antibodies, band 5 (molecular weight 60,300) was found to represent the phosphorylated form of the secretory vesicle-bound tyrosine hydroxylase. The electrophoretic mobility, the stimulatory and inhibitory effects of cyclic AMP in presence of Mg2+ and Zn,2+ respectively, and immunoreactivity toward antibodies showed band 6 to contain two forms of the regulatory subunits of the type II cyclic AMP-dependent protein kinase, distinguishable by their molecular weights (56,000 and 52,000, respectively). Phosphorylation of band 7 (molecular weight 29,800) was stimulated about 2 to 3 times by Ca2+ and calmodulin in the concentration range of both agents believed to occur in the secretory tissues under physiological conditions.
Abstract: Bovine chromaffin secretory vesicle ghosts loaded with Na+ were found to take up Ca2+ when incubated in K+ media or in sucrose media containing micromolar concentrations of free Ca2+. Li+- or choline+loaded ghosts did not take up Ca2+. The Ca2+ accumulated by Na+-loaded ghosts could be released by the Ca2+ ionophore A23187, but not by EGTA. Ca2+ uptake was inhibited by external Sr2+, Na +, Li +, or choline +. All the 45Ca2+ accumulated by Na+-dependent Ca2+ uptake could be released by external Na +, indicating that both Ca2+ influx and efflux occur in a Na+-dependent manner. Na + -dependent Ca2+ uptake and release were only slightly inhibited by Mg2+. In the presence of the Na+ ionophore Monensin the Ca2+ uptake by Na +-loaded ghosts was reduced. Ca2+ sequestered by the Na+-dependent mechanism could also be released by external Ca2+ or Sr2+ but not by Mg2+, indicating the presence of a Ca2+/Ca2+ exchange activity in secretory membrane vesicles. This Ca2+/Ca2+ exchange system is inhibited by Mg2+, but not by Sr2+. The Na + -dependent Ca2+ uptake system in the presence of Mg2+ is a saturable process with an apparent Km of 0.28 μM and a Vmax= 14.5 nmol min−1 mg protein−1. Ruthenium red inhibited neither the Na+/Ca2+ nor the Ca2+/Ca2+ exchange, even at high concentrations.
Purified secretory vesicles isolated from bovine neurohypophyses were found to take up Ca2+ when incubated at 30°C in media containing 10−7 to 10−4 M free Ca2+. At 10−4 free Ca2+ 19 nmol/mg protein were taken up within 30 min. The initial uptake at this Ca2+ concentration was about 2 nmol/mg protein per min. The uptake of Ca2+ to secretory vesicles was not affected by ATP, oligomycin, ruthenium red, trifluoperazine, Mg2+ or K+, but was inhibited by Na+ and Sr2+. From these characteristics it can be concluded that the uptake system does not utilize directly ATP (as the Ca2+-ATPases known to be present in the cell membrane and the endoplasmic reticulum) and is different from the mitochondrial Ca2+ uptake system driven by respiration and/or ATP hydrolysis. However, Ca2+-Na+ exchange may well operate: In experiments using different concentrations of Na+ we found half-maximal inhibition of Ca2+ uptake with 33.3 mM Na+. An analysis of the data in a Hill plot indicated that at least 2 Na+ would be exchanged for 1 Ca2+. Also, it was found that Ca2+ previously taken up could be released again by external Na+ but not by K+.
Intact secretory vesicles isolated from bovine adrenal medulla contain 94 nmol Na+ per mg of protein, and Ca2+ influx into the vesicles is inhibited by increasing concentrations of extravesicular Na+ (but not of K+, Li+ or choline+) or by addition of the Na+ ionophore monensin. Thus Ca2+ influx is determined by the Na+ gradient across the vesicular membrane. Half maximal inhibition of Ca2+ influx occurs with 34 mM Na+ extravesicularly. The fact that Ca2+ can also be released from the vesicles by inversion of the Na+ gradient provides direct evidence that an Na+-Ca2+ exchange may operate. According to an analysis of the inhibition of Ca2+ uptake by Na+ in a Hill plot 2 Na+ would be exchanged for 1 Ca2+. Ca2+ influx into the vesicles increases with temperature (energy of activation: 16 kcal/mol), can be observed already with 10−7 M free Ca2+ and increases up to 10−4 M Ca2+. Ca2+ influx is not affected by Mg2+ but Sr2+ is inhibitory. Since the process is only slightly influenced by the pH of the incubation medium and is insensitive to Mg2+-ATP or inhibitors of the proton translocating Mg2+-ATPase the electrochemical proton gradient across the vesicular membrane does not affect directly the Ca2+ influx into the secretory vesicles. Ca2+ uptake is insensitive to ruthenium red and oligomycin.
Thu, 1 Jan 1981 12:00:00 +0100 https://epub.ub.uni-muenchen.de/7199/1/7199.pdf Krieger-Brauer, H.; Gratzl, Manfred
A new procedure is described for the preparation of highly purified and stable secretory vesicles from adrenal medulla. Two forms of acetylcholinesterase, a membrane bound form as well as a soluble form, were found within these vesicles. The secretory vesicles, isolated by differential centrifugation, were further purified on a continuous isotonic Percoll™ gradient. In this way, secretory vesicles were separated from mitochondrial, microsomal and cell membrane contamination. The secretory vesicles recovered from the gradient contained an average of 2.26 μmol adrenalin/mg protein. On incubation for 30 min at 37°C in media differing in ionic strength, pH, Mg2+ and Ca2+ concentration, the vesicles released less than 20% of total adrenalin. Acetylcholinesterase could hardly be detected in the secretory vesicle fraction when assayed in isotonic media. However, in hypotonic media (
Secretory vesicles isolated from adrenal medulla were found to fuse in vitro in response to incubation with Ca2+. Intervesicular fusion was detected by electron microscopy and was indicated by the appearance of twinned vesicles in freeze-fractured suspensions of vesicles and in thin-sectioned pellet. Two types of fusion could be distinguished: Type I, occurring between 10−7 M and 10−4 M Ca2+, was specific for Ca2+, was inhibited by other divalent cations and was abolished by pretreatment of vesicles with glutaraldehyde, neuraminidase or trypsin. Fusion type I was linear with temperature. A second type of intervesicular fusion was elicited by Ca2+ in concentrations higher than 2.5 mM and was morphologically characterized by multiple fusions of secretory vesicles. This type of fusion was found to be similar to fusion of liposomes prepared from the membrane lipids of adrenal medullary secretory vesicles: Ca2+ could be replaced by other divalent cations, the effect of different divalent cations was additive and pretreatments attacking membrane proteins were ineffective. Fusion type II of intact secretory vesicles as well as liposome fusion was discontinuous with temperature. Liposome fusion could be detected within 35 ms and persisted for 180 min. Using liposomes containing defined Ca2+ concentrations we have not found a major influence of Ca2+ asymmetry on fusion. Incorporation of the ganglioside GM3, which is present in the membranes of intact adrenal medullary secretory vesicles did not change the properties of liposomes fusion. Using a Ca2+-selective electrode we have identified in secretory vesicle membranes both high affinity binding sites for Ca2+ (Kd = 1.6 · 10−6M) and low affinity sites (Kd = 1.2 · 10−4M).
Secretory vesic1es from adrenal medulla contain catecholamines, nuc1eotides and proteins, all of which are released into the extracellular fluid during exocytosis. Adrenal medullary secretory vesic1es also contain high concentrations of Ca'+ [1]. The mechanism of the aecumulation of Ca 2+ into the vesicles is largely unknown and the experimental data eoncerning the uptake of Ca'+ into isolated secretory vesicles are contradictory. It has been reported that secretory vesicle membranes are impermeable to Ca'+ [2], that secretory vesicles take up Ca 2+ independently of ATP [3] and that they possess an ATP-stimulated uptake system [4,5]. In earlier work relatively impure and unstable seeretory vesicle fractions were used for the determination of Ca 2+ -uptake. We have developed a method to isolate highly purified and stable secretory vesicles from bovine medulla [6]. With these vesic1es we repeated earlier Ca'+ -uptake experiments and found that: (i) The vesic1es take up
Tue, 1 Jan 1980 12:00:00 +0100 https://epub.ub.uni-muenchen.de/7131/1/7131.pdf Thorn, N. A.; Treiman, M.; Dartt, D.; Torp-Pedersen, C.; Gratzl, Manfred ddc:610,
Secretory vesicles isolated from rat liver were found to fuse after exposure to Ca2+. Vescle fusion is characterized by the occurrence of twinned vesicles with a continuous cleavage plane between two vesicles in freeze-fracture electron microscopy. The number of fused vesicles increases with increasing Ca2+-concentrations and is half maximal around 10–6 m. Other divalent cations (Ba2+, Sr2+, and Mg2+) were ineffective. Mg2+ inhibits Ca2+-induced fusion. Therefore, the fusion of secretory vesiclesin vitro is Ca2+ specific and exhibits properties similar to the exocytotic process of various secretory cells. Various substances affecting secretionin vivo (microtubular inhibitors, local anethetics, ionophores) were tested for their effect on membrane fusion in our system. The fusion of isolated secretory vesicles from liver was found to differ from that of pure phospholipid membranes in its temperature dependence, in its much lower requirement for Ca2+, and in its Ca2+-specificity. Chemical and enzymatic modifications of the vesicle membrane indicate that glycoproteins may account for these differences.
During the transport of plasma proteins from the cytoplasma of hepatocytes to the extracellular fluid srnall vesicles may act as shuttles between the Golgi complex and the plasma membrane. This type of intracellular transfer is weil established for various secretory cells and may be adopted also for the hepatocyte. Recent investigations have shown that secretory vesicles fuse with each other during secretion in mast cells [4] exocrine [5,6] and endocrine pancreatic tissue [7]. The intervesicular fusion provides a tool for studies on membrane fusion, since Golgi-derived vesicles can be isolated from the hepatocyte and their interaction with various agents, suggested to trigger membrane fusion, can be monitored by freeze-cleaving.
Thu, 1 Jan 1976 12:00:00 +0100 https://epub.ub.uni-muenchen.de/7133/1/7133.pdf Gratzl, Manfred; Dahl, G. dd
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