Particulate matter 10 exposure affects intestinal functionality in both inflamed 2D intestinal epithelial cell and 3D intestinal organoid models DOI Creative Commons
Ye Seul Son, Naeun Son,

Won Dong Yu

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: June 26, 2023

Background A growing body of evidence suggests that particulate matter (PM10) enters the gastrointestinal (GI) tract directly, causing GI epithelial cells to function less efficiently, leading inflammation and an imbalance in gut microbiome. PM10 may, however, act as exacerbation factor patients with inflamed intestinal epithelium, which is associated inflammatory bowel disease. Objective The purpose this study was dissect pathology mechanism exposure intestines. Methods In study, we established chronically epithelium models utilizing two-dimensional (2D) human (hIECs) 3D organoids (hIOs), mimic vivo cellular diversity function, order examine deleterious effects intestine-like vitro models. Results Inflamed 2D hIECs hIOs exhibited pathological features, such inflammation, decreased markers, defective barrier function. addition, found induced a more severe disturbance peptide uptake than control cells. This due fact it interferes calcium signaling, protein digestion, absorption pathways. findings demonstrate PM10-induced alterations contribute disorders caused by intestine. Conclusions According our findings, hIEC hIO could be powerful platforms for evaluation causal relationship between PM abnormal functions.

Language: Английский

The CLDN5 gene at the blood-brain barrier in health and disease DOI Creative Commons
Yosuke Hashimoto, Chris Greene, Arnold Münnich

et al.

Fluids and Barriers of the CNS, Journal Year: 2023, Volume and Issue: 20(1)

Published: March 28, 2023

Abstract The CLDN5 gene encodes claudin-5 (CLDN-5) that is expressed in endothelial cells and forms tight junctions which limit the passive diffusions of ions solutes. blood–brain barrier (BBB), composed brain microvascular associated pericytes end-feet astrocytes, a physical biological to maintain microenvironment. expression CLDN-5 tightly regulated BBB by other junctional proteins supports from astrocytes. most recent literature clearly shows compromised with decline increasing risks developing neuropsychiatric disorders, epilepsy, calcification dementia. purpose this review summarize known diseases function. In first part review, we highlight understanding how as well astrocytes cells. We detail some drugs can enhance these are being developed or currently use treat decline. then summarise mutagenesis-based studies have facilitated better physiological role protein at demonstrated functional consequences recently identified pathogenic missense mutation patients alternating hemiplegia childhood. This gain-of-function CLDN family all others representing loss-of-function mutations resulting mis-localization and/or attenuated Finally, reports about dosage-dependent effect on development neurological mice discuss what cellular for regulation human diseases.

Language: Английский

Citations

65
Patterning of the cell cortex by Rho GTPases DOI
William M. Bement, Andrew B. Goryachev, Ann L. Miller

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(4), P. 290 - 308

Published: Jan. 3, 2024

Language: Английский

Citations

50
Structure of human TRPV4 in complex with GTPase RhoA DOI Creative Commons
Kirill D. Nadezhdin, Irina A. Talyzina, Aravind Parthasarathy

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: June 23, 2023

Abstract Transient receptor potential (TRP) channel TRPV4 is a polymodal cellular sensor that responds to moderate heat, cell swelling, shear stress, and small-molecule ligands. It involved in thermogenesis, regulation of vascular tone, bone homeostasis, renal pulmonary functions. implicated neuromuscular skeletal disorders, edema, cancers, represents an important drug target. The cytoskeletal remodeling GTPase RhoA has been shown suppress activity. Here, we present structure the human TRPV4-RhoA complex shows interaction with membrane-facing surface ankyrin repeat domains. contact interface reveals residues are mutated neuropathies, providing insight into disease pathogenesis. We also identify binding sites agonist 4α-PDD inhibitor HC-067047 at base S1-S4 bundle, show leads pore opening, while inhibition involves π-to-α transition pore-forming helix S6. Our structures elucidate between hTRPV4 RhoA, as well this disease-causing mutations. They shed light on activation provide template for design future therapeutics treatment TRPV4-related diseases.

Language: Английский

Citations

35
Storming the gate: New approaches for targeting the dynamic tight junction for improved drug delivery DOI Creative Commons
Isabela Ramirez-Velez, Brian Belardi

Advanced Drug Delivery Reviews, Journal Year: 2023, Volume and Issue: 199, P. 114905 - 114905

Published: June 3, 2023

Language: Английский

Citations

23
Tight junction membrane proteins regulate the mechanical resistance of the apical junctional complex DOI Creative Commons
Thanh Phuong Nguyen, Tetsuhisa Otani, Motosuke Tsutsumi

et al.

The Journal of Cell Biology, Journal Year: 2024, Volume and Issue: 223(5)

Published: March 22, 2024

Epithelia must be able to resist mechanical force preserve tissue integrity. While intercellular junctions are known important for the resistance of epithelia, roles tight (TJs) remain established. We previously demonstrated that epithelial cells devoid TJ membrane proteins claudins and JAM-A completely lack TJs exhibit focal breakages their apical junctions. Here, we demonstrate fracture when claudin/JAM-A–deficient undergo spontaneous cell stretching. The junction was accompanied by actin disorganization, polymerization required integrity in cells. Further deletion CAR resulted disruption ZO-1 molecule ordering at junctions, severe defects These results regulate junctional complex

Language: Английский

Citations

12
Tight junctions control lumen morphology via hydrostatic pressure and junctional tension DOI Creative Commons
Markus Mukenhirn,

Chen-Ho Wang,

Tristan Guyomar

et al.

Developmental Cell, Journal Year: 2024, Volume and Issue: 59(21), P. 2866 - 2881.e8

Published: Aug. 12, 2024

Formation of fluid-filled lumina by epithelial tissues is essential for organ development. How cells control the hydraulic and cortical forces to lumen morphology not well understood. Here, we quantified mechanical role tight junctions in formation using MDCK-II cysts. We found that paracellular ion barrier formed claudin receptors required inflation a lumen. However, depletion zonula occludens scaffold resulted collapse folding apical membranes. Combining quantitative measurements hydrostatic pressure junctional tension with modeling enabled us explain morphologies from pressure-tension force balance. Tight promote decreasing via inhibition myosin. In addition, our results suggest excess area contributes opening. Overall, provide understanding how use modulate tissue shape.

Language: Английский

Citations

9
S100A11 promotes focal adhesion disassembly via myosin II-driven contractility and Piezo1-mediated Ca2+ entry DOI
Tareg Omer Mohammed, You-Rong Lin, Lucky Akter

et al.

Journal of Cell Science, Journal Year: 2024, Volume and Issue: 137(2)

Published: Jan. 15, 2024

ABSTRACT S100A11 is a small Ca2+-activatable protein known to localize along stress fibers (SFs). Analyzing localization in HeLa and U2OS cells further revealed enrichment at focal adhesions (FAs). Strikingly, levels FAs increased sharply, yet transiently, just before FA disassembly. Elevating intracellular Ca2+ with ionomycin stimulated both recruitment subsequent However, pre-incubation the non-muscle myosin II (NMII) inhibitor blebbistatin or an of stretch-activatable channel Piezo1 suppressed recruitment, implicating actomyosin-driven mechanism involving Piezo1-dependent influx. Applying external forces on peripheral likewise recruited even if NMII activity was inhibited, corroborating mechanosensitive S100A11. extracellular function were indispensable, indicating that contraction act upstream Piezo1-mediated influx, turn leading activation recruitment. S100A11-knockout display enlarged had delayed disassembly during cell membrane retraction, consistent impaired turnover these cells. Our results thus demonstrate novel for promoting actomyosin contractility-driven

Language: Английский

Citations

7
Structural Pharmacology of TRPV4 Antagonists DOI
Junping Fan, Chang Guo, Daohong Liao

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: 11(25)

Published: April 24, 2024

Abstract The nonselective calcium‐permeable Transient Receptor Potential Cation Channel Subfamily V Member4 (TRPV4) channel regulates various physiological activities. Dysfunction of TRPV4 is linked to many severe diseases, including edema, pain, gastrointestinal disorders, lung and inherited neurodegeneration. Emerging antagonists show potential clinical benefits. However, the molecular mechanisms antagonism remain poorly understood. Here, cryo‐electron microscopy (cryo‐EM) structures human are presented in‐complex with two potent antagonists, revealing detailed binding pockets regulatory gating. Both bind voltage‐sensing‐like domain (VSLD) stabilize in closed states. These induce undergo an apparent fourfold twofold symmetry transition. Moreover, it demonstrated that one binds VSLD extended pocket, which differs from canonical pocket. Complemented functional dynamics simulation results, this study provides crucial mechanistic insights into regulation by small‐molecule may facilitate future drug discovery targeting TRPV4.

Language: Английский

Citations

7
Mechanosensitive recruitment of Vinculin maintains junction integrity and barrier function at epithelial tricellular junctions DOI
Lotte van den Goor, Jolene Iseler,

Katherine Koning

et al.

Current Biology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 1, 2024

Language: Английский

Citations

7
Adenosine in Intestinal Epithelial Barrier Function DOI Creative Commons
Mariya Stepanova, Carol M. Aherne

Cells, Journal Year: 2024, Volume and Issue: 13(5), P. 381 - 381

Published: Feb. 23, 2024

At the intestinal front, several lines of defense are in place to resist infection and injury, mucus layer, gut microbiome strong epithelial junctions, name a few. Their collaboration creates resilient barrier. In disorders, such as inflammatory bowel disease (IBD), barrier function is compromised, which results rampant inflammation tissue injury. response destruction, epithelium releases adenosine, small but powerful nucleoside that functions an alarm signal. Amidst chaos inflammation, adenosine aims restore order. Within scope its effects ability regulate integrity. This review define contributions production, microbiome-dependent protection, tight junction dynamics, chloride secretion acid–base balance reinforce importance

Language: Английский

Citations

6