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Last update 08 May 2025

MLC

Last update 08 May 2025

Basic Info

Synonyms

KIAA0027, LVM, Membrane protein MLC1

+ [5]

Introduction

Transmembrane protein mainly expressed in brain astrocytes that may play a role in transport across the blood-brain and brain-cerebrospinal fluid barriers (PubMed:22328087). Regulates the response of astrocytes to hypo-osmosis by promoting calcium influx (PubMed:22328087). May function as regulatory protein of membrane protein complexes such as ion channels (Probable).

Drugs associated with MLC

MLC1 gene therapy(CIBER)

Target

MLC

Mechanism

MLC modulators

Active Org.

CIBER International LLC

Originator Org.

CIBER International LLC

Active Indication

Leukoencephalopathies

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

YM-198313

Target

MLC

Mechanism

MLC inhibitors

Active Org.-

Originator Org.

Yamanouchi Pharmaceutical Co., Ltd.

Active Indication-

Inactive Indication

Arrhythmias, Cardiac

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with MLC

100 Translational Medicine associated with MLC

0 Patents (Medical) associated with MLC

2,653

Literatures (Medical) associated with MLC

01 May 2025·Gastroenterology

In Obesity, Esophagogastric Junction Fat Impairs Esophageal Barrier Function and Dilates Intercellular Spaces via Hypoxia-Inducible Factor 2α

Article

Author: Ustaoglu, Ahsen ; Leeds, Steven ; Genta, Robert M ; Kale, Ishani ; Ekeanyanwu, Rebecca ; Nguyen, Anh D ; Davis, Daniel ; Spechler, Stuart Jon ; Wang, Xuan ; Ward, Marc ; Pan, Zui ; Zhang, Qiuyang ; Sifrim, Daniel ; Paris, Sheré ; Podgaetz, Eitan ; Chang, Yan ; Souza, Rhonda F ; Woodland, Philip J ; Zhang, Xi

BACKGROUND & AIMSDilated intercellular space in esophageal epithelium, a sign of impaired barrier function, is a characteristic finding of gastroesophageal reflux disease that is also found in obese patients without gastroesophageal reflux disease. We explored molecular mechanisms whereby adipose tissue products might impair esophageal barrier integrity.METHODSCultures of visceral fat obtained during foregut surgery from obese and nonobese patients were established. Monolayer and air-liquid interface cultures of human esophageal cells were grown with conditioned medium (CM) from fat cultures. RNA sequencing, enzyme-linked immunosorbent assay, western blot, immunostaining, histology, and analyses of barrier function were performed; inhibitors of hypoxia-inducible factor 2α (HIF-2α [PT2385]), caspase-1 (AC-YVAD-CHO), myosin light chain kinase (Dreverse PIK), and myosin light chain phosphatase (permeant inhibitor of phosphatase 250) were applied; blebbistatin was used to disrupt actin-myosin interactions; N-acetylcysteine was used to scavenge reactive oxygen species.RESULTSCM from esophagogastric junction fat of obese patients caused dilated intercellular space with impaired barrier function in esophageal air-liquid interface cultures; these effects were blocked by PT2385. CM from esophagogastric junction fat of obese patients induced reactive oxygen species production that activated HIF-2α in esophageal cells. RNA-sequencing analyses linked CM from esophagogastric junction fat of obese patient-induced HIF-2α increases with innate immune response pathways. Cross-talk between HIF-2α and caspase-1 in esophageal cells led to interleukin 1β secretion, and interleukin 1β/interleukin 1 receptor 1 signaling caused dilated intercellular space with impaired esophageal barrier function via actin-myosin interactions induced by myosin light chain phosphorylation.CONCLUSIONSWe have elucidated molecular mechanisms whereby visceral fat of obese patients can impair esophageal barrier integrity by secreting substances that generate reactive oxygen species, which activate HIF-2α in esophageal epithelial cells. These mechanisms could render the esophagus of obese individuals vulnerable to damage from acid and other noxious agents.

01 May 2025·International Journal of Biological Macromolecules

Proline rich-39 (PR-39) antimicrobial protein alleviated lipopolysaccharide-induced intestinal barrier dysfunction in piglets by altering intestinal flora associated bile acid metabolism and in turn regulating TGR-5/NF-κB/MLCK/MLC pathway

Article

Author: Wang, Xuemei ; Liu, Zhineng ; Chen, Wanyan ; Zhang, Bin ; Yang, Zheng ; Qin, Xinyun ; Liu, Xiande ; Shi, Huiyu ; Li, Lianbin ; Zhang, Haiwen ; Nong, Keyi ; Lang, Wen

Proline rich-39 (PR-39) is a natural antimicrobial protein with good antibacterial and anti-inflammatory activities. The miniature Wuzhishan pig (WZSP) has important similarities to humans in anatomical structure, physiological characteristics, and nutrient metabolism that make it an important model animal for biomedical research. This study aimed to investigate the protective effect and therapeutic mechanism of PR-39 on intestinal barrier function using the LPS-induced enteritis model in WZSPs. We found that PR-39 treatment reversed the decrease in growth performance and peripheral organ damage, regulated serum indices (IL-1β, IL-6, TNF-α, IL-10, TGF-β, IgA, IgG, DAO, D-LA) and enhanced the antioxidant capacity (MDA, CAT, GSH-Px, T-AOC) of piglets. PR-39 protected the integrity of the jejunal barrier by upregulating the density of goblet cells and the expression of tight junction proteins ZO-1, Claudin-1, and Occludin. Additionally, PR-39 increased the abundance of jejunal probiotics (e.g., Lactococcus), and increased the cecal abundance of Lactobacillus johnsonii, then promoted the production of 7-keto deoxycholic acid to activate the bile acid receptor TGR5, which in turn inhibited the NF-κB-MLCK-MLC signaling pathway and the secretion of proinflammatory factors by macrophages. In summary, these findings suggest that PR-39 supplementation may be an effective strategy to improve the intestinal damage and dysfunction.

01 Apr 2025·Annals of Surgery

Endothelial Cell Calcium Influx Mediates Trauma-induced Endothelial Permeability

Article

Author: Schaid, Terry R. ; DeBot, Margot ; Silliman, Christopher C. ; Cohen, Mitchell J. ; Hallas, William ; Mitra, Sanchayita ; Cralley, Alexis ; Stafford, Preston ; Jeffrey, Danielle ; D’Alessandro, Angelo ; Dabertrand, Fabrice ; Thielen, Otto ; Hansen, Kirk C. ; Gallagher, Lauren

Objective:To investigate whether ex vivo plasma from injured patients causes endothelial calcium (Ca2+) influx as a mechanism of trauma-induced endothelial permeability.Background:Endothelial permeability after trauma contributes to postinjury organ dysfunction. While the mechanisms remain unclear, emerging evidence suggests intracellular Ca2+ signaling may play a role.Methods:Ex vivo plasma from injured patients with “low injury/low shock” (injury severity score <15, base excess ≥−6 mEq/L) and “high injury/high shock” (injury severity score ≥15, base excess <−6 mEq/L) were used to treat endothelial cells. Experimental conditions included Ca2+ removal from the extracellular buffer, cyclopiazonic acid pretreatment to deplete intracellular Ca2+ stores, and GSK2193874 pretreatment to block the transient receptor potential vanilloid 4 (TRPV4) Ca2+ channel. Live cell fluorescence microscopy and electrical cell-substrate impedance sensing were used to assess cytosolic Ca2+ increases and permeability, respectively. Western blot and live cell actin staining were used to assess myosin light chain phosphorylation and actomyosin contraction.Results:Compared with low injury/low shock plasma, high injury/high shock induced greater cytosolic Ca2+ increase. Cytosolic Ca2+ increase, myosin light chain phosphorylation, and actin cytoskeletal contraction were lower without extracellular Ca2+ present. High injury/high shock plasma did not induce endothelial permeability without extracellular Ca2+ present. TRPV4 inhibition lowered trauma plasma-induced endothelial Ca2+ influx and permeability.Conclusions:This study illuminates a novel mechanism of postinjury endotheliopathy involving Ca2+ influx through the TRPV4 channel. TRPV4 inhibition mitigates trauma-induced endothelial permeability. Moreover, widespread endothelial Ca2+ influx may contribute to trauma-induced hypocalcemia. This study provides the mechanistic basis for the development of Ca2+-targeted therapies and interventions in the care of severely injured patients.

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MLC

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