SPAK Deficiency Attenuates Chemotherapy-Induced Intestinal Mucositis

IntroductionSte20-related protein proline/alanine-rich kinase (SPAK) affects cell proliferation, differentiation, and transformation, and sodium and chloride transport in the gut. However, its role in gut injury pathogenesis is unclear.ObjectiveWe determined the role of SPAK in chemotherapy-induced intestinal mucositis using in vivo and in vitro models.MethodsUsing SPAK-knockout (KO) mice, we evaluated the severity of intestinal mucositis induced by 5-fluorouracil (5-FU) by assessing body weight loss, histological changes in the intestinal mucosa, length of villi in the small intestine, pro-inflammatory cytokine levels, proliferative indices, and apoptotic indices. We also evaluated changes in gut permeability and tight junction-associated protein expression. Changes in cell permeability, proliferation, and apoptosis were assessed in SPAK siRNA-transfected 5FU-treated IEC-6 cells.Results5-FU-treated SPAK-KO mice exhibited milder intestinal mucositis, reduced pro-inflammatory cytokine expression, increased villus length, good maintenance of proliferative indices of villus cells, decreased apoptotic index of enterocytes, reduced gut permeability, and restoration of tight junction protein expression (vs. 5-FU-treated wild-type mice). Under in vitro conditions, siRNA-mediated SPAK-knockdown in IEC-6 cells decreased cell permeability and maintained homeostasis following 5-FU treatment.ConclusionSPAK deficiency attenuated chemotherapy-induced intestinal mucositis by modulating gut permeability and tight junction-associated protein expression and maintaining gut homeostasis in murine small intestinal tissues following gut injury. The expression of SPAK may influence the pathogenesis of chemotherapy-induced intestinal mucositis.

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Geniposide protects against hypoxia/reperfusion-induced blood-brain barrier impairment by increasing tight junction protein expression and decreasing inflammation, oxidative stress, and apoptosis in an in vitro system

European Journal of Pharmacology ◽

10.1016/j.ejphar.2019.04.021 ◽

2019 ◽

Vol 854 ◽

pp. 224-231 ◽

Cited By ~ 9

Author(s):

Changxiang Li ◽

Xueqian Wang ◽

Fafeng Cheng ◽

Xin Du ◽

Juntang Yan ◽

...

Keyword(s):

Oxidative Stress ◽

Protein Expression ◽

Tight Junction ◽

Blood Brain Barrier ◽

Tight Junction Protein ◽

Brain Barrier ◽

In Vitro System ◽

Tight Junction Protein Expression ◽

Junction Protein

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HIV-1 gp120 Proteins Alter Tight Junction Protein Expression and Brain Endothelial Cell Permeability: Implications for the Pathogenesis of HIV-Associated Dementia

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/64.6.498 ◽

2005 ◽

Vol 64 (6) ◽

pp. 498-505 ◽

Cited By ~ 97

Author(s):

Georgette D. Kanmogne ◽

Charles Primeaux ◽

Paula Grammas

Keyword(s):

Endothelial Cell ◽

Protein Expression ◽

Tight Junction ◽

Tight Junction Protein ◽

Cell Permeability ◽

Brain Endothelial Cell ◽

Tight Junction Protein Expression ◽

Junction Protein ◽

Endothelial Cell Permeability ◽

Hiv 1

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1-Trifluoromethoxyphenyl-3-(1-Propionylpiperidin-4-yl) Urea Protects the Blood-Brain Barrier Against Ischemic Injury by Upregulating Tight Junction Protein Expression, Mitigating Apoptosis and Inflammation InVivo and In Vitro Model

Frontiers in Pharmacology ◽

10.3389/fphar.2020.01197 ◽

2020 ◽

Vol 11 ◽

Cited By ~ 1

Author(s):

Xingyang Yi ◽

Chongxi Xu ◽

Pan Huang ◽

Linlei Zhang ◽

Ting Qing ◽

...

Keyword(s):

Protein Expression ◽

Tight Junction ◽

Blood Brain Barrier ◽

In Vitro Model ◽

Tight Junction Protein ◽

Tight Junction Protein Expression ◽

Junction Protein ◽

Vitro Model ◽

Apoptosis And Inflammation

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ZO-3, a Novel Member of the MAGUK Protein Family Found at the Tight Junction, Interacts with ZO-1 and Occludin

The Journal of Cell Biology ◽

10.1083/jcb.141.1.199 ◽

1998 ◽

Vol 141 (1) ◽

pp. 199-208 ◽

Cited By ~ 389

Author(s):

Julie Haskins ◽

Lijie Gu ◽

Erika S. Wittchen ◽

Jennifer Hibbard ◽

Bruce R. Stevenson

Keyword(s):

Amino Acid ◽

Tight Junction ◽

Molecular Mass ◽

Mdck Cells ◽

Cdna Libraries ◽

Pdz Domains ◽

Large Tumor ◽

Junction Protein ◽

Discs Large

A 130-kD protein that coimmunoprecipitates with the tight junction protein ZO-1 was bulk purified from Madin-Darby canine kidney (MDCK) cells and subjected to partial endopeptidase digestion and amino acid sequencing. A resulting 19–amino acid sequence provided the basis for screening canine cDNA libraries. Five overlapping clones contained a single open reading frame of 2,694 bp coding for a protein of 898 amino acids with a predicted molecular mass of 98,414 daltons. Sequence analysis showed that this protein contains three PSD-95/SAP90, discs-large, ZO-1 (PDZ) domains, a src homology (SH3) domain, and a region similar to guanylate kinase, making it homologous to ZO-1, ZO-2, the discs large tumor suppressor gene product of Drosophila, and other members of the MAGUK family of proteins. Like ZO-1 and ZO-2, the novel protein contains a COOH-terminal acidic domain and a basic region between the first and second PDZ domains. Unlike ZO-1 and ZO-2, this protein displays a proline-rich region between PDZ2 and PDZ3 and apparently contains no alternatively spliced domain. MDCK cells stably transfected with an epitope-tagged construct expressed the exogenous polypeptide at an apparent molecular mass of ∼130 kD. Moreover, this protein colocalized with ZO-1 at tight junctions by immunofluorescence and immunoelectron microscopy. In vitro affinity analyses demonstrated that recombinant 130-kD protein directly interacts with ZO-1 and the cytoplasmic domain of occludin, but not with ZO-2. We propose that this protein be named ZO-3.

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Tight junction protein expression and barrier properties of immortalized mouse brain microvessel endothelial cells

Brain Research ◽

10.1016/j.brainres.2006.10.083 ◽

2007 ◽

Vol 1130 ◽

pp. 17-30 ◽

Cited By ~ 188

Author(s):

Rachel C. Brown ◽

Andrew P. Morris ◽

Roger G. O'Neil

Keyword(s):

Endothelial Cells ◽

Protein Expression ◽

Tight Junction ◽

Mouse Brain ◽

Barrier Properties ◽

Tight Junction Protein ◽

Tight Junction Protein Expression ◽

Junction Protein ◽

Microvessel Endothelial Cells ◽

Brain Microvessel

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Changes in tight junction protein expression in intrinsic aging and photoaging in human skin in vivo

Journal of Dermatological Science ◽

10.1016/j.jdermsci.2016.07.002 ◽

2016 ◽

Vol 84 (1) ◽

pp. 99-101 ◽

Cited By ~ 10

Author(s):

Seon-Pil Jin ◽

Sang Bum Han ◽

Yeon Kyung Kim ◽

Elizabeth Eunkyung Park ◽

Eun Jin Doh ◽

...

Keyword(s):

Protein Expression ◽

Tight Junction ◽

Human Skin ◽

Tight Junction Protein ◽

Tight Junction Protein Expression ◽

Junction Protein

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Granny Smith apple procyanidin extract upregulates tight junction protein expression and modulates oxidative stress and inflammation in lipopolysaccharide-induced Caco-2 cells

Food & Function ◽

10.1039/c8fo00525g ◽

2018 ◽

Vol 9 (6) ◽

pp. 3321-3329 ◽

Cited By ~ 21

Author(s):

H. Wu ◽

T. Luo ◽

Y. M. Li ◽

Z. P. Gao ◽

K. Q. Zhang ◽

...

Keyword(s):

Oxidative Stress ◽

Protein Expression ◽

Tight Junction ◽

Tight Junction Protein ◽

Tight Junction Protein Expression ◽

Junction Protein

Granny Smith apple procyanidin extracts upregulate tight junction protein expression, probably acting via the modulation of oxidative stress and inflammation in lipopolysaccharide-induced Caco-2 cells.

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