MPA Modulates Tight Junctions' Permeability via Midkine/PI3K Pathway in Caco-2 Cells: A Possible Mechanism of Leak-Flux Diarrhea in Organ Transplanted Patients

Khan, Niamat; Binder, Lutz; Pantakani, D. V. Krishna; Asif, Abdul R.

doi:10.3389/fphys.2017.00438

Cited by 40 publications

(19 citation statements)

References 88 publications

(129 reference statements)

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“…increased tight junction permeability (45,46). This may be occurring via MPA-stimulated activation of the midkine-dependent PI3K pathway (47). Our previous work supports these observations of MPA-induced epithelial barrier dysfunction as we found that MMF exposure led to an increase in serum lipopolysaccharide, an indirect measure of intestinal epithelial barrier function (20,48).…”

Section: Assessment Of Bacterial Gus Activity In Vivosupporting

confidence: 86%

Vancomycin Relieves Mycophenolate Mofetil-Induced Gastrointestinal Toxicity by Eliminating Gut Bacterial β-Glucuronidase Activity

Taylor

Flannigan

Rahim

et al. 2019

Preprint

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Mycophenolate mofetil (MMF) is commonly prescribed after transplantation and has proven advantages over other immunosuppressive drugs but gastrointestinal (GI) side effects frequently limit its use. The pathways involved in the metabolism of the prodrug MMF and the bioactive derivative mycophenolic acid (MPA) are well characterized but the mechanism responsible for toxicity is unknown. Here we extend our previous observation that an intact gut microbiome is required for MMF-induced toxicity and demonstrate that gut bacterial metabolism is responsible for the GI inflammation and weight loss associated with MMF exposure. In mice consuming MMF, the introduction of vancomycin alone was sufficient to prevent or reverse MMF-induced weight loss and colonic inflammation. MMF induced the expansion of bacteria expressing b-glucuronidase (GUS) in the cecum and proximal colon. GUS activity, which is responsible for the catabolism of glucuronidated MPA (MPAG) to free MPA, was increased in the presence of MMF and eliminated by vancomycin. Vancomycin eliminated multiple Bacteroides spp. that flourished in the presence of MMF and prevented the breakdown of MPAG without negatively affecting serum MPA levels. Human data suggests that increased stool GUS activity can be associated with MMF-related toxicity. Our work provides a mechanism for the GI toxicity associated with MMF and a future direction for the development of therapeutics.3

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Section: Assessment Of Bacterial Gus Activity In Vivosupporting

confidence: 86%

Vancomycin Relieves Mycophenolate Mofetil-Induced Gastrointestinal Toxicity by Eliminating Gut Bacterial β-Glucuronidase Activity

Taylor

Flannigan

Rahim

et al. 2019

Preprint

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“…7 ). However, it might be interesting to mention that intracellular MK is also capable to activate pI3K ( Khan et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Midkine Controls Arteriogenesis by Regulating the Bioavailability of Vascular Endothelial Growth Factor A and the Expression of Nitric Oxide Synthase 1 and 3

Lautz¹,

Lasch²,

Borgolte³

et al. 2018

EBioMedicine

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Midkine is a pleiotropic factor, which is involved in angiogenesis. However, its mode of action in this process is still ill defined. The function of midkine in arteriogenesis, the growth of natural bypasses from pre-existing collateral arteries, compensating for the loss of an occluded artery has never been investigated. Arteriogenesis is an inflammatory process, which relies on the proliferation of endothelial cells and smooth muscle cells. We show that midkine deficiency strikingly interferes with the proliferation of endothelial cells in arteriogenesis, thereby interfering with the process of collateral artery growth. We identified midkine to be responsible for increased plasma levels of vascular endothelial growth factor A (VEGFA), necessary and sufficient to promote endothelial cell proliferation in growing collaterals. Mechanistically, we demonstrate that leukocyte domiciled midkine mediates increased plasma levels of VEGFA relevant for upregulation of endothelial nitric oxide synthase 1 and 3, necessary for proper endothelial cell proliferation, and that non-leukocyte domiciled midkine additionally improves vasodilation.The data provided on the role of midkine in endothelial proliferation are likely to be relevant for both, the process of arteriogenesis and angiogenesis. Moreover, our data might help to estimate the therapeutic effect of clinically applied VEGFA in patients with vascular occlusive diseases.

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“…3b,c). MDK has been reported to signal through multiple different intracellular pathways involving Akt, Atf 21 , Stat4, NFAT1, NFAT2 22 , and Src 23 . While no differences in Akt, Atf, Stat4, NFAT2 activation were observed ( Supplementary Fig.…”

Section: Mdk Induces T Cell Ccl4 Via Lrp1/calcineurin/nfat1 Signalingmentioning

confidence: 99%

Midkine activation of CD8+ T cells establishes a neuron–immune–cancer axis responsible for low-grade glioma growth

et al. 2020

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Brain tumors (gliomas) are heterogeneous cellular ecosystems, where non-neoplastic monocytic cells have emerged as key regulators of tumor maintenance and progression. However, relative to macrophages/microglia, comparatively less is known about the roles of neurons and T cells in glioma pathobiology. Herein, we leverage genetically engineered mouse models and human biospecimens to define the axis in which neurons, T cells, and microglia interact to govern Neurofibromatosis-1 (NF1) low-grade glioma (LGG) growth. NF1mutant human and mouse brain neurons elaborate midkine to activate naïve CD8 + T cells to produce Ccl4, which induces microglia to produce a key LGG growth factor (Ccl5) critical for LGG stem cell survival. Importantly, increased CCL5 expression is associated with reduced survival in patients with LGG. The elucidation of the critical intercellular dependencies that constitute the LGG neuroimmune axis provides insights into the role of neurons and immune cells in controlling glioma growth, relevant to future therapeutic targeting.

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MPA Modulates Tight Junctions' Permeability via Midkine/PI3K Pathway in Caco-2 Cells: A Possible Mechanism of Leak-Flux Diarrhea in Organ Transplanted Patients

Cited by 40 publications

References 88 publications

Vancomycin Relieves Mycophenolate Mofetil-Induced Gastrointestinal Toxicity by Eliminating Gut Bacterial β-Glucuronidase Activity

Vancomycin Relieves Mycophenolate Mofetil-Induced Gastrointestinal Toxicity by Eliminating Gut Bacterial β-Glucuronidase Activity

Midkine Controls Arteriogenesis by Regulating the Bioavailability of Vascular Endothelial Growth Factor A and the Expression of Nitric Oxide Synthase 1 and 3

Midkine activation of CD8+ T cells establishes a neuron–immune–cancer axis responsible for low-grade glioma growth

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