scholarly journals Protocadherin 19 Clustering Epilepsy and Neurosteroids: Opportunities for Intervention

2021 ◽  
Vol 22 (18) ◽  
pp. 9769
Author(s):  
Rebekah de Nys ◽  
Raman Kumar ◽  
Jozef Gecz

Steroids yield great influence on neurological development through nuclear hormone receptor (NHR)-mediated gene regulation. We recently reported that cell adhesion molecule protocadherin 19 (encoded by the PCDH19 gene) is involved in the coregulation of steroid receptor activity on gene expression. PCDH19 variants cause early-onset developmental epileptic encephalopathy clustering epilepsy (CE), with altered steroidogenesis and NHR-related gene expression being identified in these individuals. The implication of hormonal pathways in CE pathogenesis has led to the investigation of various steroid-based antiepileptic drugs in the treatment of this disorder, with mixed results so far. Therefore, there are many unmet challenges in assessing the antiseizure targets and efficiency of steroid-based therapeutics for CE. We review and assess the evidence for and against the implication of neurosteroids in the pathogenesis of CE and in view of their possible clinical benefit.

2003 ◽  
Vol 284 (2) ◽  
pp. C422-C428 ◽  
Author(s):  
Makoto Sasaki ◽  
D. Ostanin ◽  
J. W. Elrod ◽  
T. Oshima ◽  
P. Jordan ◽  
...  

It is strongly suspected that cytokine-induced gene expression in inflammation is oxidant mediated; however, the intracellular sources of signaling oxidants remain controversial. In inflammatory bowel disease (IBD) proinflammatory cytokines, such as TNF-α, trigger gene expression of endothelial adhesion molecules including mucosal addressin cell adhesion molecule-1 (MAdCAM-1). MAdCAM-1 plays an essential role in gut inflammation by governing the infiltration of leukocytes into the intestine. Several groups suggest that endothelial-derived reduced NADP (NADPH) oxidase produces signaling oxidants that control the expression of adhesion molecules (E-selectin, ICAM-1, VCAM-1). In addition to NADPH oxidase, cytochrome P-450 (CYP450) monooxygenases have also been shown to trigger cytokine responses. We found that in high endothelial venular cells (SVEC4-10), multiple inhibitors of CYP450 monooxygenases (SKF-525a, ketoconazole, troleandomycin, itraconazole) attenuated TNF-α induction of MAdCAM-1, whereas NADPH oxidase inhibition (PR-39) did not. Conversely, E-selectin, ICAM-1, and VCAM-1 induction requires both NADPH oxidase and CYP450-derived oxidants. We show here that MAdCAM-1 induction may depend exclusively on CYP450-derived oxidants, suggesting that CYP450 blockers might represent a possible novel therapeutic treatment for human IBD.


2019 ◽  
Vol 14 (1) ◽  
pp. 32-36
Author(s):  
Salmi ◽  
Nurliyani ◽  
Sunarti

Synbiotic cheese made of goat milk, bacterial starter Lactobacillus rhamnosus, and porang glucomannan has been reported to have anti-inflammatory effects. This study aimed to determine the effect of synbiotic cheese on gene expression and protein levels of intercellular cell adhesion molecule-1 in a rat model of gastric injury. Male Wistar rats were divided into six groups. For 28 days, three groups received an increasing dosage of synbiotic cheese and one group received one dosage of probiotic cheese. For comparison, there was a placebo group receiving nothing and another group receiving indomethacin alone. On day 29, all rats received 20 mg/kg indomethacin intragastrically to induce gastric injury. Twenty-four hours later, rats were euthanized, and gastric tissue was taken for the quantification of intercellular cell adhesion molecule-1 gene and protein expressions. The results showed that pretreatment of synbiotic cheese caused significant suppression of intercellular cell adhesion molecule-1 expression. Synbiotic cheese at a dose of 0.36 g/day significantly suppressed intercellular cell adhesion molecule-1 protein expression (P < 0.05), whereas synbiotic cheese at a dose of 0.72 g/day significantly suppressed both gene expression and protein levels of intercellular cell adhesion molecule-1 (P < 0.05) compared to the indomethacin alone group. We conclude that synbiotic cheese may protect from gastric injury through modulation of intercellular cell adhesion molecule-1.


1993 ◽  
Vol 13 (10) ◽  
pp. 6283-6289 ◽  
Author(s):  
H B Shu ◽  
A B Agranoff ◽  
E G Nabel ◽  
K Leung ◽  
C S Duckett ◽  
...  

Vascular cell adhesion molecule 1 (VCAM-1) is expressed in both endothelial and epithelial cell types, where it contributes to lymphocyte migration to sites of inflammation. Its expression is regulated by cytokines, in part through two kappa B-like regulatory elements. Because NF-kappa B can be composed of multiple alternative subunits with differential effects on gene expression, the role of different specific NF-kappa B family members subunits in VCAM-1 regulation is unknown. In this report, we define the contribution of different NF-kappa B family members to VCAM-1 gene regulation. We show that both kappa B sites in the VCAM-1 enhancer are required to optimally stimulate gene expression, but the enhancer is differentially regulated by specific combinations of NF-kappa B subunits. At low concentrations, RelA(p65) acted in concert with the approximately 50-kDa product of p105 NF-kappa B, NF-kappa B1(p50), to stimulate transcription, and at high concentrations, RelA(p65) alone stimulated the VCAM-1 promoter. In contrast, NF-kappa B2 inhibited functional activation of the VCAM reporter by p65. Consistent with this finding, an additional binding complex was detected by using recombinant NF-kappa B2(p49)/RelA(p65) with radiolabeled VCAM kappa B site probes. Interestingly, the human immunodeficiency virus enhancer responded differently to stimulation by NF-kappa B subunits, with optimal response to p49(100)/p65. Analysis of NF-kappa B mRNA in human umbilical vein endothelial cells revealed that nfkb1, nfkb2, and relA NF-kappa B but not c-rel were induced by tumor necrosis factor alpha and lipopolysaccharide, which also induce VCAM-1. These data suggest that specific subunits of NF-kappa B regulate VCAM-1 and differentially activate other genes in these cells.


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