Molecular hydrogen suppresses activated Wnt/β-catenin signaling

Abstract

Molecular hydrogen (H2) is effective for many diseases. However, molecular bases of H2 have not been fully elucidated. Cumulative evidence indicates that H2 acts as a gaseous signal modulator. We found that H2 suppresses activated Wnt/β-catenin signaling by promoting phosphorylation and degradation οf β-catenin. Either complete inhibition of GSK3 or mutations at CK1- and GSK3-phosphorylation sites of β-catenin abolished the suppressive effect of H2. H2 did not increase GSK3-mediated phosphorylation of glycogen synthase, indicating that H2 has no direct effect on GSK3 itself. Knock-down of adenomatous polyposis coli (APC) or Axin1, which form the β-catenin degradation complex, minimized the suppressive effect of H2 on β-catenin accumulation. Accordingly, the effect of H2 requires CK1/GSK3-phosphorylation sites of β-catenin, as well as the β-catenin degradation complex comprised of CK1, GSK3, APC, and Axin1. We additionally found that H2 reduces the activation of Wnt/β-catenin signaling in human osteoarthritis chondrocytes. Oral intake of H2 water tended to ameliorate cartilage degradation in a surgery-induced rat osteoarthritis model through attenuating β-catenin accumulation. We first demonstrate that H2 suppresses abnormally activated Wnt/β-catenin signaling, which accounts for the protective roles of H2 in a fraction of diseases.

Molecular Hydrogen Protects Human Melanocytes from Oxidative Stress by Activating Nrf2 Signaling

“…Additionally, H 2 pretreatment prevented the H 2 O 2 -induced inhibition of cellular migration and melanin production in both PIG1 and PIG3V cells ( Figure 2d and e, Supplementary Figure S6). The microenvironment of melanocytes and keratinocytes can indirectly regulate the survival and function of melanocytes through secretion of various chemokines and growth factors during the pathogenesis of vitiligo (Lee et al, 2005;Lin et al, 2016;Richmond et al, 2017). As expected, H 2 O 2 treatment led to a drastic upregulation of the chemokines CXCL9, CXCL10, and CXCL16 and decreased the production of stem cell factors in keratinocytes (Figure 2f and g).…”

“…In this study, we found that H 2 antagonized the reduction in the b-catenin level in melanocytes induced by H 2 O 2 . It has been reported that H 2 suppresses abnormal b-catenin activation against cartilage degradation (Lin et al, 2016). Thus, H 2 might regulate the Wnt/b-catenin pathway differently in different tissues and/or cell types to protect against various diseases.…”

Fluoxetine ameliorates cartilage degradation in osteoarthritis by inhibiting Wnt/β-catenin signaling

“…To examine a direct in vitro effect of fluoxetine on the degradation complex, we immunoprecipitated Axin1 in vitro with an antibody against Axin1 in the presence of 0.1, 1.0, and 10 μM fluoxetine, and detected coimmunoprecipitated β-catenin, GSK3, and CK1 ( Fig 4E and 4F ). For harvesting enough amounts of those proteins [ 42 ], we used cell extracts of L cells. Fluoxetine had no effect on coimmunoprecipitation of GSK3 or CK1.…”

<p>Brain Metastases Completely Disappear in Non-Small Cell Lung Cancer Using Hydrogen Gas Inhalation: A Case Report</p>

“…In 2014, Kafka et al10 reported altered expression of dishevelled (DVL)-1, DVL-3, E-cadherin, and β-catenin in brain metastases of adenocarcinomas, which again suggested the importance of Wnt signaling. Lin et al11 were the first (in 2016) to demonstrate that hydrogen gas suppresses abnormal activation of Wnt/β-catenin signaling.…”