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The roles of JAK2/STAT3 signaling in fusion of the secondary palate.

ABSTRACT: Cleft palate has a multifactorial etiology. In palatal fusion, the contacting medial edge epithelium (MEE) forms the epithelial seam, which is subsequently removed with the reduction of p63. Failure in this process results in a cleft palate. We herein report the involvement of janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling in palatal fusion and that folic acid rescues the fusing defect by reactivating JAK2/STAT3. In closure of bilateral palatal shelves, STAT3 phosphorylation was activated at the fusing MEE and mesenchyme underlying the MEE. JAK2 inhibition by AG490 inhibited STAT3 phosphorylation and resulted in palatal fusion failure without removal of the epithelial seam, in which p63 and keratin 17 (K17) periderm markers were retained. Folic acid application restored STAT3 phosphorylation in AG490-treated palatal explants and rescued the fusion defect, in which the p63- and K17-positive epithelial seam were removed. The AG490-induced palatal defect was also rescued in p63 haploinsufficient explants. These findings suggest that JAK2/STAT3 signaling is involved in palatal fusion by suppressing p63 expression in MEE and that folate restores the fusion defect by reactivating JAK2/STAT3.

SUBMITTER: Yoshida N

PROVIDER: S-EPMC10602007 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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The roles of JAK2/STAT3 signaling in fusion of the secondary palate.

Yoshida Naoki N Inubushi Toshihiro T Hirose Takumi T Aoyama Gozo G Kurosaka Hiroshi H Yamashiro Takashi T

Disease models & mechanisms 20231017 10

Cleft palate has a multifactorial etiology. In palatal fusion, the contacting medial edge epithelium (MEE) forms the epithelial seam, which is subsequently removed with the reduction of p63. Failure in this process results in a cleft palate. We herein report the involvement of janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling in palatal fusion and that folic acid rescues the fusing defect by reactivating JAK2/STAT3. In closure of bilateral palatal shelves ...[more]

PMID: 37846594

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Project description:As the current clinical treatment of acetaminophen (APAP)‑induced liver injury (AILI) has its limitations, new and effective treatment methods are required. Fingolimod (FTY720) is an immunosuppressive drug developed in recent years that has been shown to have a protective effect against ischemia/reperfusion liver injury. However, the role of FTY720 in AILI remains unclear. The aim of the present study was to determine whether FTY720 has a protective effect on AILI. AILI was induced using intraperitoneal injection of 300 mg/kg APAP in male C57BL/6J mice. Following APAP challenge, the mice were administered 5 mg/kg FTY720 for 30 min. Protein expression levels were measured using western blot analysis. Cell viability was examined using Cell Counting Kit‑8 assays. mRNA levels were measured using reverse transcription‑quantitative PCR. Inflammation levels were evaluated using immunohistochemistry. Cell death and reactive oxygen species levels were examined using immunofluorescence. Furthermore, laser scanning intravital microscopy was used to directly observe immune cell recruitment. APAP treatment increased the serum levels of alanine transaminase and aspartate transaminase at the 6‑ and 12‑h time‑points, suggesting liver tissue damage. However, FTY720 attenuated the liver injury induced by APAP by reducing the recruitment of immune cells and the release of pro‑inflammatory cytokines and chemokines. FTY720 activated JAK2/STAT3 signaling and regulated the expression of BAX, BCL‑2 and p65 to inhibit apoptosis and inflammation. In addition, compared with APAP treatment, the viability of primary hepatocytes treated with APAP and FTY720 was increased. Inhibition of JAK2/STAT3 signaling attenuated the protective, antioxidant effects of FTY720. In conclusion, FTY720 reduced liver injury by regulating the JAK2/STAT3 signaling pathway. This compound was capable of inhibiting oxidative stress to reduce hepatocyte death and the infiltration of neutrophils in the liver.

Dataset Information

The roles of JAK2/STAT3 signaling in fusion of the secondary palate.

Publications

The roles of JAK2/STAT3 signaling in fusion of the secondary palate.

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