Targeting Soluble Epoxide Hydrolase with TPPU Alleviates Irradiation‐Induced Hyposalivation in Mice via Preventing Apoptosis and Microcirculation Disturbance

Abstract

IR irradiation-induced dysfunction of the salivary gland and hyposalivation are one of the main complications of radiotherapy treatment for malignant head and neck tumors, and its mechanisms are not fully understood. IR-induced microcirculation disturbance and apoptosis is one of the most important mechanisms. Most recent studies have focused on the regenerative effects of epoxyeicosatrienoic acids (EETs) through the process of increased angiogenesis. This study suggests that increasing endogenous EETs by the soluble epoxide hydrolase (sEH) inhibitor TPPU can reverse dysfunctional salivary glands and hyposalivation by improving the associated microenvironment and tissue regeneration. The findings suggest that TPPU alleviates hyposalivation and histological lesions, increases angiogenesis and reduces apoptosis of acinar cells significantly in IR-damaged mice. The results in vitro demonstrate that TPPU promotes the proliferation and inhibits apoptosis of human salivary gland (HSG) cells, and enhances the motility and angiogenesis of human umbilical vein endothelial cells (HUVECs). The results also suggest that TPPU-induced synergy and crosstalk between acinar cells and vascular endothelial cells might contribute to angiogenesis. Together, this study proves the feasibility of targeting sEH using TPPU to promote angiogenesis and reduce apoptosis, and also indicates the potential of sEH inhibitors for functional reconstruction of IR-induced salivary glands damage.

TPPU inhibits inflammation-induced excessive autophagy to restore the osteogenic differentiation potential of stem cells and improves alveolar ridge preservation

“…EETs protect the heart and liver by autophagy regulation 45 , 46 . Our previous study has shown that TPPU can significantly increase angiogenesis, and reduce acinar cell apoptosis and histological damage in ir-injured mice 47 .…”

“…TPPU (Sigma‑Aldrich, Merck KGaA, Darmstadt, Germany) was dissolved in dimethyl sulfoxide (DMSO, Coolaber, Beijing, China) as a stock solution (10 mg/ml), and further diluted to 10 μM TPPU for cell treatment in vitro or 20 μM TPPU for local injection in vivo 26 , 47 . Cells were treated with or without an autophagy inhibitor 3-methyladenine (3-MA, 10 mM; Solarbio, Beijing, China), an autophagy inducer Rapamycin (Rapa, 5 µM; Solarbio, Beijing, China).…”

CCL25/CCR9 interaction promotes the malignant behavior of salivary adenoid cystic carcinoma via the PI3K/AKT signaling pathway

“…3E and 3F ). EMT plays a key role in the process of invasion and metastasis of epithelial tumor cells ( Zhang et al, 2020 ). These results suggested that CCL25 could cause SACC-LM cells to lose polarity and connections with each other and further enhance the degradation of ECM, thus promoting the migration and invasion of SACC cells.…”

“…The Colorimetric TUNEL Apoptosis Assay Kit (Vazyme Biotech, Nanjing, China) was used to detect the apoptosis ability of mouse xenograft tumors. According to the manufacturer’s instructions and our previous procedure ( Zhang et al, 2020 ), the tissues were fixed in 4% paraformaldehyde and embedded in paraffin. Next, the tissues were cut into 4 µm sections and then subjected to conventional deparaffinization and hydration.…”

LIS1 interacts with CLIP170 to promote tumor growth and metastasis via the Cdc42 signaling pathway in salivary gland adenoid cystic carcinoma

“…no. A112-01; Vazyme Biotech, Co., Ltd.) and a previous study by the authors (27). Briefly, the sections were incubated with the Equilibration Buffer for 30 min at room temperature and then marked with the labeling mix buffer for 1 h at 37˚C.…”