# Berberine augments the secretory function of salivary gland in homeostasis and after radiation exposure

## TL;DR

Berberine helps improve saliva production in normal and radiation-exposed salivary glands, suggesting it could treat dry mouth caused by head and neck radiation.

## Contribution

This study is the first to show that berberine enhances salivary gland function and protects against radiation-induced xerostomia through specific molecular mechanisms.

## Key findings

- Berberine increases saliva secretion in normal and radiation-exposed salivary glands.
- Berberine upregulates AQP5, NKCC1, MIST1, and MUC2, and reduces apoptosis and inflammation in salivary gland tissues.
- Berberine preserves cellular proliferation and reduces HNR-induced xerostomia in mouse models.

## Abstract

Radiotherapy serves as an essential therapeutic modality for head and neck malignancies. However, many patients who undergo head and neck radiation (HNR) frequently experience different severities of xerostomia. Berberine (BBR) has a variety of pharmacological functions and has shown favorable clinical efficacy. However, its therapeutic potential and mechanistic basis in xerostomia have not been explored.

The histological expressions of Aquaporin 5 (AQP5), Na-K-Cl cotransporter 1 (NKCC1), Muscle intestine stomach expression 1 (MIST1), Proliferating cell nuclear antigen (PCNA), Phospho-GSK-3beta (p-GSK3β) and β-Catenin were examined by immunohistochemistry (IHC). Mucin2 (MUC2), were examined by immunofluorescence. The degree of apoptosis was assessed by TUNEL. The mRNA expression levels of AQP5, NKCC1, PCNA, MUC2, and MIST1 were detected by qRT-PCR assay. The degree of inflammatory was evaluated by detecting the mRNA expression levels of Il1b, Tgfb1, Tnf, and Il10. The Proliferation level was performed by salivary gland organoids.

BBR significantly enhanced saliva secretion in normal physiological conditions and after radiation injury. Mechanistically, BBR upregulated the expression of AQP5, NKCC1 and MIST1. Moreover, BBR conferred its protection via the upregulation of mucin 2 (MUC2) expression, and qPCR analysis revealed elevated Bhlha15 levels. Additionally, BBR preserved cellular proliferation, decreased TUNEL+ apoptotic cells and the inflammatory response in SMG tissues and organoids in HNR-induced xerostomia models.

In conclusion, this study demonstrates that BBR can increase saliva secretion in healthy and HNR mice, indicating its potentiality for the treatment of radiation-induced xerostomia.