Xerostomia (dry mouth) is the most common side effect of radiation therapy in patients with head and neck cancer and causes difficulty speaking and swallowing. Since aldehyde dehydrogenase 3A1 (ALDH3A1) is highly expressed in mouse salivary stem/progenitor cells (SSPCs), we sought to determine the role of ALDH3A1 in SSPCs using genetic loss-of-function and pharmacologic gain-of-function studies. Using DarkZone dye to measure intracellular aldehydes, we observed higher aldehyde accumulation in irradiated Aldh3a1-/- adult murine salisphere cells and in situ in whole murine embryonic salivary glands enriched in SSPCs compared with wild-type glands. To identify a safe ALDH3A1 activator for potential clinical testing, we screened a traditional Chinese medicine library and isolated d-limonene, commonly used as a food-flavoring agent, as a single constituent activator. ALDH3A1 activation by d-limonene significantly reduced aldehyde accumulation in SSPCs and whole embryonic glands, increased sphere-forming ability, decreased apoptosis, and improved submandibular gland structure and function in vivo after radiation. A phase 0 study in patients with salivary gland tumors showed effective delivery of d-limonene into human salivary glands following daily oral dosing. Given its safety and bioavailability, d-limonene may be a good clinical candidate for mitigating xerostomia in patients with head and neck cancer receiving radiation therapy.

中文翻译：

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醛脱氢酶 3A1 激活通过保护唾液干细胞免受有毒醛的侵害来预防辐射引起的口干症。

口干症（口干）是头颈癌患者放射治疗最常见的副作用，会导致说话和吞咽困难。由于醛脱氢酶 3A1 (ALDH3A1) 在小鼠唾液干/祖细胞 (SSPC) 中高度表达，我们试图通过遗传功能丧失和药理学功能获得研究来确定 ALDH3A1 在 SSPC 中的作用。使用 DarkZone 染料测量细胞内醛类，我们观察到与野生型腺体相比，经辐照的 Aldh3a1-/- 成年小鼠唾液球细胞和富含 SSPC 的整个小鼠胚胎唾液腺原位醛积累更高。为了确定用于潜在临床试验的安全 ALDH3A1 激活剂，我们筛选了一个中药库并分离出通常用作食品调味剂的 d-柠檬烯，作为单一成分的活化剂。d-柠檬烯激活 ALDH3A1 显着减少了 SSPC 和整个胚胎腺体中的醛积累，增加了球体形成能力，减少了细胞凋亡，并改善了放射后体内的下颌下腺结构和功能。一项针对唾液腺肿瘤患者的 0 期研究表明，每日口服给药后，d-柠檬烯可有效输送到人类唾液腺中。鉴于其安全性和生物利用度，d-柠檬烯可能是减轻接受放射治疗的头颈癌患者口干症的良好临床候选药物。并改善了放射后体内的下颌下腺结构和功能。一项针对唾液腺肿瘤患者的 0 期研究表明，每日口服给药后，d-柠檬烯可有效输送到人类唾液腺中。鉴于其安全性和生物利用度，d-柠檬烯可能是减轻接受放射治疗的头颈癌患者口干症的良好临床候选药物。并改善了放射后体内的下颌下腺结构和功能。一项针对唾液腺肿瘤患者的 0 期研究表明，每日口服给药后，d-柠檬烯可有效输送到人类唾液腺中。鉴于其安全性和生物利用度，d-柠檬烯可能是减轻接受放射治疗的头颈癌患者口干症的良好临床候选药物。