Title |
Aldehyde dehydrogenase 3A1 activation prevents radiation-induced xerostomia by protecting salivary stem cells from toxic aldehydes
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Published in |
Proceedings of the National Academy of Sciences of the United States of America, May 2018
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DOI | 10.1073/pnas.1802184115 |
Pubmed ID | |
Authors |
Julie P Saiki, Hongbin Cao, Lauren D Van Wassenhove, Vignesh Viswanathan, Joshua Bloomstein, Dhanya K Nambiar, Aaron J Mattingly, Dadi Jiang, Che-Hong Chen, Matthew C Stevens, Amanda L Simmons, Hyun Shin Park, Rie von Eyben, Eric T Kool, Davud Sirjani, Sarah M Knox, Quynh Thu Le, Daria Mochly-Rosen |
Abstract |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 3 | 27% |
United Kingdom | 1 | 9% |
Unknown | 7 | 64% |
Demographic breakdown
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Members of the public | 9 | 82% |
Practitioners (doctors, other healthcare professionals) | 1 | 9% |
Scientists | 1 | 9% |
Mendeley readers
Geographical breakdown
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Unknown | 69 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Ph. D. Student | 11 | 16% |
Student > Bachelor | 10 | 14% |
Student > Master | 9 | 13% |
Researcher | 5 | 7% |
Student > Postgraduate | 4 | 6% |
Other | 11 | 16% |
Unknown | 19 | 28% |
Readers by discipline | Count | As % |
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Medicine and Dentistry | 17 | 25% |
Biochemistry, Genetics and Molecular Biology | 14 | 20% |
Agricultural and Biological Sciences | 6 | 9% |
Pharmacology, Toxicology and Pharmaceutical Science | 2 | 3% |
Nursing and Health Professions | 2 | 3% |
Other | 7 | 10% |
Unknown | 21 | 30% |