Chemistry:Didymin

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Didymin (also known as isosakuranetin 7-O-rutinoside or neoponcirin) is an O-methylated flavanone glycoside occurring naturally in citrus fruits, consisting of the flavanone isosakuranetin linked to the disaccharide rutinose.

Occurrence

History of isolation

Didymin was first described in 1965 by German scientists Carl Heinz Brieskorn and Gerhard Meister, who identified isosakuranetin-7-rhamnosidoglucoside in the leaves of Monarda didyma L.[1] The structure of didymin was subsequently clarified and confirmed by total synthesis in 1968 by Wagner, Hörhammer, Aurnhammer, and Farkas.[2]

Distribution in plants

Didymin is found in a variety of citrus fruits, including mandarin oranges, sweet oranges, grapefruit, and lemons, as well as in Origanum vulgare (oregano).[3][4] In immature dropped fruits of Citrus sinensis, didymin has been quantified alongside other flavanone glycosides such as hesperidin and narirutin, with its content being better preserved by freeze-drying than by hot-air oven drying.[5] It was first identified in grapefruit as a tasteless rutinoside-type flavanone glycoside, in contrast to the bitter neohesperidoside-type glycosides such as naringin.[6] It is also present in chenpi (dried citrus peel), a traditional ingredient in Chinese medicine.[7]

Biological activities

Antioxidant activity

Didymin exhibits antioxidant properties by scavenging free radicals and reducing reactive oxygen species (ROS). In neuronal cell studies, it was found to protect cells against hydrogen peroxide-induced oxidative damage, increase cell viability, and stimulate antioxidant defence enzymes including superoxide dismutase, catalase, and glutathione peroxidase.[8] Didymin is among the flavonoids present in orange juice that have been associated with a reduction in markers of oxidative stress and DNA damage.[9]

Neuroprotective activity

In vitro studies have demonstrated that didymin can rescue neuronal cells from oxidative damage. In a membrane-based neuronal cell model, it inhibited hydrogen peroxide-induced mitochondrial dysfunction, reduced caspase-3 activation, and suppressed JNK phosphorylation, suggesting potential relevance for neurodegenerative diseases associated with oxidative stress.[8]

Anticancer activity

Didymin has been studied for its effects on various cancer cell lines in vitro. In human hepatocellular carcinoma (HepG2) cells, it inhibited cell viability, migration, and colony formation, induced apoptosis, and caused G2/M cell cycle arrest. These effects were associated with changes in the Bcl-2/Bax ratio and activation of caspase-mediated apoptosis, as well as upregulation of Raf kinase inhibitor protein (RKIP) and suppression of the ERK/MAPK and PI3K/Akt pathways.[4]

Cardioprotective activity

Didymin has been shown to protect against doxorubicin-induced cardiotoxicity in mouse models and cardiomyocyte cell cultures, reducing oxidative stress, mitochondrial dysfunction, and apoptosis via activation of the PI3K/Akt/Nrf2 signalling pathway.[10] In endothelial cell studies, didymin prevented hyperglycaemia-induced dysfunction and death in human umbilical vein endothelial cells (HUVECs) by reducing ROS generation, lipid peroxidation, and inflammatory cytokine release, and by inhibiting NF-κB activation.[11]

Metabolic activity

Several studies have investigated didymin's potential in metabolic disorders. In high-fat diet mouse models, didymin reduced postprandial blood glucose levels and improved insulin secretion by enhancing mitochondrial biogenesis and function in pancreatic beta cells.[12] In a separate study, didymin alleviated metabolic dysfunction-associated fatty liver disease (MAFLD) in mice by activating Sirt1, thereby stimulating lipophagy and mitochondrial biogenesis.[7] In insulin-resistant HepG2 cells, didymin enhanced glucose uptake and activated insulin receptor substrate-1, PI3K, Akt, and glycogen synthase kinase-3 (GSK-3), while inhibiting key enzymes of gluconeogenesis.[3]

Geroprotective activity

Didymin is the principal flavonoid constituent of Monarda didyma L. (scarlet beebalm) extract, occurring at concentrations approximately 80-fold higher than the only other detectable flavonoid, isosakuranetin.[13] In a randomized clinical trial, supplementation with 100 mg/day of Monarda didyma L. extract over 12 weeks was associated with reduced telomere attrition and improvements in markers of biological aging and quality of life, with the effects attributed primarily to didymin.[13]

References

  1. ↑ Brieskorn, Carl Heinz; Meister, Gerhard (1965). "Zum Vorkommen von Isosacuranetin-7-rhamnosidoglucosid in den Blättern von Monarda didyma L." (in de). Archiv der Pharmazie 298 (7): 435–440. doi:10.1002/ardp.19652980706. PMID 5218336. 
  2. ↑ Wagner, H.; Hörhammer, L.; Aurnhammer, G.; Farkas, L. (1968). "Strukturaufklärung und Synthese des Didymins, eines Isosakuranetin-7-β-Rutinosids aus Monarda didyma L." (in de). Chemische Berichte 101 (2): 445–449. doi:10.1002/cber.19681010208. PMID 5683142. 
  3. ↑ 3.0 3.1 Ali, Md Yousof; Zaib, Sumera; Rahman, M. Mizanur; Jannat, Susoma; Iqbal, Jamshed; Park, Seong Kyu; Chang, Mun Seog (2019). "Didymin, a dietary citrus flavonoid exhibits anti-diabetic complications and promotes glucose uptake through the activation of PI3K/Akt signaling pathway in insulin-resistant HepG2 cells". Chemico-Biological Interactions 305: 180–194. doi:10.1016/j.cbi.2019.03.019. PMID 30930107. 
  4. ↑ 4.0 4.1 Wei, Jinbin; Huang, Quanfang; Bai, Facheng; Lin, Jun; Nie, Jinlan; Lu, Shengjuan; Lu, Chunyuang; Huang, Renbin et al. (2017). "Didymin induces apoptosis through mitochondrial dysfunction and up-regulation of RKIP in human hepatoma cells". Chemico-Biological Interactions 261: 118–126. doi:10.1016/j.cbi.2016.11.026. PMID 27889589. 
  5. ↑ Kumar, Dinesh; Ladaniya, M. S.; Gurjar, Manju; Kumar, Sunil (2022). "Impact of drying methods on natural antioxidants, phenols and flavanones of immature dropped Citrus sinensis L. Osbeck fruits". Scientific Reports 12: 6684. doi:10.1038/s41598-022-10661-7. PMID 35449208. 
  6. ↑ Mizelle, J. W.; Dunlap, W. J.; Hagen, R. E.; Wender, S. H.; Lime, B. J.; Albach, R. F.; Griffiths, F. P. (1965). "Isolation and Identification of Some Flavanone Rutinosides of the Grapefruit". Analytical Biochemistry 12: 316–324. doi:10.1016/0003-2697(65)90009-3. PMID 5837454. 
  7. ↑ 7.0 7.1 Yang, Jing-wen; Zou, Ying; Chen, Jun; Cui, Chen; Song, Jia; Yang, Meng-meng; Gao, Jing; Hu, Hui-qing et al. (2023). "Didymin alleviates metabolic dysfunction-associated fatty liver disease (MAFLD) via the stimulation of Sirt1-mediated lipophagy and mitochondrial biogenesis". Journal of Translational Medicine 21: 921. doi:10.1186/s12967-023-04790-4. PMID 38110963. 
  8. ↑ 8.0 8.1 Morelli, Sabrina; Piscioneri, Antonella; Salerno, Simona; Al-Fageeh, Mohamed B.; Drioli, Enrico; De Bartolo, Loredana (2014). "Neuroprotective Effect of Didymin on Hydrogen Peroxide-Induced Injury in the Neuronal Membrane System". Cells Tissues Organs 199 (2–3): 184–200. doi:10.1159/000365072. PMID 25402337. 
  9. ↑ Rangel-Huerta, Oscar D.; Aguilera, Concepcion M.; Martin, Maria V.; Soto, Maria J.; Rico, Maria C.; Vallejo, Fernando; Tomas-Barberan, Francisco; Perez-de-la-Cruz, Antonio J. et al. (2015). "Normal or High Polyphenol Concentration in Orange Juice Affects Antioxidant Activity, Blood Pressure, and Body Weight in Obese or Overweight Adults". Journal of Nutrition 145 (8): 1808–1816. doi:10.3945/jn.115.211698. PMID 26109581. 
  10. ↑ Chen, Rongchang; Sun, Guibo; Xu, Lijiao; Zhang, Xu; Zeng, Wenying; Sun, Xiaobo (2022). "Didymin attenuates doxorubicin-induced cardiotoxicity by inhibiting oxidative stress". Chinese Herbal Medicines 14 (1): 70–78. doi:10.1016/j.chmed.2021.07.006. PMID 36117638. 
  11. ↑ Shukla, Kirtikar; Sonowal, Himangshu; Saxena, Ashish; Ramana, Kota V. (2018). "Didymin prevents hyperglycemia-induced human umbilical endothelial cells dysfunction and death". Biochemical Pharmacology 152: 1–10. doi:10.1016/j.bcp.2018.03.012. PMID 29551519. 
  12. ↑ Yang, Jingwen; Zou, Ying; Lv, Xiaoyu; Chen, Jun; Cui, Che; Song, Jia; Yang, Mengmeng; Hu, Huiqing et al. (2024). "Didymin protects pancreatic beta cells by enhancing mitochondrial function in high-fat diet-induced impaired glucose tolerance". Diabetology & Metabolic Syndrome 16: 7. doi:10.1186/s13098-023-01244-1. PMID 38178225. 
  13. ↑ 13.0 13.1 Campisi, M.; Cannella, L.; Paccagnella, O.; Brazzale, A. R.; Agnolin, A.; Grothe, T.; Baumann, J.; Pavanello, S. (2025). "Unveiling the geroprotective potential of Monarda didyma L.: insights from in vitro studies and a randomized clinical trial on slowing biological aging and improving quality of life". Ageing Research Reviews. doi:10.1016/j.arr.2025.102694. PMID 40023222. 



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