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Urolitin a (UA) is a secondary metabolite of natural polyphenol compound ellagitannins (ETS) . Uro-A does not exist in its natural state, it is produced by a series of transformation of ET through intestinal flora [1-2] . Et-rich food in the human body through the stomach, small intestine, and ultimately in the colon for Uro-A metabolism, in the lower part of the small intestine can also be detected in small amounts. Uro-aets are found mainly in pomegranates, raspberries, strawberries, walnuts and red wine [1-2] .
Many studies have demonstrated that UA has many biological activities, such as anti-oxidation, anti-inflammation, anti-aging, regulation of estrogen/androgen and induction of mitophagy. In recent years, it has been found that UA can induce mitophagy and play an important role in delaying aging and treating cardiovascular diseases! [1-2].
[1] Shi Ying, Du Feng, Wang Yue, etc. . Research progress on pharmacological action and mechanism of urolith A J ] . Zhongnan Pharmacy, 2022,20(01) : 113-120.
[2] Garcia-vilalba R, Gim énez-bastida JA, Cort és-martin a, Avila-galvez MA, Tomas-barberan FA, Selma MV, Espin JC, Gonzalez-Sarnas A. Urolithins; a Comprehensive Update on their Metabolism, Bioactivity, and Associated Gut microbiota. Mol Nutr Food Res. 2022 Nov; 66(21) : e2101019. Doi: 10.1002/MNFR.202101019. Epub 2022feb 15. PMID: 35118817; pmcid: pmc9787965.
The catabolic pathway ofellagitannin and ellagic acid to urolithin(5-0H, 4-0H, 3-0H, 2-0H, and 1-0H refers to the number of hydroxylgroups for each urolithin group (five, four, tri, di, andmonohydroxyurolithin, respectively))
Anti-aging
Activation of mitochondrial autophagy
Results: UA activated mitochondrial autophagy throughout the course of treatment, leading to higher mitochondrial content in muscle and intestine by RNA interference (RNAi) of Beclin1, a major regulator of mitochondrial autophagy, RNA interference (RNAi) at day 5 compared tocontrol worms. Lifespan extension after UA exposure was dependent on the expression ofthe mitochondrial autophagy gene skn-1,identified as a transcription factor regulatingmitochondrial autophagy gene expression.
RyuD, MouchiroudL, AndreuxPA, et al. Urocitin A induces bacterial myeloid cells and prolongs their lifespan to increase muscle function in rodents. Nat Med. 2016 Aug;22(8):879-888.
Improving Mitochondrial Health
Subject: OA chondrocytes (obtained from knee joints of OA patients)
Dosage: 6.25uM/12uM 24hAssessment parameters: Mitochondrial content and respiration
Result: Mitochondrial respiration was lwer in diseased patients, and UA treatment led to a significantincreasein basal (Fig.2a), maximal Fig.2b)and ATP mitochondrial respiration in 0A chondrocytes in a dose-dependent manner fig.2d). Higzher doses of UA were more effective in rescuingmitochondrial defects in diseased ioints compared to healthy oints, The basal glvcolytic activity of proton leakage lFig. 2e and OA HC was noialtered by UA treatment fig.2e.respiration in 0A was accompanied by an increase in mitochondrial autophagic fux (fig.2c) and an increase inmitochondrial autophagy levels.
D'Amico D, 0lmer M, Fouassier AM, Valdés P,Andreux PA, Rinsch c, Lotz M. Urolithin A improves mitochondrnialheath, reduces cartilage degeneration, steoarthritis,Aging cell, 2022 Aug:21(8):e13662
Fig.2 UA improves mitochondrial health in OA patient-derived chondrocytes (a. basal respiration; b. primary chondrocyte maximal respiration.
c. mitochondrial autophagic flux; d. mitochondrial respiration, e. mitochondrial proton leak; f. basal glycolytic activity.
Improving Aging-induced Motor Dysfunction
Subiect: C57BL/6Jmice、male Wistar Han rats
Dosage: 50mg/kg/d(mice,34weeks) 25mg/kg/d (rats, 24weeks)
Assessment parameters: exercise capacity
Result: Compared to control HFD-fed mice, UA treatmentresulted in a significant increase in muscle function measuredat 22 and 24 months of age, as evidenced by a 9% increase ingrip strength and a 57% increase in spontaneous locomotoractivitylevels measured usinga runningwheel, and UA resultedin an average increase in running endurance of 42%; activitylevels of the rats were randomised, with UA-treated runnersbeing 65% more able to run than controls.
Ryu D, Mouchiroud L,Andreux PA, Katsyuba E, Moullan N, Nicolet-Dit-felix AA,Wiliams EG, Jha P, Lo Sasso G, Huzard D, Aebischer ,Sandi c, Rinsch C, Auwerx y. Urolithin A induces mitophagy and prolongs lifespan in C, elegans and increases muscle function inrodents.Nat Med.2016 Aug:22(8):879-88. doi: 10.1038/nm.4132.Epub 2016 Jul11.PMID:27400265
Maintain Cardiovascular Health
Subject: Male adult c57BL/6 mice (20-25 g)(mice model: myocardial ischemia reperfusion injury)Dosage:1 mg/kg UA; (1) the Sham group, which received Sham operation without coronary arteryigation and were used as the normal control; (2) the l/R (!/R) group, which were pretreated with 0.5 mdimethylsulfoxide; (3) the l/R + UA (!/R + UA) group, which were pretreated with UA (1 mg/kg) in 0.5 mldimethylsulfoxide.
Assessment parameters: Cell death assessment
Result: In myocardial ischaemia/reperfusion injury, UA can restore and improve cardiac function bymodulating the Pl3K/Akt pathway. In a mouse model of ischemia/reperfusion injury, cardiac infarct sizewas reduced and ejection fraction was somewhat maintained in WA-pretreated animals compared withcontrols.
Tang L,Mo Y, i y, Zhong Y,He s, ZhangY, TangY, fu s, WangX, Chen A. Urolithin A aleviates myocardial ischemia/reperfusion iniuryvia Pi3K/Aktpathway, Biochem Biophys Res commun.2017 May 6:486(31:774-780. doi: 10.1016/i.bbrc.2017.03.119. Epub 2017 Mar23. PMID: 28343995.