Milanović Žiko
University of Kragujevac, Institute for Information Technologies, Department of Science, Jovana Cvijića bb, 34000, Kragujevac, Serbia.
Chem Biol Interact. 2025 Apr 25;411:111444. doi: 10.1016/j.cbi.2025.111444. Epub 2025 Feb 21.
The objective of this research is to examine the function of urolithin D (UroD, 3,4,8,9-tetrahydroxy-6H-benzo[c]chromen-6-one), a metabolite obtained from ellagitannins, in the mitigation of oxidative stress. The research is based on estimating the mechanisms through which UroD acts as an antioxidant under physiological conditions, emphasizing standard antioxidant mechanisms such as formal Hydrogen Aatom Transfer (f-HAT), Radical Adduct Formation (RAF)/Radical Coupling Formation (RCF), and Single Electron Transfer followed by Proton Transfer (SET-PT). This study utilised advanced quantum mechanical techniques, specifically density functional theory (DFT) and the Quantum Mechanics-based test for Overall free Radical Scavenging activity (QM-ORSA) methodology, to assess the thermodynamic and kinetic parameters of UroD in the presence of reactive radical species HOO, CHOO and CClOO. The estimated overall rate constants (k) indicate a reactivity order of CClOO (k = 2.06 × 10 Ms) > HOO (k = 2.59 × 10 Ms) > CHOO (k = 1.89 × 10 Ms). The examination of the relative proportions of products (%) indicates that UroD exhibits antiradical action primarily through all examined mechanisms, with the predominant involvement of mononion and dianion acid-base species. In addition to its capacity to directly counteract ROS, UroD can restore oxidative DNA damage, specifically targeting oxidative byproducts commonly associated with 2-deoxyguanosine (2 dG), which are susceptible to oxidative stress. The UroD regenerates G-centered radical cations (2 dG) through the SET mechanism, C-centered radicals (2 dG) in the sugar moiety through f-HAT, and repairs i-OH-2dG lesions through sequential hydrogen atom transfer dehydration (SHATD). Additionally, the radical products formed during antioxidant action can be regenerated in the presence of O into anionic species, which are subsequently protonated into neutral species that can re-engage in antioxidant activity. These findings underscore the efficiency of UroD in scavenging free radicals and suggest its potential role in preserving cellular integrity and protecting against oxidative stress-related diseases.
本研究的目的是考察尿石素D（UroD，3,4,8,9-四羟基-6H-苯并[c]色烯-6-酮）（一种从鞣花单宁中获得的代谢产物）在减轻氧化应激方面的作用。该研究基于评估UroD在生理条件下作为抗氧化剂发挥作用的机制，重点关注标准抗氧化机制，如形式氢原子转移（f-HAT）、自由基加合物形成（RAF）/自由基偶联形成（RCF）以及单电子转移后质子转移（SET-PT）。本研究利用先进的量子力学技术，特别是密度泛函理论（DFT）和基于量子力学的总自由基清除活性测试（QM-ORSA）方法，来评估UroD在活性自由基物种HOO、CHOO和CClOO存在下的热力学和动力学参数。估计的总速率常数（k）表明反应活性顺序为CClOO（k = 2.06×10 Ms）＞HOO（k = 2.59×10 Ms）＞CHOO（k = 1.89×10 Ms）。对产物相对比例（%）的考察表明，UroD主要通过所有考察机制表现出抗自由基作用，其中单阴离子和双阴离子酸碱物种起主要作用。除了直接对抗活性氧的能力外，UroD还可以修复氧化性DNA损伤，特别是针对通常与2-脱氧鸟苷（2 dG）相关的氧化性副产物，这些副产物易受氧化应激影响。UroD通过SET机制再生以G为中心的自由基阳离子（2 dG），通过f-HAT再生糖部分中以C为中心的自由基（2 dG），并通过顺序氢原子转移脱水（SHATD）修复i-OH-2dG损伤。此外，抗氧化作用过程中形成的自由基产物在有O存在的情况下可以再生为阴离子物种，随后质子化成为中性物种，从而能够重新参与抗氧化活性。这些发现强调了UroD清除自由基的效率，并表明其在维持细胞完整性和预防氧化应激相关疾病方面的潜在作用。
