Reactive Sulfur Species: Challenging the Reactive Oxygen Species Paradigm

活性硫物种：挑战活性氧物种范式

• 批准号: 2012106
• 负责人: Kenneth Olson
• 金额: $ 83.32万
• 依托单位: Indiana University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2012106&HistoricalAwards=false
• 关键词: Reactive; Sulfur; Species; Challenging; Oxygen

The proposed research will use biochemical and cellular techniques to examine metabolism and biochemical pathways of reactive sulfur species (RSS) in cells under physiologically relevant oxygen levels. Derivatives of oxygen form reactive oxygen species (ROS), the most biologically relevant oxidant and the target of most antioxidants, which are thought to improve human health. Natural and synthetic antioxidants, however, have either had limited therapeutic value or their activity appears independent of ROS. This research proposes that many of the assumed actions of reactive oxygen species are better explained by reactive sulfur species. This hypothesis builds upon recent work by the principal researcher, and is based on the following observations: sulfur and oxygen are chemically and biologically similar, cellular antioxidant pathways efficiently metabolize RSS, ‘antioxidant’ health foods affect RSS, many ROS assays cannot distinguish between ROS and RSS and thereby overestimate ROS, and most experiments are performed in room air where oxygen levels are many times greater than the levels within cells, which artificially increases ROS and depletes RSS. In this research project, RSS metabolism by canonical antioxidant pathways will be examined in greater detail and the effects of antioxidant health food ‘nutraceuticals’ on cellular RSS will be examined in detail. The results will have broad implications for basic biology as well as for human health and nutrition. This research will help train one graduate student, one postdoctoral fellow, and several undergraduate students. A solid postdoctoral mentoring program guided by senior faculty will ensure future success in any professional setting.Oxidants, antioxidants, and oxidative stress from reactive oxygen species (ROS) are implicated in endogenous signaling systems and associated with pathophysiological conditions in virtually all organ systems. Work, mainly from the principal investigator’s laboratory, has shown that many of the effects attributed to ROS can be mediated by reactive sulfur species (RSS) due to their chemical similarity, interchangeability in cysteine-mediated signaling systems (hydrogen peroxide ~ hydrogen disulfide), inability to analytically distinguish between the two, and the preponderance of experiments performed under supra-physiological oxygen tensions (room air). The proposed research will show that canonical ROS antioxidant pathways affect RSS metabolism independent of ROS and identify these catalytic mechanisms, will examine RSS metabolism by nutraceutical and synthetic antioxidants, and will show that cellular RSS metabolism is greatly enhanced and diversified when experiments are conducted in ‘physioxic’ environments. Combinations of antioxidants, antioxidant pathway inhibitors, hydrogen sulfide scavengers, and genetically altered cells will be used to manipulate and understand RSS metabolism, measured in buffer and in cells under physiological oxygen concentrations, using specific fluorophores, amperometric electrodes, and mass spectrometry. The proposed research will provide the biochemical and physiological basis for the role of RSS in cell signaling and homeostasis under physiologically relevant conditions. These results will broaden our understanding of RSS in health and disease and open novel areas in biological and biomedical research. It will also provide training for one postdoctoral fellow, one graduate student, and numerous undergraduate students, preparing them for professional careers in the biomedical sciences.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

这项拟议的研究将使用生化和细胞技术来检查细胞中活性硫物种(RSS)在生理相关氧气水平下的代谢和生化途径。氧的衍生物形成了活性氧物种(ROS)，它是与生物最相关的氧化剂，也是大多数抗氧化剂的靶标，被认为可以改善人类健康。然而，天然和合成的抗氧化剂要么治疗价值有限，要么其活性似乎独立于ROS。这项研究提出，活性硫物种可以更好地解释活性氧物种的许多假设行为。这一假说建立在首席研究人员最近的工作基础上，并基于以下观察：硫和氧在化学和生物上是相似的，细胞抗氧化途径有效地代谢RSS，“抗氧化剂”保健食品影响RSS，许多ROS检测无法区分ROS和RSS，从而高估ROS，大多数实验是在氧气水平比细胞内水平高出许多倍的房间空气中进行的，这会人为地增加ROS并消耗RSS。在这项研究项目中，将更详细地研究典型的抗氧化剂途径对RSS的新陈代谢，并将详细研究抗氧化剂保健食品‘营养食品’对细胞RSS的影响。这一结果将对基础生物学以及人类健康和营养产生广泛的影响。这项研究将帮助培养一名研究生、一名博士后研究员和几名本科生。由资深教师指导的扎实的博士后指导计划将确保未来在任何专业设置中取得成功。来自活性氧簇(ROS)的氧化剂、抗氧化剂和氧化应激与内源性信号系统有关，并与几乎所有器官系统的病理生理状况有关。主要来自首席研究员实验室的工作表明，许多归因于ROS的影响可以由活性硫物种(RSS)介导，因为它们的化学相似，在半胱氨酸介导的信号系统(过氧化氢~二硫化氢)中的互换性，无法分析区分两者，以及大多数实验是在超生理氧分压(室内空气)下进行的。这项拟议的研究将显示典型的ROS抗氧化途径独立于ROS影响RSS新陈代谢，并确定这些催化机制，将研究营养食品和合成抗氧化剂对RSS新陈代谢的影响，并将显示当实验在‘物理’环境中进行时，细胞RSS新陈代谢大大增强和多样化。抗氧化剂、抗氧化途径抑制剂、硫化氢清除剂和转基因细胞的组合将用于操纵和了解RSS新陈代谢，使用特定的荧光团、安培电极和质谱仪在缓冲液中和生理氧浓度下的细胞中进行测量。这项研究将为RSS在生理相关条件下在细胞信号和动态平衡中的作用提供生化和生理学基础。这些结果将拓宽我们对RSS在健康和疾病方面的理解，并在生物和生物医学研究中开辟新的领域。它还将为一名博士后研究员、一名研究生和众多本科生提供培训，为他们在生物医学科学领域的专业生涯做好准备。该奖项反映了NSF的法定使命，并通过使用基金会的学术价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Oxidation of Hydrogen Sulfide to Polysulfide and Thiosulfate by a Carbon Nanozyme: Therapeutic Implications with an Emphasis on Down Syndrome

• DOI: 10.1002/adma.202211241
• 发表时间: 2023-07-23
• 期刊: ADVANCED MATERIALS
• 影响因子: 29.4
• 作者: Derry，Paul J.;Liopo，Anton V.;Kent，Thomas A.
• 通讯作者: Kent，Thomas A.

Coenzyme Q10 and related quinones oxidize H2S to polysulfides and thiosulfate

• DOI: 10.1016/j.freeradbiomed.2022.02.018
• 发表时间: 2022-03-01
• 期刊: FREE RADICAL BIOLOGY AND MEDICINE
• 影响因子: 7.4
• 作者: Olson, Kenneth R.;Clear, Kasey J.;Straub, Karl D.
• 通讯作者: Straub, Karl D.