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Leveraging an enzyme/artificial substrate system to enhance cellular persulfides and mitigate neuroinflammation† † Electronic supplementary information (ESI) available. See DOI: 10.1039/d1sc03828a

ABSTRACT: Persulfides and polysulfides, collectively known as the sulfane sulfur pool along with hydrogen sulfide (H2S), play a central role in cellular physiology and disease. Exogenously enhancing these species in cells is an emerging therapeutic paradigm for mitigating oxidative stress and inflammation that are associated with several diseases. In this study, we present a unique approach of using the cell's own enzyme machinery coupled with an array of artificial substrates to enhance the cellular sulfane sulfur pool. We report the synthesis and validation of artificial/unnatural substrates specific for 3-mercaptopyruvate sulfurtransferase (3-MST), an important enzyme that contributes to sulfur trafficking in cells. We demonstrate that these artificial substrates generate persulfides in vitro as well as mediate sulfur transfer to low molecular weight thiols and to cysteine-containing proteins. A nearly 100-fold difference in the rates of H2S production for the various substrates is observed supporting the tunability of persulfide generation by the 3-MST enzyme/artificial substrate system. Next, we show that the substrate 1a permeates cells and is selectively turned over by 3-MST to generate 3-MST-persulfide, which protects against reactive oxygen species-induced lethality. Lastly, in a mouse model, 1a is found to significantly mitigate neuroinflammation in the brain tissue. Together, the approach that we have developed allows for the on-demand generation of persulfides in vitro and in vivo using a range of shelf-stable, artificial substrates of 3-MST, while opening up possibilities of harnessing these molecules for therapeutic applications. A persulfide/hydrogen sulfide generation strategy through artificial substrates for 3-mercaptopyruvate sulfurtransferase (3-MST) is reported, which enhances cellular persulfides, attenuates reactive oxygen species (ROS), and alleviates inflammation.

SUBMITTER: Bora P

PROVIDER: S-EPMC8513928 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The rapid development, introduction, and global uptake of COVID-19 vaccines required countries to have strong pharmacovigilance systems in place to monitor and address adverse events following immunization (AEFIs). These systems provide timely data on vaccine safety that support decisions about the potential risks of vaccine adverse events relative to the benefit of disease prevention. In Ethiopia, the monitoring system was limited by the lack of data being submitted through its passive surveillance system, delays in investigating serious adverse events and conducting causality assessments, and the lack of reporting to the World Health Organization (WHO) global database, VigiBase. In Pakistan, the pharmacovigilance system lacked reporting requirements and guidance documentation, regulatory policies were insufficient, and staff lacked the capacity to evaluate AEFI reports. Several interventions were implemented in both countries to improve pharmacovigilance systems and processes necessary to collect, analyze, and report AEFIs from health care facilities to the national level and facilitate the use of global and national electronic reporting tools. In addition, Pakistan improved the regulatory policy environment and engaged vaccine manufacturers and private sector health facilities in AEFI reporting for the first time in the country. Outcomes include an increased number of COVID-19 vaccine-related AEFIs reported and causality assessments completed, which means that potential safety issues were being analyzed more quickly, comprehensively, and accurately. The number of AEFI reports submitted to VigiBase by Pakistan's regulatory authority more than quintupled from approximately 5,000/quarter in 2021 to 28,555/quarter in 2022. In Ethiopia, by October 2022, 44,000 AEFI reports had been received, and 40 causality assessments completed. In both countries, timely AEFI data review and analysis led to prompt recommendations and regulatory actions, highlighting the far-reaching implications of strengthening the country-level pharmacovigilance systems. These strengthened systems are now in place for use with all vaccines.

Dataset Information

Leveraging an enzyme/artificial substrate system to enhance cellular persulfides and mitigate neuroinflammation† † Electronic supplementary information (ESI) available. See DOI: 10.1039/d1sc03828a

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