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Trypanothione reductase from Trypanosoma brucei (TbTR) is a key enzyme of the parasite responsible for human African trypanosomiasis. TbTR catalyzes the reduction of trypanothione, an antioxidant dithiol that protects trypanosomatid parasites from oxidative stress induced by the mammalian host as a defense system. TbTR is considered an attractive target for the development of novel anti‐parasitic drugs because it is essential for parasite survival and has no close homologues in humans. Previous studies have shown that metal compounds can act as potent inhibitors of trypanothione reductase and of related enzymes and may be considered for disease treatment. To better understand the molecular basis of such inhibition, we report the study of the interactions of a small group of metal compounds with TbTR, analyzed by ESI MS measurements. This technique allows direct visualization of the enzyme in solution and the detection and characterization of the metal binding process. Accordingly, TbTR was reacted with a panel of metal compounds including thimerosal, auranofin, its halogen analogues, and bismuth acetate. ESI MS results provide a detailed description of the interactions taking place for each metal compound tested. The implications of these results for the development of novel metal‐based compounds as potential anti‐trypanosomal agents are discussed. [ABSTRACT FROM AUTHOR]

Aurothiomalate (AuTM) is an FDA‐approved antiarthritic gold drug with unique anticancer properties. To enhance its anticancer activity, we prepared a bioconjugate with human apoferritin (HuHf) by attaching some AuTM moieties to surface protein residues. The reaction of apoferritin with excess AuTM yielded a single adduct, that was characterized by ESI MS and ICP‐OES analysis, using three mutant ferritins and trypsinization experiments. The adduct contains ~3 gold atoms per ferritin subunit, arranged in a small cluster bound to Cys90 and Cys102. MD simulations provided a plausible structural model for the cluster. The adduct was evaluated for its pharmacological properties and was found to be significantly more cytotoxic than free AuTM against A2780 cancer cells mainly due to higher gold uptake. NMR‐metabolomics showed that AuTM bound to HuHf and free AuTM induced qualitatively similar changes in treated cancer cells, indicating that the effects on cell metabolism are approximately the same, in agreement with independent biochemical experiments. In conclusion, we have demonstrated here that a molecularly precise bioconjugate formed between AuTM and HuHf exhibits anticancer properties far superior to the free drug, while retaining its key mechanistic features. Evidence is provided that human ferritin can serve as an excellent carrier for this metallodrug. [ABSTRACT FROM AUTHOR]

The reaction of Pt-based anticancer agents with arsenic trioxide affords robust complexes known as arsenoplatins. The prototype of this family of anticancer compounds is arsenoplatin-1 (AP-1) that contains an As(OH)2 fragment linked to a Pt(II) moiety derived from cisplatin. Crystallographic and spectrometric studies of AP-1 binding to a B-DNA double helix dodecamer are presented here, in comparison with cisplatin and transplatin. Results reveal that AP-1, cisplatin and transplatin react differently with the DNA model system. Notably, in the AP-1/DNA systems, the Pt–As bond can break down with time and As-containing fragments can be released. These results have implications for the understanding of the mechanism of action of arsenoplatins. [ABSTRACT FROM AUTHOR]

Medicinal gold compounds, a novel class of potential anticancer drugs, are believed to produce their pharmacological effects mainly through direct gold binding to protein targets at the level of solvent exposed cysteine (or selenocysteine) residues. We have explored therein the reactions of a panel of seven representative gold compounds with the cysteine protease cathepsin B according to an established ESI MS approach. Detailed information on the mode of protein binding of these gold compounds is gained; notably, quite distinct patterns of cathepsin B metalation have emerged from these studies. It is shown that panel gold compounds interact preferentially, often exclusively, with the free cysteine located in the active site of the enzyme. [ABSTRACT FROM AUTHOR]

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Objective This study aimed at exploring the perspectives and experiences of individuals with neck pain by synthesizing all available qualitative studies. Methods A systematic, qualitative meta-summary and meta-synthesis was conducted following the 5-step methodology proposed by Sandelowski and Barroso. A systematic search of 9 electronic databases was conducted in May 2021. Methodological quality was assessed using the Critical Appraisal Skills Programme tool. Results Nine studies were included in the meta-synthesis for a total of 103 participants (73 women). Eleven categories were identified as belonging to 3 main themes: physical ("My neck has gone wrong"); psychological ("I am worried about my recovery"); and social ("Pain limits my life"). In the physical theme, the categories with the highest frequency were symptoms (67%) followed by body perception (44%). The psychological theme frequencies from highest to lowest were psychological consequences (100%), coping strategies (100%), mindset (67%), expectations from health care professionals (44%), and gender influence (22%). In the social theme, frequencies from highest to lowest were social relationships (56%), work, and activities of daily living and physical activity (44%, respectively). Conclusion An individual's experience with neck pain is a multidimensional phenomenon in which physical, psychological, and social dimensions influence each other. These findings suggested that health care professionals should be aware of recognizing and evaluating all of the individual's experiences to offer a truly patient-centered care pathway. Impact This qualitative meta-synthesis responded to a call to action to explore perspectives and experiences of individuals with neck pain. These findings can provide crucial guidance for clinicians as they plan and implement evidence-based recommendations for neck pain. [ABSTRACT FROM AUTHOR]