Biology subjects

Ologunagba, T. I.

Publications and source records attributed to Ologunagba, T. I..

3 recordsLinked to original sources

bioRxiv2022

Influence of Diphenyl Diselenide on Thiol Redox Homeostasis and Electrogenic Membrane Transport in Rotenone-Induced Parkinsons Disease

The central role of oxidative stress in the etiology of Parkinsons disease defines a key therapeutic role for antioxidant compounds in the management of the disease. Redox-sensitive proteins such as the Na+/K+-ATPase have also been implicated as one of the targets of oxidative stress. The present study sought to investigate the role of diphenyl diselenide (DPDSe) in amelioration of disturbed redox homeostasis and modulation of enzyme activity caused by rotenone administration to Wistar albino rats. In determining the best route of rotenone administration, animals were grouped into four namely: control, oral, intraperitoneal (IP) and subcutanoeus (SC) and administered rotenone (3mg/kg) via oral, intraperitoneal (IP) and subcutaneous routes, with controls receiving the vehicle (2% DMSO + 98% normal saline (0.85%)). Having observed a more deleterious impact in the with he IP route, this mode of rotenone administration was selected along with oral administration of DPDSe (10mg/kg). this was done with four groups of animals namely: control, DPDSe, rotenone and DPDSe+rotenone. The effect of treatment was evaluated after seven days for total and non-protein thiol levels, lipid peroxidation and Na+/K+-ATPase activity. The result demonstrated the antioxidant potential of DPDSe in attenuating depletion of thiols, and lipid peroxidation caused by rotenone. It is apparent that DPDSe is a promising therapeutic agent in the management of PD, hence further investigations into its impact on different pathways is expedient in the search for an effective treatment for PD. HighlightsO_LIIntraperitoneal administration of rotenone gives a comparatively faster development of Parkinsons disease features in rodents C_LIO_LIRotenone mediates depletion of total and non-protein thiol levels in the pathogenesis of Parkinsons disease C_LIO_LIDiphenyl diselenide significantly attenuates thiol depletion and lipid peroxidation mediated by rotenone C_LIO_LIRotenone-mediated inactivation of Na+/K+-ATPase in Parkinsons disease etiology may involve ATP depletion C_LI

pharmacology and toxicology↗

bioRxiv2022

Cross-Linking of Catalytically Essential Vicinal Thiols at Active Sites of the Cerebral Sodium Transporter Inactivates its Electrogenic Function

The inactivation of the electrogenic function of the transmembrane sodium transporter in oxidative stress conditions has been intrinsically linked with the oxidation of its catalytically essential thiols. However, the spatial proximity of these catalytically relevant thiols is yet to be fully elucidated and thus still open. Herein, the influence of a thiol cross-linking [diamide, DA (0.1-2mM)] and a thiol alkylating [iodoacetamide, IA (0.1-5mM)] agent on the activity of the synaptosomal Na+/K+-ATPase were determined. In addition, the ability of dithiothreitol to either prevent or reverse the inhibition imposed by the thiol modifiers on the enzyme activity was also evaluated. The results showed that the thiol cross-linker inactivates the electrogenic function of the synaptosomal Na+/K+-ATPase when exposed to the thiols located at either the nucleotide or cation-binding sites. Conversely, irrespective of the exposed active sites, the thiol alkylating agents have no overt effect on the activity of the pump. Furthermore, dithiothreitol markedly prevented but did not reverse the inactivation of the electrogenic pump caused by cross-linking of its critical thiols. Interestingly, both the thiol cross-linker and alkylating agents markedly oxidize dithiothreitol in a time and concentration-dependent fashion. Consequently, within the limit of the present data, it appears that the catalytically relevant thiols of the transmembrane electrogenic pump located at the cationic and nucleotide binding sites, are in close proximity sufficient enough to allow for their cross-linking. HighlightsO_LIThe presence of Na+/K+-ATPase catalytically important thiols at the nucleotide and cationic sites of the enzyme define its vulnerability to oxidative assault. C_LIO_LIThe spatial location of these thiols at vicinal positions at these domains favour the formation of disulphide linkages under oxidative conditions C_LIO_LIThe disulphide crosslinking of these thiols culminate in enzyme inactivation C_LIO_LIThe inactivation can be prevented but not reversed by exogenous thiol compound C_LI

biochemistry↗

bioRxiv2022

A Hydrophobic Microenvironment Significantly Influences the Reactivity of the Catalytically Relevant Thiols of the Na+/K+-ATPase

The transmembrane protein responsible for the electrogenic transport of Na+ and K+ across the plasma membrane, the Na+/K+-ATPase, highly vulnerable redox modulations and thiol modifying agents due to the presence of thiol groups at the nucleotide and cationic sites. However, reports have demonstrated a preferential interaction of these protein thiols with oxidizing agents. The reactivity of protein thiols is strongly linked with the nature of the microenvironment of these thiols, hence, the present study sought to experimentally elucidate key features of the microenvironment of the catalytically relevant thiols at the substrate-binding sites of this crucial enzyme. Two thiol modifiers with similar thiol-reactive mechanism, but different molecular properties, iodoacetamide (IA) and N-acetyl-4-phenyliodoacetamide (APIAM), were employed. It was observed that while both compounds demonstrated excellent thiol-oxidizing properties in the chemical model, only APIAM had an inhibitory effect on the activity of the Na+/K+-ATPase. The involvement of the catalytically relevant thiols at the nucleotide and cation-binding sites of the enzyme in APIAM-mediated inhibition was confirmed by the protective effect of preincubating the reaction system with dithiothreitol (DTT). The findings from this study suggest that the catalytically relevant thiols of this enzyme are likely buried in a hydrophobic microenvironment. This could be a part of the protective measure of nature for these vulnerable protein thiols. Further details from our findings can be explored in the therapeutic management of diseases for which a dysfunction in the Na+/K+-ATPase have been identified. HighlightsO_LIThe transmembrane Na+/K+-ATPase has well-defined substrate-binding domains exposed to both aqueous microenvironment and buried within the hydrophobic transmembrane microenvironment C_LIO_LIThese microenvironments influence vulnerability of the critical thiols of the enzyme to oxidative assault C_LIO_LIThese thiols are likely buried in the hydrophobic core of the enzyme, thus selecting its susceptibility to thiol modfying agents C_LI

biochemistry↗