► Oxidative stress (OS), particularly in mitochondria, is a common feature of iron (Fe), Mn and Hg toxicity. ► The primary molecular targets triggering of OS are distinct for each of the above ...metals. ► These metals are transported by distinct transporters.
Essential metals are crucial for the maintenance of cell homeostasis. Among the 23 elements that have known physiological functions in humans, 12 are metals, including iron (Fe) and manganese (Mn). Nevertheless, excessive exposure to these metals may lead to pathological conditions, including neurodegeneration. Similarly, exposure to metals that do not have known biological functions, such as mercury (Hg), also present great health concerns. This review focuses on the neurodegenerative mechanisms and effects of Fe, Mn and Hg. Oxidative stress (OS), particularly in mitochondria, is a common feature of Fe, Mn and Hg toxicity. However, the primary molecular targets triggering OS are distinct. Free cationic iron is a potent pro-oxidant and can initiate a set of reactions that form extremely reactive products, such as OH. Mn can oxidize dopamine (DA), generating reactive species and also affect mitochondrial function, leading to accumulation of metabolites and culminating with OS. Cationic Hg forms have strong affinity for nucleophiles, such as –SH and –SeH. Therefore, they target critical thiol- and selenol-molecules with antioxidant properties. Finally, we address the main sources of exposure to these metals, their transport mechanisms into the brain, and therapeutic modalities to mitigate their neurotoxic effects.
The SARS-CoV-2 pandemic has prompted global efforts to develop therapeutics. The main protease of SARS-CoV-2 (Mpro) and the papain-like protease (PLpro) are essential for viral replication and are ...key targets for therapeutic development. In this work, we investigate the mechanisms of SARS-CoV-2 inhibition by diphenyl diselenide (PhSe)2 which is an archetypal model of diselenides and a renowned potential therapeutic agent. The in vitro inhibitory concentration of (PhSe)2 against SARS-CoV-2 in Vero E6 cells falls in the low micromolar range. Molecular dynamics (MD) simulations and density functional theory (DFT) calculations level of theory: SMD-B3LYP-D3(BJ)/6-311G(d,p), cc-pVTZ are used to inspect non-covalent inhibition modes of both proteases via π-stacking and the mechanism of covalent (PhSe)2 + Mpro product formation involving the catalytic residue C145, respectively. The in vitro CC50 (24.61 μM) and EC50 (2.39 μM) data indicate that (PhSe)2 is a good inhibitor of the SARS-CoV-2 virus replication in a cell culture model. The in silico findings indicate potential mechanisms of proteases’ inhibition by (PhSe)2; in particular, the results of the covalent inhibition here discussed for Mpro, whose thermodynamics is approximatively isoergonic, prompt further investigation in the design of antiviral organodiselenides.
In the last 2 years, different pharmacological agents have been indicated as potential inhibitors of SARS‐CoV‐2 in vitro. Specifically, drugs termed as functional inhibitors of acid sphingomyelinase ...(FIASMAs) have proved to inhibit the SARS‐CoV‐2 replication using different types of cells. Those therapeutic agents share several chemical structure characteristics and some well‐known representatives are fluoxetine, escitalopram, fluvoxamine, and others. Most of the FIASMAs are primarily used as effective therapeutic agents to treat different pathologies, therefore, they are natural drug candidates for repositioning strategy. In this review, we summarize the two main proposed mechanisms mediating acid sphingomyelinase (ASM) inhibition and how they can explain the inhibition of SARS‐CoV‐2 replication by FIASMAs. The first mechanism implies a disruption in the lysosomal pH fall as the endosome–lysosome moves toward the interior of the cell. In fact, changes in cholesterol levels in endosome–lysosome membranes, which are associated with ASM inhibition is thought to be mediated by lysosomal proton pump (ATP‐ase) inactivation. The second mechanism involves the formation of an extracellular ceramide‐rich domain, which is blocked by FIASMAs. The ceramide‐rich domains are believed to facilitate the SARS‐CoV‐2 entrance into the host cells.
Significance statement
ASM functional inhibitors (FIASMAs) have been shown to inhibit SARS‐CoV‐2 in vitro.
There are two mechanisms proposed to explain the inhibitory effects of FIASMAs against SARS‐CoV‐2.
In this review, we discuss the two main hypotheses as well as the controversies about the potential efficacy of FIASMAs in COVID‐19 disease.
•VAL was effective against rotenone toxicity in D. melanogaster.•VAL protects flies from lethality and movement disorders caused by rotenone.•Protection of VAL was proposed by some biochemical ...parameters and genes related to PD.
In this study, we investigated the potential protective effects of Valeriana officinalis (V. officinalis) against the toxicity induced by rotenone in Drosophila melanogaster (D. melanogaster). Adult wild-type flies were concomitantly exposed to rotenone (500μM) and V. officinalis aqueous extract (10mg/mL) in the food during 7 days. Rotenone-fed flies had a worse performance in the negative geotaxis assay (i.e. climbing capability) and open-field test (i.e. mobility time) as well as a higher incidence of mortality when compared to control group. V. officinalis treatment offered protection against these detrimental effects of rotenone. In contrast, the decreased number of crossings observed in the flies exposed to rotenone was not modified by V. officinalis. Rotenone toxicity was also associated with a marked decrease on the total-thiol content in the homogenates and cell viability of flies, which were reduced by V. officinalis treatment. Indeed, rotenone exposure caused a significant increase in the mRNA expression of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) and also in the tyrosine hydroxylase (TH) gene. The expression of SOD and CAT mRNAs was normalized by V. officinalis treatment. Our results suggest that V. officinalis extract was effective in reducing the toxicity induced by rotenone in D. melanogaster as well as confirm the utility of this model to investigate potential therapeutic strategies on movement disorders, including Parkinson disease (PD).
► Diphenyl diselenide, bismethoxydiphenyl and bischlorodiphenyl are substrate of brain TrxR. ► Diphenyl diselenide mimicking GPx and also is substrate of rat brain TrxR. ► Ebselen has not proven to ...be a good substrate of rat brain TrxR. ► Neuroprotective property of Ebselen can be associated with its GPx like activity.
Thioredoxin reductase (TrxR) isoforms play important roles in cell physiology, protecting cells against oxidative processes. In addition to its endogenous substrates (Trx isoforms), hepatic TrxR can reduce organic selenium compounds such as ebselen and diphenyl diselenide to their selenol intermediates, which can be involved in their hepatoprotective properties. Taking this into account, the aim of the present study was to evaluate the hypothesis that ebselen, diphenyl diselenide and its analogs (4,4′-bistrifluoromethyldiphenyl diselenide, 4,4′-bismethoxydiphenyl diselenide, 4.4′-biscarboxy-diphenyl diselenide, 4,4′-bischlorodiphenyl diselenide, 2,4,6,2′,4′,6′-hexamethyldiphenyl diselenide) could be substrates of rat brain TrxR. In the presence of partially purified rat brain TrxR, diphenyl diselenide, bismethoxydiphenyl diselenide and bischlorodiphenyl diselenide (at 10, 15 and 20μM) stimulated NADPH oxidation, indicating that they are substrates of brain TrxR. In contrast, ebselen and bistrifluoromethyldiphenyl diselenide, that have been previously demonstrated to be substrate of hepatic TrxR, were not reduced by rat brain TrxR. The results presented here suggest that diphenyl diselenide can exert neuroprotective effects by mimicking glutathione peroxidase activity and also via its reduction by TrxR. However, ebselen was not reduced by brain TrxR, indicating that the neuroprotective properties of this compound is possibly mediate by its glutathione peroxidase-like activity.
Caffeine is a psychostimulant with positive effects on cognition. Recent studies have suggested the participation of the cholinergic system in the effects of caffeine on wakefulness. However, there ...are few studies assessing the contribution of cholinergic system in the cognitive enhancer properties of caffeine. In the present study, the effects of a dose and schedule of administration of caffeine that improved memory recognition were investigated on scopolamine-induced impairment of memory in adult mice. Inhibitory avoidance and novel object recognition tasks were used to assess learning and memory. Caffeine (10
mg/kg, i.p.) was administered during 4 consecutive days, and the treatment was interrupted 24
h before scopolamine administration (2
mg/kg, i.p.). Scopolamine was administered prior to or immediately after training. Short-term and long-term memory was evaluated in both tasks. In the novel object recognition task, pre treatment with caffeine prevented the disruption of short- and long-term memory by scopolamine. In the inhibitory avoidance task, caffeine prevented short- but not long-term memory disruption by pre training administration of scopolamine. Caffeine prevented short- and long-term memory disruption by post training administration of scopolamine. Both treatments did not affect locomotor activity of the animals. These findings suggest that acute treatment with caffeine followed by its withdrawal may be effective against cholinergic-induced disruption of memory assessed in an aversive and non-aversive task. Finally, our results revealed that the cholinergic system is involved in the positive effects of caffeine on cognitive functions.
In this paper, we report the synthesis and biological evaluation of picolylamide-based diselenides with the aim of developing a new series of diselenides with O···Se non-bonded interactions. The ...synthesis of diselenides was performed by a simple and efficient synthetic route. All the products were obtained in good yields and their structures were determined by 1H-NMR, 13C-NMR and HRMS. All these new compounds showed promising activities when tested in different antioxidant assays. These amides exhibited strong thiol peroxidase-like (TPx) activity. In fact one of the compounds showed 4.66 times higher potential than the classical standard i.e., diphenyl diselenide. The same compound significantly inhibited iron (Fe)-induced thiobarbituric acid reactive species (TBARS) production in rat's brain homogenate. In addition, the X-ray structure of the most active compound showed non-bonded interaction between the selenium and the oxygen atom that are in close proximity and may be responsible for the increased antioxidant activity. The present study provides evidence about the possible biochemical influence of nonbonding interactions on organochalcogens potency.
Most pharmacological studies concerning the beneficial effects of organoselenium compounds have focused on their ability to mimic glutathione peroxidase (GPx). However, mechanisms other than GPx-like ...activity might be involved on their biological effects. This study was aimed to investigate and compare the protective effects of two well known (PhSe)
2
and PhSeZnCl and two newly developed (MRK Picolyl and MRK Ester) organoselenium compounds against oxidative challenge in cultured neuronal HT22 cells. The thiol peroxidase and oxidase activities were performed using the glutathione reductase (GR)-coupled assay. In order to evaluate protective effects of the organoselenium compounds against oxidative challenge in neuronal HT22 cells, experiments based on glutamate-induced oxytosis and SIN-1-mediated peroxynitrite generation were performed. The thiol peroxidase activities of the studied organoselenium compounds were smaller than bovine erythrocytes GPx enzyme. Besides, (PhSe)
2
and PhSeZnCl showed higher thiol peroxidase and lower thiol oxidase activities compared to the new compounds. MRK Picolyl and MRK Ester, which showed lower thiol peroxidase activity, showed higher thiol oxidase activity. Both pre- or co-treatment with (PhSe)
2
, PhSeZnCl, MRK Picolyl and MRK Ester protected HT22 cells against glutamate-induced cytotoxicity. (PhSe)
2
and MRK Picolyl significantly prevented peroxinitrite-induced dihydrorhodamine oxidation, but this effect was observed only when HT22 were pre-treated with these compounds. The treatment with (PhSe)
2
increased the protein expression of antioxidant defences (Prx3, CAT and GCLC) in HT22 cells. Taking together, our results suggest that the biological effects elicited by these compounds are not directly related to their GPx-mimetic and thiol oxidase activities, but might be linked to the up-regulation of endogenous antioxidant defences trough their thiol-modifier effects.
Copper is a transition metal that exists in different chemical forms (e.g., Cu
2+
,Cu
+
, and Cu
0
) and at high concentrations it is toxic. Here, we investigated the Cu
2+
-induced toxicity in
...Drosophila melanogaster
, evaluating the survival, locomotion, and the activity of acetylcholinesterase (AChE) and glutathione
S
-transferase (GST) enzymes. Flies were exposed to Cu
2+
(0.1–1 mmol CuSO
4
/kg of diet or approximately 0.1–1 mM Cu
2+
) and allowed to mate during 24 h. GST and AChE enzymes were evaluated in the larvae and in the head and the body (thorax + abdomen) of the adult male and females flies. The total number of adult females (0.4–1 mM) and males (0.75 and 1 mM) was decreased by CuSO
4
. The climbing ability was hampered in flies exposed to 1 mM Cu
2+
. In larvae, Cu
2+
(0.4–1 mM) increased AChE activity (
P
< 0.002). In males’ heads, 0.4 mM Cu
2+
increased the AChE activity (
P <
0.01). In adults’ bodies, Cu
2+
inhibited the activity in both sexes, but with greater effectiveness in males (0.1 to 1 mM) than in females (1 mM). Regarding GST activity, 0.1 mM Cu
2+
increased, but 1 mM decrease GST in larvae. In the head of flies, Cu
2+
decreased the GST activity at intermediate (0.4 mM) and increased GST at the highest concentration (1 mM) in males. In the bodies, the effect of Cu
2+
was similar. In conclusion, Cu
2+
exposure in
D. melanogaster
disrupted locomotion and enzymatic parameters that can be related to changes in AChE and in the detoxifying GST enzyme.
Methylmercury is a highly toxic compound and human exposure is mainly related to consumption of polluted fish and seafood. The inactivation of thiol‐based enzymes, promoted by the strong affinity ...binding of electrophilic mercuric ions to thiol and selenol groups of proteins, is likely an important factor explaining its toxicity. A key role is played by the chemistry and reactivity of the mercury–chalcogens bond, particularly HgS and HgSe, which is the focus of this computational work (level of theory: (COSMO)‐ZORA‐BLYP‐D3(BJ)/TZ2P). We analyze nine ligand‐exchange model reactions (the so‐called Rabenstein's reactions) involving an entering ligand (methylchalcogenolate) and a substrate (methylchalcogenolatemethylmercury). Trends in reaction and activation energies are discussed and a change in mechanism is reported for all cases when going from gas phase to water, that is, from a single‐well potential energy surface (PES) to a canonical SN2‐like mechanism. The reasons accounting for the biochemically challenging and desired displacement of methylmercury from a seleno/thiol protein can be found already in these model reactions, as can be seen from the similarities of the ligand exchange reactions in solution in thermodynamics and kinetics.
Density functional theory mechanistic investigation on model reactions to understand the chemistry and reactivity of mercury–chalcogen bonds.
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