Эбселен инструкция по применению цена

7 Ebselen

Ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one] is FDA-approved organoselenium compound with antiinflammatory, antioxidant, and cytoprotective properties against mammalian cells, while demonstrating cytotoxicity against yeast, fungi, and bacteria [51].

Ebselen demonstrated potent bactericidal activity against S. aureus (0.125–0.5 μg/mL), E. faecalis (0.25–0.5 μg/mL), E. faecium (0.25–0.5 μg/mL), Streptococcus pyogenes (0.5 μg/mL), and Streptococcus agalactiae (0.5 μg/mL), including MDR clinical isolates of methicillin and vancomycin-resistant strains. However, ebselen demonstrated modest antibacterial activity against Gram-negative pathogens such as A. baumannii (16 μg/mL), E. coli (32 μg/mL), Salmonella typhimurium (32 μg/mL), K. pneumoniae (64 μg/mL), and P. aeruginosa (>256 μg/mL) [52]. Ebselen and its analog were found to be potently active against B. subtilis (0.12 μg/mL), Bacillus cereus (0.86 μg/mL), and Mtb (10 μg/mL) [53]. Additionally, ebselen has demonstrated antibiofilm activity and reduced the already-established staphylococcal biofilms [54]. Ebselen does not interact negatively with other FDA-approved tested drugs and exhibits synergy with daptomycin, retapamulin, fusidic acid, and mupirocin. Further, ebselen demonstrates synergy with silver and this combination causes rapid depletion of glutathione and inhibits thioredoxin system, resulting in inhibition of ribonucleotide reductase (RR) and DNA synthesis [55].

The in vivo therapeutic efficacy of ebselen was evaluated in a mice model of staphylococcal skin infections. Ebselen (1% and 2% in petroleum jelly) significantly reduced the mean bacterial counts compared with the control vehicle–treated group (P ≤ .01). The severity of S. aureus skin infection is mediated by host pro-inflammatory cytokines rather than by bacterial burden. Ebselen is already known for its immune-modulatory, antiinflammatory, and antioxidant activities, thus, can be a good option for treatment of skin infections. In the skin model of S. aureus infection, ebselen exhibited reduction in levels of the pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-6, IL-1 beta, and monocyte chemo attractant protein-1 in MRSA USA300 skin lesions [56]. In mice peritonitis model, a combination of ebselen and silver was tested for the in vivo efficacy against E. coli infection since combination demonstrated potent antibacterial activity in vitro. Briefly, mice were infected intraperitoneally with ∼10⁷ cfu of MDR E. coli to mimicking acute peritonitis. After infection, the mice were treated with ebselen, silver, and ebselen + silver intraperitoneally. The combination of silver and ebselen led to a significant reduction (100-fold reduction) in bacterial load compared to the ebselen alone or untreated. Furthermore, 80% mice survived at end of the experiment in combination-treated group as compared to 30% in the control group [55].

Ebselen acts as a glutathione peroxidase mimetic and is thereby able to prevent cellular damage induced by reactive oxygen species. It interferes with proton-translocation function and ATPase activity in yeast [51]. In E. coli, it competitively inhibits thioredoxin reductase. Ebselen exhibited potent activity in those bacteria in which thioredoxin reductase and thioredoxin are essential for DNA synthesis and are lacking glutathione reductase, and glutaredoxin [57]. However, in Gram-positive bacteria, the exact mechanism of action of ebselen is still unclear. In addition, ebselen acts by inhibition of protein synthesis and also inhibits toxin production [54]. However, further work is needed to identify the cellular target of ebselen in S. aureus. In addition, ebselen exhibits a high barrier against resistance development.

Taken together, ebselen demonstrates broad-spectrum antibacterial activity against Gram-positive bacteria and Gram-negative bacteria either alone or in combination. Furthermore, it exhibited excellent in vivo efficacy as topical antimicrobial agent targeting Staphylococcal lesion and in murine peritonitis model of E. coli. All together, these findings suggest ebselen can be repurposed and developed as a potential treatment for MDR bacterial infections.

4.07.12.2.2 Enzyme inhibitors

3.07.12 Important Compounds and Applications

Ebselen (3a), a benzisoselenazolinone (BISA), displays anti-inflammatory activity and antioxidant capabilities by catalytically reducing hydroperoxides in the presence of thiols, akin to the enzyme glutathione peroxidase 〈84BP3235, 84BP3241, 84BP3247〉. A study of the metabolism and structure–activity relationships was reported 〈90MI 307-02〉. The 2-pyridyl analogue RP61605 showed greater activity with less toxicity and the 7-nitro analogue showed similar activity with less toxicity 〈89MI 307-01〉. Ebselen has also been tested as an anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) antibiotic 〈89MI 307-02〉. Analogues of ebselen and related compounds have also been tested as immunomodulators 〈93LA1239〉. A discussion of the mode of bioactivity is presented. A comparison study of the 1,3-benzoselenazolinone shows these to be completely inactive, comfirming the importance of the 1,2-relationship of the selenium–nitrogen bond to activity 〈94JMC2903〉. Metabolites of ebselen were prepared 〈87BSB383〉.

Some heterofused isoselenazoles (15) and (31) have found activity as antitumor agents 〈85MI 307-01, 88CPB2902, 90MI 307-03〉.

2.1 Derivatives of ebselen

A trifluoromethyl-substituted EBS derivative, 3b, was reported to inhibit SARS-Cov-2 viral replication in infected Calu-3 cells (EC₅₀ = 1.3 μM) and Vero E6 cells (EC₅₀ = 0.8 μM), which were equipotent to the reference drug remdesivir (Calu-3 cells: EC₅₀ = 0.8 μM; and E6 cells: EC₅₀ = 1.8 μM) and were more potent than the parental EBS (Calu-3 cells: EC₅₀ = 5 μM; E6 cells: EC₅₀ > 20 μM) [27]. Mechanistic studies indicated a rare His41-assisted and H₂O-particapted Se release process, as confirmed by the crystallographic structure of M^pro and EBS [22].

It was reported that benzoselenazolone (the core of EBS) derivative 3d could potently inhibit aurora kinase A and protein kinase C (PKC) isoforms α, β₁, β₂, and θ with at least five- to 13.6-fold improvement in potency compared with the parent 3c (IC₅₀ > 250 nM) [28]. Further replacement of the cyclohexane with tetrahydroselenophene generated the more potent derivative 3e (IC₅₀ = 4.2–16.9 nM), which exhibited excellent enzymatic inhibitory activities as well as good in vitro antiproliferative activity and antimetastatic activity. These results highlight the importance of Se in both 3d and 3e. Further molecular dynamics simulations and docking studies indicated that Se in the tetrahydroselenophene and benzoselenazolone moieties might form σ hole effects and/or additional hydrogen bond interactions to modulate the protein dynamics.

Merging benzoselenazolone with other pharmacophores is a useful strategy for producing hybrid derivatives with increased pharmacologic activities. For example, 3f is a hybrid of lipophilic bioorganometallic ferrocene and benzoselenazolone [29]. In vitro biological activity evaluation results indicated that 3f had moderate but more potent cytotoxicity (IC₅₀ = 75 μM) than EBS (IC₅₀ = 216.9 μM) in the tested human breast MCF-7 cancer cells. In addition, it displayed potent TrxR inhibitory activity (IC₅₀ = 4.2 μM).

Fructose-1,6-bisphosphate aldolase (FBA) is an attractive antifungal target. 3g and 3h were discovered as first-in-class covalent allosteric inhibitors of FBA from Candida albicans employing a structure-based optimization strategy. Both exhibited excellent inhibitory activities against FBA-II from C. albicans (CaFBA) with IC₅₀ value of 82.3 and 92 nM, respectively. Furthermore, compound 3h inhibited the growth of azole-resistant strains with an minimum inhibitory concentration required to inhibit the growth of 80% (MIC₈₀) of 1 μg/mL [30].

3i is a hybrid of the key pharmacophore of BACE-1 inhibitor verubecestat and benzoselenazolone. It was designed as a multitarget compound to regulate both β-amyloid and the oxidative stress pathway to treat Alzheimer’s disease (AD). It displayed both good BACE-1 inhibitory activity (IC₅₀ = 1.06 μМ) and GPx-like activity (ν₀ = 183.0 μM min⁻¹). An Aβ production experiment indicated that 3i reduced the secretion of Aβ1-40 in HEK APPswe 293T cells. 3i also exerted a cytoprotective effect against H₂O₂ or 6-OHDA, causing cell damage by alleviating intracellular ROS, mitochondrial dysfunction, Ca²⁺ overload, and cell apoptosis. Mechanism studies indicated that 3i had a cytoprotective effect by activating the Keap1-Nrf2/ARE pathway and stimulating downstream antioxidant proteins including HO-1, NQO1, TrxR1, GCLC, and GCLM [31].

Merging benzoselenazolone moiety with sugar or some natural products could also improve the antitumor activities of the parent molecules. For example, sugar-benzoselenazolone hybrid 3j inhibited the growth and migration of human breast MDA-231 cancer cells (IC₅₀ = 9.8 μM), in accordance with its selective inhibition of focal adhesion kinase (IC₅₀ = 0.42 μM), AKT-1 (IC₅₀ = 0.83 μM), and PKC-α (IC₅₀ = 0.22 μM). Moreover, an evaluation of in vivo anticancer activity of compound 3j using an invasive human breast cancer orthotopic mouse model (MDA-231-M2 cells) revealed potent antimetastatic activity at well-tolerated doses (60 mg/kg, intraperitoneally, three times a week) [32]. Se-containing steroidal derivatives 3k and 3l were synthesized by conjugating benzoselenazolone with dehydroepiandrosterone [33]. In vitro antiproliferative activity evaluation results showed that 3k (IC₅₀ = 5.4 μM) and 3l (IC₅₀ = 6.49 μM) had more potent inhibitory activity against hormone-associated human ovarian SKOV-3 cancer cells than the clinical drug abiraterone (IC₅₀ = 51.51 μM). Both 3k and 3l showed only weak inhibitory activities against normal human HEK293T cells (IC₅₀ = 75.16 and 68.19 μM), with selectivity index (SI) values of 13.9 and 10.5, respectively.

GPx Mimetics

Ebselen is a selenium-based organic complex, which can mimic the activity of GPx (Rahman, 2012a,b). It is a strong antioxidant, which increases the efficiency of glutathione and has a strong neutralizing effect against peroxynitrite radicals. Ebselen prevents lipopolysaccharide-induced airway inflammation (Haddad et al., 2002, Zhang et al., 2002) and cigarette smoke-induced inflammation (Duong et al., 2010) in vivo. BXT-51072 and BXT-51077 are low molecular weight, orally active, organoselenium GPx mimetics. BXT-51072 and BXT-51077 increase the rate of peroxide metabolism, inhibits inflammation and oxidative damage by preventing the activation of inflammatory mediators (Moutet et al., 1998).

To summarize, it is well documented that oxidant imbalance is a key feature in the pathogenesis and progression of COADs like asthma and COPD. Oxidative stress and proinflammatory response complement each other in COAD pathogenesis. Genetic predisposition like variations and altered regulation of the antioxidant genes and redox sensitive transcription factors may also render susceptibility to COADs. Dietary supplementation particularly of nonenzymatic antioxidants such as vitamin E and C are suggested as preventive measures for COAD development. Thiols, and antioxidant mimetics like spin traps, are also being explored as potential therapeutic options for COADs. Further studies with particular focus on the effect of oxidative stress during lung development may provide novel insights into COAD pathogenesis.

H Other treatment strategies

Ebselen (a selenium containing antioxidant), melatonin, and cyclosporine A markedly prevented mustard-induced anoikis, pointing to these drugs as interesting candidates for the treatment of mustard-induced airway epithelial lesions (Sourdeval et al., 2006). It has been previously suggested that acetylcholinesterase is activated during apoptotic processes and may be involved in apoptosis regulation, and acetylcholinesterase activity may be a potential marker of apoptosis in A549 cells after SM injury. If the mechanism of the involvement of acetylcholinesterase in apoptosis regulation during SM poisoning is known, drugs can be targeted (Steinritz et al., 2007). The therapeutic effects of recombinant human erythropoietin (rh-EPO) and recombinant human granulocyte colony stimulating factor (rhG-CSF) on SM-induced toxicity in dogs was evaluated and they stimulate the growth of the erythrocyte, reticulocyte, and leukocyte. The use of rh-EPO and rhG-CSF can be considered as adjuncts to other therapeutic agents (Cai et al., 2004). Though SM is a blistering agent it can also induce neutropenia in exposed individuals, increasing their susceptibility to infection. Granulocyte colony-stimulating factor (G-CSF) and pegylated G-CSF (peg-G-CSF) have been approved by the US Food and Drug Administration as hematopoietic growth factors to treat neutropenia induced by chemotherapeutic agents. African green monkeys untreated but exposed to SM recovered from neutropenia in 28 days, whereas G-CSF or peg-G-CS-treated animals recovered in 8 to 19 days after exposure. G-CSF or peg-G-CSF may reduce the duration of SM-induced neutropenia (Anderson et al., 2006). Improving the fluid balance and electrolyte concentration also has been proved to be very effective in the treatment of SM poisoning in animals (Callaway et al., 1958; Vojvodić et al., 1985; Sugendran et al., 1998).

The toxicity of SM was found to be dependent on extracellular pH. CHO-K1 cell cultures were exposed to SM and the pH was adjusted to between 5 and 10.0. An eight-fold increase in LD₅₀ was observed at pH 9.5 compared to pH 5.0. It is possible that SM causes an extracellular acidification through chemical hydrolysis resulting in cytosolic acidification. This decline in pH initiates the cascade of events that results in SM-induced cell death (Sawyer et al., 2007).

Antioxidants

Tempol and ebselen protect the endothelium by preventing eNOS uncoupling, thus restoring endothelial functions. More recently, a synthetic triterpenoid bardoxolone methyl, an activator of the antioxidant Keap1–Nrf2 pathway, has been advocated as a potential therapeutic agent restoring endothelial dysfunction⁷³ and improving renal function in CKD patients with type 2 diabetes.⁷⁴ Its phase 3 clinical trials, however, have been halted due to safety concerns. A possible therapeutic role of an endogenous antioxidant, lipoic acid, in vascular and renal protection against elevated levels of angiotensin II-induced injury has been demonstrated in transgenic rats harboring human renin and angiotensinogen genes.⁷⁵

Several well-rationalized experimental strategies for vascular protection have recently emerged and are briefly noted below.

2.10 Isoselenazolones

Ebselen was also tested in vivo in animal models of human breast carcinoma (Engman et al., 1997). In these studies Ebselen was found to be a competitive inhibitor of human TrxRd (K_i 2.8 μM), thereby leading to develop a defective NADPH-dependent reduction of Trx. Thioredoxin is a redox-active protein overexpressed and actively involved in the abnormal redox that characterizes the development of several human cancers. In the studies of Engman et al. Ebselen was used as a reference compound to assess the activity of a series of organotellurium compounds that were demonstrated to behave as noncompetitive inhibitors (K_i from 2.3 to 35.2 μM).

High-throughput screening experiments carried out by Lake and coworkers, identified Ebselen as an inhibitor of quiescin sulfhydryl oxidase 1 (QSOX1), which is a redox enzyme overexpressed in several tumors. In pancreatic and renal cancer cell lines Ebselen stalled cell growth, and its oral administration to mice bearing human pancreatic tumor xenografts resulted in a 58% reduction in tumor growth (Hanavan et al., 2015). Ebselen was found to be a covalent inhibitor of QSOX1, perhaps to be expected since it reacts with cysteine residues of that enzyme protein. The former Cys-containing enzyme to be identified in cellular tests and in vivo as a target of Ebselen inhibitory activity was GST (Nikawa, Schuch, Wagner, & Sies, 1994a, 1994b), which is now confirmed to represent a preferential redox-sensitive node for mediating the pharmacological action of this and other Se organic compounds with high redox cycling activity on cellular thiols, such as compounds 10 and 12 (Bartolini, Piroddi, et al., 2015).

Chemical structure of Ebselen (31) was, and continues to be, a source of inspiration among the chemists who practice with selenoorganic compounds for biological purposes. For example, Schianowski and coworkers synthesized a series of alkyl derivatives and among these the cyclohexyl-containing compound 32 (Fig. 10) displayed superior redox properties also reducing cell growth in both MCF-7 and DU145 cancer cell lines with IC₅₀values that were in the low micromolar range (Pacula et al., 2017).

Other examples of this class of compounds include the combination of the pharmacophores of resveratrol and 31 (Fig. 10) designed to develop a series of multitarget redox-active agents, such as compound 33. Resveratrol and 31 are antiproliferative agents, and this appears to represent an important anticancer property for the hybrid derivatives. Indeed, biological evaluations indicated that all the developed test compounds behaved as antiproliferative agents in the human cancer cell lines Bel-7402, A549, HeLa, and MCF-7. The test compounds were also demonstrated to be TrxRd inhibitors. Moreover, mechanistic studies clearly revealed that compound 33 increases intracellular ROS implicating this as a cause of apoptosis in cancer cells (Yan et al., 2015).

Chen and colleagues incorporated the scaffold of compound 31 in a series of 1,2,4-triazole derivatives that were assessed in human cancer cell lines SMMC-7721, HeLa, and A549. Among the compounds, derivative 34 is worthy of mention since it exhibited higher antiproliferative capacity than Ethaselen (compound 35) and 5-FU (Li et al., 2016). Among all of the selenoorganic compounds, 35 is the most studied as an anticancer agent and currently (march 2017) is in phase I clinical trial for the treatment of TrxRd-overexpressing advanced nonsmall cell lung cancer (NSLCLC) (Wang et al., 2012). TrxRd is a component of several redox-sensitive pathways that mediate important biological processes, such as cell survival, growth, migration, and inhibition of apoptosis, though its overexpression is linked to various tumors via an unknown mechanism (Saccoccia et al., 2014). The mechanism by which compound 35 inhibits TrxRd and how this inhibition translates into an antiproliferative effect was studied by Zeng and coworkers using a NSLCLC xenograft mouse model (Ye, Li, Ji, Zeng, & Lu, 2017). In vitro experiments proved that this compound can reverse the malignant phenotype of MCF-7 cells (Dong et al., 2016). Synergistic anticancer effects were also observed in colorectal cancer cell models when 35 was coadministrated with the tyrosine kinase inhibitor Sunitinib (Sutent) (Zheng et al., 2016).

7.7 SPI-1005: Sound Pharmaceuticals

The development of 27 for treating SNHL and tinnitus has been the subject of reviews [119,229,235]. Genetic induced glutathione peroxidase (GPx1) depletion in mice demonstrated a role for GPx1 in maintaining normal cochlear functions and found GPx1 depletion increases vulnerability to NIHL [236]. The ability of 27 to mimic the activity of GPx was found in animal studies to reduce acoustic damage [237–239]. In light of these and other data, 27 (SPI-1005) was taken forward by Sound Pharmaceuticals (www.soundpharma.com) into clinical studies to prevent NIHL. In a Phase I study (ClinicalTrials.gov Identifier: NCT01452607), 32 subjects received either a single oral dose of placebo or four different doses (200, 400, 800, and 1600 mg) of SPI-1005. There were no treatment or dose-related trends in the overall incidence of adverse effects. A dose-proportional increase in exposure of 27 was observed, and the human pharmacokinetics of 27 supported twice-daily dosing by the oral route [235]. Sound Pharmaceuticals examined hearing protection with 27 in a Phase II study (ClinicalTrials.gov Identifier: NCT01444846) in healthy subjects exposed to loud sounds or noise via a Calibrated Sound Challenge (CSC). In this study, 83 subjects were given a placebo or one of three doses (200, 400 or 600 mg) of SPI-1005 for 4 days, twice daily by oral administration [240]. The primary outcome measure was protecting against induced temporary threshold shift (TTS) in hearing at 1 week. A TTS is a temporary shift in the measured auditory threshold following acoustic overexposure. A TTS may occur suddenly after exposure to a high level of noise, a situation in which most individuals may experience reduced hearing. A TTS results in temporary hearing loss for a variable period of hours to days, but is not permanent. Similar to the Phase I study, there were no treatment- or dose-related trends in overall AE incidence. Only the 400 mg 27 mid dose group demonstrated reduced the incidence and severity of the noise-induced TTS induced by the CSC compared to the placebo group [240].

Preclinical studies provide evidence for the protective effect of 27 in aminoglycoside and cisplatin-induced hearing loss [241–249]. Sound Pharmaceuticals progressed 27 to an ongoing Phase I/II clinical trial (ClinicalTrials.gov Identifier: NCT02819856) investigating safety and efficacy in cystic fibrosis patients receiving intravenous aminoglycoside tobramycin at risk of DIHL. Dosing of 27 is planned to start within the first 2 days of intravenous tobramycin treatment and will be administered concomitantly. At the end of the 21-day course of 27 (orally dosed twice daily at 200, 400 or 600 mg) and 28 days following the cessation of 27 dosing, patients will have hearing loss, tinnitus and vertigo reassessed.

Selenium-Mediated Protection of Pancreatic β-Cells and Promotion of Insulin Secretion

There is compelling evidence from cell culture and animal studies that supplementation/treatment with dietary Se compounds (e.g., selenite and selenate) and the seleno-organic drug ebselen or overexpression of the antioxidant selenoenzyme GPx1 may protect pancreatic β-cells from ROS-induced apoptosis, increase islet/β-cell mass, and stimulate insulin production and/or secretion [67,74,77–85]. A small in vitro study published in 2008 provided the first evidence for Se-mediated improvement of islet/β-cell function by demonstrating that selenite and selenate (at low concentrations of only 30 nM) increased promoter activity, biosynthesis, and/or secretion of insulin in the murine β-cell line Min6 and in isolated rat islets [77]. Since then, this primary finding has been corroborated and extended in several in vivo studies, using different dietary Se compounds (e.g., selenite, selenate, and Se-enriched yeast) from moderate to high Se doses and different animal models (e.g., mice, rats, and pigs): despite the differences in their experimental protocols, all those studies have in common that Se supplementation of the animals resulted in elevated plasma/serum levels of insulin but also in concomitant insulin resistance or at least in altered lipid and/or carbohydrate metabolism in insulin target organs [79,81,82,85]. Most interestingly, supplementation of diabetic db/db mice, a popular animal model of T2DM, with a moderate dose of selenate (0.8 ppm Se) increased insulin production and gene expression of proteins involved in β-cell proliferation and differentiation while apoptosis-associated genes were downregulated in the islets [82]. However, the beneficial islet-protective effects of Se supplementation were accompanied by (unfavorable) upregulation of lipogenic and inflammatory genes and increased fat accumulation in the liver that was most likely driven by the chronic hyperinsulinemia [82].

A probable explanation for the Se-induced effects observed in the aforementioned animal studies is given by the fact that all dietary Se compounds can stimulate biosynthesis and activity of the antioxidant selenoenzyme GPx1. GPx1 is highly dependent on Se supply and has been implicated in both protection of pancreatic β-cells from oxidative damage and impairment of insulin action [67]. Indeed, the manifestation of a T2DM-like phenotype (hyperglycemia, insulin resistance, and obesity) in transgenic mice with global overexpression of GPx1 was also associated with chronic hyperinsulinemia [74]. When those GPx1-overexpressing mice were set on dietary restriction, they did not develop obesity anymore but they still showed elevated plasma insulin levels [84]. Chronic hyperinsulinemia was associated with greater pancreatic β-cell mass and insulin content and enhanced GSIS, pointing to dysregulation of pancreatic β-cell proliferation/differentiation, insulin production and secretion as the primary cause of the unfavorable outcome of global GPx1 overexpression [84]. On the other hand, overexpression of GPx1 specifically in the β-cells has been proven to be beneficial through protecting two animal models of diabetes, C57BLKS/J mice treated with the β-cell toxin streptozotocin and db/db mice, from β-cell loss and the resulting hyperglycemia [78]. The reasons for the discrepancy between the two transgenic mouse models of global and β-cell-specific GPx1 overexpression [74,78] are still not completely understood; beside pro-diabetic actions of GPx1 in insulin target tissues, different levels of GPx1 expression/activity in the β-cells itself might account for. Interestingly, two recently published studies reported independent of each other beneficial (β-cell-protective) effects of the GPx mimic ebselen in vitro and in vivo [80,83]: early treatment with ebselen rescued Zucker diabetic fatty rats from glucotoxicity-induced β-cell deterioration through suppression of oxidative stress and apoptosis, resulting in improved glucose homeostasis [80]. In accordance with the findings of the animal study, ebselen improved GSIS in islets isolated from both wild-type and GPx1 knock-out mice [83].

Overall, the mixed results of the studies discussed here highlight both the therapeutic potential (rescue of pancreatic insulin production) and the problems (risk of hyperinsulinemia and worsening of insulin resistance) that might be associated with the use of Se compounds for adjuvant treatment of diabetes, which is, as a consequence, not recommended for humans at present [67]. The development of synthetic seleno-organic compounds that should be capable of targeting discrete ROS at specific intracellular sites may better fulfill the needs to preserve β-cells and their insulin secretory capacity with minimal side effects, compared to dietary (over)supplementation with Se or mixtures of antioxidants.