Liposomal delivery of organoselenium-cisplatin complex as a novel therapeutic approach for colon cancer therapy.

Cisplatin is a widely-used chemotherapeutic agent for the treatment of various solid neoplasms including colon cancer. Cisplatin-induced DNA damage is restricted due to dose-related adverse reactions as well as primary resistance mechanisms. Therefore, it is imperative to utilize novel therapeutic approaches to circumvent cisplatin limitations and attenuate its normal tissues toxicity. In this study, we exploited a novel PEGylated liposomes with greater efficiency to treat colon cancer. For this, an organoselenium compound (diselanediylbis decanoic acid (DDA)) was synthesized, and liposomes composed of Egg PC or HSPC, as well as DOPE, mPEG2000-DSPE, cholesterol and DDA at varying molar ratios were prepared by using thin-film method. Cisplatin loading was performed through incubation with liposomes. Characterization of nanoliposomes indicated a favarable size range of 91-122 nm and negative zeta potential of -9 to -22 mv. The organoselenium compound significantly improved cisplatin loading efficiency within the liposomes (83.4 %). Results also revealed an efficient bioactivity of cisplatin liposome on C26 cells compared to the normal cells. Further, DDA bearing liposomes significantly improved drug residence time in circulation, reduced toxicity associated with the normal tissues, and enhanced drug accumulation within the oxidative tumor microenvironment. Collectively, results indicated that cisplatin encasement within liposomes by using this method could significantly improve the therapeutic efficacy in vivo, and merits further investigations.

Iodine/Oxone® oxidative system for the synthesis of selenylindoles bearing a benzenesulfonamide moiety as carbonic anhydrase I, II, IX, and XII inhibitors.

A wide range of 3-selenylindoles were synthesized via an eco-friendly approach that uses Oxone® as the oxidant in the presence of a catalytic amount of iodine. This mild and economical protocol showed broad functional group tolerance and operational simplicity. A series of novel selenylindoles bearing a benzenesulfonamide moiety were also synthesized and evaluated as carbonic anhydrase inhibitors of the human (h) isoforms hCa I, II, IX, and XII, which are involved in pathologies such as glaucoma and cancer. Several derivatives showed excellent inhibitory activity towards these isoforms in the nanomolar range, lower than that shown by acetazolamide.

Redox-sensitive hydrogel based on hyaluronic acid with selenocystamine cross-linking for the delivery of Limosilactobacillus reuteri in a DSS-induced colitis mouse model.

Disrupted gut microbiota homeostasis is an important cause of inflammatory colitis. Studies have shown that effective supplementation with probiotics can maintain microbial homeostasis and alleviate colitis. Here, to increase the viability of probiotics in the harsh gastrointestinal environments and enable targeted delivery, a redox-sensitive selenium hyaluronic acid (HA-Se) hydrogel encapsulating probiotics was developed. HA was modified with selenocystamine dihydrochloride and crosslinked by an amide reaction to generate a redox-sensitive hydrogel with stable mechanical properties, a low hemolysis rate and satisfactory biocompatibility. The HA-Se hydrogel exhibited suitable sensitivity to 10 mM GSH or 100 µM H2O2. The encapsulation of Limosilactobacillus reuteri (LR) in the HA-Se hydrogel (HA-Se-LR) significantly increased the survival rate of the probiotics in simulated gastric and intestinal fluid. HA-Se-LR administration increased the survival rate of mice with dextran sulfate sodium (DSS)-induced colitis, significantly alleviated oxidative stress and inflammation, and increased the effect of LR on microbiota α diversity. These results indicate that the HA-Se hydrogel constructed in this study can be used as a delivery platform to treat colitis, expanding the targeted applications of the natural polymer HA in disease treatment and the administration of probiotics as drugs to alleviate disease symptoms.

Ultrasmall magnolol/ebselen nanomicelles for preventing renal ischemia/reperfusion injury.

Renal ischemia/reperfusion injury (RIRI) is an inevitable complication following kidney transplantation surgery, accompanied by the generation of a large amount of free radicals. A cascade of events including oxidative stress, extreme inflammation, cellular apoptosis, and thrombosis disrupts the microenvironment of renal cells and the hematological system, ultimately leading to the development of acute kidney injury (AKI). The current research primarily focuses on reducing inflammation and mitigating damage to renal cells through antioxidative approaches. However, studies on simultaneously modulating the renal hematologic system remain unreported. Herein, potent and novel drug-loaded nanomicelles can be efficiently self-assembled with magnolol (MG) and ebselen (EBS) by π-π conjugation, hydrophobic action and the surfactant properties of Tween-80. The ultrasmall MG/EBS nanomicelles (average particle size: 10-25 nm) not only fully preserve the activity of both drugs, but also greatly enhance drug utilization (encapsulation rates: MG: 90.1%; EBS: 49.3%) and reduce drug toxicity. Furthermore, EBS, as a glutathione peroxidase mimic and NO catalyst, combines with the multifunctional MG to scavenge free radicals and hydroperoxides, significantly inhibiting inflammation and thrombosis while effectively preventing apoptosis of vascular endothelial cells and renal tubular epithelial cells. This study provides a new strategy and theoretical foundation for the simultaneous regulation of kidney cells and blood microenvironment stability.

Recent Progress in Synthetic and Biological Application of Diorganyl Diselenides.

Diorganyl diselenides have emerged as privileged structures because they are easy to prepare, have distinct reactivity, and have broad biological activity. They have also been used in the synthesis of natural products as an electrophile in the organoselenylation of aromatic systems and peptides, reductions of alkenes, and nucleophilic substitution. This review summarizes the advancements in methods for the transformations promoted by diorganyl diselenides in the main functions of organic chemistry. Parallel, it will also describe the main findings on pharmacology and toxicology of diorganyl diselenides, emphasizing anti-inflammatory, hypoglycemic, chemotherapeutic, and antimicrobial activities. Therefore, an examination detailing the reactivity and biological characteristics of diorganyl diselenides provides valuable insights for academic researchers and industrial professionals.

Di- and Triselenoesters-Promising Drug Candidates for the Future Therapy of Triple-Negative Breast Cancer.

Breast cancer is a major malignancy among women, characterized by a high mortality rate. The available literature evidence indicates that selenium, as a trace element, has chemopreventive properties against many types of cancer; as such, compounds containing it in their structure may potentially exhibit anticancer activity. Accordingly, we have undertaken a study to evaluate the effects of novel selenoesters (EDAG-1, -7, -8, -10) on MCF-7 and MDA-MB-231 breast cancer cells. Our analysis included investigations of cell proliferation and viability as well as cytometric determinations of apoptosis/autophagy induction, changes in mitochondrial membrane polarity (ΔΨm), caspase 3/7, 8, and 9 activities, and Bax, Bcl-2, p53, Akt, AMPK, and LC3A/B proteins. The obtained data revealed that the tested derivatives are highly cytotoxic and inhibit cell proliferation even at nanomolar doses (0.41-0.79 µM). Importantly, their strong proapoptotic properties (↑ caspase 3/7) are attributable to the effects on both the extrinsic (↑ caspase 8) and intrinsic (↓ ΔΨm and Bcl-2, ↑ Bax, p53, and caspase 9) pathways of apoptosis. Moreover, the tested compounds are autophagy activators (↓ Akt, ↑ autophagosomes and autolysosomes, AMPK, LC3A/B). In summary, the potent anticancer activity suggests that the tested compounds may be promising drug candidates for future breast cancer therapy.

Unexpected diselenide metathesis in selenocysteine-substituted biologically active peptides.

Substitution of disulfide bonds with a diselenide bonds in peptides and proteins is an often-used strategy to increase the stability of naturally occurring peptides and proteins. In this paper, diselenide metathesis between model diselenide dimer peptides, as well as that in diselenide(s)-substituted biologically active peptides, were analyzed. Surprisingly, depending on the tertiary structure of the peptides, we observed that the metathesis reaction occurs under physiological conditions even in the absence of reducing agents, light and heating.

Development of a Biosafety Level 1 Cellular Assay for Identifying Small-Molecule Antivirals Targeting the Main Protease of SARS-CoV-2: Evaluation of Cellular Activity of GC376, Boceprevir, Carmofur, Ebselen, and Selenoneine.

While research has identified several inhibitors of the main protease (Mpro) of SARS-CoV-2, a significant portion of these compounds exhibit reduced activity in the presence of reducing agents, raising concerns about their effectiveness in vivo. Furthermore, the conventional biosafety level 3 (BSL-3) for cellular assays using viral particles poses a limitation for the widespread evaluation of Mpro inhibitor efficacy in a cell-based assay. Here, we established a BSL-1 compatible cellular assay to evaluate the in vivo potential of Mpro inhibitors. This assay utilizes mammalian cells expressing a tagged Mpro construct containing N-terminal glutathione S-transferase (GST) and C-terminal hemagglutinin (HA) tags and monitors Mpro autodigestion. Using this method, GC376 and boceprevir effectively inhibited Mpro autodigestion, suggesting their potential in vivo activity. Conversely, carmofur and ebselen did not exhibit significant inhibitory effects in this assay. We further investigated the inhibitory potential of selenoneine on Mpro using this approach. Computational analyses of binding energies suggest that noncovalent interactions play a critical role in facilitating the covalent modification of the C145 residue, leading to Mpro inhibition. Our method is straightforward, cost-effective, and readily applicable in standard laboratories, making it accessible to researchers with varying levels of expertise in infectious diseases.

Selenium-containing compounds: a new hope for innovative treatments in Alzheimer's disease and Parkinson's disease.

Neurodegenerative diseases are challenging to cure. To date, no cure has been found for Alzheimer's disease or Parkinson's disease, and current treatments are able only to slow the progression of the diseases and manage their symptoms. After an introduction to the complex biology of these diseases, we discuss the beneficial effect of selenium-containing agents, which show neuroprotective effects in vitro or in vivo. Indeed, selenium is an essential trace element that is being incorporated into innovative organoselenium compounds, which can improve outcomes in rodent or even primate models with neurological deficits. Herein, we critically discuss recent findings in the field of selenium-based applications in neurological disorders.

Machine learning-based QSAR and LB-PaCS-MD guided design of SARS-CoV-2 main protease inhibitors.

The global outbreak of the COVID-19 pandemic caused by the SARS-CoV-2 virus had led to profound respiratory health implications. This study focused on designing organoselenium-based inhibitors targeting the SARS-CoV-2 main protease (Mpro). The ligand-binding pathway sampling method based on parallel cascade selection molecular dynamics (LB-PaCS-MD) simulations was employed to elucidate plausible paths and conformations of ebselen, a synthetic organoselenium drug, within the Mpro catalytic site. Ebselen effectively engaged the active site, adopting proximity to H41 and interacting through the benzoisoselenazole ring in a π-π T-shaped arrangement, with an additional π-sulfur interaction with C145. In addition, the ligand-based drug design using the QSAR with GFA-MLR, RF, and ANN models were employed for biological activity prediction. The QSAR-ANN model showed robust statistical performance, with an r2training exceeding 0.98 and an RMSEtest of 0.21, indicating its suitability for predicting biological activities. Integration the ANN model with the LB-PaCS-MD insights enabled the rational design of novel compounds anchored in the ebselen core structure, identifying promising candidates with favorable predicted IC50 values. The designed compounds exhibited suitable drug-like characteristics and adopted an active conformation similar to ebselen, inhibiting Mpro function. These findings represent a synergistic approach merging ligand and structure-based drug design; with the potential to guide experimental synthesis and enzyme assay testing.

Polyfunctionalized organoselenides: New synthetic approach from selenium-containing cyanohydrins and anti-melanoma activity.

A series of seleno-containing polyfunctionalized compounds was synthesized exploring cyanohydrin chemistry, including α-hydroxy esters, α-hydroxy acids, 1,2-diols, and 1,2-diacetates, with yields ranging from 26 up to 99 %. The cytotoxicity of all synthesized compounds was then evaluated using a non-tumor cell line (BALB/3T3 murine fibroblasts), and those deemed non-cytotoxic had their anti-melanoma activity evaluated using B16-F10 murine melanoma cells. These assays identified two compounds with selective cytotoxic activity against the tested melanoma cell line, showing a potential anti-melanoma application.

Synthesis of a New Class of ß-Carbonyl Selenides Functionalized with Ester Groups with Antioxidant and Anticancer Properties-Part II.

A series of phenyl ß-carbonyl selenides with o-ester functionality substituted on the oxygen atom with chiral and achiral alkyl groups was synthesized. All compounds are the first examples of this type of organoselenium derivatives with an ester substituent in the ortho position. The obtained derivatives were tested as antioxidants and anticancer agents to see the influence of an ester functionality on the bioactivity of ß-carbonyl selenides by replacing the o-amide group with an o-ester group. The best results as an antioxidant agent were observed for O-((1R,2S,5R)-(-)-2-isopropyl-5-methylcyclohexyl)-2-((2-oxopropyl)selanyl)benzoate. The most cytotoxic derivative against breast cancer MCF-7 cell lines was O-(methyl)-2-((2-oxopropyl)selanyl)benzoate and against human promyelocytic leukemia HL-60 was O-(2-pentyl)-2-((2-oxopropyl)selanyl)benzoate.

Ebselen improves lipid metabolism by activating PI3K/Akt and inhibiting TLR4/JNK signaling pathway to alleviate nonalcoholic fatty liver.

Nonalcoholic fatty liver disease (NAFLD), a metabolic disease associated with obesity and type 2 diabetes. Due to its complex pathogenesis, there are still limitations in the knowledge of the disease. To date, no drug has been approved to treat NAFLD. This study aims to explore the role and mechanism of Ebselen (EbSe) in NAFLD. A high-fat diet-induced mouse model of NAFLD was employed to investigate EbSe function in NAFLD mice by EbSe gavage and to regularly monitor the mouse body weight. HE and oil red O staining were performed, respectively, to detect the pathological damage and lipid accumulation in mouse liver tissues. The biochemical and ELISA kits were employed to measure the levels of ALT, AST, TG, TC, LDL-C, HDL-C and pro-inflammatory cytokines within mouse serum or liver tissue. The expression of key proteins of PPARα, fatty acid ß oxidation-related protein, PI3K/Akt and TLR4/JNK signaling pathway was detected by western blot. EbSe significantly downregulated body weight, liver weight and liver lipid accumulation in NAFLD mice and downregulated ALT, AST, TG, TC, LDL-C and increased HDL-C serum levels. EbSe upregulated the expression levels of PPARα and fatty acid ß oxidation-associated proteins CPT1α, ACOX1, UCP2 and PGC1α. EbSe promoted Akt and PI3K phosphorylation, and inhibited TLR4 expression and JNK phosphorylation. EbSe can upregulate PPARα to promote fatty acid ß-oxidation and improve hepatic lipid metabolism. Meanwhile, EbSe also activated PI3K/Akt and inhibited TLR4/JNK signaling pathway. EbSe is predicted to be an effective therapeutic drug for treating NAFLD.

Acute 2-phenyl-3-(phenylselanyl)benzofuran treatment reverses the neurobehavioral alterations induced by sleep deprivation in mice.

Sleep is a fundamental state for maintaining the organism homeostasis. Disruptions in sleep patterns predispose to the appearance of memory impairments and mental disorders, including depression. Recent pre-clinical studies have highlighted the antidepressant-like properties of the synthetic compound 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF1). To further investigate the neuromodulatory effects of SeBZF1, this study aimed to assess its therapeutic efficacy in ameliorating neurobehavioral impairments induced by sleep deprivation (SD) in mice. For this purpose, a method known as multiple platforms over water was used to induce rapid eye movement (REM) SD. Two hours after acute SD (24 h), male Swiss mice received a single treatment of SeBZF1 (5 mg/kg, intragastric route) or fluoxetine (a positive control, 20 mg/kg, intraperitoneal route). Subsequently, behavioral tests were conducted to assess spontaneous motor function (open-field test), depressive-like behavior (tail suspension test), and memory deficits (Y-maze test). Brain structures were utilized to evaluate oxidative stress markers, monoamine oxidase (MAO) and acetylcholinesterase (AChE) activities. Our findings revealed that SD animals displayed depressive-like behavior and memory impairments, which were reverted by SeBZF1 and fluoxetine treatments. SeBZF1 also reverted the increase in lipoperoxidation levels and glutathione peroxidase activity in the pre-frontal cortex in mice exposed to SD. Besides, the increase in hippocampal AChE activity induced by SD was overturned by SeBZF1. Lastly, cortical MAO-B activity was reestablished by SeBZF1 in mice that underwent SD. Based on the main findings of this study, it can be inferred that the compound SeBZF1 reverses the neurobehavioral alterations induced by sleep deprivation in male Swiss mice.

Synthesis and characterization of organoselenium based BODIPY and its application in living cells.

Phenylselenide based BODIPY probe was successfully synthesized and characterized by NMR spectroscopic techniques (1H, 13C and 77Se NMR), mass spectrometry and single crystal XRD. Surprisingly, crystal packing diagram of the probe showed formation of 1-D strip through intermolecular F---H interaction. The probe was screened with various Reactive Oxygen Species (ROS) and found to be selective for superoxide ion over other ROS via "turn-on" fluorescence response. The probe selectively and sensitively detects superoxide with a lower detection limit (43.34 nM) without interfering with other ROS. The quantum yield of the probe was found to increase from 0.091 % to 30.4 % (334-fold) after oxidation. Theoretical calculations (DFT and TD-DFT) were also performed to understand the sensing mechanism of the probe. The probe was able to effectively detect superoxide inside living cells without any toxic effect.

Recent research progress of selenotungstate-based biomolecular sensing materials.

Polyoxometalates (POMs) have drawn significant attention on account of their structural designability, compositional diversity and great potential applications. As an indispensable branch of POMs, selenotungstates (SeTs) have been synthesized extensively. Some SeTs have been applied as sensing materials for detecting biomarkers (e.g., metabolites, hormones, cancer markers). To gain a comprehensive understanding of advancements in SeT-based sensing materials, we present an overview that encapsulates the sensing performances and mechanisms of SeT-based biosensors. SeT-based biosensors are categorized into electrochemical catalytic biosensors, electrochemical affinity biosensors, "turn-off" fluorescence biosensors and "turn-on" fluorescence biosensors. We anticipate the expansive potential of SeT-based biosensors in wearable and implantable sensing technologies, which promises to catalyze significant breakthroughs in SeT-based biosensors.

Se-methylselenocysteine inhibits the progression of non-small cell lung cancer via ROS-mediated NF-κB signaling pathway.

Se-methylselenocysteine (MSC) is recognized for its potential in cancer prevention, yet the specific effects and underlying processes it initiates within non-small cell lung cancer (NSCLC) remain to be fully delineated. Employing a comprehensive array of assays, including CCK-8, colony formation, flow cytometry, MitoSOX Red staining, wound healing, transwell, and TUNEL staining, we evaluated MSC's effects on A549 and 95D cell lines. Our investigation extended to the ROS-mediated NF-κB signaling pathway, utilizing Western blot analysis, P65 overexpression, and the application of IκB-α inhibitor (BAY11-7082) or N-acetyl-cysteine (NAC) to elucidate MSC's mechanism of action. In vivo studies involving subcutaneous xenografts in mice further confirmed MSC's inhibitory effect on tumor growth. Our findings indicated that MSC inhibited the proliferation of A549 and 95D cells, arresting cell cycle G0/G1 phase and reducing migration and invasion, while also inducing apoptosis and increasing intracellular ROS levels. This was accompanied by modulation of key proteins, including the upregulation of p21, p53, E-cadherin, Bax, cleaved caspase-3, cleaved-PARP, and downregulation of CDK4, SOD2, GPX-1. MSC was found to inhibit the NF-κB pathway, as evidenced by decreased levels of P-P65 and P-IκBα. Notably, overexpression of P65 and modulation of ROS levels with NAC could attenuate MSC's effects on cellular proliferation and metastasis. Moreover, MSC significantly curtailed tumor growth in vivo and disrupted the NF-κB signaling pathway. In conclusion, our research demonstrates that MSC exhibits anticancer effects against NSCLC by modulating the ROS/NF-κB signaling pathway, suggesting its potential as a therapeutic agent in NSCLC treatment.

Ebselen analogues delay disease onset and its course in fALS by on-target SOD-1 engagement.

Amyotrophic lateral sclerosis (ALS) selectively affects motor neurons. SOD1 is the first causative gene to be identified for ALS and accounts for at least 20% of the familial (fALS) and up to 4% of sporadic (sALS) cases globally with some geographical variability. The destabilisation of the SOD1 dimer is a key driving force in fALS and sALS. Protein aggregation resulting from the destabilised SOD1 is arrested by the clinical drug ebselen and its analogues (MR6-8-2 and MR6-26-2) by redeeming the stability of the SOD1 dimer. The in vitro target engagement of these compounds is demonstrated using the bimolecular fluorescence complementation assay with protein-ligand binding directly visualised by co-crystallography in G93A SOD1. MR6-26-2 offers neuroprotection slowing disease onset of SOD1G93A mice by approximately 15 days. It also protected neuromuscular junction from muscle denervation in SOD1G93A mice clearly indicating functional improvement.

Effects of ebselen addition on emotional processing and brain neurochemistry in depressed patients unresponsive to antidepressant medication.

Lithium is an effective augmenting agent for depressed patients with inadequate response to standard antidepressant therapy, but numerous adverse effects limit its use. We previously reported that a lithium-mimetic agent, ebselen, promoted a positive emotional bias-an indicator of potential antidepressant activity in healthy participants. We therefore aimed to investigate the effects of short-term ebselen treatment on emotional processing and brain neurochemistry in depressed patients with inadequate response to standard antidepressants. We conducted a double-blind, placebo-controlled 7-day experimental medicine study in 51 patients with major depressive disorder who were currently taking antidepressants but had an inadequate response to treatment. Participants received either ebselen 600 mg twice daily for seven days or identical matching placebo. An emotional testing battery, magnetic resonance spectroscopy and depression and anxiety rating scales were conducted at baseline and after seven days of treatment. Ebselen did not increase the recognition of positive facial expressions in the depressed patient group. However, ebselen increased the response bias towards fear emotion in the signal detection measurement. In the anterior cingulate cortex, ebselen significantly reduced the concentrations of inositol and Glx (glutamate+glutamine). We found no significant differences in depression and anxiety rating scales between visits. Our study did not find any positive shift in emotional bias in depressed patients with an inadequate response to antidepressant medication. We confirmed the ability of ebselen to lower inositol and Glx in the anterior cingulate cortex. These latter effects are probably mediated through inhibition of inositol monophosphatase and glutaminase respectively.

Selenization of Small Molecule Drugs: A New Player on the Board.

There is an urgent need to develop safer and more effective modalities for the treatment of a wide range of pathologies due to the increasing rates of drug resistance, undesired side effects, poor clinical outcomes, etc. Throughout the years, selenium (Se) has attracted a great deal of attention due to its important role in human health. Besides, a growing body of work has unveiled that the inclusion of Se motifs into a great number of molecules is a promising strategy for obtaining novel therapeutic agents. In the current Perspective, we have gathered the most recent literature related to the incorporation of different Se moieties into the scaffolds of a wide range of known drugs and their feasible pharmaceutical applications. In addition, we highlight different representative examples as well as provide our perspective on Se drugs and the possible future directions, promises, opportunities, and challenges of this ground-breaking area of research.