κ-Selenocarrageenan Oligosaccharides Prepared by Deep-Sea Enzyme Alleviate Inflammatory Responses and Modulate Gut Microbiota in Ulcerative Colitis Mice.

κ-Selenocarrageenan (KSC) is an organic selenium (Se) polysaccharide. There has been no report of an enzyme that can degrade κ-selenocarrageenan to κ-selenocarrageenan oligosaccharides (KSCOs). This study explored an enzyme, κ-selenocarrageenase (SeCar), from deep-sea bacteria and produced heterologously in Escherichia coli, which degraded KSC to KSCOs. Chemical and spectroscopic analyses demonstrated that purified KSCOs in hydrolysates were composed mainly of selenium-galactobiose. Organic selenium foods through dietary supplementation could help regulate inflammatory bowel diseases (IBD). This study discussed the effects of KSCOs on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in C57BL/6 mice. The results showed that KSCOs alleviated the symptoms of UC and suppressed colonic inflammation by reducing the activity of myeloperoxidase (MPO) and regulating the unbalanced secretion of inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-10). Furthermore, KSCOs treatment regulated the composition of gut microbiota, enriched the genera Bifidobacterium, Lachnospiraceae_NK4A136_group and Ruminococcus and inhibited Dubosiella, Turicibacter and Romboutsia. These findings proved that KSCOs obtained by enzymatic degradation could be utilized to prevent or treat UC.

Selenium as an emerging versatile player in heterocycles and natural products modification.

The diverse pharmacological activities of organoselenium compounds are closely correlated to their ability to scavenge and induce reactive oxygen species (ROS), their intrinsic oxidative properties, and their Se(0) release property. The incorporation of selenium into small molecules, and particularly into heterocycles and natural products, has shown great potential in altering the potency and selectivity of these molecules. Therefore, selenium will play an important role in drug discovery in the near future. We summarize how different organoselenium species affect cellular oxidative stress levels, and try to correlate the structural properties of selenium-containing heterocycles and natural product derivatives to their biological activities and therapeutic applications. We also provide some information to guide the rational design of selenium-containing drugs.

Synthesis and evaluation of multi-target-directed ligands with BACE-1 inhibitory and Nrf2 agonist activities as potential agents against Alzheimer's disease.

Cumulative evidence suggests that ß-amyloid and oxidative stress are closely related with each other and play key roles in the process of Alzheimer's disease (AD). Multitarget regulation of both pathways might represent a promising therapeutic strategy. Here, a series of selenium-containing compounds based on ebselen and verubecestat were designed and synthesized. Biological evaluation showed that 13f exhibited good BACE-1 inhibitory activity (IC50 = 1.06 µΜ) and potent GPx-like activity (ν0 = 183.0 µM min-1). Aß production experiment indicated that 13f could reduce the secretion of Aß1-40 in HEK APPswe 293T cells. Moreover, 13f exerted a cytoprotective effect against the H2O2 or 6-OHDA caused cell damage via alleviation of intracellular ROS, mitochondrial dysfunction, Ca2+ overload and cell apoptosis. The mechanism studies indicated that 13f exhibited cytoprotective effect by activating the Keap1-Nrf2-ARE pathway and stimulating downstream anti-oxidant protein including HO-1, NQO1, TrxR1, GCLC, and GCLM. In addition, 13f significantly reduced the production of NO and IL-6 induced by LPS in BV2 cells, which confirmed its anti-inflammatory activity as a Nrf2 activator. The BBB permeation assay predicted that 13f was able to cross the BBB. In summary, 13f might be a promising multi-target-directed ligand for the treatment of AD.

Diphenyl diselenide ameliorates diabetic nephropathy in streptozotocin-induced diabetic rats via suppressing oxidative stress and inflammation.

Oxidative stress and inflammation are implicated in the occurrence and progression of diabetic nephropathy (DN). Diphenyl diselenide (DPDS) is a stable and simple diaryl diselenide with anti-hyperglycemic, anti-inflammatory, and antioxidant activities. However, the effects of DPDS on DN are still unclear to date. Herein, we aimed to explore whether DPDS could improve renal dysfunction in streptozotocin (STZ)-induced diabetic rats and its underlying mechanisms. STZ-induced DN rats were administered with DPDS (5 or 15 mg/kg) or metformin (200 mg/kg) once daily by intragastric gavage for 12 weeks. DPDS supplementation significantly improved hyperglycemia, glucose intolerance, dyslipidemia, and the renal pathological abnormalities, concurrent with significantly reduced serum levels of creatinine, urea nitrogen, urine volume, and urinary levels of micro-albumin, ß2-microglobulin and N-acetyl-glucosaminidase activities. Moreover, DPDS effectively promoted the activities of antioxidant enzymes, and reduced the levels of MDA and pro-inflammatory factors in serum and the kidney. Furthermore, DPDS supplementation activated the renal Nrf2/Keap1 signaling pathway, but attenuated the high phosphorylation levels of NFκB, JNK, p38 and ERK1/2. Altogether, the current study indicated for the first time that DPDS ameliorated STZ-induced renal dysfunction in rats, and its mechanism of action may be attributable to suppressing oxidative stress via activating the renal Nrf2/Keap1 signaling pathway and mitigating inflammation by suppressing the renal NFκB/MAPK signaling pathways, suggesting a potential therapeutic approach for DN.

Glutathione peroxidase-1 and neuromodulation: Novel potentials of an old enzyme.

Glutathione peroxidase (GPx) acts in co-ordination with other signaling molecules to exert its own antioxidant role. We have demonstrated the protective effects of GPx,/GPx-1, a selenium-dependent enzyme, on various neurodegenerative disorders (i.e., Parkinson's disease, Alzheimer's disease, cerebral ischemia, and convulsive disorders). In addition, we summarized the recent findings indicating that GPx-1 might play a role as a neuromodulator in neuropsychiatric conditions, such as, stress, bipolar disorder, schizophrenia, and drug intoxication. In this review, we attempted to highlight the mechanistic scenarios mediated by the GPx/GPx-1 gene in impacting these neurodegenerative and neuropsychiatric disorders, and hope to provide new insights on the therapeutic interventions against these disorders.

Selenium and selenoproteins in viral infection with potential relevance to COVID-19.

Selenium is a trace element essential to human health largely because of its incorporation into selenoproteins that have a wide range of protective functions. Selenium has an ongoing history of reducing the incidence and severity of various viral infections; for example, a German study found selenium status to be significantly higher in serum samples from surviving than non-surviving COVID-19 patients. Furthermore, a significant, positive, linear association was found between the cure rate of Chinese patients with COVID-19 and regional selenium status. Moreover, the cure rate continued to rise beyond the selenium intake required to optimise selenoproteins, suggesting that selenoproteins are probably not the whole story. Nonetheless, the significantly reduced expression of a number of selenoproteins, including those involved in controlling ER stress, along with increased expression of IL-6 in SARS-CoV-2 infected cells in culture suggests a potential link between reduced selenoprotein expression and COVID-19-associated inflammation. In this comprehensive review, we describe the history of selenium in viral infections and then go on to assess the potential benefits of adequate and even supra-nutritional selenium status. We discuss the indispensable function of the selenoproteins in coordinating a successful immune response and follow by reviewing cytokine excess, a key mediator of morbidity and mortality in COVID-19, and its relationship to selenium status. We comment on the fact that the synthetic redox-active selenium compound, ebselen, has been found experimentally to be a strong inhibitor of the main SARS-CoV-2 protease that enables viral maturation within the host. That finding suggests that redox-active selenium species formed at high selenium intake might hypothetically inhibit SARS-CoV-2 proteases. We consider the tactics that SARS-CoV-2 could employ to evade an adequate host response by interfering with the human selenoprotein system. Recognition of the myriad mechanisms by which selenium might potentially benefit COVID-19 patients provides a rationale for randomised, controlled trials of selenium supplementation in SARS-CoV-2 infection.

Selenoneine Ameliorates Hepatocellular Injury and Hepatic Steatosis in a Mouse Model of NAFLD.

Selenoneine is a novel organic selenium compound markedly found in the blood, muscles, and other tissues of fish. This study aimed to determine whether selenoneine attenuates hepatocellular injury and hepatic steatosis in a mouse model of non-alcoholic fatty liver disease (NAFLD). Mice lacking farnesoid X receptor (FXR) were used as a model for fatty liver disease, because they exhibited hepatomegaly, hepatic steatosis, and hepatic inflammation. Fxr-null mice were fed a 0.3 mg Se/kg selenoneine-containing diet for four months. Significant decreases in the levels of hepatomegaly, hepatic damage-associated diagnostic markers, hepatic triglycerides, and total bile acids were found in Fxr-null mice fed with a selenoneine-rich diet. Hepatic and blood clot total selenium concentrations were 1.7 and 1.9 times higher in the selenoneine group than in the control group. A marked accumulation of selenoneine was found in the liver and blood clot of the selenoneine group. The expression levels of oxidative stress-related genes (heme oxygenase 1 (Hmox1), glutathione S-transferase alpha 1 (Gsta1), and Gsta2), fatty acid synthetic genes (stearoyl CoA desaturase 1(Scd1) and acetyl-CoA carboxylase 1 (Acc1)), and selenoprotein (glutathione peroxidase 1 (Gpx1) and selenoprotein P (Selenop)) were significantly decreased in the selenoneine group. These results suggest that selenoneine attenuates hepatic steatosis and hepatocellular injury in an NAFLD mouse model.

Poly(selenoviologen)-Assembled Upconversion Nanoparticles for Low-Power Single-NIR Light-Triggered Synergistic Photodynamic and Photothermal Antibacterial Therapy.

The development of a highly effective photosensitizer (PS) that can be activated with a low-power single light is a pressing issue. Herein, we report a PS for synergistic photodynamic and photothermal therapy constructed through self-assembly of poly(selenoviologen) on the surface of core-shell NaYF4:Yb/Tm@NaYF4 upconversion nanoparticles. The hybrid UCNPs/PSeV PS showed strong ROS generation ability and high photothermal conversion efficiency (∼52.5%) under the mildest reported-to-date irradiation conditions (λ = 980 nm, 150 mW/cm2, 4 min), leading to a high efficiency in killing methicillin-resistant Staphylococcus aureus (MRSA) both in vitro and in vivo. Remarkably, after intravenous injection, the reported PS accumulated preferentially in deep MRSA-infected tissues and achieved an excellent therapeutic index. This PS design realizes a low-power single-NIR light-triggered synergistic phototherapy and provides a simple and versatile strategy to develop safe clinically translatable agents for efficient treatment of deep tissue bacterial inflammations.

Ebselen as template for stabilization of A4V mutant dimer for motor neuron disease therapy.

Mutations to the gene encoding superoxide dismutase-1 (SOD1) were the first genetic elements discovered that cause motor neuron disease (MND). These mutations result in compromised SOD1 dimer stability, with one of the severest and most common mutations Ala4Val (A4V) displaying a propensity to monomerise and aggregate leading to neuronal death. We show that the clinically used ebselen and related analogues promote thermal stability of A4V SOD1 when binding to Cys111 only. We have developed a A4V SOD1 differential scanning fluorescence-based assay on a C6S mutation background that is effective in assessing suitability of compounds. Crystallographic data show that the selenium atom of these compounds binds covalently to A4V SOD1 at Cys111 at the dimer interface, resulting in stabilisation. This together with chemical amenability for hit expansion of ebselen and its on-target SOD1 pharmacological chaperone activity holds remarkable promise for structure-based therapeutics for MND using ebselen as a template.

Biodegradable Bi2 O2 Se Quantum Dots for Photoacoustic Imaging-Guided Cancer Photothermal Therapy.

As new 2D layered nanomaterials, Bi2 O2 Se nanoplates have unique semiconducting properties that can benefit biomedical applications. Herein, a facile top-down approach for the synthesis of Bi2 O2 Se quantum dots (QDs) in a solution is described. The Bi2 O2 Se QDs with a size of 3.8 nm and thickness of 1.9 nm exhibit a high photothermal conversion coefficient of 35.7% and good photothermal stability. In vitro and in vivo assessments demonstrate that the Bi2 O2 Se QDs possess excellent photoacoustic (PA) performance and photothermal therapy (PTT) efficiency. After systemic administration, the Bi2 O2 Se QDs accumulate passively in tumors enabling efficient PA imaging of the entire tumors to facilitate imaging-guided PTT without obvious toxicity. Furthermore, the Bi2 O2 Se QDs which exhibit degradability in aqueous media not only have sufficient stability during in vivo circulation to perform the designed therapeutic functions, but also can be discharged harmlessly from the body afterward. The results reveal the great potential of Bi2 O2 Se QDs as a biodegradable multifunctional agent in medical applications.

A combination of selenium and polysaccharides: Promising therapeutic potential.

Currently, selenium and polysaccharide combinations can be identified as three forms: natural selenium polysaccharides, synthetic selenium polysaccharides and selenium nanoparticles decorated with polysaccharides. Previous studies have indicated that these three combinations generally show better bioactivities, including immunomodulation, anti-tumour, antioxidation and glucose regulation, than those of either selenium or polysaccharides alone. Although they have not yet been developed as new drugs for clinical trials, results from previous studies have already shown their therapeutic potential for the future. In this article, we summarize our current state of understanding of the sources, preparation methods, physicochemical characteristics and bioactivities of these combinations for the discovery of novel therapeutic drugs and adjuvants.

(p-ClPhSe)2 stabilizes metabolic function in a rat model of neuroendocrine obesity induced by monosodium glutamate.

Obesity is a chronic and complex medical condition characterized by excessive fat accumulation and its complications include metabolic syndrome, diabetes and chronic inflammation. The aim of this study was to expand the knowledge about p-chloro-diphenyl diselenide (p-ClPhSe)2 effects on enzymes and proteins involved in the metabolism of lipids and carbohydrates in a model of neuroendocrine obesity induced by MSG. Male Wistar rats were treated during the first ten postnatal days with MSG (4 g/kg, s.c.) and received (p-ClPhSe)2 (10 mg/kg, i.g.) from 90th to 97th postnatal day. The hypothalamic function, insulin resistance and other biochemical parameters were determined in the rat blood, liver and skeletal muscle. The MSG administration induced hypothalamic neurotoxicity accompanied by metabolic disorders, including obesity, a transient insulin resistance, and metabolic alterations, demonstrated in the blood, liver and skeletal muscle, and lipotoxicity, characterized in the liver and skeletal muscle. The metabolic disorders in the liver and skeletal muscle were accompanied by the decrease in AMPK phosphorylation and activation of Akt. (p-ClPhSe)2 restored most of metabolic parameters altered by MSG administration in rats. The hypothalamic neurotoxicity induced by MSG was accompanied by metabolic disorders in rats, which were regulated by (p-ClPhSe)2.

p,p'-Methoxyl-diphenyl diselenide-loaded polymeric nanocapsules as a novel approach to inflammatory pain treatment: Behavioral, biochemistry and molecular evidence.

The current study investigated the effect of organoselenium compound p,p'-methoxyl-diphenyl diselenide [(OMePhSe)2], free or incorporated into nanocapsules, on behavioral, biochemical and molecular alterations in an inflammatory pain model induced by complete Freund's adjuvant (CFA). Male Swiss mice received an intraplantar injection of CFA in the hindpaw and 24 h later they were treated via the intragastric route with a single (OMePhSe)2 administration, in its free form (dissolved in canola oil) or (OMePhSe)2 NC. The anti-hypernociceptive time- and dose-response curves were carried out using the von Frey hair test. Biochemical and histological parameters were determined in samples of injected paws and those of cerebral contralateral cortex were collected to determine immuno content of inflammatory proteins. Both (OMePhSe)2 forms reduced the hypernociception induced by CFA as well as attenuated the altered parameters of the inflammatory process in the paw (paw edema, myeloperoxidase and histological). However, the (OMePhSe)2 NC had a more prolonged anti-hypernociceptive action (7h) at a lower dose (10mg/kg) and superior effects on the paw alterations than the free compound form (4h and 25mg/kg). Furthermore, independent of the (OMePhSe)2 form, its administration decreased the MAPKs pathway activation (JNK;ERK1,2; p38) as well as iNOS, COX-2, Nf-κB and IL-1ß protein contents in the cerebral contralateral cortex that were increased by paw CFA injection. Therefore, (OMePhSe)2 NC had superior anti-inflammatory action, which possibly occurs by the inflammatory protein content modulation and also attenuates paw biochemical and histological inflammatory alterations induced by CFA injection.

Dietary Supplementation with Methylseleninic Acid Inhibits Mammary Tumorigenesis and Metastasis in Male MMTV-PyMT Mice.

Male breast cancer, which makes up approximately 1% of all breast cancers, is an aggressive disease with poor prognosis. We investigated the effects of dietary supplementation with selenium in the form of methylseleninic acid [(MSeA) 2.5 mg selenium/kg] on mammary tumorigenesis in male MMTV-PyMT mice. The mammary tumor latency was 14.6 weeks for the MSeA-fed group and 13.8 weeks for the controls fed the AIN93G diet (p < 0.05). Dietary supplementation with MSeA, versus the control, resulted in a 72% reduction in tumor progression, a 46% reduction in both final volume and weight of mammary tumors, and a 70% reduction in the number of lung metastases. Mammary tumorigenesis in MMTV-PyMT mice, versus non-tumor-bearing wild-type mice, resulted in significant increases in concentrations of plasminogen activator inhibitor-1, urokinase plasminogen activator, monocyte chemotactic protein-1, and vascular endothelial growth factor, but not aromatase and estrogen, in the plasma. Concentrations of all variables mentioned above in both plasma and mammary tumors were lower in MSeA-fed mice. Mammary tumorigenesis reduced plasma levels of adiponectin compared to non-tumor-bearing controls. Adiponectin concentrations in mammary tumors, but not in plasma, were higher in MSeA-fed mice than in controls. In summary, dietary supplementation with selenium in the form of MSeA inhibits mammary tumorigenesis and its pulmonary metastasis in male MMTV-PyMT mice.

Effectiveness of bis(phenylimidazoselenazolyl) diselenide on a mouse model of inflammatory nociception.

The injection of complete Freund's adjuvant (CFA) in the hindpaw of rodents induces tissue inflammation and nociceptive hypersensitivity. In addition, it has been reported that organoselenium compounds have antinociceptive properties in animal models. The purpose of this study was to investigate the potential antinociceptive effect of bis(phenylimidazoselenazolyl) diselenide (BPIS) in the inflammatory nociception model in mice and its possible mechanism of action. C57BL/6 mice received CFA intraplantar in right hindpaw and the inflammatory response was verified 24h after injection as well as the antinociceptive effect of BPIS. The CFA-induced mechanical allodynia was reversed by BPIS treatment (1mg/kg, p.o.) observed through the von Frey hair test. Additionally, L-arginine (600mg/kg; i.p.), administered before BPIS treatment, blocked its antinociceptive effect. Regarding myeloperoxidase activity, NOx and 3-nitrotyrosine levels, BPIS administration did not reverse alterations observed in the paw of animals injected with CFA. BPIS reversed the increase in spinal NOx content induced by CFA. In the spinal cord, it was also found that CFA induced an increase in malondialdehyde content and a decrease in glutamate uptake, and these alterations were reversed by BPIS. Moreover, BPIS treatment induced an increase in non-protein thiol levels in spinal cord of animals that received CFA injection. No alterations were found in glutathione peroxidase, reductase and S-transferase activities of experimental groups. The obtained data reinforce the relevance of BPIS as an antinociceptive agent as well as highlight the importance of the nitric oxide pathway in the spinal cord and its antioxidant potential for its mechanism of action.

Chemical Speciation of Selenium and Mercury as Determinant of Their Neurotoxicity.

The antagonism of mercury toxicity by selenium has been well documented. Mercury is a toxic metal, widespread in the environment. The main target organs (kidneys, lungs, or brain) of mercury vary depending on its chemical forms (inorganic or organic). Selenium is a semimetal essential to mammalian life as part of the amino acid selenocysteine, which is required to the synthesis of the selenoproteins. This chapter has the aim of disclosing the role of selenide or hydrogen selenide (Se-2 or HSe-) as central metabolite of selenium and as an important antidote of the electrophilic mercury forms (particularly, Hg2+ and MeHg). Emphasis will be centered on the neurotoxicity of electrophile forms of mercury and selenium. The controversial participation of electrophile mercury and selenium forms in the development of some neurodegenerative disease will be briefly presented. The potential pharmacological use of organoseleno compounds (Ebselen and diphenyl diselenide) in the treatment of mercury poisoning will be considered. The central role of thiol (-SH) and selenol (-SeH) groups as the generic targets of electrophile mercury forms and the need of new in silico tools to guide the future biological researches will be commented.

Myo-inositol and selenium reduce the risk of developing overt hypothyroidism in patients with autoimmune thyroiditis.

OBJECTIVE: The beneficial effects obtained by myo-inositol in association with seleno-methionine in patients affected by subclinical hypothyroidism have been recently demonstrated. Here, we evaluate the immune-modulating effect of myo-inositol in association with seleno-methionine in patients with euthyroid autoimmune thyroiditis (AT). PATIENTS AND METHODS: Twenty-one consecutive Caucasian patients with newly diagnosed euthyroid chronic AT were evaluated. All subjects were treated with myo-inositol in association with selenium (600 mg/83 mg) tablets, twice per day, for six months. A complete thyroid assessment was done before the treatment, and after six months. RESULTS: After the treatment thyroid-stimulating hormone (TSH) levels significantly declined with respect to basal values, overall in patients with an initial TSH value in the high normal range (2.1

Bis(phenylimidazoselenazolyl) diselenide elicits antinociceptive effect by modulating myeloperoxidase activity, NOx and NFkB levels in the collagen-induced arthritis mouse model.

Bis(phenylimidazoselenazolyl) diselenide (BPIS) is an organoselenium with acute antinociceptive and antioxidant properties. OBJECTIVES: The aim of this study was to investigate BPIS effect on a collagen-induced arthritis (CIA) model in mice. METHODS: Protocol of exposure consisted in arthritis induction by chicken collagen type II on day 0 with booster injection on day 21. On day 60 after collagen injection, incidence of mechanic allodynia (Von Frey test) or thermal hyperalgesia (hot plate test) was evaluated. During following 5 days, mice were treated with BPIS (0.1-1 mg/kg; p.o.; daily) or vehicle. On day 65, mice were killed, and paws and spinal cord were removed for analyses. KEY FINDINGS: Mice submitted to CIA model developed both mechanical allodynia and thermal hyperalgesia, which were reversed by BPIS at the highest dose. In paw, BPIS reversed the increase in myeloperoxidase activity in the CIA group. In the spinal cord, BPIS decreased NOx and NFkB levels increased in the CIA group. BPIS-treated animals had lower cyclooxygenase-2 levels in the spinal cord. CONCLUSIONS: The myeloperoxidase activity in paw and NOx and NFkB levels in spinal cord are related to antinociceptive properties of BPIS in CIA model.

Progress does not just come in giant leaps: adapting techniques for the study of inflammation to novel applications.

INTRODUCTION: Discussion of the relevance of suitable experimental models for the effective translation of drug effects to clinical inflammatory diseases has a long history. Much emphasis is placed these days on genetically transformed mice, which may have developmental drawbacks. But are established models redundant? FINDINGS: Drawn from personal experience, examples are provided of the success of tinkering with technology in the context of inflammation. These include the use of specific dietary deficiency conditions, the development of new applications for established drugs and the introduction of a variety of readouts to assess outcome in studies on established disease models. Such approaches have been used to demonstrate inflammation-modulating effects of prostaglandin E, in the development of ebselen, for the introduction of immunomodulatory macrolide drugs and in new approaches to the therapy of multiple sclerosis. CONCLUSION: Fine tuning of experimental approaches and evaluation technologies can often still provide innovative, clinically relevant insights into the potential beneficial effects of drugs and pharmacological agents.