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1.
Int J Nanomedicine ; 17: 3043-3054, 2022.
Article in English | MEDLINE | ID: covidwho-1951780

ABSTRACT

Introduction: Porcine reproductive and respiratory syndrome virus (PRRSV) is a highly prevalent and endemic swine pathogen that causes significant economic losses to the global swine industry. Selenium nanoparticles (SeNPs) have attracted increasing attention in the biomedical field, given their antiviral effects. This study aimed to investigate the inhibitory effect of chitosan-coated SeNPs (CS-SeNPs) on PRRSV replication. Methods: In this study, CS-SeNPs were synthesized by chemical reduction and characterized by assessing the morphology, size distribution, zeta potential, and element composition. Marc-145 cells were infected with r-PRRSV-EGFP (0.1 MOI) and inoculated with CS-SeNPs (10 µM). Subsequently, the concentrations of hydrogen peroxide (H2O2) and glutathione (GSH), and glutathione peroxidase (GSH-Px) activity were measured using specific commercial assay kits. ORF5 RNA expression, viral titer, and nucleocapsid (N) protein expression were assessed using qRT-PCR, TCID50, and Western blot. ROS generation, apoptosis rates, and JNK /caspase-3/PARP protein expression were evaluated using dihydroethidium staining, flow cytometry, and Western blot. Results: The results showed that CS-SeNPs treatment significantly suppressed oxidative stress induced by r-PRRSV-EGFP infection by increasing GSH-Px activity, promoting GSH production, and inhibiting H2O2 synthesis. CS-SeNPs treatment significantly inhibited ORF5 gene expression, viral titers, and N protein of r-PRRSV-EGFP at 24 and 48 hours post-infection (hpi) in Marc-145 cells. The increase in apoptosis rates induced by r-PRRSV-EGFP infection was significantly decreased by CS-SeNPs inoculation through inhibiting ROS generation, JNK phosphorylation levels, and cleavage of caspase-3 and PARP mainly at 48 hpi. Conclusion: These results demonstrated that CS-SeNPs suppress PRRSV-induced apoptosis in Marc-145 cells via the ROS/JNK signaling pathway, thereby inhibiting PRRSV replication, which suggested the potential antiviral activity of CS-SeNPs that deserves further investigation for clinical applications.


Subject(s)
Chitosan , Nanoparticles , Porcine respiratory and reproductive syndrome virus , Selenium , Animals , Antioxidants/pharmacology , Antiviral Agents/pharmacology , Apoptosis , Caspase 3/metabolism , Chitosan/chemistry , Chitosan/pharmacology , Hydrogen Peroxide/pharmacology , Nanoparticles/chemistry , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Porcine respiratory and reproductive syndrome virus/metabolism , Reactive Oxygen Species/metabolism , Selenium/chemistry , Selenium/pharmacology , Swine , Virus Replication
2.
Int J Mol Sci ; 23(4)2022 Feb 17.
Article in English | MEDLINE | ID: covidwho-1701976

ABSTRACT

Selenium has been extensively evaluated clinically as a chemopreventive agent with variable results depending on the type and dose of selenium used. Selenium species are now being therapeutically evaluated as modulators of drug responses rather than as directly cytotoxic agents. In addition, recent data suggest an association between selenium base-line levels in blood and survival of patients with COVID-19. The major focus of this mini review was to summarize: the pathways of selenium metabolism; the results of selenium-based chemopreventive clinical trials; the potential for using selenium metabolites as therapeutic modulators of drug responses in cancer (clear-cell renal-cell carcinoma (ccRCC) in particular); and selenium usage alone or in combination with vaccines in the treatment of patients with COVID-19. Critical therapeutic targets and the potential role of different selenium species, doses, and schedules are discussed.


Subject(s)
COVID-19/drug therapy , Neoplasms/drug therapy , Selenium/therapeutic use , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , COVID-19/virology , DNA Repair/drug effects , Drug Resistance, Neoplasm/drug effects , Humans , NF-E2-Related Factor 2/chemistry , NF-E2-Related Factor 2/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification , Selenium/chemistry , Selenium/metabolism , Selenium/pharmacology
3.
Arch Toxicol ; 95(4): 1179-1226, 2021 04.
Article in English | MEDLINE | ID: covidwho-1384375

ABSTRACT

Here, we addressed the pharmacology and toxicology of synthetic organoselenium compounds and some naturally occurring organoselenium amino acids. The use of selenium as a tool in organic synthesis and as a pharmacological agent goes back to the middle of the nineteenth and the beginning of the twentieth centuries. The rediscovery of ebselen and its investigation in clinical trials have motivated the search for new organoselenium molecules with pharmacological properties. Although ebselen and diselenides have some overlapping pharmacological properties, their molecular targets are not identical. However, they have similar anti-inflammatory and antioxidant activities, possibly, via activation of transcription factors, regulating the expression of antioxidant genes. In short, our knowledge about the pharmacological properties of simple organoselenium compounds is still elusive. However, contrary to our early expectations that they could imitate selenoproteins, organoselenium compounds seem to have non-specific modulatory activation of antioxidant pathways and specific inhibitory effects in some thiol-containing proteins. The thiol-oxidizing properties of organoselenium compounds are considered the molecular basis of their chronic toxicity; however, the acute use of organoselenium compounds as inhibitors of specific thiol-containing enzymes can be of therapeutic significance. In summary, the outcomes of the clinical trials of ebselen as a mimetic of lithium or as an inhibitor of SARS-CoV-2 proteases will be important to the field of organoselenium synthesis. The development of computational techniques that could predict rational modifications in the structure of organoselenium compounds to increase their specificity is required to construct a library of thiol-modifying agents with selectivity toward specific target proteins.


Subject(s)
Organoselenium Compounds/pharmacology , Organoselenium Compounds/toxicity , Amino Acids/chemistry , Animals , Azoles , Humans , Isoindoles , Molecular Structure , Selenium/chemistry , Selenium/physiology , Selenoproteins/chemistry , Sulfhydryl Compounds/chemistry
4.
Molecules ; 26(14)2021 Jul 12.
Article in English | MEDLINE | ID: covidwho-1323315

ABSTRACT

Ebselen is the leader of selenorganic compounds, and starting from its identification as mimetic of the key antioxidant enzyme glutathione peroxidase, several papers have appeared in literature claiming its biological activities. It was the subject of several clinical trials and it is currently in clinical evaluation for the treatment of COVID-19 patients. Given our interest in the synthesis and pharmacological evaluation of selenorganic derivatives with this review, we aimed to collect all the papers focused on the biological evaluation of ebselen and its close analogues, covering the timeline between 2016 and most of 2021. Our analysis evidences that, even if it lacks specificity when tested in vitro, being able to bind to every reactive cysteine, it proved to be always well tolerated in vivo, exerting no sign of toxicity whatever the administered doses. Besides, looking at the literature, we realized that no review article dealing with the synthetic approaches for the construction of the benzo[d][1,2]-selenazol-3(2H)-one scaffold is available; thus, a section of the present review article is completely devoted to this specific topic.


Subject(s)
Azoles/chemistry , Azoles/chemical synthesis , Azoles/pharmacology , Organoselenium Compounds/chemistry , Organoselenium Compounds/chemical synthesis , Organoselenium Compounds/pharmacology , Animals , Anti-Infective Agents/pharmacology , Antioxidants/pharmacology , Antiviral Agents/pharmacology , Biomimetics/methods , Cyclooxygenase Inhibitors/pharmacology , Glutathione Peroxidase/metabolism , Glutathione Peroxidase/pharmacology , Humans , Isoindoles , Molecular Structure , Neuroprotective Agents/pharmacology , Selenium/chemistry , Selenoproteins/chemical synthesis , Selenoproteins/pharmacology
5.
J Mater Chem B ; 9(28): 5636-5644, 2021 07 21.
Article in English | MEDLINE | ID: covidwho-1291040

ABSTRACT

DNA polymerization is of high specificity in vivo. However, its specificity is much lower in vitro, which limits advanced applications of DNA polymerization in ultrasensitive nucleic acid detection. Herein, we report a unique mechanism of single selenium-atom modified dNTP (dNTPαSe) to enhance polymerization specificity. We have found that both dNTPαSe (approximately 660 fold) and Se-DNA (approximately 2.8 fold) have lower binding affinity to DNA polymerase than canonical ones, and the Se-DNA duplex has much lower melting-temperature (Tm) than the corresponding canonical DNA duplex. The reduced affinity and Tm can destabilize the substrate-primer-template-enzyme assembly, thereby largely slowing down the mismatch of DNA polymerization and enhancing the amplification specificity and in turn detection sensitivity. Furthermore, the Se-strategy enables us to develop the selenium enhanced specific isothermal amplification (SEA) for nucleic acid detection with high specificity and sensitivity (up to detection of single-digit copies), allowing convenient detection of clinical HPV and COVID-19 viruses in the low-copy number. Clearly, we have discovered the exciting mechanism for enhancing DNA polymerization accuracy, amplification specificity and detection sensitivity by SEA, up to two orders of magnitude higher.


Subject(s)
DNA, Viral/analysis , Human papillomavirus 16/isolation & purification , Phosphates/chemistry , SARS-CoV-2/isolation & purification , Selenium/chemistry , DNA, Viral/biosynthesis , Human papillomavirus 16/metabolism , Humans , Nucleic Acid Amplification Techniques , Polymerization , SARS-CoV-2/metabolism , Temperature
6.
Int J Mol Sci ; 22(13)2021 Jun 30.
Article in English | MEDLINE | ID: covidwho-1288904

ABSTRACT

The development of new antiviral drugs against SARS-CoV-2 is a valuable long-term strategy to protect the global population from the COVID-19 pandemic complementary to the vaccination. Considering this, the viral main protease (Mpro) is among the most promising molecular targets in light of its importance during the viral replication cycle. The natural flavonoid quercetin 1 has been recently reported to be a potent Mpro inhibitor in vitro, and we explored the effect produced by the introduction of organoselenium functionalities in this scaffold. In particular, we report here a new synthetic method to prepare previously inaccessible C-8 seleno-quercetin derivatives. By screening a small library of flavonols and flavone derivatives, we observed that some compounds inhibit the protease activity in vitro. For the first time, we demonstrate that quercetin (1) and 8-(p-tolylselenyl)quercetin (2d) block SARS-CoV-2 replication in infected cells at non-toxic concentrations, with an IC50 of 192 µM and 8 µM, respectively. Based on docking experiments driven by experimental evidence, we propose a non-covalent mechanism for Mpro inhibition in which a hydrogen bond between the selenium atom and Gln189 residue in the catalytic pocket could explain the higher Mpro activity of 2d and, as a result, its better antiviral profile.


Subject(s)
Antiviral Agents/chemistry , Quercetin/chemistry , SARS-CoV-2/metabolism , Selenium/chemistry , Viral Matrix Proteins/antagonists & inhibitors , Animals , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Binding Sites , COVID-19/pathology , COVID-19/virology , Catalytic Domain , Chlorocebus aethiops , Humans , Hydrogen Bonding , Molecular Docking Simulation , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacology , Quercetin/metabolism , Quercetin/pharmacology , SARS-CoV-2/isolation & purification , Selenium/metabolism , Vero Cells , Viral Matrix Proteins/metabolism , Virus Replication/drug effects
7.
Chem Commun (Camb) ; 57(44): 5434-5437, 2021 Jun 01.
Article in English | MEDLINE | ID: covidwho-1216471

ABSTRACT

Nucleobase mismatches can jeopardize DNA polymerization specificity, causing mutations and errors in DNA replication and detection. Herein we report the first synthesis of novel 2-Se-thymidine triphosphate (SeTTP), describe the single-selenium atom-specific modification strategy (SAM) against T/G mismatches, and demonstrate SAM-assisted polymerization and detection with much higher specificity and sensitivity. SAM can effectively suppress the formation of non-specific products in DNA polymerization and detection. Thus, SAM enhances the specificity of DNA synthesis by approximately 10 000 fold, and in turn, it allows the detection of clinical COVID-19 viral RNA in low copy numbers (single-digit copies), while the conventional RT-qPCR does not.


Subject(s)
DNA/chemistry , Polymerization , Selenium/chemistry , Thymine/chemistry
8.
Med Hypotheses ; 147: 110475, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-988867

ABSTRACT

Coagulopathy has recently been recognized as a recurring complication of COVID-19, most typically associated with critical illness. There are epidemiological, mechanistic and transcriptomic evidence that link Selenium with SARS-CoV-2's intracellular latency. Taking into consideration the vital role of selenoproteins in maintaining an adequate immune response, endothelial homeostasis and a non-prothrombotic platelet activation status, we propose that impairment in selenocysteine synthesis, via perturbations in the aforementioned physiological functions, potentially constitutes a mechanism of coagulopathy in COVID 19 patients other than those developed in critical illness.


Subject(s)
Blood Coagulation Disorders/complications , COVID-19/complications , SARS-CoV-2/pathogenicity , Selenocysteine/biosynthesis , Blood Coagulation Disorders/virology , Blood Platelets/metabolism , Critical Illness , Endothelium, Vascular/metabolism , Homeostasis , Humans , Immune System , Inflammation , Models, Theoretical , Oxidative Stress , Platelet Activation , Selenium/chemistry , Selenocysteine/chemistry , Transcriptome
9.
Lab Chip ; 20(22): 4255-4261, 2020 11 10.
Article in English | MEDLINE | ID: covidwho-872742

ABSTRACT

COVID-19 is a widespread and highly contagious disease in the human population. COVID-19 is caused by SARS-CoV-2 infection. There is still a great demand for point-of-care tests for detection, epidemic prevention and epidemiological investigation, both now and after the epidemic. We present a lateral flow immunoassay kit based on a selenium nanoparticle-modified SARS-CoV-2 nucleoprotein, which detects anti-SARS-CoV-2 IgM and anti-SARS-CoV-2 IgG in human serum, and the results can be read by the naked eye in 10 minutes. We expressed and purified the SARS-CoV-2 nucleoprotein in HEK293 cells, with a purity of 98.14% and a concentration of 5 mg mL-1. Selenium nanoparticles were synthesized by l-ascorbic acid reduction of seleninic acid at room temperature. After conjugation with the nucleoprotein, a lateral flow kit was successfully prepared. The IgM and IgG detection limits of the lateral flow kit reached 20 ng mL-1 and 5 ng mL-1, respectively, in human serum. A clinical study sample comprising 90 COVID-19-diagnosed patients and 263 non-infected controls was used to demonstrate a sensitivity and specificity of 93.33% and 97.34%, respectively, based on RT-PCR and clinical results. No cross-reactions with rheumatoid factor and positive serum for anti-nuclear antibodies, influenza A, and influenza B were observed. Moreover, the lateral flow kit remained stable after storage for 30 days at 37 °C. Our results demonstrate that the selenium nanoparticle lateral flow kit can conveniently, rapidly, and sensitively detect anti-SARS-CoV-2 IgM and IgG in human serum and blood; it can also be suitable for the epidemiological investigation of COVID-19.


Subject(s)
Antibodies, Viral/blood , Betacoronavirus/immunology , Clinical Laboratory Techniques , Coronavirus Infections/blood , Immunoglobulin G/blood , Immunoglobulin M/blood , Pneumonia, Viral/blood , Antibodies, Viral/immunology , COVID-19 , COVID-19 Testing , Coronavirus Infections/diagnosis , Coronavirus Infections/immunology , Equipment Design , HEK293 Cells , Humans , Immunoglobulin G/immunology , Immunoglobulin M/immunology , Lab-On-A-Chip Devices , Limit of Detection , Nanoparticles/chemistry , Pandemics , Pneumonia, Viral/immunology , Point-of-Care Testing , Reagent Strips/analysis , SARS-CoV-2 , Selenium/chemistry
10.
Med Hypotheses ; 143: 109878, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-343576

ABSTRACT

Selenium (Se) is a ubiquitous element akin to sulfur (S) existing in the Earth crust in various organic and inorganic forms. Selenium concentration varies greatly depending on the geographic area. Consequently, the content of selenium in food products is also variable. It is known that low Se is associated with increased incidence of cancer and heart diseases. Therefore, it is advisable to supplement diet with this element albeit in a proper form. Although blood increased concentrations of Se can be achieved with various pharmacological preparations, only one chemical form (sodium selenite) can offer a true protection. Sodium selenite, but not selenate, can oxidize thiol groups in the virus protein disulfide isomerase rendering it unable to penetrate the healthy cell membrane. In this way selenite inhibits the entrance of viruses into the healthy cells and abolish their infectivity. Therefore, this simple chemical compound can potentially be used in the recent battle against coronavirus epidemic.


Subject(s)
Antiviral Agents/therapeutic use , Coronavirus Infections/prevention & control , Dietary Supplements , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Selenium/chemistry , Sodium Selenite/therapeutic use , Antioxidants , Betacoronavirus , Blood Coagulation/drug effects , COVID-19 , Hemostasis , Humans , Protein Disulfide-Isomerases/metabolism , SARS-CoV-2 , Sulfhydryl Compounds
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