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1.
Pharmacol Res ; 187: 106624, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36563868

RESUMO

Selenium has good antitumor effects in vitro, but the hypoxic microenvironment in solid tumors makes its clinical efficacy unsatisfactory. We hypothesized that the combination with oxygen therapy might improve the treatment efficacy of selenium in hypoxic tumors through the changes of redox environment. In this work, two selenium compounds, Na2SeO3 and CysSeSeCys, were selected to interrogate their therapeutic effects on hepatocellular carcinoma (HCC) under different oxygen levels. In tumor-bearing mice, both selenium compounds significantly inhibited the tumor growth, and combined with oxygen therapy further reduced the tumor volume about 50 %. In vitro HepG2 cell experiments, selenium induced autophagy and delayed apoptosis under hypoxia (1 % O2), while inhibited autophagy and accelerated apoptosis under hyperoxia (60 % O2). We found that, in contrast to hypoxia, the hyperoxic environment facilitated the H2Se, produced by the selenium metabolism in cells, to be rapidly oxidized to generate H2O2, leading to inhibit the expression level of Nrf2 and to increase that of phosphorylation of p38 and MKK4, resulting in inhibiting autophagy and accelerating apoptosis. Once the Nrf2 gene was knocked down, selenium compounds combined with hyperoxia treatment would further activate the MAPK signaling pathway and further increase apoptosis. These findings highlight oxygen can significantly enhance the anti-HCC effect of selenium compounds through regulating the Nrf2 and MAPK signaling pathways, thus providing novel therapeutic strategy for the hypoxic tumors and pave the way for the application of selenium in clinical treatment.


Assuntos
Carcinoma Hepatocelular , Hiperóxia , Neoplasias Hepáticas , Compostos de Selênio , Selênio , Animais , Camundongos , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Selênio/farmacologia , Selênio/uso terapêutico , Compostos de Selênio/metabolismo , Compostos de Selênio/farmacologia , Compostos de Selênio/uso terapêutico , Peróxido de Hidrogênio/farmacologia , Transdução de Sinais , Apoptose , Hipóxia , Oxigênio , Microambiente Tumoral
2.
Bioorg Chem ; 138: 106624, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37295238

RESUMO

Nowadays, leishmaniasis is still treated with outdated drugs that present several obstacles related to their high toxicity, long duration, parenteral administration, high costs and drug resistance. Therefore, there is an urgent demand for safer and more effective novel drugs. Previous studies indicated that selenium compounds are promising derivatives for innovative therapy in leishmaniasis treatment. With this background, a new library of 20 selenocyanate and diselenide derivatives were designed based on structural features present in the leishmanicidal drug miltefosine. Compounds were initially screened against promastigotes of L. major and L. infantum and their cytotoxicity was evaluated in THP-1 cells. Compounds B8 and B9 were the most potent and less cytotoxic and were further screened for the intracellular back transformation assay. The results obtained revealed that B8 and B9 showed EC50 values of 7.7 µM and 5.7 µM, respectively, in L. major amastigotes, while they presented values of 6.0 µM and 7.4 µM, respectively, against L. infantum amastigotes. Furthermore, they exerted high selectivity (60 < SI > 70) towards bone marrow-derived macrophages. Finally, these compounds exhibited higher TryR inhibitory activity than mepacrine (IC50 7.6 and 9.2 µM, respectively), and induced nitric oxide (NO) and reactive oxygen species (ROS) production in macrophages. These results suggest that the compounds B8 and B9 could not only exert a direct leishmanicidal activity against the parasite but also present an indirect action by activating the microbicidal arsenal of the macrophage. Overall, these new generation of diselenides could constitute promising leishmanicidal drug candidates for further studies.


Assuntos
Antiprotozoários , Leishmaniose , Compostos de Selênio , Animais , Camundongos , Antiprotozoários/química , Macrófagos , Leishmaniose/tratamento farmacológico , Compostos de Selênio/farmacologia , Camundongos Endogâmicos BALB C
3.
Georgian Med News ; (335): 54-59, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37042589

RESUMO

The purpose of this study was to analyze the effects of cadmium toxicity on rat embryogenesis when exposed to other heavy metal citrates. Despite the variety of scientific publications discussing the influence of cadmium on mammalian postnatal development, the effect of this metal on embryogenesis has not yet been sufficiently studied. In this experimental study, cadmium chloride was administered to experimental pregnant female Wistar rats at a daily dose of 1.0 mg/kg. Rats were allocated at random into groups receiving either cadmium chloride alone or additional zinc citrate, cerium citrate, or nanocomposite (based on iodine, sulfur, and selenium citrate). The control group received distilled water at an equivalent volume. In each group, operational intervention occurred at the 13th and 20th day of gestation to assess numbers of live fetuses, corpora lutea, pre-implantation losses, post-implantation losses, and total implantation losses. When cadmium chloride alone was administered, a pronounced embryotoxic effect was observed, manifested as a significant decrease in the number of live fetuses. Experimental groups which received cadmium chloride with zinc citrate, cerium citrate, or nanocomposite had an increased number of live fetuses and corpora lutea, as well as a decreased number of implantation losses, compared to the group which only received cadmium chloride. Each combination of cerium, zinc, and selenium nanocomposite citrates demonstrated a compensatory effect on all measures of embryogenesis impacted by cadmium embryotoxicity. Thus, administration of the citrates of cerium, zinc, and selenium nanocomposite reduces cadmium embryotoxicity and its accumulation in the body.


Assuntos
Cloreto de Cádmio , Citratos , Desenvolvimento Embrionário , Metais Pesados , Animais , Feminino , Gravidez , Ratos , Cloreto de Cádmio/toxicidade , Citratos/farmacologia , Implantação do Embrião/efeitos dos fármacos , Mamíferos , Ratos Wistar , Doença Crônica , Desenvolvimento Embrionário/efeitos dos fármacos , Metais Pesados/farmacologia , Metais Pesados/toxicidade , Cério/farmacologia , Nanocompostos , Compostos de Zinco/farmacologia , Compostos de Selênio/farmacologia , Compostos de Iodo/farmacologia , Compostos de Enxofre/farmacologia
4.
Bioconjug Chem ; 33(9): 1602-1608, 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36018225

RESUMO

Selenium plays an important role in the biological system and can be used to treat various types of diseases. However, the current selenium delivery systems face the problems of low activity of released Se-containing compounds or nonspecific toxicity of reactive organic selenium donors in living systems. In response to these problems, we constructed a reactive organic selenium delivery platform by the activation of HOCl. Compared with prodrugs without activation capability, the hypochloroselenoite derivatives released from the present platform after activation displayed higher reactivity and could react with various nucleophiles to participate in specific life processes. Taking the selected compound (DHU-Se1) as an example, we found that it could alleviate the process of inflammation by blocking the polarization of macrophages from M0 to M1. Therefore, the development of this system is of great significance for expanding the application of selenium-containing compounds and treating related diseases.


Assuntos
Pró-Fármacos , Compostos de Selênio , Selênio , Humanos , Inflamação/tratamento farmacológico , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Selênio/farmacologia , Compostos de Selênio/farmacologia
5.
Nanomedicine ; 42: 102539, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35183761

RESUMO

The biological applicability of nanomaterials has been limited due to cytotoxicity. Studies have described the effects of nanomaterials on different tissues and cell types, but their actions on immune cells are less elucidated. This study describes unprecedented in vitro and in vivo antioxidant activities of cadmium selenide magic-sized quantum dots (CdSe MSQDs) with implications on rheumatoid arthritis. While the generation of ROS induced by nanomaterials is linked to cytotoxicity, we found that CdSe MSQDs reduced ROS production by neutrophils and macrophages following opsonized-zymosan stimuli, and we did not find cytotoxic effects. Interestingly, inherent antioxidant properties of CdSe MSQDs were confirmed through DPPH, FRAP, and ORAC assays. Furthermore, CdSe MSQDs reduced ROS levels generated by infiltrating leukocytes into joints in experimental model of rheumatoid arthritis. Briefly, we describe a novel application of CdSe MSQDs in modulating the inflammatory response in experimental rheumatoid arthritis through an unexpected antioxidant activity.


Assuntos
Artrite Reumatoide , Compostos de Cádmio , Pontos Quânticos , Compostos de Selênio , Antioxidantes/farmacologia , Artrite Reumatoide/tratamento farmacológico , Compostos de Cádmio/química , Compostos de Cádmio/farmacologia , Humanos , Macrófagos , Neutrófilos , Pontos Quânticos/química , Espécies Reativas de Oxigênio , Compostos de Selênio/química , Compostos de Selênio/farmacologia
6.
Int J Mol Sci ; 23(4)2022 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-35216476

RESUMO

The review presents the latest data on the role of selenium-containing agents in the regulation of diseases of the immune system. We mainly considered the contributions of selenium-containing compounds such as sodium selenite, methylseleninic acid, selenomethionine, and methylselenocysteine, as well as selenoproteins and selenium nanoparticles in the regulation of defense mechanisms against various viral infections, including coronavirus infection (COVID-19). A complete description of the available data for each of the above selenium compounds and the mechanisms underlying the regulation of immune processes with the active participation of these selenium agents, as well as their therapeutic and pharmacological potential, is presented. The main purpose of this review is to systematize the available information, supplemented by data obtained in our laboratory, on the important role of selenium compounds in all of these processes. In addition, the presented information makes it possible to understand the key differences in the mechanisms of action of these compounds, depending on their chemical and physical properties, which is important for obtaining a holistic picture and prospects for creating drugs based on them.


Assuntos
Antivirais/farmacologia , Tratamento Farmacológico da COVID-19 , Agentes de Imunomodulação/farmacologia , Compostos de Selênio/farmacologia , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antivirais/química , Humanos , Sistema Imunitário/efeitos dos fármacos , Agentes de Imunomodulação/química , Compostos Organosselênicos/imunologia , Compostos Organosselênicos/farmacocinética , Compostos Organosselênicos/farmacologia , Compostos de Selênio/imunologia , Selenocisteína/análogos & derivados , Selenocisteína/imunologia , Selenocisteína/farmacologia , Selenometionina/farmacocinética , Selenometionina/farmacologia , Selenito de Sódio/farmacologia
7.
Molecules ; 27(3)2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-35164247

RESUMO

The reactivity of thiophene in Diels-Alder reactions is investigated with different maleimide derivatives. In this paper, we have synthesized for the first time the Diels-Alder adducts of thiophene at room temperature and atmospheric pressure. Maleimido-thiophene adducts were promoted by AlCl3. The effects of solvent, time, temperature and the use of different Lewis acids were studied, showing dramatic effects for solvent and Lewis acid. Furthermore, the catalysis with AlCl3 is highly stereoselective, preferably providing the exo form of the adduct. Additionally, we also discovered the ability of AlCl3 to catalyze the arylation of maleimides to yield 3-aryl succinimides in a straightforward manner following a Friedel-Crafts-type addition. The inclusion of a selenocyanate group contributes to the cytotoxic activity of the adduct. This derivatization (from compound 7 to compound 15) results in an average GI50 value of 1.98 µM in the DTP (NCI-60) cell panel, resulting in being especially active in renal cancer cells.


Assuntos
Antineoplásicos/farmacologia , Cianatos/farmacologia , Compostos de Selênio/farmacologia , Tiofenos/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cianatos/química , Reação de Cicloadição , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ácidos de Lewis/química , Compostos de Selênio/química , Tiofenos/farmacologia
8.
Angew Chem Int Ed Engl ; 61(45): e202210754, 2022 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-36104298

RESUMO

Arylthioamides have been frequently employed to assess the chemical biology and pharmacology of hydrogen sulfide (H2 S). From this class of donors, however, extremely low H2 S releasing efficiencies have been reported and proper mechanistic studies have been omitted. Consequently, millimolar concentrations of arylthioamides are required to liberate just trace amounts of H2 S, and via an unidentified mechanistic pathway, which obfuscates the interpretation of any biological activity that stems from their use. Herein, we report that H2 S release from this valuable class of donors can be markedly enhanced through intramolecular nucleophilic assistance. Specifically, we demonstrate that both disulfide- and diselenide-linked thioamides are responsive to biologically relevant concentrations of glutathione and release two molar equivalents of H2 S via an intramolecular cyclization that significantly augments their rate and efficiency of sulfide delivery in both buffer and live human cells.


Assuntos
Sulfeto de Hidrogênio , Compostos de Selênio , Humanos , Sulfeto de Hidrogênio/química , Compostos de Sulfidrila/química , Compostos de Selênio/farmacologia , Dissulfetos/química
9.
Int J Obes (Lond) ; 45(1): 122-129, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32467614

RESUMO

BACKGROUND/OBJECTIVES: Polymethoxyselenoflavone (PMSF) is a compound that substitutes the oxygen atom in a flavonoid with selenium. This study aimed to investigate the effects of PMSFs on lipid metabolism in adipocytes and their anti-obesity potential. SUBJECTS/METHODS: To test lipolytic and thermogenic effects of the compounds in vitro, adipocytes differentiated from immortalized pre-brown adipocyte progenitors and pre-white adipocyte cell lines were treated with 19 PMSFs. The expression levels of brown adipocyte markers and genes related to mitochondrial metabolism were analyzed by qPCR and western blot. In vivo anti-obesity effect was investigated using diet-induced obesity mouse models and adipocyte-specific ATGL knockout mice. RESULTS: The qPCR analysis identified 2-(3,4-dimethoxyphenyl)-4H-selenochromen-4-one (DMPSC) as the most potent brown adipogenic candidate among the 19 compounds tested in this study. DMPSC treatment significantly increased the mitochondrial content and oxidative metabolism in adipocytes in vitro. Mechanistically, DMPSC treatment increased lipolysis through activation of PKA downstream signaling. Consistently, the in vivo treatment of DMPSC increased energy consumption, reduced body weight, and improved glucose tolerance in mice fed with high-fat diets. Moreover, DMPSC treatment increased brown adipocyte marker expression and mitochondrial content in adipose tissue of mice. The anti-obesity effects were absent in adipocyte-specific ATGL knockout mice, indicating that the DMPSC effect is mediated by cytosolic lipase-dependent mechanisms. CONCLUSIONS: Collectively, our results indicated that DMPSC exerted anti-obesity effects partially through the PKA signaling-mediated activation of lipolysis and brown adipose tissue metabolism.


Assuntos
Adipócitos Marrons/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Flavonoides/farmacologia , Lipólise/efeitos dos fármacos , Compostos de Selênio/farmacologia , Células 3T3-L1 , Adipócitos Marrons/metabolismo , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Knockout , Obesidade/metabolismo
10.
Neurochem Res ; 46(3): 535-549, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33548035

RESUMO

Extensive data have reported the involvement of oxidative stress in the pathogenesis of neuropsychiatric disorders, prompting the pursuit of antioxidant molecules that could become adjuvant pharmacological agents for the management of oxidative stress-associated disorders. The 3-[(4-chlorophenyl)selanyl]-1-methyl-1H-indole (CMI) has been reported as an antioxidant and immunomodulatory compound that improves depression-like behavior and cognitive impairment in mice. However, the exact effect of CMI on specific brain cells is yet to be studied. In this context, the present study aimed to evaluate the antioxidant activity of CMI in H2O2-induced oxidative stress on human dopaminergic neuroblastoma cells (SH-SY5Y) and to shed some light into its possible mechanism of action. Our results demonstrated that the treatment of SH-SY5Y cells with 4 µM CMI protected them against H2O2 (343 µM)-induced oxidative stress. Specifically, CMI prevented the increased number of reactive oxygen species (ROS)-positive cells induced by H2O2 exposure. Furthermore, CMI treatment increased the levels of reduced glutathione in SH-SY5Y cells. Molecular docking studies demonstrated that CMI might interact with enzymes involved in glutathione metabolism (i.e., glutathione peroxidase and glutathione reductase) and H2O2 scavenging (i.e., catalase). In silico pharmacokinetics analysis predicted that CMI might be well absorbed, metabolized, and excreted, and able to cross the blood-brain barrier. Also, CMI was not considered toxic overall. Taken together, our results suggest that CMI protects dopaminergic neurons from H2O2-induced stress by lowering ROS levels and boosting the glutathione system. These results will facilitate the clinical application of CMI to treat nervous system diseases associated with oxidative stress.


Assuntos
Peróxido de Hidrogênio/toxicidade , Indóis/farmacologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Compostos de Selênio/farmacologia , Domínio Catalítico , Linhagem Celular Tumoral , Glutationa/metabolismo , Glutationa Transferase/química , Glutationa Transferase/metabolismo , Humanos , Indóis/química , Indóis/metabolismo , Indóis/farmacocinética , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacocinética , Oxirredutases/química , Oxirredutases/metabolismo , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo , Compostos de Selênio/química , Compostos de Selênio/metabolismo , Compostos de Selênio/farmacocinética
11.
Inorg Chem ; 60(17): 12984-12999, 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34369772

RESUMO

Three new classes of ionic organoselenium compounds containing cationic benzimidazolium and imidazolium ring systems with selenocyanates as counterions are described. The cyclization of N,N'-disubstituted benzimidazolium and imidazolium bromides having N-(CH2)2-Br and N-(CH2)3-Br groups in the presence of potassium selenocyanate (KSeCN) led to formation of the corresponding selenazolium selenocyanates (21a, 21b, 22a, and 22b) and selenazinium selenocyanates (21c, 21d, 22c, and 22d). However, the open-chain selenocyanates with additional selenocyanate counterions (21e, 21f, 22e, and 22f) were formed from the N,N'-disubstituted benzimidazolium and imidazolium bromides having N-(CH2)6-Br groups. Mechanistic studies were carried out to understand the feasibility of such cyclization processes in the presence of KSeCN. The compounds were studied further for their potencies to catalytically reduce H2O2 in the presence of thiols. Interestingly, the cyclic selenazolium (21a, 21b, 22a, and 22b) and selenazinium compounds (21c, 21d, 22c, and 22d) exhibited significantly higher antioxidant activities than the corresponding acyclic selenocyanates (21f, 22e, and 22f). Selected compounds (22d and 22e) were further evaluated for their potencies in modulating the intracellular level of reactive oxygen species (ROS) in a representative macrophage cell line (RAW 264.7). Owing to the cationic nature of compounds, they may target and scavenge mitochondrial ROS in the cellular medium.


Assuntos
Antioxidantes/farmacologia , Benzimidazóis/farmacologia , Compostos Organosselênicos/farmacologia , Animais , Antioxidantes/síntese química , Benzimidazóis/síntese química , Cianatos/síntese química , Cianatos/farmacologia , Ciclização , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/metabolismo , Camundongos , Compostos Organosselênicos/síntese química , Oxirredução , Células RAW 264.7 , Compostos de Selênio/síntese química , Compostos de Selênio/farmacologia
12.
Mar Drugs ; 19(4)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805447

RESUMO

Fish oil (FO) and selenium (Se) possess antiangiogenic potential in malignant tumors. This study aimed to determine whether combination of FO and Se enhanced treatment efficacy of low-dose antiangiogenic agent Avastin (bevacizumab) in a dose-dependent manner and targeted multiple signaling pathways in triple-negative breast cancer (TNBC)-bearing mice. Randomized into five groups, mice received treatment with either physiological saline (control), Avastin alone, or Avastin in combination with low, medium, and high doses of FO/Se. The target signaling molecules for anticancer were determined either by measuring protein or mRNA expression. Avastin-treated mice receiving FO/Se showed lower tumor growth and metastasis than did mice treated with Avastin alone. Combination-treated mice exhibited lower expressions in multiple proangiogenic (growth) factors and their membrane receptors, and altered cytoplasmic signaling molecules (PI3K-PTEN-AKT-TSC-mTOR-p70S6K-4EBP1, Ras-Raf-MEK-ERK, c-Src-JAK2-STAT3-TMEPAI-Smad, LKB1-AMPK, and GSK3ß/ß-catenin). Dose-dependent inhibition of down-stream targets including epithelial-to-mesenchymal transition transcription factors, nuclear cyclin and cyclin-dependent kinases, cancer stem cell markers, heat shock protein (HSP-90), hypoxia-inducible factors (HIF-1α/-2α), matrix metalloprotease (MMP-9), and increased apoptosis were observed. These results suggest that combination treatment with FO and Se increases the therapeutic efficacy of Avastin against TNBC in a dose-dependent manner through multiple signaling pathways in membrane, cytoplasmic, and nucleic targets.


Assuntos
Inibidores da Angiogênese/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Bevacizumab/farmacologia , Óleos de Peixe/farmacologia , Compostos de Selênio/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Camundongos Endogâmicos BALB C , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Carga Tumoral/efeitos dos fármacos
13.
Ecotoxicol Environ Saf ; 211: 111946, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33493718

RESUMO

Increased applications of quantum dots (QDs) in the biomedical field have aroused attention for their potential toxicological effects. Although numerous studies have been carried out on the toxicity of QDs, their effects on reproductive and development are still unclear. In this study, we systematically evaluated the male reproductive toxicity and developmental toxicity of CdSe/ZnS QDs in BALB/c mice. The male mice were injected intravenously with CdSe/ZnS QDs at the dosage of 2.5 mg/kg BW or 25 mg/kg BW, respectively, and the survival status, biodistribution of QDs in testes, serum sex hormone levels, histopathology, sperm motility and acrosome integrity was measured on Day 1, 7, 14, 28 and 42 after injection. On Day 35 after treatment, male mice were housed with non-exposed female mice, and then offspring number, body weight, organ index and histopathology of major organs, blood routine and biochemical tests of offspring were measured to evaluate the fertility and offspring health. The results showed that CdSe/ZnS QDs could rapidly distribute in the testis, and the fluorescence of QDs could still be detected on Day 42 post-injection. QDs had no adverse effect on the structure of testis and epididymis, but high-dose QDs could induce apoptosis of Leydig cells in testis at an early stage. No significant differences in survival of state, body weight organ index of testis and epididymis, sex hormones levels, sperm quality, sperm acrosome integrity and fertility of male mice were observed in QDs exposed groups. However, the development of offspring was obviously influenced, which was mainly manifested in the slow growth of offspring, changes in organ index of main organs, and the abnormality of liver and kidney function parameters. Our findings revealed that CdSe/ZnS QDs were able to cross the blood-testis barrier (BTB), produce no discernible toxic effects on the male reproductive system, but could affect the healthy growth of future generations to some extent. In view of the broad application prospect of QDs in biomedical fields, our findings might provide insight into the biological safety evaluation of the reproductive health of QDs.


Assuntos
Pontos Quânticos/toxicidade , Acrossomo , Animais , Compostos de Cádmio/química , Compostos de Cádmio/toxicidade , Epididimo , Feminino , Fertilidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pontos Quânticos/química , Reprodução , Compostos de Selênio/farmacologia , Motilidade dos Espermatozoides , Espermatozoides , Sulfetos/toxicidade , Testículo , Distribuição Tecidual , Testes de Toxicidade , Compostos de Zinco/toxicidade
14.
Drug Chem Toxicol ; 44(1): 92-100, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31146593

RESUMO

Pulmonary fibrosis (PF) is an interstitial lung disease, in which the exact pathologic mechanisms are not fully understood. Drug trials for the treatment of PF have shown disappointing results and controversial. Recently, selenium nanoparticles (SeNPs) have received great attention for potential use in treatments, due to high bioactivity features and lower toxicity. This study evaluated the protective effect of SeNPs against pulmonary injury induced by bleomycin (single dose, 4 mg/kg, intratracheal) in male rats in early and late phases of the disease. The rats were treated with SeNPs by intraperitoneal injection (0.5 mg SeNP/kg) for five consecutive days in the early phase (a day after injection of bleomycin) and late phase (a week after injection of bleomycin). The results showed that injection of SeNPs in the early phase improved the degree of alveolitis and inflammation and lung structure damage. Also, led to significant decreases in density of transforming growth factor- ß1 (TGF-ß1) in the lung and tumor necrosis factor-α (TNF-α) levels in the serum and lung homogenates compared with bleomycin-administrated group. Notably, treatment with the SeNP during the late phase did not show any ameliorative effects. Thus, the data suggest that SeNP has a protective effect against bleomycin-induced pulmonary injury in rats in the early phase of the disease. This might mean that SeNPs may be a new therapeutic agent for the improvement of this disease in the early phases.


Assuntos
Anti-Inflamatórios/farmacologia , Pulmão/efeitos dos fármacos , Nanopartículas , Pneumonia/prevenção & controle , Fibrose Pulmonar/prevenção & controle , Compostos de Selênio/farmacologia , Animais , Bleomicina , Modelos Animais de Doenças , Pulmão/metabolismo , Pulmão/patologia , Masculino , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Pneumonia/patologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Ratos Wistar , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
15.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33806825

RESUMO

Metabolically active gasotransmitters (nitric oxide, carbon monoxide and hydrogen sulfide) are important signalling molecules that show therapeutic utility in oxidative pathologies. The reduced form of selenium, hydrogen selenide (HSe-/H2Se), shares some characteristics with these molecules. The simple selenide salt, sodium hydroselenide (NaHSe) showed significant metabolic activity, dose-dependently decreasing ex vivo O2 consumption (rat soleus muscle, liver) and transiently inhibiting mitochondrial cytochrome C oxidase (liver, heart). Pharmacological manipulation of selenoprotein expression in HepG2 human hepatocytes revealed that the oxidation status of selenium impacts on protein expression; reduced selenide (NaHSe) increased, whereas (oxidized) sodium selenite decreased the abundance of two ubiquitous selenoproteins. An inhibitor of endogenous sulfide production (DL-propargylglycine; PAG) also reduced selenoprotein expression; this was reversed by exogenous NaHSe, but not sodium hydrosulfide (NaHS). NaHSe also conferred cytoprotection against an oxidative challenge (H2O2), and this was associated with an increase in mitochondrial membrane potential. Anesthetized Wistar rats receiving intravenous NaHSe exhibited significant bradycardia, metabolic acidosis and hyperlactataemia. In summary, NaHSe modulates metabolism by inhibition of cytochrome C oxidase. Modification of selenoprotein expression revealed the importance of oxidation status of selenium therapies, with implications for current clinical practice. The utility of NaHSe as a research tool and putative therapeutic is discussed.


Assuntos
Compostos de Selênio/farmacologia , Compostos de Selênio/uso terapêutico , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Compostos de Selênio/síntese química , Compostos de Selênio/química , Selenoproteínas/genética , Sódio/química , Selenito de Sódio/química
16.
Bull Exp Biol Med ; 171(2): 247-250, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34173103

RESUMO

We studied the effect of nanostructured clathrate complex 9-phenyl-symm-octahydoselenoxanthene (selenopyran) with ß-cyclodextrin on the generation of ОН· radicals in the Fenton system and parameters of oxidative stress in rat liver cells incubated at 37°Ð¡ for 1 h. The complex inhibits the development of free-radical oxidative processes induced by ROS and the most toxic ОН· radicals, reduces the increased level of ROS induced by prooxidants, and exhibits antioxidant activity.


Assuntos
Antioxidantes/farmacologia , Estresse Oxidativo/efeitos dos fármacos , beta-Ciclodextrinas/farmacologia , Animais , Antioxidantes/síntese química , Antioxidantes/química , Células Cultivadas , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Substâncias Macromoleculares/síntese química , Substâncias Macromoleculares/química , Substâncias Macromoleculares/farmacologia , Masculino , Modelos Biológicos , Nanoestruturas/química , Piranos/síntese química , Piranos/química , Piranos/farmacologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Compostos de Selênio/síntese química , Compostos de Selênio/química , Compostos de Selênio/farmacologia , Terpenos/química , Terpenos/farmacologia , beta-Ciclodextrinas/síntese química , beta-Ciclodextrinas/química
17.
Bioorg Med Chem Lett ; 30(17): 127371, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738977

RESUMO

A series of thirty-one selenocompounds covering a wide chemical space was assessed for in vitro leishmanicidal activities against Leishmania infantum amastigotes. The cytotoxicity of those compounds was also evaluated on human THP-1 cells. Interestingly most tested derivatives were active in the low micromolar range and seven of them (A.I.3, A.I.7, B.I.1, B.I.2, C.I.7 C.I.8 and C.II.8) stood out for selectivity indexes higher than the ones exhibited by reference compounds mitelfosine and edelfosine. These leader compounds were evaluated against infected macrophages and their trypanothione reductase (TryR) inhibition potency was measured to further approach the mechanism by which they caused their action. Among them diselenide tested structures were pointed out for their ability to reduce infection rates. Three of the leader compounds inhibited TryR effectively, therefore this enzyme may be implicated in the mechanism of action by which these compounds cause their leishmanicidal effect.


Assuntos
Antiprotozoários/farmacologia , Cianatos/química , Leishmania infantum/efeitos dos fármacos , Compostos de Selênio/química , Antiprotozoários/química , Sobrevivência Celular/efeitos dos fármacos , Cianatos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Humanos , Leishmania infantum/fisiologia , NADH NADPH Oxirredutases/antagonistas & inibidores , NADH NADPH Oxirredutases/metabolismo , Testes de Sensibilidade Parasitária , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/metabolismo , Compostos de Selênio/farmacologia , Relação Estrutura-Atividade , Células THP-1
18.
Chem Biodivers ; 17(5): e1900603, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32198823

RESUMO

In the present study, twenty-four selenocyanate and diselenide compounds were synthesized and characterized, and their anticancer activities against the human cancer cell lines Caco2, BGC-823, MCF-7 and PC-3 were determined. Interestingly, most of the new compounds were active in reducing the viability of different cancer cell lines. Two compounds exhibited higher promising activities than other derivatives. The most active compound showed the least IC50 values against the four cancer cell lines, particularly to PC-3 with IC50 values below 5 µm. Two compounds were selected to monitor the expression levels of Bcl-2, IL-2 and caspase-3 molecular biomarkers. Interestingly, the two compounds downregulated the Bcl-2 expression levels and upregulated the expression of IL-2 and caspase-3 in PC-3 cells compared to untreated cells. Moreover, most of the synthesized organoselenides exhibited good Gpx-like activities comparable to ebselen. These results appear that introduction of selenocyanate (-SeCN) or diselenides (-Se-Se-) moiety to some carboxy derivatives could serve as a promising launch point for the further design of this type of organic selenium anticancer agent.


Assuntos
Antineoplásicos/farmacologia , Cianatos/farmacologia , Compostos Organosselênicos/farmacologia , Compostos de Selênio/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Cianatos/síntese química , Cianatos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/química , Compostos de Selênio/síntese química , Compostos de Selênio/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
19.
Molecules ; 25(24)2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33322081

RESUMO

Selenium (Se) is an essential trace element, which represents an integral part of glutathione peroxidase and other selenoproteins involved in the protection of cells against oxidative damage. Selenomethionine (SeMet), selenocysteine (SeCys), and methylselenocysteine (MeSeCys) are the forms of Se that occur in living systems. Se-containing compounds have been found to reduce carcinogenesis of animal models, and dietary supplemental Se might decrease cancer risk. Se is mainly taken up by plant roots in the form of selenate via high-affinity sulfate transporters. Consequently, owing to the chemical similarity between Se and sulfur (S), the availability of S plays a key role in Se accumulation owing to competition effects in absorption, translocation, and assimilation. Moreover, naturally occurring S-containing compounds have proven to exhibit anticancer potential, in addition to other bioactivities. Therefore, it is important to understand the interaction between Se and S, which depends on Se/S ratio in the plant or/and in the growth medium. Brassicaceae (also known as cabbage or mustard family) is an important family of flowering plants that are grown worldwide and have a vital role in agriculture and populations' health. In this review we discuss the distribution and further interactions between S and Se in Brassicaceae and provide several examples of Se or Se/S biofortifications' experiments in brassica vegetables that induced the chemopreventive effects of these crops by enhancing the production of Se- or/and S-containing natural compounds. Extensive further research is required to understand Se/S uptake, translocation, and assimilation and to investigate their potential role in producing anticancer drugs.


Assuntos
Anticarcinógenos/química , Anticarcinógenos/farmacologia , Brassicaceae/química , Quimioprevenção , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Selênio/química , Enxofre/química , Animais , Humanos , Compostos de Selênio/química , Compostos de Selênio/farmacologia , Relação Estrutura-Atividade , Compostos de Enxofre/química , Compostos de Enxofre/farmacologia , Verduras
20.
Bull Exp Biol Med ; 169(1): 95-99, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32495165

RESUMO

We studied changes in the transcription of genes encoding cytokines (TNF, IL-6, IL-10, and IL-32), cell activation markers (ICAM1, CD38, Fas, and FCGRIII), ROS production catalyst (NOX2), autophagy (Beclin 1, LC3B, and p62) and apoptosis (BAX, BCL2) regulators in peripheral blood mononuclear cells upon contact with quantum dots CdSe/ZnS-MPA and CdSe/CdSeZnS/ZnS-PTVP. Up-regulation of TNF, ICAM1, Fas, p62 mRNA and down-regulation of the FCGRIII and NOX2 mRNA in response to the presence of quantum dots were revealed. The formation of serum protein corona on the surface of quantum dots abolished this effect.


Assuntos
Inflamação/genética , Leucócitos Mononucleares/efeitos dos fármacos , Coroa de Proteína/química , Pontos Quânticos , Adulto , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Compostos de Cádmio/farmacologia , Compostos de Cádmio/toxicidade , Citocinas/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Pontos Quânticos/química , Pontos Quânticos/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Compostos de Selênio/farmacologia , Compostos de Selênio/toxicidade , Compostos de Zinco/farmacologia , Compostos de Zinco/toxicidade
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