RESUMO
Mitochondrial dysfunction is an early pathological feature of Alzheimer disease and plays a crucial role in the development and progression of Alzheimer's disease. Strategies to rescue mitochondrial function and cognition remain to be explored. Cyclophilin D (CypD), the peptidylprolyl isomerase F (PPIase), is a key component in opening the mitochondrial membrane permeability transition pore, leading to mitochondrial dysfunction and cell death. Blocking membrane permeability transition pore opening by inhibiting CypD activity is a promising therapeutic approach for Alzheimer's disease. However, there is currently no effective CypD inhibitor for Alzheimer's disease, with previous candidates demonstrating high toxicity, poor ability to cross the blood-brain barrier, compromised biocompatibility and low selectivity. Here, we report a new class of non-toxic and biocompatible CypD inhibitor, ebselen, using a conventional PPIase assay to screen a library of â¼2000 FDA-approved drugs with crystallographic analysis of the CypD-ebselen crystal structure (PDB code: 8EJX). More importantly, we assessed the effects of genetic and pharmacological blockade of CypD on Alzheimer's disease mitochondrial and glycolytic bioenergetics in Alzheimer's disease-derived mitochondrial cybrid cells, an ex vivo human sporadic Alzheimer's disease mitochondrial model, and on synaptic function, inflammatory response and learning and memory in Alzheimer's disease mouse models. Inhibition of CypD by ebselen protects against sporadic Alzheimer's disease- and amyloid-ß-induced mitochondrial and glycolytic perturbation, synaptic and cognitive dysfunction, together with suppressing neuroinflammation in the brain of Alzheimer's disease mouse models, which is linked to CypD-related membrane permeability transition pore formation. Thus, CypD inhibitors have the potential to slow the progression of neurodegenerative diseases, including Alzheimer's disease, by boosting mitochondrial bioenergetics and improving synaptic and cognitive function.
Assuntos
Doença de Alzheimer , Isoindóis , Mitocôndrias , Compostos Organosselênicos , Peptidil-Prolil Isomerase F , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptidil-Prolil Isomerase F/metabolismo , Animais , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Camundongos , Humanos , Cognição/efeitos dos fármacos , Azóis/farmacologia , Azóis/uso terapêutico , Ciclofilinas/metabolismo , Ciclofilinas/antagonistas & inibidores , Camundongos Transgênicos , Camundongos Endogâmicos C57BL , Masculino , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêuticoRESUMO
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.
Assuntos
Apoptose , Carcinoma Pulmonar de Células não Pequenas , Proliferação de Células , Neoplasias Pulmonares , NF-kappa B , Espécies Reativas de Oxigênio , Selenocisteína , Transdução de Sinais , Humanos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Animais , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , NF-kappa B/metabolismo , Selenocisteína/análogos & derivados , Selenocisteína/farmacologia , Proliferação de Células/efeitos dos fármacos , Camundongos , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular Tumoral , Células A549 , Compostos Organosselênicos/farmacologia , Camundongos Endogâmicos BALB CRESUMO
Oxidative stress is a key factor in the disruption of cartilage homeostasis during the development of osteoarthritis (OA). Organic selenium (Se)-containing compounds such as diselenides have excellent antioxidant activity and may prevent related diseases. We aimed to examine the benefits of the synthetic small molecule diphenyl diselenide (DPDSe) in OA models in vitro and in vivo. Our findings showed that DPDSe could maintain extracellular matrix (ECM) homeostasis and inhibit reactive oxygen species (ROS) production in IL-1ß-treated chondrocytes. In a destabilization of the medial meniscus (DMM)-induced OA mouse model, intra-articular administration of DPDSe alleviated joint degeneration, as evidenced by a decrease in the OARSI score and the restoration of collagen II (COL2) and MMP-13 expression in cartilage tissues. We confirmed that DDS activated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in IL-1ß-treated chondrocytes, and its chondroprotective effects were significantly counteracted when Nrf2 signaling was blocked by the inhibitor ML385 or by siRNA-mediated Nrf2 knockdown. The relatively strong performance of DPDSe makes it an ideal candidate for further trials as a disease-modifying OA drug (DMOAD).
Assuntos
Derivados de Benzeno , Compostos Organosselênicos , Osteoartrite , Camundongos , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Transdução de Sinais , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/uso terapêutico , Condrócitos/metabolismo , Interleucina-1beta/metabolismoRESUMO
Organoselenium compounds modulate the metabolism by regulating carbohydrate and lipid syntheses and degradation in the liver, muscle, and adipose tissue. Notably, p-chloro-diphenyl diselenide (p-ClPhSe)2 can directly regulate the activities of enzymes involved in glucose metabolism, suggesting an insulin-like effect in rodents; however, there is still a lack of scientific evidence to confirm this hypothesis. The objective of this study was to investigate (p-ClPhSe)2 effects on glucose and lipid metabolism in Caenorhabditis elegans. The contribution of AGE-1/PI3K, AKT-1, AKT-2, PFK-1, DAF-16, and DAF-2 in the (p-ClPhSe)2 effects were also investigated. Our results demonstrate that (p-ClPhSe)2 acute exposure presented some toxicity to the worms, and therefore, lower concentrations were further used. (p-ClPhSe)2 reduced glucose and triglyceride levels to the baseline levels, after induction with glucose or fructose, in wild-type worms. This effect required proteins involved in the insulin/IGF-1 like signaling, such as the DAF-2, AGE-1, AKT-1 and AKT-2, PFK-1, but also DAF-16, which would be negatively regulated by DAF-2 activation. Moreover, the reduction in glucose and triglyceride levels, caused by (p-ClPhSe)2per se was lost in age-1/daf-16 worms, suggesting that insulin/IGF-1-like signaling in a DAF-2 and AGE-1/DAF-16 dependent-manner in C. elegans are necessary to effects of (p-ClPhSe)2. In conclusion, (p-ClPhSe)2 requires proteins involved in the IIS pathway to modulate carbohydrate and lipid metabolism.
Assuntos
Proteínas de Caenorhabditis elegans , Compostos Organosselênicos , Animais , Caenorhabditis elegans/metabolismo , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Metabolismo dos Lipídeos , Compostos Organosselênicos/farmacologia , Proteínas de Caenorhabditis elegans/metabolismo , Glucose/metabolismo , Triglicerídeos/metabolismo , Longevidade , Fatores de Transcrição Forkhead/metabolismoRESUMO
The synthesis of diarylamine-based organoselenium compounds via the nucleophilic substitution reactions has been described. Symmetrical monoselenides and diselenides were conveniently synthesized by the reduction of their corresponding selenocyanates using sodium borohydride. Selenocyanates were obtained from 2-chloro acetamides by the nucleophilic displacement with potassium selenocyanate. Selenides were synthesized by treating the 2-chloro acetamides with inâ situ generated sodium butyl selenolate as nucleophile. Further, the newly synthesized organoselenium compounds were evaluated for their glutathione peroxidase (GPx)-like activity in thiophenol assay. This study revealed that the methoxy-substituted organoselenium compounds showed significant effect on the GPx-like activity. The catalytic parameters for the most efficient catalysts were also determined. The anti-ferroptotic activity for all GPx-mimics evaluated in a 4-OH-tamoxifen (TAM) inducible GPx4 knockout cell line using liproxstatin as standard.
Assuntos
Ferroptose , Compostos Organosselênicos , Glutationa Peroxidase/metabolismo , Aminas , Compostos Organosselênicos/farmacologia , Antioxidantes/metabolismo , AcetamidasRESUMO
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.
Assuntos
Isoindóis , Metabolismo dos Lipídeos , Fígado , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica , Compostos Organosselênicos , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Receptor 4 Toll-Like , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptor 4 Toll-Like/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Masculino , Camundongos , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/uso terapêutico , Isoindóis/farmacologia , Fígado/metabolismo , Fígado/efeitos dos fármacos , Azóis/farmacologia , Azóis/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Dieta Hiperlipídica , Transdução de Sinais/efeitos dos fármacos , Modelos Animais de DoençasRESUMO
A low pKa (5.2), high polarizable volume (3.8â Å), and proneness to oxidation under ambient conditions make selenocysteine (Sec, U) a unique, natural reactive handle present in most organisms across all domains of life. Sec modification still has untapped potential for site-selective protein modification and probing. Herein we demonstrate the use of a cyclometalated gold(III) compound, [Au(bnpy)Cl2 ], in the arylation of diselenides of biological significance, with a scope covering small molecule models, peptides, and proteins using a combination of multinuclear NMR (including 77 Se NMR), and LC-MS. Diphenyl diselenide (Ph-Se)2 and selenocystine, (Sec)2 , were used for reaction optimization. This approach allowed us to demonstrate that an excess of diselenide (Au/Se-Se) and an increasing water percentage in the reaction media enhance both the conversion and kinetics of the C-Se coupling reaction, a combination that makes the reaction biocompatible. The C-Se coupling reaction was also shown to happen for the diselenide analogue of the cyclic peptide vasopressin ((Se-Se)-AVP), and the Bos taurus glutathione peroxidase (GPx1) enzyme in ammonium acetate (2â mM, pH=7.0). The reaction mechanism, studied by DFT revealed a redox-based mechanism where the C-Se coupling is enabled by the reductive elimination of the cyclometalated Au(III) species into Au(I).
Assuntos
Cistina/análogos & derivados , Compostos Organosselênicos , Selênio , Animais , Bovinos , Ouro/química , Peptídeos , Glutationa Peroxidase/metabolismo , Selenocisteína/químicaRESUMO
Neurotoxicity associated with chemotherapy is a debilitating side effect of cancer management in humans which reportedly involves inflammatory and oxidative stress responses. Diphenyl diselenide (DPDS) is an organoselenium compound which exhibits its anti-tumoral, anti-oxidant, anti-inflammatory and anti-mutagenic effects. Nevertheless, its possible effect on chemotherapy-induced neurotoxicity is not known. Using rat model, we probed the behavioral and biochemical effects accompanying administration of antineoplastic agent doxorubicin (7.5 mg/kg) and DPDS (5 and 10 mg/kg). Anxiogenic-like behavior, motor and locomotor insufficiencies associated with doxorubicin were considerably abated by both DPDS doses with concomitant enhancement in exploratory behavior as demonstrated by reduced heat maps intensity and enhanced track plot densities. Moreover, with exception of cerebral glutathione (GSH) level, superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, biochemical data demonstrated reversal of doxorubicin-mediated decline in cerebral and cerebellar antioxidant status indices and the increase in acetylcholinesterase (AChE) activity by both doses of DPDS. Also, cerebellar and cerebral lipid peroxidation, hydrogen peroxide as well as reactive oxygen and nitrogen species levels were considerably diminished in rats administered doxorubicin and DPDS. In addition, DPDS administration abated myeloperoxidase activity, tumour necrosis factor alpha and nitric oxide levels along with caspase-3 activity in doxorubicin-administered rats. Chemoprotection of doxorubicin-associated neurotoxicity by DPDS was further validated by histomorphometry and histochemical staining. Taken together, DPDS through offsetting of oxido-inflammatory stress and caspase-3 activation elicited neuroprotection in doxorubicin-treated rats.
Assuntos
Compostos Organosselênicos , Temefós , Humanos , Ratos , Animais , Caspase 3 , Temefós/farmacologia , Acetilcolinesterase , Estresse Oxidativo , Antioxidantes/farmacologia , Derivados de Benzeno/farmacologia , Derivados de Benzeno/uso terapêutico , Derivados de Benzeno/química , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/uso terapêutico , Glutationa/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Doxorrubicina/toxicidadeRESUMO
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.
Assuntos
Compostos Organosselênicos , Compostos Organosselênicos/química , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/farmacologia , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Anti-Infecciosos/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Produtos Biológicos/química , Produtos Biológicos/síntese química , Produtos Biológicos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologiaRESUMO
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.
Assuntos
Antineoplásicos , Nitrilas , Compostos Organosselênicos , Animais , Camundongos , Anidridos/química , Anidridos/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Células 3T3 BALB , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Melanoma/tratamento farmacológico , Melanoma/patologia , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Estrutura Molecular , Nitrilas/química , Nitrilas/farmacologia , Nitrilas/síntese química , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/síntese química , Selênio/química , Selênio/farmacologia , Relação Estrutura-Atividade , Acetatos/síntese química , Acetatos/química , Acetatos/farmacologiaRESUMO
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.
Assuntos
Antivirais , Proteases 3C de Coronavírus , Desenho de Fármacos , Isoindóis , Aprendizado de Máquina , Simulação de Dinâmica Molecular , Compostos Organosselênicos , Inibidores de Proteases , Relação Quantitativa Estrutura-Atividade , SARS-CoV-2 , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/síntese química , Isoindóis/química , Isoindóis/farmacologia , Isoindóis/síntese química , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/metabolismo , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Inibidores de Proteases/síntese química , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Humanos , Azóis/química , Azóis/farmacologia , Azóis/síntese química , COVID-19/virologia , Domínio CatalíticoRESUMO
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.
Assuntos
Peptídeos , Selenocisteína , Selenocisteína/química , Peptídeos/química , Peptídeos/síntese química , Compostos Organosselênicos/química , Compostos Organosselênicos/síntese químicaRESUMO
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.
Assuntos
Benzenossulfonamidas , Inibidores da Anidrase Carbônica , Anidrases Carbônicas , Indóis , Iodo , Oxirredução , Sulfonamidas , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/síntese química , Humanos , Anidrases Carbônicas/metabolismo , Indóis/química , Indóis/farmacologia , Indóis/síntese química , Iodo/química , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/síntese química , Relação Estrutura-Atividade , Estrutura MolecularRESUMO
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.
Assuntos
Compostos de Boro , Corantes Fluorescentes , Compostos Organosselênicos , Compostos de Boro/química , Compostos de Boro/síntese química , Humanos , Compostos Organosselênicos/química , Compostos Organosselênicos/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Estrutura Molecular , Teoria da Densidade Funcional , Superóxidos/análise , Células HeLa , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Oxigênio/análiseRESUMO
Selenium-containing agents showed novel anticancer activity by triggering pro-oxidative mechanism. Studies confirmed that methylseleninic acid (MeSe) displayed broad-spectrum anti-tumor activity against kinds of human cancers. However, the anticancer effects and mechanism of MeSe against human glioma growth have not been explored yet. Herein, the present study showed that MeSeA dose-dependently inhibited U251 and U87 human glioma cells growth in vitro. Flow cytometry analysis indicated that MeSe induced significant U251 cells apoptosis with a dose-dependent manner, followed by the activation of caspase-7, caspase-9 and caspase-3. Immunofluorescence staining revealed that MeSe time-dependently caused reactive oxide species (ROS) accumulation and subsequently resulted in oxidative damage, as convinced by the increased phosphorylation level of Ser428-ATR, Ser1981-ATM, Ser15-p53 and Ser139-histone. ROS inhibition by glutathione (GSH) effectively attenuated MeSe-induced ROS generation, oxidative damage, caspase-3 activation and cytotoxicity, indicating that ROS was an upstream factor involved in MeSe-mediated anticancer mechanism in glioma. Importantly, MeSe administration in nude mice significantly inhibited glioma growth in vivo by inducing apoptosis through triggering oxidative damage. Taken together, our findings validated the possibility that MeSe as a selenium-containing can act as potential tumor chemotherapy agent for therapy of human glioma.
Assuntos
Apoptose , Glioma , Camundongos Nus , Compostos Organosselênicos , Estresse Oxidativo , Espécies Reativas de Oxigênio , Humanos , Glioma/tratamento farmacológico , Glioma/metabolismo , Glioma/patologia , Apoptose/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/uso terapêutico , Animais , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Estresse Oxidativo/efeitos dos fármacos , Camundongos , Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Proliferação de Células/efeitos dos fármacos , Camundongos Endogâmicos BALB CRESUMO
OBJECTIVES: To compare the diagnostic efficiency of 19G fine-needle aspiration (FNA) and 22G fine-needle biopsy (FNB) in endoscopic ultrasound (EUS)-guided sampling for subepithelial tumors (SETs). METHODS: The data of patients with SETs who underwent 19G FNA or 22G FNB were reviewed retrospectively in two tertiary hospitals. Tissue cores were assessed by macroscopic on-site evaluation (MOSE). Cytological or histological diagnosis were classified as definite, suspect, or no diagnosis. RESULTS: Seventy five patients (mean age: 55 years, 44 males) underwent 19G EUS-FNA (31) or 22G EUS-FNB (44). The overall diagnostic yield was 82.7%. The rate of definite cytological diagnoses was 9.7% (3/31) in 19G and 13.6% (6/44) in 22G group (x2 = 1.520, P = .468). In terms of MOSE, 19G needle, requiring only two punctures, achieved a higher good tissue core rate than 22G group (100.0% [31/31] versus 84.1% [37/44], x2 = 5.440, P = .020]). For histological diagnosis, the 19G group achieved higher definite rate than the 22G group, 93.6% (29/31) versus 65.9% (29/44) (x2 = 7.957, P = .019) on the first puncture, 90.3% (28/31) versus 63.6% (28/44) (x2 = 7.139, P = .028) on the second puncture, 96.8% (30/31) versus 70.5% (31/44) (x2 = 7.319, P = .026) on both the first and second punctures, and 96.8% (30/31) versus 72.7% (32/44) (x2 = 7.538, P = .023) on all three punctures. CONCLUSIONS: The 19G EUS-FNA requires only two punctures to achieve better tissue core quality by MOSE and yields a higher rate of histological diagnosis than 22G ProCore needle for SETs. The bigger 19G FNA needle seems to play an important role in the evaluation of SETs.
Assuntos
Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Morfolinas , Compostos Organosselênicos , Neoplasias Pancreáticas , Masculino , Humanos , Pessoa de Meia-Idade , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Estudos Retrospectivos , Endossonografia , Neoplasias Pancreáticas/diagnósticoRESUMO
Favipiravir (FP) and ebselen (EB) belong to a diverse class of antiviral drugs known for their significant efficacy in treating various viral infections. Utilizing molecular dynamics (MD) simulations, machine learning, and van der Waals density functional theory, we accurately elucidate the binding properties of these antiviral drugs on a phosphorene single-layer. To further investigate these characteristics, this study employs four distinct machine learning models-Random Forest, Gradient Boosting, XGBoost, and CatBoost. The Hamiltonian of antiviral molecules within a monolayer of phosphorene is appropriately trained. The key aspect of utilizing machine learning (ML) in drug design revolves around training models that are efficient and precise in approximating density functional theory (DFT). Furthermore, the study employs SHAP (SHapley Additive exPlanations) to elucidate model predictions, providing insights into the contribution of each feature. To explore the interaction characteristics and thermodynamic properties of the hybrid drug, we employ molecular dynamics and DFT calculations in a vacuum interface. Our findings suggest that this functionalized 2D complex exhibits robust thermostability, indicating its potential as an effective and enabled entity. The observed variations in free energy at different surface charges and temperatures suggest the adsorption potential of FP and EB molecules from the surrounding environment.
Assuntos
Antivirais , Aprendizado de Máquina , Simulação de Dinâmica Molecular , Antivirais/química , Antivirais/farmacologia , Teoria da Densidade Funcional , Termodinâmica , Isoindóis/química , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Azóis/química , Azóis/farmacologiaRESUMO
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.
Assuntos
Antivirais , Azóis , Proteases 3C de Coronavírus , Isoindóis , Compostos Organosselênicos , Prolina , SARS-CoV-2 , Antivirais/farmacologia , Antivirais/química , Humanos , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/química , Isoindóis/farmacologia , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/metabolismo , Azóis/farmacologia , Azóis/química , Prolina/análogos & derivados , Prolina/farmacologia , Prolina/química , Simulação de Acoplamento Molecular , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , Tratamento Farmacológico da COVID-19 , COVID-19/virologia , Células HEK293 , Lactamas , Leucina/análogos & derivados , Ácidos SulfônicosRESUMO
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.
Assuntos
Antineoplásicos , Apoptose , Autofagia , Proliferação de Células , Neoplasias de Mama Triplo Negativas , Humanos , Apoptose/efeitos dos fármacos , Feminino , Proliferação de Células/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Linhagem Celular Tumoral , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/uso terapêutico , Compostos Organosselênicos/química , Sobrevivência Celular/efeitos dos fármacos , Ésteres/química , Ésteres/farmacologia , Células MCF-7RESUMO
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.