Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.438
Filtrar
1.
Arch Biochem Biophys ; 712: 109027, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34520732

RESUMO

The dithiol reagents phenylarsine oxide (PAO) and dibromobimane (DBrB) have opposite effects on the F1FO-ATPase activity. PAO 20% increases ATP hydrolysis at 50 µM when the enzyme activity is activated by the natural cofactor Mg2+ and at 150 µM when it is activated by Ca2+. The PAO-driven F1FO-ATPase activation is reverted to the basal activity by 50 µM dithiothreitol (DTE). Conversely, 300 µM DBrB decreases the F1FO-ATPase activity by 25% when activated by Mg2+ and by 50% when activated by Ca2+. In both cases, the F1FO-ATPase inhibition by DBrB is insensitive to DTE. The mitochondrial permeability transition pore (mPTP) formation, related to the Ca2+-dependent F1FO-ATPase activity, is stimulated by PAO and desensitized by DBrB. Since PAO and DBrB apparently form adducts with different cysteine couples, the results highlight the crucial role of cross-linking of vicinal dithiols on the F1FO-ATPase, with (ir)reversible redox states, in the mPTP modulation.


Assuntos
Cisteína/química , Poro de Transição de Permeabilidade Mitocondrial/metabolismo , ATPases Translocadoras de Prótons/metabolismo , Animais , Arsenicais/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Cálcio/metabolismo , Ditioeritritol/farmacologia , Ativadores de Enzimas/farmacologia , Inibidores Enzimáticos/farmacologia , Magnésio/metabolismo , Mitocôndrias/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , ATPases Translocadoras de Prótons/antagonistas & inibidores , ATPases Translocadoras de Prótons/química , Suínos
2.
Viruses ; 13(5)2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946406

RESUMO

Following our observation that clofoctol led to Epstein-Barr virus (EBV) lytic gene expression upon activation of the integrated stress response (ISR), we decided to investigate the impact of As2O3 on viral lytic gene expression. As2O3 has also been reported to activate the ISR pathway by its activation of the heme-regulated inhibitor (HRI). Our investigations show that As2O3 treatment leads to eIF2α phosphorylation, upregulation of ATF4 and TRB3 expression, and an increase of EBV Zta gene expression in lymphoid tumor cell lines as well as in naturally infected epithelial cancer cell lines. However, late lytic gene expression and virion production were blocked after arsenic treatment. In comparison, a small molecule HRI activator also led to increased Zta expression but did not block late lytic gene expression, suggesting that As2O3 effects on EBV gene expression are also mediated through other pathways.


Assuntos
Arsenicais/farmacologia , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/efeitos dos fármacos , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Estresse Fisiológico , Biomarcadores , Linhagem Celular Tumoral , Células Cultivadas , Humanos , Modelos Biológicos , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/genética , Ativação Viral , Replicação Viral/efeitos dos fármacos
3.
Gene ; 788: 145666, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33887368

RESUMO

BACKGROUND: Recent studies in cancer biology suggest that metabolic glucose reprogramming is a potential target for cancer treatment. However, little is known about drug intervention in the glucose metabolism of cancer stem cells (CSCs) and its related underlying mechanisms. METHODS: The crude realgar powder was Nano-grinded to meets the requirements of Nano-pharmaceutical preparations, and Nano-realgar solution (NRS) was prepared for subsequent experiments. Isolation and characterization of lung cancer stem cells (LCSCs) was performed by magnetic cell sorting (MACS) and immunocytochemistry, respectively. Cell viability and intracellular glucose concentration were detected by MTT assay and glucose oxidase (GOD) kit. Protein expressions related to metabolic reprogramming was detected by ELISA assay. Determination of the expression of HIF-1α and PI3K/Akt/mTOR pathways was carried out by RT-PCR and western blotting analysis. A subcutaneous tumor model in BALB/c-nu mice was successfully established to evaluate the effects of Nano-realgar on tumor growth and histological structure, and the expression of HIF-1α in tumor tissues was measured by immunofluorescence. RESULTS: Nano-realgar inhibits cell viability and induces glucose metabolism in LCSCs, and inhibits protein expression related to metabolic reprogramming in a time- and dose-dependent manner. Nano-realgar downregulated the expression of HIF-1α and PI3K/Akt/mTOR pathways in vitro and in vivo. Nano-realgar inhibits tumor growth and changes the histological structure of tumors through in vivo experiments and consequently inhibits the constitutive activation of HIF-1α signaling. CONCLUSIONS: These results reveal that Nano-realgar inhibits tumor growth in vitro and in vivo by repressing metabolic reprogramming. This inhibitory effect potentially related to the downregulation HIF-1α expression via PI3K/Akt/mTOR pathway.


Assuntos
Antineoplásicos/administração & dosagem , Arsenicais/administração & dosagem , Glucose/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Células-Tronco Neoplásicas/metabolismo , Sulfetos/administração & dosagem , Células A549 , Antígeno AC133/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Arsenicais/química , Arsenicais/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas , Células-Tronco Neoplásicas/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Sulfetos/química , Sulfetos/farmacologia , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Trace Elem Med Biol ; 66: 126720, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33676114

RESUMO

BACKGROUND: As4S4 is widely used in Chinese traditional medicine compound. However, based on some recent studies, we found that the cardiotoxicity risk of using As4S4 in ischemic heart disease patients may be increased. To study this potential risk, we compared the effects of As4S4 on rat ventricular H9c2 cell line with or without hypoxic pretreatment, and to elucidate mechanisms of c-Cbl mediated ubiquitination/degradation of integrin ß1. METHODS: The present study was conducted on rat ventricular H9c2 cell line in the absence or presence of hypoxic pretreatment for 6 h followed by As4S4 treatment for 24 h. Following As4S4 treatment, cell viability assay, flow cytometric quantification of apoptotic cells, caspase-3 activity assay and DAPI staining were conducted. Western blotting was carried out to detect expressions of ubiquitination related proteins. In addition, the ubiquitination/degradation of integrin ß1 and the role of c-Cbl in it was evaluated by immunoprecipitation and immunoblot assay. RESULTS: The viability of cells with hypoxic pretreatment followed by As4S4 treatment was decreased significantly, apoptosis rate and the activity of caspase-3 were increased than As4S4 treatment alone. The ubiquitin-proteasome degradation pathway induced by As4S4 was further enhanced by hypoxic pretreatment. The results of IP and immunoblot assay showed hypoxic enhanced down-regulation effect of As4S4 on integrin ß1 probably through c-Cbl activation. CONCLUSIONS: This study demonstrated that the hypoxia enhanced cytotoxicity of As4S4 on H9c2 cells may through increasing the ubiquitin-proteasome degradation of integrin ß1 mediated by the E3 ligase c-Cbl. The results provide an important clue that, in patients with ischemic heart disease, use of As4S4 may be associated with increased cardiotoxicity. We believe that the results worth to be further illuminated by in vivo and clinical research.


Assuntos
Arsenicais/farmacologia , Hipóxia , Complexo de Endopeptidases do Proteassoma/metabolismo , Sulfetos/farmacologia , Ubiquitina/antagonistas & inibidores , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ratos , Ubiquitina/metabolismo
5.
Am J Chin Med ; 49(2): 461-485, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33641653

RESUMO

Traditional Chinese Medicine (TCM) is a practical medicine based on thousands of years of medical practice in China. Arsenic dispensing powder (ADP) has been used as a treatment for MDS patients with a superior efficacy on anemia at Xiyuan Hospital of China Academy of Chinese Medical Sciences. In this study, we retrospectively analyzed MDS patients that received ADP treatment in the past 9 years and confirmed that ADP improves patients' anemia and prolongs overall survival in intermediate-risk MDS patients. Then, we used the MDS transgenic mice model and cell line to explore the drug mechanism. In normal and MDS cells, ADP does not show cellular toxicity but promotes differentiation. In mouse MDS models, we observed that ADP showed significant efficacy on promoting erythropoiesis. In the BFU-E and CFU-E assays, ADP could promote erythropoiesis not only in normal clones but also in MDS clones. Mechanistically, we found that ADP could downregulate HIF1A in MDS clones through upregulation of VHL, P53 and MDM2, which is involved in two parallel pathways to downregulate HIF1A. We also confirmed that ADP upregulates GATA factors in normal clones. Thus, our clinical and experimental studies indicate that ADP is a promising drug to promote erythropoiesis in both MDS and normal clones with a superior outcome than current regular therapies. ADP promotes erythropoiesis in myelodysplastic syndromes via downregulation of HIF1A and upregulation of GATA factors.


Assuntos
Arsenicais/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Eritropoese/efeitos dos fármacos , Fatores de Transcrição GATA/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Síndromes Mielodisplásicas/tratamento farmacológico , Animais , Linhagem Celular , Regulação para Baixo , Humanos , Camundongos , Pós , Estudos Retrospectivos , Regulação para Cima
6.
In Vivo ; 35(1): 155-162, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33402461

RESUMO

BACKGROUND/AIM: Arsenic trioxide (As2O3) is an environmental pollutant. However, the detailed mechanisms about As2O3-induced loss of endothelial integrity are unknown. This study aimed at investigating how As2O3 causes endothelial dysfunction and whether baicalin can reverse such dysfunction. MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVECs) were used to examine As2O3-induced oxidative stress, and apoptosis. The influence of baicalin on As2O3-induced endothelial dysfunction were investigated. RESULTS: The viability of HUVECs was inhibited by As2O3 and cells underwent apoptosis. As2O3 treatment increased NADPH oxidase activity, and elevated the level of reactive oxygen species (ROS). Formamidopyrimidine DNA-glycosylase- and endonuclease III-digestible adducts were accumulated. Baicalin reversed As2O3-induced apoptosis and As2O3-suppressed cell viability. Baicalin caused a decrease in NADPH oxidase activity, and re-balanced the ROS level. As2O3-induced formamidopyrimidine DNA-glycosylase- and endonuclease III-digestible adducts were down-regulated. CONCLUSION: Baicalin was found to have the potential capacity to protect endothelial cells from As2O3-induced cytotoxicity.


Assuntos
Arsenicais , Apoptose , Trióxido de Arsênio , Arsenicais/farmacologia , Flavonoides , Células Endoteliais da Veia Umbilical Humana , Humanos , Estresse Oxidativo , Óxidos/toxicidade , Espécies Reativas de Oxigênio
7.
J Enzyme Inhib Med Chem ; 36(1): 372-376, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33390061

RESUMO

Burkholderia territorii, a Gram-negative bacterium, encodes for the ι-class carbonic anhydrase (CA, EC 4.2.1.1) BteCAι, which was recently characterised. It acts as a good catalyst for the hydration of CO2 to bicarbonate and protons, with a kcat value of 3.0 × 105 s-1 and kcat/KM value of 3.9 × 107 M-1 s-1. No inhibition data on this new class of enzymes are available to date. We report here an anion and small molecules inhibition study of BteCAι, which we prove to be a zinc(II)- and not manganese(II)-containing enzyme, as reported for diatom ι-CAs. The best inhibitors were sulphamic acid, stannate, phenylarsonic acid, phenylboronic acid and sulfamide (KI values of 6.2-94 µM), whereas diethyldithiocarbamate, tellurate, selenate, bicarbonate and cyanate were submillimolar inhibitors (KI values of 0.71-0.94 mM). The halides (except iodide), thiocyanate, nitrite, nitrate, carbonate, bisulphite, sulphate, hydrogensulfide, peroxydisulfate, selenocyanate, fluorosulfonate and trithiocarbonate showed KI values in the range of 3.1-9.3 mM.


Assuntos
Ânions/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Burkholderia/enzimologia , Anidrases Carbônicas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Arsenicais/farmacologia , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Ácidos Borônicos/farmacologia , Burkholderia/química , Dióxido de Carbono/química , Dióxido de Carbono/metabolismo , Anidrases Carbônicas/química , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Sulfonamidas/farmacologia , Ácidos Sulfônicos/farmacologia , Compostos de Estanho/farmacologia , Zinco/química , Zinco/metabolismo
8.
Infect Disord Drug Targets ; 21(4): 608-618, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32718300

RESUMO

BACKGROUND: COVID-19 is a life-threatening novel corona viral infection to our civilization and spreading rapidly. Tremendousefforts have been made by the researchers to search for a drug to control SARS-CoV-2. METHODS: Here, a series of arsenical derivatives were optimized and analyzed with in silico study to search the inhibitor of RNA dependent RNA polymerase (RdRp), the major replication factor of SARS-CoV-2. All the optimized derivatives were blindly docked with RdRp of SARS-CoV-2 using iGEMDOCK v2.1. RESULTS: Based on the lower idock score in the catalytic pocket of RdRp, darinaparsin (-82.52 kcal/- mol) was revealed to be the most effective among them. Darinaparsin strongly binds with both Nsp9 replicase protein (-8.77 kcal/mol) and Nsp15 endoribonuclease (-8.3 kcal/mol) of SARS-- CoV-2 as confirmed from the AutoDock analysis. During infection, the ssRNA of SARS-CoV-2 is translated into large polyproteins forming viral replication complex by specific proteases like 3CL protease and papain protease. This is also another target to control the virus infection where darinaparsin also performs the inhibitory role to proteases of 3CL protease (-7.69 kcal/mol) and papain protease (-8.43 kcal/mol). CONCLUSION: In the host cell, the furin protease serves as a gateway to the viral entry and darinaparsin docked with furin protease, which revealed a strong binding affinity. Thus, screening of potential arsenic drugs would help in providing the fast in-vitro to in-vivo analysis towards the development of therapeutics against SARS-CoV-2.


Assuntos
Antivirais/farmacologia , Arsenicais , Glutationa , SARS-CoV-2/efeitos dos fármacos , Arsenicais/farmacologia , COVID-19 , Simulação por Computador , Glutationa/análogos & derivados , Glutationa/farmacologia , Humanos , Simulação de Acoplamento Molecular , Peptídeo Hidrolases , Inibidores de Proteases/farmacologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores
9.
Chem Soc Rev ; 50(4): 2260-2279, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33367452

RESUMO

Pnictogens (the non-metal phosphorus, metalloids arsenic and antimony, and metal bismuth) possess diverse chemical characteristics that support the formation of extended molecular structures. As witnessed by the centuries-old (and ongoing) clinical utilities, pnictogen-based compounds have secured their places in history as "magic bullet" therapeutic drugs in medicinal contexts. Moreover, with the development of recent metalloproteomics and bio-coordination chemistry, the pnictogen-based drugs functionally binding to proteins/enzymes in biological systems have been underlaid for "drug repurposing" with promising opportunities. Furthermore, advances in the modern materials science and nonotechnology have stimulated a revolution in other newly discovered forms of pnictogens-phosphorene, arsenene, antimonene, and bismuthine (layered pnictogens). Based on their favorable optoelectronic properties, layered pnictogens have shown dramatic superiority as emerging photonic nanomedicines for the treatment of various diseases. This tutorial review outlines the history and mechanism of action of ancient pnictogen-based drugs (e.g., arsenical compounds in traditional Chinese medicine) and their repurposing into modern therapeutics. Then, the revolutionary use of emerging layered pnictogens as photonic nanomedicines, alongside assessments of their in vivo biosafety, is discussed. Finally, the challenges to further development of pnictogens are set forth and insights for further exploration of their appealing properties are offered. This tutorial review may also provide some deep insights into the fields of integrated traditional Chinese and Western medicines from the perspective of materials science and nanotechnology.


Assuntos
Antimônio/química , Arsenicais/química , Bismuto/química , Nanoestruturas/química , Preparações Farmacêuticas/química , Compostos de Fósforo/química , Animais , Antimônio/farmacologia , Arsenicais/farmacologia , Materiais Biocompatíveis/química , Bismuto/farmacologia , Humanos , Imunoterapia , Estrutura Molecular , Nanomedicina , Dispositivos Ópticos , Compostos de Fósforo/farmacologia , Fototerapia , Ligação Proteica , Radioterapia
10.
J Ethnopharmacol ; 268: 113559, 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33159994

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Realgar has been used in traditional remedies for a long history in China and India. It is clinically used to treat diverse cancers, especially acute promyelocytic leukemia (APL), chronic myelogenous leukemia (CML) in China. However, paradoxic roles of realgar to increase or decrease immunity are reported. It is urgent to address this question, due to immune depression can be strongly benefit to cancer development, but detrimental to patients. AIM OF THE STUDY: This present work is to explore whether realgar promote or suppress immune responses, and shed light on its mode of action. Our results should provide cues for rational strategy to explore realgar for clinical use. MATERIAL AND METHODS: Infection model in vivo was established by using Enterococcus faecalis to attack Caenorhabditis elegans, then realgar was used to treat the infected worms to investigate its effects on infectivity and the underlying mechanism. Killing analysis was carried out to test whether realgar can mitigate worm infection. Thermotolerance resistance analysis was used to evaluate if realgar functions hormetic effect. Quantification of live E. faecalis in nematode intestine was employed to ascertain if realgar alleviate the bacterial load in worm gut. Quantitative real-time PCR (qRT-PCR) was used to test the expression of antibacterial effectors. Western blot was used to test the effect of realgar on the expressions of p38 and phospho-p38 in worms infected by E. faecalis. RESULTS: Realgar alleviated the infected worms in strains of N2, glp-4, and daf-2, but failed in sek-1, glp-4; sek-1, and daf-2; daf-16 when p38 MAPK or daf-16 was blocked or inactivated. Western blot assay demonstrated that realgar increased the expression of phosph-p38. Thermotolerance assay showed that realgar played a hormetic role on nemtodes, triggered protective response and reduced bacterial load after realgar treatment for 120 h qRT-PCR demonstrated that realgar significantly increased antibacterial effectors, thus leading to pathogen elimination. CONCLUSION: Realgar increased defenses against E. faecalis in C. elegans by inducing both immune responses and protective responses. It was regulated by p38 MAPK pathway and DAF-16.


Assuntos
Arsenicais/uso terapêutico , Enterococcus faecalis/efeitos dos fármacos , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Sulfetos/uso terapêutico , Animais , Animais Geneticamente Modificados , Arsenicais/farmacologia , Caenorhabditis elegans , Enterococcus faecalis/enzimologia , Enterococcus faecalis/imunologia , Infecções por Bactérias Gram-Positivas/enzimologia , Infecções por Bactérias Gram-Positivas/imunologia , Sulfetos/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
11.
Commun Biol ; 3(1): 792, 2020 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-33361775

RESUMO

The stereocilia of the inner ear sensory cells contain the actin-binding protein radixin, encoded by RDX. Radixin is important for hearing but remains functionally obscure. To determine how radixin influences hearing sensitivity, we used a custom rapid imaging technique to visualize stereocilia motion while measuring electrical potential amplitudes during acoustic stimulation. Radixin inhibition decreased sound-evoked electrical potentials. Other functional measures, including electrically induced sensory cell motility and sound-evoked stereocilia deflections, showed a minor amplitude increase. These unique functional alterations demonstrate radixin as necessary for conversion of sound into electrical signals at acoustic rates. We identified patients with RDX variants with normal hearing at birth who showed rapidly deteriorating hearing during the first months of life. This may be overlooked by newborn hearing screening and explained by multiple disturbances in postnatal sensory cells. We conclude radixin is necessary for ensuring normal conversion of sound to electrical signals in the inner ear.


Assuntos
Proteínas do Citoesqueleto/metabolismo , Células Ciliadas Auditivas Externas/metabolismo , Proteínas de Membrana/metabolismo , Estereocílios/metabolismo , Estimulação Acústica , Alelos , Animais , Arsenicais/farmacologia , Pré-Escolar , Proteínas do Citoesqueleto/genética , Modelos Animais de Doenças , Feminino , Imunofluorescência , Expressão Gênica , Variação Genética , Genótipo , Cobaias , Células Ciliadas Auditivas Externas/efeitos dos fármacos , Perda Auditiva/diagnóstico , Perda Auditiva/genética , Humanos , Mecanotransdução Celular/genética , Proteínas de Membrana/genética , Modelos Biológicos , Linhagem , Estereocílios/efeitos dos fármacos
12.
Sci Rep ; 10(1): 17872, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087770

RESUMO

The FDA-approved prophylactic antimalarial drug atovaquone (ATO) recently was repurposed as an antitumor drug. Studies show that ATO exerts a profound antiproliferative effect in several cancer cells, including breast, ovarian, and glioma. Analogous to the mechanism of action proposed in parasites, ATO inhibits mitochondrial complex III and cell respiration. To enhance the chemotherapeutic efficacy and oxidative phosphorylation inhibition, we developed a mitochondria-targeted triphenylphosphonium-conjugated ATO with varying alkyl side chains (Mito4-ATO, Mito10-ATO, Mito12-ATO, and Mito16-ATO). Results show, for the first time, that triphenylphosphonium-conjugated ATO potently enhanced the antiproliferative effect of ATO in cancer cells and, depending upon the alkyl chain length, the molecular target of inhibition changes from mitochondrial complex III to complex I. Mito4-ATO and Mito10-ATO inhibit both pyruvate/malate-dependent complex I and duroquinol-dependent complex III-induced oxygen consumption whereas Mito12-ATO and Mito16-ATO inhibit only complex I-induced oxygen consumption. Mitochondrial target shifting may have immunoregulatory implications.


Assuntos
Atovaquona/farmacologia , Proliferação de Células/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Animais , Antimaláricos/farmacologia , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Arsenicais/farmacologia , Atovaquona/química , Atovaquona/metabolismo , Linhagem Celular Tumoral , Respiração Celular/efeitos dos fármacos , Complexo I de Transporte de Elétrons/efeitos dos fármacos , Complexo III da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Humanos , Camundongos , Mitocôndrias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Compostos Organofosforados/química , Fosforilação Oxidativa , Óxidos/farmacologia , Consumo de Oxigênio/efeitos dos fármacos
13.
J Nat Prod ; 83(9): 2809-2813, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32830503

RESUMO

Arsinothricin [AST (1)], a new broad-spectrum organoarsenical antibiotic, is a nonproteinogenic analogue of glutamate that effectively inhibits glutamine synthetase. We report the chemical synthesis of an intermediate in the pathway to 1, hydroxyarsinothricin [AST-OH (2)], which can be converted to 1 by enzymatic methylation catalyzed by the ArsM As(III) S-adenosylmethionine methyltransferase. This is the first report of semisynthesis of 1, providing a source of this novel antibiotic that will be required for future clinical trials.


Assuntos
Antibacterianos/síntese química , Arsenicais/síntese química , Antibacterianos/farmacologia , Arsenicais/farmacologia , Cromatografia Líquida de Alta Pressão , Inibidores Enzimáticos/farmacologia , Glutamato-Amônia Ligase/antagonistas & inibidores , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , S-Adenosilmetionina/antagonistas & inibidores
14.
J Biochem Mol Toxicol ; 34(11): e22581, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32662241

RESUMO

Consecutive substitution reactions of arsenic(III)chloride with sodium salts of various oximes and morpholinedithiocarbamate (morphdtc) were carried out in 1:2:1 stoichiometry to obtain six new arsenic(III) mixed derivatives of the type: [(R)(R1 )C = NO]2 Sb[S2 CN(CH2 CH2 )2 O] [where R is -C6 H5 , R1 = -CH3 (1); R = -C6 H4 CH3 , R1 = -CH3 (2); R = -C6 H4 Cl, R1 = -CH3 (3); R = -C6 H4 Br, R1 = -CH3 (4); R = -C6 H4 OH, R1 = -H (5); R(R1 )C = (6)]. These derivatives are characterized by elemental and physicochemical analyses and the tentative distorted trigonalbipyramidal geometry around arsenic assigned using spectral data of infrared (1 H, 13 C) nuclear magnetic resonance and liquid chromatography-mass. Powder X-ray diffraction study revealed their nanoranged particle size to be approximately 40 nm and crystalline nature. These derivatives examined against microbes and results revealed that these derivatives expressed more antifungal potential than antibacterial. The antioxidant activity was carried out by ferric reducing ability of plasma assay, and the cytotoxic study was performed in 3T3 fibroblast cell lines by tetrazolium-based colorimetric assay.


Assuntos
Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Arsenicais/farmacologia , Morfolinas/farmacologia , Oximas/farmacologia , Tiocarbamatos/farmacologia , Testes de Sensibilidade Microbiana , Morfolinas/química , Análise Espectral/métodos , Tiocarbamatos/química
15.
Dalton Trans ; 49(25): 8774-8784, 2020 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-32555816

RESUMO

Four triphenylamine/carbazole-modified half-sandwich ruthenium(ii) compounds [(η6-p-cymene)Ru(N/O^N)Cl]0/+ with Schiff base chelating ligands (N/O^N) are synthesized and characterized. The introduction of Schiff base units effectively increases the antitumor activity of these compounds (IC50: 1.70 ± 0.56-17.75 ± 3.10 µM), which, meanwhile, can inhibit the metastasis of tumor cells effectively. These compounds follow an energy-dependent cellular uptake mechanism, mainly accumulate in lysosomes to destroy their integrity, and then eventually promote apoptosis. In addition, these compounds can induce an increase of intracellular reactive oxygen species (ROS) levels and provide an antitumor mechanism of oxidation, which is confirmed by the decrease of mitochondrial membrane potential (MMP) and the catalytic oxidation of the coenzyme nicotinamide-adenine dinucleotide (NADH). All these indicate that these ruthenium(ii) compounds are expected to be dual-functional antitumor agents: anti-metastasis and lysosomal damage.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Organelas/efeitos dos fármacos , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Arsenicais/química , Arsenicais/farmacologia , Carbazóis/química , Carbazóis/farmacologia , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Conformação Molecular , Imagem Óptica , Organelas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Rutênio/química , Rutênio/farmacologia , Bases de Schiff/química , Bases de Schiff/farmacologia , Relação Estrutura-Atividade
16.
Arch Toxicol ; 94(8): 2587-2601, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32435915

RESUMO

Arsenic is a well-known environmental carcinogen and chronic exposure to arsenic through drinking water has been reported to cause skin, bladder and lung cancers, with arsenic metabolites being implicated in the pathogenesis. In contrast, arsenic trioxide (As2O3) is an effective therapeutic agent for the treatment of acute promyelocytic leukemia, in which the binding of arsenite (iAsIII) to promyelocytic leukemia (PML) protein is the proposed initial step. These findings on the two-edged sword characteristics of arsenic suggest that after entry into cells, arsenic reaches the nucleus and triggers various nuclear events. Arsenic is reduced, conjugated with glutathione, and methylated in the cytosol. These biotransformations, including the production of reactive metabolic intermediates, appear to determine the intracellular dynamics, target organs, and biological functions of arsenic.


Assuntos
Antineoplásicos/farmacologia , Intoxicação por Arsênico/etiologia , Trióxido de Arsênio/farmacologia , Arsenicais/farmacologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Animais , Antineoplásicos/metabolismo , Intoxicação por Arsênico/metabolismo , Trióxido de Arsênio/metabolismo , Arsenicais/metabolismo , Biotransformação , Humanos , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Medição de Risco , Testes de Toxicidade
17.
Drug Des Devel Ther ; 14: 1641-1650, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32431489

RESUMO

Background: Previous studies have shown that DNA methylation plays a significant role in myelodysplastic syndrome (MDS). In addition to hypermethylation, aberrant hypomethylation can result in the transcriptional activation of oncogenes in cancer, including MDS. Therefore, drugs targeting DNA hypomethylation are needed for the treatment of MDS. This study aimed to investigate whether As2S2 promoted hypomethylation by increasing DNA methyltransferases (DNMTs) expression in MDS. Patients and Methods: Ten bone marrow samples from MDS patients and 3 healthy donors were obtained for the examination of the DNA methylation with a Human Methylation 850K BeadChip. The mRNA expressions for the DNMTs in the ten MDS patients and 3 controls were compared by Q-PCR. Then, the MDS cell line SKM-1 was treated with As2S2. After 2 days of treatment, Human Methylation 850K BeadChip was applied to analyze the changes of gene methylation status in the cells. Q-PCR and Western blot were taken to test the changes of mRNA and protein expressions for DNMTs in SKM-1 cells after treatment. Results: Five hundred ninety-two abnormally hypomethylated genes were found in MDS patients compared to those in controls by Human Methylation 850K. The mRNA expressions of DNMTs (DNMT1, DNMT3a and DNMT3b) in MDS patients were significantly lower than those in healthy individuals. The IC50 value of As2S2 for SKM-1 cells was 4.97 µmol/L.Treatment with As2S2 at 2 µmoL/L resulted in significant alterations in the methylation levels at 1718 sites in SKM-1 cells compared to those in the controls. Hypermethylation was observed in 1625 sites (94.58%), corresponding to 975 genes, compared to those in the controls. Finally, the expression levels of DNMTs (DNMT1, DNMT3a, and DNMT3b) significantly increased in SKM-1 cells treated with As2S2 at 2 µmoL/L and 4 µmoL/L. Conclusion: These data show a potential clinical application of As2S2 as an innovative hypermethylation agent in MDS.


Assuntos
Arsenicais/farmacologia , DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA/efeitos dos fármacos , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/enzimologia , Sulfetos/farmacologia , Adulto , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , DNA (Citosina-5-)-Metiltransferases/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Relação Estrutura-Atividade , Adulto Jovem
18.
Zhongguo Zhong Yao Za Zhi ; 45(1): 142-148, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-32237423

RESUMO

The aim of this paper was to observe the effect of Realgar and arsenic trioxide on gut microbiota. The mice were divided into low-dose Realgar group(RL), medium-dose Realgar group(RM), high-dose Realgar group(RH), and arsenic trioxide group(ATO), in which ATO and RL groups had the same trivalent arsenic content. Realgar and arsenic trioxide toxicity models were established after intragastric administration for 1 week, and mice feces were collected 1 h after intragastric administration on day 8. The effects of Realgar on gut microbiota of mice were observed through bacterial 16 S rRNA gene sequences. The results showed that Lactobacillus was decreased in all groups, while Ruminococcus and Adlercreutzia were increased. The RL group and ATO group were consistent in the genera of Prevotella, Ruminococcus, and Adlercreutzia but different in the genera of Lactobacillus and Bacteroides. Therefore, the effects of Realgar and arsenic trioxide with the same amount of trivalent arsenic on gut microbiota were similar, but differences were still present. Protective bacteria such as Lactobacillus were reduced after Realgar administration, causing inflammation. At low doses, the number of anti-inflammatory bacteria, such as Ruminococcus, Adlercreutzia and Parabacteroides increased, which can offset the slight inflammation caused by the imbalance of bacterial flora. At high doses, the flora was disturbed and the number of Proteobacteria was increased, with aggravated intestinal inflammation, causing edema and other inflammatory reactions. Based on this, authors believe that the gastrointestinal reactions after clinical use of Realgar may be related to flora disorder. Realgar should be used at a small dose in combination with other drugs to reduce intestinal inflammation.


Assuntos
Trióxido de Arsênio/farmacologia , Arsenicais/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Sulfetos/farmacologia , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Camundongos
19.
J Proteome Res ; 19(5): 1999-2010, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32223133

RESUMO

Arsenic trioxide (ATO) is a therapeutic agent used to treat acute promyelocytic leukemia (APL), a disease caused by a chromosomal translocation of the retinoic acid receptor α (RARα) gene that can occur reciprocally with the promyelocytic leukemia (PML) gene. The mechanisms through which ATO exerts its effects on cells are not fully characterized though they involve the SUMOylation, the ubiquitylation, and the degradation of the PML/RARα oncoprotein through the PML moiety. To better understand the mechanisms that underlie the cytotoxicity induced with increasing ATO levels, we profiled the changes in protein SUMOylation, phosphorylation, and ubiquitylation on HEK293 cells following exposure to low (1 µM) or elevated (10 µM) ATO for 4 h. Our analyses revealed that a low dose of ATO resulted in the differential modification of selected substrates including the SUMOylation (K380, K394, K490, and K497) and ubiquitylation (K337, K401) of PML. These experiments also highlighted a number of unexpected SUMOylated substrates involved in DNA damage response (e.g., PCNA, YY1, and poly[ADP-ribose] polymerase 1 (PARP1)) and messenger RNA (mRNA) splicing (e.g., ACIN1, USP39, and SART1) that were regulated at higher ATO concentrations. Interestingly, additional enzymatic assays revealed that SUMOylation of PARP1 impeded its proteolytic cleavage by caspase-3, suggesting that SUMOylation could have a protective role in delaying cell apoptosis.


Assuntos
Antineoplásicos , Arsenicais , Antineoplásicos/farmacologia , Trióxido de Arsênio , Arsenicais/farmacologia , Células HEK293 , Humanos , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Óxidos/farmacologia , Ubiquitina , Proteases Específicas de Ubiquitina
20.
Mater Sci Eng C Mater Biol Appl ; 110: 110683, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32204110

RESUMO

Multifunctional nanoparticulate systems, especially those used in medicine, are currently of great interest. In this work, the in-vitro anticancer activity of As4S4/Fe3O4 composites dispersed in a water solution of Poloxamer 407 on breast MCF-7 and tongue SCC-25 cancer cells was verified. An increase in apoptotic cells as a consequence of higher caspase activities, a decrease in mitochondrial membrane potential and an accumulation of cells in the G2/M and subG0/G1 phases were detected after treatment with the As4S4/Fe3O4 nanosuspensions. The sterically stabilized nanosuspensions were characterized in relation to their particle size distribution, zeta potential and long-term stability properties. The interaction between the solid and liquid phases of the nanosuspensions was also studied using Fourier transform infrared spectroscopy.


Assuntos
Antineoplásicos/farmacologia , Arsenicais/farmacologia , Compostos Férricos/farmacologia , Nanopartículas/química , Sulfetos/farmacologia , Suspensões/química , Caspases/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Fenômenos Magnéticos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Nanocompostos/química , Nanocompostos/ultraestrutura , Tamanho da Partícula , Reprodutibilidade dos Testes , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática , Temperatura
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...