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1.
Anticancer Res ; 39(9): 4687-4698, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519568

RESUMO

BACKGROUND/AIM: Propagermanium (PG) inhibits the CCL2/CCR2 axis, and has been shown to function as an immune modulator. This study investigated its anti-tumor mechanism in patients with refractory cancers. MATERIALS AND METHODS: Five healthy volunteers and 23 patients with refractory oral (n=8) or gastric (n=15) cancer received PG (30 mg/day). We performed flow cytometry (FCM) of peripheral blood mononuclear cells and in vitro killing assays. RESULTS: FCM revealed that CD16+/CD56Dim NK cells (i.e., mature, cytolytic subset) increased, and the apoptosis induction rate of cancer cells increased after PG administration. Among gastric cancer patients, median OS was 172.0 days. Two patients showed complete remission of lung or liver metastasis. Survival of patients with oral cancer also tended to be prolonged. CONCLUSION: PG induces NK cell maturation, and may potentiate anti-tumor activity.


Assuntos
Antineoplásicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Neoplasias/imunologia , Neoplasias/mortalidade , Compostos Organometálicos/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Estimativa de Kaplan-Meier , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Tomografia Computadorizada por Raios X
2.
Inorg Chem ; 58(17): 11294-11299, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31411862

RESUMO

The first two examples of polyoxopalladates(II) (POPs) containing tetravalent metal ion guests, [MO8Pd12(PO4)8]12- (M = SnIV, PbIV), have been prepared and structurally characterized in the solid state, solution, and gas phase. The interactions of the metal ion guests and the palladium-oxo shell were studied by theoretical calculations. The POPs were shown to possess anticancer activity by causing oxidative stress inducing caspase activation and consecutive apoptosis of leukemic cells.


Assuntos
Antineoplásicos/farmacologia , Metais Pesados/química , Compostos Organometálicos/farmacologia , Polímeros/química , Antineoplásicos/síntese química , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Humanos , Íons/química , Modelos Moleculares , Compostos Organometálicos/síntese química , Compostos Organometálicos/química
3.
Inorg Chem ; 58(17): 11782-11792, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31433630

RESUMO

Reproduction of the dominant vector of Zika and dengue diseases, Aedes aegypti mosquito, is controlled by an active heterodimer complex composed of the 20-hydroxyecdysone receptor (EcR) and ultraspiracle protein. Although A. aegypti EcR shares the structural and functional organization with other nuclear receptors, its C-terminus has an additional long F domain (AaFEcR). Recently, we showed that the full length AaFEcR is intrinsically disordered with the ability to specifically bind divalent metal ions. Here, we describe the details of the exhaustive structural and thermodynamic properties of Zn2+- and Cu2+-complexes with the AaFEcR domain, based on peptide models of its two putative metal binding sites (Ac-HGPHPHPHG-NH2 and Ac-QQLTPNQQQHQQQHSQLQQVHANGS-NH2). Unexpectedly, only in the presence of increasing concentrations of Cu2+ ions, the Ac-HGPHPHPHG-NH2 peptide gained a metal ion-induced poly-l-proline type II helical structure, which is unique for members of the family of nuclear receptors.


Assuntos
Aedes/efeitos dos fármacos , Antivirais/farmacologia , Cobre/farmacologia , Compostos Organometálicos/farmacologia , Peptídeos/farmacologia , Receptores de Esteroides/antagonistas & inibidores , Animais , Antivirais/química , Sítios de Ligação/efeitos dos fármacos , Cobre/química , Dengue/tratamento farmacológico , Dengue/metabolismo , Estrutura Molecular , Compostos Organometálicos/química , Peptídeos/química , Receptores de Esteroides/metabolismo , Termodinâmica , Infecção por Zika virus/tratamento farmacológico , Infecção por Zika virus/metabolismo
4.
Inorg Chem ; 58(17): 11649-11655, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31436093

RESUMO

A new mixed-valent dicopper complex [5] was generated from ligand exchange by dissolving a bis(CH3CN) precursor [3] in acetone. Introduction of a water molecule in place of an acetonitrile ligand was evidenced by base titration and the presence of a remaining coordinated CH3CN by IR, 19F NMR, and theoretical methods. The proposed structure (CH3CN-Cu-(SR)-Cu-OH2) was successfully DFT-optimized and the calculated parameters are in agreement with the experimental data. [5] has a unique temperature-dependence EPR behavior, with a localized valence from 10 to 120 K that undergoes delocalized at room temperature. The electrochemical signatures are in the line of the other aquo parent [2] and sensibly different from the rest of the series. Similar to the case of [2], [5] was finally capable of single turnover N2O reduction at room temperature. N2 was detected by GC-MS, and the redox character was confirmed by EPR and ESI-MS. Kinetic data indicate a reaction rate order close to 1 and a rate 10 times faster compared to [2]. [5] is thus the second example of that kind and highlights not only the main role of the Cu-OH2 motif, but also that the adjacent Cu-X partner (X = OTf- in [2] and CH3CN in [5]) is a new actor in the casting to establish structure/activity correlations.


Assuntos
Cobre/farmacologia , Inibidores Enzimáticos/farmacologia , Compostos Organometálicos/farmacologia , Oxirredutases/antagonistas & inibidores , Peptídeos/farmacologia , Cobre/química , Teoria da Densidade Funcional , Técnicas Eletroquímicas , Inibidores Enzimáticos/química , Estrutura Molecular , Compostos Organometálicos/química , Oxirredutases/metabolismo , Peptídeos/química
5.
Photochem Photobiol Sci ; 18(8): 2012-2022, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31282525

RESUMO

Organic-metal complexes are promising molecules for use in photodynamic therapy (PDT). The aim of this study was to investigate in vitro effects of novel Ru(ii) and Ir(iii) BODIPY complexes for PDT. These hybrid organic-metal molecules (Ru-BD and Ir-BD) have been synthesized via reactions of a BODIPY precursor (BD) with a phenanthroline unit bearing Ru(ii) (3) and novel Ir(iii) (4) compounds. The crystal structures of the new distyryl BODIPY (BD) and Ru(ii) complex (3) are also reported. The photophysical and singlet oxygen generation properties of Ru-BD and Ir-BD were investigated in comparison with unsubstituted BODIPY (BD). Moreover, Ru-BD and Ir-BD have been biologically evaluated in vitro in chronic myeloid leukemia and cervical cancer cell lines in terms of photodynamic therapy efficacy in the presence of BD control. These complexes were not toxic in the dark but red light was needed to induce cell death. These data support the fact that Ru-BD could be accepted as a valuable photosensitizer-drug for further PDT treatment.


Assuntos
Antineoplásicos/farmacologia , Compostos de Boro/farmacologia , Corantes/farmacologia , Compostos Organometálicos/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos de Boro/síntese química , Compostos de Boro/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Corantes/síntese química , Corantes/química , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Irídio/química , Irídio/farmacologia , Modelos Moleculares , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Rutênio/química , Rutênio/farmacologia , Oxigênio Singlete/análise , Oxigênio Singlete/metabolismo , Células Tumorais Cultivadas
6.
Mol Immunol ; 112: 163-174, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31153046

RESUMO

Exposure to airborne particulate matter (PM) not only causes lung inflammation and chronic respiratory diseases, but also increases the incidence and mortality of cardiopulmonary diseases. The nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome activation has been shown to play a critical role in the formation of many chronic disorders. On the other hand, carbon monoxide (CO) has been shown to possess anti-inflammatory and antioxidant effects in many tissues and organs. Here, we investigated the effects and mechanisms of carbon monoxide releasing molecule-2 (CORM-2) on PM-induced inflammatory responses in human pulmonary alveolar epithelial cells (HPAEpiCs). We found that PM induced C-reactive protein (CRP) expression, NLRP3 inflammasome activation, IL-1ß secretion, and caspase-1 activation, which were inhibited by pretreatment with CORM-2. In addition, transfection with siRNA of Toll-like receptor 2 (TLR2) or TLR4 and pretreatment with an antioxidant (N-acetyl-cysteine, NAC), the inhibitor of NADPH oxidase (diphenyleneiodonium, DPI), or a mitochondria-specific superoxide scavenger (MitoTEMPO) reduced PM-induced inflammatory responses. CORM-2 also inhibited PM-induced NADPH oxidase activity and NADPH oxidase- and mitochondria-derived ROS generation. However, pretreatment with inactivate CORM-2 (iCORM-2) had no effects on PM-induced inflammatory responses. Finally, we showed that CORM-2 inhibited PM-induced CRP, NLRP3 inflammasome, and ASC protein expression in the lung tissues of mice and IL-1ß levels in the serum of mice. PM-enhanced leukocyte count in bronchoalveolar lavage fluid in mice was reduced by CORM-2. The results of this study suggested a protective role of CORM-2 in PM-induced lung inflammation by inhibiting the TLR2 and TLR4/ROS-NLRP3 inflammasome-CRP axial.


Assuntos
Inflamassomos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Compostos Organometálicos/farmacologia , Pneumonia/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/imunologia , Animais , Líquido da Lavagem Broncoalveolar , Monóxido de Carbono/efeitos adversos , Caspase 1/metabolismo , Humanos , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Material Particulado/efeitos adversos , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos
7.
Mol Med Rep ; 19(6): 5142-5152, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059081

RESUMO

The purpose of the present study was to investigate the effect of carbon monoxide (CO) released from CO­releasing molecule 2 (CORM­2) on mice with acute pancreatitis (AP). To perform the investigation, a mouse AP model was established using caerulein. The mice were treated with or without CORM­2. The survival rate of the mice in the different groups was analyzed, and serum amylase and lipase levels were measured to assess the degree of pancreatic injury. The severity of AP was also evaluated by histological examination, and histopathological scoring of the pancreatic damage was performed. Pancreatic cell apoptosis was analyzed using a terminal deoxynucleotidyl­transferase­mediated dUTP nick end labelling assay. The function of the lung and liver was also assessed in the present study. Furthermore, the role of CORM­2 on oxidative stress, intercellular adhesion molecule 1 (ICAM­1) and vascular cell adhesion molecule 1 (VCAM­1) expression, pro­inflammatory cytokine production, and nuclear factor (NF)­κB activation in the pancreas of AP mice was determined. The results demonstrated that CORM­2 reduced the mortality, pancreatic damage, and lung and liver injury of AP mice. CORM­2 administration also reduced systemic and localized inflammatory cell factors. Furthermore, treatment with CORM­2 inhibited the expression of ICAM­1 and VCAM­1, and the activation of NF­κB and phosphorylated inhibitor of NF­κB subunit α, in the pancreas of AP mice. These results indicated that CO released from CORM­2 exerted protective effects on AP mice, and the beneficial effects were likely due to inhibition of NF­κB pathway activation.


Assuntos
Monóxido de Carbono/metabolismo , Compostos Organometálicos/farmacologia , Pancreatite/prevenção & controle , Doença Aguda , Amilases/sangue , Animais , Ceruletídeo/toxicidade , Citocinas/metabolismo , Modelos Animais de Doenças , Molécula 1 de Adesão Intercelular/metabolismo , Lipase/sangue , Pulmão/metabolismo , Pulmão/patologia , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Compostos Organometálicos/química , Compostos Organometálicos/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Pâncreas/metabolismo , Pâncreas/patologia , Pancreatite/induzido quimicamente , Pancreatite/patologia , Peroxidase/metabolismo
8.
Eur J Med Chem ; 175: 269-286, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31096151

RESUMO

Organometallic complexes have widely been used for the treatment of various diseases viz., malaria, arthritis, syphilis, pernicious anemia, tuberculosis and particular in cancers. Recent decades have witnessed an upsurging interest in the application of organometallic compounds to treat various phenotypes of cancers with multiple etiologies. The unique and exceptional properties of organometallic compounds, intermediate between classical inorganic and organic materials provide new insight in the progress of inorganic medicinal chemistry. Herein, we have selectively focused on various organometallic sandwich and half-sandwich complexes of ruthenium (Ru), titanium (Ti), gold (Au) and iron (Fe) exhibiting promising activity towards a panel of cancer cell lines and resistant cancer cell lines. These complexes exhibit novel mechanisms of drug action through incorporation of outer-sphere recognition of molecular targets and controlled activation features based on ligand substitution along with monometallic and heterometallic redox processes. Furthermore, they are usually found to be uncharged or neutral possessing metals in a low oxidation state, exhibit kinetic stability, relative lipophilicity and are amenable to a host of various chemical transformations. This review mainly sheds light on the successful advancement of organometallic complexes as anticancer drug aspirants in relation to their versatile structural chemistry and innovative mechanisms of action targeting nucleic acids, several enzymes viz; thioredoxin reductases (Thrx), EGFR, transferrin, cathepsin B, topoisomerases etc.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Compostos Organometálicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Catepsina B/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , DNA Topoisomerases/efeitos dos fármacos , Receptores ErbB/efeitos dos fármacos , Ouro/química , Humanos , Neoplasias/patologia , Ácidos Nucleicos/efeitos dos fármacos , Compostos Organometálicos/química , Compostos Organometálicos/uso terapêutico , Rutênio/química , Tiorredoxina Dissulfeto Redutase/efeitos dos fármacos , Titânio/química , Transferrina/efeitos dos fármacos
9.
Cancer Sci ; 110(7): 2090-2099, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31111571

RESUMO

Inflammation plays an essential role in the development and progression of most cancers. Chemokine C-C motif chemokine 2 (CCL2) and its receptor C-C chemokine receptor type 2 (CCR2) constitute a key signaling axis in inflammation that has recently attracted much interest on the basis of evidence showing its association with cancer progression. Propagermanium (3-oxygermylpropionic acid polymer) is an organogermanium compound that is given for the treatment of hepatitis B in Japan and which inhibits the CCL2-CCR2 signaling pathway. Herein, we review the importance of the CCL2-CCR2 axis as a target in cancer treatment as shown by studies in mice and humans with pharmacological agents including propagermanium.


Assuntos
Antineoplásicos/farmacologia , Quimiocina CCL2/metabolismo , Neoplasias/tratamento farmacológico , Compostos Organometálicos/farmacologia , Receptores CCR2/metabolismo , Animais , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Japão , Camundongos , Neoplasias/imunologia , Compostos Organometálicos/química , Compostos Organometálicos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico
10.
Zhonghua Xin Xue Guan Bing Za Zhi ; 47(4): 311-317, 2019 Apr 24.
Artigo em Chinês | MEDLINE | ID: mdl-31060191

RESUMO

Objective: To investigate the protective effect of carbon monoxide releasing molecule 2 (CORM-2) on post-resuscitation myocardial dysfunction in rats. Methods: Forty male SD rats which were healthy were randomly divided into 5 groups: sham operated group(sham group), cardiopulmonary resuscitation(PCR) group, DMSO group, inactivated CORM-2(iCORM-2) group and CORM-2 group (n=8 each). Established the model of post-cardiac arrest myocardial dysfunction by intravenous potassium chloride (4 ℃) injection combined with asphyxiation for 4 minutes and then followed by artificial chest compression for 3 minutes. Sham group: rats were instrumented with catheter without inducing cardiac arrest and resuscitation, and intraperitoneal injection of 0.9% normal saline (4 ml/kg) was performed 12 hours before catheterization. CPR group: rats were instrumented with catheters and underwent CPR, and intraperitoneal injection of 0.9% normal saline (4 ml/kg) was performed 12 hours before surgery.CORM-2 group: rats were instrumented with catheters and underwent CPR, intraperitoneally injected the prepared CORM-2 solution (4 mg/kg) at 12 hours before surgery. DMSO group: rats were instrumented with catheters and underwent CPR, intraperitoneally injected the prepared DMSO solution (4 ml/kg) at 12 hours before surgery. iCORM-2 group: rats were instrumented with catheters and underwent CPR, iCORM-2 solution (4 mg/kg) was intraperitoneally injected at 12 hours before surgery. Hemodynamic data (MAP, +dp/dtmax, -dp/dt) were continuously monitored and recorded for 4 hours after resuscitation (or catheterization) in each group. Myocardial tissue specimen and blood samples were taken after resuscitation (or catheterization). The myocardial ultrastructure was observed by transmission electron microscope. Lactate dehydrogenase (LDH) activity was measured by lactate-pyruvate method. Serum creatine kinase isoenzyme (CK-MB) concentration was measured by ELISA. Western blot was used to detect the levels of Caspase-3, Caspase-9 and Cyt-C protein in myocardial tissue. Results: MAP, +dp/dtmax and -dp/dt at 0.5, 1, 2, 3 and 4 hours post resuscitation were significantly lower than those immediately after catheterization in CRP, DMSO, iCORM-2 groups (all P<0.05). MAP at 0.5, 1, 2, 3, and 4 hours post resuscitation were significantly lower in CRP, DMSO and iCORM-2 groups than those at respective time points in sham group (all P<0.05), while MAP was similar between CORM-2 group and Sham group at these time points (all P>0.05). +dp/dtmax and -dp/dt values at 0.5, 1, 2, 3, and 4 hours post resuscitation were lower than those at respective time points in sham group and significance was found at 0.5, 1 and 2 hours post resuscitation (both P<0.05), while +dp/dtmax and -dp/dt values were similar between CORM-2 group and sham group at various time points (all P>0.05). Myocardial ultrastructure, especially mitochondrial structural integrity was better preserved in the CORM-2 group than those in the other resuscitation groups at 4 hours after resuscitation. Serum LDH activity and CK-MB concentration were significantly elevated at 4 hours after resuscitation in the CPR group, DMSO group and iCORM-2 group than those in sham group (all P<0.01); CK-MB concentration was also higher in CORM-2 group than that in sham group,and LDH level was similar between CORM-2 group and sham group (P>0.05). Serum LDH activity and CK-MB concentrations were significantly lower in the CORM-2 group than those in the other resuscitation groups (all P<0.01). The myocardial expressions of Caspase-3, Caspase-9 and Cyt-C at 4 hours after resuscitation were significantly higher in the CPR group, DMSO group and iCORM-2 group than those in sham group; the myocardial expressions of Caspase-3 and Caspase-9 were significantly higher in CORM-2 group than those in sham group (both P<0.05), while Cyt-C expression was similar between CORM-2 group and sham group. The expressions of the above 3 proteins were significantly lower in the CORM-2 group than those in the other resuscitation groups (all P<0.05). Conclusions: CORM-2 can effectively alleviate post-resuscitation myocardial injury in rats with cardiopulmonary resuscitation and improve cardiac function. Protecting myocardial mitochondria and inhibiting mitochondrial apoptosis pathway may serve as the protective mechanisms in this model.


Assuntos
Reanimação Cardiopulmonar , Parada Cardíaca , Compostos Organometálicos , Animais , Monóxido de Carbono , Reanimação Cardiopulmonar/métodos , Parada Cardíaca/terapia , Masculino , Compostos Organometálicos/farmacologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
11.
Meat Sci ; 155: 85-90, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31100641

RESUMO

The study was conducted with 40 lambs Merino × Texel in order to determine the effects of 10 or 30 mg of Cu/kg DM of copper sulphate and copper-methionine on the lipid and cholesterol metabolism. The lambs were randomly distributed into 5 treatments, with 8 animals each. The treatments were: control, without cooper additions; 10 or 30 mg of Cu/kg DM in the form of copper sulphate; 10 or 30 mg of Cu/kg DM in the form of copper-methionine. The hepatic concentration of copper was higher in lambs supplemented with copper. Total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides in the serum, as well as the SFTU did not differ between treatments. The supplementation of copper regardless of source or level reduced the concentration of cholesterol in the LT muscle, and reduced the concentration of GSH and increased the concentration of GSSG in the liver. Additionally, there was a minimal effect on the fatty acid profile of lipid in lambs.


Assuntos
Ração Animal/análise , Sulfato de Cobre/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Metionina/farmacologia , Compostos Organometálicos/farmacologia , Animais , Colesterol/sangue , Cobre/análise , Sulfato de Cobre/administração & dosagem , Dieta/veterinária , Ácidos Graxos/análise , Fígado/química , Masculino , Distribuição Aleatória , Carneiro Doméstico , Triglicerídeos/sangue
12.
Mol Immunol ; 112: 30-39, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31075560

RESUMO

Traumatic brain injury (TBI) is a major cause of motor and cognitive impairment in young adults. It is associated with high mortality rates and very few effective treatment options. Bisperoxovanadium (pyridine-2-carboxyl) [bpV(pic)] is an commercially available inhibitor of Phosphatase and tensin homolog (PTEN). Previous studies have shown that bpV(pic) has protective effects in central nervous system. However, the role of bpV(pic) in TBI is unclear. In this study we aimed to investigate the neuroprotective role of bpV(pic) in rat TBI model. We found that injection of bpV(pic) significantly reduces brain edema and neurological dysfunction after TBI and this is mediated by AKT pathway. TBI is known to promote the M1 pro-inflammatory phenotype of microglial polarization and this effect is inhibited by bpV(pic) treatment which, instead promotes M2 microglial polarization in vivo and in vitro. We also found evidence of bpV(pic)-regulated neuroinflammation mediated by AKT activation and NF-κB p65 inhibition. BpV(pic) treatment also suppressed microglia in the peri-TBI region. MCP-1 is known to recruit monocytes and macrophages to promote inflammation, we show that bpV(pic) can inhibit TBI-induced up-regulation of MCP-1 via the AKT/NF-κB p65 signaling pathway. Taken together, our findings demonstrate that bpV(pic) plays a neuroprotective role in rat TBI, which may be achieved by inhibiting M1 microglia polarization and MCP-1 expression by modulating AKT/NF-κB p65 signaling pathway.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/metabolismo , Quimiocina CCL2/metabolismo , Microglia/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Microglia/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , NF-kappa B/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley
13.
Int J Mol Sci ; 20(9)2019 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-31060340

RESUMO

Heme oxygenase 1 (HO-1) and carbon monoxide were shown to normalize oxidative stress and inflammatory reactions induced by neuropathic pain in the central nervous system, but their effects in the locus coeruleus (LC) of animals with peripheral inflammation and their interaction with nitric oxide are unknown. In wild-type (WT) and knockout mice for neuronal (NOS1-KO) or inducible (NOS2-KO) nitric oxide synthases with inflammatory pain induced by complete Freund's adjuvant (CFA), we assessed: 1) antinociceptive actions of cobalt protoporphyrin IX (CoPP), an HO-1 inducer; 2) effects of CoPP and tricarbonyldichlororuthenium(II)dimer (CORM-2), a carbon monoxide-liberating compound, on the expression of HO-1, NOS1, NOS2, CD11b/c, GFAP,and mitogen-activated protein kinases (MAPK)in the LC. CoPP reduced inflammatory pain in different time-dependent manners in WT and KO mice. Peripheral inflammation activated astroglia in the LC of all genotypes and increased the levels of NOS1 and phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK 1/2) in WT mice. CoPP and CORM-2 enhanced HO-1 and inhibited astroglial activationin all genotypes. Both treatments blocked NOS1 overexpression,and CoPP normalized ERK 1/2 activation. This study reveals an interaction between HO-1 and NOS1/NOS2 during peripheral inflammation andshows that CoPP and CORM-2 improved HO-1 expression and modulated the inflammatory and/or plasticity changes caused by peripheral inflammation in the LC.


Assuntos
Inflamação/etiologia , Inflamação/metabolismo , Óxido Nítrico/metabolismo , Compostos Organometálicos/farmacologia , Protoporfirinas/farmacologia , Animais , Biomarcadores , Inflamação/patologia , Masculino , Camundongos , Camundongos Knockout , Óxido Nítrico Sintase Tipo I/genética , Óxido Nítrico Sintase Tipo II/genética , Compostos Organometálicos/química , Protoporfirinas/química
14.
Chem Commun (Camb) ; 55(32): 4695-4698, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30942201

RESUMO

This report demonstrates that changing the position of the carbon-metal bond in a polypyridyl cyclopalladated complex, i.e. going from PdL1 (N^N^C^N) to PdL2 (N^N^N^C), dramatically influences the photodynamic properties of the complex in cancer cells. This effect is primarily attributed to the significantly difference in absorbance and singlet oxygen quantum yields between the two isomers.


Assuntos
Antineoplásicos/farmacologia , Compostos Organometálicos/farmacologia , Paládio/química , Fármacos Fotossensibilizantes/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Linhagem Celular Tumoral , Teoria da Densidade Funcional , Humanos , Isomerismo , Luz , Modelos Químicos , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Compostos Organometálicos/efeitos da radiação , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Oxigênio Singlete/metabolismo
15.
Eur J Med Chem ; 171: 364-371, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30928708

RESUMO

The present work describes the synthesis and spectroscopic characterization of ten different metal complexes of sulfabenzamide and sulfamethoxazole as ligands (M-SBZ, M-SMZ). Spectroscopic methods such as 1H NMR, UV-Vis spectroscopy analysis, FTIR and XRD confirmed the coordination of both ligands to metals through the nitrogen and oxygen atoms of the sulfonamide group. Both sulfabenzamide and sulfamethoxazole metal complexes were active against Gram-positive and negative bacterial strains. Sulfamethoxazole complexes showed their MIC values from 0.125 to 2.000 g ml-1 and sulfabenzamide complexes exhibited related MIC values from 1.000 to 2.000 g ml-1. Finally Zn (II) sulfamethoxazole with an inexpensive and common metal displayed more activity than its free ligand drug.


Assuntos
Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Sulfametoxazol/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Relação Estrutura-Atividade , Sulfametoxazol/química , Sulfonamidas/química , Sulfonamidas/farmacologia
16.
Chem Biol Interact ; 306: 78-88, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30954465

RESUMO

SALEN- and SALAN-based complexes with catalytically active metal centers are very promising small molecules to be utilized as part of antioxidant therapies. Here we discuss a modified SALAN-type molecule armed with two phosphonate groups that significantly increase its water solubility and aid to furnish mono- or dinuclear complexes with Cu2+ ions. The regulation of the SOD-mimicking (i.e., catalytic) disproportionation reaction of the superoxide radical anion (O2•-) at pH ~7.5 could be achieved by adjusting the metal-to-ligand stoichiometry as confirmed by McCord-Fridovich and pulse radiolysis tests. The higher antioxidant activity of the dicopper complex can be explained by the better access of O2•- to the copper centers and their more positive Cu(II)/Cu(I) redox potential. Simultaneously the analysis of in vitro effect on cells morphology indicates that cytotoxicity is also affected by the metal-to-ligand ratio, however, the active complex molecules do not show notable cytotoxicity that, together with the observed SOD-like activities, makes them potential candidates for antioxidant therapies.


Assuntos
Antioxidantes/metabolismo , Cobre/farmacologia , Compostos Organometálicos/metabolismo , Superóxido Dismutase/metabolismo , Células 3T3-L1 , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cobre/química , Ligantes , Camundongos , Conformação Molecular , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Oxirredução
18.
Chem Commun (Camb) ; 55(26): 3833-3836, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30869688
19.
Toxicol Lett ; 308: 17-23, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30902667

RESUMO

Three-dimensional T1-weighted MRI of mouse brain in vivo (9.4 T, 80 µm isotropic resolution) identified assemblies of nerve cell bodies in the habenula, hippocampal formation, locus coeruleus, dorsal motor nucleus of vagus, and nucleus ambiguus as high signal intensities, while suppressing the signals of white matter by magnetization transfer and of extracellular water protons by saturation. These observations indicate the presence of intracellular water protons with T1 values shortened by paramagnetic ions as the source of the bright signal. One day after an intraventricular injection of gadobutrol, a macrocyclic gadolinium-based contrast agent, T1-weighted MRI signal intensities of the nerve cell assemblies in the habenula, hippocampal formation, and locus coeruleus increased significantly. With simultaneous saturation of long-T1 protons of extracellular water, this finding indicates a T1-shortening of the intracellular water protons as a result of their interaction with gadolinium ions.


Assuntos
Encéfalo/diagnóstico por imagem , Meios de Contraste/administração & dosagem , Imagem de Difusão por Ressonância Magnética/métodos , Aumento da Imagem/métodos , Compostos Organometálicos/administração & dosagem , Animais , Encéfalo/patologia , Meios de Contraste/farmacologia , Feminino , Injeções Intraventriculares , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/patologia , Compostos Organometálicos/farmacologia , Prótons , Água/análise
20.
Eur J Med Chem ; 168: 123-133, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30818174

RESUMO

The 1:1 stoichiometric reactions of 3-methoxy salicylaldehyde-4(N)-substituted thiosemicarbazones (H2L1-4) with [RuCpCl(PPh3)2] was carried out in methanol. The obtained complexes (1-4) were characterized by analytical, IR, absorption and 1H NMR spectroscopic studies. The structures of ligand [H2-3MSal-etsc] (H2L3) and complex [RuCp(Msal-etsc) (PPh3)] (3), were characterized by single crystal X-ray diffraction studies. The interaction of the ruthenium(II) complexes (1-4) with calfthymus DNA (CT-DNA) has been explored by absorption and emission titration methods. Based on the observations, an intercalative binding mode of DNA has been proposed. The protein binding abilities of the new complexes were monitored by quenching the tryptophan and tyrosine residues of BSA, as model protein. From the studies, it was found that the new ruthenium metallacycles exhibited better affinity than their precursors. The free radical scavenging assay suggests that all complexes effectively scavenged the DPPH radicals as compared to that of standard control ascorbic acid and scavenging activities of complexes are in the order of 4 > 2 > 3 > 1. In addition, ruthenium(II) complexes (2-4) also exhibited an excellent in vivo antioxidant activity as it was able to increase the survival of worms exposed to lethal oxidative and thermal stresses possibly through reducing the intracellular ROS levels. It was interesting to note that complexes 2-4 failed to increase the lifespan of mev-1 mutant worms having shortened lifespan due to the over production of free radicals. This data confirmed that complexes 2-4 conferred stress resistance in C. elegans, but they also require an endogenous detoxification mechanism for doing so. The genetic and reporter gene expression analysis revealed that complexes 2-4 maintained the intracellular redox status and offered stress protection through transactivation of antioxidant defence machinery genes gst-4 and sod-3 which are directly regulated by SKN-1 and DAF-16 transcription factors, respectively. Altogether, our results suggested that complexes 2-4 might play a crucial role in stress modulation and they perhaps exert almost similar effects in higher models, which is an important issue to be validated in future.


Assuntos
Antioxidantes/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Rutênio/farmacologia , Animais , Antioxidantes/síntese química , Antioxidantes/química , Caenorhabditis elegans/metabolismo , Relação Dose-Resposta a Droga , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Rutênio/química , Relação Estrutura-Atividade
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