RESUMO
The ongoing SARS-CoV-2 pandemic has caused a high demand for novel innovative antiviral drug candidates. Despite promising results, metal complexes have been relatively unexplored as antiviral agents in general and in particular against SARS-CoV-2. Here we report on silver NHC complexes with chloride or iodide counter ligands that are potent inhibitors of the SARS-CoV-2 papain-like protease (PLpro) but inactive against 3C-like protease (3CLpro) as another SARS-CoV-2 protease. Mechanistic studies on a selected complex confirmed zinc removal from a zinc binding domain of PLpro as relevant factor of their activity. In addition, enzyme kinetic experiments revealed that the complex is an uncompetitive inhibitor and with this rare type of inhibition it offers great pharmacological advantages in terms selectivity. The silver NHC complexes with iodide ligands showed very low or absent host cell toxicity and triggered strong effects on viral replication in cells infected with SARS-CoV-2, making them promising future antiviral drug candidates.
RESUMO
The urgent need to combat antibiotic resistance and develop novel antimicrobial therapies has triggered studies on novel metal-based formulations. N-heterocyclic carbene (NHC) complexes coordinate transition metals to generate a broad range of anticancer and/or antimicrobial agents, with ongoing efforts being made to enhance the lipophilicity and drug stability. The lead silver(I) acetate complex, 1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene (NHC*) (SBC3), has previously demonstrated promising growth and biofilm-inhibiting properties. In this work, the responses of two structurally different bacteria to SBC3 using label-free quantitative proteomics were characterised. Multidrug-resistant Pseudomonas aeruginosa (Gram-negative) and Staphylococcus aureus (Gram-positive) are associated with cystic fibrosis lung colonisation and chronic wound infections, respectively. SBC3 increased the abundance of alginate biosynthesis, the secretion system and drug detoxification proteins in P. aeruginosa, whilst a variety of pathways, including anaerobic respiration, twitching motility and ABC transport, were decreased in abundance. This contrasted the affected pathways in S. aureus, where increased DNA replication/repair and cell redox homeostasis and decreased protein synthesis, lipoylation and glucose metabolism were observed. Increased abundance of cell wall/membrane proteins was indicative of the structural damage induced by SBC3 in both bacteria. These findings show the potential broad applications of SBC3 in treating Gram-positive and Gram-negative bacteria.
RESUMO
The antimicrobial properties of silver have been exploited for many centuries and continue to gain interest in the fight against antimicrobial drug resistance. The broad-spectrum activity and low toxicity of silver have led to its incorporation into a wide range of novel antimicrobial agents, including N-heterocyclic carbene (NHC) complexes. The antimicrobial activity and in vivo efficacy of the NHC silver(I) acetate complex SBC3, derived from 1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene (NHC*), have previously been demonstrated, although the mode(s) of action of SBC3 remains to be fully elucidated. Label-free quantitative proteomics was applied to analyse changes in protein abundance in the pathogenic yeast Candida parapsilosis in response to SBC3 treatment. An increased abundance of proteins associated with detoxification and drug efflux were indicative of a cell stress response, whilst significant decreases in proteins required for protein and amino acid biosynthesis offer potential insight into the growth-inhibitory mechanisms of SBC3. Guided by the proteomic findings and the prolific biofilm and adherence capabilities of C. parapsilosis, our studies have shown the potential of SBC3 in reducing adherence to epithelial cells and biofilm formation and hence decrease fungal virulence.
Assuntos
Anti-Infecciosos , Candida parapsilosis , Anti-Infecciosos/química , Biofilmes , Testes de Sensibilidade Microbiana , Proteoma , Proteômica , Prata/química , Prata/farmacologia , VirulênciaRESUMO
Escherichia coli ranks as the number one clinical isolate in the past years in China according to The China Antimicrobial Surveillance Network (CHINET), and its multidrug-resistant (MDR) pathogenic strains account for over 160 million cases of dysentery and one million deaths per year. Here, our work demonstrates that E. coli is highly sensitive to the synergistic combination of SBC3 [1,3-Dibenzyl-4,5-diphenyl-imidazol-2-ylidene silver (I) acetate] and Ebselen, which shows no synergistic toxicity on mammalian cells. The proposed mechanism for the synergistic antibacterial effect of SBC3 in combination with Ebselen is based on directly inhibiting E. coli thioredoxin reductase and rapidly depleting glutathione, resulting in the increase of reactive oxygen species that cause bacterial cell death. Furthermore, the bactericidal efficacy of SBC3 in combination with Ebselen has been confirmed in mild and acute peritonitis mice. In addition, the five most difficult to treat Gram-negative bacteria (including E. coli, Acinetobacter baumannii, Enterobacter cloacae, Klebsiella pneumoniae, and Pseudomonas aeruginosa) are also highly sensitive to a synergistic combination of SBC3 and Ebselen. Thus, SBC3 in combination with Ebselen has potential as a treatment for clinically important Gram-negative bacterial infections.
RESUMO
N-heterocyclic silver carbene compounds have been extensively studied and shown to be active agents against a host of pathogenic bacteria and fungi. By incorporating hypothesized virulence targeting substituents into NHC-silver systems via salt metathesis, an atom-efficient complexation process can be used to develop new complexes to target the passive and active systems of a microbial cell. The incorporation of fatty acids and an FtsZ inhibitor have been achieved, and creation of both the intermediate salt and subsequent silver complex has been streamlined into a continuous flow process. Biological evaluation was conducted with in vitro toxicology assays showing these novel complexes had excellent inhibition against Gram-negative strains E. coli, P. aeruginosa, and K. pneumoniae; further studies also confirmed the ability to inhibit biofilm formation in methicillin-resistant Staphylococcus aureus (MRSA) and C. Parapsilosis. In vivo testing using a murine thigh infection model showed promising inhibition of MRSA for the lead compound SBC3, which is derived from 1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene (NHC*).
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Prata/química , Prata/farmacologia , Antibacterianos/síntese química , Complexos de Coordenação/síntese química , Ácidos Graxos/síntese química , Ácidos Graxos/química , Ácidos Graxos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Metano/análogos & derivados , Metano/síntese química , Metano/química , Metano/farmacologia , Modelos MolecularesRESUMO
Antibiotic resistance is a growing problem for public health and associated with increasing economic costs and mortality rates. Silver and silver-related compounds have been used for centuries due to their antimicrobial properties. In this work, we show that 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene silver(I) acetate/NHC*-Ag-OAc (SBC3) is a reversible, high affinity inhibitor of E. coli thioredoxin reductase (TrxR; Ki =10.8±1.2â nM). Minimal inhibition concentration (MIC) tests with different E. coli and P. aeruginosa strains demonstrated that SBC3 can efficiently inhibit bacterial cell growth, especially in combination with established antibiotics like gentamicin. Our results show that SBC3 is a promising antibiotic drug candidate targeting bacterial TrxR.
Assuntos
Antibacterianos/química , Proteínas de Escherichia coli/antagonistas & inibidores , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , Complexos de Coordenação/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/enzimologia , Proteínas de Escherichia coli/metabolismo , Gentamicinas/farmacologia , Imidazolinas/química , Imidazolinas/metabolismo , Imidazolinas/farmacologia , Cinética , Testes de Sensibilidade Microbiana , Compostos Organometálicos/química , Compostos Organometálicos/metabolismo , Compostos Organometálicos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Tiorredoxina Dissulfeto Redutase/metabolismoRESUMO
N-Heterocyclic carbene gold(I) complexes derived from 1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene (NHC*) represent a promising class of anticancer drugs. Complexes of the type NHC*-Au-L (L = Br-, I-, C≡C-R) and [NHC*-Au-L]+ (L = NHC*, PPh3) have been synthesised. The X-ray crystal structures of all gold(I) complexes are presented; aurophilic interactions were observed in five of the complexes. The anticancer activity was assessed via MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)-based proliferation assays against the human colon carcinoma cell line HCT-116wt and the multidrug-resistant human breast carcinoma cell line MCF-7topo. Most complexes showed good cytotoxicity with IC50 values in the low micromolar range, while excellent sub-micromolar activity was observed for 2c, 3a and 3b. Generally, the activity of the ligands studied was as follows: carbene > phosphine > alkyne > halide, with an exception for the highly active iodido derivative 2c.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Complexos de Coordenação/farmacologia , Ouro/química , Compostos Heterocíclicos/farmacologia , Antineoplásicos/química , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/patologia , Complexos de Coordenação/química , Feminino , Compostos Heterocíclicos/química , Humanos , Modelos Moleculares , Células Tumorais CultivadasRESUMO
The anticancer drug candidates 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative exhibited nanomolar in-vitro activity against prostate cancer cells advanced prostate cancer (PC3) and micromolar inhibition of mammalian thioredoxin reductase. Encouraging maximum tolerable dose experiments led to human prostate cancer subcutaneous xenograft experiments; 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative were applied twelve times at two doses in groups of n = 5 PC3 to tumor-bearing NMRI:nu/nu mice. 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative at the dose of 10 and 20 mg/kg showed good tolerability, while no significant body weight loss was seen in both groups. In particular, for the drug 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate the tumor growth inhibition suggested to be dose dependent, reflected by the respective optimal T/C values of 0.45 at the dose of 10 mg/kg and of 0.31 at the dose of 20 mg/kg. By contrast, the 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative treated groups showed no indication for dose-dependent antitumoral activity, as reflected by the optimal T/C values of 0.44 for the 10 mg/kg and for the 20 mg/kg treated mice. Immunohistochemical experiments involving Ki67 staining of tumor tissue showed that both compounds reduced PC3 cell proliferation against the difficult to treat advanced human prostate tumors derived from PC3.
Assuntos
Ouro/farmacologia , Compostos Organometálicos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Tiocarbamatos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Processos de Crescimento Celular/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Transportador de Glucose Tipo 1/química , Transportador de Glucose Tipo 1/metabolismo , Ouro/química , Humanos , Masculino , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Células PC-3 , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Distribuição Aleatória , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/química , Compostos de Sulfidrila/farmacologia , Tiocarbamatos/síntese química , Tiocarbamatos/química , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Tiorredoxina Dissulfeto Redutase/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The reactions of N-heterocyclic carbene CuI and AgI halides with potassium thio- or seleno-cyanate gave unexpected products. The attempted substitution reaction of bromido-(1,3-dibenzyl-4,5-di-phenyl-imidazol-2-yl-idene)silver (NHC*-Ag-Br) with KSCN yielded bis-[bis-(1,3-dibenzyl-4,5-di-phenyl-imidazol-2-yl-idene)silver(I)] tris-(thio-cyanato)-argentate(I) diethyl ether disolvate, [Ag(C29H24N2)2][Ag(NCS)3]·2C4H10O or [NHC*2Ag]2[Ag(SCN)3]·2Et2O, (1), while reaction with KSeCN led to bis-(µ-1,3-dibenzyl-4,5-diphenyl-2-seleno-imidazole-κ2 Se:Se)bis-[bromido-(1,3-dibenzyl-4,5-diphenyl-2-seleno-imid-azole-κSe)silver(I)] di-chloro-methane hexa-solvate, [Ag2Br2(C29H24N2Se)4]·6CH2Cl2 or (NHC*Se)4Ag2Br2·6CH2Cl2, (2), via oxidation of the NHC* fragment to 2-seleno-imidazole. This oxidation was observed again in the reaction of NHC*-Cu-Br with KSeCN, yielding catena-poly[[[(1,3-dibenzyl-4,5-diphenyl-2-seleno-imidazole-κSe)copper(I)]-µ-cyanido-κ2 C:N] aceto-nitrile monosolvate], {[Cu(CN)(C29H24N2Se)]·C2H3N} n or NHC*Se-CuCN·CH3CN, (3). Compound (1) represents an organic/inorganic salt with AgI in a linear coordination in each of the two cations and in a trigonal coordination in the anion, accompanied by diethyl ether solvent mol-ecules. The tri-blade boomerang-shaped complex anion [Ag(SCN)3]2- present in (1) is characterized by X-ray diffraction for the first time. Compound (2) comprises an isolated centrosymmetric mol-ecule with AgI in a distorted tetra-hedral BrSe3 coordination, together with di-chloro-methane solvent mol-ecules. Compound (3) exhibits a linear polymeric 1 ∞[Cu-C≡N-Cu-] chain structure with a seleno-imidazole moiety additionally coordinating to each CuI atom, and completed by aceto-nitrile solvent mol-ecules. Electron densities associated with an additional ether solvent mol-ecule in (1) and two additional di-chloro-methane solvent mol-ecules in (2) were removed with the SQUEEZE procedure [Spek (2015 â¸). Acta Cryst. C71, 9-18] in PLATON.
RESUMO
Ten novel N-heterocyclic carbene gold(I) complexes derived from lepidiline A (1,3-dibenzyl-4,5-dimethylimidazolium chloride) are reported here with full characterisation and biological testing. (1,3-Dibenzyl-4,5-diphenylimidazol-2-ylidene)gold(I) chloride (NHC*-AuCl) (1) was modified by substituting the chloride for the following: cyanide (2), dithiocarbamates (3â»5), p-mercaptobenzoate derivatives (12â»14) and N-acetyl-l-cysteine derivatives (15â»17). All complexes were synthesised in good yields of 57â»78%. Complexes 2, 12, 13, and 14 were further characterised by X-ray crystallography. Initial evaluation of the biological activity was conducted on all ten complexes against the multidrug resistant MCF-7topo breast cancer, HCT-116wt, and p53 knockout mutant HCT-116-/- colon carcinoma cell lines. Across the three cell lines tested, mainly single-digit micromolar IC50 values were observed. Nanomolar activity was exhibited on the MCF-7topo cell line with 3 displaying an IC50 of 0.28 µM ± 0.03 µM. Complexes incorporating a Auâ»S bond resulted in higher cytotoxic activity when compared to complexes 1 and 2. Theoretical calculations, carried out at the MN15/6â»311++G(2df,p) computational level, show that NHC* is the more favourable ligand for Au(I)-Cl when compared to PPh3.
Assuntos
Ouro , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Metano/análogos & derivados , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ouro/química , Compostos Heterocíclicos/química , Humanos , Espectroscopia de Ressonância Magnética , Metano/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Difração de Raios XRESUMO
Targeted delivery of potent cytotoxic drugs to cancer cells minimizes systemic toxicity and several side effects. NHC*-Au-Cl has already been proven to be a potent anticancer agent. In this study, we explore a strategy based on chemoselective cysteine conjugation of NHC*-Au-Cl to albumin and trastuzumab (Thiomab LC-V205C) to potentiate drug-ligand ratio, pharmacokinetics, as well as drug efficacy and safety. This strategy is a step forward towards the use of gold-based anticancer agents as targeted therapies.
Assuntos
Antineoplásicos/síntese química , Ouro/química , Imidazolinas/química , Albumina Sérica/química , Compostos de Sulfidrila/química , Trastuzumab/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisteína/química , Portadores de Fármacos/química , Meia-Vida , Humanos , Trastuzumab/farmacologiaRESUMO
Gold monochloride and monobromide can be transformed into monomeric complexes by ligands such as CO, PPh3 or Me2S, and such ligand-stabilized gold monochloride compounds have been investigated as catalysts, luminescent materials and anticancer drugs, especially when coordinated to a lipophilic benzyl-substituted N-heterocyclic carbene (NHC) ligand. The triclinic structures of NHC-Au-Cl {chlorido(1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene)gold, [AuCl(C29H24N2)]} and NHC-Au-Br {bromido(1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene)gold, [AuBr(C29H24N2)]}, determined by X-ray crystallography at 100â K, have one and four molecules, respectively, in their asymmetric units. The chloride compound shows an almost linear C-Au-Cl fragment [179.76â (8)°], with an Au-C distance of 1.976â (3)â Å and an Au-Cl distance of 2.3013â (6)â Å, while the bromide compound shows surprisingly large geometry deviations, from 1.969â (12) to 2.016â (10)â Å for the Au-C distance and from 2.4279â (14) to 2.4796â (12)â Å for the Au-Br distance, in the four independent molecules.
RESUMO
Late transition metal complexes that bear N-heterocyclic carbene (NHC) ligands have seen a speedy growth in their use as both, metal-based drug candidates and potentially active homogeneous catalysts in a plethora of C-C and C-N bond forming reactions. This review article focuses on the recent developments and advances in preparation and characterization of NHC-metal complexes (metal: silver, gold, copper, palladium, nickel and ruthenium) and their biomedical applications. Their design, syntheses and characterization have been reviewed and correlated to their antimicrobial and anticancer efficacies. All these initial discoveries help validate the great potential of NHC-metal derivatives as a class of effective antimicrobial and anticancer agents.
Assuntos
Anti-Infecciosos/química , Antineoplásicos/química , Complexos de Coordenação/química , Compostos Heterocíclicos/química , Metais/química , Metano/análogos & derivados , Animais , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/uso terapêutico , Humanos , Metais/farmacologia , Metais/uso terapêutico , Metano/química , Metano/farmacologia , Metano/uso terapêutico , Neoplasias/tratamento farmacológicoRESUMO
The antimicrobial drug candidate 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene silver(I) acetate (SBC3) was evaluated for its ability to function in vivo using larvae of Galleria mellonella. A SBC3 concentration of 25 µg/ml inhibited the growth of Staphylococcus aureus by 71.2% and Candida albicans by 86.2% in vitro. Larvae inoculated with 20 µl of SBC3 solution showed no ill effects up to a concentration of 250 µg/ml but administration of 500 µg/ml resulted in a 40% reduction in larval survival and administration of a dose of 1,000 µg/ml resulted in total larval death at 24 h. Larvae inoculated with S. aureus or C. albicans and subsequently administered SBC3 showed increased survival. Administration of SBC3 to larvae did not boost the insect immune response as indicated by lack of an increase in the density of circulating haemocytes (immune cells). The abundance of a number of proteins involved in the insect immune response was reduced in larvae that received 20 µl SBC3 solution of 100 µg/ml. This is the first demonstration of the in vivo activity of SBC3 against S. aureus and C. albicans and demonstrates that SBC3 does not stimulate a non-specific immune response in larvae.
Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Imidazolinas/farmacologia , Compostos Organometálicos/farmacologia , Animais , Candida albicans/efeitos dos fármacos , Candida albicans/imunologia , Imunidade Humoral , Proteínas de Insetos/metabolismo , Larva/efeitos dos fármacos , Larva/imunologia , Larva/metabolismo , Larva/microbiologia , Testes de Sensibilidade Microbiana , Mariposas/efeitos dos fármacos , Mariposas/imunologia , Mariposas/metabolismo , Mariposas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/imunologiaRESUMO
OBJECTIVES: Muscle wasting is common in patients with chronic heart failure (HF) and worsens functional status. Protein catabolism is characteristic of muscle wasting and contributes to resting energy expenditure (REE). Glucagonlike peptide 1 (GLP-1) is linked to REE in healthy individuals. We aimed to evaluate (1) whether REE is elevated in patients with HF with muscle wasting, and (2) whether basal GLP-1 levels are linked to REE in HF. DESIGN: Cross-sectional study. SETTING: Ambulatory patients with HF were recruited at the Charité Medical School, Campus Virchow-Klinikum, Berlin, Germany. PARTICIPANTS: A total of 166 patients with HF and 27 healthy controls participating in the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF) were enrolled. GLP-1 was measured in 55 of these patients. MEASUREMENTS: Body composition was measured by dual-energy X-ray absorptiometry (DEXA). Muscle wasting was defined as appendicular lean mass of at least 2 SDs below values of a healthy young reference group. REE was measured by indirect calorimetry. GLP-1 was assessed by ELISA. RESULTS: Thirty-four of 166 patients (mean age 67.4 ± 10.2 years, 77.7% male, New York Heart Association class 2.3 ± 0.6) presented with muscle wasting. REE in controls and patients with muscle wasting was significantly lower than in patients without muscle wasting (1579 ± 289 and 1532 ± 265 vs 1748 ± 359 kcal/d, P = .018 and P = .001, respectively). REE normalized for fat-free mass (FFM) using the ratio method (REE/FFM) and analysis of covariance was not different (P = .23 and .71, respectively). GLP-1 did not significantly correlate with REE (P = .49), even not after controlling for FFM using multivariable regression (P = .15). CONCLUSIONS: Differences in REE are attributable to lower FFM. GLP-1 does not relate to REE in patients with HF, possibly because of HF-related effects on REE.
Assuntos
Metabolismo Energético , Insuficiência Cardíaca/fisiopatologia , Descanso , Sarcopenia/fisiopatologia , Absorciometria de Fóton , Idoso , Composição Corporal , Doença Crônica , Comorbidade , Estudos Transversais , Feminino , Alemanha , Peptídeo 1 Semelhante ao Glucagon/análise , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Titanium(IV) complexes with a salan or cyclopentadienyl ligand showed different biological behaviour concerning binding to biomolecules, cellular accumulation and intracellular distribution. Binding efficacy as well as trafficking on the cellular level are crucial parameters for their biological effects.
Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Compostos Organometálicos/farmacologia , Titânio/farmacologia , Albuminas/metabolismo , Animais , Antineoplásicos/química , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , DNA/metabolismo , Embrião não Mamífero/efeitos dos fármacos , Células HT29 , Humanos , Ligantes , Células MCF-7 , Compostos Organometálicos/química , Titânio/química , Peixe-ZebraRESUMO
BACKGROUND: Smoking is a major risk factor in the development of coronary artery disease and thus chronic heart failure (HF). The value of self-reported smoking behaviour has not been validated in patients with HF. We sought to assess serum cotinine levels, a marker of recent tobacco exposure, in a cohort of clinically stable patients with chronic HF. METHODS AND RESULTS: We analysed serum cotinine values in 75 patients with chronic HF [mean age ± SD 64 ± 16 years, 85 % male, left ventricular ejection fraction 30 ± 1 %, New York Heart Association class (I/II vs. III/IV) 73 %/27 %, haemoglobin (Hb) 13.4 ± 1.5 g/dL, serum creatinine 1.21 ± 0.51 mg/dL] and 30 control subjects of similar age (63 ± 11 years, 43 % male, Hb 14.1 ± 1.5 g/dL, creatinine 1.12 ± 0.92 mg/dL) using a chemiluminescence immunoassay. Patients were interviewed about their smoking habits, and routine laboratory parameters were analysed. In patients with HF, cotinine values ranged from undetectable to 829 µg/L (mean 110 ± 208 µg/L). Similar findings were evident in healthy subjects with cotinine ranging from undetectable to 860 µg/L (mean 105 ± 208 µg/L). Serum cotinine levels correlated with leukocyte count and haemoglobin concentration (both p < 0.05). Self-reported smoking behaviour did not correspond to serum cotinine level in serum in 16.9 % of the patients with chronic HF. No such finding was evident in control subjects. CONCLUSIONS: Serum cotinine measurement provides an easily applicable means to analyse smoking behaviour in patients with chronic HF. Its assessment may permit analysis of smoking deception in daily clinical routine.
Assuntos
Cotinina/sangue , Comportamentos Relacionados com a Saúde , Conhecimentos, Atitudes e Prática em Saúde , Insuficiência Cardíaca/sangue , Autorrelato , Fumar/sangue , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Biomarcadores/sangue , Estudos de Casos e Controles , Doença Crônica , Creatinina/sangue , Feminino , Alemanha , Hábitos , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/psicologia , Hemoglobinas/análise , Humanos , Contagem de Leucócitos , Londres , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Análise de Regressão , Fumar/efeitos adversos , Fumar/psicologia , Volume Sistólico , Função Ventricular EsquerdaRESUMO
AIMS: To assess the prevalence and clinical impact of reductions in the skeletal muscle mass of patients with chronic heart failure (HF). Chronic HF is accompanied by co-morbidities that influence the quality of life and outcomes. METHODS AND RESULTS: We prospectively enrolled 200 patients with chronic HF. The appendicular skeletal muscle mass of the arms and the legs combined, was assessed by dual energy X-ray absorptiometry. We analysed the muscle strength in arms and legs, and all patients underwent a 6-min walk test, a 4-m walk test, and spiroergometry testing. Muscle wasting was defined as the appendicular muscle mass 2 SD below the mean of a healthy reference group of adults aged 18-40 years, as suggested for the diagnosis of muscle wasting in healthy ageing (sarcopenia). Muscle wasting was detected in 39 (19.5%) subjects. Patients with muscle wasting had significantly lower values for handgrip and quadriceps strength as well as lower total peak oxygen consumption (peakVO2, 1173 ± 433 vs. 1622 ± 456 mL/min), lower exercise time (7.7 ± 3.8 vs. 10.22 ± 3.0 min, both P < 0.001), and lower left ventricular ejection fraction (LVEF, P = 0.05) than patients without. The distance walked during 6 min and the gait speed during the 4-m walk were lower in patients with muscle wasting (both P < 0.05). Serum levels of interleukin-6 were significantly elevated in patients with muscle wasting (P = 0.001). Logistic regression showed muscle wasting to be independently associated with reduced peak VO2 adjusted for age, sex, New York Heart Association class, haemoglobin, LVEF, distance walked in 6 minutes, and the number of co-morbidities (odds ratio 6.53, p = 0.01). CONCLUSION: Muscle wasting is a frequent co-morbidity among patients with chronic HF. Patients with muscle wasting present with reduced exercise capacity and muscle strength, and advanced disease.
Assuntos
Insuficiência Cardíaca/complicações , Distrofias Musculares/complicações , Absorciometria de Fóton , Idoso , Doença Crônica , Feminino , Força da Mão/fisiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Força Muscular/fisiologia , Músculo Esquelético/fisiopatologia , Distrofias Musculares/fisiopatologia , Estudos Prospectivos , Músculo Quadríceps/fisiopatologia , Sarcopenia/complicações , Sarcopenia/fisiopatologia , Volume Sistólico/fisiologia , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
First-line treatment of small cell lung cancer (SCLC) with combination chemotherapy consisting of cis-diamminedichloroplatinum(II) (cisplatin) and etoposide is frequently followed by early relapses and a dismal prognosis. Survival of a fraction of tumor cells and development of chemoresistance may be influenced by an initial cellular stress response against the administered xenobiotics. Therefore, we compared the short-term effects of cisplatin and non-cross-resistant bis-[(p-methoxybenzyl)cyclopentadienyl] titanium(IV) dichloride (Titanocene Y) on phosphorylation of 46 sites of a total of 38 signaling proteins in tumor suppressor protein 53 (p53)-wild-type NCI-H526 SCLC cells. The functional significance of selected kinases for the cytotoxicity of both drugs was tested using specific inhibitors and an activator. The cisplatin-induced cellular stress response involved activation of p38α mitogen-activated protein kinase, whereas Titanocene Y-triggered signaling affected c-Jun N-terminal kinase. Phosphorylation of adenosine monophosphate (AMP)-activated protein kinase α1 (AMPKα1) was increased by both drugs, which promoted cell survival, as indicated by results obtained using AMPK inhibitor compound C and AMPK activator 5-aminoimidazole-4-carboxamide 1-ß-d-ribofuranoside. This is in good agreement with previous reports, where AMPKα1 was demonstrated to represent an important factor for the sensitivity to cisplatin in colon and ovarian cancers, most likely by induction of autophagy. Thus, AMPKα1 constitutes a potential target to be exploited for chemotherapeutic treatment of SCLC to circumvent resistance to metal-based compounds.
Assuntos
Antineoplásicos/toxicidade , Cisplatino/toxicidade , Neoplasias Pulmonares/metabolismo , Compostos Organometálicos/toxicidade , Fosfoproteínas/metabolismo , Carcinoma de Pequenas Células do Pulmão/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Compostos Organometálicos/farmacologia , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismoRESUMO
Six new titanocene compounds have been isolated and characterised. These compounds were synthesised from their fulvene precursors using Super Hydride (LiBEt3H) followed by transmetallation with titanium tetrachloride to yield the corresponding titanocene dichloride derivatives. These complexes are bis-[((1-methyl-3-diethylaminomethyl)indol-2-yl)methylcyclopentadienyl] titanium (IV) dichloride (5a), bis-[((5-methoxy-1-methyl,3-diethylaminomethyl)indol-2-yl)methylcyclopentadienyl] titanium (IV) dichloride (5b), bis-[((1-methyl,3-diethylaminomethyl)indol-4-yl)methylcyclopentadienyl] titanium (IV) dichloride (5c), bis-[((5-bromo-1-methyl)indol-3-yl)methylcyclopentadienyl] titanium (IV) dichloride (5d), bis-[((5-chloro-1-methyl)indol-3-yl)methylcyclopentadienyl] titanium (IV) dichloride (5e), and bis-[((5-fluoro-1-methyl)indol-3-yl)methylcyclopentadienyl] titanium (IV) dichloride (5f). All six titanocenes 5a-5f were tested for their cytotoxicity through MTT-based in vitro tests on CAKI-1 cell lines using DMSO and Soluphor P as solubilising agents in order to determine their IC50 values. Titanocenes 5a-5f were found to have IC50 values of 10 (±2), 21 (±3), 29 (±4), 140 (±6), and 450 (±10) µM when tested using DMSO.