RESUMO
In recent times, exploring the protective potential of medicinal plants has attracted increasing attention. To fight reactive oxygen species (ROS), which are key players in hepatic, cerebral and renal diseases, scientists have directed their efforts towards identifying novel compounds with antioxidant effects. Due to its unique composition, significant attention has been given to Cactus Seed Oil (CSO). Iron, as a metal, can be a potent generator of reactive oxygen species, especially hydroxyl radicals, via the Fenton and Haber-Weiss reactions. Here, we employed ferrous sulfate (FeSO4) to induce oxidative stress and DNA damage in mice. Then, we used CSO and Colza oil (CO) and evaluated the levels of the antioxidants (superoxide dismutase [SOD], glutathione peroxidase [GPx] and glutathione [GSH]) as well as a metabolite marker for lipid peroxidation (malondialdehyde [MDA]) relating to the antioxidant balance in the liver, brain and kidney. In addition, we measured DNA damage levels in hepatic tissue and the effects of CSO on it. Our study found that iron-dependent GPx activity decreases in the liver and the kidney tissues. Additionally, while iron decreased SOD activity in the liver, it increased it in the kidney. Interestingly, iron treatment resulted in a significant increase in hepatic MDA levels. In contrast, in brain tissue, there was a significant decrease under iron treatment. In addition, we found varying protective effects of CSO in alleviating oxidative stress in the different tissues with ameliorating DNA damage after iron overload in a mouse liver model, adding compelling evidence to the protective potential of CSO.
Assuntos
Antioxidantes , Encéfalo , Ferro , Rim , Fígado , Estresse Oxidativo , Óleos de Plantas , Sementes , Animais , Estresse Oxidativo/efeitos dos fármacos , Camundongos , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Antioxidantes/farmacologia , Fígado/metabolismo , Fígado/efeitos dos fármacos , Rim/metabolismo , Rim/efeitos dos fármacos , Óleos de Plantas/farmacologia , Óleos de Plantas/química , Sementes/química , Ferro/metabolismo , Masculino , Cactaceae/química , Peroxidação de Lipídeos/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Glutationa Peroxidase/metabolismo , Superóxido Dismutase/metabolismo , Glutationa/metabolismo , Compostos Ferrosos/farmacologia , Malondialdeído/metabolismoRESUMO
GalNAc-modified ferrous sulfide nanoparticles have been developed to conduct chemodynamic and gas therapy for fighting against orthotopic hepatocellular carcinoma. This nanomedicine owns good liver targeting ability, which takes full advantage of the tumor microenvironment to ensure the therapy effect and improve the safety.
Assuntos
Carcinoma Hepatocelular , Compostos Ferrosos , Neoplasias Hepáticas , Nanopartículas , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Humanos , Animais , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Nanopartículas/química , Camundongos , Antineoplásicos/química , Antineoplásicos/farmacologiaRESUMO
Kinesin-5 inhibitors offer cancer cell-targeted approach, thus securing reduced systemic toxicity compared to other antimitotic agents. By modifying the 1,4-dihydropyridine-based kinesin-5 inhibitor CPUYL064 with a ferrocenyl moiety (Fc), we designed and prepared a series of organometallic hybrids that show high antiproliferative activity, with the best compounds exhibiting up to 19-fold increased activity. This enhanced activity can be attributed to the presence of the ferrocenyl moiety.
Assuntos
Antineoplásicos , Proliferação de Células , Di-Hidropiridinas , Desenho de Fármacos , Compostos Ferrosos , Cinesinas , Di-Hidropiridinas/química , Di-Hidropiridinas/farmacologia , Di-Hidropiridinas/síntese química , Cinesinas/antagonistas & inibidores , Cinesinas/metabolismo , Humanos , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Metalocenos/química , Metalocenos/farmacologiaRESUMO
The antimicrobial and pro-healing properties remain critical clinical objectives for skin wound management. However, the escalating problem of antibiotic overuse and the corresponding rise in bacterial resistance necessitates an urgent shift towards an antibiotic-free approach to antibacterial treatment. The quest for antimicrobial efficacy while accelerating wound healing without antibiotic treatment have emerged as innovative strategies in skin wound treatment. Here, a dual-function hydrogel with antimicrobial and enhanced tissue-healing properties was developed by utilizing cyclodextrin, ferrocene, polyethyleneimine (PEI), and Bletilla striata polysaccharide (BSP), through multiple non-covalent interactions, which can intelligently release BSP by recognizing the wound inflammatory microenvironment through the cyclodextrin-ferrocene unit. Moreover, the porosity (65 % - 85 %), Young's modulus (400 KPa - 140 KPa), and DPPH scavenge rate (18 % - 40 %) of the hydrogel are modulated by varying the BSP content. The hydrogel exhibits outstanding antibacterial properties (98.3 % reduction of Escherichia coli observed after exposure to HTFC@BSP-20 for 24 h) and favorable biocompatibility. Furthermore, in a rat full-thickness skin wound model, the dual-function hydrogel significantly accelerates wound healing, increased CD31 expression promotes vascular regeneration, reduced TNF-α express and inhibited the inflammation. This multifunctional ROS responsive hydrogel provides a new perspective for antibiotics-free treatment of skin injuries.
Assuntos
Antibacterianos , Bandagens , Hidrogéis , Polissacarídeos , Espécies Reativas de Oxigênio , Cicatrização , Cicatrização/efeitos dos fármacos , Hidrogéis/química , Hidrogéis/farmacologia , Animais , Polissacarídeos/química , Polissacarídeos/farmacologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Antibacterianos/farmacologia , Antibacterianos/química , Inflamação/tratamento farmacológico , Orchidaceae/química , Escherichia coli/efeitos dos fármacos , Humanos , Pele/efeitos dos fármacos , Ciclodextrinas/química , Ciclodextrinas/farmacologia , Ratos Sprague-Dawley , Masculino , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , MetalocenosRESUMO
Frequent occurrence of wound infection caused by multiple-resistant bacteria (MRB) has posed a serious challenge to the current healthcare system relying on antibiotics. The development of novel antimicrobial materials with high safety and efficacy to heal wound infection is of great importance in combating this crisis. Herein, we prepared a promising antibacterial hydrogel by cross-linking ferrous ions (Fe2+) with the deprotonated carboxyl anion in sodium alginate (Na-ALG) to cure wound infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Interestingly, ferrous-modified Na-ALG (Fe-ALG) hydrogel demonstrated better properties compared to the traditional Na-ALG-based hydrogels, including injectability, self-healing, appropriate fluidity, high-water retention, potent MRSA-killing efficacy, and excellent biocompatibility. Importantly, the addition of Fe2+ enhances the antibacterial efficacy of the Na-ALG hydrogel, enabling it to effectively eliminate MRSA and accelerate the healing of antibiotic-resistant bacterial-infected wounds in a remarkably short period (10 days). This modification not only facilitates wound closure and fur generation, but also mitigates systemic inflammation, thereby effectively impeding the spread of MRSA to the lungs. Taken together, Fe-ALG hydrogel is a promising therapeutic material for treating wound infections by Staphylococcus aureus, especially by antibiotic-resistant strains like MRSA.
Assuntos
Alginatos , Antibacterianos , Compostos Ferrosos , Hidrogéis , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Cicatrização , Infecção dos Ferimentos , Alginatos/química , Alginatos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Hidrogéis/química , Hidrogéis/farmacologia , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Cicatrização/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/química , Animais , Infecções Estafilocócicas/tratamento farmacológico , Infecção dos Ferimentos/tratamento farmacológico , Infecção dos Ferimentos/microbiologia , Camundongos , Testes de Sensibilidade Microbiana , MasculinoRESUMO
Herein, we developed a paclitaxel prodrug (PSFc) through the conjugation of paclitaxel (PTX) and ferrocene via a redox-responsive disulfide bond. PSFc displays acid-enhanced catalytic activity of Fenton reaction and is capable of forming stable nanoparticles (PSFc NPs) through the assembly with distearoyl phosphoethanolamine-PEG2000. After being endocytosed, PSFc NPs could release PTX to promote cell apoptosis in response to overexpressed redox-active species of tumor cells. Meanwhile, the ferrocene-mediated Fenton reaction promotes intracellular accumulation of hydroxyl radicals and depletion of glutathione, thus leading to ferroptosis. Compared with the clinically used Taxol, PSFc NPs exhibited more potent in vivo antitumor outcomes through the combined effect of chemotherapy and ferroptosis. This study may offer insight into a facile design of a prodrug integrating different tumor treatment methods for combating malignant tumors.
Assuntos
Ferroptose , Compostos Ferrosos , Metalocenos , Paclitaxel , Pró-Fármacos , Paclitaxel/química , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Metalocenos/química , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Humanos , Animais , Camundongos , Ferroptose/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Camundongos Endogâmicos BALB C , Nanopartículas/química , Apoptose/efeitos dos fármacos , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologiaRESUMO
The clinical utility of chemotherapy is often compromised by its limited efficacy and significant side effects. Addressing these concerns, we have developed a self-assembled nanomicelle, namely SANTA FE OXA, which consists of hyaluronic acid (HA) conjugated with ferrocene methanol (FC), oxaliplatin prodrug (OXA(IV)) and ethylene glycol-coupled linoleic acid (EG-LA). Targeted delivery is achieved by HA binding to the CD44 receptors that are overexpressed on tumor cells, facilitating drug uptake. Once internalized, hyaluronidase (HAase) catalyzes the digestion of the SANTA FE OXA, releasing FC and reducing OXA(IV) into an active form. The active oxaliplatin (OXA) induces DNA damage and increases intracellular hydrogen peroxide (H2O2) levels via cascade reactions. Simultaneously, FC disrupts the redox balance within tumor cells, inducing ferroptosis. Both in vivo and in vitro experiments confirmed that SANTA FE OXA inhibited tumor growth by combining cascade chemotherapy and self-sensitized ferroptosis, achieving a tumor inhibition rate of up to 76.61 %. Moreover, this SANTA FE OXA significantly mitigates the systemic toxicity commonly associated with platinum-based chemotherapeutics. Our findings represent a compelling advancement in nanomedicine for enhanced cascade cancer therapy.
Assuntos
Antineoplásicos , Ferroptose , Compostos Ferrosos , Ácido Hialurônico , Micelas , Oxaliplatina , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Ferroptose/efeitos dos fármacos , Oxaliplatina/farmacologia , Oxaliplatina/química , Humanos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/química , Camundongos , Linhagem Celular Tumoral , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Metalocenos/química , Metalocenos/farmacologia , Pró-Fármacos/farmacologia , Pró-Fármacos/química , Ácido Linoleico/química , Ácido Linoleico/farmacologia , Camundongos Endogâmicos BALB C , Feminino , Camundongos Nus , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/farmacologia , Neoplasias/tratamento farmacológicoRESUMO
Photodynamic therapy (PDT) can destroy tumor cells by generating singlet oxygen (1O2) under light irradiation, which is limited by the hypoxia of the neoplastic tissue. Chemodynamic therapy (CDT) can produce toxic hydroxyl radical (â OH) to eradicate tumor cells by catalytic decomposition of endogenous hydrogen peroxide (H2O2), the therapeutic effect of which is highly dependent on the concentration of H2O2. Herein, we propose a BODIPY-ferrocene conjugate with a balanced 1O2 and â OH generation capacity, which can serve as a high-efficiency antitumor agent by combining PDT and CDT. The ferrocene moieties endow the as-prepared conjugates with the ability of chemodynamic killing of tumor cells. Moreover, combined PDT/CDT therapy with improved antitumor efficiency can be realized after exposure to light irradiation. Compared with the monotherapy by PDT or CDT, the BODIPY-ferrocene conjugates can significantly increase the intracellular ROS levels of the tumor cells after light irradiation, thereby inducing the tumor cell apoptosis at low drug doses. In this way, a synergistic antitumor treatment is achieved by the combination of PDT and CDT.
Assuntos
Antineoplásicos , Compostos de Boro , Compostos Ferrosos , Metalocenos , Fotoquimioterapia , Fármacos Fotossensibilizantes , Oxigênio Singlete , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Metalocenos/química , Compostos de Boro/química , Compostos de Boro/farmacologia , Humanos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Antineoplásicos/química , Antineoplásicos/farmacologia , Oxigênio Singlete/metabolismo , Oxigênio Singlete/química , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Peróxido de Hidrogênio/química , Radical Hidroxila/química , Radical Hidroxila/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
The immune-suppressive microenvironment of solid tumors is a key factor limiting the effectiveness of immunotherapy, which seriously threatens human life and health. Ferroptosis and apoptosis are key cell-death pathways implicated in cancers, which can synergistically activate tumor immune responses. Here, we developed a multifunctional composite hydrogel (CE-Fc-Gel) based on the self-assembly of poloxamer 407, cystamine-linked ιota-carrageenan (CA)-eicosapentaenoic acid (EPA), and ferrocene (Fc). CE-Fc-Gel improved targeting in tumor microenvironment due to its disulfide bonds. Moreover, CE-Fc-Gel promoted lipid peroxidation, enhanced reactive oxygen species (ROS) production, and decreased glutathione peroxidase 4 (GPX4), inducing ferroptosis by the synergistic effect of Fc and EPA. CE-Fc-Gel induced apoptosis and immunogenic cell death (ICD), thereby promoting dendritic cells (DCs) maturation and T cell infiltration. As a result, CE-Fc-Gel significantly inhibited primary and metastatic tumors in vivo. Our findings provide a novel strategy for enhancing tumor immunotherapy by combining apoptosis, ferroptosis, and ICD.
Assuntos
Apoptose , Carragenina , Ácido Eicosapentaenoico , Ferroptose , Compostos Ferrosos , Hidrogéis , Metalocenos , Ferroptose/efeitos dos fármacos , Animais , Hidrogéis/química , Hidrogéis/farmacologia , Metalocenos/química , Metalocenos/farmacologia , Apoptose/efeitos dos fármacos , Camundongos , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Carragenina/farmacologia , Ácido Eicosapentaenoico/farmacologia , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/química , Humanos , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Metástase Neoplásica , Microambiente Tumoral/efeitos dos fármacos , Feminino , Recidiva Local de Neoplasia/tratamento farmacológico , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacosRESUMO
Tris(pyrazolyl)methane (tpm), 2,2,2-tris(pyrazolyl)ethanol (tpmOH) and its esterification derivatives with ibuprofen and flurbiprofen (tpmIBU and tpmFLU) were used as ligands to obtain complexes of the type [Fe(tpmX)2]Cl2 (1-4). The tpmIBU and tpmFLU ligands and corresponding complexes 3 and 4 were characterized by IR and multinuclear NMR spectroscopy, and the structure of tpmIBU was elucidated by single crystal X-ray diffraction. Complexes 1-4 were also assessed for their behaviour in aqueous media (solubility in D2O, octanol/water partition coefficient, stability in physiological-like conditions). The antiproliferative activity of ligands and complexes was determined on A2780, A2780cis and A549 cancer cell lines and the non-cancerous HEK 293T and BJ cell lines. The ligands and complexes were investigated for their ability to inhibit COX-2 (cyclooxygenase) and HNE (4-hydroxynonenal) enzymes. Complexes 3 and 4 exhibited cytotoxicity that may be attributed predominantly to their bioactive fragments, while DNA binding and enhancement of ROS production do not appear to play any significant role.
Assuntos
Anti-Inflamatórios não Esteroides , Antineoplásicos , Complexos de Coordenação , Pirazóis , Humanos , Ligantes , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/síntese química , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/síntese química , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Metano/química , Metano/análogos & derivados , Metano/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Ciclo-Oxigenase 2/metabolismo , Aldeídos/química , Aldeídos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Estrutura Molecular , Ibuprofeno/química , Ibuprofeno/farmacologia , Modelos MolecularesRESUMO
Background: The regulation of divalent metal transporter-1 (DMT1) by insulin has been previously described in Langerhans cells and significant neuroprotection was found by insulin and insulin-like growth factor 1 treatment during experimental cerebral ischemia in acute ischemic stroke patients and in a rat 6-OHDA model of Parkinson's disease, where DMT1 involvement is described. According to the regulation of DMT1, previously described as a target gene of NF-kB in the early phase of post-ischemic neurodegeneration, both in vitro and in vivo, and because insulin controls the NFkB signaling with protection from ischemic cell death in rat cardiomyocytes, we evaluated the role of insulin in relation to DMT1 expression and function during ischemic neurodegeneration. Methods: Insulin neuroprotection is evaluated in differentiated human neuroblastoma cells, SK-N-SH, and in primary mouse cortical neurons exposed to oxygen glucose deprivation (OGD) for 8 h or 3 h, respectively, with or without 300 nM insulin. The insulin neuroprotection during OGD was evaluated in both cellular models in terms of cell death, and in SK-N-SH for DMT1 protein expression and acute ferrous iron treatment, performed in acidic conditions, known to promote the maximum DMT1 uptake as a proton co-transporter; and the transactivation of 1B/DMT1 mouse promoter, already known to be responsive to NF-kB, was analyzed in primary mouse cortical neurons. Results: Insulin neuroprotection during OGD was concomitant to the down-regulation of both DMT1 protein expression and 1B/DMT1 mouse promoter transactivation. We also showed the insulin-dependent protection from cell death after acute ferrous iron treatment. In conclusion, although preliminary, this evaluation highlights the peculiar role of DMT1 as a possible pharmacological target, involved in neuroprotection by insulin during in vitro neuronal ischemia and acute ferrous iron uptake.
Assuntos
Proteínas de Transporte de Cátions , Morte Celular , Regulação para Baixo , Insulina , Neurônios , Animais , Insulina/metabolismo , Insulina/farmacologia , Humanos , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Transporte de Cátions/genética , Camundongos , Morte Celular/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Linhagem Celular Tumoral , Fármacos Neuroprotetores/farmacologia , Ferro/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/patologia , Glucose/metabolismo , Compostos Ferrosos/farmacologiaRESUMO
The medicinal chemistry of ferrocene has gained its momentum after the discovery of biological activities of ferrocifen and ferroquine. These ferrocenyl drugs have been designed by replacing the aromatic moiety of the organic drugs, tamoxifen and chloroquine respectively, with a ferrocenyl unit. The promising biological activities of these ferrocenyl drugs have paved a path to explore the medicinal applications of several ferrocenyl conjugates. In these conjugates, the ferrocenyl moiety has played a vital role in enhancing or imparting the anticancer activity to the molecule. The ferrocenyl conjugates induce the cytotoxicity by generating reactive oxygen species and thereby damaging the DNA. In medicinal chemistry, the five membered nitrogen heterocycles (azoles) play a significant role due to their rigid ring structure and hydrogen bonding ability with the biomolecules. Several potent drug candidates with azole groups have been in use as chemotherapeutics. Considering the importance of ferrocenyl moiety and azole groups, several ferrocenyl azole conjugates have been synthesized and screened for their biological activities. Hence, in the view of a wide scope in the development of potent drugs based on ferrocenyl azole conjugates, herein we present the details of synthesis and the anticancer activities of ferrocenyl compounds bearing azole groups such as imidazole, triazoles, thiazole and isoxazoles.
Assuntos
Antineoplásicos , Azóis , Compostos Ferrosos , Compostos Heterocíclicos , Metalocenos , Azóis/química , Azóis/farmacologia , Azóis/síntese química , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Compostos Ferrosos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Humanos , Metalocenos/química , Metalocenos/farmacologia , Metalocenos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/síntese químicaRESUMO
Sonodynamic therapy (SDT) has been extensively studied as a new type of non-invasive treatment for mammary cancer. However, the poor water solubility and defective biocompatibility of sonosensitizers during SDT hinder the sonodynamic efficacy. Herein, a nanoplatform has been developed to achieve high efficient SDT against mammary cancer through the host-guest interaction of ß-cyclodextrin/5-(4-hydroxyphenyl)-10,15,20-triphenylporphyrin (ß-CD-TPP) and ferrocenecarboxylic acid/chitooligosaccharides (FC-COS). Moreover, the glucose oxidase (GOx) was loaded through electrostatic adsorption, which efficiently restricts the energy supply in tumor tissues, thus enhancing the therapeutic efficacy of SDT for tumors. Under optimal conditions, the entire system exhibited favorable water solubility, suitable particle size and viable biocompatibility. This facilitated the integration of the characteristics of starvation therapy and sonodynamic therapy, resulting in efficient inhibition of tumor growth with minimal side effects in vivo. This work may provide new insights into the application of natural oligosaccharides for construct multifunctional nanocarrier systems, which could optimize the design and development of sonodynamic therapy strategies and even combination therapy strategies.
Assuntos
Quitosana , Oligossacarídeos , Espécies Reativas de Oxigênio , Terapia por Ultrassom , Oligossacarídeos/química , Oligossacarídeos/farmacologia , Animais , Quitosana/química , Quitosana/farmacologia , Feminino , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Terapia por Ultrassom/métodos , beta-Ciclodextrinas/química , beta-Ciclodextrinas/farmacologia , Camundongos Endogâmicos BALB C , Linhagem Celular Tumoral , Glucose Oxidase/metabolismo , Glucose Oxidase/química , Nanopartículas/química , Quitina/química , Quitina/análogos & derivados , Quitina/farmacologia , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Neoplasias da Mama/terapia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Metalocenos/química , Metalocenos/farmacologia , Porfirinas/química , Porfirinas/farmacologiaRESUMO
The propagation of antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARGs) induced by the release of antibiotics poses great threats to ecological safety and human health. In this study, periodate (PI)/FeS2/simulated sunlight (SSL) system was employed to remove representative ARB, ARGs and antibiotics in water. 1 × 107 CFU mL-1 of gentamycin-resistant Escherichia coli was effectively disinfected below limit of detection in PI/FeS2/SSL system under different water matrix and in real water samples. Sulfadiazine-resistant Pseudomonas and Gram-positive Bacillus subtilis could also be efficiently sterilized. Theoretical calculation showed that (110) facet was the most reactive facet on FeS2 to activate PI for the generation of reactive species (·OH, ·O2-, h+ and Fe(IV)=O) to damage cell membrane and intracellular enzyme defense system. Both intracellular and extracellular ARGs could be degraded and the expression levels of multidrug resistance-related genes were downregulated during the disinfection process. Thus, horizontal gene transfer (HGT) of ARB was inhibited. Moreover, PI/FeS2/SSL system could disinfect ARB in a continuous flow reactor and in an enlarged reactor under natural sunlight irradiation. PI/FeS2/SSL system could also effectively degrade the HGT-promoting antibiotic (ciprofloxacin) via hydroxylation and ring cleavage process. Overall, PI/FeS2/SSL exhibited great promise for the elimination of antibiotic resistance from water.
Assuntos
Antibacterianos , Ciprofloxacina , Farmacorresistência Bacteriana , Compostos Ferrosos , Ciprofloxacina/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Farmacorresistência Bacteriana/genética , Luz Solar , Desinfecção/métodos , Purificação da Água/métodos , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Poluentes Químicos da Água , Microbiologia da Água , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/metabolismo , Bactérias/efeitos da radiação , Transferência Genética HorizontalRESUMO
Human African trypanosomiasis (HAT, sleeping sickness) and American trypanosomiasis (Chagas disease) are endemic zoonotic diseases caused by genomically related trypanosomatid protozoan parasites (Trypanosoma brucei and Trypanosoma cruzi, respectively). Just a few old drugs are available for their treatment, with most of them sharing poor safety, efficacy, and pharmacokinetic profiles. Only fexinidazole has been recently incorporated into the arsenal for the treatment of HAT. In this work, new multifunctional Ru(II) ferrocenyl compounds were rationally designed as potential agents against these pathogens by including in a single molecule 1,1'-bis(diphenylphosphino)ferrocene (dppf) and two bioactive bidentate ligands: pyridine-2-thiolato-1-oxide ligand (mpo) and polypyridyl ligands (NN). Three [Ru(mpo)(dppf)(NN)](PF6) compounds and their derivatives with chloride as a counterion were synthesized and fully characterized in solid state and solution. They showed in vitro activity on bloodstream T. brucei (EC50 = 31-160 nM) and on T. cruzi trypomastigotes (EC50 = 190-410 nM). Compounds showed the lowest EC50 values on T. brucei when compared to the whole set of metal-based compounds previously developed by us. In addition, several of the Ru compounds showed good selectivity toward the parasites, particularly against the highly proliferative bloodstream form of T. brucei. Interaction with DNA and generation of reactive oxygen species (ROS) were ruled out as potential targets and modes of action of the Ru compounds. Biochemical assays and in silico analysis led to the insight that they are able to inhibit the NADH-dependent fumarate reductase from T. cruzi. One representative hit induced a mild oxidation of low molecular weight thiols in T. brucei. The compounds were stable for at least 72 h in two different media and more lipophilic than both bioactive ligands, mpo and NN. An initial assessment of the therapeutic efficacy of one of the most potent and selective candidates, [Ru(mpo)(dppf)(bipy)]Cl, was performed using a murine infection model of acute African trypanosomiasis. This hit compound lacks acute toxicity when applied to animals in the dose/regimen described, but was unable to control parasite proliferation in vivo, probably because of its rapid clearance or low biodistribution in the extracellular fluids. Future studies should investigate the pharmacokinetics of this compound in vivo and involve further research to gain deeper insight into the mechanism of action of the compounds.
Assuntos
Compostos Ferrosos , Rutênio , Tripanossomicidas , Trypanosoma cruzi , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Compostos Ferrosos/síntese química , Trypanosoma cruzi/efeitos dos fármacos , Ligantes , Tripanossomicidas/farmacologia , Tripanossomicidas/química , Tripanossomicidas/síntese química , Animais , Rutênio/química , Rutênio/farmacologia , Camundongos , Metalocenos/química , Metalocenos/farmacologia , Metalocenos/síntese química , Trypanosoma brucei brucei/efeitos dos fármacos , Testes de Sensibilidade Parasitária , Estrutura Molecular , Compostos Organometálicos/farmacologia , Compostos Organometálicos/química , Compostos Organometálicos/síntese química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese químicaRESUMO
Supramolecular hydrogels serve as an excellent platform to enable in situ reactive oxygen species (ROS) generation while maintaining controlled localized conditions, thereby mitigating cytotoxicity. Herein, we demonstrate hydrogel formation using guanosine-5'-monophosphate (GMP) with tetra(4-carboxylphenyl) ethylene (1) to exhibit aggregation-induced emission (AIE) and tunable mechanical strength in the presence of divalent metal ions such as Ca2+, Mg2+, and Fe2+. The addition of divalent metal ions leads to structural transformation in the metallogels (M-1GMP). Furthermore, the incorporation of Fe2+ ions into the hydrogel (Fe-1GMP) promotes the Fenton reaction that could be upregulated upon adding ascorbic acid (AA), demonstrating antibacterial efficacy via ROS generation. In vitro studies on AA-loaded Fe-1GMP demonstrate excellent bacterial killing efficacy against E. coli, S. aureus and vancomycin-resistant enterococci (VRE) strains. Finally, in vivo studies involving topical administration of Fe-1GMP to Balb/c mice with skin infections further suggest the potential antibacterial efficacy of the hydrogel. Taken together, the hydrogel with its unique combination of mechanical tunability, ROS generation capability and antibacterial efficacy can be used for biomedical applications, particularly in wound healing and infection control.
Assuntos
Antibacterianos , Escherichia coli , Hidrogéis , Ferro , Camundongos Endogâmicos BALB C , Espécies Reativas de Oxigênio , Staphylococcus aureus , Antibacterianos/farmacologia , Antibacterianos/química , Hidrogéis/química , Hidrogéis/farmacologia , Animais , Staphylococcus aureus/efeitos dos fármacos , Camundongos , Escherichia coli/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Ferro/química , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/farmacologia , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Testes de Sensibilidade Microbiana , Ácido Ascórbico/química , Ácido Ascórbico/farmacologia , Ácido Ascórbico/análogos & derivadosRESUMO
Combination therapy has emerged as a promising approach for treating tumors, although there is room for improvement. This study introduced a novel strategy that combined the enhancement of apoptosis, ferroptosis, and DNA damage to improve therapeutic outcomes for prostate cancer. Specifically, we have developed a supramolecular oxidative stress nanoamplifier, which was comprised of ß-cyclodextrin, paclitaxel, and ferrocene-poly(ethylene glycol). Paclitaxel within the system disrupted microtubule dynamics, inducing G2/M phase arrest and apoptosis. Concurrently, ferrocene utilized hydrogen peroxide to generate toxic hydroxyl radicals in cells through the Fenton reaction, triggering a cascade of reactive oxygen species expansion, reduction of glutathione levels, lipid peroxidation, and ferroptosis. The increased number of hydroxyl radicals and the inhibitory effect of THZ531 on DNA repair mechanisms exacerbated DNA damage within tumor cells. As expected, the supramolecular nanoparticles demonstrated excellent drug delivery ability to tumor cells or tissues, exhibited favorable biological safety in vivo, and enhanced the killing effect on prostate cancer.
Assuntos
Estresse Oxidativo , Paclitaxel , Neoplasias da Próstata , Paclitaxel/farmacologia , Paclitaxel/química , Humanos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Animais , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Camundongos , Metalocenos/química , Nanopartículas/química , Apoptose/efeitos dos fármacos , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Linhagem Celular Tumoral , beta-Ciclodextrinas/química , Polietilenoglicóis/química , Camundongos Nus , Ferroptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Dano ao DNA/efeitos dos fármacosRESUMO
We have red-shifted the light absorbance property of a Re(I)-tricarbonyl complex via distant conjugation of a ferrocene moiety and developed a novel complex ReFctp, [Re(Fctp)(CO)3Cl], where Fctp = 4'-ferrocenyl-2,2':6',2â³-terpyridine. ReFctp showed green to red light absorption ability and blue emission, indicating its potential for photodynamic therapy (PDT) application. The conjugation of ferrocene introduced ferrocene-based transitions, which lie at a higher wavelength within the PDT therapeutic window. The time-dependent density functional theory and excited state calculations revealed an efficient intersystem crossing for ReFctp, which is helpful for PDT. ReFctp elicited both PDT type I and type II pathways for reactive oxygen species (ROS) generation and facilitated NADH (1,4-dihydro-nicotinamide adenine dinucleotide) oxidation upon exposure to visible light. Importantly, ReFctp showed effective penetration through the layers of clinically relevant 3D multicellular tumor spheroids and localized primarily in mitochondria (Pearson's correlation coefficient, PCC = 0.65) of A549 cancer cells. ReFctp produced more than 20 times higher phototoxicity (IC50 â¼1.5 µM) by inducing ROS generation and altering mitochondrial membrane potential in A549 cancer cells than the nonferrocene analogue Retp, [Re(CO)3(tp)Cl], where tp = 2,2':6',2â³-terpyridine. ReFctp induced apoptotic mode of cell death with a notable photocytotoxicity index (PI, PI = IC50dark/IC50light) and selectivity index (SI, SI = normal cell's IC50dark/cancer cell's IC50light) in the range of 25-33.
Assuntos
Antineoplásicos , Compostos Ferrosos , Luz , Metalocenos , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Humanos , Metalocenos/química , Metalocenos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/efeitos da radiação , Antineoplásicos/síntese química , Espécies Reativas de Oxigênio/metabolismo , Teoria da Densidade Funcional , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/efeitos da radiação , Fármacos Fotossensibilizantes/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/efeitos da radiação , Complexos de Coordenação/síntese química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Luz VermelhaRESUMO
Ferrocene, ruthenium(II) and iridium(III) organometallic complexes, potential substitutes for platinum-based drugs, have shown good application prospects in the field of cancer therapy. Therefore, in this paper, six ferrocene-modified half-sandwich ruthenium(II) and iridium(III) propionylhydrazone complexes were prepared, and the anticancer potential was evaluated and compared with cisplatin. These complexes showed potential in-vitro anti-proliferative activity against A549 cancer cells, especially for Ir-based complexes, and showing favorable synergistic anticancer effect. Meanwhile, these complexes showed little cytotoxicity and effective anti-migration activity. Ir3, the most active complex (ferrocene-appended iridium(III) complex), could accumulate in the intracellular mitochondria, disturb the cell cycle (S-phase), induce the accumulation of reactive oxygen species, and eventually cause the apoptosis of A549 cells. Then, the design of these complexes provides a good structural basis for the multi-active nonplatinum organometallic anticancer complexes.
Assuntos
Antineoplásicos , Apoptose , Complexos de Coordenação , Compostos Ferrosos , Hidrazonas , Irídio , Metalocenos , Rutênio , Humanos , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Irídio/química , Irídio/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Metalocenos/química , Metalocenos/farmacologia , Rutênio/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Hidrazonas/química , Hidrazonas/farmacologia , Hidrazonas/síntese química , Células A549 , Apoptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Proliferação de Células/efeitos dos fármacosRESUMO
Due to the unique structure, carbon nanomaterials could convert near-infrared (NIR) light into heat efficiently in tumor ablation using photothermal therapy (PTT). However, none of them has been applied in clinical treatment, because they have not been approved for clinical evaluations and the precise temperature control facility is scarce. In this study, we designed a temperature-responsive controller for PTT and used carbon nanoparticles-Fe(II) complex (CNSI-Fe) as photothermal conversion agent (PTA) for PTT of tumor in vitro and in vivo. CNSI-Fe was an innovative drug under the evaluations in clinical trials. CNSI-Fe showed excellent photothermal conversion ability in water to increase the water temperature by 40⯰C within 5â¯min under irradiation of 808â¯nm laser at 0.5â¯W/cm2. The temperature was precisely controlled at 52⯰C for both in vitro and in vivo tumor inhibition. CNSI-Fe with NIR irradiation showed higher tumor cell inhibition than CNSI. In tumor bearing mice, CNSI-Fe with NIR irradiation achieved an inhibition rate of 84.7â¯% and 71.4â¯% of them were completely cured. Mechanistically, CNSI-Fe under NIR irradiation induced the radical generation, oxidative damage and ferroptosis to kill tumor. In addition, CNSI-Fe showed good biosafety during PTT according to hematological, serum biological and histopathological examinations. These results indicated that the combination of chemotherapy and PTT provided higher antitumor efficiency using CNSI-Fe as PTA.