RESUMO
Pentamethinium indolium salts are promising fluorescence probes and anticancer agents with high mitochondrial selectivity. We synthesized two indolium pentamethinium salts: a cyclic form with quinoxaline directly incorporated in the pentamethinium chain (cPMS) and an open form with quinoxaline substitution in the γ-position (oPMS). To better understand their properties, we studied their interaction with mitochondrial phospholipids (cardiolipin and phosphatidylcholine) by spectroscopic methods (UV-Vis, fluorescence, and NMR spectroscopy). Both compounds displayed significant affinity for cardiolipin and phosphatidylcholine, which was associated with a strong change in their UV-Vis spectra. Nevertheless, we surprisingly observed that fluorescence properties of cPMS changed in complex with both cardiolipin and phosphatidylcholine, whereas those of oPMS only changed in complex with cardiolipin. Both salts, especially cPMS, display high usability in mitochondrial imaging and are cytotoxic for cancer cells. The above clearly indicates that conjugates of pentamethinium and quinoxaline group, especially cPMS, represent promising structural motifs for designing mitochondrial-specific agents.
Assuntos
Antineoplásicos , Cardiolipinas , Quinoxalinas/farmacologia , Sais , Antineoplásicos/farmacologia , Antineoplásicos/química , FosfatidilcolinasRESUMO
Recent evidence indicates that targeting IL-6 provides broad therapeutic approaches to several diseases. In patients with cancer, autoimmune diseases, severe respiratory infections [e.g. coronavirus disease 2019 (COVID-19)] and wound healing, IL-6 plays a critical role in modulating the systemic and local microenvironment. Elevated serum levels of IL-6 interfere with the systemic immune response and are associated with disease progression and prognosis. As already noted, monoclonal antibodies blocking either IL-6 or binding of IL-6 to receptors have been used/tested successfully in the treatment of rheumatoid arthritis, many cancer types, and COVID-19. Therefore, in the present review, we compare the impact of IL-6 and anti-IL-6 therapy to demonstrate common (pathological) features of the studied diseases such as formation of granulation tissue with the presence of myofibroblasts and deposition of new extracellular matrix. We also discuss abnormal activation of other wound-healing-related pathways that have been implicated in autoimmune disorders, cancer or COVID-19.
Assuntos
Doenças Autoimunes , COVID-19 , Neoplasias , Humanos , Autoimunidade , Inflamação , Doenças Autoimunes/tratamento farmacológico , Neoplasias/tratamento farmacológico , Cicatrização , Microambiente TumoralRESUMO
Non-psychotropic cannabinoids (e.g., cannabidiol, cannabinol and cannabigerol) are contained in numerous alimentary and medicinal products. Therefore, predicting and studying their possible side effects, such as changes in DNA methylation, is an important task for assessing the safety of these products. Interference with TET enzymes by chelating ferrous ions can contribute to the altered methylation pattern. All tested cannabinoids displayed a strong affinity for Fe(II) ions. Cannabidiol and cannabinol exhibited potent inhibitory activities (IC50 = 4.8 and 6.27 µM, respectively) towards the TET1 protein, whereas cannabigerol had no effect on the enzyme activity. An in silico molecular docking study revealed marked binding potential within the catalytic cavity for CBD/CBN, but some affinity was also found for CBG, thus the total lack of activity remains unexplained. These results imply that cannabinoids could affect the activity of the TET1 protein not only due to their affinity for Fe(II) but also due to other types of interactions (e.g., hydrophobic interactions and hydrogen bonding).
Assuntos
Canabidiol , Canabinoides , Cannabis , Canabidiol/química , Canabidiol/farmacologia , Canabinoides/farmacologia , Canabinol/farmacologia , Cannabis/química , Compostos Ferrosos , Simulação de Acoplamento MolecularRESUMO
Targeting of epigenetic mechanisms, such as the hydroxymethylation of DNA, has been intensively studied, with respect to the treatment of many serious pathologies, including oncological disorders. Recent studies demonstrated that promising therapeutic strategies could potentially be based on the inhibition of the TET1 protein (ten-eleven translocation methylcytosine dioxygenase 1) by specific iron chelators. Therefore, in the present work, we prepared a series of pyrrolopyrrole derivatives with hydrazide (1) or hydrazone (2-6) iron-binding groups. As a result, we determined that the basic pyrrolo[3,2-b]pyrrole derivative 1 was a strong inhibitor of the TET1 protein (IC50 = 1.33 µM), supported by microscale thermophoresis and molecular docking. Pyrrolo[3,2-b]pyrroles 2-6, bearing substituted 2-hydroxybenzylidene moieties, displayed no significant inhibitory activity. In addition, in vitro studies demonstrated that derivative 1 exhibits potent anticancer activity and an exclusive mitochondrial localization, confirmed by Pearson's correlation coefficient of 0.92.
Assuntos
Dioxigenases , Pirróis , DNA , Dioxigenases/metabolismo , Hidrazonas/química , Ferro , Quelantes de Ferro , Proteínas Mitocondriais , Simulação de Acoplamento Molecular , Pirróis/química , Pirróis/farmacologiaRESUMO
Cholesterol is not only a major component of the cell membrane, but also plays an important role in a wide range of biological processes and pathologies. It is therefore crucial to develop appropriate tools for visualizing intracellular cholesterol transport. Here, we describe new cationic analogues of BODIPY-Cholesterol (TopFluor-Cholesterol, TF-Chol), which combine a positive charge on the sterol side chain and a BODIPY group connected via a C-4 linker. In contrast to TF-Chol, the new analogues TF-1 and TF-3 possessing acetyl groups on the A ring (C-3 position on steroid) internalized much faster and displayed slightly different levels of intracellular localization. Their applicability for cholesterol monitoring was indicated by the fact that they strongly label compartments with accumulated cholesterol in cells carrying a mutation of the Niemann-Pick disease-associated cholesterol transporter, NPC1.
Assuntos
Compostos de Boro/análise , Colesterol/análise , Transporte Biológico , Compostos de Boro/síntese química , Compostos de Boro/química , Compostos de Boro/metabolismo , Linhagem Celular , Colesterol/análogos & derivados , Colesterol/síntese química , Colesterol/metabolismo , Humanos , Imagem ÓpticaRESUMO
Flavonoids are common plant natural products able to suppress ROS-related damage and alleviate oxidative stress. One of key mechanisms, involved in this phenomenon is chelation of transition metal ions. From a physiological perspective, iron is the most significant transition metal, because of its abundance in living organisms and ubiquitous involvement in redox processes. The chemical, pharmaceutical, and biological properties of flavonoids can be significantly affected by their interaction with transition metal ions, mainly iron. In this review, we explain the interaction of various flavonoid structures with Fe(II) and Fe(III) ions and critically discuss the influence of chelated ions on the flavonoid biochemical properties. In addition, specific biological effects of their iron metallocomplexes, such as the inhibition of iron-containing enzymes, have been included in this review.
Assuntos
Antioxidantes/química , Antioxidantes/farmacologia , Complexos de Coordenação/química , Flavonoides/química , Ferro/química , Animais , Quelantes/química , Quelantes/farmacologia , Heme/química , Humanos , Íons/química , Íons/metabolismo , Estrutura Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
COVID-19 is a pandemic respiratory disease caused by the SARS-CoV-2 coronavirus. The worldwide epidemiologic data showed higher mortality in males compared to females, suggesting a hypothesis about the protective effect of estrogens against severe disease progression with the ultimate end being patient's death. This article summarizes the current knowledge regarding the potential effect of estrogens and other modulators of estrogen receptors on COVID-19. While estrogen receptor activation shows complex effects on the patient's organism, such as an influence on the cardiovascular/pulmonary/immune system which includes lower production of cytokines responsible for the cytokine storm, the receptor-independent effects directly inhibits viral replication. Furthermore, it inhibits the interaction of IL-6 with its receptor complex. Interestingly, in addition to natural hormones, phytestrogens and even synthetic molecules are able to interact with the estrogen receptor and exhibit some anti-COVID-19 activity. From this point of view, estrogen receptor modulators have the potential to be included in the anti-COVID-19 therapeutic arsenal.
Assuntos
COVID-19/patologia , Moduladores de Receptor Estrogênico/farmacologia , SARS-CoV-2/efeitos dos fármacos , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , COVID-19/complicações , COVID-19/virologia , Moduladores de Receptor Estrogênico/metabolismo , Moduladores de Receptor Estrogênico/uso terapêutico , Feminino , Humanos , Receptores de Estrogênio/química , Receptores de Estrogênio/metabolismo , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/fisiologia , Proteínas da Matriz Viral/antagonistas & inibidores , Proteínas da Matriz Viral/metabolismo , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacosRESUMO
Interleukin-6 (IL-6) is a cytokine with multifaceted effects playing a remarkable role in the initiation of the immune response. The increased level of this cytokine in the elderly seems to be associated with the chronic inflammatory setting of the microenvironment in aged individuals. IL-6 also represents one of the main signals in communication between cancer cells and their non-malignant neighbours within the tumour niche. IL-6 also participates in the development of a premetastatic niche and in the adjustment of the metabolism in terminal-stage patients suffering from a malignant disease. IL-6 is a fundamental factor of the cytokine storm in patients with severe COVID-19, where it is responsible for the fatal outcome of the disease. A better understanding of the role of IL-6 under physiological as well as pathological conditions and the preparation of new strategies for the therapeutic control of the IL-6 axis may help to manage the problems associated with the elderly, cancer, and serious viral infections.
Assuntos
Envelhecimento/metabolismo , Infecções por Coronavirus/metabolismo , Interleucina-6/metabolismo , Neoplasias/metabolismo , Pneumonia Viral/metabolismo , Envelhecimento/patologia , Animais , COVID-19 , Infecções por Coronavirus/patologia , Humanos , Interleucina-6/genética , Neoplasias/patologia , Pandemias , Pneumonia Viral/patologia , Transdução de SinaisRESUMO
Ten-eleven translocation protein (TET) 1 plays a key role in control of DNA demethylation and thereby of gene expression. Dysregulation of these processes leads to serious pathological states such as oncological and neurodegenerative ones and thus TET 1 targeting is highly requested. Therefore, in this work, we examined the ability of hydrazones (acyl-, aroyl- and heterocyclic hydrazones) to inhibit the TET 1 protein and its mechanism of action. Inhibitory activity of hydrazones 1-7 towards TET 1 was measured. The results showed a high affinity of the tested chelators for iron(II). The study clearly showed a significant correlation between the chelator's affinity for iron(II) ions (represented by the binding constant) and TET 1 protein inhibitory activity (represented by IC50 values).
Assuntos
Dioxigenases/antagonistas & inibidores , Inibidores Enzimáticos/química , Hidrazonas/química , Quelantes de Ferro/química , Dioxigenases/química , Ensaios Enzimáticos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/toxicidade , Epigênese Genética/efeitos dos fármacos , Hidrazonas/síntese química , Hidrazonas/toxicidade , Ferro/química , Quelantes de Ferro/síntese química , Quelantes de Ferro/toxicidadeRESUMO
Modifications of DNA cytosine bases and histone posttranslational modifications play key roles in the control of gene expression and specification of cell states. Such modifications affect many important biological processes and changes to these important regulation mechanisms can initiate or significantly contribute to the development of many serious pathological states. Therefore, recognition and determination of chromatin modifications is an important goal in basic and clinical research. Two of the most promising tools for this purpose are optical probes and sensors, especially colourimetric and fluorescence devices. The use of optical probes and sensors is simple, without highly expensive instrumentation, and with excellent sensitivity and specificity for target structural motifs. Accordingly, the application of various probes and sensors in the recognition and determination of cytosine modifications and structure of histones and histone posttranslational modifications, are discussed in detail in this review.
Assuntos
DNA/química , Epigênese Genética , Sondas Moleculares , Metilação de DNA , Óptica e FotônicaRESUMO
We report design and synthesis of set of novel anticancer agents based on caffeine-hydrazones bearing 2-hydroxyaryl- or 2-N-heteroaryl moiety. Anticancer activity evaluation using seven cancer cell lines and two non-malignant cell lines demonstrated that several derivatives display significant anticancer activity and great selectivity index toward T-lymphoblastic leukaemia cells. In general, hydrazones bearing 2-N-heteroaryl moiety are more active and selective than those with 2-hydroxyaryl moiety. Tested compounds exhibit dose-dependent inhibition of both RNA and DNA synthesis, with some exceptions. Antimicrobial activities were tested on set of twelve bacterial and yeast strains, however prepared compounds were not active, suggesting for a molecular target specific for eukaryotic cells.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Cafeína/química , Cafeína/farmacologia , Hidrazonas/química , Hidrazonas/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Apoptose/efeitos dos fármacos , Bactérias/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Fungos/efeitos dos fármacos , Humanos , Relação Estrutura-AtividadeRESUMO
Objectives: To advance our knowledge of disease mechanisms and therapeutic options, understanding cell cycle regulation is critical. Recent research has highlighted the importance of reactive oxygen species (ROS) in cell cycle regulation. Although excessive ROS levels can lead to age-related pathologies, ROS also play an essential role in normal cellular functions. Many cell cycle regulatory proteins are affected by their redox status, but the precise mechanisms and conditions under which ROS promote or inhibit cell proliferation are not fully understood.Methods: This review presents data from the scientific literature and publicly available databases on changes in redox state during the cell cycle and their effects on key regulatory proteins.Results: We identified redox-sensitive targets within the cell cycle machinery and analysed different effects of ROS (type, concentration, duration of exposure) on cell cycle phases. For example, moderate levels of ROS can promote cell proliferation by activating signalling pathways involved in cell cycle progression, whereas excessive ROS levels can induce DNA damage and trigger cell cycle arrest or cell death.Discussion: Our findings encourage future research focused on identifying redox-sensitive targets in the cell cycle machinery, potentially leading to new treatments for diseases with dysregulated cell proliferation.
Assuntos
Ciclo Celular , Oxirredução , Espécies Reativas de Oxigênio , Espécies Reativas de Oxigênio/metabolismo , Humanos , Proliferação de Células , Transdução de Sinais , Dano ao DNA , AnimaisRESUMO
BACKGROUND: Angiotensin-converting enzyme (ACE) is responsible for the production of angiotensin II, and increased production of angiotensin II is observed in diabetes. What is more, ACE polymorphisms may play a role in the development of diabetic nephropathy. The aim of this study was to assess the role of selected ACE polymorphisms (rs4343 and rs4646994) in the risk of development of diabetic nephropathy and in the likelihood of renal replacement therapy. METHODS: ACE polymorphisms were analyzed in a group of 225 patients who were divided into three subgroups. The rs4343 polymorphism was determined using the PCR-RFLP, and the rs4646994 polymorphism was determined using the PCR. Molecular docking between domains of ACE and its ligands was performed by using AutoDock Vina. RESULTS: The G/G genotype of rs4343 polymorphism is associated with increased odds of developing diabetic nephropathy. The G allele is also associated with a higher risk of this disease. Similar results were obtained in patients who had already had a kidney transplant as a result of diabetic nephropathy. CONCLUSIONS: The presence of G/G and G/A genotypes, and the G allele increases the likelihood of developing diabetic nephropathy. This may also be a risk factor for renal replacement therapy.
RESUMO
A simple, sensitive and quick HPLC method was developed for the determination of ketoprofen in cell culture media (EMEM, DMEM, RPMI). Separation was performed using a gradient on the C18 column with a mobile phase of acetonitrile and miliQ water acidified by 0.1 % (v/v) formic acid. The method was validated for parameters including linearity, accuracy, precision, limit of quantitation and limit of detection, as well as robustness. The response was found linear over the range of 3-100â µg/mL as demonstrated by the acquired value of correlation coefficient R2=0.9997. The described method is applicable for determination of various pharmacokinetic aspects of ketoprofen inâ vitro.
Assuntos
Cetoprofeno , Cetoprofeno/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Indicadores e ReagentesRESUMO
Immune checkpoints regulate the immune system response. Recent studies suggest that flavonoids, known as phytoestrogens, may inhibit the PD-1/PD-L1 axis. We explored the potential of estrogens and 17 Selective Estrogen Receptor Modulators (SERMs) as inhibiting ligands for immune checkpoint proteins (CTLA-4, PD-L1, PD-1, and CD80). Our docking studies revealed strong binding energy values for quinestrol, quercetin, and bazedoxifene, indicating their potential to inhibit PD-1 and CTLA-4. Quercetin and bazedoxifene, known to modulate EGFR and IL-6R alongside estrogen receptors, can influence the immune checkpoint functionality. We discuss the impact of SERMs on PD-1 and CTLA-4, suggesting that these SERMs could have therapeutic effects through immune checkpoint inhibition. This study highlights the potential of SERMs as inhibitory ligands for immune checkpoint proteins, emphasizing the importance of considering PD-1 and CTLA-4 inhibition when evaluating SERMs as therapeutic agents. Our findings open new avenues for cancer immunotherapy by exploring the interaction between various SERMs and immune checkpoint pathways.
Assuntos
Proteínas de Checkpoint Imunológico , Neoplasias , Humanos , Antígeno CTLA-4 , Antígeno B7-H1 , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Receptor de Morte Celular Programada 1 , Moduladores de Receptor Estrogênico , Quercetina , Imunoterapia , Neoplasias/terapiaRESUMO
Mitochondrial dysregulation plays a significant role in the carcinogenesis. On the other hand, its destabilization strongly represses the viability and metastatic potential of cancer cells. Photodynamic and photothermal therapies (PDT and PTT) target mitochondria effectively, providing innovative and non-invasive anticancer therapeutic modalities. Cyanine dyes, with strong mitochondrial selectivity, show significant potential in enhancing PDT and PTT. The potential and limitations of cyanine dyes for mitochondrial PDT and PTT are discussed, along with their applications in combination therapies, theranostic techniques, and optimal delivery systems. Additionally, novel approaches for sonodynamic therapy using photoactive cyanine dyes are presented, highlighting advances in cancer treatment.
RESUMO
The enantioseparation of seven Tröger's base derivatives (TBs) was carried out by capillary electrophoresis using α-, ß-, and γ-cyclodextrins as chiral selectors and phosphate at 20 mmol/l concentration, pH 2.5, as background electrolyte. The method was optimized with respect to the concentration of chosen chiral selectors (0-50 mmol/l) and the amount of organic solvent (acetonitrile, 0-25 % (v/v)) in the electrolyte. The results indicate that all the studied variables, i.e., type of chiral selector, its concentration, and the amount of the added organic solvent, have a significant impact on the enantioseparation of the studied TBs. The best results for the majority of the separated TBs were obtained utilizing ß-cyclodextrin at 5 mmol/l concentration and with various amounts of acetonitrile added ranging from 5 to 15% (v/v) in the background electrolyte. For the two smallest studied TBs, γ-cyclodextrin with 10% (v/v) acetonitrile also provided good resolution.
RESUMO
Most cancer-related deaths among patients with solid tumors are caused by metastases. Migrastatic strategies represent a unique therapeutic approach to prevent all forms of cancer cell migration and invasion. Because the migration machinery has been shown to promote metastatic dissemination, successful migrastatic therapy may reduce the need for high-dose cytotoxic therapies that are currently used to prevent the risk of metastatic dissemination. In this review we focus on anti-invasive and antimetastatic strategies that hold promise for the treatment of solid tumors. The best targets for migrastatic therapy would be those that are required by all forms of motility, such as ATP availability, mitochondrial metabolism, and cytoskeletal dynamics and cell contractility.
Assuntos
Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Movimento CelularRESUMO
Treatment of metastatic cancer is one of the biggest challenges in anticancer therapy. Curcumin is interesting nature polyphenolic compound with unique biological and medicinal effects, including repression of metastases. High impact studies imply that curcumin can modulate the immune system, independently target various metastatic signalling pathways, and repress migration and invasiveness of cancer cells. This review discusses the potential of curcumin as an antimetastatic agent and describes potential mechanisms of its antimetastatic activity. In addition, possible strategies (curcumin formulation, optimization of the method of administration and modification of its structure motif) to overcome its limitation such as low solubility and bioactivity are also presented. These strategies are discussed in the context of clinical trials and relevant biological studies.
Assuntos
Antineoplásicos , Curcumina , Neoplasias , Humanos , Curcumina/farmacologia , Curcumina/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Neoplasias/tratamento farmacológicoRESUMO
TET proteins (methylcytosine dioxygenases) play an important role in the regulation of gene expression. Dysregulation of their activity is associated with many serious pathogenic states such as oncological diseases. Regulation of their activity by specific inhibitors could represent a promising therapeutic strategy. Therefore, this review describes various types of TET protein inhibitors in terms of their inhibitory mechanism and possible applicability. The potential and possible limitations of this approach are thoroughly discussed in the context of TET protein functionality in living systems. Furthermore, possible therapeutic strategies based on the inhibition of TET proteins are presented and evaluated, especially in the field of oncological diseases.