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Liver cancer is the second leading cause of cancer-related death in males. It is estimated that approximately one million deaths will occur by 2030 due to hepatic cancer. Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer subtype and is commonly diagnosed at an advanced stage. The drug arsenal used in systemic therapy for HCC is very limited. Multikinase inhibitors sorafenib (Nexavar®) and lenvatinib (Lenvima®) have been used as first-line drugs with modest therapeutic effects. In this scenario, it is imperative to search for new therapeutic strategies for HCC. Herein, the antiproliferative activity of N-acylhydrazone derivatives was evaluated on HCC cells (HepG2 and Hep3B), which were chemically planned on the ALL-993 scaffold, a potent inhibitor of vascular endothelial growth factor 2 (VEGFR2). The substances efficiently reduced the viability of HCC cells, and the LASSBio-2052 derivative was the most effective. Further, we demonstrated that LASSBio-2052 treatment induced FOXM1 downregulation, which compromises the transcriptional activation of genes required for G2/M transition, such as AURKA and AURKB, PLK1, and CDK1. In addition, LASSBio-2052 significantly reduced CCNB1 and CCND1 expression in HCC cells. Our findings indicate that LASSBio-2052 is a promising prototype for further in vivo studies.
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Sepsis can trigger acute respiratory distress syndrome (ARDS), which can lead to a series of physiological changes, modifying the effectiveness of therapy and culminating in death. For all experiments, male Wistar rats (200-250 g) were split into the following groups: control and sepsis-induced by endotoxin lipopolysaccharide (LPS); the control group received only intraperitoneal saline or saline + CEF while the treated groups received ceftriaxone (CEF) (100 mg/kg) IP; previously or not with sepsis induction by LPS (1 mg/kg) IP. We evaluated respiratory mechanics, and alveolar bronchial lavage was collected for nitrite and vascular endothelial growth factor (VEGF) quantification and cell evaluation. For pharmacokinetic evaluation, two groups received ceftriaxone, one already exposed to LPS. Respiratory mechanics shows a decrease in total airway resistance, dissipation of viscous energy, and elastance of lung tissues in all sepsis-induced groups compared to the control group. VEGF and NOx values were higher in sepsis animals compared to the control group, and ceftriaxone was able to reduce both parameters. The pharmacokinetic parameters for ceftriaxone, such as bioavailability, absorption, and terminal half-life, were smaller in the sepsis-induced group than in the control group since clearance was higher in septic animals. Despite the pharmacokinetic changes, ceftriaxone showed a reduction in resistance in the airways. In addition, CEF lowers nitrite levels in the lungs and acts on their adverse effects, reflecting pharmacological therapy of the disease.
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Breast cancer is the leading cause of cancer death among women worldwide. About 75% of all diagnosed cases are hormone-positive, which are treated with hormone therapy. However, many patients are refractory or become resistant to the drugs used in therapeutic protocols. In this scenario, it is essential to identify new substances with pharmacological potential against breast cancer. VEGFR2 inhibitors are considered promising antitumor agents not only due to their antiangiogenic activity but also by inhibiting the proliferation of tumor cells. Thus, the present study aimed to evaluate the effects of N-acylhydrazone derivative LASSBio-2029 on the proliferative behavior of MCF-7 cells. We observed a promising antitumor potential of this substance due to its ability to modulate critical cell cycle regulators including mitotic kinases (CDK1, AURKA, AURKB, and PLK1) and CDK inhibitor (CDKN1A). Increased frequencies of abnormal mitosis and apoptotic cells were observed in response to treatment. A molecular docking analysis predicts that LASSBio-2029 could bind to the proto-oncoprotein ABL1, which participates in cell cycle control, interacting with other controller proteins and regulating centrosome-associated tubulins. Finally, we created a gene signature with the downregulated genes, whose reduced expression is associated with a higher relapse-free survival probability in breast cancer patients.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Células MCF-7 , Proteínas de Ciclo Celular/genética , Simulação de Acoplamento Molecular , Mitose , Pontos de Checagem do Ciclo Celular , Estrogênios/farmacologia , Apoptose , Linhagem Celular Tumoral , Proliferação de CélulasRESUMO
Melanoma is considered the most aggressive form of skin cancer, showing high metastatic potential and persistent high mortality rates despite the introduction of immunotherapy and targeted therapies. Thus, it is important to identify new drug candidates for melanoma. The design of hybrid molecules, with different pharmacophore fragments combined in the same scaffold, is an interesting strategy for obtaining new multi-target and more effective anticancer drugs. We designed nine hybrid compounds bearing piperine and chlorogenic acid pharmacophoric groups and evaluated their antitumoral potential on melanoma cells with distinct mutational profiles SK-MEL-147, CHL-1 and WM1366. We identified the compound named PQM-277 (3a) to be the most cytotoxic one, inhibiting mitosis progression and promoting an accumulation of cells in pro-metaphase and metaphase by altering the expression of genes that govern G2/M transition and mitosis onset. Compound 3a downregulated FOXM1, CCNB1, CDK1, AURKA, AURKB, and PLK1, and upregulated CDKN1A. Molecular docking showed that 3a could interact with the CUL1-RBX1 complex, which activity is necessary to trigger molecular events essential for FOXM1 transactivation and, in turn, G2/M gene expression. In addition, compound 3a effectively induced apoptosis by increasing BAX/BCL2 ratio. Our findings demonstrate that 3a is an important antitumor candidate prototype and support further investigations to evaluate its potential for melanoma treatment, especially for refractory cases to BRAF/MEK inhibitors.
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Ruthenium compounds are known to be potential drug candidates since they offer the potential for reduced toxicity. Furthermore, the various oxidation states, different mechanisms of action and ligand substitution kinetics give them advantages over platinum-based complexes, making them suitable for use in biological applications. So, herein, novel ruthenium(II) complexes with metronidazole as ligand were obtained [RuCl(MTNZ)(dppb)(4,4'-Mebipy)]PF6 (1), [RuCl(MTNZ)(dppb)(4,4'-Methoxybipy)]PF6 (2), [RuCl(MTNZ)(dppb)(bipy)]PF6 (3) and [RuCl(MTNZ)(dppb)(phen)]PF6 (4) where, MTNZ = metronidazole, dppb = 1,4-bis(diphenylphosphino)butane, 4,4'-Mebipy = 4,4'-dimethyl-2,2'-bipyridine, 4,4'-Methoxybipy = 4,4'-dimethoxy-2,2'-bipyridine, bipy = 2,2'-bipyridine and phen = 1,10-phenanthroline. The complexes were characterized by elemental analysis, molar conductivity, infrared and UV-Vis spectroscopy, cyclic voltammetry, 31P{1H}, 1H, 13C{1H} and Dept 135 NMR and mass spectrometry. The interaction of complexes 1-4 with DNA was evaluated, and their cytotoxicity profiles were determined on four different tumor cell lines derived from human cancers (SK-MEL-147, melanoma; HepG2, hepatocarcinoma; MCF-7, estrogen-positive breast cancer; A549, non-small cell lung cancer). We demonstrated that complexes (1) and (3) are promising antitumor agents once inhibited the proliferative behavior of MCF-7 cells and induced apoptosis.
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Complexos de Coordenação , Neoplasias Pulmonares , Rutênio , Humanos , Rutênio/química , Células MCF-7 , Metronidazol , 2,2'-Dipiridil/química , Complexos de Coordenação/química , Ligantes , Antineoplásicos/química , Linhagem Celular Tumoral , Pontos de Checagem do Ciclo Celular , ApoptoseRESUMO
Obesity and the corresponding variations in female sex hormones are associated with severe lung disease. We determined the potential effects of obesity and sex hormones in female mice by investigating changes in lung structure and respiratory function in an obesity model induced by postnatal overnutrition. Obese female mice exhibited pronounced weight gain, abdominal fat accumulation and collagen type I deposition in the airways. However, neither elastic tissue nor estrogen receptors-α/-ß were affected in obese female mice after ovariectomy or sham-operated mice. Bronchoconstriction in response to methacholine challenge in obese sham-operated mice was higher than in the obese group after ovariectomy. Our results suggest that the coexistence of obesity and ovariectomy impacted on respiratory system and airway resistance (attenuates bronchoconstriction after methacholine), on collagen I deposition and on airway estrogen ß-receptors of mice.
Assuntos
Resistência das Vias Respiratórias/fisiologia , Broncoconstrição/fisiologia , Colágeno Tipo I/metabolismo , Receptor beta de Estrogênio/metabolismo , Obesidade , Ovariectomia , Transtornos Respiratórios , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Obesidade/complicações , Obesidade/metabolismo , Obesidade/fisiopatologia , Ovariectomia/efeitos adversos , Transtornos Respiratórios/etiologia , Transtornos Respiratórios/metabolismo , Transtornos Respiratórios/fisiopatologiaRESUMO
Mammals airways are extensively innervated by the vagus nerve, which controls the airway diameter and bronchial tone. However, very few studies described the respiratory function and lung morphology after vagal section. In the present study, we evaluated the respiratory mechanics after aerosolization of vehicle (to obtain control values), a muscarinic agonist (methacholine), a ß2-adrenergic agonist (salbutamol) or a muscarinic antagonist (ipratropium bromide) in intact (Vi) and bilaterally vagotomized (Vx) Swiss male mice. Different group was established for morphometric analyze. The total lung resistance, airway resistance, elastance, compliance, lung tissue damping, lung tissue elastance, and morphological parameters (collagen and elastic fibers) were significantly different in the Vx group compared to the Vi group. Bronchoconstrictor and bronchodilators change the respiratory function of the Vx group. In conclusion, the vagus nerve modulates the lung function in response to bronchoconstriction and bronchodilation, as well as lung architecture of mice.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Broncoconstritores/farmacologia , Broncodilatadores/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/fisiologia , Antagonistas Muscarínicos/farmacologia , Mecânica Respiratória/efeitos dos fármacos , Mecânica Respiratória/fisiologia , Vagotomia , Nervo Vago/fisiologia , Albuterol/farmacologia , Animais , Colágeno , Tecido Elástico , Ipratrópio/farmacologia , Pulmão/ultraestrutura , Masculino , Cloreto de Metacolina/farmacologia , Camundongos , Agonistas Muscarínicos/farmacologiaRESUMO
Uterine natural killer (uNK) cells are the dominant lymphocytes found in pregnant mammals that develop uterine decidualization. Four stages of mouse uNK cell differentiation are recognized using Dolichos biflorus agglutinin (DBA) lectin histochemistry. Each uNK cell subtype has a preferential domain. In human and mouse normal pregnancies, uNK cells are activated interferon gamma-producing cells that promote angiogenesis and development of the decidua and placenta. Murine transplant models suggest that uNK cells differentiate from self-renewing progenitors found in peripheral secondary lymphoid tissues, particularly spleen and lymph nodes. In this work, the spleen was removed 7 days before mice were mated to address whether absence of the spleen reduced uNK cell numbers or altered the distributions of maturing uNK cell subsets using quantitative lectin histochemistry. Splenectomy delayed uNK cell maturation within implantation sites. This coincided with delayed decidual and placental development and a significant (48 hr) lengthening of gestation without loss of viability. These studies characterize spleen as a biologically important progenitor tissue for uNK precursor cells.
Assuntos
Implantação do Embrião/fisiologia , Células Matadoras Naturais/fisiologia , Esplenectomia , Útero/fisiologia , Animais , Feminino , Humanos , Células Matadoras Naturais/citologia , Masculino , Camundongos , Lectinas de Plantas , Gravidez , Baço/citologia , Baço/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Útero/citologiaRESUMO
Uterine natural killer (uNK) cells are the dominant lymphocytes of pregnant mammals' uterus. Studies have identified four differentiation stage of mouse uNK cells based on Dolichos biflorus lectin cytochemistry, and their distribution showed preferential domain in the uterus through out the pregnancy. This work was done to investigate the expression of alpha5, alpha6, and beta7 integrins on uNK cells and their ligands distribution. Section of mouse uterus from sixth to seventeenth gestational days were submitted to immunocytochemistry and positive reactions for alpha5, alpha6, and beta7 integrins were found on uNK from eighth to tenth gestational days but not after twelfth gestational days. Fibronectin reactions were seemed from sixth to tenth gestational days around uNK from the myometrium and endometrium close to the myometrium. No reaction for fibronectin was seen in the decidualized and nondecidualized endometrium near the placenta. Laminin reaction was seen just in the antimesometrial side. beta7 integrin seems to be the active receptor to bind with VCAM-1 or MAdCAM-1 of endothelial cells, promoting the uNK cross through the vessels. The absence of laminin in an uNK domain suggests these cells are not dependent of laminin and alpha6 integrin for their establishment. However, fibronectin seems to support uNK migration, proliferation, differentiation, and survival in the uterus by binding with alpha5 integrin. The loss of alpha5 integrin ligation by the down regulation of fibronectin could inhibits these events and further studies are need to investigate whether unligated alpha5 can actively and initiate apoptosis, maybe in a caspase 8-dependent way that has been called integrin-mediated death.