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1.
Dalton Trans ; 53(22): 9330-9349, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38747564

RESUMO

Four neutral Rh1-Rh4 complexes of the general formula [Rh2(CH3COO)4L2], where L is an N-alkylimidazole ligand, were synthesized and characterized using various spectroscopic techniques, and in the case of Rh4 the crystal structure was confirmed. Investigation of the interactions of these complexes with HSA by fluorescence spectroscopy revealed that the binding constants Kb are moderately strong (∼104 M-1), and site-marker competition experiments showed that the complexes bind to Heme site III (subdomain IB). Competitive binding studies for CT DNA using EB and HOE showed that the complexes bind to the minor groove, which was also confirmed by viscosity experiments. Molecular docking confirmed the experimental data for HSA and CT DNA. Antimicrobial tests showed that the Rh2-Rh4 complexes exerted a strong inhibitory effect on G+ bacteria B. cereus and G- bacteria V. parahaemolyticus as well as on the yeast C. tropicalis, which showed a higher sensitivity compared to fluconazole. The cytotoxic activity of Rh1-Rh4 complexes tested on three cancer cell lines (HeLa, HCT116 and MDA-MB-231) and on healthy MRC-5 cells showed that all investigated complexes elicited more efficient cytotoxicity on all tested tumor cells than on control cells. Investigation of the mechanism of action revealed that the Rh1-Rh4 complexes inhibit cell proliferation via different mechanisms of action, namely apoptosis (increase in expression of the pro-apoptotic Bax protein and caspase-3 protein in HeLa and HCT116 cells; changes in mitochondrial potential and mitochondrial damage; release of cytochrome c from the mitochondria; cell cycle arrest in G2/M phase in both HeLa and HCT116 cells together with a decrease in the expression of cyclin A and cyclin B) and autophagy (reduction in the expression of the protein p62 in HeLa and HCT116 cells).


Assuntos
Antineoplásicos , Apoptose , Complexos de Coordenação , Ródio , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Apoptose/efeitos dos fármacos , Ródio/química , Ródio/farmacologia , Simulação de Acoplamento Molecular , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Candida tropicalis/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Células HeLa
2.
Eur J Med Chem ; 227: 113869, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34710747

RESUMO

New twelve in silico designed coumarin-based ERα antagonists, namely 3DQ-1a to 3DQ-1е, were synthesized and confirmed as selective ERα antagonists, showing potencies ranging from single-digit nanomolar to picomolar. The hits were confirmed as selective estrogen receptor modulators and validated as antiproliferative agents using MCF-7 breast cancer cell lines exerting from picomolar to low nanomolar potency, at the same time showing no agonistic activity within endometrial cell lines. Their mechanism of action was inspected and revealed to be through the inhibition of the Raf-1/MAPK/ERK signal transduction pathway, preventing hormone-mediated gene expression on either genomic direct or genomic indirect level, and stopping the MCF-7 cells proliferation at G0/G1 phase. In vivo experiments, by means of the per os administration to female Wistar rats with pre-induced breast cancer, distinguished six derivatives, 3DQ-4a, 3DQ-2a, 3DQ-1a, 3DQ-1b, 3DQ-2b, and 3DQ-3b, showing remarkable potency as tumor suppressors endowed with optimal pharmacokinetic profiles and no significant histopathological profiles. The presented data indicate the new compounds as potential candidates to be submitted in clinical trials for breast cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Cumarínicos/farmacologia , Desenho de Fármacos , Antagonistas do Receptor de Estrogênio/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Antagonistas do Receptor de Estrogênio/síntese química , Antagonistas do Receptor de Estrogênio/química , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Células MCF-7 , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Estrutura Molecular , Ratos , Ratos Wistar , Relação Estrutura-Atividade
3.
J Chem Inf Model ; 61(10): 5028-5053, 2021 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-34648283

RESUMO

The estrogen receptor α (ERα) represents a 17ß-estradiol-inducible transcriptional regulator that initiates the RNA polymerase II-dependent transcriptional machinery, pointed for breast cancer (BC) development via either genomic direct or genomic indirect (i.e., tethered) pathway. To develop innovative ligands, structure-based (SB) three-dimensional (3-D) quantitative structure-activity relationship (QSAR) studies have been undertaken from structural data taken from partial agonists, mixed agonists/antagonists (selective estrogen receptor modulators (SERMs)), and full antagonists (selective ERα downregulators (SERDs)) correlated with either wild-type or mutated ERα receptors. SB and ligand-based (LB) alignments allow us to rule out guidelines for the SB/LB alignment of untested compounds. 3-D QSAR models for ERα ligands, coupled with SB/LB alignment, were revealed to be useful tools to dissect the chemical determinants for ERα-based anticancer activity as well as to predict their potency. The herein developed protocol procedure was verified through the design and potency prediction of 12 new coumarin-based SERMs, namely, 3DQ-1a to 3DQ-1e, that upon synthesis turned to be potent ERα antagonists by means of either in vitro or in vivo assays (described in the second part of this study).


Assuntos
Neoplasias da Mama , Receptor alfa de Estrogênio , Neoplasias da Mama/tratamento farmacológico , Cumarínicos , Estradiol , Moduladores de Receptor Estrogênico , Feminino , Humanos , Ligantes , Relação Quantitativa Estrutura-Atividade
4.
Saudi Pharm J ; 28(1): 136-146, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31920439

RESUMO

Acetylshikonin (AcSh), as a red colored pigment found in roots of the plants from family Boraginaceae, showed excellent cytotoxic activity. Due to its hydrophobic nature, and thus poor bioavailability, the aim of this study was to prepare acetylshikonin/ß-cyclodextrin (AcSh/ß-CD) inclusion complex by using coprecipitation method, characterize obtained system by using UV/VIS, IR and 1H NMR spectroscopy, and determine cytotoxic activity. Phase solubility test indicated formation of AL-type binary system (substrate/ligand ratio was 1:1 M/M), with stability constant Ks of 306.01 M-1. Formation of noncovalent bonds between inner layer of the hole of ß-CD and AcSh was observed using spectroscopic methods. Notable changes in chemical shifts of two protons (-0.020 ppm) from naphthoquinone moiety (C6-H and C7-H), as well as protons from hydroxyl groups (-0.013 and -0.009, respectively) attached to C5 and C8 carbons from naphthoquinone part indicate that the molecule of AcSh enters the ß-CD cavity from the aromatic side. Cytotoxic activity against HCT-116 and MDA-MB-231 cell lines was measured by MTT test and clonogenic assay. Mechanisms of action of free AcSh and inclusion complex were assessed by flow cytometry. In comparison to free AcSh, AcSh/ß-CD showed stronger short-term effect on HCT-116 cells and superior long-term effect on both cell lines. Inclusion complex induced more pronounced cell cycle arrest and autophagy inhibition, and induced increase in accumulation of intracellular ROS more effectively than free AcSh. In conclusion, AcSh/ß-CD binary system showed better performances regarding cytotoxic activity against tested tumor cell lines.

5.
Chem Biol Drug Des ; 91(4): 885-892, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29164806

RESUMO

Endometrial hyperplasia is a condition that may lead to the development of endometrial carcinoma. Initially, changes of the endometrium are caused by the estrogen's hyperstimulation that may lead to the development of an irregular bleeding and the infertility problems. Therapy of endometrial hyperplasia is limited to medical and surgical approaches. During the past decade, the new types of drugs were developed for the treatment of the endometrial hyperplasia. Here, for the first time, we investigated the cytotoxic effects of the various combinations of estrogen, raloxifene, and methotrexate in human ThESC cell line as a possible potential treatment of the endometrial hyperplasia. Our aim was to investigate and to determine the most efficient combination of investigated drugs in ThESC cells during 24-hr period using MTT assay, FACS analysis, and immunofluorescence staining. Our results demonstrated that the combination of raloxifene with methotrexate efficiently induced both the cytotoxicity and apoptosis in ThESC cells when compared to their single effect, as well as to the effect of combined treatment of raloxifene with estrogen. The application of the low doses of methotrexate combined with raloxifene offers all advantages of a potential beneficial antitumor match in cancer chemoprevention and therapy.


Assuntos
Apoptose/efeitos dos fármacos , Estrogênios/farmacologia , Metotrexato/farmacologia , Cloridrato de Raloxifeno/farmacologia , Caspase 3/metabolismo , Linhagem Celular , Endométrio/citologia , Feminino , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Células Estromais/citologia , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Proteína X Associada a bcl-2/metabolismo
6.
J Biol Inorg Chem ; 22(7): 1007-1028, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28695374

RESUMO

With the aim of assessing how the aromaticity of the inert chelating ligand can influence the activity of ruthenium(II) polypyridyl complexes, two new monofunctional ruthenium(II) complexes, [Ru(Cl-Ph-tpy)(phen)Cl]Cl (1) and [Ru(Cl-Ph-tpy)(o-bqdi)Cl]Cl (2) (where Cl-Ph-tpy = 4'-(4-chlorophenyl)-2,2':6',2″-terpyridine, phen = 1,10-phenanthroline, o-bqdi = o-benzoquinonediimine), were synthesized. All complexes were fully characterized by elemental analysis and spectroscopic techniques (IR, UV-Vis, 1D and 2D NMR, XRD). Their chemical behavior in aqueous solution was studied by UV-Vis and NMR spectroscopy showing that both compounds are relatively labile leading to the formation of the corresponding aqua species 1a and 2a. 1H NMR spectroscopy studies performed on complexes 1 and 2 demonstrated that after the hydrolysis of the Cl ligand, they are capable to interact with guanine derivatives (i.e., 9-methylguanine (9MeG) and 5'-GMP) through the N7, forming monofunctional adduct. The kinetics and the mechanism of the reaction of complexes 1 and 2 with the biologically more relevant 5'-GMP ligand were studied by UV-Vis spectroscopy. DNA/protein interactions of the complexes have been examined by photophysical studies, which demonstrated a bifunctional binding mode of the complexes with DNA and the complexes strongly quench the fluorescence intensity of bovine serum albumin (BSA) through the mechanism of both static and dynamic quenching. Complexes 1 and 2 strongly induced apoptosis of treated cancer cells with high percentages of apoptotic cells and negligible percentage of necrotic cells. In addition, both ruthenium complexes decreased Bcl-2/Bax ratio causing cytochrome c mitochondrial release, the activation of caspase-3 and induction of apoptosis.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Piridinas/química , Piridinas/farmacologia , Rutênio/química , Rutênio/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , DNA/metabolismo , Humanos , Modelos Moleculares , Neoplasias/metabolismo , Soroalbumina Bovina/metabolismo
7.
Cytokine ; 96: 185-188, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28433893

RESUMO

The data addressing cytokine profile in chronically infected HCV patients are conflicting, ranging from Th1 or Th2 cytokine prevalence to the expression of both types of cytokines. Therefore, the aim of this study was to evaluate cytokine profile in these patients. Cytokine sera levels in HCV patients and healthy controls were evaluated using 13plex FlowCytomix Multiplex. Median values of both proinflammatory and anti-inflammatory cytokines were lower in HCV patients then in controls. In addition, the number of subjects producing detectable quantities of cytokines was significantly lower in the group of HCV patients. Yet, cytokine levels in those patients were remarkably heterogeneous ranging from low to extremely high, much higher than the maximal values in control group. Similarly, grouping data according to HCV genotype, HCV RNA load, ALT/AST ratio and the stage of fibrosis showed marked standard deviations, reflecting high intragroup diversity. No correlation was found between each disease-related factor and cytokine levels. Patients investigated in our and similar studies were disparate pursuant to characteristics of the hosts, pathogen and course of the disease. Therefore, the inconsistency of the literature data regarding cytokine pattern in chronic HCV patients may be a consequence of the disregarded/overlooked heterogeneity of these patients.


Assuntos
Citocinas/sangue , Hepatite C Crônica/sangue , Adulto , Idoso , Biópsia , Citocinas/imunologia , Feminino , Genótipo , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C Crônica/imunologia , Humanos , Interferon gama/sangue , Interleucina-10/sangue , Interleucina-2/sangue , Interleucina-4/sangue , Fígado/patologia , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Células Th1 , Células Th2
8.
Arch Med Sci ; 13(2): 293-301, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28261281

RESUMO

INTRODUCTION: Endometrial hyperplasia is a condition that occurs as a result of hormonal imbalance between estrogen and progesterone. Morphological disturbance of endometrial cells occurs consequently leading towards endometrial cancer. In therapy of endometrial hyperplasia SERMs are used to supress effects of locally high estrogen level in uterus. There is strong evidence suggesting that estrogen could be involved in cell death - apoptosis. There are no experimental data demstrating the direct apoptotic effect of both raloxifene and estrogen on the ThESC cell line. The aim of our study wa sto investigate both cytotoxic and apototic mechanism of raloxifene and estrogen - induced death in the ThESC cell line. MATERIAL AND METHODS: In order to determine their cytotoxic and apoptotic effects, various doses of raloxifene and estrogen were applied to the ThESC cell line for 24 h. After the treatment MTT assay, FACS analysis and immunofluoroscence method were conducted. RESULTS: The results of this study for the first time demonstrated the cytotoxic and apoptotic effects of raloxifene and estrogen on human endometrial stromal cell line suggesting the involvement of the inner, mitochondrial apoptotic pathway. CONCLUSIONS: Our results demonstrated apoptotic effects of investigated drugs in the ThESC cell line through increasing the Bax/Bcl-2 ratio and activation of caspase 3.

9.
Int J Clin Pharmacol Ther ; 54(8): 628-33, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27191768

RESUMO

OBJECTIVE: Hypothyroidism is one of most common endocrine disorders resulting from deficiency of thyroid hormones. The aim of our study was to investigate whether cardiovascular drugs as well as gender, age, body-mass index, and habits, like smoking or drinking coffee affect thyroid-stimulating hormone (TSH) level in hypothyroid patients with thyroxine replacement therapy who suffer from cardiovascular disease. MATERIALS: The study was conducted on 150 hypothyroid patients who underwent total thyroidectomy for benign reasons; they were divided into five treatment groups: levothyroxine only group and, according to the drugs they had in therapy alongside levothyroxine, the angiotensinconverting enzyme inhibitors group, the selective ß-blockers group, the calcium antagonists group, as well as the nitrates group. A retrospective cohort study was conducted in the Clinical Center Kragujevac, Serbia, during the period of January 2012 to October 2014. All patients' data were collected both from participants' health records and questionnaires that patients completed, including data about habits, like smoking or drinking coffee. RESULTS: TSH values were significantly higher in the group of patients with selective ß-blockers in therapy alongside levothyroxine, compared to all the other study groups. The values of TSH level did not significantly differ among the other therapy groups. On the other hand, cigarette smoking was a risk factor that decreased TSH levels in patients on thyroid replacement therapy. CONCLUSIONS: Our study shows that selective ß-1 blockers can increase, while cigarette smoking can decrease TSH serum levels in hypothyroid patients on thyroid-replacement therapy.


Assuntos
Fármacos Cardiovasculares/farmacologia , Terapia de Reposição Hormonal , Tireoidectomia , Tireotropina/sangue , Tiroxina/uso terapêutico , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fumar/sangue
10.
Acta Pol Pharm ; 72(3): 455-64, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26642654

RESUMO

Uterine leiomyomas (fibroids) are the most common benign tumors in women of reproductive age. Although the local application of low doses of methotrexate (MTX) is used as an effective treatment of the myomas, myotrexate could be a promising new drug. This study investigated the cytotoxic and apoptotic effects of both MTX and myotrexate in human fibroblasts derived from the uterine fibroids (T hES cell line). The myotrexate adduct is an aqueous solution of MTX and L-arginine. Cells were treated with a graded concentrations of both MTX and myothrexate (0.1-16 µM) for 24 h. The cytotoxicity was assayed by MTT test, apoptosis was evaluated by Annexin V-FITC assay and their possible role in apoptosis was determined by immnu- flourescence. Both MTX and myotrexate induced apoptosis in T hES cells in a dose dependent manner (p < 0.001). Myotrexate significantly increased the percentage of AnnexinV positive cells, BAX/Bcl-2 ratio and subsequent caspase-3 activation compared to the MTX treated cells (p < 0.05). Both MTX or myotrexate treatment showed a diffuse staining of cytochrome c indicating its release from mitochondria to the cytosol, suggesting that their mechanisms of action most likely involves the mitochondrial apoptotic pathway.


Assuntos
Apoptose/efeitos dos fármacos , Leiomioma/tratamento farmacológico , Metotrexato/farmacologia , Mitocôndrias/efeitos dos fármacos , Neoplasias Uterinas/tratamento farmacológico , Caspase 3/fisiologia , Células Cultivadas , Feminino , Fibroblastos/efeitos dos fármacos , Humanos , Leiomioma/patologia , Mitocôndrias/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/análise , Neoplasias Uterinas/patologia , Proteína X Associada a bcl-2/análise
11.
Anticancer Agents Med Chem ; 15(2): 189-95, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25257897

RESUMO

Chronic lymphocytic leukemia (CLL) develops due to an imbalance between apoptosis and proliferation of B lymphocytes. Chrysin induced apoptosis in leukemia cell lines such as U937, MO7e, THP-1 and HL-60, but there has not yet been data demonstrating the apoptotic effect of chrysin on CLL cells. Therefore, in our investigation we examined the cytotoxicity of chrysin against two leukemia cell lines, MOLT-4 and JVM-13, peripheral blood lymphocytes isolated from B-CLL patients and peripheral blood mononuclear cells (PBMC) from healthy individuals in vitro. The effect of chrysin on viability of MOLT-4 and JVM-13 cell lines, B-CLL cells derived from 28 patients and PBMC from 16 healthy subjects was determined by MTT assay. The type of cell death induced by chrysin was verified by Annexin V/7AAD assay and acridine orange and ethidium bromide (AO/EB) staining assay. Intracellular localisation and endogenic expression of apoptotic proteins including Bax, Bcl-2, cytochrome c and caspase-3 were determined by flow cytometry and fluorescent microscopy. Our results demonstrated that exposure of MOLT-4, JVM-13 cell lines and B-CLL cells to the concentration of chrysin of 10µM and higher selectively decreased viability of cells in this cell population, but not in the PBMC derived from healthy subjects; LC50 values of chrysin for B-CLL cells were 51µM for 24 hours and 32µM for 48 hours of incubation, respectively. Our findings demonstrated that chrysin induces the activation of proapoptotic Bax and decreases the expression of antiapoptotic Bcl-2 protein, releases cytochrome c from mitochondria into cytosol and cleavages/activates caspase-3, subsequently leading to the activation of apoptosis of B-CLL cells. Together, these findings suggest that chrysin selectively induces apoptosis of peripheral blood lymphocytes isolated from human chronic lymphocytic leukemia patients via mitochondrial pathway in vitro and that it might have a promising role as a potential future antileukemic remedy.


Assuntos
Apoptose/efeitos dos fármacos , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucócitos Mononucleares/efeitos dos fármacos , Estudos de Casos e Controles , Caspase 3/metabolismo , Linhagem Celular Tumoral , Citocromos c/metabolismo , Citosol/efeitos dos fármacos , Citosol/metabolismo , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucócitos Mononucleares/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo
12.
J Enzyme Inhib Med Chem ; 28(5): 1061-6, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22994585

RESUMO

Adenylyl cyclases, comprise of a large family of enzymes that catalyze synthesis of the cyclic AMP from ATP. The aim of our study was to determine the effect of monovalent ions on both basal, stimulated adenylate cyclase EC 4.6.1.1 (AC) activity and C unit of AC and on GTPase active G-protein in the synaptic membranes of rat brain cortex. The effect of ion concentration from 30 to 200 mM (1 mM MgCl2) showed dose-dependent and significant inhibition of the basal AC activity, stimulated and unstimulated C unit activity. Stimulation of AC with 5 µM GTPγS in the presence of 50-200 mM of tested salts showed inhibitory effect on the AC activity. From our results it could be postulated that the investigated monovalent ions exert inhibitory effect on the AC complex activity by affecting the intermolecular interaction of the activated α subunit of G/F protein and the C unit of AC complex an inhibitory influence of tested monovalent ions on these molecular interaction.


Assuntos
Inibidores de Adenilil Ciclases , Encéfalo/enzimologia , Córtex Cerebral/enzimologia , Inibidores Enzimáticos/farmacologia , Cloreto de Magnésio/farmacologia , Adenilil Ciclases/metabolismo , Animais , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Íons/química , Íons/farmacologia , Cloreto de Magnésio/química , Masculino , Ratos , Ratos Wistar , Relação Estrutura-Atividade
13.
J Hepatol ; 56(1): 26-33, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21703183

RESUMO

BACKGROUND & AIMS: We used Concanavalin A-induced liver injury to study the role of Interleukin 33 and its receptor ST2 in the induction of inflammatory pathology and hepatocellular damage. METHODS: We tested susceptibility to Concanavalin A induced hepatitis in ST2 deficient and wild type BALB/c mice and analyzed the effects of single injection of Interleukin 33 as evaluated by liver enzyme test, quantitative histology, mononuclear cell infiltration, cytokine production, intracellular staining of immune cells, and markers of apoptosis in the liver. RESULTS: ST2 deficient mice developed significantly more severe hepatitis and had significantly higher number of mononuclear cells in the liver, CD4+ and CD8+ T cells, NKp46+ and CD3+NKp46+ cells, and F4/80+ macrophages. The level of pro-inflammatory cytokines in the sera and number of TNF alpha, IFN gamma, and IL-17 producing cells was higher in ST2 deficient mice. In contrast, number of CD4+Foxp3+ cells was statistically higher in wild type mice. Additionally, treatment of wild type mice with single (1 µg) injection of Interleukin 33 led to attenuation of the liver injury and milder infiltration of mononuclear cells, increase in total number of liver CD4+Foxp3+ cells and IL-4 producing CD4+ T cells. Interleukin 33 also suppressed the activation of caspase 3, prevented the expression of BAX, and enhanced the expression of antiapoptotic Bcl-2 in the liver. CONCLUSIONS: We concluded that Interleukin 33/ST2 axis downregulated Concanavalin A-induced liver injury and should be evaluated as potential target in fulminant hepatitis in humans.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Interleucinas/metabolismo , Receptores de Interleucina/metabolismo , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Concanavalina A/toxicidade , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-33 , Interleucinas/administração & dosagem , Falência Hepática Aguda/terapia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptores de Interleucina/deficiência , Receptores de Interleucina/genética , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/imunologia
14.
Biochem Biophys Res Commun ; 395(2): 225-31, 2010 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-20361936

RESUMO

Proteins of the BCL-2 family are important regulators of apoptosis. The BCL-2 family includes three main subgroups: the anti-apoptotic group, such as BCL-2, BCL-XL, BCL-W, and MCL-1; multi-domain pro-apoptotic BAX, BAK; and pro-apoptotic "BH3-only" BIK, PUMA, NOXA, BID, BAD, and SPIKE. SPIKE, a rare pro-apoptotic protein, is highly conserved throughout the evolution, including Caenorhabditis elegans, whose expression is downregulated in certain tumors, including kidney, lung, and breast. In the literature, SPIKE was proposed to interact with BAP31 and prevent BCL-XL from binding to BAP31. Here, we utilized the Position Weight Matrix method to identify SPIKE to be a BH3-only pro-apoptotic protein mainly localized in the cytosol of all cancer cell lines tested. Overexpression of SPIKE weakly induced apoptosis in comparison to the known BH3-only pro-apoptotic protein BIK. SPIKE promoted mitochondrial cytochrome c release, the activation of caspase 3, and the caspase cleavage of caspase's downstream substrates BAP31 and p130CAS. Although the informatics analysis of SPIKE implicates this protein as a member of the BH3-only BCL-2 subfamily, its role in apoptosis remains to be elucidated.


Assuntos
Apoptose , Citosol/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Mitocôndrias/fisiologia , Neoplasias/metabolismo , Sequência de Aminoácidos , Proteínas Reguladoras de Apoptose/metabolismo , Caspase 3/biossíntese , Linhagem Celular , Proteína Substrato Associada a Crk/metabolismo , Citocromos c/metabolismo , Ativação Enzimática , Humanos , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais , Dados de Sequência Molecular
15.
Med Pregl ; 63(9-10): 624-9, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21443057

RESUMO

The reactive oxygen species, the highly reactive metabolites of oxygen, play a crucial role in both the normal function and the metabolism of sperm cells. Oxygen radicals achieve their physiological effects in the cells only if there is a proper balance between their production and degradation. In case of radicals' production exceeding the antioxidant capacity of the semen, there is an oxidative damage of the membrane lipids and proteins as well as the DNA damage followed by the fragmentation and decondensation of DNA. The ejaculates were obtained from seventy-seven infertile and fertile healthy individuals. The semen samples were collected and classified according to the WHO criteria. The activities of superoxide dismutase and catalase as well as the concentration of malondialdehyde were measured spectrophotometrically. The fertile, healthy donors showed the significantly higher activities of both superoxide dismutase and catalase, as well as the lower concentration of malondialdehyde compared to the infertile donors. The activities of superoxide dismutase and catalase, as well as the HOS test, correlated positively with the sperm cell number, but negatively with the concentration of malondialdehyde. The activity of superoxide dismutase and the concentration of malondialdehyde were highest in the group of patients with the lowest success of the HOS test. The assessment of the antioxidant enzymes and malondialdehyde in addition to the semen analysis and the HOS test may be greatly useful in diagnosing infertility in men having oxidative stress in their etiology.


Assuntos
Catalase/metabolismo , Infertilidade Masculina/metabolismo , Malondialdeído/metabolismo , Sêmen/metabolismo , Superóxido Dismutase/metabolismo , Adulto , Humanos , Masculino , Pessoa de Meia-Idade
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