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1.
Int Endod J ; 2024 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-39291291

RESUMO

BACKGROUND: Root resorption consists of complex, multistep processes that involve cell signalling caused by inflammation and stromal cells, which promotes the secretion of receptor activator of nuclear factor κB ligand/ macrophage-colony stimulating factor (RANKL/M-CSF) resulting in a resorptive process. OBJECTIVE: The aim of this narrative review was to analyse the literature related to root resorption resulting from microbial infection and to comparing it with non-microbial infection. METHODS: An electronic literature search was performed using the PubMed database and applying keywords of articles published in English. Eligible papers were reviewed to reveal the descriptions of bone and root resorption processes. The abstracts were searched manually to identify articles about infection-stimulating bone and root resorption. RESULTS: Three main types of root resorption were identified, two associated with primary bacterial infection and one secondary to bacterial infection. These include external inflammatory resorption, internal inflammatory resorption and external cervical (invasive) resorption. DISCUSSION: The magnitude of cytokine involvement that promotes resorption and M-CSF/RANKL production depends on multiple factors, including pathogen virulence, site of infection and host genetic factors that activate the inflammation at the infection site. Two mechanisms activate the resorption mechanisms-the canonical and non-canonical pathways that can activate clastic cells independently of the RANKL/RANK canonical pathways. CONCLUSIONS: Two pathways of root resorption co-exist in the body. When resorption is caused by infection, chronic inflammation due to bacterial infection prolongs the secretions of pro-inflammatory cytokines that intensify root and bone resorption. The second pathway is bacterial independent of the non-infection root resorption that is part of the wound healing process, which is limited in time due to its innate ability.

2.
J Surg Oncol ; 128(4): 660-666, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37144623

RESUMO

BACKGROUND AND OBJECTIVES: Bone resection and endoprosthetic reconstruction (EPR) in the setting of soft tissue sarcoma (STS) management is rare and incurs unique challenges. We aim to report on the surgical and oncological outcomes of this relatively previously undocumented cohort. METHODS: This is a single-center retrospective review of prospectively collected data for patients who required EPRs following resection of STSs of the lower extremity. Following inclusion criteria, we assessed 29 cases of EPR for primary STS of the lower limb. RESULTS: The mean age was 54 years (range 18-84). Of the 29 patients, there were 6 total femur, 11 proximal femur, 4 intercalary, and 8 distal femur EPRs. Fourteen of 29 patients (48%) underwent re-operations for surgical complications, with 9 relating to infection (31%). When a matched cohort analysis was performed comparing our cohort to STSs that did not necessitate EPR, a reduced rate of overall survival and metastasis-free survival was found in those requiring EPR. CONCLUSION: This series identifies a high rate of complication from EPRs performed for STS. Patients should be cautioned about the high rate of infection, surgical complications, and lower overall survival in this setting.


Assuntos
Neoplasias Ósseas , Procedimentos de Cirurgia Plástica , Sarcoma , Humanos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/cirurgia , Resultado do Tratamento , Sarcoma/cirurgia , Extremidade Inferior/cirurgia , Estudos Retrospectivos
3.
Int J Biometeorol ; 66(11): 2195-2203, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36053297

RESUMO

Early peaks of airborne ragweed (Ambrosia L.) pollen concentrations were observed at several monitoring stations in Hungary in June 2017 and 2018, one month before the usual start of the pollen season at the end of July. Backward trajectories were calculated to simulate potential sources of pollen collected at different locations in the Pannonian Biogeographical Region. In a collaboration between aerobiological and phenological networks, a nationwide campaign was conducted to collect field data of ragweed blooming. During field surveys, ragweed plants having extremely early blooming were found most abundantly in a rural site near Vaja (North-East Hungary) and other locations in Hungary. Field observations matched with source areas identified by trajectory analyses; i.e., early-flowering ragweed plants were found at some of these locations. Although similar peaks of airborne pollen concentrations were not detected in other years (e.g., 2016, 2019-2021), alarming results suggest the possibility of expanding seasons of ragweed allergy.


Assuntos
Ambrosia , Hipersensibilidade , Monitoramento Ambiental/métodos , Pólen , Estações do Ano , Alérgenos/análise
4.
J Antimicrob Chemother ; 71(9): 2654-62, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27330061

RESUMO

OBJECTIVES: We sought to evaluate associations between CD4 at ART initiation (AI), achieving CD4 >750 cells/mm(3) (CD4 >750), long-term immunological recovery and survival. METHODS: This was a prospective observational cohort study. We analysed data from ART-naive patients seen in 1996-2012 and followed ≥3 years after AI. We used Kaplan-Meier (KM) methods and log-rank tests to compare time to achieving CD4 >750 by CD4 at AI (CD4-AI); and Cox regression models and generalized estimating equations to identify factors associated with achieving CD4 >750 and mortality risk. RESULTS: Of 1327 patients, followed for a median of 7.9 years, >85% received ART for ≥75% of follow-up time; 64 died. KM estimates evaluating likelihood of CD4 >750 during 5 years of follow-up, stratified by CD4-AI <50, 50-199, 200-349, 350-499 and 500-750, were 20%, 25%, 56%, 80% and 87%, respectively (log-rank P < 0.001). In adjusted models, CD4-AI ≥200 (versus CD4-AI <200) was associated with achievement of CD4 >750 [adjusted HR (aHR) = 4.77]. Blacks were less likely than whites to achieve CD4 >750 (33% versus 49%, aHR = 0.77). Mortality rates decreased with increasing CD4-AI (P = 0.004 across CD4 strata for AIDS causes and P = 0.009 for non-AIDS death causes). Among decedents with CD4-AI ≥50, 56% of deaths were due to non-AIDS causes. CONCLUSIONS: Higher CD4-AI resulted in greater long-term CD4 gains, likelihood of achieving CD4 >750, longer survival and decreased mortality regardless of cause. Over 80% of persons with CD4-AI ≥350 achieved CD4 >750 by 4 years while 75% of persons with CD4-AI <200 did not. These data confirm the hazards of delayed AI and support early AI.


Assuntos
Antirretrovirais/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/mortalidade , Adulto , Feminino , Infecções por HIV/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Medição de Risco , Análise de Sobrevida , Resultado do Tratamento
5.
HIV Med ; 16 Suppl 1: 37-45, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25711322

RESUMO

OBJECTIVES: A small subset of HIV-positive adults have low HIV RNA in the absence of therapy, sometimes for years. Clinical factors associated with low HIV RNA in early infection have not been well defined. METHODS: We assessed factors associated with low plasma HIV RNA level at study entry in the Strategic Timing of AntiRetroviral Treatment (START) trial. All START participants had a baseline HIV RNA assessment within 60 days prior to randomization. The key covariables considered for this analysis were race, and hepatitis B virus (HBV) and hepatitis C virus (HCV) status. We assessed factors associated with HIV RNA ≤ 50 and ≤ 400 HIV-1 RNA copies/mL using logistic regression. Because of the strong association between region of randomization and baseline low HIV RNA, analyses were stratified by region. RESULTS: We found that, of 4676 eligible participants randomized in START with a baseline HIV RNA assessment, 113 (2.4%) had HIV RNA ≤ 50 copies/mL at baseline, and a further 257 (5.5%) between 51 and 400 copies/mL. We found that HIV exposure routes other than male homosexual contact, higher high-density lipoprotein (HDL) cholesterol levels, higher CD4 cell counts, and higher CD4:CD8 ratio were associated with increased odds of low HIV RNA. HCV antibody positivity was borderline statistically significantly associated with low HIV RNA. Race and HBV surface antigen positivity were not significantly associated with low HIV RNA. CONCLUSIONS: In a modern cohort of individuals with early untreated HIV infection, we found that HIV exposure routes other than male homosexual contact and higher HDL cholesterol were associated with increased odds of low HIV RNA.


Assuntos
Antirretrovirais/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Demografia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , Carga Viral , Adulto , Contagem de Linfócito CD4 , Estudos de Coortes , Feminino , Infecções por HIV/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento
6.
Bull Entomol Res ; 104(3): 323-33, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24555527

RESUMO

Control of the malaria vector An. gambiae is still largely obtained through chemical intervention using pyrethroids, such as permethrin. However, strains of An. gambiae that are resistant to the toxic effects of pyrethroids have become widespread in several endemic areas over the last decade. The objective of this study was to assess differences in five life-history traits (larval developmental time and the body weight, fecundity, hatch rate, and longevity of adult females) and energy metabolism between a strain of An. gambiae that is resistant to permethrin (RSP), due to knockdown resistance and enhanced metabolic detoxification, and a permethrin susceptible strain reared under laboratory conditions. We also quantified the expression levels of five antioxidant enzyme genes: GSTe3, CAT, GPXH1, SOD1, and SOD2. We found that the RSP strain had a longer developmental time than the susceptible strain. Additionally, RSP adult females had higher wet body weight and increased water and glycogen levels. Compared to permethrin susceptible females, RSP females displayed reduced metabolic rate and mitochondrial coupling efficiency and higher mitochondrial ROS production. Furthermore, despite higher levels of GSTe3 and CAT transcripts, RSP females had a shorter adult life span than susceptible females. Collectively, these results suggest that permethrin resistance alleles might affect energy metabolism, oxidative stress, and adult survival of An. gambiae. However, because the strains used in this study differ in their genetic backgrounds, the results need to be interpreted with caution and replicated in other strains to have significant implications for malaria transmission and vector control.


Assuntos
Anopheles/efeitos dos fármacos , Resistência a Inseticidas , Inseticidas/farmacologia , Permetrina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Anopheles/genética , Anopheles/crescimento & desenvolvimento , Anopheles/fisiologia , Peso Corporal/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Feminino , Larva/efeitos dos fármacos , Larva/genética , Larva/crescimento & desenvolvimento , Larva/fisiologia , Longevidade/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Reprodução/efeitos dos fármacos
7.
Antimicrob Agents Chemother ; 57(5): 2087-94, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23422913

RESUMO

This study investigated the potential of the novel systemic pleuromutilin antibiotic BC-3781 to treat patients with an acute bacterial skin and skin structure infection (ABSSSI) caused by a Gram-positive pathogen. Patients were randomized to intravenous BC-3781 100 mg, BC-3781 150 mg, or vancomycin 1 g every 12 h. Response to treatment was assessed daily and at test of cure (TOC). The primary endpoint was the clinical success rate at TOC in the modified intent-to-treat (MITT) and clinically evaluable (CE) analysis populations. Baseline characteristics, including the frequency of methicillin-resistant Staphylococcus aureus (MRSA), were comparable between the different treatment groups. Of 210 patients randomized, 186 (88.6%) patients completed the study. Clinical success at TOC in the CE population occurred in 54 (90.0%) patients in the BC-3781 100-mg group, 48 (88.9%) in the BC-3781 150-mg group, and 47 (92.2%) in the vancomycin group. At day 3, the clinical response rate was similar across the three treatment groups. Six patients discontinued study medication following an adverse event. The incidence rate for drug-related adverse events was lower for patients receiving BC-3781 (34.3% and 39.4% in the 100-mg and 150-mg groups, respectively) than those receiving vancomycin (53.0%). When BC-3781 was used to treat ABSSSIs caused by a Gram-positive pathogen, including MRSA, clinical success rates were comparable to those of the comparator, vancomycin. BC-3781 was generally well tolerated. These results provide the first proof of concept for the systemic use of a pleuromutilin antibiotic for the treatment of ABSSSIs.


Assuntos
Antibacterianos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Dermatopatias Bacterianas/tratamento farmacológico , Pele/efeitos dos fármacos , Infecções Estafilocócicas/tratamento farmacológico , Doença Aguda , Adulto , Diterpenos/farmacologia , Esquema de Medicação , Feminino , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Compostos Policíclicos , Pele/microbiologia , Pele/patologia , Dermatopatias Bacterianas/microbiologia , Dermatopatias Bacterianas/patologia , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/patologia , Resultado do Tratamento , Vancomicina/farmacologia , Pleuromutilinas
8.
Clin Exp Immunol ; 167(3): 422-8, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22288585

RESUMO

Patients with hereditary angioedema (HAE) tend to produce autoantibodies and have a propensity to develop immunoregulatory disorders. We characterize the profile of autoantibodies in a group of HAE patients and investigate their memory B cells' phenotype and activation status. We studied the activity status phenotype, Toll-like receptor (TLR)-9 expression and total phosphotyrosine in B cells isolated from HAE patients. Additionally, the following autoantibodies were assessed in the serum of 61 HAE patients: anti-nuclear, rheumatoid factor, anti-cardiolipin, anti-tissue transglutaminase, anti-endomysial, anti-Saccharomyces cerevisiae, anti-thyroid and anti-neutrophil cytoplasmic antibodies. In 47·5% of HAE patients we detected at least one of the tested autoantibodies. Expression of CD69, CD5 and CD21 was found to be significantly higher on memory B cells from HAE patients compared to healthy controls (4·59 ± 4·41 versus 2·06 ± 1·81, P = 0·04, 8·22 ± 7·17 versus 3·65 ± 3·78, P = 0·05, 2·43 ± 0·54 versus 1·92 ± 0·41, P = 0·01, respectively). Total phosphotyrosine in B cells from HAE patients was significantly higher compared to healthy controls (4·8 ± 1·1 versus 2·7 ± 1·3, P = 0·0003). Memory B cells isolated from the HAE group contained higher amounts of TLR-9 compared to healthy controls (8·17 ± 4·1 versus 4·56 ± 1·6, P = 0·0027). Furthermore, the expression of TLR-9 in memory B cells from HAE patients with autoantibodies was significantly higher than the control group (10 ± 4·7 versus 4·56 ± 1·6, P = 0·0002) and from that in HAE patients without autoantibodies (10 ± 4·7 versus 5·8 ± 0·9, P = 0·036). HAE patients have enhanced production of autoantibodies due most probably to the increased activation of B cells, which was found to be in association with a high expression of TLR-9.


Assuntos
Autoimunidade , Linfócitos B/imunologia , Proteínas Inativadoras do Complemento 1/deficiência , Angioedema Hereditário Tipos I e II/imunologia , Adulto , Idoso , Autoanticorpos/sangue , Linfócitos B/classificação , Estudos de Casos e Controles , Proteína Inibidora do Complemento C1 , Feminino , Angioedema Hereditário Tipos I e II/etiologia , Humanos , Memória Imunológica , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Transdução de Sinais/imunologia , Receptor Toll-Like 9/metabolismo , Adulto Jovem
9.
Nat Med ; 5(3): 298-302, 1999 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10086385

RESUMO

Half of the survivors of bacterial meningitis experience motor deficits, seizures, hearing loss or cognitive impairment, despite adequate bacterial killing by antibiotics. We demonstrate that the broad-spectrum caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl-ketone (z-VAD-fmk) prevented hippocampal neuronal cell death and white blood cell influx into the cerebrospinal fluid compartment in experimental pneumococcal meningitis. Hippocampal neuronal death was due to apoptosis derived from the inflammatory response in the cerebrospinal fluid. Apoptosis was induced in vitro in human neurons by inflamed cerebrospinal fluid and was blocked by z-VAD-fmk. As apoptosis drives neuronal loss in pneumococcal meningitis, caspase inhibitors might provide a new therapeutic option directed specifically at reducing brain damage.


Assuntos
Clorometilcetonas de Aminoácidos/farmacologia , Inibidores de Caspase , Inibidores de Cisteína Proteinase/farmacologia , Meningites Bacterianas/patologia , Fármacos Neuroprotetores/farmacologia , Infecções Pneumocócicas/patologia , Animais , Apoptose , Antígenos CD18/imunologia , Linhagem Celular , Hipocampo/citologia , Humanos , Masculino , Meningites Bacterianas/imunologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Infecções Pneumocócicas/imunologia , Coelhos
10.
J Anim Physiol Anim Nutr (Berl) ; 95(4): 424-33, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21039931

RESUMO

The objective of this study was to evaluate effects of two commercially available probiotic additives, containing Bacillus spores, on carcass and meat characteristics, serum lipids and concentration of cecal volatile fatty acids of meat type chickens. Birds were fed regular corn-soy meal based feed (control), supplemented with additive A, containing 1.6 × 10(6) spores per gram of feed of Bacillus subtilis and Bacillus licheniformis (group A) or additive B, containing the same concentration of Bacillus cereus var. toyoi spores (group B). One hundred and twenty birds (20 per replicate) were slaughtered at the age of 55 days. Results showed that birds in group B had higher (p < 0.05) final body weight compared to birds from group A and higher carcass weights and yield percentages compared with control. Breasts and whole legs were also heavier in group B, compared to control, but not the yield. Group A had higher yield of wings and lower abdominal fat weight compared to group B (p< 0.05), but not compared with control. Total cholesterol was not affected by the dietary treatment, on contrary both probiotics elevated the LDL (p < 0.05) and lowered HDL cholesterol, thus unfavourably changed animal's blood serum cholesterol profile. Both probiotics influenced the cecal fermentation, which was observed as decrease in cecal concentrations of propionic, butyric, n-butyric and n-valeric acids, but the differences compared to control group were statistically significant for group A only. It was established that probiotic additive B was more effective regarding carcass and meat part weights than additive A, however the animals from group B also had more abdominal fat and their meat had significantly higher conductivity than control group, which is not considered as beneficial.


Assuntos
Bacillus , Composição Corporal/efeitos dos fármacos , Galinhas/fisiologia , Lipídeos/sangue , Probióticos/farmacologia , Esporos Bacterianos , Animais , Ceco/efeitos dos fármacos , Ceco/metabolismo , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Feminino , Conteúdo Gastrointestinal/química , Concentração de Íons de Hidrogênio , Masculino , Carne
11.
Nanotechnology ; 21(16): 165701, 2010 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-20348591

RESUMO

Au-Fe nanoparticles constitute one of the simplest prototypes of a multifunctional nanomaterial that can exhibit both magnetic and optical (plasmonic) properties. This solid solution, not feasible in the bulk phase diagram in thermal equilibrium, can be formed as a nanostructure by out-of-equilibrium processes. Here, the novel magnetic, optical and magneto-optical properties of ion-implanted Au-Fe solid solution nanoparticles dispersed in a SiO(2) matrix are investigated and correlated. The surface plasmon resonance of the Au-Fe nanoparticles with almost equicomposition is strongly damped when compared to pure Au and to Au-rich Au-Fe nanoparticles. In all cases, the Au atoms are magnetically polarized, as measured by x-ray magnetic circular dichroism, and ferromagnetically coupled with Fe atoms. Although the chemical stability of Au-Fe nanoparticles is larger than that of Fe nanoparticles, both the magnetic moment per Fe atom and the order temperature are smaller. These results suggest that electronic and magnetic properties are more influenced by the hybridization of the electronic bands in the Au-Fe solid solution than by size effects. On the other hand, the magneto-optical transitions allowed in the vis-nIR spectral regions are very similar. In addition, we also observe, after studying the properties of thermally treated samples, that the Au-Fe alloy is stabilized, not by surface effects, but by the combination of the out-of-equilibrium nature of the ion implantation technique and by changes in the properties due to size effects.


Assuntos
Cristalização/métodos , Ouro/química , Ferro/química , Nanoestruturas/química , Nanoestruturas/ultraestrutura , Nanotecnologia/métodos , Ressonância de Plasmônio de Superfície/métodos , Luz , Substâncias Macromoleculares/química , Magnetismo , Teste de Materiais , Conformação Molecular , Tamanho da Partícula , Espalhamento de Radiação , Soluções , Propriedades de Superfície
12.
Science ; 207(4426): 86-7, 1980 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-7350646

RESUMO

The activity of cyanide-sensitive, Cu-Zn superoxide dismutase (SOD) was studied in liver sytosols from H-2 congenic strains of mice. Higher SOD activity was found in livers of mice having H-2b/A.BY, B10, and C3H.SW/haplotypes than in those of H-2a, H-2k and H-2d haplotypes. Segregation studies supported these correlations. In H-2 recombinant strains of mice, the genes influencing the liver SOD activity occur, as ascertained by mapping techniques, at or near the H-2d region of the major histocompatibility complex.


Assuntos
Antígenos H-2/genética , Complexo Principal de Histocompatibilidade , Superóxido Dismutase/genética , Animais , Evolução Biológica , Genes , Genes Reguladores , Ligação Genética , Fígado/enzimologia , Camundongos
13.
Science ; 292(5520): 1334-9, 2001 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-11359002

RESUMO

In the current paradigm, Oort cloud comets formed in the giant planets' region of the solar nebula, where temperatures and other conditions varied greatly. The measured compositions of four such comets (Halley, Hyakutake, Hale-Bopp, and Lee) are consistent with formation from interstellar ices in the cold nebular region beyond Uranus. The composition of comet C/1999 S4 (LINEAR) differs greatly, which suggests that its ices condensed from processed nebular gas, probably in the Jupiter-Saturn region. Its unusual organic composition may require reevaluation of the prebiotic organic material delivered to the young Earth by comets.

15.
J Natl Cancer Inst ; 93(10): 776-82, 2001 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-11353788

RESUMO

BACKGROUND: Proliferative breast disease (PBD) may increase a woman's risk of developing breast cancer, perhaps by decreasing cellular sensitivity to apoptosis. To determine whether resistance to apoptosis develops during PBD, we investigated apoptosis initiated through the Fas pathway in a series of cell lines that recapitulates the morphologic changes of PBD in nude/beige mice. METHODS: The series of cell lines used was MCF-10A cells (parental preneoplastic human breast epithelial cells), MCF-10AT cells (transformed with T(24) Ha-ras), and MCF-10ATG3B cells (derivative cells that progress to carcinoma). Fas-mediated apoptosis, induced when a Fas monoclonal antibody bound to and activated the Fas receptor on these cells, was assessed morphologically and by flow cytometry. Levels of proteins involved in Fas-mediated apoptosis and cleavage of poly(adenosine diphosphate-ribose) polymerase (PARP), an end product of caspase activation, were determined by immunoblotting. Bcl-2 and Bax heterodimerization was examined by coimmunoprecipitation. All statistical tests were two-sided. RESULTS: Sensitivity to Fas-mediated apoptosis decreased with the tumorigenic potential of cells: MCF-10A cells were extremely susceptible, MCF-10AT cells were less susceptible, and MCF-10ATG3B cells were resistant. The percentage of apoptotic cells declined, from 24% to 8% to 6%, respectively. All lines produced Fas ligand (FasL) and had comparable levels of Fas receptor, FasL, Fas-associated death-domain protein, and caspases 3 and 6. Levels of caspase 8 were similar in MCF-10A and MCF-10AT cells but about 30% lower in MCF-10ATG3B cells (P>.01 but <.05). Levels of caspase 10 were about 20% lower in MCF-10AT cells (P>.005 but <.01) and about 59% lower in MCF-10ATG3B cells than in MCF-10A cells (P>.01 but <.05). PARP cleavage was detected in MCF-10A and MCF-10AT cells but not in MCF-10ATG3B cells. Levels of Bax, Bid, and Bak proteins were similar in all lines, but levels of Bcl-2 were lower in MCF-10AT and MCF-10ATG3B cells than in MCF-A cells, and Bcl-2-Bax heterodimerization progressively declined in the series. CONCLUSION: Resistance to Fas-mediated apoptosis appears to develop progressively in the MCF-10AT cell series.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Apoptose , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Animais , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3 , Proteínas de Transporte/biossíntese , Proteínas de Transporte/metabolismo , Caspase 10 , Caspase 3 , Caspase 6 , Caspase 8 , Caspase 9 , Caspases/biossíntese , Linhagem Celular Transformada , Linhagem da Célula , Dimerização , Proteína Ligante Fas , Proteína de Domínio de Morte Associada a Fas , Feminino , Citometria de Fluxo , Humanos , Immunoblotting , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Nus , Poli(ADP-Ribose) Polimerases/metabolismo , Testes de Precipitina , Ligação Proteica , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fatores de Tempo , Tubulina (Proteína)/metabolismo , Células Tumorais Cultivadas , Proteína Killer-Antagonista Homóloga a bcl-2 , Proteína X Associada a bcl-2 , Receptor fas/metabolismo
16.
Cancer Res ; 50(17): 5333-9, 1990 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-2167153

RESUMO

The metabolism of 3-hydroxypyridine, a significant constituent of tobacco smoke, to 2,5-dihydroxypyridine has been characterized in hepatic microsomes and in the reconstituted enzyme system using purified forms of P450. The redox cycling activity of the metabolite and its ability to damage DNA in vitro have been examined. Pyridine-induced microsomes, which contain elevated levels of P450IIE1 (Kim et al., J. Pharmacol. Exp. Ther., 246: 1175-1182, 1988), catalyzed an 8-fold increase in the production of 2,5-dihydroxypyridine, relative to control, which showed biphasic kinetics. Pyridine-induced rabbit hepatic microsomes exhibited a Vmax of 5.9 nmol 2,5-dihydroxypyridine/min/mg protein and a Km value of 110 microM. In contrast, phenobarbital- and isosafrole-induced microsomes had Vmax values of 2.5 and 1.2 nmol/min/mg protein and Km values of 590 and 134 microM, respectively. Pyridine-induced rat hepatic microsomes also exhibited elevated catalytic activity toward the hydroxylation of 3-hydroxypyridine, with an 8-fold increase in Vmax (2.74 nmol/min/mg protein) relative to uninduced rat hepatic microsomes (Vmax = 0.34 nmol/min/mg protein). In the reconstituted system, cytochrome P450IIE1 displayed the greatest activity in the production of 2,5-dihydroxypyridine of the major forms of rabbit P450 examined. P450IIE1 was 34-fold more active than P450IIB1 and 12-fold more active than P450IA2 in the production of 2,5-dihydroxypyridine. The redox cycling activity of 2,5-dihydroxypyridine has been characterized. The rate of NADPH oxidation in the presence of 0.5 mM 2,5-dihydroxypyridine was stimulated approximately 4-fold (69.2 nmol NADPH oxidized/min/mg protein), relative to control (16 nmol/min/mg protein). 2,5-Dihydroxypyridine at 0.5 and 1.0 mM produced a 12- and 17-fold increase, respectively, in the rate of superoxide anion production compared to control, as monitored by the SOD-inhibitable reduction of acetylated cytochrome c. 3-Hydroxypyridine alone failed to increase the rate of superoxide production. Inclusion of reduced glutathione in the incubation resulted in a pronounced decrease in the 2,5-dihydroxypyridine-stimulated rate of cofactor oxidation and superoxide production. The ability of 2,5-dihydroxypyridine to damage DNA was assessed by monitoring phi X-174 DNA strand scission. The band intensity of the supercoiled form of DNA, when incubated with 1 mM 2,5-dihydroxypyridine, decreased substantially, with a concomitant increase in intensity of the band associated with the open circular form of DNA. The change in phi X-174 DNA topology produced by 2,5-dihydroxypyridine was accelerated in a dose-dependent manner, with an estimated EC50 of approximately 60 microM.(ABSTRACT TRUNCATED AT 400 WORDS)


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Dano ao DNA , Microssomos Hepáticos/metabolismo , Piridinas/metabolismo , Piridinas/farmacologia , Fumaça , Animais , Biotransformação , Catalase/farmacologia , Glutationa/farmacologia , Cinética , Masculino , Microssomos Hepáticos/efeitos dos fármacos , NADP/metabolismo , Oxirredução , Fenobarbital/farmacologia , Coelhos , Safrol/farmacologia , Superóxido Dismutase/farmacologia , Superóxidos/metabolismo
17.
Cancer Res ; 36(12): 4513-9, 1976 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-187326

RESUMO

Lymphocytoid and plasmacytoid blasts have been identified in both normal and chronic lymphocytic leukemia lymphocyte cultures exposed to NaIO4. However, the appearance of ultrastructurally abnormal blasts in chronic lymphocytic leukemia cultures suggests that NaIO4 also stimulates the transformation of an abnormal subpopulation of lymphocytes. Development of invaginated nuclei produced morphological features similar to nuclear blebs, a cellular abnormally described in blood cells from other cancers. Furthermore, the consistent localization of nuclear invagination only to portions of nuclei adjacent to developing cytoplasmic microtublar complexes suggests a role for microtubules in the transformation process. The absence of these unusual blasts in cultures stimulated with other mitogens may indicate that these NaIO4-sensitive cells are not responsive to the more commonly used plant lectins.


Assuntos
Leucemia Linfoide/ultraestrutura , Ativação Linfocitária , Linfócitos/ultraestrutura , Ácido Periódico/farmacologia , Núcleo Celular/ultraestrutura , Células Cultivadas , Citoplasma/ultraestrutura , Humanos , Leucemia Linfoide/imunologia , Neoplasias/ultraestrutura , Plasmócitos/imunologia , Plasmócitos/ultraestrutura
18.
Cancer Res ; 43(1): 287-94, 1983 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-6182991

RESUMO

The effect of methylazoxymethanol acetate on rat liver nuclear and nucleolar RNA synthesis is investigated at various doses (5 to 50 mg/100 g body weight) and for various lengths of time (1 to 24 hr). The results show that this carcinogen is a potent inhibitor of both nuclear and nucleolar RNA synthesis. Like other carcinogens studied previously in this laboratory, e.g., N-hydroxy-2-acetylaminofluorene, aflatoxin B1, and actinomycin D, methylazoxymethanol acetate inhibits RNA synthesis at multiple sites. It impairs chromatin template function and selectively inhibits the activity of RNA polymerase II. Experimental evidence suggests the mechanism of inhibition of RNA polymerase II activity is due to a decrease in catalytic efficiency rather than in the total number of the enzyme. In addition, it is found that methylazoxymethanol acetate induces a dramatic condensation of nucleoplasmic chromatin.


Assuntos
Compostos Azo/farmacologia , Fígado/efeitos dos fármacos , Acetato de Metilazoximetanol/farmacologia , RNA/biossíntese , Animais , Nucléolo Celular/efeitos dos fármacos , Nucléolo Celular/metabolismo , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Relação Dose-Resposta a Droga , Fígado/metabolismo , Masculino , RNA Polimerase II/antagonistas & inibidores , Ratos , Ratos Endogâmicos , Fatores de Tempo
19.
Biochim Biophys Acta ; 1174(1): 43-53, 1993 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-8334163

RESUMO

CYP 2B1/B2 and 1A1 expression in primary rat hepatocytes plated on a substratum of Vitrogen using Chee's Essential Medium has been reported to be responsive to xenobiotic treatment (Jauregui, H.O., Ng, S.F., Gann, K.L. and Waxman, D.J. (1991) Xenobiotica 21, 1091-1106). Class alpha, mu and pi glutathione S-transferase (GST) gene expression in response to xenobiotic treatment using this primary hepatocyte culture system was examined and the results compared with those obtained for P4502B1/B2 and 1A1 expression. Cytosolic GST activity decreased approx. 75% during the first 48 h of culture relative to freshly isolated hepatocytes and subsequently, increased, attaining a level at 96 h that was 134% of the activity at 48 h post-plating. Treatment of the hepatocyte cultures with phenobarbital (2 mM) or 3-methylcholanthene (5 microM) for 24, 48, or 72 h, beginning 24 h after plating, resulted in significant increases in glutathione S-transferase activity relative to control, with maximal increases of 158 and 164% measured at 72 h following phenobarbital or 3-methylcholanthrene treatment, respectively. SDS-PAGE analysis of cytosolic proteins showed a substantial increase in the intensities of protein bands migrating in the region of the GSTs following phenobarbital, beta-naphthoflavone or 3-methylcholanthrene treatment. Immunoblot analysis of cytosolic fractions using affinity-purified class-specific GST IgGs confirmed that alpha, mu and pi-class GST isozymes were elevated approx. 1.5- to 2-fold following phenobarbital, or beta-naphthoflavone treatment; 3-methylcholanthrene was less effective in enhancing GST expression in cultured hepatocytes as compared to phenobarbital or beta-naphthoflavone. Although GST pi was below the limit of detection in freshly-isolated hepatocytes, enhanced expression of this form was observed in untreated hepatocytes cultured for longer than 72 h. Immunoblot analysis of microsomal fractions revealed that cytochrome P-4502B1/2B2 and 1A1 levels were increased significantly in hepatocyte cultures treated with phenobarbital or 3-methylcholanthrene, respectively, relative to the undetectable levels found in untreated controls. Northern blot analysis of poly(A)+ mRNA isolated from cultures that had been treated with phenobarbital or 3-methylcholanthrene showed an approx. 2- and 4-fold increase in the expression of alpha and pi class glutathione S-transferase mRNAs, respectively, as compared to untreated cells. The level of P-4501A1 or 2B1 mRNA was also markedly elevated following 3-methylcholanthrene or phenobarbital treatment, respectively. The results of this study demonor the first time, that expression of alpha, mu and pi-class glutathione S-transferase genes is effectively modulated in primary yet culture system by different classes of xenobiotics.


Assuntos
Glutationa Transferase/genética , Fígado/efeitos dos fármacos , Xenobióticos/toxicidade , Animais , Sequência de Bases , Células Cultivadas , Sistema Enzimático do Citocromo P-450/biossíntese , Indução Enzimática , Regulação da Expressão Gênica , Glutationa Transferase/biossíntese , Fígado/enzimologia , Masculino , Metilcolantreno , Dados de Sequência Molecular , Fenobarbital , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie
20.
Arch Intern Med ; 138(11): 1695-6, 1978 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-718321

RESUMO

Exacerbation of focal sclerosing glomerulopathy (FSGN) during pregnancy was noted in the three patients. All had antecedent asymptomatic proteinuria. Toxemia developed in two of the women during pregnancy and progressed rapidly to renal failure. Severe nephrotic syndrome developed in one patient with pregnancy and remitted after delivery. These cases suggest a deleterious effect of pregnancy on the course of FSGN and indicate the necessity for doing renal biopsy in women of childbearing age with asymptomatic fixed proteinuria or nephrotic syndrome so that those patients with FSGN can be properly counseled about future pregnancies.


Assuntos
Glomerulonefrite/complicações , Glomerulosclerose Segmentar e Focal/complicações , Complicações na Gravidez , Adulto , Biópsia , Aconselhamento , Feminino , Glomerulosclerose Segmentar e Focal/patologia , Humanos , Rim/patologia , Síndrome Nefrótica/etiologia , Gravidez , Proteinúria/etiologia
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