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1.
Radiol Med ; 125(3): 280-287, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31823293

RESUMO

OBJECTIVE: To report our experience with the use of intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) and dynamic contrast-enhanced (DCE)-MRI in bone marrow before and after administration of granulocyte colony-stimulating factor (GCSF). Moreover, a small series of patients with bone metastases from breast cancer have been evaluated by IVIM DW-MRI and DCE-MRI before and after GCSF administration. MATERIALS AND METHODS: We studied with IVIM-MRI and DCE-MRI 14 patients with rectal or uterine cervix cancer studied before and 4-18 days after administration of GCSF; the second MR examination was obtained after three chemotherapy courses. IVIM perfusion fraction (f), pseudo-diffusion coefficient (D*), true diffusion coefficient (D) and apparent diffusion coefficient (ADC) as well area under the curve at 60 s (AUC60) were calculated for bone marrow before and after GCSF administration. Moreover, two different IVIM parametric maps (i.e., ADC and ADClow) were generated by selecting two different intervals of b values (0-1000 and 0-80, respectively). Furthermore, four patients affected by pelvic bone metastases from breast adenocarcinoma who received GCSF administration were also qualitatively evaluated for evidence of lesions on ADC maps, ADClow maps and DCE-MRI. RESULTS: ADC, D, D*, f and AUC60 values were significantly higher in hyperplastic bone marrow than in untreated bone marrow (p values < 0.0001, < 0.0001, < 0.001, < 0.001, < 0.0001, respectively). All bone metastases were clearly differentiable from hyperplastic bone marrow on ADClow maps, but not on ADC maps and DCE-MRI. CONCLUSION: MR functional imaging techniques, such as DW-, IVIM DW- and DCE-MRI are effective tools in assessing the response of bone marrow to the administration of growth factors. Although an overlap between signal of hyperplastic bone marrow and lytic bone metastases can occur on ADC maps and DCE-MRI, evaluation of ADClow maps by IVIM DW-MRI could permit to differentiate hyperplastic bone marrow from lytic bone metastases. Further studies are needed to confirm our data.


Assuntos
Medula Óssea/efeitos dos fármacos , Medula Óssea/diagnóstico por imagem , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/secundário , Imagem de Difusão por Ressonância Magnética/métodos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Adulto , Idoso , Área Sob a Curva , Medula Óssea/patologia , Neoplasias da Mama/patologia , Meios de Contraste , Feminino , Humanos , Hiperplasia/diagnóstico por imagem , Hiperplasia/patologia , Masculino , Pessoa de Meia-Idade , Ossos Pélvicos/diagnóstico por imagem , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/patologia , Fatores de Tempo , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia
2.
Toxicol Lett ; 318: 92-98, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31678399

RESUMO

Sulfur mustard (SM) is a vesicant chemical warfare agent. Recent studies reported alleged use of SM by non-state actors in Syria and Iraq. It has been shown that SM induced immunological and hematological complications. The aim of this study was to determine acute toxic effects of SM exposure on hematological parameters. Blood samples from a group of Syrian exposed to SM in 2016 were taken daily during the follow-up of the patients in intensive care unit. Initial leukocytosis was observed in all patients (100%) on the first 48 h after exposure. Following leukocytosis, isolated lymphopenia was observed in all patients (100%) between 2nd and 4th days. A decrease in hemoglobin level was noted in five patients (62.5%) between 4th and 5th days. Thrombocytopenia was observed in 75% of patients between 4th and 6th days for mild cases and between 9th and 11th days for severe cases. Three patients (37.5%) developed distinct leucopenia/neutropenia on 11th and 12th days. It was observed that human exposure to high dose of SM has direct toxic effect on hematological cells and bone marrow. New strategies on treatment of SM-induced myelosuppression could reduce the effects of hematological complications and could increase the survival rate in these patients.


Assuntos
Medula Óssea/efeitos dos fármacos , Terrorismo Químico , Substâncias para a Guerra Química/envenenamento , Leucocitose/induzido quimicamente , Leucopenia/induzido quimicamente , Linfopenia/induzido quimicamente , Gás de Mostarda/envenenamento , Trombocitopenia/induzido quimicamente , Adolescente , Adulto , Biomarcadores/sangue , Medula Óssea/patologia , Feminino , Hemoglobinas/metabolismo , Humanos , Leucocitose/sangue , Leucocitose/patologia , Leucopenia/sangue , Leucopenia/patologia , Linfopenia/sangue , Linfopenia/patologia , Masculino , Síria , Trombocitopenia/sangue , Trombocitopenia/patologia , Adulto Jovem
3.
Nat Cell Biol ; 21(11): 1309-1320, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31685996

RESUMO

With ageing, intrinsic haematopoietic stem cell (HSC) activity decreases, resulting in impaired tissue homeostasis, reduced engraftment following transplantation and increased susceptibility to diseases. However, whether ageing also affects the HSC niche, and thereby impairs its capacity to support HSC function, is still widely debated. Here, by using in-vivo long-term label-retention assays we demonstrate that aged label-retaining HSCs, which are, in old mice, the most quiescent HSC subpopulation with the highest regenerative capacity and cellular polarity, reside predominantly in perisinusoidal niches. Furthermore, we demonstrate that sinusoidal niches are uniquely preserved in shape, morphology and number on ageing. Finally, we show that myeloablative chemotherapy can selectively disrupt aged sinusoidal niches in the long term, which is linked to the lack of recovery of endothelial Jag2 at sinusoids. Overall, our data characterize the functional alterations of the aged HSC niche and unveil that perisinusoidal niches are uniquely preserved and thereby protect HSCs from ageing.


Assuntos
Envelhecimento/genética , Capilares/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Homeostase/genética , Nicho de Células-Tronco/genética , Envelhecimento/metabolismo , Animais , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Capilares/citologia , Capilares/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Polaridade Celular/efeitos dos fármacos , Rastreamento de Células/métodos , Doxiciclina/farmacologia , Fluoruracila/farmacologia , Regulação da Expressão Gênica , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Histonas/genética , Histonas/metabolismo , Homeostase/efeitos dos fármacos , Proteína Jagged-2/genética , Proteína Jagged-2/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Agonistas Mieloablativos/farmacologia , Nicho de Células-Tronco/efeitos dos fármacos
4.
Pharm Res ; 36(12): 163, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31617004

RESUMO

PURPOSE: There is ongoing concern regarding increased toxicity from paclitaxel in elderly patients, particularly of severe neutropenia. Yet, data so far is controversial and this concern is not supported by a clinically relevant age-dependent difference in pharmacokinetics (PK) of paclitaxel. This study assessed whether age is associated with increased risk for paclitaxel-induced neutropenia. METHODS: Paclitaxel plasma concentration-time data, pooled from multiple different studies, was combined with available respective neutrophil count data during the first treatment cycle. Paclitaxel pharmacokinetic-pharmacodynamic (PK-PD) data was modeled using a non-linear mixed effects approach and a semiphysiological neutropenia model, where systemic paclitaxel exposure was linked to reduced proliferation of neutrophils. The impact of age was evaluated on relevant variables in the model, using a significance threshold of p < 0.005. RESULTS: Paclitaxel PK-PD data was evaluated from 300 patients, with a median age of 65 years (range 23-84 years), containing 116 patients ≥70 years (39%). First cycle neutrophil counts were adequately described by a threshold effect model of paclitaxel on the proliferation rate of neutrophils. Age as a continuous or dichotomous variable (≥70 versus <70 years) did not significantly impact sensitivity of the bone marrow to paclitaxel nor the average maturation time of neutrophils (both p > 0.005), causing a decline in the respective interindividual variability of <1%. CONCLUSION: Results from this large retrospective patient cohort do not suggest elderly patients to be at an increased risk of developing paclitaxel-associated neutropenia during the first treatment cycle. Reflexive dose reductions of paclitaxel in elderly patients are unlikely to improve the risk of severe neutropenia and may be deleterious.


Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Neutropenia/induzido quimicamente , Paclitaxel/efeitos adversos , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Estudos Retrospectivos
5.
Molecules ; 24(20)2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31623098

RESUMO

Oleoyl serine (OS), an endogenous fatty acyl amide (FAA) found in bone, has been shown to have an anti-osteoporotic effect. OS, being an amide, can be hydrolyzed in the body by amidases. Hindering its amide bond by introducing adjacent substituents has been demonstrated as a successful method for prolonging its skeletal activity. Here, we tested the therapeutic efficacy of two methylated OS derivatives, oleoyl α-methyl serine (HU-671) and 2-methyl-oleoyl serine (HU-681), in an ovariectomized mouse model for osteoporosis by utilizing combined micro-computed tomography, histomorphometry, and cell culture analyses. Our findings indicate that daily treatment for 6 weeks with OS or HU-671 completely rescues bone loss, whereas HU-681 has only a partial effect. The increased bone density was primarily due to enhanced trabecular thickness and number. Moreover, the most effective dose of HU-671 was 0.5 mg/kg/day, an order of magnitude lower than with OS. The reversal of bone loss resulted from increased bone formation and decreased bone resorption, as well as reversal of bone marrow adiposity. These results were further confirmed by determining the serum levels of osteocalcin and type 1 collagen C-terminal crosslinks, as well as demonstrating the enhanced antiadipogenic effect of HU-671. Taken together, these data suggest that methylation interferes with OS's metabolism, thus enhancing its effects by extending its availability to its target cells.


Assuntos
Adiposidade/efeitos dos fármacos , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Ácidos Oleicos/química , Osteoporose/etiologia , Osteoporose/metabolismo , Serina/análogos & derivados , Serina/farmacologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Medula Óssea/diagnóstico por imagem , Modelos Animais de Doenças , Feminino , Camundongos , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoporose/diagnóstico , Ovariectomia/efeitos adversos , Serina/química , Microtomografia por Raio-X
6.
Life Sci ; 238: 116981, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31639394

RESUMO

AIM: Endothelial cell damage is critical to understand since its presence in the entire body makes the damage widespread instead of being localized. Being a major component of stem cell niche in bone marrow, deems it essential to gain knowledge of the damage to endothelium associated with bone marrow. Since radiation exposure has become common to numerous therapeutic modalities, its effects on bone marrow and its endothelial cells are crucial to understand. MATERIAL & METHODS: Microarray analysis was performed on irradiated human bone marrow endothelial cells (hBMECs) with and without prior treatment with radioprotectant amifostine to assess the effects of radiation on signalling pathways and the subsequent changes in pathways when treated with radioprotectant prior to radiation exposure. KEY FINDINGS: It was seen that adhesion pathways that were usually inactivated under normal circumstances were stimulated post radiation. However, where in the case of radiation exposure, these adhesion pathways included leukocyte adhesion and migration; in the case of radioprotected conditions the pathways revolve around cell-substrate adhesion and cell spreading. Genes like ROCK1, FLNA, RAC1, PRKCZ and MAP3K8 were seen to regulate the molecular switch between leukocyte-cell adhesion to cell-substrate adhesion. SIGNIFICANCE: Our study demonstrated that irradiated endothelium supports leukocyte adhesion and migration but shifts to substrate adhesion dependent cell spreading under radioprotected conditions in order to repair the monolayer damage from the radiation. The genes responsible for the shift were identified and can be employed to manipulate cell adhesion characteristics for the treatment of diseases caused by radiation or inflammation.


Assuntos
Amifostina/farmacologia , Biomarcadores/metabolismo , Medula Óssea/metabolismo , Adesão Celular , Endotélio Vascular/metabolismo , Raios gama , Leucócitos/metabolismo , Medula Óssea/efeitos dos fármacos , Medula Óssea/efeitos da radiação , Células Cultivadas , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/efeitos da radiação , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos da radiação , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos da radiação , Humanos , Leucócitos/efeitos dos fármacos , Leucócitos/efeitos da radiação , Protetores contra Radiação/farmacologia
7.
Mar Drugs ; 17(10)2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31546680

RESUMO

The deterioration of bone formation is a leading cause of age-related bone disorders. Lack of bone formation is induced by decreased osteoblastogenesis. In this study, osteoblastogenesis promoting effects of algal phlorotannin, phlorofucofuroeckol A (PFF-A), were evaluated. PFF-A was isolated from brown alga Ecklonia cava. The ability of PFF-A to enhance osteoblast differentiation was observed in murine pre-osteoblast cell line MC3T3-E1 and human bone marrow-derived mesenchymal stem cells (huBM-MSCs). Proliferation and alkaline phosphatase (ALP) activity of osteoblasts during differentiation was assayed following PFF-A treatment along extracellular mineralization. In addition, effect of PFF-A on osteoblast maturation pathways such as Runx2 and Smads was analyzed. Treatment of PFF-A was able to enhance the proliferation of differentiating osteoblasts. Also, ALP activity was observed to be increased. Osteoblasts showed increased extracellular mineralization, observed by Alizarin Red staining, following PFF-A treatment. In addition, expression levels of critical proteins in osteoblastogenesis such as ALP, bone morphogenetic protein-2 (BMP-2), osteocalcin and ß-catenin were stimulated after the introduction of PFF-A. In conclusion, PFF-A was suggested to be a potential natural product with osteoblastogenesis enhancing effects which can be utilized against bone-remodeling imbalances and osteoporosis-related complications.


Assuntos
Benzofuranos/farmacologia , Medula Óssea/efeitos dos fármacos , Dioxinas/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Feófitas/química , Células 3T3 , Fosfatase Alcalina/metabolismo , Animais , Produtos Biológicos/farmacologia , Medula Óssea/metabolismo , Proteína Morfogenética Óssea 2/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Humanos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Osteoblastos/metabolismo , Osteogênese/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , beta Catenina/metabolismo
8.
Medicina (Kaunas) ; 55(9)2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31480729

RESUMO

Background and Objectives: Side effects of anti-cancer drugs are usually accompanied by oxidative stress, including myelotoxicity. We evaluated the potential of oral highly activated micro-/macroporous carbon adsorbents (bulk density of 0.16 g/cm3, surface area calculation by Brunauer-Emmett-Teller model (SBET) > 2200 m2/g, derived from proprietary phenolic resin beads) to alleviate oxidative stress and myelotoxicity in rats. Materials and Methods: A single injection of cytostatic melphalan (L-PAM) at a dose of 4 mg/kg was used for modelling. Two forms of activated carbon were used: AC1-primary beads with the particle size range of 125-250 µm, and AC2-micronized AC1 with a mean particle size of ~1 µm. We measured haematological parameters white blood cells, red blood cells, platelet count, and haemoglobin level. Oxidative stress intensity was evaluated using the following markers: total levels of reactive oxygen species (ROS) in blood plasma; catalase activity (CAT) and pro-oxidant/antioxidant ratio in blood haemolysate samples; level of reduced glutathione (GSH) in liver tissues; oxidative modification of proteins, OPM (APHD, aldehyde-dinitrophenylhydrazone derivatives and KPHD, ketone dinitrophenylhydrazone derivatives) and malonic dialdehyde (MDA) in blood plasma and liver samples. Results: AC2 administration promoted significant myeloprotective effect: 1.5-fold increase in leukocytes, 2-fold in neutrophils, 1.5-fold in lymphocytes, and 1.23-fold in platelet count compared to the experimental Melphalan Group. At the same time, AC1 administration resulted in a slight increase in haematological parameters. Both ACs positively corrected important, but diverse, components of oxidative stress. They significantly reduced oxidative modification of blood and liver proteins (especially the AC1 form), normalized the level of reduced glutathione, pro-oxidant/antioxidant ratio and other markers. For some markers, such as ROS production in blood plasma, the use of enterosorbents resulted in non-significant a shift towards normal parameters. Conclusions: Oral activated carbon adsorbents reduce oxidative stress intensity and myelotoxicity; they can be promising means to combat the adverse effects of chemotherapy in clinical practice.


Assuntos
Antineoplásicos Alquilantes/toxicidade , Medula Óssea/efeitos dos fármacos , Carvão Vegetal/farmacologia , Enteroadsorção , Melfalan/toxicidade , Microesferas , Estresse Oxidativo/efeitos dos fármacos , Adsorção , Animais , Contagem de Células Sanguíneas , Peso Corporal , Portadores de Fármacos , Feminino , Ratos , Ratos Endogâmicos , Espécies Reativas de Oxigênio/sangue
9.
Toxicol Ind Health ; 35(8): 548-557, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31370753

RESUMO

Metal oxide nanoparticles (NPs) have widespread uses ranging from nanoelectronics to nanotherapeutics. Because of their expanding industrial applications, a better understanding of their toxicity is needed. So far, limited reports are available on chromium oxide NPs (Cr2O3 NPs) toxicity. In this work, Cr2O3 NPs were synthesized and characterized in a sequential manner using X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, and transmission electron microscopy. Dose- and time-dependent toxicity assessment of Cr2O3 NPs was carried out in Wistar rats by examining liver function biomarkers, tissue histopathology, micronuclei (MN) formation, and chromosomal aberrations (CAs) in bone marrow along with sperm abnormalities. The results of this study demonstrated typical XRD and FTIR patterns of Cr2O3 NPs with a size of approximately 23.47 nm. Animals exposed to Cr2O3 NPs, exhibited a significant increase in aspartate transaminase, alanine transaminase, alkaline phosphatase, gamma glutamyltransferase, and total bilirubin, signifying liver injury. Histopathology data also supported the marked alterations in the liver biochemistry of NPs-exposed animals. Further, an increase in the frequency of MN, CA, and sperm abnormalities suggested Cr2O3 NPs-mediated genotoxicity. It is, therefore, suggested that possible safety issues of Cr2O3 NPs should be addressed promptly with limited future use in occupational settings.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Compostos de Cromo/toxicidade , Aberrações Cromossômicas/induzido quimicamente , Nanopartículas Metálicas/toxicidade , Administração Oral , Animais , Medula Óssea/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/patologia , Compostos de Cromo/administração & dosagem , Relação Dose-Resposta a Droga , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Nanopartículas Metálicas/administração & dosagem , Testes para Micronúcleos , Ratos , Ratos Wistar , Espermatozoides/efeitos dos fármacos
10.
Indian J Med Res ; 149(4): 508-516, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31411175

RESUMO

Background & objectives: Hepatocyte growth factor (HGF) produced by endothelial cells, fibroblasts, fat cells and other interstitial cells, can promote angiogenesis, repair damaged tissues and resist fibrosis. Mesenchymal stem cells (MSCs) are located in bone marrow and secrete a variety of cytokines and are often used in the repair and regeneration of damaged tissues. This study was aimed to investigate the influence of HGF-transfected bone marrow-derived MSCs towards renal fibrosis in rats. Methods: The HGF gene-carrying adenoviral vector (Ad-HGF) was transfected into MSCs, and the Ad-HGF-modified MSCs were transplanted into rats with unilateral ureteral obstruction (UUO). The localization of renal transplanted cells in the frozen section was observed with fluorescence microscope. The Masson's trichrome staining was performed to observe the renal collagen deposition, and the immunohistochemistry was performed to detect the expressions of α-smooth muscle actin (α-SMA) and HGF in renal tissues. Reverse transcription (RT)-PCR was used to detect the mRNA expressions of α-SMA, HGF and fibronectin (FN). Results: Ad-HGF-modified MSCs could highly express HGF in vitro. On the post-transplantation 3rd, 7th and 14th day, the 4',6-diamidino-2-phenylindole (DAP)-labelled transplanted cells were seen inside renal tissues. Compared with UUO group, the renal collagen deposition in transplantation group was significantly reduced, and the expressions of α-SMA mRNA and protein were significantly decreased, while the expressions of HGF mRNA and protein were significantly increased, and the expression of FN mRNA was significantly decreased (P<0.001). Interpretation & conclusions: Trans-renal artery injection of HGF-modified MSCs can effectively reduce the renal interstitial fibrosis in UUO rat model.


Assuntos
Fibrose/terapia , Fator de Crescimento de Hepatócito/genética , Rim/metabolismo , Transplante de Células-Tronco Mesenquimais , Actinas/genética , Adenoviridae/genética , Animais , Medula Óssea/efeitos dos fármacos , Modelos Animais de Doenças , Fibronectinas/genética , Fibrose/genética , Fibrose/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Vetores Genéticos/farmacologia , Fator de Crescimento de Hepatócito/farmacologia , Humanos , Rim/patologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Ratos , Transfecção , Obstrução Ureteral/fisiopatologia
11.
Anticancer Res ; 39(8): 4455-4462, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366544

RESUMO

BACKGROUND/AIM: Platinum-based chemotherapy often fails due to its severe adverse effects. The aim of this study was to examine the adverse effects profile and efficacy of dicycloplatin and compare them to those of cisplatin and carboplatin. MATERIALS AND METHODS: Cystoscopy surveillance of the first American cancer patient treated with dicycloplatin was performed quarterly. In vitro and in vivo studies were conducted using immunoblotting and flow cytometry to assess immune status of spleen and bone marrow of mice treated with dicycloplatin, cisplatin and carboplatin. RESULTS: The American patient did not suffer clinically significant myelosuppression; dicycloplatin has sustained remission in this patient to date. Experimental studies showed that dicycloplatin is less toxic to bone marrow and spleen of mice than cisplatin and carboplatin. CONCLUSION: Dicycloplatin is a promising drug in cancer chemotherapy with less aggressive side-effects than those typically associated with cisplatin and carboplatin. This is an important therapeutic advantage in cancer chemotherapy. Clinical investigation of dicycloplatin as an alternative to cisplatin or carboplatin is warranted.


Assuntos
Medula Óssea/efeitos dos fármacos , Glutamatos/administração & dosagem , Neoplasias/tratamento farmacológico , Compostos Organoplatínicos/administração & dosagem , Baço/efeitos dos fármacos , Animais , Medula Óssea/patologia , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Cistoscopia , Modelos Animais de Doenças , Combinação de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Glutamatos/efeitos adversos , Humanos , Camundongos , Compostos Organoplatínicos/efeitos adversos , Baço/patologia
12.
Biomarkers ; 24(7): 720-725, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31464141

RESUMO

Background: Fungicides describe all chemicals used to control fungi that infect plants. Luna Experience SC-400 is a new line of fungicide that consist of Fluopyram and Tebuconazole. Objective: In this study, We investigated the genotoxicty and cytotoxicty of Luna Experience-SC 400 using comet assay, micronucleus test and polychromatic erythrocytes number in rat bone marrow. The present study is the first report indicating the effects of genotoxic and cytotoxic of Luna experience SC-400 on rat bone marrow cells. Material and Methods: We used three different doses (5mg/kg, 10mg/kg, 20mg/kg) of Luna Experience SC 400 at 48 h intervals during 30 days by gavage in rats.Genotoxicity was evaluated using comet assay and micronucleus test and cytotoxicity was measured the PCE/NCE rate in rat bone marrow. Results: Based on these experimental results, we report that Luna Experience-SC 400 fungicide presents genotoxic and cytotoxic potential on rat bone marrow. There is a significant difference between negative control group and all the doses of Luna Experience-SC 400 (p < 0.05) for comet assay and micronucleus. Even moderate and high doses of fungicides seem to have reached the values of almost positive control group for Genetic Damage Index (GDI) and Damaged Cell Percentage (DCP). In this study, we also investigated the PCE/NCE rate. Fungicide caused a decrease in the level of significant in the PCE/NCE ratio (p < 0.05). Conclusion: Our in vivo study suggests that the gavage exposure to Luna experience SC 400 used in the present investigation may be genotoxic and cytotoxic in rat bone marrow in view of these findings. Because this findings is first report represented in the pesticide biology, it is important to carry out more investigations using various cytogenetic tests under different experimental conditions to definitively resolve the the possible genotoxic and cytotoxic risk associated with new generation pesticides-fungicides.


Assuntos
Benzamidas/toxicidade , Medula Óssea/efeitos dos fármacos , Fungicidas Industriais/toxicidade , Piridinas/toxicidade , Triazóis/toxicidade , Animais , Ensaio Cometa , Citotoxinas/farmacologia , Relação Dose-Resposta a Droga , Testes para Micronúcleos , Mutagênicos/farmacologia , Ratos
13.
Int J Pharm ; 570: 118648, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31465833

RESUMO

Skin is the first protection of human body. It is always challenged by a range of external factors, resulting in the wounds of skin. Hydrogel, as a dressing with multiple advantages, causes increasing interests or the applications in wound treatment. However, the function and importance of micro-environment of wound region are frequently neglected. In this study, we successfully developed a chemokine loaded biomimetic hydrogel as a functional reservoir to stimulate the rapid in situ recruitment of BMSCs for fast wound repair and regeneration. The biomimetic hydrogel was fabricated by using the Polyvinyl alcohol (PVA) combined with chitosan (CS) as the hybrid materials. The fabricated hydrogel possesses many features such as the porous structure, high swelling rate and moisture retention property. More importantly, the incorporated chemokine could be released with a sustained manner from the hydrogel and recruited the bone marrow mesenchymal stem cells (BMSCs) significantly both in vitro & in vivo. Moreover, the hydrogel was demonstrated to be highly biocompatible to the skin tissue without any side effect or irritation observed. Topical delivery of chemokine by the biomimetic PVA/CS hybrid material based hydrogel is demonstrated as a promising carrier to accelerate wound repair and regeneration without inducing scar formation and any other negative complications. The PVA/CS/SDF-1 hydrogel was shown a novel therapeutic system for wound therapy.


Assuntos
Materiais Biomiméticos/administração & dosagem , Materiais Biomiméticos/química , Quimiocinas/metabolismo , Regeneração/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Animais , Bandagens , Biomimética/métodos , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Quitosana/química , Sistemas de Liberação de Medicamentos/métodos , Humanos , Hidrogéis/química , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Álcool de Polivinil/química , Ratos , Ratos Sprague-Dawley , Pele/efeitos dos fármacos , Pele/metabolismo
14.
Food Chem Toxicol ; 132: 110664, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31279043

RESUMO

Cylindrospermopsin (CYN) is a potent cyanotoxin recognized as an emerging human threat due to its cytotoxicity and potential carcinogenicity. Although the genotoxicity of CYN has been extensively studied in vitro, limited data are available on its in vivo genotoxicity. The aim of this study was to evaluate the in vivo genotoxicity of pure CYN (7.5-75 µg/kg body weight) after oral exposure of rats through a combined assay of the micronucleus test (MN) in bone marrow, and the standard and modified comet assay in stomach, liver and blood. Also, histopathological changes in stomach and liver were evaluated. Positive results in the MN test were observed in bone marrow in the exposed rats at all the tested concentrations. However, the comet assay revealed that CYN did not induce DNA strand breaks nor oxidative DNA damage in any of the tissues investigated. Finally, histopathological changes were observed in stomach and liver (7.5-75 µg/kg) in intoxicated rats. These results could indicate that CYN is able to induce irritation in stomach before its biotransformation in rats orally exposed, and genotoxicity in bone marrow.


Assuntos
Toxinas Bacterianas/toxicidade , Ensaio Cometa , Testes para Micronúcleos , Mutagênicos/toxicidade , Uracila/análogos & derivados , Animais , Medula Óssea/efeitos dos fármacos , Dano ao DNA , Fígado/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Estômago/efeitos dos fármacos , Uracila/toxicidade
15.
Environ Mol Mutagen ; 60(9): 766-777, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31335992

RESUMO

Arylboronic acids and esters (referred to collectively as arylboronic compounds) are commonly used intermediates in the synthesis of pharmaceuticals but pose a challenge for chemical syntheses because they are often positive for bacterial mutagenicity in vitro. As such, arylboronic compounds are then typically controlled to levels that are acceptable for mutagenic impurities, that is, the threshold of toxicological concern (TTC). This study used ICH M7 guidance to design and conduct a testing strategy to investigate the in vivo relevance of the in vitro positive findings of arylboronic compounds. Eight arylboronic compounds representing a variety of chemical scaffolds were tested in Sprague Dawley and/or Wistar rats in the in vivo Pig-a (peripheral blood reticulocytes and mature red blood cells) and/or comet assays (duodenum and/or liver). Five of the eight compounds were also tested in the micronucleus (peripheral blood) assay. The arylboronic compounds tested orally demonstrated high systemic exposure; thus the blood and bone marrow were adequately exposed to test article. One compound was administered intravenously due to formulation stability issues. This investigation showed that arylboronic compounds that were mutagenic in vitro were not found to be mutagenic in the corresponding in vivo assays. Therefore, arylboronic compounds similar to the scaffolds tested in this article may be considered non-mutagenic and managed in accordance with the ICH Q3A/Q3B guidelines. Environ. Mol. Mutagen. 2019. © 2019 Wiley Periodicals, Inc.


Assuntos
Ácidos Borônicos/toxicidade , Ésteres/toxicidade , Mutagênicos/toxicidade , Animais , Medula Óssea/efeitos dos fármacos , Ensaio Cometa/métodos , Duodeno/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Fígado/diagnóstico por imagem , Masculino , Testes para Micronúcleos/métodos , Mutagênese/efeitos dos fármacos , Testes de Mutagenicidade/métodos , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Reticulócitos/efeitos dos fármacos
16.
Int J Pharm ; 567: 118421, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176849

RESUMO

Intratumoral injection of biocompatible gels is increasingly used for the sustained delivery of drugs and vaccines to enhance the anti-cancer immune response. Granulocyte-macrophage colony stimulating factor (GM-CSF) has become an attractive adjuvant thanks to its ability to boost the antitumor immune response by inducing proliferation, maturation and migration of the dendritic-cells (DCs) and the differentiation of lymphocytes. Killed Mycobacteria, such as Heat-killed Mycobacterium tuberculosis (HKMT) have been used in several studies as TLR-2 agonist to increase maturation of DCs. In this study, we designed a mucoadhesive thermosensitive formulation for the local delivery of GM-CSF and HKMT in order to enhance DCs activation and improve the local antitumor immune response. This formulation was selected based on its elastic and mucoadhesive properties obtained thanks to rheological studies. More importantly, intratumoral residence time of the labelled gel and protein were evidenced by means of MRI and non invasive in vivo optical imaging. Then, the efficacy of the combination of immunomodulators loaded thermogel was demonstated in vitro and in vivo. The selected thermogel exhibits rheological properties which confer a good elasticity and increased residence time of the immunostimulatory agents in the tumor, thus increasing the recruitment of DCs and T cytotoxic CD8+ lymphocytes.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Hidrogéis/administração & dosagem , Fatores Imunológicos/administração & dosagem , Mycobacterium tuberculosis , Neoplasias/tratamento farmacológico , Adesividade , Animais , Medula Óssea/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Células Dendríticas/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/química , Hidrogéis/química , Fatores Imunológicos/química , Camundongos , Camundongos Endogâmicos BALB C , Mucinas/química , Células NIH 3T3 , Neoplasias/imunologia , Neoplasias/patologia , Imagem Óptica , Poloxâmero/administração & dosagem , Poloxâmero/química , Reologia
17.
World J Gastroenterol ; 25(21): 2539-2548, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31210708

RESUMO

Inflammatory bowel disease (IBD) is a chronic and heterogeneous intestinal inflammatory disorder. The medical management of IBD aims for long-lasting disease remission to prevent complications and disease progression. Early introduction of immunosuppression forms the mainstay of medical IBD management. Large inter-individual variability in drug responses, in terms of both efficacy and toxicity, leads to high rates of therapeutic failure in the management of IBD. Better patient stratification is needed to maximize patient benefit and minimize the harm caused by adverse events. Pre-treatment pharmacogenetic testing has the potential to optimize drug selection and dose, and to minimize harm caused by adverse drug reactions. In addition, optimizing the use of cheap conventional drugs, and avoiding expensive ineffective drugs, will lead to a significant reduction in costs. Genetic variation in both TPMT and NUDT15, genes involved in thiopurine metabolism, is associated to an increased risk of thiopurine-induced myelosuppression. Moreover, specific HLA haplotypes confer risk to thiopurine-induced pancreatitis and to immunogenicity to tumor necrosis factor-antagonists, respectively. Falling costs and increased availability of genetic tests allow for the incorporation of pre-treatment genetic tests into clinical IBD management guidelines. In this paper, we review clinically useful pharmacogenetic associations for individualized treatment of patients with IBD and discuss the path from identification of a predictive pharmacogenetic marker to implementation into IBD clinical care.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Gastroenterologia/métodos , Imunossupressores/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Medicina de Precisão/métodos , Variação Biológica da População/genética , Medula Óssea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Gastroenterologia/normas , Testes Genéticos , Antígenos HLA/genética , Antígenos HLA/imunologia , Hematopoese/efeitos dos fármacos , Humanos , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Metiltransferases/genética , Metiltransferases/metabolismo , Seleção de Pacientes , Guias de Prática Clínica como Assunto , Medicina de Precisão/normas , Prognóstico , Pirofosfatases/genética , Pirofosfatases/metabolismo , Medição de Risco/métodos , Resultado do Tratamento
19.
Ann Hematol ; 98(8): 1905-1918, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31104089

RESUMO

Efficient and safe delivery of siRNA in vivo is the biggest roadblock to clinical translation of RNA interference (RNAi)-based therapeutics. To date, lipid nanoparticles (LNPs) have shown efficient delivery of siRNA to the liver; however, delivery to other organs, especially hematopoietic tissues still remains a challenge. We developed DLin-MC3-DMA lipid-based LNP-siRNA formulations for systemic delivery against a driver oncogene to target human chronic myeloid leukemia (CML) cells in vivo. A microfluidic mixing technology was used to obtain reproducible ionizable cationic LNPs loaded with siRNA molecules targeting the BCR-ABL fusion oncogene found in CML. We show a highly efficient and non-toxic delivery of siRNA in vitro and in vivo with nearly 100% uptake of LNP-siRNA formulations in bone marrow of a leukemic model. By targeting the BCR-ABL fusion oncogene, we show a reduction of leukemic burden in our myeloid leukemia mouse model and demonstrate reduced disease burden in mice treated with LNP-BCR-ABL siRNA as compared with LNP-CTRL siRNA. Our study provides proof-of-principle that fusion oncogene specific RNAi therapeutics can be exploited against leukemic cells and promise novel treatment options for leukemia patients.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Nanopartículas/administração & dosagem , RNA Interferente Pequeno/farmacologia , Animais , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Medula Óssea/patologia , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Expressão Gênica , Marcação de Genes/métodos , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Lipídeos/administração & dosagem , Lipídeos/química , Camundongos , Camundongos Nus , Nanopartículas/química , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , RNA Interferente Pequeno/farmacocinética , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Mol Med Rep ; 19(6): 4743-4752, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059030

RESUMO

Interleukin 17A (IL­17A) exerts pleiotropic effects on periodontitis, partially through enhancement of alveolar bone loss. Osteoclasts are the main culprits that absorb alveolar bone. However, studies describing the correlation between IL­17A and osteoclasts are not conclusive. Previously, autophagy was revealed to be involved in osteoclast differentiation and bone resorption. However, the role of autophagy in IL­17A­mediated osteoclast formation is yet to be clarified. In the present study, bone marrow macrophages (BMMs) were treated with or without IL­17A. 3­Methyladenine (3­MA) was applied to inhibit autophagy. Osteoclast formation was detected by tartrate­resistant acid phosphatase (TRAP) staining, immunofluorescence, and scanning electron microscope. The effects of IL­17A on osteoclast­specific genes and autophagy­related genes during osteoclast differentiation were examined by real­time quantitative polymerase chain reaction and western blot analysis. Autophagosomes were observed by transmission electron microscope. Hematoxylin and eosin (H&E), and TRAP staining was adopted to assess alveolar bone destruction and the number of osteoclasts, respectively in a rat periodontitis model. Consequently, IL­17A stimulated osteoclast differentiation and bone resorption of BMMs accompanied by an increase in the mRNA expression of osteoclast­specific genes. Furthermore, IL­17A increased the levels of autophagy­related genes and proteins, and inhibition of autophagy with 3­MA attenuated the IL­17A­mediated osteoclastogenesis. In addition, there was an increase in the number of osteoclasts and alveolar bone resorption with IL­17A treatment in the periodontitis rat model. Collectively, these findings indicated that IL­17A facilitated osteoclast differentiation and bone resorption in vitro and in vivo, which may contribute to the understanding of the molecular basis of IL­17A in alveolar bone destruction and provide insight on the clinical therapeutic targets for periodontitis.


Assuntos
Autofagia/efeitos dos fármacos , Medula Óssea/metabolismo , Reabsorção Óssea/metabolismo , Diferenciação Celular/efeitos dos fármacos , Interleucina-17/farmacologia , Macrófagos/metabolismo , Osteoclastos/metabolismo , Actinas/metabolismo , Adenina/análogos & derivados , Adenina/antagonistas & inibidores , Perda do Osso Alveolar/tratamento farmacológico , Perda do Osso Alveolar/patologia , Animais , Autofagossomos/patologia , Autofagia/genética , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Reabsorção Óssea/patologia , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Periodontite/tratamento farmacológico , Periodontite/patologia , Ratos , Ratos Sprague-Dawley
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