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1.
Adv Exp Med Biol ; 1226: 57-72, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32030676

RESUMO

It has been appreciated that the cross talk between bone metastatic cancer cells and bone marrow microenvironment influence one another to worsen bone metastatic disease progression. Bone marrow contains various cell types, including (1) cells of mesenchymal origin (e.g., osteoblasts, osteocytes, and adipocytes), (2) cells of hematopoietic origin (e.g., osteoclast and immune cells), and (3) others (e.g., endothelial cells and nerves). The recent studies have enabled us to discover many important cancer-derived factors responsible for the development of bone metastasis. However, many critical questions regarding the roles of bone microenvironment in bone metastatic progression remain elusive. To answer these questions, a deeper understanding of the cross talk between bone metastatic cancer and bone marrow microenvironment is clearly warranted.


Assuntos
Células da Medula Óssea/patologia , Medula Óssea/patologia , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Microambiente Tumoral , Humanos
2.
Ann Hematol ; 99(5): 913-924, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32065290

RESUMO

Fanconi anemia (FA) is a DNA repair disorder resulting from mutations in genes encoding for FA DNA repair complex components and is characterized by variable congenital abnormalities, bone marrow failure (BMF), and high incidences of malignancies. FA mosaicism arises from reversion or other compensatory mutations in hematopoietic cells and may be associated with BMF reversal and decreased blood cell sensitivity to DNA-damaging agents (clastogens); this sensitivity is a phenotypic and diagnostic hallmark of FA. Uncertainty regarding the clinical significance of FA mosaicism persists; in some cases, patients have survived multiple decades without BMF or hematologic malignancy, and in others hematologic failure occurred despite the presence of clastogen-resistant cell populations. Assessment of mosaicism is further complicated because clinical evaluation is frequently based on clastogen resistance in lymphocytes, which may arise from reversion events both in lymphoid-specific lineages and in more pluripotent hematopoietic stem/progenitor cells (HSPCs). In this review, we describe diagnostic methods and outcomes in published mosaicism series, including the substantial intervals (1-6 years) over which blood counts normalized, and the relatively favorable clinical course in cases where clastogen resistance was demonstrated in bone marrow progenitors. We also analyzed published FA mosaic cases with emphasis on long-term clinical outcomes when blood count normalization was identified. Blood count normalization in FA mosaicism likely arises from reversion events in long-term primitive HSPCs and is associated with low incidences of BMF or hematologic malignancy. These observations have ramifications for current investigational therapeutic programs in FA intended to enable gene correction in long-term repopulating HSPCs.


Assuntos
Células da Medula Óssea/metabolismo , Anemia de Fanconi , Neoplasias Hematológicas , Células-Tronco Hematopoéticas/metabolismo , Mosaicismo , Células da Medula Óssea/patologia , Anemia de Fanconi/sangue , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/genética , Anemia de Fanconi/terapia , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Humanos
3.
Mutat Res ; 849: 503130, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32087857

RESUMO

Human risk assessment of the toxic potency of chemicals typically includes genotoxicity assays for predicting carcinogenicity. Gene mutation frequency and chromosomal aberration are two major genotoxicity endpoints in standardized in vitro and in vivo assays. The weight-of-evidence approach in risk assessment is more focused on in vivo assay results; however, animal welfare considerations are aimed at the reduction, replacement, and refinement (3R's) of animal experiments, including a reduction in the number of experimental animals. Proposals to reduce experimental animals in genotoxicity testing include the incorporation of genotoxicity endpoint(s) into other toxicological studies and the combination of two or more assays detecting different genotoxicity endpoints in the same animals. In this study, we used 1,2-dimethylhydrazine as a model chemical of colon carcinogen to assess gene mutation frequency and chromosomal aberration in vivo simultaneously. Specifically, a gene mutation frequency assay was combined with a multiple-organ micronucleus test (peripheral blood, bone marrow, liver, and colon) in F344 gpt delta transgenic rats. Both gpt mutant frequency and micronucleated cell frequency significantly increased in colon and liver but not in bone marrow. Interestingly, we found that the colon carcinogen induced both gene mutations and micronuclei in the targeted colon tissue. Thus, we demonstrated that the mechanism of a carcinogen could be derived from an animal experiment using a lower number of experimental animals as currently recommended. Moreover, a significant increase in mutant frequency in colon and liver was already observed on the first day after treatment completion, as well as on the third day, which is the guideline-recommended period. Thus, this endpoint is compatible with other genotoxicity assays. We confirmed that performing the micronucleus assay in combination with a gene mutation assay in F344 gpt delta transgenic rats is useful to evaluate different genotoxic endpoints simultaneously in the same animals, which reduces the number of experimental animals.


Assuntos
1,2-Dimetilidrazina/toxicidade , Carcinógenos/toxicidade , Aberrações Cromossômicas/efeitos dos fármacos , Neoplasias do Colo/diagnóstico , Determinação de Ponto Final , Testes de Mutagenicidade , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Micronúcleos com Defeito Cromossômico/efeitos dos fármacos , Taxa de Mutação , Especificidade de Órgãos , Ratos , Ratos Endogâmicos F344 , Ratos Transgênicos
4.
Einstein (Sao Paulo) ; 18: eAO4966, 2020.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31994605

RESUMO

OBJECTIVE: To validate multilineage score system correlating results of flow cytometry, cytogenetics, cytomorphology and histology from samples of patients with suspected myelodysplastic syndrome or cytopenia of unknown origin. METHODS: A retrospective study analyzing laboratory data of 49 patients with suspected myelodysplastic syndrome or cytopenia of unknown origin, carried out between May and September 2017. The inclusion criteria were availability of flow cytometry results, and at least one more method, such as morphology, histology or cytogenetics. Thirty-eight patients were classified as diagnosis of myelodysplastic syndromes, whereas 11 were classified as normal. Patients were evaluated based on score systems, Ogata score and flow cytometry multilineage score. RESULTS: Comparing the scores obtained in the Ogata score and the multilineage score, it was observed that in four cases the Ogata score was zero or 1 point, while the multilineage score was higher than 3 points. In addition, in 12 cases with Ogata score of 2, the multilineage score was greater than 3. CONCLUSION: The flow cytometry multilineage score system demonstrated to be more effective in dysplasia analysis, by assessing the erythroid, monocytic, granulocytic and precursor cell lineages, apart from the parameters evaluated by the Ogata score.


Assuntos
Citometria de Fluxo/normas , Síndromes Mielodisplásicas/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Células da Medula Óssea/patologia , Criança , Pré-Escolar , Análise Citogenética/métodos , Análise Citogenética/normas , Células Eritroides/patologia , Feminino , Citometria de Fluxo/métodos , Granulócitos/patologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Monócitos/patologia , Padrões de Referência , Reprodutibilidade dos Testes , Estudos Retrospectivos , Adulto Jovem
5.
Ann Hematol ; 99(1): 7-19, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31650290

RESUMO

Myelodysplastic syndromes (MDS) are hematopoietic stem cell malignancies associated with an erythroid maturation defect, resulting in anemia. Treatments for MDS include erythropoiesis-stimulating agents (ESAs). The identification of prognostic markers is important to help predict response and improve outcomes. Various scoring systems have been developed to help predict response to ESAs. Despite limitations in its assessment, serum erythropoietin (sEPO) level is an important predictor of hematologic response to ESAs in patients with lower-risk MDS. Numerous studies have reported significantly lower sEPO levels among responders versus non-responders. Furthermore, treatment response is significantly more likely among those with sEPO levels below versus those above various cutoffs. Other prognostic indicators for response to ESAs include lower transfusion requirement, fewer bone marrow blasts, higher hemoglobin, lower serum ferritin, lower-risk MDS, and more normal cytogenetics. Studies of other MDS therapies (e.g., lenalidomide and luspatercept) have also reported that lower sEPO levels are indicative of hematologic response. In addition, lower sEPO levels (up to 500 IU/L) have been included in treatment algorithms for patients with lower-risk MDS to define whether ESAs are indicated. Lower sEPO levels are predictive of hematologic response-particularly to ESAs. Further, clinical trials should use sEPO thresholds to ensure more homogeneous cohorts.


Assuntos
Receptores de Activinas Tipo II/uso terapêutico , Eritropoetina/sangue , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Lenalidomida/uso terapêutico , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Feminino , Ferritinas/sangue , Hemoglobinas/metabolismo , Humanos , Masculino , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/patologia , Prognóstico , Fatores de Risco
7.
Cell Prolif ; 53(1): e12725, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31746058

RESUMO

OBJECTIVES: Activation of the sympathetic system and adrenergic ß-receptors following traumatic bone defects negatively impairs bone regeneration. Whether preventing ß-receptor activation could potentially improve bone defect repair is unknown. In this study, we investigated the effect of systematic administration and local delivery of propranolol through composite scaffolds on bone healing. MATERIALS AND METHODS: Collagen/PVA/propranolol/hydroxyapatite(CPPH)composite scaffolds were fabricated with 3D printing technique and characterized by scanning electron microscope (SEM). Micro-CT analysis and bone formation histology were performed to detect new bone formation. Osteogenic differentiation of bone marrow stromal cells (BMSCs) and osteoclastogenesis of bone marrow monocytes cultured with scaffolds extract were performed for further verification. RESULTS: Intraperitoneal injection of propranolol did not significantly improve bone repair, as indicated by micro-CT analysis and bone formation histology. However, CPPH scaffolds exhibited sustained release of propranolol in vitro and significantly enhanced bone regeneration compared with vehicle collagen/PVA/hydroxyapatite (CPH) scaffolds in vivo. Moreover, in vitro experiments indicated the scaffolds containing propranolol promoted the osteogenic differentiation and migration of rat BMSCs and inhibited osteoclastogenesis by preventing ß-receptor activation. CONCLUSIONS: This study demonstrates that local adrenergic ß-receptor blockade can effectively enhance the treatment of bone defects by stimulating osteogenic differentiation, inhibiting osteoclastogenesis and enhancing BMSCs migration.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Células da Medula Óssea/metabolismo , Regeneração Óssea/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Propranolol/farmacologia , Tecidos Suporte/química , Antagonistas Adrenérgicos beta/química , Animais , Células da Medula Óssea/patologia , Colágeno/química , Colágeno/farmacologia , Implantes de Medicamento/farmacologia , Durapatita/química , Durapatita/farmacologia , Masculino , Álcool de Polivinil/química , Álcool de Polivinil/farmacologia , Propranolol/química , Ratos , Ratos Sprague-Dawley , Células Estromais/metabolismo , Células Estromais/patologia
9.
Adv Exp Med Biol ; 1131: 1065-1078, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646545

RESUMO

Our blood serum Ca2+ levels are maintained within a narrow range (Ca2+ homeostasis) through a complex feedback system. However, local bone marrow Ca2+ levels can reach high concentrations, at least transiently, due to bone resorption, which is one of the notable features of the bone marrow stroma. Bone homeostasis is maintained by both the balance between osteoblastic bone formation and osteoclastic bone resorption and the balance of mesenchymal stem cell differentiation into osteoblasts and adipocytes. It has been reported that under culture conditions of infrequent adipocyte differentiation (no treatment with insulin or dexamethasone), high extracellular Ca2+ enhances osteoblast but not adipocyte accumulation in bone marrow stromal cells. In contrast, under culture conditions of predominant adipocyte differentiation (treatment with insulin and dexamethasone), high extracellular Ca2+ enhances adipocyte but not osteoblast accumulation in bone marrow stromal cells. Thus, the increased extracellular Ca2+ caused by bone resorption might enhance osteoblast development to reform missing bone under conditions of infrequent adipocyte differentiation (such as the normal physiological state) and might accelerate adipocyte accumulation instead of osteoblastic bone formation under conditions of predominant adipocyte differentiation (such as aging, obesity, use of glucocorticoids, and postmenopause). Moreover, increased adipocyte accumulation in bone marrow suppresses lymphohematopoiesis and contributes to a dysfunction of osteogenesis.


Assuntos
Medula Óssea , Cálcio , Células-Tronco Mesenquimais , Adipócitos/citologia , Medula Óssea/metabolismo , Células da Medula Óssea/citologia , Células da Medula Óssea/patologia , Cálcio/metabolismo , Diferenciação Celular , Humanos , Células-Tronco Mesenquimais/citologia , Osteoblastos/citologia
10.
Mol Cell Biochem ; 465(1-2): 103-114, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31858380

RESUMO

MicroRNA-125b (miR-125b) reduces myocardial infarct area and restrains myocardial ischemia reperfusion injury (I/R). In this study, we aimed to investigate the effect of bone marrow mesenchymal stem cell (BMSC)-derived exosomes carrying miR-125b on I/R rats. The myocardial I/R model in rats was constructed by ligation of the left anterior descending coronary artery (LAD). Rats were randomly divided into I/R and Sham group. Lv-cel-miR-67 (control) or Lv-miR-125b was transfected into BMSCs. Exosomes were extracted from transfected BMSCs, and separately named BMSC-Exo-67, BMSC-Exo-125b, and BMSC-Exo. MTT assay and flow cytometry were used to detect the viability and apoptosis of I/R myocardium cells, respectively. The expression of cell apoptosis proteins and the levels of inflammatory factors were examined by Western blot and ELISA assay, respectively. The target relationship between miR-125b and SIRT7 was predicted by using StarBase3.0, and was confirmed by using dual-luciferase reporter gene assay. qRT-PCR, immunohistochemistry staining, and Western blot were used to evaluate the expression of SIRT7 in myocardium tissues in I/R rats. BMSC-derived exosomes were successfully isolated and identified by TEM and positive expression of CD9 and CD63. The expression of miR-125b was down-regulated in I/R myocardium tissues and cells. BMSC-Exo-125b significantly up-regulated miR-125b in I/R myocardium cells. The intervention of BMSC-Exo-125b significantly increased the cell viability, decreased the apoptotic ratio, down-regulated Bax and caspase-3, up-regulated Bcl-2, and decreased the levels of IL-1ß, IL-6, and TNF-α in I/R myocardium cells. SIRT7 was a target of miR-125b, and BMSC-Exo-125b significantly down-regulated SIRT7 in myocardium cells. In addition, the injection of BMSC-Exo-125b alleviated the pathological damages and down-regulated SIRT7 in myocardium tissues of I/R rats. BMSC-derived exosomes carrying miR-125b protected against myocardial I/R by targeting SIRT7.


Assuntos
Células da Medula Óssea/metabolismo , Exossomos , Células-Tronco Mesenquimais/metabolismo , MicroRNAs , Traumatismo por Reperfusão Miocárdica , Sirtuínas , Animais , Apoptose/genética , Células da Medula Óssea/patologia , Citocinas/genética , Citocinas/metabolismo , Exossomos/genética , Exossomos/metabolismo , Exossomos/patologia , Exossomos/transplante , Masculino , Células-Tronco Mesenquimais/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/terapia , Ratos , Ratos Sprague-Dawley , Sirtuínas/genética , Sirtuínas/metabolismo
11.
Iran J Immunol ; 16(4): 278-290, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31885005

RESUMO

BACKGROUND: Multiple myeloma (MM) is a malignant plasma cell proliferative disorder with limited immunotherapy treatment because of T cell dysfunction. OBJECTIVE: To investigate the immunomodulatory function of bone marrow mesenchymal stromal cells (MM-BMSCs) on CD8+ T cells. METHODS: Proliferation and cytotoxicity were detected by cell counting kit-8 assay. Cell cycle was detected by flow cytometry, and p16 expression was detected by PCR. The expression of fibroblast activation protein α (FAPα) was evaluated by immunohistochemistry. RESULTS: Co-culture of CD8+ T cells with MM-BMSCs decreased the cell survival rate and increased the killing rate (p=0.03, p=0.001, respectively), the percentage of cells in G0/G1 phase and p16 expression (p<0.001). FAPα was mainly in the mesenchymal matrix of the MM microenvironment and elevated in MM derived bone marrow compared to healthy donors (p<0.001). The FAPα inhibitor PT-100, increased survival and the killing rate (p<0.001, p=0.043, respectively), and decreased the percentage of cells in G0/G1 phase and p16 expression (p=0.024, p=0.004, respectively). CONCLUSION: Therefore, MM-BMSCs inhibit the proliferation and cytotoxicity of CD8+ T cells, significantly block the cell cycle and increase p16 expression in co-cultured CD8+ T cells in a cell-cell contact-dependent manner.


Assuntos
Células da Medula Óssea/imunologia , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células , Gelatinases/imunologia , Proteínas de Membrana/imunologia , Células-Tronco Mesenquimais/imunologia , Mieloma Múltiplo/imunologia , Proteínas de Neoplasias/imunologia , Serina Endopeptidases/imunologia , Adulto , Idoso , Células da Medula Óssea/patologia , Linfócitos T CD8-Positivos/patologia , Técnicas de Cocultura , Feminino , Humanos , Masculino , Células-Tronco Mesenquimais/patologia , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia
12.
Blood Cancer J ; 9(12): 103, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31844041

RESUMO

Fluorescence in situ hybridization (FISH) is currently the gold-standard assay to detect recurrent genomic abnormalities of prognostic significance in multiple myeloma (MM). Since most translocations in MM involve a position effect with heterogeneous breakpoints, we hypothesize that FISH has the potential to miss translocations involving these regions. We evaluated 70 bone marrow samples from patients with plasma cell dyscrasia by FISH and whole-genome mate-pair sequencing (MPseq). Thirty cases (42.9%) displayed at least one instance of discordance between FISH and MPseq for each primary and secondary abnormality evaluated. Nine cases had abnormalities detected by FISH that went undetected by MPseq including 6 tetraploid clones and three cases with missed copy number abnormalities. In contrast, 19 cases had abnormalities detected by MPseq that went undetected by FISH. Seventeen were MYC rearrangements and two were 17p deletions. MPseq identified 36 MYC abnormalities and 17 (50.0% of MYC abnormal group with FISH results) displayed a false negative FISH result. MPseq identified 10 cases (14.3%) with IgL rearrangements, a recent marker of poor outcome, and 10% with abnormalities in genes associated with lenalidomide response or resistance. In summary, MPseq was superior in the characterization of rearrangement complexity and identification of secondary abnormalities demonstrating increased clinical value compared to FISH.


Assuntos
Variação Genética , Genômica , Hibridização in Situ Fluorescente , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/patologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Aberrações Cromossômicas , Feminino , Rearranjo Gênico , Genes myc , Genômica/métodos , Genômica/normas , Humanos , Hibridização in Situ Fluorescente/métodos , Hibridização in Situ Fluorescente/normas , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
14.
Medicine (Baltimore) ; 98(39): e17337, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574871

RESUMO

RATIONALE: Diamond-Blackfan anemia (DBA) is a rare inherited marrow disorder, characterized by erythrocyte aplasia and is associated with congenital anomalies and a susceptibility to cancer. Although congenital abnormalities have been observed in ∼50% of DBA patients, the occurrence of an associated congenital diaphragmatic hernia (CDH) has rarely been reported. PATIENT CONCERNS: A 19-month-old male child was referred to our pediatric hematology-oncology outpatient clinic with anemic appearance. He presented to us with recurrent anemia, short stature, and developmental delay. DIAGNOSIS: On bone marrow examination, only erythropoietic cells were markedly decreased in number, whereas other cell lines were unaffected. An abdominal computed tomography scan revealed a Bochdalek type of CDH. A genetic analysis revealed heterozygous mutation of RPS19; therefore, he was diagnosed as having DBA with CDH. INTERVENTIONS: The patient received an initial packed red blood cell transfusion, followed by an administration of oral prednisone. OUTCOMES: The patient is maintained on oral prednisone administered at a dose of 0.3 mg/kg every alternate day and has since a hemoglobin level of >9.0 g/dL without further RBC transfusions. LESSONS: We learned that a Bochdalek type of CDH can manifest in a DBA patient with RPS19 gene mutation. Therefore, patients diagnosed with the latter disorder should also be screened for an early detection of potential CDHs.


Assuntos
Anemia de Diamond-Blackfan , Células da Medula Óssea/patologia , Transfusão de Eritrócitos/métodos , Hérnias Diafragmáticas Congênitas/diagnóstico , Prednisona/administração & dosagem , Proteínas Ribossômicas/genética , Anemia de Diamond-Blackfan/genética , Anemia de Diamond-Blackfan/fisiopatologia , Exame de Medula Óssea/métodos , Glucocorticoides/administração & dosagem , Humanos , Masculino , Mutação , Radioterapia Assistida por Computador/métodos , Resultado do Tratamento , Adulto Jovem
16.
Mater Sci Eng C Mater Biol Appl ; 105: 110071, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31546377

RESUMO

In the current study, in vitro analysis of the osteogenic potential of different scaffolds based on strontium-substituted ß-TCP (Sr-TCP) and bioactive glass (BG) ceramics was conducted using rabbit bone marrow-derived mesenchymal stem cells (rBMSCs) and the osteogenic ability of the prepared Sr-TCP and BG scaffold was evaluated through alkaline phosphatase activity, mineral deposition by Alizarin red staining, and osteoblastic gene expression experiments. The obtained in vitro results revealed that among experimental Sr-TCP/BG nanocomposite scaffold samples with the composition of Sr-TCP/BG: 100/0, 50/50, 75/25, and 25/75, the 50Sr-TCP/50BG sample presented better osteoinductive properties. Therefore, the optimized 50Sr-TCP/50BG nanocomposite scaffold was chosen for further in vivo experiments. In vivo implantation of 50Sr-TCP/50BG scaffold and hydroxyapatite (HA)/TCP granules in a rabbit calvarial defect model showed slow degradation of 50Sr-TCP/50BG scaffold and high resorption rate of HA/TCP granules at 5 months' post-surgery. However, the 50Sr-TCP/50BG scaffolds loaded by mesenchymal stem cells (MSCs) were mainly replaced with new bone even at 2 months post-implantation. Based on the obtained engineering and biological results, 50Sr-TCP/50BG nanocomposite scaffold containing MSCs could be considered as a promising alternative substitute even for load-bearing bone tissue engineering applications.


Assuntos
Células da Medula Óssea/metabolismo , Fosfatos de Cálcio/química , Células Imobilizadas , Cerâmica/química , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Nanocompostos/química , Estrôncio/química , Tecidos Suporte/química , Animais , Células da Medula Óssea/patologia , Células Imobilizadas/metabolismo , Células Imobilizadas/patologia , Células Imobilizadas/transplante , Células-Tronco Mesenquimais/patologia , Porosidade , Coelhos
17.
ACS Appl Mater Interfaces ; 11(38): 34744-34754, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31475824

RESUMO

Here, kartogenin (KGN), an emerging stable nonprotein compound with the ability to promote differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) into chondrocytes, was grafted onto the surface of modified ultrasmall superparamagnetic iron-oxide (USPIO) and then integrated into cellulose nanocrystal/dextran hydrogels. The hydrogels served as a carrier for the USPIO-KGN and a matrix for cartilage repair. We carried out in vitro and in vivo studies, the results of which demonstrated that KGN undergoes long-term stable sustained release, recruits endogenous host cells, and induces BMSCs to differentiate into chondrocytes, thus enabling in situ cartilage regeneration. Meanwhile, the USPIO-incorporated theranostic hydrogels exhibited a distinct magnetic resonance contrast enhancement and maintained a stable relaxation rate, with almost no loss, both in vivo and in vitro. According to noninvasive in vivo observation results and immunohistochemistry analyses, the regenerated cartilage tissue was very similar to natural hyaline cartilage. This innovative diagnosis and treatment system increases the convenience and effectiveness of chondrogenesis.


Assuntos
Anilidas , Cartilagem , Hidrogéis , Nanopartículas de Magnetita , Ácidos Ftálicos , Regeneração/efeitos dos fármacos , Anilidas/química , Anilidas/farmacologia , Animais , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Cartilagem/lesões , Cartilagem/patologia , Cartilagem/fisiologia , Diferenciação Celular/efeitos dos fármacos , Condrócitos/metabolismo , Condrócitos/patologia , Hidrogéis/química , Hidrogéis/farmacologia , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/uso terapêutico , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Ácidos Ftálicos/química , Ácidos Ftálicos/farmacologia , Coelhos , Nanomedicina Teranóstica
18.
Molecules ; 24(18)2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31540026

RESUMO

Osteogenesis is an orchestrated process regulated by osteoclastogenesis and osteoblastogenesis. Excessive osteoclastogenesis causes bone diseases, such as osteoporosis. Although a few drugs are effective in osteoporosis treatment, these drugs lead to side effects, including cellulitis, flatulence, and hypocalcemia. In this study, we reported a 2-(N-Phenylmethylsulfonamido)-N-(2-(phenylthio)phenyl)propanamide (PSTP) compound, PSTP-3,5-Me, as a potential therapeutic agent for osteoporosis. Mouse bone marrow-derived macrophages (BMMs) were differentiated into osteoclasts by receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) in the presence of PSTP-3,5-Me. PSTP-3,5-Me inhibited osteoclast differentiation by reduced tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts, and suppressed the expression of osteoclast marker genes, such as cathepsin K (Ctsk) and TRAP (Acp5). We investigated signaling pathways mediated by RANKL and its receptor, RANK, and found that PSTP-3,5-Me inhibits nucleus translocation of nuclear factor of activated T cell cytoplasmic-1 (NFATc1). Moreover, PSTP-3,5-Me inhibited F-actin ring formation and mineral resorption. Overall, our data suggests that PSTP-3,5-Me attenuates osteoclast differentiation by blocking the activation of NFATc1.


Assuntos
Antígenos de Diferenciação/biossíntese , Células da Medula Óssea/metabolismo , Reabsorção Óssea/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Osteoclastos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Células da Medula Óssea/patologia , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Feminino , Camundongos , Osteoclastos/patologia , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Osteoporose/patologia , Sulfonamidas/farmacologia
19.
Prostate ; 79(14): 1715-1727, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31449673

RESUMO

BACKGROUND: Disseminated tumor cells (DTCs) have been reported in the bone marrow (BM) of patients with localized prostate cancer (PCa). However, the existence of these cells continues to be questioned, and few methods exist for viable DTC isolation. Therefore, we sought to develop novel approaches to identify and, if detected, analyze localized PCa patient DTCs. METHODS: We used fluorescence-activated cell sorting (FACS) to isolate a putative DTC population, which was negative for CD45, CD235a, alkaline phosphatase, and CD34, and strongly expressed EPCAM. We examined tumor cell content by bulk cell RNA sequencing (RNA-Seq) and whole-exome sequencing after whole genome amplification. We also enriched for BM DTCs with α-EPCAM immunomagnetic beads and performed quantitative reverse trancriptase polymerase chain reaction (qRT-PCR) for PCa markers. RESULTS: At a threshold of 4 cells per million BM cells, the putative DTC population was present in 10 of 58 patients (17%) with localized PCa, 4 of 8 patients with metastatic PCa of varying disease control, and 1 of 8 patients with no known cancer, and was positively correlated with patients' plasma PSA values. RNA-Seq analysis of the putative DTC population collected from samples above (3 patients) and below (5 patients) the threshold of 4 putative DTCs per million showed increased expression of PCa marker genes in 4 of 8 patients with localized PCa, but not the one normal donor who had the putative DTC population present. Whole-exome sequencing also showed the presence of single nucleotide polymorphisms and structural variants in the gene characteristics of PCa in 2 of 3 localized PCa patients. To examine the likely contaminating cell types, we used a myeloid colony formation assay, differential counts of cell smears, and analysis of the RNA-Seq data using the CIBERSORT algorithm, which most strongly suggested the presence of B-cell lineages as a contaminant. Finally, we used EPCAM enrichment and qRT-PCR for PCa markers to estimate DTC prevalence and found evidence of DTCs in 21 of 44 samples (47%). CONCLUSION: These data support the presence of DTCs in the BM of a subset of patients with localized PCa and describe a novel FACS method for isolation and analysis of viable DTCs.


Assuntos
Células da Medula Óssea/patologia , Medula Óssea/patologia , Metástase Neoplásica/patologia , Neoplasias da Próstata/patologia , Idoso , Biomarcadores Tumorais/análise , Separação Celular/métodos , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Polimorfismo de Nucleotídeo Único/genética , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/genética , Análise de Sequência de RNA , Sequenciamento Completo do Exoma
20.
Mol Med Rep ; 20(4): 3065-3074, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432152

RESUMO

Human bone marrow­derived mesenchymal stromal cells (hBMSCs) have been revealed to be beneficial for the regeneration of tissues and cells in several diseases. The present study aimed to elucidate the mechanisms underlying the effect of hBMSC transplantation on neuron regeneration in a rat model of middle cerebral artery occlusion (MCAO). The hBMSCs were isolated, cultured and identified. A rat model of MCAO was induced via the modified Longa method. Neurological severity scores (NSS) were adopted for the evaluation of neuronal function in the model rats after cell transplantation. Next, the expression levels of nestin, ß­III­tubulin (ß­III­Tub), glial fibrillary acidic protein (GFAP), HNA and neuronal nuclear antigen (NeuN) were examined, as well as the positive expression rates of human neutrophil alloantigen (HNA), nestin, NeuN, ß­III­Tub and GFAP. The NSS, as well as the mRNA and protein expression of nestin, decreased at the 1st, 2nd, 4 and 8th weeks, while the mRNA and protein expression of NeuN, ß­III­Tub and GFAP increased with time. In addition, after treatment, the MCAO rats showed decreased NSS and mRNA and protein expression of nestin, but elevated mRNA and protein expression of NeuN, ß­III­Tub and GFAP at the 2nd, 4 and 8th weeks, and decreased positive expression of HNA and nestin with enhanced expression of NeuN, ß­III­Tub and GFAP. Therefore, the present findings demonstrated that hBMSC transplantation triggered the formation of nerve cells and enhanced neuronal function in a rat model of MCAO.


Assuntos
Células da Medula Óssea , Infarto da Artéria Cerebral Média , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Neurônios , Regeneração , Animais , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Modelos Animais de Doenças , Xenoenxertos , Humanos , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Infarto da Artéria Cerebral Média/terapia , Masculino , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Neurônios/metabolismo , Neurônios/patologia , Ratos , Ratos Sprague-Dawley
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