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2.
Ann Hematol ; 99(3): 539-547, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31953585

RESUMEN

Macrophages within tissues display a strong plastic ability in respond to environmental cues in both physiologic influences and disease. However, the macrophage phenotype and its distribution in the bone marrow biopsies (BMB) samples of human acute leukemia (AL) remain poorly understood. In this study, 97 BMB samples of patients with acute leukemia and 30 iron-deficiency anemias (IDA) as control group were evaluated with immunohistochemistry. In comparison with controls, the counts of CD68+, CD163+, and CD206+macrophages were remarkably increased in BMB samples of acute leukemia (P < 0.01), as well as their infiltration density was roaring up-regulation (P < 0.01). The expression levels of CD68+, CD163+, and CD206+macrophages were decreased in patients with complete remission, but there still existed statistically significant contrast to the control group (P < 0.01). The ratios of the CD163-positive cells or CD206-positive cells to CD68-positive cells were most prevalent in the BMB samples of human acute leukemia compared with the control group (P < 0.01), which support that macrophages were polarized to M2 macrophages.


Asunto(s)
Antígenos de Diferenciación/metabolismo , Médula Ósea , Leucemia , Macrófagos , Proteínas de Neoplasias/metabolismo , Enfermedad Aguda , Adolescente , Adulto , Anciano , Biopsia , Médula Ósea/metabolismo , Médula Ósea/patología , Femenino , Humanos , Leucemia/metabolismo , Leucemia/patología , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Persona de Mediana Edad
3.
Ann Hematol ; 99(3): 513-518, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31974678

RESUMEN

Clinical trials and treatment guidelines for myelodysplastic syndrome depend on several prognostic scoring systems to stratify patients by risk. These include different variables: the degree of cytopenia, percentage of bone marrow blasts, and cytogenetics. Little is known about the impact of bone marrow blasts in patients with adverse cytogenetics. In this retrospective study, we analyzed 536 patients with high-grade myelodysplastic syndrome to examine the differences in survival for patients with different percentages of bone marrow blasts. The median overall survival in patients with ≥ 5% marrow blasts was not statistically different from that for patients with < 5% marrow blasts; however, the former group had a higher risk of progression to acute myeloid leukemia (p < 0.001). Therefore, cytogenetics is the most important factor in our prognostic tools to determine survival outcomes for patients with myelodysplastic syndrome, and patients with high-risk disease have poor prognosis irrespective of their marrow blasts percentage.


Asunto(s)
Crisis Blástica , Médula Ósea , Síndromes Mielodisplásicos , Adulto , Anciano , Anciano de 80 o más Años , Crisis Blástica/metabolismo , Crisis Blástica/mortalidad , Crisis Blástica/patología , Médula Ósea/metabolismo , Médula Ósea/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/metabolismo , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/patología , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia
5.
Life Sci ; 240: 117071, 2020 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-31783051

RESUMEN

AIMS: AML (Acute myeloid leukemia) is characterized as a heterogeneous cancer. Chemokines play fundamental roles in the onset, progression cellular, migration, survival and improvement of AML therapy outcomes. The CCR5 receptors together with their ligands have indirect effects on the progression of cancer. In the present study, we have decided to investigate the impact of chemotherapy on the expression of CCR5 and its related ligands (CCL5, CCL4 and CCL3). MAIN METHODS: In this study, peripheral blood and bone marrow specimens were collected prior and post the first stage of (7 + 3) chemotherapy from 25 AML-M4/M5 patients. The expression of CCR by Lymphocytes in peripheral blood was examined by flow cytometry and QRT-PCR. The serum levels of chemokines were measured by ELISA. KEY FINDINGS: There was not observed leukemic blast cells in peripheral blood smear at post first stage of chemotherapy. We found that the expression of CCR5 was attenuated in patients post the first stage of chemotherapy and the healthy control subjects. We have also observed that the serum levels of chemokines were elevated in AML patients prior to chemotherapy. Although in post-chemotherapy stage, only CCL3 was found to reach to the baseline level, CCL5 and CCL4 have not returned to the basal level and were significantly higher than healthy control subjects. SIGNIFICANCE: The current chemotherapy protocol was not able to completely inhibit CCL5 and CCL4. In conclusion, our findings in harmony with previous studies suggest that inhibition of chemokines along with chemotherapy in AML patients may aid therapy.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimiocina CCL3/efectos de los fármacos , Quimiocina CCL4/efectos de los fármacos , Quimiocina CCL5/efectos de los fármacos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Monocitos/patología , Receptores CCR5/efectos de los fármacos , Adulto , Médula Ósea/metabolismo , Médula Ósea/patología , Linaje de la Célula , Quimiocina CCL3/biosíntesis , Quimiocina CCL4/biosíntesis , Quimiocina CCL5/biosíntesis , Quimiocinas/sangre , Progresión de la Enfermedad , Femenino , Humanos , Leucemia Mieloide Aguda/patología , Recuento de Leucocitos , Linfocitos/metabolismo , Linfocitos/patología , Masculino , Persona de Mediana Edad , Receptores CCR5/biosíntesis
6.
Adv Exp Med Biol ; 1131: 1065-1078, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31646545

RESUMEN

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.


Asunto(s)
Médula Ósea , Calcio , Células Madre Mesenquimatosas , Adipocitos/citología , Médula Ósea/metabolismo , Células de la Médula Ósea/citología , Células de la Médula Ósea/patología , Calcio/metabolismo , Diferenciación Celular , Humanos , Células Madre Mesenquimatosas/citología , Osteoblastos/citología
7.
PLoS Pathog ; 15(12): e1008239, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31877196

RESUMEN

Cells sensing infection produce Type I interferons (IFN-I) to stimulate Interferon Stimulated Genes (ISGs) that confer resistance to viruses. During lympho-hematogenous spread of the mouse pathogen ectromelia virus (ECTV), the adaptor STING and the transcription factor IRF7 are required for IFN-I and ISG induction and resistance to ECTV. However, it is unknown which cells sense ECTV and which pathogen recognition receptor (PRR) upstream of STING is required for IFN-I and ISG induction. We found that cyclic-GMP-AMP (cGAMP) synthase (cGAS), a DNA-sensing PRR, is required in bone marrow-derived (BMD) but not in other cells for IFN-I and ISG induction and for resistance to lethal mousepox. Also, local administration of cGAMP, the product of cGAS that activates STING, rescues cGAS but not IRF7 or IFN-I receptor deficient mice from mousepox. Thus, sensing of infection by BMD cells via cGAS and IRF7 is critical for resistance to a lethal viral disease in a natural host.


Asunto(s)
Médula Ósea/virología , Virus de la Ectromelia/patogenicidad , Ectromelia Infecciosa/virología , Nucleótidos Cíclicos/metabolismo , Animales , Médula Ósea/metabolismo , Interacciones Huésped-Patógeno/inmunología , Inmunidad Innata/inmunología , Interferón Tipo I/metabolismo , Ratones Transgénicos , Nucleotidiltransferasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo
8.
Nat Cell Biol ; 21(11): 1309-1320, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31685996

RESUMEN

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.


Asunto(s)
Envejecimiento/genética , Capilares/metabolismo , Células Madre Hematopoyéticas/metabolismo , Homeostasis/genética , Nicho de Células Madre/genética , Envejecimiento/metabolismo , Animales , Médula Ósea/efectos de los fármacos , Médula Ósea/metabolismo , Capilares/citología , Capilares/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Polaridad Celular/efectos de los fármacos , Rastreo Celular/métodos , Doxiciclina/farmacología , Fluorouracilo/farmacología , Regulación de la Expresión Génica , Genes Reporteros , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/efectos de los fármacos , Histonas/genética , Histonas/metabolismo , Homeostasis/efectos de los fármacos , Proteína Jagged-2/genética , Proteína Jagged-2/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Agonistas Mieloablativos/farmacología , Nicho de Células Madre/efectos de los fármacos
9.
Nat Commun ; 10(1): 4768, 2019 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-31628339

RESUMEN

B-1a cells are long-lived, self-renewing innate-like B cells that predominantly inhabit the peritoneal and pleural cavities. In contrast to conventional B-2 cells, B-1a cells have a receptor repertoire that is biased towards bacterial and self-antigens, promoting a rapid response to infection and clearing of apoptotic cells. Although B-1a cells are known to primarily originate from fetal tissues, the mechanisms by which they arise has been a topic of debate for many years. Here we show that in the fetal liver versus bone marrow environment, reduced IL-7R/STAT5 levels promote immunoglobulin kappa gene recombination at the early pro-B cell stage. As a result, differentiating B cells can directly generate a mature B cell receptor (BCR) and bypass the requirement for a pre-BCR and pairing with surrogate light chain. This 'alternate pathway' of development enables the production of B cells with self-reactive, skewed specificity receptors that are peculiar to the B-1a compartment. Together our findings connect seemingly opposing lineage and selection models of B-1a cell development and explain how these cells acquire their unique properties.


Asunto(s)
Subgrupos de Linfocitos B/inmunología , Linfocitos B/inmunología , Diferenciación Celular/inmunología , Receptores de Células Precursoras de Linfocitos B/inmunología , Receptores de Antígenos de Linfocitos B/inmunología , Animales , Subgrupos de Linfocitos B/metabolismo , Linfocitos B/metabolismo , Médula Ósea/inmunología , Médula Ósea/metabolismo , Diferenciación Celular/genética , Inmunoglobulina de Cadenas Ligeras Subrogadas/genética , Inmunoglobulina de Cadenas Ligeras Subrogadas/inmunología , Inmunoglobulina de Cadenas Ligeras Subrogadas/metabolismo , Hígado/embriología , Hígado/inmunología , Hígado/metabolismo , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Células Precursoras de Linfocitos B/genética , Receptores de Células Precursoras de Linfocitos B/metabolismo , Receptores de Antígenos de Linfocitos B/genética , Receptores de Antígenos de Linfocitos B/metabolismo , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/inmunología , Receptores de Interleucina-7/metabolismo , Factor de Transcripción STAT5/genética , Factor de Transcripción STAT5/inmunología , Factor de Transcripción STAT5/metabolismo
10.
Life Sci ; 238: 116981, 2019 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-31639394

RESUMEN

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.


Asunto(s)
Amifostina/farmacología , Biomarcadores/metabolismo , Médula Ósea/metabolismo , Adhesión Celular , Endotelio Vascular/metabolismo , Rayos gamma , Leucocitos/metabolismo , Médula Ósea/efectos de los fármacos , Médula Ósea/efectos de la radiación , Células Cultivadas , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/efectos de la radiación , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/efectos de la radiación , Redes Reguladoras de Genes/efectos de los fármacos , Redes Reguladoras de Genes/efectos de la radiación , Humanos , Leucocitos/efectos de los fármacos , Leucocitos/efectos de la radiación , Protectores contra Radiación/farmacología
11.
Exp Oncol ; 41(3): 207-209, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31569935

RESUMEN

According to the modern concept, leukemic stem cells (LSC) in acute myeloid leukemia (AML) are distinct from the bulk of leukemic cells in bone marrow and peripheral blood of AML patients. Nevertheless, LSC are responsible for managing all the hierarchy of the bulk of leukemic blast populations. This mini-review provides brief information on the distinctive features of LSC and blast cells in cytologically recognized types of AML. The study of different phenotypes of LSC and blast cells in AML with the aid of up-to-date flow cytometric techniques is important both for the deep insight into the mechanisms of leukemogenesis and development of novel strategies of target therapy. The urgent need for extending the diagnostic panel of monoclonal antibodies used for diagnosing AML is beyond doubt.


Asunto(s)
Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Biomarcadores , Médula Ósea/metabolismo , Médula Ósea/patología , Humanos , Inmunofenotipificación , Clasificación del Tumor , Fenotipo
12.
Biomed Res Int ; 2019: 4714279, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31531354

RESUMEN

Little is known about the function of acid-sensing ion channels (ASICs) in bone cells or osteoporotic vertebral fractures (OVF). This study delineated ASICs expression in adult human bone marrow-mesenchymal stem cells- (BM-MSC-) derived osteoblasts and in OVF bone cells. Adult BM-MSC-derived osteoblasts were isolated and cultured in different pH values. Osteogenic markers as alkaline phosphatase (ALP), osteopontin (OPN), and osteocalcin (OC) mRNA were assessed. Western blots method was applied to analyze ASICs protein expression in different pH values. Amiloride was added into the osteogenic media to analyze the Na+/K+ ATPase change. We harvested the vertebral cancellous bone through a bone biopsy needle in 26 OVF patients when performing percutaneous vertebroplasty. Six vertebral bone specimens obtained from 4 patients with high-energy vertebral fractures were used as the control. The reverse transcription polymerase chain reaction was performed to analyze the quantitative mRNA expression of ASICs. Osteogenic markers as ALP, OPN, and OC mRNA were higher expressed in increasing pH values throughout osteoblastogenesis. ASIC proteins were higher expressed in lower pH media, especially ASIC3, and ASIC4. The highest protein expression at days 7, 14, and 21 was ASIC2, ASIC4, and ASIC3, respectively. Expression of Na+/K+ ATPase was significantly decreased in cultured osteoblasts by addition of amiloride into the pH 6.9 osteogenic media. ASIC2 mRNA was most highly expressed with a 65.93-fold increase in the biopsied vertebral bone cells in OVF compared with the control. In conclusion, we found osteoblastogenesis was reduced in an acidic environment, and ASIC2, ASIC3, and ASIC4 were most highly expressed in turn during osteoblastogenesis within acidic media. ASIC2 was the most abundantly expressed gene in human bone cells in OVF compared with the control. ASIC2 could be crucial in the pathogenesis of osteoporosis and could serve as a therapeutic target for antiosteoporotic therapies.


Asunto(s)
Canales Iónicos Sensibles al Ácido/metabolismo , Huesos/metabolismo , Fracturas Osteoporóticas/metabolismo , Fracturas de la Columna Vertebral/metabolismo , Columna Vertebral/metabolismo , Animales , Médula Ósea/metabolismo , Células Cultivadas , Humanos , Células Madre Mesenquimatosas/metabolismo , Osteoblastos/metabolismo , Osteocitos/metabolismo , Osteopontina/metabolismo , ARN Mensajero/metabolismo
13.
Med Sci Monit ; 25: 7182-7190, 2019 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-31550244

RESUMEN

BACKGROUND The role of bone marrow-derived mesenchymal stem cells (BM-MSCs) in liver fibrosis remains poorly understood. This study aimed to use a mouse model of carbon tetrachloride (CCL4)-induced liver fibrosis to investigate the effects of BM-MSCs during liver hypoxia and the involvement of the transforming growth factor beta 1 (TGF-ß1) and SMADs pathway. MATERIAL AND METHODS Thirty C57BL/6 mice were randomly divided into the control group (n=10), the model group (n=10), and the BM-MSC-treated model group (n=10). In the model group, liver fibrosis was induced by intraperitoneal injection of CCl4. BM-MSCs were transplanted after 12 weeks of CCl4 treatment. The serum biochemical parameters and histological changes in the liver, using histochemical stains, were investigated. The expression of collagen type I (collagen I), alpha-smooth muscle actin (alpha-SMA), TGF-ß1, SMAD3, SMAD7, hypoxia-inducible factor 1 alpha (HIF-1alpha), and vascular endothelial grow factor (VEGF) were assessed by immunohistochemistry and quantitative real-time polymerase chain (RT-qPCR) reaction. RESULTS Treatment with BM-MSCs reduced the expression of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) compared with the model group, and reduced liver fibrosis determined histologically using hematoxylin and eosin (H&E) and Masson's trichrome staining compared with the model group. The area of liver fibrosis decreased after BM-MSCs treatment (p<0.05). Protein expression of HIF-1alpha and VEGF were decreased after BM-MSCs treatment (p<0.05). Transplantation of BM-MSCs reduced the mRNA expression of TGF-ß1, collagen I, alpha-SMA, and SMAD3 (p<0.05). CONCLUSIONS BM-MSC transplantation reduced CCl4-induced murine liver fibrosis, indicating that in a hypoxic microenvironment, BM-MSCs may inhibit the TGFß-1/SMADs pathway.


Asunto(s)
Fibrosis/metabolismo , Cirrosis Hepática/terapia , Células Madre Mesenquimatosas/fisiología , Alanina Transaminasa/metabolismo , Animales , Aspartato Aminotransferasas/metabolismo , Médula Ósea/metabolismo , Tetracloruro de Carbono/farmacología , Hipoxia de la Célula/fisiología , China , Modelos Animales de Enfermedad , Fibrosis/fisiopatología , Hipoxia/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia , Hígado/patología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/patología , Masculino , Trasplante de Células Madre Mesenquimatosas/métodos , Ratones , Ratones Endogámicos C57BL , Proteínas Smad/metabolismo , Proteínas Smad/fisiología , Factor de Crecimiento Transformador beta/metabolismo
14.
Biochem Soc Trans ; 47(5): 1307-1325, 2019 10 31.
Artículo en Inglés | MEDLINE | ID: mdl-31551354

RESUMEN

Chronic myeloid leukaemia (CML) is a paradigm of precision medicine, being one of the first cancers to be treated with targeted therapy. This has revolutionised CML therapy and patient outcome, with high survival rates. However, this now means an ever-increasing number of patients are living with the disease on life-long tyrosine kinase inhibitor (TKI) therapy, with most patients anticipated to have near normal life expectancy. Unfortunately, in a significant number of patients, TKIs are not curative. This low-level disease persistence suggests that despite a molecularly targeted therapeutic approach, there are BCR-ABL1-independent mechanisms exploited to sustain the survival of a small cell population of leukaemic stem cells (LSCs). In CML, LSCs display many features akin to haemopoietic stem cells, namely quiescence, self-renewal and the ability to produce mature progeny, this all occurs through intrinsic and extrinsic signals within the specialised microenvironment of the bone marrow (BM) niche. One important avenue of investigation in CML is how the disease highjacks the BM, thereby remodelling this microenvironment to create a niche, which enables LSC persistence and resistance to TKI treatment. In this review, we explore how changes in growth factor levels, in particular, the bone morphogenetic proteins (BMPs) and pro-inflammatory cytokines, impact on cell behaviour, extracellular matrix deposition and bone remodelling in CML. We also discuss the challenges in targeting LSCs and the potential of dual targeting using combination therapies against BMP receptors and BCR-ABL1.


Asunto(s)
Médula Ósea/patología , Proteínas Morfogenéticas Óseas/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Microambiente Tumoral , Médula Ósea/metabolismo , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/patología
15.
Cell Prolif ; 52(6): e12688, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31557368

RESUMEN

OBJECTIVES: With age, bone marrow mesenchymal stem cells (BMSC) have reduced ability of differentiating into osteoblasts but have increased ability of differentiating into adipocytes which leads to age-related bone loss. MicroRNAs (miRNAs) play major roles in regulating BMSC differentiation. This paper explored the role of miRNAs in regulating BMSC differentiation swift fate in age-related osteoporosis. MATERIAL AND METHODS: Mice and human BMSC were isolated from bone marrow, whose miR-130a level was measured. The abilities of BMSC differentiate into osteoblast or fat cell under the transfected with agomiR-130a or antagomiR-130a were analysed by the level of ALP, osteocalcin, Runx2, osterix or peroxisome proliferator-activated receptorγ (PPARγ), Fabp4. Related mechanism was verified via qT-PCR, Western blotting (WB) and siRNA transfection. Animal phenotype intravenous injection with agomiR-130a or agomiR-NC was explored by Micro-CT, immunochemistry and calcein double-labelling. RESULTS: MiR-130a was dramatically decreased in BMSC of advanced subjects. Overexpression of miR-130a increased osteogenic differentiation of BMSC and attenuated adipogenic differentiation in BMSC, conversely, Inhibition of miR-130a reduced osteogenic differentiation and facilitated lipid droplet formation. Consistently, overexpression of miR-130a in elderly mice dropped off the bone loss. Furthermore, the protein levels of Smad regulatory factors 2 (Smurf2) and PPARγ were regulated by miR-130a with an negative effect through directly combining the 3'UTR of Smurf2 and PPARγ. CONCLUSIONS: The results indicated that miR-130a promotes osteoblastic differentiation of BMSC by negatively regulating Smurf2 expression and suppresses adipogenic differentiation of BMSC by targeting the PPARγ, and supply a new target for clinical therapy of age-related bone loss.


Asunto(s)
Adipogénesis/genética , Células Madre Mesenquimatosas/citología , MicroARNs/genética , Osteoblastos/citología , Adipocitos/metabolismo , Animales , Médula Ósea/metabolismo , Células de la Médula Ósea/citología , Diferenciación Celular/efectos de los fármacos , Ratones , Osteogénesis/efectos de los fármacos , Osteogénesis/genética , ARN Mensajero/metabolismo
16.
Mar Drugs ; 17(10)2019 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-31546680

RESUMEN

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.


Asunto(s)
Benzofuranos/farmacología , Médula Ósea/efectos de los fármacos , Dioxinas/farmacología , Células Madre Mesenquimatosas/efectos de los fármacos , Osteoblastos/efectos de los fármacos , Phaeophyta/química , Células 3T3 , Fosfatasa Alcalina/metabolismo , Animales , Productos Biológicos/farmacología , Médula Ósea/metabolismo , Proteína Morfogenética Ósea 2/metabolismo , Diferenciación Celular/efectos de los fármacos , Línea Celular , Humanos , Células Madre Mesenquimatosas/metabolismo , Ratones , Osteoblastos/metabolismo , Osteogénesis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , beta Catenina/metabolismo
17.
Nat Commun ; 10(1): 3931, 2019 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-31477722

RESUMEN

Natural killer (NK) cells are critical to both innate and adaptive immunity. However, the development and heterogeneity of human NK cells are yet to be fully defined. Using single-cell RNA-sequencing technology, here we identify distinct NK populations in human bone marrow and blood, including one population expressing higher levels of immediate early genes indicative of a homeostatic activation. Functionally matured NK cells with high expression of CX3CR1, HAVCR2 (TIM-3), and ZEB2 represents terminally differentiated status with the unique transcriptional profile. Transcriptomic and pseudotime analyses identify a transitional population between CD56bright and CD56dim NK cells. Finally, a donor with GATA2T354M mutation exhibits reduced percentage of CD56bright NK cells with altered transcriptome and elevated cell death. These data expand our understanding of the heterogeneity and development of human NK cells.


Asunto(s)
Médula Ósea/metabolismo , Células Asesinas Naturales/metabolismo , Análisis de la Célula Individual/métodos , Transcriptoma/genética , Células de la Médula Ósea/metabolismo , Antígeno CD56/genética , Antígeno CD56/metabolismo , Receptor 1 de Quimiocinas CX3C/genética , Receptor 1 de Quimiocinas CX3C/metabolismo , Heterogeneidad Genética , Receptor 2 Celular del Virus de la Hepatitis A/genética , Receptor 2 Celular del Virus de la Hepatitis A/metabolismo , Humanos , Células Asesinas Naturales/inmunología , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/genética , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/metabolismo
18.
Exp Hematol ; 78: 1-10, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31494174

RESUMEN

Hematopoietic stem and progenitor cells (HSPCs) are essential for daily mature blood cell production, host immunity, and osteoclast-mediated bone turnover. The timing at which stem cells give rise to mature blood and immune cells while maintaining the bone marrow (BM) reservoir of undifferentiated HSPCs and how these opposite tasks are synchronized are poorly understood. Previous studies revealed that daily light onset activates norepinephrine (NE)-induced BM CXCL12 downregulation, followed by CXCR4+ HSPC release to the circulation. Recently, we reported that daily light onset induces transient elevations of BM NE and tumor necrosis factor (TNF), which metabolically program BM HSPC differentiation and recruitment to replenish the blood. In contrast, darkness onset induces lower elevations of BM NE and TNF, activating melatonin production, which metabolically reprograms HSPCs, increasing their short- and long-term repopulation potential, and BM maintenance. How the functions of BM-retained HSPCs are influenced by daily light and darkness cycles and their clinical potential are further discussed.


Asunto(s)
Médula Ósea/metabolismo , Diferenciación Celular/fisiología , Ritmo Circadiano/fisiología , Oscuridad , Células Madre Hematopoyéticas/metabolismo , Luz , Melatonina/metabolismo , Norepinefrina/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Células Madre Hematopoyéticas/citología , Humanos
19.
Biomed Pharmacother ; 119: 109434, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31536933

RESUMEN

Our previous research had firstly shown that MM cells overexpressed IQGAP1 gene and activated Ras/Raf/MEK/ERK pathway. But the mechanism of IQGAP1 overexpression and IQGAP1 gene transcription regulation remains uncertain. The mechanism of IQGAP1 overexpression and transcriptional regulation of IQGAP1 gene in myeloma cells was explored in the study. Through bioinformatics analysis and prediction we predicted and screened transcription factor Sp1 as a possible upstream regulator of IQGAP1.The proliferation, cell cycle and downstream ERK1/2 and p-ERK1/2 proteins were detected after siRNA-IQGAP1 was transfected to myeloma cells. The expression of Sp1, p300, IQGAP1, p-ERK1/2 and ERK1/2 were detected after Sp1 and p300 were inhibited or overexpressed respectively. The dual-luciferase reporter system was used to detect the activity of IQGAP1 gene promoter. CHIP was used to detect the binding of the Sp1 and IQGAP1 promoter regions.CO-IP was used to explore the interaction between Sp1 and p300.The mRNA expression levels of Sp1,p300 and IQGAP1 of the myeloma patients were detected, and the correlation analysis of their mRNA expression levels were carried out. The results showed IQGAP1-siRNA inhibits cell proliferation, cell cycle, IQGAP1 expression and phosphorylation of ERK1/2 protein. Inhibition of Sp1 or p300 down-regulated ERK1/2 and IQGAP1 expression; overexpression of Sp1 or p300 up-regulated ERK1/2 and IQGAP1 expression; Sp1 and p300 had a positive regulation effect on IQGAP1.Over expression of Sp1 or p300 significantly increased activity of IQGAP1 gene promoter. The transcription factor Sp1 plays a regulatory role in the IQGAP1 promoter region. There is an interaction between Sp1 and p300 in myeloma cells. The mRNA expression levels of Sp1, IQGAP1 and p300 in MM samples showed a positive correlation. In summary IQGAP1 is required for cell proliferation in MM cells, and the transcription of Sp1/p300 complex regulates expression of IQGAP1 gene.


Asunto(s)
Proteína p300 Asociada a E1A/metabolismo , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Factor de Transcripción Sp1/metabolismo , Transcripción Genética , Proteínas Activadoras de ras GTPasa/genética , Médula Ósea/metabolismo , Médula Ósea/patología , Línea Celular Tumoral , Proliferación Celular/genética , Regulación hacia Abajo/genética , Proteína p300 Asociada a E1A/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Regiones Promotoras Genéticas , Unión Proteica , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/metabolismo , Factor de Transcripción Sp1/genética , Proteínas Activadoras de ras GTPasa/metabolismo
20.
Hematol Oncol ; 37(5): 595-600, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31486522

RESUMEN

Daratumumab, an anti-CD38 antibody, is effective in AL amyloidosis with low tumor burden. Data of daratumumab treatment in patients with AL amyloidosis but high tumor burden (≥10% bone marrow plasma cells) are limited. We report retrospective data of 10 consecutive patients with high tumor burden treated with daratumumab for relapsed/refractory AL amyloidosis. The median age at diagnosis was 62.3 years; all patients had cardiac involvement, and six (60%) patients had renal involvement. Median bone marrow plasma cell infiltration was 15% (range 10%-40%), and the median difference between involved and noninvolved free light-chains (dFLC) was 446 mg/L (range 102-1392 mg/L). Patients had a median of three prior lines of therapy, including bortezomib in all patients and lenalidomide in seven (70%) patients. The median time to first hematological response was 14 days (range 7-28 days), and the median time to best hematological response was 64 days (range 7-301 days). The hematological overall response was 90%, with high-quality response (≥ very good partial remission [VGPR]) in 70% of the patients. Fifty percent of the patients had a cardiac response after a median of 3.8 months (range 0.7-9.1). Infusion-related adverse events ≤ grade 2 occurred in seven (70%) patients and grade 3 adverse events in one patient. After a median follow-up time of 10 months, eight (80%) patients continued to receive daratumumab. We conclude that daratumumab is a very effective and safe treatment option in AL patients with relapsed/refractory disease and high disease burden at diagnosis. Daratumumab leads to rapid disease control and improvement of organ function.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/diagnóstico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/tratamiento farmacológico , Recuento de Linfocitos , Células Plasmáticas/patología , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Médula Ósea/metabolismo , Médula Ósea/patología , Resistencia a Antineoplásicos , Femenino , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/mortalidad , /terapia , Masculino , Persona de Mediana Edad , Recurrencia , Retratamiento , Índice de Severidad de la Enfermedad , Resultado del Tratamiento
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