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1.
BMC Endocr Disord ; 24(1): 55, 2024 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-38679740

RESUMO

BACKGROUND: Glucocorticoids and sclerostin act as inhibitors of the Wnt signaling pathway, thereby hindering bone formation. Given the pathway's intricate association with mesenchymal stem cells, the hypothesis suggests that heightened sclerostin levels may be intricately linked to an augmentation in marrow adiposity induced by glucocorticoids. This study endeavored to delve into the nuanced relationship between circulating sclerostin and bone marrow adipose tissue in postmenopausal women grappling with glucocorticoid-induced osteoporosis (GIO). METHODS: In this cross-sectional study, 103 patients with autoimmune-associated diseases underwent glucocorticoid treatment, boasting an average age of 61.3 years (standard deviation 7.1 years). The investigation encompassed a thorough assessment, incorporating medical history, anthropometric data, biochemical analysis, and dual-energy X-ray absorptiometry measurements of lumbar and femoral bone mineral density (BMD). Osteoporosis criteria were established at a T-score of -2.5 or lower. Additionally, MR spectroscopy quantified the vertebral marrow fat fraction. RESULTS: BMD at the femoral neck, total hip, and lumbar spine showcased an inverse correlation with marrow fat fraction (r = -0.511 to - 0.647, P < 0.001). Serum sclerostin levels exhibited a positive correlation with BMD at various skeletal sites (r = 0.476 to 0.589, P < 0.001). A noteworthy correlation emerged between circulating sclerostin and marrow fat fraction at the lumbar spine (r = -0.731, 95% CI, -0.810 to -0.627, P < 0.001). Multivariate analysis brought to light that vertebral marrow fat fraction significantly contributed to sclerostin serum concentrations (standardized regression coefficient ß = 0.462, P < 0.001). Even after adjusting for age, body mass index, physical activity, renal function, BMD, and the duration and doses of glucocorticoid treatment, serum sclerostin levels maintained a significant correlation with marrow fat fraction. CONCLUSIONS: Circulating sclerostin levels exhibited a noteworthy association with marrow adiposity in postmenopausal women grappling with GIO.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Adiposidade , Densidade Óssea , Medula Óssea , Glucocorticoides , Pós-Menopausa , Humanos , Feminino , Pessoa de Meia-Idade , Glucocorticoides/efeitos adversos , Estudos Transversais , Adiposidade/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Idoso , Marcadores Genéticos , Biomarcadores/sangue , Biomarcadores/análise , Osteoporose Pós-Menopausa/sangue , Absorciometria de Fóton
2.
Stem Cell Res Ther ; 15(1): 123, 2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38679747

RESUMO

BACKGROUND: Acute radiation syndrome (ARS) manifests after exposure to high doses of radiation in the instances of radiologic accidents or incidents. Facilitating regeneration of the bone marrow (BM), namely the hematopoietic stem and progenitor cells (HSPCs), is key in mitigating ARS and multi-organ failure. JNJ-26366821, a PEGylated thrombopoietin mimetic (TPOm) peptide, has been shown as an effective medical countermeasure (MCM) to treat hematopoietic-ARS (H-ARS) in mice. However, the activity of TPOm on regulating BM vascular and stromal niches to support HSPC regeneration has yet to be elucidated. METHODS: C57BL/6J mice (9-14 weeks old) received sublethal or lethal total body irradiation (TBI), a model for H-ARS, by 137Cs or X-rays. At 24 h post-irradiation, mice were subcutaneously injected with a single dose of TPOm (0.3 mg/kg or 1.0 mg/kg) or PBS (vehicle). At homeostasis and on days 4, 7, 10, 14, 18, and 21 post-TBI with and without TPOm treatment, BM was harvested for histology, BM flow cytometry of HSPCs, endothelial (EC) and mesenchymal stromal cells (MSC), and whole-mount confocal microscopy. For survival, irradiated mice were monitored and weighed for 30 days. Lastly, BM triple negative cells (TNC; CD45-, TER-119-, CD31-) were sorted for single-cell RNA-sequencing to examine transcriptomics after TBI with or without TPOm treatment. RESULTS: At homeostasis, TPOm expanded the number of circulating platelets and HSPCs, ECs, and MSCs in the BM. Following sublethal TBI, TPOm improved BM architecture and promoted recovery of HSPCs, ECs, and MSCs. Furthermore, TPOm elevated VEGF-C levels in normal and irradiated mice. Following lethal irradiation, mice improved body weight recovery and 30-day survival when treated with TPOm after 137Cs and X-ray exposure. Additionally, TPOm reduced vascular dilation and permeability. Finally, single-cell RNA-seq analysis indicated that TPOm increased the expression of collagens in MSCs to enhance their interaction with other progenitors in BM and upregulated the regeneration pathway in MSCs. CONCLUSIONS: TPOm interacts with BM vascular and stromal niches to locally support hematopoietic reconstitution and systemically improve survival in mice after TBI. Therefore, this work warrants the development of TPOm as a potent radiation MCM for the treatment of ARS.


Assuntos
Síndrome Aguda da Radiação , Medula Óssea , Camundongos Endogâmicos C57BL , Trombopoetina , Animais , Camundongos , Trombopoetina/farmacologia , Síndrome Aguda da Radiação/tratamento farmacológico , Síndrome Aguda da Radiação/patologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/efeitos da radiação , Medula Óssea/metabolismo , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/efeitos da radiação , Nicho de Células-Tronco/efeitos dos fármacos , Nicho de Células-Tronco/efeitos da radiação , Masculino , Irradiação Corporal Total
3.
Exp Hematol ; 133: 104212, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38552942

RESUMO

Extensive research over the past 50 years has resulted in significant improvements in survival for patients diagnosed with leukemia. Despite this, a subgroup of patients harboring high-risk genetic alterations still suffer from poor outcomes. There is a desperate need for new treatments to improve survival, yet consistent failure exists in the translation of in vitro drug development to clinical application. Preclinical screening conventionally utilizes tumor cell monocultures to assess drug activity; however, emerging research has acknowledged the vital role of the tumor microenvironment in treatment resistance and disease relapse. Current co-culture drug screening methods frequently employ fibroblasts as the designated stromal cell component. Alternative stromal cell types that are known to contribute to chemoresistance are often absent in preclinical evaluations of drug efficacy. This review highlights mechanisms of chemoresistance by a range of different stromal constituents present in the bone marrow microenvironment. Utilizing an array of stromal cell types at the early stages of drug screening may enhance the translation of in vitro drug development to clinical use. Ultimately, we highlight the need to consider the bone marrow microenvironment in drug screening platforms for leukemia to develop superior therapies for the treatment of high-risk patients with poor prognostic outcomes.


Assuntos
Leucemia , Microambiente Tumoral , Humanos , Microambiente Tumoral/efeitos dos fármacos , Leucemia/patologia , Leucemia/tratamento farmacológico , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Animais , Medula Óssea/patologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Células Estromais/patologia , Células Estromais/metabolismo , Células Estromais/efeitos dos fármacos , Técnicas de Cocultura , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/patologia
4.
Nature ; 625(7993): 166-174, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38057662

RESUMO

Myeloid cells are known to suppress antitumour immunity1. However, the molecular drivers of immunosuppressive myeloid cell states are not well defined. Here we used single-cell RNA sequencing of human and mouse non-small cell lung cancer (NSCLC) lesions, and found that in both species the type 2 cytokine interleukin-4 (IL-4) was predicted to be the primary driver of the tumour-infiltrating monocyte-derived macrophage phenotype. Using a panel of conditional knockout mice, we found that only deletion of the IL-4 receptor IL-4Rα in early myeloid progenitors in bone marrow reduced tumour burden, whereas deletion of IL-4Rα in downstream mature myeloid cells had no effect. Mechanistically, IL-4 derived from bone marrow basophils and eosinophils acted on granulocyte-monocyte progenitors to transcriptionally programme the development of immunosuppressive tumour-promoting myeloid cells. Consequentially, depletion of basophils profoundly reduced tumour burden and normalized myelopoiesis. We subsequently initiated a clinical trial of the IL-4Rα blocking antibody dupilumab2-5 given in conjunction with PD-1/PD-L1 checkpoint blockade in patients with relapsed or refractory NSCLC who had progressed on PD-1/PD-L1 blockade alone (ClinicalTrials.gov identifier NCT05013450 ). Dupilumab supplementation reduced circulating monocytes, expanded tumour-infiltrating CD8 T cells, and in one out of six patients, drove a near-complete clinical response two months after treatment. Our study defines a central role for IL-4 in controlling immunosuppressive myelopoiesis in cancer, identifies a novel combination therapy for immune checkpoint blockade in humans, and highlights cancer as a systemic malady that requires therapeutic strategies beyond the primary disease site.


Assuntos
Medula Óssea , Carcinogênese , Interleucina-4 , Mielopoese , Transdução de Sinais , Animais , Humanos , Camundongos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinogênese/patologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Inibidores de Checkpoint Imunológico/imunologia , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Interleucina-4/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Monócitos/efeitos dos fármacos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Recidiva , Transdução de Sinais/efeitos dos fármacos
5.
Toxicology ; 492: 153532, 2023 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-37141935

RESUMO

Thallium (Tl) is a high-priority toxic metal that poses a severe threat to human health. The toxicity characteristics induced by Tl have been partially discussed. However, the immunotoxic effects of Tl exposure have remained largely unexplored. Our findings demonstrated that 50 ppm of Tl exposure for one week induced severe weight loss in mice, which was accompanied by appetite suppression. Moreover, although Tl exposure did not induce significant pathological damage to skeletal muscle and bone, Tl inhibited the expression of B cell development-related genes in the bone marrow. Additionally, Tl exposure increased B cell apoptosis and reduced its generation in the bone marrow. Analysis of B cells in the blood indicated that the percentage of B-2 cells decreased significantly, whereas B-2 cell proportions in the spleen did not. The percentage of CD4+ T cells in the thymus increased significantly, and the proportion of CD8+ T cells did not. Furthermore, although the proportion of the total CD4+ and CD8+ T cells was not significantly altered in the blood and spleen, Tl exposure promoted the migration of naïve CD4+ T cells and recent thymic emigrants (RTEs) from the thymus to the spleen. These results suggest that Tl exposure can affect B and T cell generation and migration, which provides new evidence for Tl-induced immunotoxicity.


Assuntos
Linfócitos B , Linfócitos T , Tálio , Tálio/toxicidade , Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Animais , Camundongos , Movimento Celular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Timo/citologia , Timo/efeitos dos fármacos , Medula Óssea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos
6.
J Med Case Rep ; 16(1): 294, 2022 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-35907896

RESUMO

BACKGROUND: Liver involvement in adults with acute myeloid leukemia is uncommon. Most of the case reports describe acute liver failure or obstructive jaundice, while acute hepatitis is rarely mentioned. We report a patient with acute myeloid leukemia who presented with clinical, biochemical, and radiological signs of acute hepatitis that totally regressed after chemotherapy. CASE PRESENTATION: A 38-year-old Caucasian man presented with fever, cough, and mild fatigue. Laboratory workup showed anemia, thrombocytopenia, severe leukocytosis, transaminitis, and hyperbilirubinemia. Imaging of the abdomen (ultrasound and magnetic resonance) showed hepatomegaly, splenomegaly, upper limits portal veins diameters, increased thickness of the gallbladder wall, and significant abdominal lymph nodes. Peripheral blood smear and bone marrow evaluation were consistent with acute myeloid leukemia, and liver biopsy showed massive sinusoidal and portal infiltration by leukemic cells. After remission-inducing chemotherapy, there was complete normalization of liver function tests, and liver, spleen, and portal vein size. CONCLUSIONS: This case highlights the importance of taking acute myeloid leukemia into account as a possible cause of liver damage to make a rapid diagnosis and start appropriate treatment that may lead to hematological remission and hepatic dysfunction resolution.


Assuntos
Colestase , Subunidade beta de Fator de Ligação ao Core , Hepatite , Leucemia Mieloide Aguda , Cadeias Pesadas de Miosina , Doença Aguda , Adulto , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Colestase/complicações , Colestase/tratamento farmacológico , Colestase/patologia , Hepatite/complicações , Hepatite/diagnóstico , Hepatite/tratamento farmacológico , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/tratamento farmacológico , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/fisiologia , Fígado/fisiopatologia , Masculino
7.
Mar Drugs ; 20(3)2022 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-35323500

RESUMO

Hematopoietic damage is a serious side effect of cytotoxic drugs, and agents promoting hematopoiesis are quite important for decreasing the death rate in cancer patients. In our previous work, we prepared the simulated digestive product of fucoidan from Sargassum fusiforme, DSFF, and found that DSFF could activate macrophages. However, more investigations are needed to further evaluate whether DSFF could promote hematopoiesis in the chemotherapy process. In this study, the protective effect of DSFF (1.8-7.2 mg/kg, i.p.) on cyclophosphamide-induced hematopoietic damage in mice and the underlying mechanisms were investigated. Our results show that DSFF could restore the numbers of white blood cells, neutrophils, and platelets in the peripheral blood, and could also retard bone marrow cell decrease in mice with cyclophosphamide-induced hematopoietic damage. UPLC/Q-Extraction Orbitrap/MS/MS-based lipidomics results reveal 16 potential lipid biomarkers in a serum that responded to hematopoietic damage in mice. Among them, PC (20:1/14:0) and SM (18:0/22:0) were the key lipid molecules through which DSFF exerted protective actions. In a validation experiment, DSFF (6.25-100 µg/mL) could also promote K562 cell proliferation and differentiation in vitro. The current findings indicated that DSFF could affect the blood cells and bone marrow cells in vivo and thus showed good potential and application value in alleviating the hematopoietic damage caused by cyclophosphamide.


Assuntos
Ciclofosfamida/toxicidade , Hematopoese/efeitos dos fármacos , Agonistas Mieloablativos/toxicidade , Polissacarídeos/farmacologia , Substâncias Protetoras/farmacologia , Sargassum , Animais , Biomarcadores/sangue , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Proliferação de Células/efeitos dos fármacos , DNA/metabolismo , Humanos , Células K562 , Contagem de Leucócitos , Lipidômica , Camundongos , Neutrófilos/efeitos dos fármacos , Contagem de Plaquetas
8.
Toxins (Basel) ; 14(2)2022 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-35202133

RESUMO

The aim of this study was to determine whether low doses of zearalenone (ZEN) influence the carry-over of ZEN and its metabolites to the bone marrow microenvironment and, consequently, haematological parameters. Pre-pubertal gilts (with a body weight of up to 14.5 kg) were exposed to daily ZEN doses of 5 µg/kg BW (group ZEN5, n = 15), 10 µg/kg BW (group ZEN10, n = 15), 15 µg/kg BW (group ZEN15, n = 15), or were administered a placebo (group C, n = 15) throughout the entire experiment. Bone marrow was sampled on three dates (exposure dates 7, 21, and 42-after slaughter) and blood for haematological analyses was sampled on 10 dates. Significant differences in the analysed haematological parameters (WBC White Blood Cells, MONO-Monocytes, NEUT-Neutrophils, LYMPH-Lymphocytes, LUC-Large Unstained Cells, RBC-Red Blood Cells, HGB-Haemoglobin, HCT-Haematocrit, MCH-Mean Corpuscular Volume, MCHC-Mean Corpuscular Haemoglobin Concentrations, PLT-Platelet Count and MPV-Mean Platelet Volume) were observed between groups. The results of the experiment suggest that exposure to low ZEN doses triggered compensatory and adaptive mechanisms, stimulated the local immune system, promoted eryptosis, intensified mycotoxin biotransformation processes in the liver, and produced negative correlations between mycotoxin concentrations and selected haematological parameters.


Assuntos
Medula Óssea/efeitos dos fármacos , Plasma/efeitos dos fármacos , Zearalenona/toxicidade , Animais , Feminino , Testes Hematológicos , Nível de Efeito Adverso não Observado , Maturidade Sexual , Suínos
9.
Blood Cancer J ; 12(1): 19, 2022 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-35091554

RESUMO

Hypomethylating agents (HMA) like azacitidine are licensed for the treatment of acute myeloid leukemia (AML) patients ineligible for allogeneic hematopoietic stem cell transplantation. Biomarker-driven identification of HMA-responsive patients may facilitate the choice of treatment, especially in the challenging subgroup above 60 years of age. Since HMA possesses immunomodulatory functions that constitute part of their anti-tumor effect, we set out to analyze the bone marrow (BM) immune environment by next-generation sequencing of T cell receptor beta (TRB) repertoires in 51 AML patients treated within the RAS-AZIC trial. Patients with elevated pretreatment T cell diversity (11 out of 41 patients) and those with a boost of TRB richness on day 15 after azacitidine treatment (12 out of 46 patients) had longer event-free and overall survival. Both pretreatment and dynamic BM T cell metrics proved to be better predictors of outcome than other established risk factors. The favorable broadening of the BM T cell space appeared to be driven by antigen since these patients showed significant skewing of TRBV gene usage. Our data suggest that one course of AZA can cause reconstitution to a more physiological T cell BM niche and that the T cell space plays an underestimated prognostic role in AML.Trial registration: DRKS identifier: DRKS00004519.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Medula Óssea/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Linfócitos T/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/patologia , Feminino , Humanos , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Linfócitos T/patologia
10.
Nat Commun ; 13(1): 121, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013215

RESUMO

HIV is difficult to eradicate due to the persistence of a long-lived reservoir of latently infected cells. Previous studies have shown that natural killer cells are important to inhibiting HIV infection, but it is unclear whether the administration of natural killer cells can reduce rebound viremia when anti-retroviral therapy is discontinued. Here we show the administration of allogeneic human peripheral blood natural killer cells delays viral rebound following interruption of anti-retroviral therapy in humanized mice infected with HIV-1. Utilizing genetically barcoded virus technology, we show these natural killer cells efficiently reduced viral clones rebounding from latency. Moreover, a kick and kill strategy comprised of the protein kinase C modulator and latency reversing agent SUW133 and allogeneic human peripheral blood natural killer cells during anti-retroviral therapy eliminated the viral reservoir in a subset of mice. Therefore, combinations utilizing latency reversal agents with targeted cellular killing agents may be an effective approach to eradicating the viral reservoir.


Assuntos
Fármacos Anti-HIV/farmacologia , Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/terapia , HIV-1/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Inibidores de Proteínas Quinases/farmacologia , Viremia/terapia , Animais , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Medula Óssea/virologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , Técnicas de Cocultura , Feminino , Infecções por HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/genética , HIV-1/imunologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Células Matadoras Naturais/transplante , Masculino , Camundongos , Camundongos Transgênicos , Proteína Quinase C/genética , Proteína Quinase C/imunologia , Baço/efeitos dos fármacos , Baço/imunologia , Baço/virologia , Carga Viral/efeitos dos fármacos , Viremia/genética , Viremia/imunologia , Viremia/virologia , Latência Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
11.
Clin Breast Cancer ; 22(1): e1-e7, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34078565

RESUMO

BACKGROUND: The coronavirus disease 2019 pandemic is a global public health event. Wuhan used to be the epicenter of China and finally controlled the outbreak through city lockdown and many other policies. However, the pandemic and the prevention strategies had a huge impact on the medical care procedures for patients with breast cancer, leading to the delay or interruption of anticancer therapies. PATIENTS AND METHODS: To better serve patients with breast cancer under the premise of epidemic control, many strategies have been proposed and optimized in our center. One of the most important parts of these strategies is the promotion of telemedicine, including online consultation, online prescription, and drug mailing services. RESULTS: In keeping with the city and hospital policies, we have also introduced stricter ward management policies and more precise care. CONCLUSION: Here, we collected the diagnosis and treatment process of patients with breast cancer in our center during the coronavirus disease 2019 pandemic, which was found to be correlated to a reduction in chemotherapy-related myelosuppression and hepatic dysfunction, hoping to provide a reference for other cancer centers that may suffer from the similar situation.


Assuntos
Neoplasias da Mama/tratamento farmacológico , COVID-19/epidemiologia , SARS-CoV-2 , Adulto , Idoso , Antineoplásicos/efeitos adversos , Medula Óssea/efeitos dos fármacos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , China/epidemiologia , Feminino , Humanos , Pessoa de Meia-Idade , Telemedicina
13.
Acta Radiol ; 63(2): 245-252, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33497273

RESUMO

BACKGROUND: Polyphenols in extra virgin olive oil (EVOO) have been found to reduce the expression of PPARγ2, inhibit adipocyte differentiation, and enhance the formation of osteoblasts from bone marrow stem cells. However, the underlying mechanisms of their action remain unknown. PURPOSE: To determine the sequential effects of EVOO on marrow fat expansion induced by estrogen deprivation using 3.0-T proton magnetic resonance (MR) spectroscopy in an ovariectomy (OVX) rabbit model of postmenopausal bone loss over a six-month period. MATERIAL AND METHODS: A total of 45 female New Zealand rabbits were equally divided into sham-operation, OVX controls, and OVX treated with EVOO for six months. Marrow fat fraction was measured by MR spectroscopy at baseline conditions, and three and six months postoperatively, respectively. Serum bone biomarkers, lumbar and femoral bone mineral density, microtomographic parameters, biomechanical properties, and quantitative parameters of marrow adipocytes were studied. RESULTS: OVX was associated with marrow adiposity in a time-dependent manner, accompanied with increased bone turnover and impaired bone mass and trabecular microarchitecture. In OVX rabbits, EVOO markedly alleviated trabecular bone loss and reduced the accumulation of lipid droplets including adipocyte size, density, and areas of fat deposits in the bone marrow. EVOO prevented such changes in terms of both marrow adiposity and bone remodeling. CONCLUSION: Early EVOO treatment may exert beneficial effects on bone by modulating marrow adiposity, which would support their protective effect against bone pathologies.


Assuntos
Adiposidade/efeitos dos fármacos , Medula Óssea/efeitos dos fármacos , Azeite de Oliva/farmacologia , Osteoporose Pós-Menopausa/fisiopatologia , PPAR gama/antagonistas & inibidores , Polifenóis/farmacologia , Espectroscopia de Prótons por Ressonância Magnética , Adiposidade/fisiologia , Animais , Fenômenos Biomecânicos , Densidade Óssea/efeitos dos fármacos , Medula Óssea/fisiologia , Células da Medula Óssea/citologia , Modelos Animais de Doenças , Feminino , Humanos , Osteogênese , Ovariectomia , Coelhos
14.
J Histochem Cytochem ; 70(2): 169-179, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34915746

RESUMO

Osteoclasts are cells whose main function is the resorption of bone matrix. However, several factors, including medications, can interfere with the resorption process. Alendronate (ALN), a nitrogen-containing type of bisphosphonate, and dexamethasone (DEX), a glucocorticoid, are drugs that may affect the resorption activity. The aim of this study is to investigate the effects of ALN, and/or DEX on osteoclast gene expression and resorption activity in primary mouse marrow cultures stimulated with 1,25-dihydroxyvitamin D3, a model for the bone microenvironment. Cultures were treated only with ALN (10-5 M), DEX (10-6 M), and with a combination of both agents. Viability assays performed at days 5, 7, and 9 showed the highest number of viable cells at day 7. All the following assays were then performed at day 7 of cell culture: tartrate resistant acid phosphatase (TRAP) histochemistry, receptor activator of nuclear factor kappa B ligand (RANKL) immunofluorescence, osteoprotegerin (OPG), and RANKL gene expression by qPCR and resorption analysis by scanning electron microscopy. Treatment with ALN, DEX, and the combination of both did not promote significant changes in the number of TRAP+ cells, although larger giant cells were detected in groups treated with DEX. DEX treatment increased the gene expression of RANKL and reduced OPG. The treatment with ALN reduced the depth of the resorption pits, but their inhibitory effect was less effective when administered with DEX.


Assuntos
Alendronato/farmacologia , Medula Óssea/efeitos dos fármacos , Reabsorção Óssea/tratamento farmacológico , Dexametasona/farmacologia , Osteoclastos/efeitos dos fármacos , Animais , Bovinos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Camundongos , Camundongos Endogâmicos BALB C
15.
Endocrinology ; 163(2)2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34864986

RESUMO

Glucocorticoids (GCs) are critical modulators of the immune system. The hypothalamic-pituitary-adrenal (HPA) axis regulates circulating GC levels and is stimulated by endotoxins. Lymphoid organs also produce GCs; however, it is not known how lymphoid GC levels are regulated in response to endotoxins. We assessed whether an acute challenge of lipopolysaccharide (LPS) increases lymphoid levels of progesterone and GCs, and expression of steroidogenic enzymes and key HPA axis components (eg, corticotropin-releasing hormone [CRH], adrenocorticotropic hormone [ACTH]). We administered LPS (50 µg/kg intraperitoneally) or vehicle control to male and female C57BL/6J neonatal (postnatal day [PND] 5) and adult (PND90) mice and collected blood, bone marrow, thymus, and spleen 4 hours later. We measured progesterone, 11-deoxycorticosterone, corticosterone, and 11-dehydrocorticosterone via liquid chromatography-tandem mass spectrometry. We measured gene expression of key steroidogenic enzymes (Cyp11b1, Hsd11b1, and Hsd11b2) and HPA axis components (Crh, Crhr1, Pomc, and Mc2r) via quantitative polymerase chain reaction. At PND5, LPS induced greater increases in steroid levels in lymphoid organs than in blood. In contrast, at PND90, LPS induced greater increases in steroid levels in blood than in lymphoid organs. Steroidogenic enzyme transcripts were present in all lymphoid organs, and LPS altered steroidogenic enzyme expression predominantly in the spleen. Lastly, we detected transcripts of key HPA axis components in all lymphoid organs, and there was an effect of LPS in the spleen. Taken together, these data suggest that LPS regulates GC production by lymphoid organs, similar to its effects on the adrenal glands, and the effects of LPS might be mediated by local expression of CRH and ACTH.


Assuntos
Medula Óssea/metabolismo , Glucocorticoides/biossíntese , Lipopolissacarídeos/farmacologia , Baço/metabolismo , Timo/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , Animais , Animais Recém-Nascidos/metabolismo , Medula Óssea/efeitos dos fármacos , Medula Óssea/enzimologia , Corticosterona/análise , Corticosterona/sangue , Feminino , Glucocorticoides/sangue , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , RNA Mensageiro/análise , Receptores de Hormônio Liberador da Corticotropina/genética , Baço/efeitos dos fármacos , Baço/enzimologia , Esteroide 11-beta-Hidroxilase/genética , Timo/efeitos dos fármacos , Timo/enzimologia
16.
Leukemia ; 36(2): 333-347, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34518644

RESUMO

We show that pro-inflammatory oncostatin M (OSM) is an important regulator of hematopoietic stem cell (HSC) niches in the bone marrow (BM). Treatment of healthy humans and mice with granulocyte colony-stimulating factor (G-CSF) dramatically increases OSM release in blood and BM. Using mice null for the OSM receptor (OSMR) gene, we demonstrate that OSM provides a negative feed-back acting as a brake on HSPC mobilization in response to clinically relevant mobilizing molecules G-CSF and CXCR4 antagonist. Likewise, injection of a recombinant OSM molecular trap made of OSMR complex extracellular domains enhances HSC mobilization in poor mobilizing C57BL/6 and NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice. Mechanistically, OSM attenuates HSC chemotactic response to CXCL12 and increases HSC homing to the BM signaling indirectly via BM endothelial and mesenchymal cells which are the only cells expressing OSMR in the BM. OSM up-regulates E-selectin expression on BM endothelial cells indirectly increasing HSC proliferation. RNA sequencing of HSCs from Osmr-/- and wild-type mice suggest that HSCs have altered cytoskeleton reorganization, energy usage and cycling in the absence of OSM signaling in niches. Therefore OSM is an important regulator of HSC niche function restraining HSC mobilization and anti-OSM therapy combined with current mobilizing regimens may improve HSPC mobilization for transplantation.


Assuntos
Medula Óssea/fisiologia , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/citologia , Oncostatina M/metabolismo , Nicho de Células-Tronco , Animais , Medula Óssea/efeitos dos fármacos , Feminino , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD
17.
Cells ; 10(12)2021 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-34944006

RESUMO

Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disease characterized by inefficient hematopoiesis and the potential development of acute leukemia. Among the most notable advances in the treatment of MDS is the hypomethylating agent, decitabine (5-aza-2'deoxycytidine). Although decitabine is well known as an effective method for treating MDS patients, only a subset of patients respond and a tolerance often develops, leading to treatment failure. Moreover, decitabine treatment is costly and causes unnecessary toxicity. Therefore, clarifying the mechanism of decitabine resistance is important for improving its therapeutic efficacy. To this end, we established a decitabine-resistant F-36P cell line from the parental F-36P leukemia cell line, and applied a genetic approach employing next-generation sequencing, various experimental techniques, and bioinformatics tools to determine differences in gene expression and relationships among genes. Thirty-eight candidate genes encoding proteins involved in decitabine-resistant-related pathways, including immune checkpoints, the regulation of myeloid cell differentiation, and PI3K-Akt signaling, were identified. Interestingly, two of the candidate genes, AKT3 and FOS, were overexpressed in MDS patients with poor prognoses. On the basis of these results, we are pursuing development of a gene chip for diagnosing decitabine resistance in MDS patients, with the goal of ultimately improving the power to predict treatment strategies and the prognosis of MDS patients.


Assuntos
Biomarcadores/metabolismo , Decitabina/uso terapêutico , Resistência a Medicamentos/genética , Perfilação da Expressão Gênica , Síndromes Mielodisplásicas/tratamento farmacológico , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Linhagem Celular , Decitabina/farmacologia , Resistência a Medicamentos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Humanos , Mapas de Interação de Proteínas/efeitos dos fármacos , RNA-Seq , Reprodutibilidade dos Testes
18.
Afr Health Sci ; 21(2): 673-682, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34795722

RESUMO

BACKGROUND: Therapy-related acute myeloid leukemia (t-AML) is a well-recognized clinical syndrome occurring in a significant fraction of patients who have undergone previous chemotherapy for a solid tumour. OBJECTIVES: We aim to evaluate the effect of aqueous extract of fresh Allium sativum cloves on haematological parameters, bone marrow and DNA of etoposide treated albino wistar rats. Decoction method was used to prepare plant extracts and the rats were weighed and divided into experimental and control groups. Blood and bone marrow sample were analysed and DNA fragment analysis was carried out. RESULTS: There was progressive increase in the weight of animals that received distilled water only for the duration of the experiment while those that received etoposide only showed a sharp decrease in weight by the end of week 3. There was no significant difference in the mean of the haematological parameters in the test and control groups except for platelet count. The bone marrow smears showed no prevention of erythroblast fragmentation by the extract, in the same vein, DNA damage was not abated. CONCLUSION: Aqueous extract of fresh Allium sativum cloves may not be the option for the prevention of etoposide induced acute myeloid leukemia.


Assuntos
Dano ao DNA/efeitos dos fármacos , Etoposídeo/efeitos adversos , Alho/metabolismo , Leucemia Mieloide Aguda/induzido quimicamente , Animais , Antioxidantes/farmacologia , Medula Óssea/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/metabolismo , Extratos Vegetais/farmacologia , Ratos Wistar
19.
Nat Commun ; 12(1): 6960, 2021 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-34845188

RESUMO

Virtually all patients with multiple myeloma become unresponsive to treatment over time. Relapsed/refractory multiple myeloma (RRMM) is accompanied by the clonal evolution of myeloma cells with heterogeneous genomic aberrations and profound changes of the bone marrow microenvironment (BME). However, the molecular mechanisms that drive drug resistance remain elusive. Here, we analyze the heterogeneous tumor cell population and its complex interaction network with the BME of 20 RRMM patients by single cell RNA-sequencing before/after treatment. Subclones with chromosome 1q-gain express a specific transcriptomic signature and frequently expand during treatment. Furthermore, RRMM cells shape an immune suppressive BME by upregulation of inflammatory cytokines and close interaction with the myeloid compartment. It is characterized by the accumulation of PD1+ γδ T-cells and tumor-associated macrophages as well as the depletion of hematopoietic progenitors. Thus, our study resolves transcriptional features of subclones in RRMM and mechanisms of microenvironmental reprogramming with implications for clinical decision-making.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Mieloma Múltiplo/genética , Transcriptoma , Microambiente Tumoral/genética , Antineoplásicos/uso terapêutico , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Medula Óssea/patologia , Citocinas/genética , Citocinas/imunologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/patologia , Humanos , Linfócitos Intraepiteliais/imunologia , Linfócitos Intraepiteliais/patologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Recidiva , Análise de Sequência de RNA , Transdução de Sinais , Análise de Célula Única , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
20.
Cells ; 10(11)2021 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-34831130

RESUMO

Idiopathic acquired aplastic anemia can be successfully treated with Anti Thymocyte Globulin (ATG)-based immune suppressive therapy and is therefore considered a T cell-mediated auto immune disease. Based on this finding, several other forms of idiopathic acquired bone marrow failure are treated with ATG as well. For this review, we extensively searched the present literature for evidence that ATG can lead to enduring remissions in different forms of acquired multi- or single-lineage bone marrow failure. We conclude that ATG-based therapy can lead to an enduring hematopoietic response and increased overall survival (OS) in patients with acquired aplastic aplasia. In patients with hypocellular myelodysplastic syndrome, ATG can lead to a hematological improvement without changing the OS. ATG seems less effective in acquired single-lineage failure diseases like Pure Red Cell Aplasia, Amegakaryocytic Thrombocytopenia and Pure White Cell Aplasia, suggesting a different pathogenesis in these bone marrow failure states compared to aplastic anemia. T cell depletion is hypothesized to play an important role in the beneficial effect of ATG but, as ATG is a mixture of polyclonal antibodies binding to different antigens, other anti-inflammatory or immunomodulatory effects could play a role as well.


Assuntos
Soro Antilinfocitário/uso terapêutico , Transtornos da Insuficiência da Medula Óssea/tratamento farmacológico , Adulto , Soro Antilinfocitário/farmacologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Humanos , Estudos Prospectivos
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