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1.
Stem Cell Rev Rep ; 17(1): 285-290, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33575961

RESUMO

The paper presents the results of a standard and complex treatment method using the peptide drug thymus thymalin in patients with COVID-19. One of the mechanisms of the immunomodulatory effect of thymalin is considered to be the ability of this peptide drug to influence the differentiation of human hematopoietic stem cells (HSCs). It was found that, as a result of standard treatment, patients in the control group showed a decrease in the concentration of the pro-inflammatory cytokine IL-6, C-reactive protein, D-dimer. The addition of thymalin to standard therapy accelerated the decline in both these indicators and the indicators of the T cell system. This has helped reduce the risk of blood clots in COVID-19 patients. The revealed properties of the thymus peptide preparation are the rationale for its inclusion in the complex treatment of coronavirus infection. Peptideswith potential biological activity against SARS-CoV-2 virus [29]. Note: Nitrogen atoms are shown in blue, oxygen atoms - in red, carbon atoms - in gray, hydrogen atoms - in white, and phosphorus atoms - in yellow.


Assuntos
/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Hormônios do Timo/uso terapêutico , /genética , /virologia , Citocinas/genética , Hematopoese/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Timo/metabolismo , Hormônios do Timo/genética , Hormônios do Timo/metabolismo
2.
PLoS Biol ; 18(12): e3000919, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33351791

RESUMO

Computational protein design is rapidly becoming more powerful, and improving the accuracy of computational methods would greatly streamline protein engineering by eliminating the need for empirical optimization in the laboratory. In this work, we set out to design novel granulopoietic agents using a rescaffolding strategy with the goal of achieving simpler and more stable proteins. All of the 4 experimentally tested designs were folded, monomeric, and stable, while the 2 determined structures agreed with the design models within less than 2.5 Å. Despite the lack of significant topological or sequence similarity to their natural granulopoietic counterpart, 2 designs bound to the granulocyte colony-stimulating factor (G-CSF) receptor and exhibited potent, but delayed, in vitro proliferative activity in a G-CSF-dependent cell line. Interestingly, the designs also induced proliferation and differentiation of primary human hematopoietic stem cells into mature granulocytes, highlighting the utility of our approach to develop highly active therapeutic leads purely based on computational design.


Assuntos
Granulócitos/citologia , Engenharia de Proteínas/métodos , Diferenciação Celular , Células Cultivadas , Biologia Computacional/métodos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Granulócitos/efeitos dos fármacos , Hematopoese/efeitos dos fármacos , Hematopoese/fisiologia , Células-Tronco Hematopoéticas/citologia , Humanos , Neutrófilos , Relação Estrutura-Atividade
3.
Mol Med Rep ; 22(6): 4485-4491, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33173966

RESUMO

In December 2019, an emergence of pneumonia was detected in patients infected with a novel coronavirus (CoV) in Wuhan (Hubei, China). The International Committee on Taxonomy of Viruses named the virus severe acute respiratory syndrome­CoV­2 and the disease CoV disease­19 (COVID­19). Patients with COVID­19 present with symptoms associated with respiratory system dysfunction and hematological changes, including lymphopenia, thrombocytopenia and coagulation disorders. However, to the best of our knowledge, the pathogenesis of COVID­19 remains unclear. Therefore, understanding the mechanisms underlying the hematological changes that manifest during COVID­19 may aid in the development of treatments and may improve patient prognosis.


Assuntos
Betacoronavirus , Infecções por Coronavirus/sangue , Pneumonia Viral/sangue , Anticorpos Antivirais/imunologia , Complexo Antígeno-Anticorpo/imunologia , Antivirais/farmacologia , Antivirais/uso terapêutico , Betacoronavirus/imunologia , Microambiente Celular , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/terapia , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/prevenção & controle , Citocinas/sangue , Testes Diagnósticos de Rotina , Endotélio Vascular/patologia , Testes Hematológicos , Hematopoese/efeitos dos fármacos , Células-Tronco Hematopoéticas/patologia , Humanos , Hipoalbuminemia/etiologia , Fígado/fisiopatologia , Pulmão/fisiopatologia , Linfopenia/etiologia , Linfopenia/fisiopatologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/terapia , Traumatismo por Reperfusão/etiologia , Trombocitopenia/etiologia , Trombocitopenia/fisiopatologia , Trombofilia/etiologia
4.
Proc Natl Acad Sci U S A ; 117(38): 23336-23338, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32900927

RESUMO

Colony-stimulating factor 1 receptor (CSF1R) inhibition has been proposed as a method for microglia depletion, with the assumption that it does not affect peripheral immune cells. Here, we show that CSF1R inhibition by PLX5622 indeed affects the myeloid and lymphoid compartments, causes long-term changes in bone marrow-derived macrophages by suppressing interleukin 1ß, CD68, and phagocytosis but not CD208, following exposure to endotoxin, and also reduces the population of resident and interstitial macrophages of peritoneum, lung, and liver but not spleen. Thus, small-molecule CSF1R inhibition is not restricted to microglia, causing strong effects on circulating and tissue macrophages that perdure long after cessation of the treatment. Given that peripheral monocytes repopulate the central nervous system after CSF1R inhibition, these changes have practical implications for relevant experimental data.


Assuntos
Hematopoese/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Microglia/efeitos dos fármacos , Compostos Orgânicos/farmacologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/imunologia , Feminino , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/imunologia , Fagocitose/efeitos dos fármacos , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/imunologia , Especificidade da Espécie
5.
PLoS Comput Biol ; 16(7): e1007620, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32701980

RESUMO

Myelosuppression is one of the most common and severe adverse events associated with anti-cancer therapies and can be a source of drug attrition. Current mathematical modeling methods for assessing cytopenia risk rely on indirect measurements of drug effects and primarily focus on single lineage responses to drugs. However, anti-cancer therapies have diverse mechanisms with varying degrees of effect across hematopoietic lineages. To improve predictive understanding of drug-induced myelosuppression, we developed a quantitative systems pharmacology (QSP) model of hematopoiesis in vitro for quantifying the effects of anti-cancer agents on multiple hematopoietic cell lineages. We calibrated the system parameters of the model to cell kinetics data without treatment and then validated the model by showing that the inferred mechanisms of anti-proliferation and/or cell-killing are consistent with the published mechanisms for three classes of drugs with different mechanisms of action. Using a set of compounds as a reference set, we then analyzed novel compounds to predict their mechanisms and magnitude of myelosuppression. Further, these quantitative mechanisms are valuable for the development of translational in vivo models to predict clinical cytopenia effects.


Assuntos
Antineoplásicos/farmacologia , Doenças Hematológicas/induzido quimicamente , Hematopoese/efeitos dos fármacos , Modelos Biológicos , Células Sanguíneas/efeitos dos fármacos , Células Cultivadas , Citocinas/farmacologia , Humanos , Concentração Inibidora 50 , Análise de Componente Principal , Células-Tronco/efeitos dos fármacos , Biologia de Sistemas
6.
Int J Hematol ; 112(3): 316-330, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32572826

RESUMO

Vitamin K2 in the form of menatetrenone has clinical benefits for osteoporosis and cytopenia. Given the dominant role of mesenchymal-osteolineage cells in the regulation of hematopoiesis, we investigated whether menatetrenone alters the hematopoiesis-supportive capability of human bone marrow mesenchymal stromal/stem cells (BM-MSCs). Menatetrenone up-regulated fibronectin protein expression in BM-MSCs without affecting their proliferation and differentiation capabilities. In addition, menatetrenone treatment of BM-MSCs enhanced generation of the CD34+ cell population in co-cultures through acceleration of the cell cycle. This effect was associated with cell-cell interactions mediated by VLA-4 and fibronectin. This proposal was supported by cytokine array and quantitative real-time PCR analyses, in which there were no significant differences between the expression levels of hematopoiesis-associated soluble factors in naïve and menatetrenone-treated BM-MSCs. Profiling of hematopoietic cells in co-cultures with menatetrenone-treated BM-MSCs demonstrated that they included significantly more CD34+CD38+ hematopoietic progenitor cells and cells skewed toward myeloid and megakaryocytic lineages than those in co-cultures with untreated BM-MSCs. Notably, myelodysplastic syndrome-derived cells were induced to undergo apoptosis when co-cultured with BM-MSCs, and this effect was enhanced by menatetrenone. Overall, our findings indicate that pharmacological treatment with menatetrenone bestows a unique hematopoiesis-supportive capability on BM-MSCs, which may contribute to the clinical improvement of cytopenia.


Assuntos
Células da Medula Óssea/fisiologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Hematopoese/efeitos dos fármacos , Células-Tronco Mesenquimais/fisiologia , Antígenos CD34/metabolismo , Células da Medula Óssea/metabolismo , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/genética , Diferenciação Celular/genética , Proliferação de Células/genética , Células Cultivadas , Técnicas de Cocultura , Fibronectinas/genética , Fibronectinas/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Células-Tronco Mesenquimais/metabolismo , Nicho de Células-Tronco/efeitos dos fármacos , Nicho de Células-Tronco/genética , Vitamina K 2/análogos & derivados
7.
Exp Hematol ; 84: 54-66, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32240658

RESUMO

Exposure to high-dose total body irradiation (TBI) can result in hematopoietic acute radiation syndrome (H-ARS), characterized by leukopenia, anemia, and coagulopathy. Death from H-ARS occurs from hematopoietic insufficiency and opportunistic infections. Following radiation exposure, red blood cells (RBCs) undergo hemolysis from radiation-induced hemoglobin denaturation, causing the release of iron. Free iron can have multiple detrimental biological effects, including suppression of hematopoiesis. We investigated the impact of radiation-induced iron release on the bone marrow following TBI and the potential impact of the ACE inhibitor captopril, which improves survival from H-ARS. C57BL/6J mice were exposed to 7.9 Gy, 60Co irradiation, 0.6 Gy/min (LD70-90/30). RBCs and reticulocytes were significantly reduced within 7 days of TBI, with the RBC nadir at 14-21 days. Iron accumulation in the bone marrow correlated with the time course of RBC hemolysis, with an ∼10-fold increase in bone marrow iron at 14-21 days post-irradiation, primarily within the cytoplasm of macrophages. Iron accumulation in the bone marrow was associated with increased expression of genes for iron binding and transport proteins, including transferrin, transferrin receptor 1, ferroportin, and integrin αMß2. Expression of the gene encoding Nrf2, a transcription factor activated by oxidative stress, also increased at 21 days post-irradiation. Captopril did not alter iron accumulation in the bone marrow or expression of iron storage genes, but did suppress Nrf2 expression. Our study suggests that following TBI, iron is deposited in tissues not normally associated with iron storage, which may be a secondary mechanism of radiation-induced tissue injury.


Assuntos
Síndrome Aguda da Radiação/metabolismo , Medula Óssea/metabolismo , Raios gama/efeitos adversos , Hematopoese/efeitos da radiação , Ferro/metabolismo , Lesões Experimentais por Radiação/metabolismo , Síndrome Aguda da Radiação/genética , Síndrome Aguda da Radiação/patologia , Animais , Medula Óssea/patologia , Captopril/farmacologia , Eritrócitos/metabolismo , Eritrócitos/patologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos da radiação , Hematopoese/efeitos dos fármacos , Hematopoese/genética , Camundongos , Camundongos Transgênicos , Fator 2 Relacionado a NF-E2/biossíntese , Fator 2 Relacionado a NF-E2/genética , Lesões Experimentais por Radiação/genética , Lesões Experimentais por Radiação/patologia
8.
Adv Exp Med Biol ; 1219: 259-293, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32130704

RESUMO

The human body requires a constant delivery of fresh blood cells that are needed to maintain body homeostasis. Hematopoiesis is the process that drives the formation of new blood cells from a single stem cell. This is a complex, orchestrated and tightly regulated process that occurs within the bone marrow. When such process is faulty or deregulated, leukemia arises, develops and thrives by subverting normal hematopoiesis and availing the supplies of this rich milieu.In this book chapter we will describe and characterize the bone marrow microenvironment and its key importance for leukemia expansion. The several components of the bone marrow niche, their interaction with the leukemic cells and the cellular pathways activated within the malignant cells will be emphasized. Finally, novel therapeutic strategies to target this sibling interaction will also be discussed.


Assuntos
Medula Óssea/metabolismo , Progressão da Doença , Leucemia/patologia , Microambiente Tumoral , Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Hematopoese/efeitos dos fármacos , Humanos , Leucemia/tratamento farmacológico , Nicho de Células-Tronco/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
9.
Rev Mal Respir ; 37(3): 193-196, 2020 Mar.
Artigo em Francês | MEDLINE | ID: mdl-32146057

RESUMO

In addition to its role in erythropoiesis, erythropoietin (Epo) plays a role in tissue protection, which includes cardioprotective, nephroprotective and neuroprotective effects. The presence of Epo and its receptor (Epo-R) in pulmonary tissue also suggests a cytoprotective effect of Epo in the lung. Our project aims to document this role in a murine model under-expressing Epo. The obtained results will lead to a better understanding of the cytoprotective effects of Epo and will also give an appreciation of its beneficial effects in cases of lung injury.


Assuntos
Lesão Pulmonar Aguda/patologia , Citoproteção , Eritropoetina/farmacologia , Eritropoetina/fisiologia , Rim , Animais , Citoproteção/efeitos dos fármacos , Citoproteção/genética , Modelos Animais de Doenças , Eritropoetina/genética , Hematopoese/efeitos dos fármacos , Hematopoese/genética , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiologia , Camundongos
10.
Protein J ; 39(2): 160-173, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32172395

RESUMO

Previously we reported that site-specific modification of the human granulocyte-macrophage colony-stimulating factor (GM-CSF) A3C analog with polyethylene glycol (PEG) dramatically improved the pharmacokinetic properties of the protein in rats. However, we could not evaluate the hematological properties of the PEG-A3C protein in rats because human GM-CSF is inactive in rodents. To study the biological effects of PEGylated GM-CSF analogs in rodents we created a homologous site-specific PEGylated murine (mu) GM-CSF (T3C) protein. muGM-CSF and the T3C protein were expressed in Escherichia coli and purified by column chromatography. The purified T3C protein was covalently modified with a linear 20 kDa- or a branched 40 kDa-maleimide-PEG, and the monoPEGylated proteins purified by column chromatography. muGM-CSF, T3C and the two PEG-T3C proteins had comparable in vitro biological activities, as measured by stimulation of proliferation of the murine FDC-P1 cell line. The PEG-T3C proteins had 10- to 25-fold longer circulating half-lives than muGM-CSF and stimulated greater and longer lasting increases in neutrophils and white blood cells than muGM-CSF following a single intravenous or subcutaneous administration to rats. Treatment of rats made neutropenic with cyclophosphamide with the PEG-T3C proteins shortened the time for recovery of neutrophils to normal levels from 9 or 10 days to 5 or 6 days, whereas muGM-CSF showed no benefit versus vehicle solution. Acceleration of neutrophil recovery in cyclophosphamide-treated rats required a minimum of three PEG-T3C treatments over five days. The PEG-T3C proteins should prove useful for evaluating the potential therapeutic benefits of GM-CSF and long-acting GM-CSF proteins in rodent disease models.


Assuntos
Fator Estimulador de Colônias de Granulócitos/farmacocinética , Hematopoese/efeitos dos fármacos , Polietilenoglicóis/farmacocinética , Animais , Linhagem Celular , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Meia-Vida , Masculino , Neutropenia/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinética
11.
Ann N Y Acad Sci ; 1466(1): 83-92, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32083314

RESUMO

Cyclic neutropenia (CyN) is a hematologic disorder in which peripheral blood absolute neutrophil counts (ANCs) show cycles of approximately 21-day intervals. The majority of CyN patients harbor ELANE mutations, but the mechanism of ANC cycling is unclear. We performed analysis of bone marrow (BM) subpopulations in CyN patients at the peak and the nadir of the ANC cycle and detected high proportions of BM hematopoietic stem cells (HSCs) and hematopoietic stem and progenitor cells (HSPCs) at the nadir of the ANC cycle, as compared with the peak. BM HSPCs produced fewer granulocyte colony-forming unit colonies at the ANC peak. To investigate the mechanism of cycling, we found that mRNA expression levels of ELANE and unfolded protein response (UPR)-related genes (ATF6, BiP (HSPA5), CHOP (DDIT3), and PERK (EIF2AK3)) were elevated, but antiapoptotic genes (Bcl-2 (BCL2) and bcl-xL (BCL2L1)) were reduced in CD34+ cells tested at the ANC nadir. Moreover, HSPCs revealed increased levels of reactive oxygen species and gH2AX at the ANC nadir. We suggest that in CyN patients, some HSPCs escape the UPR-induced endoplasmic reticulum (ER) stress and proliferate in response to granulocyte colony-stimulating factor (G-CSF) to a certain threshold at which UPR again affects the majority of HSPCs. There is a cyclic balance between ER stress-induced apoptosis of HSPCs and compensatory G-CSF-stimulated HSPC proliferation followed by granulocytic differentiation.


Assuntos
Estresse do Retículo Endoplasmático/fisiologia , Elastase de Leucócito/genética , Neutropenia/etiologia , Resposta a Proteínas não Dobradas/fisiologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Medula Óssea/patologia , Células Cultivadas , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , Seguimentos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Hematopoese/efeitos dos fármacos , Hematopoese/genética , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/patologia , Células-Tronco Hematopoéticas/fisiologia , Humanos , Elastase de Leucócito/fisiologia , Mutação , Neutropenia/tratamento farmacológico , Neutropenia/metabolismo , Neutropenia/patologia , Espécies Reativas de Oxigênio/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Resposta a Proteínas não Dobradas/genética
12.
Immunopharmacol Immunotoxicol ; 42(2): 110-118, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32066303

RESUMO

Objective: This paper aims to investigate the dynamic changes of the T-cell receptor (TCR) ß complementarity-determining region 3 (CDR3) repertoire during cyclophosphamide or Cytoxan (CTX) damage or inhibition of bone marrow hematopoiesis caused by a reduction of peripheral blood white blood cells (WBCs) in BALB/c mice.Methods: We analyze TCR CDR3 repertoire of BALB/c mice including (1) NS control group (2) CTX damage group (3) CTX damage + GM-CSF recovery group (4) CTX damage + auto-recovery group.Results: The number of WBCs in the CTX group is significantly lower than that in the NS group and after GM-CSF injection, the GM-CSF group is higher than that in the NS group. The diversity of the CTX damage group is the highest and there is a significant difference in high-frequency clonal proliferation between the CTX damage group and CTX damage + GM-CSF recovery group compared with the NS control group. In addition, the numbers of unique productive CDR3 overlapping numbers in the four experimental groups are similar.Conclusions: These data reveal that CTX significantly reduced the number of WBCs and ratio of high-frequency TCR CDR3 sequences, and indirectly increased the diversity of the TCR CDR3 repertoire. GM-CSF quickly restored the number of WBCs, and partially restored changes in the TCR CDR3 repertoire induced by CTX. Results from monitoring the dynamic changes of the TCR CDR3 repertoire can be used to assess the effects of CTX and GM-CSF on the function of peripheral blood T cells and to explore the possible underlying mechanisms.


Assuntos
Medula Óssea/efeitos dos fármacos , Regiões Determinantes de Complementaridade/metabolismo , Ciclofosfamida/toxicidade , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Hematopoese/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Animais , Medula Óssea/patologia , Relação Dose-Resposta a Droga , Feminino , Contagem de Leucócitos , Leucócitos/patologia , Camundongos Endogâmicos BALB C
13.
PLoS One ; 15(2): e0227940, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32027657

RESUMO

Tumor necrosis factor alpha (TNF) is capable of inducing regression of solid tumors. However, TNF released in response to Toll-like receptor 4 (TLR4) activation by bacterial lipopolysaccharide (LPS) is the key mediator of cytokine storm and septic shock that can cause severe tissue damage limiting anticancer applications of this cytokine. In our previous studies, we demonstrated that activation of another Toll-like receptor, TLR5, could protect from tissue damage caused by a variety of stresses including radiation, chemotherapy, Fas-activating antibody and ischemia-reperfusion. In this study, we tested whether entolimod could counteract TNF-induced toxicity in mouse models. We found that entolimod pretreatment effectively protects livers and lungs from LPS- and TNF-induced toxicity and prevents mortality caused by combining either of these agents with the sensitizer, D-galactosamine. While LPS and TNF induced significant activation of apoptotic caspase 3/7, lipid tissue peroxidation and serum ALT accumulation in mice without entolimod treatment, these indicators of toxicity were reduced by entolimod pretreatment to the levels of untreated control mice. Entolimod was effective when injected 0.5-48 hours prior to, but not when injected simultaneously or after LPS or TNF. Using chimeric mice with hematopoiesis differing in its TLR5 status from the rest of tissues, we showed that this protective activity was dependent on TLR5 expression by non-hematopoietic cells. Gene expression analysis identified multiple genes upregulated by entolimod in the liver and cultured hepatocytes as possible mediators of its protective activity. Entolimod did not interfere with the antitumor activity of TNF in mouse hepatocellular and colorectal tumor models. These results support further development of TLR5 agonists to increase tissue resistance to cytotoxic cytokines, reduce the risk of septic shock and enable safe systemic application of TNF as an anticancer therapy.


Assuntos
Antineoplásicos/farmacologia , Peptídeos/farmacologia , Receptor 5 Toll-Like/agonistas , Fator de Necrose Tumoral alfa/toxicidade , Animais , Linhagem Celular Tumoral , Células Cultivadas , Galactosamina , Hematopoese/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Lipopolissacarídeos/toxicidade , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Modelos Biológicos , NF-kappa B/metabolismo , Substâncias Protetoras/farmacologia , Análise de Sobrevida , Receptor 5 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/sangue , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
14.
Immunology ; 159(4): 441-449, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31957000

RESUMO

Signaling by Kit has been extensively studied in hematopoietic cells and is essential for the survival, proliferation and maintenance of hematopoietic stem and progenitor cells. In addition to the activation of intrinsic signaling pathways, Kit has been shown to interact with lineage-restricted type I cytokine receptors and produce cross signals, e.g. erythropoietin receptor, interleukin-7 receptor (IL-7R), IL-3R. Based on the earlier studies, we hypothesize that Kit activate other type I cytokine receptors in a cell-specific manner and execute cell-specific function. To investigate other Kit-activated receptors, we tested Kit and IL-4R cross-receptor activation in murine bone-marrow-derived mast cells, which express both Kit and IL-4R at the surface level. Kit upon activation by Kit ligand (KL), activated IL-4Rα, γC , and signal transducer and activator of transcription 6 independent of its cognate ligand IL-4. Though KL and IL-4 are individually mitogenic, combinations of KL and IL-4 synergistically promoted mast cell proliferation. Furthermore, inhibition of lipid raft formation by methyl-ß-cyclodextrin resulted in loss of synergistic proliferation. Together the data suggest IL-4R as a novel Kit-activated receptor. Such cross-receptor activations are likely to be a universal mechanism of Kit signaling in hematopoiesis.


Assuntos
Interleucina-4/farmacologia , Mastócitos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-kit/genética , Receptores de Interleucina-4/genética , Fator de Transcrição STAT6/genética , Fator de Células-Tronco/farmacologia , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Proliferação de Células/efeitos dos fármacos , Regulação da Expressão Gênica , Hematopoese/efeitos dos fármacos , Hematopoese/genética , Hematopoese/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Mastócitos/citologia , Mastócitos/imunologia , Microdomínios da Membrana/efeitos dos fármacos , Microdomínios da Membrana/imunologia , Microdomínios da Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-kit/imunologia , Receptores da Eritropoetina/genética , Receptores da Eritropoetina/imunologia , Receptores de Interleucina-3/genética , Receptores de Interleucina-3/imunologia , Receptores de Interleucina-4/imunologia , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/imunologia , Fator de Transcrição STAT6/imunologia , Transdução de Sinais , Fator de Células-Tronco/genética , Fator de Células-Tronco/imunologia , beta-Ciclodextrinas/farmacologia
15.
Molecules ; 25(3)2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31991819

RESUMO

Indigenous populations use plants as an important healthcare resource or remedy for different diseases. Here, isolated extracts from Justicia (family Acanthanceae) plant leaves used in Africa as remedy for anemia are characterized by different methods to assess composition and potential nutritional or therapeutic value. Extracts from Justicia leaves were obtained by aqueous extraction, with further isolation by centrifuging and high-performance liquid chromatography. Extracts and isolated compounds were characterized by ultraviolet-visible (UV-Vis) spectroscopy and inductively coupled plasma mass spectrometry (ICP-MS). Hemoglobin activity was assessed using different hemoglobin assays (Cayman Chemical, and Sigma-Aldrich), as well as ELISA. In addition, the safety of the isolated samples was assessed in vitro and in vivo in mice. ICP-MS study results revealed many essential metabolites found in blood plasma. The UV-Vis spectroscopy results highlighted the presence of hemoglobin, with assays showing levels over 4 times higher than that of similar mass of lyophilized human hemoglobin. Meanwhile, in vivo studies showed faster recovery from anemia in mice administered with the isolated extracts compared to untreated mice. Moreover, in vitro and in vivo studies highlighted safety of the extracts. This study reveals the presence of high levels of elements essential for blood health in the isolated extracts from Justicia plant leaves. The findings inspire further research with the potential applications in food fortification, and as remedy for blood disorders like anemia, which disproportionally affects cancer patients, pregnant women, and populations in low- and middle-income countries.


Assuntos
Hematopoese/efeitos dos fármacos , Adhatoda/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Anemia/sangue , Anemia/tratamento farmacológico , Anemia/etiologia , Animais , Linhagem Celular , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Índices de Eritrócitos/efeitos dos fármacos , Feminino , Hemoglobinas , Humanos , Espectrometria de Massas , Camundongos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação
16.
Carbohydr Polym ; 230: 115698, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31887892

RESUMO

Two fucosylated chondroitin sulfates FCShp and FCSht were isolated from the sea cucumber Holothuria polii and Holothuria tubulosa, respectively. The NMR spectroscopy and HILIC-FTMS methods were applied for their detailed structural characterization. Chemical analysis indicated that the two FCSs all contained a chondroitin sulfate backbone chondroitin sulfate-like core and fucosyl branches of α-L-Fuc2,4S, α-L-Fuc4S or α-L-Fuc3,4S linked to O-3 of glucuronic acid residues. The main branches of FCShp and FCSht were monofucose, and the small amounts of di-, tri- and tetrafucose with α-1,3-linkage type were also detected. Finally, we investigated the immunomodulatory function of FCShp and FCSht in cyclophosphamide (CTX)-induced immunosuppressed mouse models. The results showed that FCShp and FCSht had beneficial effects on hematopoietic function recovery in CTX-induced bone marrow suppression mice. Notably, the α-L-Fuc2,4S was more important to the activity than α-L-Fuc3,4S. These results provided basis for developing the drugs to reduce side effects of chemotherapy.


Assuntos
Sulfatos de Condroitina , Hematopoese/efeitos dos fármacos , Holothuria/metabolismo , Imunossupressores/farmacologia , Animais , Sulfatos de Condroitina/química , Sulfatos de Condroitina/farmacologia , Imunossupressores/química , Camundongos , Camundongos Endogâmicos BALB C
17.
Eur J Haematol ; 104(2): 125-137, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31758597

RESUMO

INTRODUCTION: Targeting the cell cycle machinery represents a rational therapeutic approach in myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (sAML). Despite substantial response rates, clinical use of the PLK inhibitor volasertib has been hampered by elevated side effects such as neutropenia and infections. OBJECTIVES: The primary objective was to analyse whether a reduced dose of volasertib was able to limit toxic effects on the healthy haematopoiesis while retaining its therapeutic effect. METHODS: Bone marrow mononuclear cells (BMMNCs) of patients with MDS/sAML (n = 73) and healthy controls (n = 28) were treated with volasertib (1 µM to 1 nM) or vehicle control. Short-term viability analysis was performed by flow cytometry after 72 hours. For long-term viability analysis, colony-forming capacity was assessed after 14 days. Protein expression of RIPK3 and MCL-1 was quantified via flow cytometry. RESULTS: Reduced dose levels of volasertib retained high cell death-inducing efficacy in primary human stem and progenitor cells of MDS/sAML patients without affecting healthy haematopoiesis in vitro. Interestingly, volasertib reduced colony-forming capacity and cell survival independent of clinical stage or mutational status. CONCLUSIONS: Volasertib offers a promising therapeutic approach in patients with adverse prognostic profile. RIPK3 and MCL-1 might be potential biomarkers for sensitivity to volasertib treatment.


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Hematopoese/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pteridinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Proteínas de Ciclo Celular/metabolismo , Feminino , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/biossíntese , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Pteridinas/efeitos adversos , Proteína Serina-Treonina Quinases de Interação com Receptores/biossíntese
18.
Hum Exp Toxicol ; 39(5): 577-595, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31884827

RESUMO

Benzene is a known hematotoxic and leukemogenic agent with hematopoietic stem cells (HSCs) niche being the potential target. Occupational and environmental exposure to benzene has been linked to the incidences of hematological disorders and malignancies. Previous studies have shown that benzene may act via multiple modes of action targeting HSCs niche, which include induction of chromosomal and micro RNA aberrations, leading to genetic and epigenetic modification of stem cells and probable carcinogenesis. However, understanding the mechanism linking benzene to the HSCs niche dysregulation is challenging due to complexity of its microenvironment. The niche is known to comprise of cell populations accounted for HSCs and their committed progenitors of lymphoid, erythroid, and myeloid lineages. Thus, it is fundamental to address novel approaches via lineage-directed strategy to elucidate precise mechanism involved in benzene-induced toxicity targeting HSCs and progenitors of different lineages. Here, we review the key genetic and epigenetic factors that mediate hematotoxicological effects by benzene and its metabolites in targeting HSCs niche. Overall, the use of combined genetic, epigenetic, and lineage-directed strategies targeting the HSCs niche is fundamental to uncover the key mechanisms in benzene-induced hematological disorders and malignancies.


Assuntos
Benzeno/toxicidade , Carcinógenos/toxicidade , Células-Tronco Hematopoéticas/efeitos dos fármacos , Neoplasias/induzido quimicamente , Animais , Benzeno/farmacocinética , Carcinógenos/farmacocinética , Epigênese Genética , Hematopoese/efeitos dos fármacos , Humanos , Neoplasias/genética , Nicho de Células-Tronco/efeitos dos fármacos
20.
Chin J Integr Med ; 25(12): 902-910, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31802424

RESUMO

OBJECTIVE: To investigate the potential efficacy of panaxadiol saponins component (PDS-C) in the treatment of aplastic anemia (AA) model mice. METHODS: Totally 70 mice were divided into 7 groups as follows: normal, model, low-, medium-, high-dose PDS-C (20, 40, 80 mg/kg, namely L-, M-, H-PDS-C), cyclosporine (40 mg/kg), and andriol (25 mg/kg) groups, respectively. An immune-mediated AA mouse model was established in BALB/c mice by exposing to 5.0 Gy total body irradiation at 1.0 Gy/min, and injecting with lymphocytes from DBA mice. On day 4 after establishment of AA model, all drugs were intragastrically administered daily for 15 days, respectively, while the mice in the normal and model groups were administered with saline solution. After treatment, the peripheral blood counts, bone marrow pathological examination, colony forming assay of bone marrow culture, T lymphocyte subpopulation analysis, as well as T-bet, GATA-3 and FoxP3 proteins were detected by flow cytometry and Western blot. RESULTS: The peripheral blood of white blood cell (WBC), platelet, neutrophil counts and hemoglobin (Hb) concentration were significantly decreased in the model group compared with the normal group (all P<0.01). In response to 3 dose PDS-C treatment, the WBC, platelet, neutrophil counts were significantly increased at a dose-dependent manner compared with the model group (all P<0.01). The myelosuppression status of AA was significantly reduced in M-, H-PDS-C groups, and hematopoietic cell quantity of bone marrow was more abundant than the model group. The colony numbers of myeloid, erythroid and megakaryocytic progenitor cells in the model group were less than those of the normal mice in bone marrow culture, while, PDS-C therapy enhanced proliferation of hematopoietic progenitor cells by significantly increasing colony numbers (all P<0.01). Furthermore, PDS-C therapy increased peripheral blood CD3+ and CD3+CD4+ cells and reduced CD3+CD8+ cells (P<0.05 or P<0.01). Meanwhile, PDS-C treatment at medium- and high doses groups also increased CD4+CD25+FoxP3+ cells, downregulated T-bet protein expression, and upregulated GATA-3 and FoxP3 protein expressions in spleen cells (P<0.05). CONCLUSION: PDS-C possesses dual activities, promoting proliferation hematopoietic progenitor cells and modulating T lymphocyte immune functions in the treatment of AA model mice.


Assuntos
Anemia Aplástica/tratamento farmacológico , Ginsenosídeos/farmacologia , Hematopoese/efeitos dos fármacos , Panax , Saponinas/farmacologia , Linfócitos T/efeitos dos fármacos , Anemia Aplástica/sangue , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos BALB C
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