Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Biomolecules ; 11(1)2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33477816

RESUMO

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by hematopoietic stem-cell-derived clonal proliferation, leading to bone marrow (BM) fibrosis. Hematopoiesis alterations are closely associated with modifications of the BM microenvironment, characterized by defective interactions between vascular and endosteal niches. As such, neoangiogenesis, megakaryocytes hyperplasia and extensive bone marrow fibrosis, followed by osteosclerosis and bone damage, are the most relevant consequences of PMF. Moreover, bone tissue deposition, together with progressive fibrosis, represents crucial mechanisms of disabilities in patients. Although the underlying mechanisms of bone damage observed in PMF are still unclear, the involvement of cytokines, growth factors and bone marrow microenvironment resident cells have been linked to disease progression. Herein, we focused on the role of megakaryocytes and their alterations, associated with cytokines and chemokines release, in modulating functions of most of the bone marrow cell populations and in creating a complex network where impaired signaling strongly contributes to progression and disabilities.


Assuntos
Progressão da Doença , Osteosclerose/parasitologia , Mielofibrose Primária/patologia , Animais , Medula Óssea , Humanos , Monócitos/patologia , Transdução de Sinais
2.
J Clin Med ; 9(8)2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32707883

RESUMO

Polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are rare hematological conditions known as myeloproliferative neoplasms (MPNs). They are characterized for being BCR-ABL negative malignancies and affected patients often present with symptoms which can significantly impact their quality of life. MPNs are characterized by a clonal proliferation of an abnormal hematopoietic stem/progenitor cell. In MPNs; cells of all myeloid lineages; including those involved in the immune and inflammatory response; may belong to the malignant clone thus leading to an altered immune response and an overexpression of cytokines and inflammatory receptors; further worsening chronic inflammation. Many of these cytokines; in particular, IL-1ß and IL-18; are released in active form by activating the inflammasome complexes which in turn mediate the inflammatory process. Despite this; little is known about the functional effects of stem cell-driven inflammasome signaling in MPN pathogenesis. In this review we focused on the role of inflammatory pathway and inflammasome in MPN diseases. A better understanding of the inflammatory-state-driving MPNs and of the role of the inflammasome may provide new insights on possible therapeutic strategies.

3.
Aging (Albany NY) ; 12(10): 9745-9760, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32401230

RESUMO

Uveal melanoma (UM) is the most common primary intraocular tumour in adults. The most accurate prognostic factor of UM is classification by gene expression profiling. Currently, the role of epigenetics is much less defined compared to genetic mechanisms. We recently showed a strong prognostic role of the expression levels of histone variant macroH2A1 in UM patients. Here, we assessed the mechanistic effects of macroH2A1 on UM progression.UM cell lines were stably knocked down (KD) for macroH2A1, and proliferation and colony formation capacity were evaluated. Mitochondrial function was assayed through qPCR and HPLC analyses. Correlation between mitochondrial gene expression and cancer aggressiveness was studied using a bioinformatics approach.MacroH2A1 loss significantly attenuated UM cells proliferation and aggressiveness. Furthermore, genes involved in oxidative phosphorylation displayed a decreased expression in KD cells. Consistently, macroH2A1 loss resulted also in a significant decrease of mitochondrial transcription factor A (TFAM) expression, suggesting impaired mitochondrial replication. Bioinformatics analyses uncovered that the expression of genes involved in mitochondrial metabolism correlates with macroH2A1 and with cancer aggressiveness in UM patients. Altogether, our results suggest that macroH2A1 controls UM cells progression and it may represent a molecular target to develop new pharmacological strategies for UM treatment.


Assuntos
Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Histonas/deficiência , Melanócitos/metabolismo , Melanoma/genética , Neoplasias Uveais/genética , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Humanos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Células-Tronco Neoplásicas/metabolismo , Fatores de Transcrição/metabolismo
4.
Int J Mol Sci ; 21(10)2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32443911

RESUMO

The COVID-19 global pandemic is caused by SARS-CoV-2, and represents an urgent medical and social issue. Unfortunately, there is still not a single proven effective drug available, and therefore, current therapeutic guidelines recommend supportive care including oxygen administration and treatment with antibiotics. Recently, patients have been also treated with off-label therapies which comprise antiretrovirals, anti-inflammatory compounds, antiparasitic agents and plasma from convalescent patients, all with controversial results. The ubiquitin-proteasome system (UPS) is important for the maintenance of cellular homeostasis, and plays a pivotal role in viral replication processes. In this review, we discuss several aspects of the UPS and the effects of its inhibition with particular regard to the life cycle of the coronaviruses (CoVs). In fact, proteasome inhibition by various chemical compounds, such as MG132, epoxomycin and bortezomib, may reduce the virus entry into the eucariotic cell, the synthesis of RNA, and the subsequent protein expression necessary for CoVs. Importantly, since UPS inhibitors reduce the cytokine storm associated with various inflammatory conditions, it is reasonable to assume that they might be repurposed for SARS-CoV-2, thus providing an additional tool to counteract both virus replication as well as its most deleterious consequences triggered by abnormal immunological response.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteassoma/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/isolamento & purificação , COVID-19 , Infecções por Coronavirus/epidemiologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , Pandemias , Pneumonia Viral/epidemiologia , Inibidores de Proteassoma/farmacologia , SARS-CoV-2
5.
J Oncol ; 2020: 2314693, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32148493

RESUMO

Gliomas are the most common primary tumors of the central nervous system (CNS) in the adult. Previous data showed that estrogen affects cancer cells, but its effect is cell-type-dependent and controversial. The present study aimed to analyze the effects of estradiol (E2, 5 nM) in human glioblastoma multiforme U87-MG cells and how it may impact on cell proliferation and mitochondrial fitness. We monitored cell proliferation by xCELLigence technology and mitochondrial fitness by assessing the expression of genes involved in mitochondrial biogenesis (PGC1α, SIRT1, and TFAM), oxidative phosphorylation (ND4, Cytb, COX-II, COX IV, NDUFA6, and ATP synthase), and dynamics (OPA1, MNF2, MNF1, and FIS1). Finally, we evaluated Nrf2 nuclear translocation by immunocytochemical analysis. Our results showed that E2 resulted in a significant increase in cell proliferation, with a significant increase in the expression of genes involved in various mechanisms of mitochondrial fitness. Finally, E2 treatment resulted in a significant increase of Nrf2 nuclear translocation with a significant increase in the expression of one of its target genes (i.e., heme oxygenase-1). Our results suggest that E2 promotes proliferation in glioblastoma cells and regulate the expression of genes involved in mitochondrial fitness and chemoresistance pathway.

6.
Mol Neurobiol ; 57(5): 2436-2446, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32108290

RESUMO

In human glioma tumours, heme oxygenase-1 (HO-1) is overexpressed when compared with normal brain tissues and during oligodendroglioma progression. However, the molecular mechanisms mediated by HO-1 to promote glioblastoma remain unknown. We therefore aimed at investigating the effect of HO-1 expression and its selective enzymatic inhibition in two different cell lines (i.e. A172 and U87-MG). HO-1 was induced by hemin treatment (10 µM), and VP13/47 (100 µM) was used as a specific non-competitive inhibitor of HO-1 activity. Cell proliferation was measured by cell index measurement (xCelligence technology) and clonogenic assay, whereas cell migration was assessed by wound healing assay. Carbon monoxide-releasing molecules (CORMs) (i.e. CORM-3 and CORM-A1) were also used in a separate set of experiments to confirm the effect of HO-1 by-product in glioblastoma progression further. Our results were further validated using GSE4412 microarray dataset analysis and comparing biopsies overexpressing HO-1 with the rest of the cases. Our results showed that hemin was able to induce both HO-1 gene and protein expression in a cell-dependent manner being A172 more responsive to pharmacological upregulation of HO-1. Hemin, but not CORMs treatment, resulted in a significant increase of cell proliferation following 24 h of treatment as measured by increased cell index and colony formation capacity and such effect was abolished by VP13/47. Interestingly, both hemin and CORMs showed a significant effect on the wound healing assay also exhibiting cell specificity. Finally, our dataset analysis showed a positive correlation of HO-1 gene expression with ITGBI and ITGBII which are membrane receptors involved in cell adhesion, embryogenesis, tissue repair, immune response and metastatic diffusion of tumour cells. In conclusion, our data suggest that HO-1 and its by-product CO exhibit a cell-specific effect on various aspects of disease progression and are associated with a complex series of molecular mechanisms driving cell proliferation, survival and metastasis.


Assuntos
Neoplasias Encefálicas/patologia , Monóxido de Carbono/fisiologia , Glioblastoma/patologia , Heme Oxigenase-1/fisiologia , Proteínas de Neoplasias/fisiologia , Boranos/farmacologia , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/genética , Carbonatos/farmacologia , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Quimiotaxia/efeitos dos fármacos , Conjuntos de Dados como Assunto , Progressão da Doença , Indução Enzimática/efeitos dos fármacos , Perfilação da Expressão Gênica , Ontologia Genética , Glioblastoma/enzimologia , Glioblastoma/genética , Heme Oxigenase-1/biossíntese , Heme Oxigenase-1/genética , Hemina/farmacologia , Humanos , Hidrocarbonetos Bromados/farmacologia , Imidazóis/farmacologia , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Compostos Organometálicos/farmacologia , Ensaio Tumoral de Célula-Tronco
7.
Cancers (Basel) ; 11(4)2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30974805

RESUMO

Epidemiological studies suggest that chronic alcohol consumption is a lifestyle risk factor strongly associated with colorectal cancer development and progression. The aim of the present study was to examine the effect of ethanol (EtOH) on survival and progression of three different colon cancer cell lines (HCT116, HT29, and Caco-2). Our data showed that EtOH induces oxidative and endoplasmic reticulum (ER) stress, as demonstrated by reactive oxygen species (ROS) and ER stress markers Grp78, ATF6, PERK and, CHOP increase. Moreover, EtOH triggers an autophagic response which is accompanied by the upregulation of beclin, LC3-II, ATG7, and p62 proteins. The addition of the antioxidant N-acetylcysteine significantly prevents autophagy, suggesting that autophagy is triggered by oxidative stress as a prosurvival response. EtOH treatment also upregulates the antioxidant enzymes SOD, catalase, and heme oxygenase (HO-1) and promotes the nuclear translocation of both Nrf2 and HO-1. Interestingly, EtOH also upregulates the levels of matrix metalloproteases (MMP2 and MMP9) and VEGF. Nrf2 silencing or preventing HO-1 nuclear translocation by the protease inhibitor E64d abrogates the EtOH-induced increase in the antioxidant enzyme levels as well as the migration markers. Taken together, our results suggest that EtOH mediates both the activation of Nrf2 and HO-1 to sustain colon cancer cell survival, thus leading to the acquisition of a more aggressive phenotype.

8.
Blood Transfus ; 17(3): 196-199, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30865583

RESUMO

BACKGROUND: Iron deficiency is the most common nutritional deficiency in advanced cancer patients and causes anaemia. Iron deficiency anaemia treatment (i.e. intravenous or oral iron administration) has been demonstrated to be effective but is often associated with adverse reactions. Micronised microencapsulated ferric pyrophosphate (MMFP) is a recently developed formulation characterised by a higher intestinal bioavailability due to the small particle size distribution at nanometer level. The aim of this study was to evaluate the efficacy of an oral administration of 30 mg of MMFP associated with 80 mg of ascorbic acid in advanced cancer patients with hyposideraemia. MATERIALS AND METHODS: This was an observational prospective cohort study (10 months) conducted on 42 adult patients with advanced cancer and serum iron levels lower than 60 µg/dL. All patients received one capsule/day for 30 days of a supplement containing 30 mg of MMFP and 80 mg of ascorbic acid. At enrolment (T0) and at 30 days (T1) patients were subjected to blood sampling for evaluation of serum iron, ferritinaemia and blood count. In addition, any undesirable effects reported by patients were evaluated. RESULTS: MMFP treatment increased sideraemia from 36.1±8.37 µg/dL to 73.22±28.60 µg/dL, haemoglobin from 10.43±1.09 g/dL to 11.52±1.90 g/dL, and ferritinaemia from 42.10±16.90 ng/mL to 123.33±55.79 ng/mL. No adverse effects were noted from the use of MMFP supplementation. DISCUSSION: The supplementation of 30 mg/d of MMFP in combination with 80 mg/d of ascorbic acid in advanced cancer patients with hyposideraemia led to a significant increase in sideraemia and ferritinaemia. Moreover, in some of the patients whose serum iron level did not increase, an increase in haemoglobin was observed.


Assuntos
Anemia Ferropriva , Difosfatos/administração & dosagem , Ferro/administração & dosagem , Neoplasias , Administração Intravenosa , Administração Oral , Idoso , Anemia Ferropriva/sangue , Anemia Ferropriva/tratamento farmacológico , Feminino , Humanos , Ferro/sangue , Ferro/deficiência , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Projetos Piloto , Estudos Prospectivos
9.
Int J Mol Sci ; 20(3)2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30717203

RESUMO

Ozone therapy has been widely used in everyday clinical practice over the last few years, leading to significant clinical results in the treatment of herniated discs and pain management. Nevertheless, further studies have demonstrated its potential efficacy and safety under other clinical and experimental conditions. However, some of these studies showed controversial results regarding the safety and efficacy of ozone therapy, thus mining its potential use in an everyday clinical practice. To this regard, it should be considered that extensive literature review reported the use of ozone in a significant different dose range and with different delivery systems. The aim of the present review is to describe the various pharmacological effects of ozone in different organs and clinical conditions and to provide possible biochemical and molecular insights for ozone biological properties, thus providing a possible explanation for various controversial clinical outcomes described in the scientific literature.


Assuntos
Doenças Cardiovasculares/terapia , Degeneração do Disco Intervertebral/terapia , Deslocamento do Disco Intervertebral/terapia , Ozônio/administração & dosagem , Dor/prevenção & controle , Substâncias Protetoras/administração & dosagem , Dermatopatias/terapia , Doença Aguda , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/patologia , Quimiotaxia/efeitos dos fármacos , Quimiotaxia/imunologia , Doença Crônica , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Imunidade Inata/efeitos dos fármacos , Disco Intervertebral/efeitos dos fármacos , Disco Intervertebral/imunologia , Disco Intervertebral/patologia , Degeneração do Disco Intervertebral/genética , Degeneração do Disco Intervertebral/imunologia , Degeneração do Disco Intervertebral/patologia , Deslocamento do Disco Intervertebral/genética , Deslocamento do Disco Intervertebral/imunologia , Deslocamento do Disco Intervertebral/patologia , Estresse Oxidativo , Ozônio/efeitos adversos , Dor/genética , Dor/imunologia , Dor/patologia , Manejo da Dor/métodos , Substâncias Protetoras/efeitos adversos , Dermatopatias/genética , Dermatopatias/imunologia , Dermatopatias/patologia
10.
Front Biosci (Landmark Ed) ; 24: 564-575, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30468674

RESUMO

Modafinil (Mo) is increasingly being used as an enhancement drug rather than for its therapeutic effects. The effects of this drug have been examined in attention deficit disorders, depression, mental fatigue, and in enhancing concentration. The drug possesses wakefulness-promoting properties which are mediated through the interaction of orexinergic system with the activated sympathetic nervous system. Mo exerts a synergistic effect on the orexin system, controls energy expenditure and strengthens the ability of the individual to exercise. Some view Mo as a drug that enhances sports performance, since it induces a prolonged wakefulness and decreasing the sense of fatigue. These characteristics being similar to conventional stimulants have allowed Mo to emerge as a novel stimulant requiring medico-legal considerations. However, more studies are needed to better understand the mid and long-term effects of the drug on user/abuser.


Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Modafinila/farmacologia , Orexinas/metabolismo , Vigília/efeitos dos fármacos , Animais , Atenção/efeitos dos fármacos , Atenção/fisiologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiologia , Cognição/efeitos dos fármacos , Cognição/fisiologia , Humanos , Modafinila/metabolismo , Modafinila/farmacocinética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Vigília/fisiologia , Promotores da Vigília/metabolismo , Promotores da Vigília/farmacocinética , Promotores da Vigília/farmacologia
11.
J Clin Med ; 7(9)2018 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-30213091

RESUMO

The term "pain threshold" refers to the measurement of the intensity of a physical stimulus that evokes pain. To estimate the pain threshold, a mechanical or electrical stimulus with increasing intensity is usually applied until the subject under evaluation refers to a pain sensation. This study aims to evaluate the autoalgometric pain threshold as a perfect technique to determine the effects of stimulation rate in relation to both gender and the site of stimulation. In this experimental model, pressure algometry was applied: the subject under evaluation pushed a finger against a small round metal tip, producing and at the same time controlling the intensity of the noxious stimulus. Through autoalgometry, the stimulus intensity was recorded over time, measuring the force change rate applied and studying the subject's behavior on approaching pain. This test was performed with 50 healthy volunteers on two days, applying a fast or slow rate of stimulation. The results described demonstrate that there is a positive correlation between the pressure increase rate and the pressure threshold evaluation. In light of these findings, autoalgometry can be proposed as an objective measure of pressure pain threshold for clinical and research use.

12.
Oncotarget ; 8(53): 91099-91111, 2017 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-29207628

RESUMO

Uveal melanoma is the most common primary intraocular tumor in adults, with about 1200-1500 new cases occurring per year in the United States. Metastasis is a frequent occurrence in uveal melanoma, and outcomes are poor once distant spread occurs and no clinically significant chemotherapeutic protocol is so far available. The aim of the present study was to test the effect of various σ1 and σ2 receptor ligands as a possible pharmacological strategy for this rare tumor. Human uveal melanoma cells (92.1) were treated with various concentrations of different σ2 ligands (haloperidol and haloperidol metabolite II) and σ1 ligand ((+)-pentazocine) at various concentrations (1, 10 and 25 µM) and time points (0, 4 h, 8 h, 24 h and 48 h). Cell proliferation and migration were evaluated respectively by continuous cell monitoring by xCELLigence analysis, clonogenic assay and wound healing. Apoptosis and autophagy were also measured by cytofluorimetric and microscopy analysis. Our results showed that σ2 receptor ligands significantly reduced cell proliferation whereas (+)-pentazocine exhibited opposite results. All tested ligands showed significant decrease in cell migration. Interestingly, both σ1 and σ2 receptor ligands showed significant increase of autophagy and apoptosis at all concentrations. Taken all together these results suggest that sigma receptors mediates opposite biological effects but they also share common pharmacological effect on apoptosis and autophagy in uveal melanoma. In conclusion, these data provide the first evidence that sigma receptors may represent a "druggable" target to develop new chemotherapic agent for uveal melanoma.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...