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1.
Anticancer Res ; 40(9): 4895-4905, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878777

RESUMO

BACKGROUND/AIM: Nicotinamide phosphoribosyl-transferase (NAMPT) is a rate-limiting enzyme in the pathway synthesizing nicotinamide adenine dinucleotide (NAD (+)) from nicotinamide (NAM). Glioma tissues exhibit up-regulated NAMPT expression associated with a poor prognosis of patients. To determine if NAMPT can be a molecular therapeutic target, we investigated the effects of short hairpin RNA (shRNA)-mediated NAMPT down-regulation. MATERIALS AND METHODS: We designed shRNA to NAMPT and transfected to T98G cells. The characteristics of these cells were analyzed. RESULTS: The NAMPT shRNA-transfected cells exhibited delayed cell growth. However, there was no difference in the increase of sensitivity to temozolomide (TMZ) or X-ray irradiation between the NAMPT and scramble shRNA-transfected cells. The expression of NAMPT in the NAMPT shRNA-transfected cells increased with cell passage. Additionally, the shRNA-mediated transfection was associated with enhanced expression of quinolinic acid phosphoribo-syltransferase (QPRT). CONCLUSION: shRNA-mediated NAMPT down-regulation may not decrease the NADt to a sufficient level to increase TMZ/radiation sensitivity.


Assuntos
Citocinas/metabolismo , Regulação para Baixo , Glioma/enzimologia , Nicotinamida Fosforribosiltransferase/metabolismo , Antineoplásicos Alquilantes/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Citocinas/genética , Glioma/metabolismo , Glioma/patologia , Humanos , NAD/metabolismo , Nicotinamida Fosforribosiltransferase/genética , Pentosiltransferases/genética , Pentosiltransferases/metabolismo , RNA Interferente Pequeno/genética , Temozolomida/farmacologia
2.
Physiol Rev ; 100(4): 1839-1850, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32721181

RESUMO

Cancer patients appear to be more likely to be diagnosed with coronavirus disease 2019 (COVID-19). This is supported by the understanding of immunometabolic pathways that intersect patients with infection and cancer. However, data derived by case series and retrospective studies do not offer a coherent interpretation, since data from China suggest an increased risk of COVID-19, while data from the United States and Italy show a prevalence of COVID-19 in cancer patients comparable with the general population. Noteworthy, cancer and COVID-19 exploit distinct patterns of macrophage activation that promote disease progression in the most severe forms. In particular, the alternative activation of M2-polarized macrophages plays a crucial role in cancer progression. In contrast, the macrophage-activation syndrome appears as the source of M1-related cytokine storm in severe COVID-19 disease, thus indicating macrophages as a source of distinct inflammatory states in the two diseases, nonetheless as a common therapeutic target. New evidence indicates that NAMPT/NAD metabolism can direct both innate immune cell effector functions and the homeostatic robustness, in both cancer and infection. Moreover, a bidirectional relationship exists between the metabolism of NAD and the protective role that angiotensin converting enzyme 2, the COVID-19 receptor, can play against hyperinflammation. Within this immunometabolic framework, the review considers possible interference mechanisms that viral infections and tumors elicit on therapies and provides an overview for the management of patients with cancer affected by COVID-19, particularly for the balance of risk and benefit when planning normally routine cancer treatments and follow-up appointments.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Neoplasias/imunologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/imunologia , Animais , Betacoronavirus/imunologia , Infecções por Coronavirus/complicações , Citocinas/metabolismo , Humanos , Neoplasias/complicações , Nicotinamida Fosforribosiltransferase/metabolismo , Pandemias , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/complicações
3.
Nat Commun ; 11(1): 3393, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32636388

RESUMO

Meiotic divisions in oocytes are extremely asymmetric and require pre- and post-anaphase-onset phases of spindle migration. The latter induces membrane protrusion that is moulded around the spindle thereby reducing cytoplasmic loss. Here, we find that depleting the NAD biosynthetic enzyme, nicotinamide phosphoribosyl-transferase (Nampt), in mouse oocytes results in markedly longer spindles and compromises asymmetry. By analysing spindle speed in live oocytes, we identify a striking and transient acceleration after anaphase-onset that is severely blunted following Nampt-depletion. Slow-moving midzones of elongated spindles induce cortical furrowing deep within the oocyte before protrusions can form, altogether resulting in larger oocyte fragments being cleaved off. Additionally, we find that Nampt-depletion lowers NAD and ATP levels and that reducing NAD using small molecule Nampt inhibitors also compromises asymmetry. These data show that rapid midzone displacement is critical for extreme asymmetry by delaying furrowing to enable protrusions to form and link metabolic status to asymmetric division.


Assuntos
Anáfase , Citocinas/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Oócitos/citologia , Fuso Acromático , Actinas/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Ciclo Celular , Segregação de Cromossomos , Citoplasma/metabolismo , Citosol/metabolismo , Feminino , Meiose , Camundongos , Microscopia Confocal , NAD/química
4.
Chem Biol Interact ; 324: 109093, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32298659

RESUMO

Polycystic Ovary Syndrome (PCOS), as a common endocrine disorder is accompanied by hyperandrogenism, insulin resistance, ovulation problems, and infertility. Various types of off-label drugs like metformin have been used for the management of targeted problems caused by PCOS such as insulin resistance and hyperandrogenism. Nicotinamide (NAM) acts as a substrate of visfatin and Nicotinamide N-Methyltransferase (NNMT) leading to the generation of Nicotinamide Adenine Dinucleotide (NAD) and N1-Methylnicotinamide (MNAM), respectively. MNAM is known as an anti-inflammatory, anti-thrombosis, and anti-diabetic agent. In this study, the effects of NAM and MNAM on metabolic and endocrine abnormalities were evaluated in the adipose and ovarian tissues of a letrozole-induced rat model of PCOS. Our results showed that MNAM and NAM reversed abnormal estrous cycle and reduced the serum testosterone levels and CYP17A1 gene expression. Furthermore, all therapeutic factors improved HOMA-IR after treatment and NAM significantly increased the expression of GLUT4 and decreased the gene expression of visfatin. Also, MNAM diminished the gene expression of visfatin and resistin. It is noteworthy that all the therapeutic factors successfully activated the AMPK. In summary, this study is the first study reported beneficial effects of NAM and MNAM on the treatment of PCOS. Additionally, the alleviative effects of our therapeutic factors may be partially mediated by the AMPK-dependent manner due to the contribution of the AMPK in the expression of CYP17A1, visfatin, resistin, and GLUT4. Although more studies are required to unravel the exact mode of actions of MNAM and NAM in the PCOS, the findings of the current study shed light on an urgent need for discovering novel therapeutic pharmaceuticals regarding the treatment of PCOS.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Ovário/efeitos dos fármacos , Síndrome do Ovário Policístico/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Citocinas/genética , Citocinas/metabolismo , Ciclo Estral/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Hiperandrogenismo/tratamento farmacológico , Hormônio Luteinizante/metabolismo , Metformina/uso terapêutico , Nicotinamida Fosforribosiltransferase/genética , Nicotinamida Fosforribosiltransferase/metabolismo , Ratos Wistar , Resistina/genética , Resistina/metabolismo , Esteroide 17-alfa-Hidroxilase/genética , Esteroide 17-alfa-Hidroxilase/metabolismo , Testosterona/metabolismo
5.
Biosci Biotechnol Biochem ; 84(3): 544-551, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31791192

RESUMO

Alveolar and bronchial epithelial cells have critical functions in acute respiratory distress syndrome progress. Genistein could protect the lungs from acute lung injury, however, whether genistein protects the alveolar epithelial cells from LPS-induced injury was less studied. Spectrophotometric method 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and enzyme-linked immunosorbent assay (ELISA) were performed to detect cell viability and levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6. Flow cytometry and western blot assay were performed to detect cells apoptosis and protein levels. In LPS-induced model of mouse lung epithelial (MLE)-12 cells, PBEF (proinflammatory cytokine) expression, and cell apoptosis were increased and cell viability was decreased, whereas NF-κB was activated and expression levels of TNF-α, IL-1ß, and IL-6 were increased. However, genistein partly reversed the effect of LPS, and it plays a protective role in lung injury by reducing expression of PBEF, inhibiting the activation of NF-κB and alleviating inflammatory response of cells.


Assuntos
Células Epiteliais/efeitos dos fármacos , Genisteína/farmacologia , Lipopolissacarídeos/toxicidade , Pneumonia/prevenção & controle , Alvéolos Pulmonares/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Quimiocinas/metabolismo , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Células Epiteliais/metabolismo , Camundongos , NF-kappa B/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/patologia
6.
Eur J Endocrinol ; 182(1): 67-77, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31705791

RESUMO

Objective: Adipokines could be a link between metabolic syndrome (MS) and infertility. While the association between circulating adipokines and fertility has been extensively studied in females, this relationship in males was less investigated, although some adipokines are detectable in seminal plasma (SP). The aim of this study was to determine adipokine levels in blood and SP and to assess the relationships between adipokines, MS and semen parameters in men from infertile couples. Design: Male partners of infertile couples referred to four medical French centers were enrolled in years 2013-2016. Methods: Subjects (n = 160) aged 18-45 years were assessed for anthropometric, biochemical, sperm, and circulating hormonal parameters. Leptin, adiponectin, resistin, chemerin, visfatin, and IL-6 were measured in serum and SP. Results: Infertility duration was higher in men with than without MS. Adipokine concentrations were higher in blood than in SP, except for IL-6 and visfatin. The most striking result was the significant correlation observed between seminal IL-6 and spermatozoid concentration, progressive motility, and sperm vitality. Moreover, while men with MS exhibited an expected lower adiponectinemia, they displayed 2.1-fold higher adiponectin levels in SP than men without MS. Finally, logistic regression analysis showed that BMI, infertility duration, and adiponectin serum/SP ratio were independently associated with MS. Conclusions: These results suggest an involvement of seminal adipokines to modulate fertility in men with MS and that seminal IL-6 could play a beneficial role on sperm functionality. Further mechanistic studies are necessary to investigate the precise roles of these adipokines in male reproduction.


Assuntos
Adipocinas/metabolismo , Infertilidade Masculina/metabolismo , Infertilidade Masculina/fisiopatologia , Adipocinas/sangue , Adolescente , Adulto , Quimiocinas/sangue , Quimiocinas/metabolismo , Feminino , Humanos , Interleucina-6/sangue , Interleucina-6/metabolismo , Leptina/sangue , Leptina/metabolismo , Masculino , Pessoa de Meia-Idade , Nicotinamida Fosforribosiltransferase/sangue , Nicotinamida Fosforribosiltransferase/metabolismo , Reprodução/fisiologia , Sêmen/metabolismo , Sêmen/fisiologia , Contagem de Espermatozoides , Motilidade Espermática/fisiologia , Espermatozoides/metabolismo , Espermatozoides/fisiologia , Adulto Jovem
7.
Cell Mol Life Sci ; 77(18): 3643-3655, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31873757

RESUMO

Prior studies have established the important role of extracellular signal-regulated kinase 1/2 (ERK1/2) as a mediator of acute kidney injury (AKI). We demonstrated rapid ERK1/2 activation induced renal dysfunction following ischemia/reperfusion (IR)-induced AKI and downregulated the mitochondrial biogenesis (MB) regulator, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) in mice. In this study, ERK1/2 regulation of cellular nicotinamide adenine dinucleotide (NAD) and PGC-1α were explored. Inhibition of ERK1/2 activation during AKI in mice using the MEK1/2 inhibitor, trametinib, attenuated renal cortical oxidized NAD (NAD+) depletion. The rate-limiting NAD biosynthesis salvage enzyme, NAMPT, decreased following AKI, and this decrease was prevented by ERK1/2 inhibition. The microRNA miR34a decreased with the inhibition of ERK1/2, leading to increased NAMPT protein. Mice treated with a miR34a mimic prevented increases in NAMPT protein in the renal cortex in the presence of ERK1/2 inhibition. In addition, ERK1/2 activation increased acetylated PGC-1α, the less active form, whereas inhibition of ERK1/2 activation prevented an increase in acetylated PGC-1α after AKI through SIRT1 and NAD+ attenuation. These results implicate IR-induced ERK1/2 activation as an important contributor to the downregulation of both PGC-1α and NAD+ pathways that ultimately decrease cellular metabolism and renal function. Inhibition of ERK1/2 activation prior to the initiation of IR injury attenuated decreases in PGC-1α and NAD+ and prevented kidney dysfunction.


Assuntos
Lesão Renal Aguda/patologia , Citocinas/metabolismo , MicroRNAs/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , NAD/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Acetilação/efeitos dos fármacos , Lesão Renal Aguda/metabolismo , Animais , Antagomirs/metabolismo , Creatinina/sangue , Citocinas/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Córtex Renal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Nicotinamida Fosforribosiltransferase/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fosforilação/efeitos dos fármacos , Piridonas/farmacologia , Pirimidinonas/farmacologia , Sirtuína 1/metabolismo
8.
Cancer Res ; 80(4): 890-900, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31857293

RESUMO

Epithelial ovarian cancer (EOC) is the most lethal of gynecologic malignancies. The standard-of-care treatment for EOC is platinum-based chemotherapy such as cisplatin. Platinum-based chemotherapy induces cellular senescence. Notably, therapy-induced senescence contributes to chemoresistance by inducing cancer stem-like cells (CSC). However, therapeutic approaches targeting senescence-associated CSCs remain to be explored. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT) inhibition suppresses senescence-associated CSCs induced by platinum-based chemotherapy in EOC. Clinically applicable NAMPT inhibitors suppressed the outgrowth of cisplatin-treated EOC cells both in vitro and in vivo. Moreover, a combination of the NAMPT inhibitor FK866 and cisplatin improved the survival of EOC-bearing mice. These phenotypes correlated with inhibition of the CSCs signature, which consists of elevated expression of ALDH1A1 and stem-related genes, high aldehyde dehydrogenase activity, and CD133 positivity. Mechanistically, NAMPT regulates EOC CSCs in a paracrine manner through the senescence-associated secretory phenotype. Our results suggest that targeting NAMPT using clinically applicable NAMPT inhibitors, such as FK866, in conjunction with platinum-based chemotherapy represents a promising therapeutic strategy by suppressing therapy-induced senescence-associated CSCs. SIGNIFICANCE: This study highlights the importance of NAMPT-mediated NAD+ biosynthesis in the production of cisplatin-induced senescence-associated cancer stem cells, as well as tumor relapse after cisplatin treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Citocinas/antagonistas & inibidores , Células-Tronco Neoplásicas/efeitos dos fármacos , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Neoplasias Ovarianas/tratamento farmacológico , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Aldeído Desidrogenase 1/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Senescência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Citocinas/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Camundongos , Células-Tronco Neoplásicas/patologia , Nicotinamida Fosforribosiltransferase/metabolismo , Neoplasias Ovarianas/patologia , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Retinal Desidrogenase/metabolismo , Esferoides Celulares , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Mol Med Rep ; 20(6): 5163-5171, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31702813

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disease of the central nervous system that is characterized by progressive cognitive dysfunction and which ultimately leads to dementia. Studies have shown that energy dysmetabolism contributes significantly to the pathogenesis of a variety of aging­associated diseases and degenerative diseases of the nervous system, including AD. One focus of research thus has been how to regulate the expression of nicotinamide phosphoribosyltransferase (NAMPT) to prevent against neurodegenerative diseases. Therefore, the present study used 6­month­old APPswe/PS1ΔE9 (APP/PS1) transgenic mice as early AD mouse models and sought to evaluate nicotinamide adenine dinucleotide (NAD+) and FK866 (a NAMPT inhibitor) treatment in APP/PS1 mice to study NAMPT dysmetabolism in the process of AD and elucidate the underlying mechanisms. As a result of this treatment, the expression of NAMPT decreased, the synthesis of ATP and NAD+ became insufficient and the NAD+/NADH ratio was reduced. The administration of NAD+ alleviated the spatial learning and memory of APP/PS1 mice and reduced senile plaques. Administration of NAD+ may also increase the expression of the key protein NAMPT and its related protein sirtuin 1 as well as the synthesis of NAD+. Therefore, increasing NAMPT expression levels may promote NAD+ production. Their regulation could form the basis for a new therapeutic strategy.


Assuntos
Acrilamidas/antagonistas & inibidores , Doença de Alzheimer/metabolismo , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , NAD/antagonistas & inibidores , Nicotinamida Fosforribosiltransferase/efeitos dos fármacos , Nicotinamida Fosforribosiltransferase/metabolismo , Piperidinas/antagonistas & inibidores , Transdução de Sinais/fisiologia , Acrilamidas/farmacologia , Amiloide/metabolismo , Animais , Comportamento Animal , Citocinas/genética , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Aprendizagem/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NAD/metabolismo , NAD/farmacologia , Nicotinamida Fosforribosiltransferase/genética , Piperidinas/farmacologia , Sirtuína 1/metabolismo
10.
BMC Cancer ; 19(1): 1027, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31675930

RESUMO

BACKGROUND: Nicotinamide phosphoribosyltransferase (NAMPT) enzyme acts as the major enzyme in the nicotinamide adenine dinucleotide (NAD) synthesis salvage pathway. Deregulation of NAD could be associated with progression of several cancers such as breast cancer. Here, the consequence of NAMPT inhibition by miR-154 was investigated on breast cancer cells. METHODS: MDA-MB-231 and MCF-7 cancer cell lines were transfected with the mimic and inhibitors of miR-154-5p and their corresponding negative controls. Consequently, levels of NAMPT and NAD were assayed employing qRT-PCR, Western blotting and enzymatic method, respectively. Subsequently, flow cytometry and colorimetric methods were performed to evaluate apoptosis and cell viability. Bioinformatics analyses as well as luciferase assay were done to investigate whether the 3'-UTR of NAMPT is directly targeted by miR-154. RESULTS: According to the obtained results, NAMPT was recognized as a target for binding of miR-154 and the levels of this miRNA was inversely associated with both mRNA and protein levels of NAMPT in breast cancer cell lines. Functionally, miR-154 inhibited the NAD salvage pathway leading to a remarkable decrease in cell viability and increased rate of cell death. When breast cancer cells were simultaneously treated with doxorubicin and miR-154 mimic, cell viability was considerably reduced compared to treatment with doxorubicin alone in both cell lines. CONCLUSIONS: It was concluded that the inhibition of NAD production by miR-154 might be introduced as an appropriate therapeutic approach in order to improve breast cancer outcome either alone or in combination with other conventional chemotherapeutic agents.


Assuntos
Neoplasias da Mama/genética , MicroRNAs/genética , Nicotinamida Fosforribosiltransferase/metabolismo , Regiões 3' não Traduzidas/genética , Antineoplásicos Alquilantes/uso terapêutico , Apoptose , Neoplasias da Mama/tratamento farmacológico , Sobrevivência Celular , Biologia Computacional , Doxorrubicina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Ativação Enzimática/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Nicotinamida Fosforribosiltransferase/genética
11.
Taiwan J Obstet Gynecol ; 58(6): 808-813, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31759533

RESUMO

OBJECTIVE: The aim was to determine the role of visfatin (VF) and human fetuin A (AHSG) in the development of gestational diabetes mellitus (GDM) and to explore the association between these variables and adverse outcomes. MATERIALS AND METHODS: We carried out our study on 68 cases of GDM pregnant women and 42 cases of healthy pregnant women, including 56 cases with diet control and 12 cases with insulin treatment. Enzyme-linked immunoassay (ELISA) was used to test the expression levels of VF and AHSG in maternal and umbilical cord serum. Immunohistochemistry (ICH) was used to test the expression level of the VF protein in placental tissue. RESULTS: The expression levels of VF and AHSG in maternal and umbilical cord serum and the expression level of VF in placental tissue in GDM pregnant women were higher than those in healthy pregnant women. The incidence of adverse outcomes in the GDM pregnant women was higher than that in healthy pregnant women, and these differences were statistically significant (P < 0.05). Those who had higher expression levels of VF or AHSG had a higher incidence of adverse outcomes (P < 0.05). CONCLUSION: The expression of VF and AHSG may participate in the development of GDM. A test of VF and AHSG in GDM pregnant women may have some predictive value for the occurrence of adverse outcomes.


Assuntos
Diabetes Gestacional/metabolismo , Sangue Fetal/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Placenta/metabolismo , Complicações na Gravidez , alfa-2-Glicoproteína-HS/metabolismo , Adulto , Biomarcadores/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imuno-Histoquímica , Recém-Nascido , Gravidez , Resultado da Gravidez , Estudos Retrospectivos
12.
Int J Mol Sci ; 20(22)2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31717318

RESUMO

Granulocyte-colony stimulating factor (G-CSF)/nicotinamide phosphoribosyltransferase (NAMPT) signaling has been shown to be crucial for the modulation of neutrophil development and functionality. As this signaling pathway is significantly suppressed by type I interferons (IFNs), we aimed to study how the regulation of neutrophil differentiation and phenotype is altered in IFN-deficient mice during granulopoiesis. The composition of bone marrow granulocyte progenitors and their Nampt expression were assessed in bone marrow of type I IFN receptor knockout (Ifnar1-/-) mice and compared to wild-type animals. The impact of NAMPT inhibition on the proliferation, survival, and differentiation of murine bone marrow progenitors, as well as of murine 32D and human HL-60 neutrophil-like cell lines, was estimated. The progressive increase of Nampt expression during neutrophil progenitor maturation could be observed, and it was more prominent in IFN-deficient animals. Altered composition of bone marrow progenitors in these mice correlated with the dysregulation of apoptosis and altered differentiation of these cells. We observed that NAMPT is vitally important for survival of early progenitors, while at later stages it delays the differentiation of neutrophils, with moderate effect on their survival. This study shows that IFN-deficiency leads to the elevated NAMPT expression in the bone marrow, which in turn modulates neutrophil development and differentiation, even in the absence of tumor-derived stimuli.


Assuntos
Diferenciação Celular , Interferons/metabolismo , Neutrófilos/citologia , Neutrófilos/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Transdução de Sinais , Animais , Apoptose , Sobrevivência Celular , Fator Estimulador de Colônias de Granulócitos/metabolismo , Células Precursoras de Granulócitos/metabolismo , Células HL-60 , Humanos , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Receptor de Interferon alfa e beta/deficiência , Receptor de Interferon alfa e beta/metabolismo
13.
Int J Mol Sci ; 20(20)2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31635187

RESUMO

Synovial membrane inflammation actively participate to structural damage during osteoarthritis (OA). Adipokines, miRNA, and oxidative stress contribute to synovitis and cartilage destruction in OA. We investigated the relationship between visfatin, resistin and miRNA in oxidative stress regulation, in human OA synovial fibroblasts. Cultured cells were treated with visfatin and resistin. After 24 h, we evaluated various pro-inflammatory cytokines, metalloproteinases (MMPs), type II collagen (Col2a1), miR-34a, miR-146a, miR-181a, antioxidant enzymes, and B-cell lymphoma (BCL)2 by qRT-PCR, apoptosis and mitochondrial superoxide production by cytometry, p50 nuclear factor (NF)-κB by immunofluorescence. Synoviocytes were transfected with miRNA inhibitors and oxidative stress evaluation after adipokines stimulus was performed. The implication of NF-κB pathway was assessed by the use of a NF-κB inhibitor (BAY-11-7082). Visfatin and resistin significantly up-regulated gene expression of interleukin (IL)-1ß, IL-6, IL-17, tumor necrosis factor (TNF)-α, MMP-1, MMP-13 and reduced Col2a1. Furthermore, adipokines induced apoptosis and superoxide production, the transcriptional levels of BCL2, superoxide dismutase (SOD)-2, catalase (CAT), nuclear factor erythroid 2 like 2 (NRF2), miR-34a, miR-146a, and miR-181a. MiRNA inhibitors counteracted adipokines modulation of oxidative stress. Visfatin and resistin effects were suppressed by BAY-11-7082. Our data suggest that miRNA may represent possible mediators of oxidative stress induced by visfatin and resistin via NF-κB pathway in human OA synoviocytes.


Assuntos
Citocinas/metabolismo , Fibroblastos/patologia , MicroRNAs/genética , NF-kappa B/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Osteoartrite/patologia , Estresse Oxidativo , Resistina/metabolismo , Membrana Sinovial/patologia , Apoptose , Células Cultivadas , Citocinas/genética , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , NF-kappa B/genética , Nicotinamida Fosforribosiltransferase/genética , Osteoartrite/genética , Osteoartrite/metabolismo , Resistina/genética , Transdução de Sinais , Membrana Sinovial/metabolismo
14.
Curr Obes Rep ; 8(4): 434-457, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31637623

RESUMO

PURPOSE: Sepsis has become a global health problem with rising incidence and high mortality, creating a substantial social and economic burden. Early diagnosis and treatment can improve outcome, but reliable sepsis biomarkers are lacking. This review summarizes current evidence of the pathophysiological mechanisms linking adipose tissue to sepsis and presents experimental and clinical data on adipokines and sepsis along with important insights into the obesity paradox in sepsis survival. RECENT FINDINGS: Sepsis is characterized by significant alterations in circulating cytokines and adipokines, biologically active molecules produced by the adipose tissue, being implicated in metabolic and inflammatory processes. Although data are inconclusive regarding classic adipokines such as leptin and adiponectin, recent evidence have highlighted the striking elevation of resistin and visfatin in critical illness and sepsis as well as their association with sepsis severity and outcomes. Given that inflammatory and metabolic pathways are involved in sepsis, studying adipokines presents an attractive, innovative, and promising research field that may provide more powerful diagnostic and prognostic biomarkers as well as novel therapeutic targets, empowering the therapeutic armamentarium for sepsis management in order to improve survival.


Assuntos
Adipocinas/metabolismo , Tecido Adiposo/metabolismo , Obesidade/metabolismo , Sepse/metabolismo , Adiponectina/metabolismo , Animais , Biomarcadores/sangue , Citocinas/metabolismo , Humanos , Hiperglicemia/complicações , Resistência à Insulina , Leptina/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Obesidade/complicações , Resistina/metabolismo , Sepse/complicações , Índice de Gravidade de Doença
15.
Curr Obes Rep ; 8(4): 413-433, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31637624

RESUMO

PURPOSE: The current review shows evidence for the role of adipokines in breast cancer (BC) pathogenesis summarizing the mechanisms underlying the association between adipokines and breast malignancy. Special emphasis is given also on intriguing insights into the relationship between obesity and BC as well as on the role of novel adipokines in BC development. RECENT FINDINGS: Recent evidence has underscored the role of the triad of obesity, insulin resistance, and adipokines in postmenopausal BC. Adipokines exert independent and joint effects on activation of major intracellular signal networks implicated in BC cell proliferation, growth, survival, invasion, and metastasis, particularly in the context of obesity, considered a systemic endocrine dysfunction characterized by chronic inflammation. To date, more than 10 adipokines have been linked to BC, and this catalog is continuously increasing. The majority of circulating adipokines, such as leptin, resistin, visfatin, apelin, lipocalin 2, osteopontin, and oncostatin M, is elevated in BC, while some adipokines such as adiponectin and irisin (adipo-myokine) are generally decreased in BC and considered protective against breast carcinogenesis. Further evidence from basic and translational research is necessary to delineate the ontological role of adipokines and their interplay in BC pathogenesis. More large-scale clinical and longitudinal studies are awaited to assess their clinical utility in BC prognosis and follow-up. Finally, novel more effective and safer adipokine-centered therapeutic strategies could pave the way for targeted oncotherapy.


Assuntos
Adipocinas/metabolismo , Neoplasias da Mama/metabolismo , Obesidade/metabolismo , Adipocinas/classificação , Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Animais , Apelina/metabolismo , Neoplasias da Mama/complicações , Proliferação de Células , Citocinas/metabolismo , Feminino , Fibronectinas/metabolismo , Humanos , Inflamação , Leptina/metabolismo , Lipocalina-2/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Obesidade/complicações , Oncostatina M/metabolismo , Osteopontina/metabolismo , Resistina/metabolismo
16.
Int J Mol Sci ; 20(18)2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31505789

RESUMO

It is well known that adipokines are endocrine factors that are mainly secreted by white adipose tissue. Their central role in energy metabolism is currently accepted. More recently, their involvement in fertility regulation and the development of some reproductive disorders has been suggested. Data concerning the role of leptin and adiponectin, the two most studied adipokines, in the control of the reproductive axis are consistent. In recent years, interest has grown about some novel adipokines, chemerin, visfatin, resistin and apelin, which have been found to be strongly associated with obesity and insulin-resistance. Here, we will review their expression and role in male and female reproduction in humans and animal models. According to accumulating evidence, they could regulate the secretion of GnRH (Gonadotropin-Releasing Hormone), gonadotropins and steroids. Furthermore, their expression and that of their receptors (if known), has been demonstrated in the human and animal hypothalamo-pituitary-gonadal axis. Like leptin and adiponectin, these novel adipokines could thus represent metabolic sensors that are able to regulate reproductive functions according to energy balance changes. Therefore, after investigating their role in normal fertility, we will also discuss their possible involvement in some reproductive troubles known to be associated with features of metabolic syndrome, such as polycystic ovary syndrome, gestational diabetes mellitus, preeclampsia and intra-uterine growth retardation in women, and sperm abnormalities and testicular pathologies in men.


Assuntos
Apelina/metabolismo , Quimiocinas/metabolismo , Citocinas/metabolismo , Diabetes Gestacional/metabolismo , Retardo do Crescimento Fetal/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Síndrome do Ovário Policístico/metabolismo , Pré-Eclâmpsia/metabolismo , Resistina/metabolismo , Doenças Testiculares/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Humanos , Resistência à Insulina , Masculino , Obesidade/metabolismo , Gravidez
17.
Nat Commun ; 10(1): 4116, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511522

RESUMO

Damage-associated molecular patterns (DAMPs) are molecules that can be actively or passively released by injured tissues and that activate the immune system. Here we show that nicotinate phosphoribosyltransferase (NAPRT), detected by antibody-mediated assays and mass spectrometry, is an extracellular ligand for Toll-like receptor 4 (TLR4) and a critical mediator of inflammation, acting as a DAMP. Exposure of human and mouse macrophages to NAPRT activates the inflammasome and NF-κB for secretion of inflammatory cytokines. Furthermore, NAPRT enhances monocyte differentiation into macrophages by inducing macrophage colony-stimulating factor. These NAPRT-induced effects are independent of NAD-biosynthetic activity, but rely on NAPRT binding to TLR4. In line with our finding that NAPRT mediates endotoxin tolerance in vitro and in vivo, sera from patients with sepsis contain the highest levels of NAPRT, compared to patients with other chronic inflammatory conditions. Together, these data identify NAPRT as a endogenous ligand for TLR4 and a mediator of inflammation.


Assuntos
Espaço Extracelular/metabolismo , Inflamação/enzimologia , Pentosiltransferases/metabolismo , Receptor 4 Toll-Like/metabolismo , Diferenciação Celular , Líquido Extracelular/enzimologia , Humanos , Inflamação/genética , Inflamação/patologia , Fator Estimulador de Colônias de Macrófagos/metabolismo , Macrófagos/metabolismo , Monócitos/citologia , Células Mieloides/metabolismo , Nicotinamida Fosforribosiltransferase/química , Nicotinamida Fosforribosiltransferase/metabolismo , Pentosiltransferases/sangue , Pentosiltransferases/química , Ligação Proteica , Fatores de Risco , Sepse/sangue , Sepse/enzimologia
18.
Nat Commun ; 10(1): 3790, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31439867

RESUMO

Pediatric high-grade gliomas are among the deadliest of childhood cancers due to limited knowledge of early driving events in their gliomagenesis and the lack of effective therapies available. In this study, we investigate the oncogenic role of PPM1D, a protein phosphatase often found truncated in pediatric gliomas such as DIPG, and uncover a synthetic lethal interaction between PPM1D mutations and nicotinamide phosphoribosyltransferase (NAMPT) inhibition. Specifically, we show that mutant PPM1D drives hypermethylation of CpG islands throughout the genome and promotes epigenetic silencing of nicotinic acid phosphoribosyltransferase (NAPRT), a key gene involved in NAD biosynthesis. Notably, PPM1D mutant cells are shown to be sensitive to NAMPT inhibitors in vitro and in vivo, within both engineered isogenic astrocytes and primary patient-derived model systems, suggesting the possible application of NAMPT inhibitors for the treatment of pediatric gliomas. Overall, our results reveal a promising approach for the targeting of PPM1D mutant tumors, and define a critical link between oncogenic driver mutations and NAD metabolism, which can be exploited for tumor-specific cell killing.


Assuntos
Antineoplásicos/farmacologia , Neoplasias do Tronco Encefálico/genética , Glioma Pontino Intrínseco Difuso/genética , Nicotinamida Fosforribosiltransferase/genética , Proteína Fosfatase 2C/genética , Animais , Antineoplásicos/uso terapêutico , Neoplasias do Tronco Encefálico/tratamento farmacológico , Neoplasias do Tronco Encefálico/patologia , Linhagem Celular Tumoral , Criança , Citocinas/antagonistas & inibidores , Metilação de DNA , Glioma Pontino Intrínseco Difuso/tratamento farmacológico , Glioma Pontino Intrínseco Difuso/patologia , Repressão Epigenética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Nicotinamida Fosforribosiltransferase/metabolismo , Ponte/citologia , Ponte/patologia , Cultura Primária de Células , Proteína Fosfatase 2C/metabolismo , Mutações Sintéticas Letais , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Neoplasia ; 21(10): 974-988, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31442917

RESUMO

We recently described a positive feedback loop connecting c-MYC, NAMPT, DBC1 and SIRT1 that contributes to unrestricted cancer cell proliferation. Here we determine the relevance of the loop for serrated route intestinal tumorigenesis using genetically well-defined BrafV600E and K-rasG12D mouse models. In both models we show that c-MYC and SIRT1 protein expression increased through progression from hyperplasia to invasive carcinomas and metastases. It correlated with high NAMPT expression and was directly associated to activation of the oncogenic drivers. Assessing functional and molecular consequences of pharmacological interference with factors of the loop, we found that inhibition of NAMPT resulted in apoptosis and reduced clonogenic growth in human BRAF-mutant colorectal cancer cell lines and patient-derived tumoroids. Blocking SIRT1 activity was only effective when combined with a PI3K inhibitor, whereas the latter antagonized the effects of NAMPT inhibition. Interfering with the positive feedback loop was associated with down-regulation of c-MYC and temporary de-repression of TP53, explaining the anti-proliferative and pro-apoptotic effects. In conclusion we show that the c-MYC-NAMPT-DBC1-SIRT1 positive feedback loop contributes to murine serrated tumor progression. Targeting the feedback loop exerted a unique, dual therapeutic effect of oncoprotein inhibition and tumor suppressor activation. It may therefore represent a promissing target for serrated colorectal cancer, and presumably for other cancer types with deregulated c-MYC.


Assuntos
Transformação Celular Neoplásica , Citocinas/metabolismo , Neoplasias Intestinais/etiologia , Neoplasias Intestinais/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Oncogenes , Proteínas Proto-Oncogênicas c-myc/metabolismo , Sirtuína 1/metabolismo , Animais , Apoptose/genética , Biomarcadores , Biópsia , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos/genética , Imuno-Histoquímica , Neoplasias Intestinais/tratamento farmacológico , Neoplasias Intestinais/patologia , Camundongos , Mutação , Metástase Neoplásica , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Transdução de Sinais , Sirtuína 1/antagonistas & inibidores
20.
Int J Mol Sci ; 20(17)2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31443349

RESUMO

Rheumatic diseases encompass a diverse group of chronic disorders that commonly affect musculoskeletal structures. Osteoarthritis (OA) and rheumatoid arthritis (RA) are the two most common, leading to considerable functional limitations and irreversible disability when patients are unsuccessfully treated. Although the specific causes of many rheumatic conditions remain unknown, it is generally accepted that immune mechanisms and/or uncontrolled inflammatory responses are involved in their etiology and symptomatology. In this regard, the bidirectional communication between neuroendocrine and immune system has been demonstrated to provide a homeostatic network that is involved in several pathological conditions. Adipokines represent a wide variety of bioactive, immune and inflammatory mediators mainly released by adipocytes that act as signal molecules in the neuroendocrine-immune interactions. Adipokines can also be synthesized by synoviocytes, osteoclasts, osteoblasts, chondrocytes and inflammatory cells in the joint microenvironment, showing potent modulatory properties on different effector cells in OA and RA pathogenesis. Effects of adiponectin, leptin, resistin and visfatin on local and systemic inflammation are broadly described. However, more recently, other adipokines, such as progranulin, chemerin, lipocalin-2, vaspin, omentin-1 and nesfatin, have been recognized to display immunomodulatory actions in rheumatic diseases. This review highlights the latest relevant findings on the role of the adipokine network in the pathophysiology of OA and RA.


Assuntos
Adipocinas/metabolismo , Artrite Reumatoide/etiologia , Artrite Reumatoide/metabolismo , Adipocinas/genética , Animais , Artrite Reumatoide/patologia , Biomarcadores , Suscetibilidade a Doenças , Regulação da Expressão Gênica , Humanos , Leptina/genética , Leptina/metabolismo , Nicotinamida Fosforribosiltransferase/genética , Nicotinamida Fosforribosiltransferase/metabolismo , Resistina/genética , Resistina/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
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