RESUMO
MicroRNAs (miRNAs) are small non-coding RNAs which contribute to the regulation of many physiological and pathological processes. Conventionally, miRNAs perform their activity in the cytoplasm where they regulate gene expression by interacting in a sequence-specific manner with mature messenger RNAs. Recent studies point to the presence of mature miRNAs in the nucleus. This review summarizes current findings regarding the molecular activities of nuclear miRNAs. These molecules can regulate gene expression at the transcriptional level by directly binding DNA on the promoter or the enhancer of regulated genes. miRNAs recruit different protein complexes to these regions, resulting in activation or repression of transcription, through a number of molecular mechanisms. Hematopoiesis is presented as a paradigmatic biological process whereby nuclear miRNAs possess a relevant regulatory role. Nuclear miRNAs can influence gene expression by affecting nuclear mRNA processing and by regulating pri-miRNA maturation, thus impacting the biogenesis of miRNAs themselves. Overall, nuclear miRNAs are biologically active molecules that can be critical for the fine tuning of gene expression and deserve further studies in a number of physiological and pathological conditions.
Assuntos
Núcleo Celular , Regulação da Expressão Gênica , MicroRNAs , MicroRNAs/genética , MicroRNAs/metabolismo , Humanos , Núcleo Celular/metabolismo , Núcleo Celular/genética , Animais , Hematopoese/genéticaRESUMO
Serum albumin (SA) is the most abundant protein in plasma and represents the main carrier of endogenous and exogenous compounds. Several evidence supports the notion that SA binds single and double-stranded deoxynucleotides and ribonucleotides at two sites, with values of the dissociation equilibrium constant (i.e., Kd ) ranging from micromolar to nanomolar values. This can be relevant from a physiological and pathological point of view, as in human plasma circulates cell-free nucleic acids (cfNAs), released by different tissues via apoptosis, necrosis, and secretions, circulates as single and double-stranded NAs. Albeit SA shows low hydrolytic reactivity toward DNA and RNA, the high plasma concentration of this protein and the occurrence of several SA receptors may be pivotal for sequestering and hydrolyzing cfNAs. Therefore, pathological conditions like cancer, characterized by altered levels of human SA or by altered SA post-translational modifications, may influence cfNAs distribution and metabolism. Besides, the stability, solubility, biocompatibility, and low immunogenicity make SA a golden share for biotechnological applications related to the delivery of therapeutic NAs (TNAs). Indeed, pre-clinical studies report the therapeutic potential of SA:TNAs complexes in precision cancer therapy. Here, the molecular and biotechnological implications of SA:NAs interaction are discussed, highlighting new perspectives on SA plasmatic functions.
Assuntos
Ácidos Nucleicos Livres , Ácidos Nucleicos , DNA/metabolismo , Humanos , Ácidos Nucleicos/metabolismo , Albumina Sérica/metabolismo , Distribuição TecidualRESUMO
The balance between neuronal apoptosis and survival sculpts the developing brain and has an important role in neurodegenerative diseases. Thus, the individuation of signals that could modulate the cell death machinery as well as enhance survival in neurons promises to provide multiple points of therapeutic intervention in neurodegenerative diseases. Neuroglobin (NGB), the first nerve globin identified in neuronal tissues of humans, seems to possess a protective role in the brain only after up-regulation. Here, the NGB physiological role in the control of neuronal survival is reviewed. In vitro studies suggested that cytosolic NGB could react very rapidly with cytochrome c released from mitochondria, thus interfering with the intrinsic pathway of apoptosis. Although very suggestive, these data do not explain either the role of NGB up-regulation in neuroprotection or the recently reported NGB localization into mitochondria. Recently, we identified the steroid hormone 17ß-estradiol (E2) as an endogenous modulator of NGB levels in neuroblastoma SK-N-BE cell line. Upon E2 stimulation, NGB reallocates mainly into mitochondria where the association with the mitochondrial cytochrome c occurs. Remarkably, E2 treatment before an apoptotic stimulus strongly enhances the NGB:cytochrome c association reducing cytochrome c release into the cytosol. As a consequence, a decrease of caspase-3 activation and, in turn, of the apoptotic cascade activation take place. Besides E2, other compounds have been reported to up-regulate the NGB expression highlighting the possibility to develop NGB-mediated therapeutic strategies against stroke damage and neurodegenerative diseases. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins.
Assuntos
Apoptose , Globinas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Animais , Sobrevivência Celular , Humanos , NeuroglobinaRESUMO
Cancer alters both local and distant tissue by influencing the microenvironment. In this regard, the interplay with the stromal fraction is considered critical as this latter can either foster or hamper the progression of the disease. Accordingly, the modality by which tumors may alter distant niches of stromal cells is still unclear, especially at early stages. In this short report, we attempt to better understand the biology of this cross-talk. In our "autologous stromal experimental setting," we found that remote adipose tissue-derived mesenchymal stem cells (mediastinal AMSC) obtained from patients with lung adenocarcinoma sustain proliferation and clonogenic ability of A549 and human primary lung adenocarcinoma cells similarly to the autologous stromal lung counterpart (LMSC). This effect is not observed in lung benign diseases such as the hamartochondroma. This finding was validated by conditioning benign AMSC with supernatants from LAC for up to 21 days. The new reconditioned media of the stromal fraction so obtained, was able to increase cell proliferation of A549 cells at 14 and 21 days similar to that derived from AMSC of patients with lung adenocarcinoma. The secretome generated by remote AMSC revealed overlapping to the corresponding malignant microenvironment of the autologous local LMSC. Among the plethora of 80 soluble factors analyzed by arrays, a small pool of 5 upregulated molecules including IL1-ß, IL-3, MCP-1, TNF-α, and EGF, was commonly shared by both malignant-like autologous A- and L-MSC derived microenvironments vs those benign. The bioinformatics analysis revealed that these proteins were strictly and functionally interconnected to lung fibrosis and proinflammation and that miR-126, 101, 486, and let-7-g were their main targets. Accordingly, we found that in lung cancer tissues and blood samples from the same set of patients here employed, miR-126 and miR-486 displayed the highest expression levels in tissue and blood, respectively. When the miR-126-3p was silenced in A549 treated with AMSC-derived conditioned media from patients with lung adenocarcinoma, cell proliferation decreased compared to control media.
RESUMO
We characterize the metabolic background in distinct Acute Myeloid Leukemias (AMLs), by comparing the metabolism of primary AML blasts isolated at diagnosis with that of normal hematopoietic maturing progenitors, using the Seahorse XF Agilent. Leukemic cells feature lower spare respiratory (SRC) and glycolytic capacities as compared to hematopoietic precursors (i.e. day 7, promyelocytes). According with Proton Leak (PL) values, AML blasts can be grouped in two well defined populations. The AML group with blasts presenting high PL or high basal OXPHOS plus high SRC levels had shorter overall survival time and significantly overexpressed myeloid cell leukemia 1 (MCL1) protein. We demonstrate that MCL1 directly binds to Hexokinase 2 (HK2) on the outer mitochondrial membrane (OMM). Overall, these results suggest that high PL and high SRC plus high basal OXPHOS levels at disease onset, arguably with the concourse of MCL1/HK2 action, are significantly linked with shorter overall survival time in AML. Our data describe a new function for MCL1 protein in AMLs' cells: by forming a complex with HK2, MCL1 co-localizes to VDAC on the OMM, thus inducing glycolysis and OXPHOS, ultimately conferring metabolic plasticity and promoting resistance to therapy.
Assuntos
Hexoquinase , Leucemia Mieloide Aguda , Humanos , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismoRESUMO
OBJECTIVES: Extracellular vesicles (EVs) are key biological mediators of several physiological functions within the cell microenvironment. Platelets are the most abundant source of EVs in the blood. Similarly, platelet lysate (PL), the best platelet derivative and angiogenic performer for regenerative purposes, is enriched of EVs, but their role is still too poorly discovered to be suitably exploited. Here, we explored the contribution of the EVs in PL, by investigating the angiogenic features extrapolated from that possessed by PL. METHODS: We tested angiogenic ability and molecular cargo in 3D bioprinted models and by RNA sequencing analysis of PL-derived EVs. RESULTS: A subset of small vesicles is highly represented in PL. The EVs do not retain aggregation ability, preserving a low redox state in human umbilical vein endothelial cells (HUVECs) and increasing the angiogenic tubularly-like structures in 3D endothelial bioprinted constructs. EVs resembled the miRNome profile of PL, mainly enriched with small RNAs and a high amount of miR-126, the most abundant angiogenic miRNA in platelets. The transfer of miR-126 by EVs in HUVEC after the in vitro inhibition of the endogenous form, restored angiogenesis, without involving VEGF as a downstream target in this system. CONCLUSION: PL is a biological source of available EVs with angiogenic effects involving a miRNAs-based cargo. These properties can be exploited for targeted molecular/biological manipulation of PL, by potentially developing a product exclusively manufactured of EVs.
Assuntos
Vesículas Extracelulares , MicroRNAs , Humanos , Células Endoteliais da Veia Umbilical Humana , MicroRNAs/genética , Neovascularização Patológica , PlaquetasRESUMO
Globins have been found in glial cells and neurons of invertebrates and vertebrates. The first nerve globin has been recognized in the nerve cord of the polychaete annelid Aphrodite aculeata in 1872. In some invertebrates, the nerve globin reaches a millimolar concentration which is likely sufficient to sustain the aerobic metabolism and thus the excitability of the nervous system. In 2000, the first vertebrate nerve globin, named neuroglobin (Ngb), has been identified in neuronal tissues of mice and humans. In contrast to invertebrate nerve globins, the concentration of Ngb, the prototype of vertebrate nerve globins, is low (µM), reaching a maximum of 100 µM in retina cells. Therefore, Ngb appears unlikely to act primarily as an O2 buffer and to facilitate O2 diffusion to the mitochondria. Indeed, Ngb has been hypothesized to catalyze the formation/decomposition of reactive nitrogen and/or oxygen species and to be part of intracellular signaling pathways enhancing cell survival. Here, we report that neuronal Ngb levels are strongly induced by the steroid hormone 17ß-estradiol. Furthermore, Ngb participates to mechanisms involved in 17ß-estradiol-induced protective effects against H2O2 -induced neurotoxicity.
Assuntos
Estrogênios/fisiologia , Globinas/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Fármacos Neuroprotetores , Animais , Apoptose , Estrogênios/metabolismo , Globinas/metabolismo , Humanos , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Neuroglobina , Regulação para CimaRESUMO
Although discovered in 2000, neuroglobin (Ngb) functions are still uncertain. A contribution to the role played by Ngb in neurons could certainly derive from the identification of Ngb endogenous modulators. Here, we evaluate the possibility that Ngb could be regulated by 17ß-estradiol (E2) signaling in both SK-N-BE human neuroblastoma cell line and mouse hippocampal neurons. 1 nM E2 rapidly induced a 300% increase in Ngb levels in both models. The E2 effect was specific, being not induced by testosterone or dihydrotestosterone. The E2-induced Ngb increase requires estrogen receptor (ER) ß, but not ERα, as evaluated by the mimetic effect of ERß-specific agonist DPN and by the blockage of E2 effect in ERß-silenced SK-N-BE cells. Furthermore, both rapid (15 min) ERß-dependent activation of p38/MAPK and transcriptional ERß activity were required for the estrogenic regulation of Ngb. Finally, E2 exerted a protective effect against H2O2-induced neuroblastoma cell death which was completely prevented in Ngb-silenced cells. Overall, these data suggest that Ngb is part of the E2 signaling mechanism that is activated to exert protective effects against H2O2-induced neurotoxicity.
Assuntos
Estradiol/fisiologia , Globinas/metabolismo , Peróxido de Hidrogênio/antagonistas & inibidores , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores , Animais , Linhagem Celular Tumoral , Células Cultivadas , Citoproteção/efeitos dos fármacos , Citoproteção/fisiologia , Estradiol/farmacologia , Globinas/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Peróxido de Hidrogênio/toxicidade , Camundongos , Proteínas do Tecido Nervoso/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Neuroglobina , Neurônios/fisiologia , Fármacos Neuroprotetores/farmacologia , Oxidantes/antagonistas & inibidores , Oxidantes/toxicidadeRESUMO
Acute promyelocytic leukemia (APL) is a hematological disease characterized by a balanced reciprocal translocation that leads to the synthesis of the oncogenic fusion protein PML-RARα. APL is mainly managed by a differentiation therapy based on the administration of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, therapy resistance, differentiation syndrome, and relapses require the development of new low-toxicity therapies based on the induction of blasts differentiation. In keeping with this, we reasoned that a better understanding of the molecular mechanisms pivotal for ATRA-driven differentiation could definitely bolster the identification of new therapeutic strategies in APL patients. We thus performed an in-depth high-throughput transcriptional profile analysis and metabolic characterization of a well-established APL experimental model based on NB4 cells that represent an unevaluable tool to dissect the complex mechanism associated with ATRA-induced granulocytic differentiation. Pathway-reconstruction analysis using genome-wide transcriptional data has allowed us to identify the activation/inhibition of several cancer signaling pathways (e.g., inflammation, immune cell response, DNA repair, and cell proliferation) and master regulators (e.g., transcription factors, epigenetic regulators, and ligand-dependent nuclear receptors). Furthermore, we provide evidence of the regulation of a considerable set of metabolic genes involved in cancer metabolic reprogramming. Consistently, we found that ATRA treatment of NB4 cells drives the activation of aerobic glycolysis pathway and the reduction of OXPHOS-dependent ATP production. Overall, this study represents an important resource in understanding the molecular "portfolio" pivotal for APL differentiation, which can be explored for developing new therapeutic strategies.
Assuntos
Diferenciação Celular/genética , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Transcrição Gênica , Tretinoína/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Linhagem da Célula/efeitos dos fármacos , Estudos de Coortes , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Glicólise/genética , Humanos , Leucemia Promielocítica Aguda/patologia , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Células Mieloides/patologia , Fosforilação Oxidativa/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacosRESUMO
During infection, Mycobacterium leprae is faced with the host macrophagic environment limiting the growth of the bacilli. However, (pseudo-)enzymatic detoxification systems, including truncated hemoglobin O (Ml-trHbO), could allow this mycobacterium to persist in vivo. Here, kinetics of peroxynitrite (ONOOH/ONOO(-)) detoxification by ferryl Ml-trHbO (Ml-trHbO-Fe(IV)=O), obtained by treatment with H(2)O(2), is reported. Values of the second-order rate constant for peroxynitrite detoxification by Ml-trHbO-Fe(IV)=O (i.e., of Ml-trHbO-Fe(III) formation; k(on)), at pH 7.2 and 22.0 degrees C, are 1.5x10(4) M(-1) s(-1), and 2.2x10(4) M(-1) s(-1), in the absence of and presence of physiological levels of CO(2) (approximately 1.2x10(-3) M), respectively. Values of k(on) increase on decreasing pH with a pK(a) value of 6.7, this suggests that ONOOH reacts preferentially with Ml-trHbO-Fe(IV)=O. In turn, peroxynitrite acts as an antioxidant of Ml-trHbO-Fe(IV)=O, which could be responsible for the oxidative damage of the mycobacterium. As a whole, Ml-trHbO can undertake within the same cycle H(2)O(2) and peroxynitrite detoxification.
Assuntos
Proteínas de Bactérias/metabolismo , Hemoglobinas/metabolismo , Hanseníase/microbiologia , Mycobacterium leprae/metabolismo , Ácido Peroxinitroso/metabolismo , Hemoglobinas Truncadas/metabolismo , Animais , Proteínas de Bactérias/química , Hemoglobinas/química , Humanos , Peróxido de Hidrogênio/toxicidade , Inativação Metabólica , Hanseníase/metabolismo , Mycobacterium leprae/efeitos dos fármacos , Ácido Peroxinitroso/química , Ácido Peroxinitroso/farmacologia , Hemoglobinas Truncadas/químicaRESUMO
Globins protect from the oxidative and nitrosative cell damage. Here, kinetics of peroxynitrite scavenging by ferryl sperm whale myoglobin (MbFe(IV)O) and human hemoglobin (HbFe(IV)O), between pH 5.8 and 8.3 at 20.0 degrees C, are reported. In the absence of CO(2), values of the second-order rate constant for peroxynitrite scavenging by MbFe(IV)O and HbFe(IV)O (i.e., for MbFe(III) and HbFe(III) formation; k(on)) are 4.6 x 10(4)M(-1)s(-1) and 3.3 x 10(4)M(-1)s(-1), respectively, at pH 7.1. Values of k(on) increase on decreasing pH with pK(a) values of 6.9 and 6.7, this suggests that the ONOOH species reacts preferentially with MbFe(IV)O and HbFe(IV)O. In the presence of CO(2) (=1.2 x 10(-3)M), values of k(on) for peroxynitrite scavenging by MbFe(IV)O and HbFe(IV)O are essentially pH-independent, the average k(on) values are 7.1 x 10(4)M(-1)s(-1) and 1.2 x 10(5)M(-1)s(-1), respectively. As a whole, MbFe(IV)O and HbFe(IV)O, obtained by treatment with H(2)O(2), undertake within the same cycle H(2)O(2) and peroxynitrite detoxification.
Assuntos
Hemoglobinas/metabolismo , Mioglobina/metabolismo , Ácido Peroxinitroso/metabolismo , Cachalote/metabolismo , Animais , Humanos , Ferro/metabolismo , Camundongos , OxirreduçãoRESUMO
Globins are generally considered as carriers of diatomic gaseous ligands (e.g., O(2) and NO) in metazoa. Recently, the (pseudo-)enzymatic activity of globins towards reactive nitrogen and oxygen species has been elucidated. In particular, some globins (e.g., hemoglobin and myoglobin) catalyze the enzymatic scavenging of NO and peroxynitrite in the presence of H(2)O(2). Indeed, H(2)O(2) oxidizes some globins leading to the formation of water and of the heme-protein ferryl derivative, which, in turn, oxidizes NO and peroxynitrite leading to the formation of the globin ferric species, NO(2)(-), and NO(3)(-). Here, we hypothesize that NO, peroxynitrite, and H(2)O(2) are co-substrates for the peroxidase activity of some globins, this catalytic activity was reported in 1900 for the first time, even though the substrates have never been identified firmly up to now.
Assuntos
Globinas/metabolismo , Peróxido de Hidrogênio/metabolismo , Óxido Nítrico/metabolismo , Peroxidases/metabolismo , Ácido Peroxinitroso/metabolismo , Animais , Catálise , Modelos BiológicosRESUMO
Ruxolitinib is a type I JAK inhibitor approved by FDA for targeted therapy of Philadelphia-negative myeloproliferative neoplasms (MPNs), all characterized by mutations activating the JAK2/STAT signaling pathway. Treatment with ruxolitinib improves constitutional symptoms and splenomegaly. However, patients can become resistant to treatment and chronic therapy has only a mild effect on molecular/pathologic remissions. Drugs interaction with plasma proteins, i.e. human serum albumin (HSA), is an important factor affecting the intensity and duration of their pharmacological actions. Here, the ruxolitinib recognition by the fatty acid binding sites (FAs) 1, 6, 7, and 9 of HSA has been investigated from the bioinformatics, biochemical and/or biological viewpoints. Docking simulations indicate that ruxolitinib binds to multiple sites of HSA. Ruxolitinib binds to the FA1 and FA7 sites of HSA with high affinity (Kr = 3.1 µM and 4.6 µM, respectively, at pH 7.3 and 37.0 °C). Moreover, HSA selectively blocks, in a dose dependent manner, the cytotoxic activity of ruxolitinib in JAK2V617F+ cellular models for MPN, in vitro. Furthermore this event is accompanied by changes in the cell cycle, p27Kip1 and cyclin D3 levels, and JAK/STAT signaling. Given the high plasma concentration of HSA, ruxolitinib trapping may be relevant in vivo.
Assuntos
Inibidores Enzimáticos/metabolismo , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Pirazóis/metabolismo , Albumina Sérica Humana/química , Albumina Sérica Humana/metabolismo , Substituição de Aminoácidos , Sítios de Ligação , Linhagem Celular , Biologia Computacional , Inibidores Enzimáticos/farmacologia , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Humanos , Técnicas In Vitro , Janus Quinase 2/antagonistas & inibidores , Células K562 , Cinética , Simulação de Acoplamento Molecular , Proteínas Mutantes/antagonistas & inibidores , Mutação de Sentido Incorreto , Transtornos Mieloproliferativos/sangue , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/genética , Nitrilas , Pirazóis/farmacologia , Pirimidinas , Transdução de Sinais , TermodinâmicaRESUMO
The rate of HIV-positive patients that fails to reach or to maintain a durable virological suppression under anti-retroviral (ARV) therapy might be as high as 50%, therefore new tools to improve ARV drug efficacy are urgently needed. Among others, therapeutic drug monitoring (TDM) is a strategy by which the dosing regimen for a patient is guided by measurement of plasma drug levels, enabling physicians to optimize ARV drug efficacy and to avoid drug-related toxicity. The most used analytical methods to determine plasma levels of ARV drugs are HPLC-UV and HPLC-MS(/MS), recently MALDI-based methods and enzyme immunoassay (EIA) technologies have been also employed. The wide inter-patient variability in ARV drug pharmacokinetic supports the application of TDM to the clinical management of HIV-infected patients. Drug-drug and drug-food interactions, drug binding to plasma proteins, drug sequestering by erythrocytes, hepatic impairment, sex, age, pregnancy, and host genetic factors are sources of inter-patient variability affecting ARV drug pharmacokinetics. Combining the information of TDM and resistance tests in genotypic inhibitory quotient (GIQ) is likely to be of great clinical utility. Indeed, only two clinical trials on GIQ, both conducted using ARV drugs not more commonly in use, have shown clinical benefits. The design of new trials with long follow-up and sample size representative of the current HIV prevalence is urgently needed to give indications for GIQ as an early predictor of virological response. Here, the basic principles and the available methods for TDM in the management of HIV-infected patients are reviewed.
Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/uso terapêutico , Monitoramento de Medicamentos , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/farmacocinética , Cromatografia Líquida de Alta Pressão , Ensaios Clínicos como Assunto , Interações Medicamentosas , Infecções por HIV/sangue , HIV-1/efeitos dos fármacos , Humanos , Técnicas Imunoenzimáticas , Espectrometria de Massas , Sensibilidade e Especificidade , Espectrofotometria UltravioletaRESUMO
Intracellular concentration of cholesterol is regulated by the balance between endogenous synthesis and exogenous uptake; endogenous synthesis is subject to feedback control of hepatic 3-hydroxy-3-methyl-glutaryl-CoA reductase activity, while the exogenous supply is mainly controlled by the modulation of the low-density lipoprotein receptor. During ageing, hepatic lipid modifications occur and caloric restriction are able to prevent these changes. So, the aim of this work was to evaluate the mechanisms underlying the effect exerted both by caloric restrictions and by a diet enriched with Omega-3 fatty acids, on the cholesterol plasma levels during ageing, by studying the regulation of the protein involved in cholesterol homeostasis maintenance. Livers from diet restricted and Omega-3 supplemented diet fed 24-month-old rat were used to analyze, the protein complex of cholesterol homeostasis maintenance and those ones that are able to modulate 3-hydroxy-3-methyl-glutaryl-CoA reductase. The data obtained demonstrate that both caloric restriction and Omega-3 supplemented diets are able to prevent hypercholesterolemia, by regulating HMG-CoAR activation state by controlling ROS production and p38 phosphorylation. Moreover also the age-dependent loss of LDLr membrane exposition is prevented.
Assuntos
Envelhecimento/metabolismo , Restrição Calórica , Colesterol/metabolismo , Ácidos Graxos Ômega-3/administração & dosagem , Proteínas Quinases Ativadas por AMP/metabolismo , Envelhecimento/sangue , Animais , Colesterol/biossíntese , Colesterol/sangue , Hidroximetilglutaril-CoA Redutases/metabolismo , Hipercolesterolemia/metabolismo , Hipercolesterolemia/prevenção & controle , Fígado/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Receptores de LDL/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Kinetics of ferric Mycobacterium leprae truncated hemoglobin O (trHbOFe(III)) oxidation by H2O2 and of trHbOFe(IV)O reduction by (.)NO and NO2- are reported. The value of the second-order rate constant for H2O2-mediated oxidation of trHbOFe(III) is 2.4 x 10(3) M(-1) s(-1). The value of the second-order rate constant for (.)NO-mediated reduction of trHbOFe(IV)O is 7.8 x 10(6) M(-1) s(-1). The value of the first-order rate constant for trHbOFe(III)ONO decay to the resting form trHbOFe(III) is 2.1 x 10(1) s(-1). The value of the second-order rate constant for NO2--mediated reduction of trHbOFe(IV)=O is 3.1 x 10(3) M(-1) s(-1). As a whole, trHbOFe(IV)O, generated upon reaction with H2O2, catalyzes (.)NO reduction to NO2-. In turn, (.)NO and NO2- act as antioxidants of trHbOFe(IV)O, which could be responsible for the oxidative damage of the mycobacterium. Therefore, Mycobacterium leprae trHbO could be involved in both H2O2 and (.)NO scavenging, protecting from nitrosative and oxidative stress, and sustaining mycobacterial respiration.
Assuntos
Proteínas de Bactérias/química , Peróxido de Hidrogênio/química , Óxido Nítrico/química , Hemoglobinas Truncadas/química , Catálise , Cinética , OxirreduçãoRESUMO
Epigenetic treatment has been approved by regulatory agencies for haematological malignancies. The success observed in cutaneous lymphomas represents a proof of principle that similar results may be obtained in solid tumours. Several agents that interfere with DNA methylation-demethylation and histones acetylation/deacetylation have been studied, and some (such as azacytidine, decitabine, valproic acid and vorinostat) are already in clinical use. The aim of this review is to provide a brief overview of the molecular events underlying the antitumour effects of epigenetic treatments and to summarise data available on clinical trials that tested the use of epigenetic agents against solid tumours. We not only list results but also try to indicate how the proper evaluation of this treatment might result in a better selection of effective agents and in a more rapid development. We divided compounds in demethylating agents and HDAC inhibitors. For each class, we report the antitumour activity and the toxic side effects. When available, we describe plasma pharmacokinetics and pharmacodynamic evaluation in tumours and in surrogate tissues (generally white blood cells). Epigenetic treatment is a reality in haematological malignancies and deserves adequate attention in solid tumours. A careful consideration of available clinical data however is required for faster drug development and possibly to re-evaluate some molecules that were perhaps discarded too early.
RESUMO
Retinoic acid (RA), the major bioactive metabolite of retinol or vitamin A, induces a spectrum of pleiotropic effects in cell growth and differentiation that are relevant for embryonic development and adult physiology. The RA activity is mediated primarily by members of the retinoic acid receptor (RAR) subfamily, namely RARα, RARß and RARγ, which belong to the nuclear receptor (NR) superfamily of transcription factors. RARs form heterodimers with members of the retinoid X receptor (RXR) subfamily and act as ligand-regulated transcription factors through binding specific RA response elements (RAREs) located in target genes promoters. RARs also have non-genomic effects and activate kinase signaling pathways, which fine-tune the transcription of the RA target genes. The disruption of RA signaling pathways is thought to underlie the etiology of a number of hematological and non-hematological malignancies, including leukemias, skin cancer, head/neck cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, renal cell carcinoma, pancreatic cancer, liver cancer, glioblastoma and neuroblastoma. Of note, RA and its derivatives (retinoids) are employed as potential chemotherapeutic or chemopreventive agents because of their differentiation, anti-proliferative, pro-apoptotic, and anti-oxidant effects. In humans, retinoids reverse premalignant epithelial lesions, induce the differentiation of myeloid normal and leukemic cells, and prevent lung, liver, and breast cancer. Here, we provide an overview of the biochemical and molecular mechanisms that regulate the RA and retinoid signaling pathways. Moreover, mechanisms through which deregulation of RA signaling pathways ultimately impact on cancer are examined. Finally, the therapeutic effects of retinoids are reported.
Assuntos
Neoplasias/metabolismo , Receptores do Ácido Retinoico/metabolismo , Tretinoína/metabolismo , Animais , Antineoplásicos/uso terapêutico , Feminino , Humanos , Masculino , Neoplasias/tratamento farmacológico , Receptores do Ácido Retinoico/genética , Elementos de Resposta/fisiologia , Receptor alfa de Ácido Retinoico , Receptor gama de Ácido RetinoicoRESUMO
The association between diabetes and neurodegenerative diseases is increasing with aging. Several common mechanisms are involved in both these diseases. The endothelial cells of the blood brain barrier, neurons and glia express typical and different receptors of the glucose metabolism (glucose transporters, insulin receptors and glucagon-like peptide-1 receptors). The impairment in insulin signaling leads to an impairment of neuronal function and increases neurodegeneration, and, conversely, neurodegeneration causes a reduction of insulin signaling on neurons. Increased detailed knowledge of common physiological processes opens up the opportunities for developing new treatments that may prevent or reduce the onset of neurodegenerative diseases. The aim of the review is to discuss the potential neuroprotective effects of the antidiabetic drugs. The article presents some promising patents on the treatment of insulin resistance in the neurodegeneration.