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1.
Proc Natl Acad Sci U S A ; 121(29): e2408649121, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-38980909

RESUMO

Elevated levels of miR-155 in solid and liquid malignancies correlate with aggressiveness of the disease. In this manuscript, we show that miR-155 targets transcripts encoding IcosL, the ligand for Inducible T-cell costimulator (Icos), thus impairing the ability of T cells to recognize and eliminate malignant cells. We specifically found that overexpression of miR-155 in B cells of Eµ-miR-155 mice causes loss of IcosL expression as they progress toward malignancy. Similarly, in mice where miR-155 expression is controlled by a Cre-Tet-OFF system, miR-155 induction led to malignant infiltrates lacking IcosL expression. Conversely, turning miR-155 OFF led to tumor regression and emergence of infiltrates composed of IcosL-positive B cells and Icos-positive T cells forming immunological synapses. Therefore, we next engineered malignant cells to express IcosL, in order to determine whether IcosL expression would increase tumor infiltration by cytotoxic T cells and reduce tumor progression. Indeed, overexpressing an IcosL-encoding cDNA in MC38 murine colon cancer cells before injection into syngeneic C57BL6 mice reduced tumor size and increased intratumor CD8+ T cell infiltration, that formed synapses with IcosL-expressing MC38 cells. Our results underscore the fact that by targeting IcosL transcripts, miR-155 impairs the infiltration of tumors by cytotoxic T cells, as well as the importance of IcosL on enhancing the immune response against malignant cells. These findings should lead to the development of more effective anticancer treatments based on maintaining, increasing, or restoring IcosL expression by malignant cells, along with impairing miR-155 activity.


Assuntos
Ligante Coestimulador de Linfócitos T Induzíveis , MicroRNAs , MicroRNAs/genética , MicroRNAs/metabolismo , Animais , Camundongos , Ligante Coestimulador de Linfócitos T Induzíveis/metabolismo , Ligante Coestimulador de Linfócitos T Induzíveis/genética , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linhagem Celular Tumoral , Camundongos Endogâmicos C57BL , Humanos , Linfócitos T Citotóxicos/imunologia , Regulação Neoplásica da Expressão Gênica , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Neoplasias/imunologia , Neoplasias/genética , Neoplasias/patologia
2.
Ann Diagn Pathol ; 61: 152057, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36334414

RESUMO

Pre-existing Alzheimer's disease is a risk factor for severe/fatal COVID-19 and infection by SARS-CoV2 virus has been associated with an increased incidence of un-masked Alzheimer's disease. The molecular basis whereby SARS-CoV2 may amplify Alzheimer's disease is not well understood. This study analyzed the molecular changes in autopsy brain tissues from people with pre-existing dementia who died of COVID-19 (n = 5) which was compared to equivalent tissues of people who died of COVID-19 with no history of dementia (n = 8), Alzheimer's disease pre-COVID-19 (n = 10) and aged matched controls (n = 10) in a blinded fashion. Immunohistochemistry analyses for hyperphosphorylated tau protein, α-synuclein, and ß-amyloid-42 confirmed the diagnoses of Alzheimer's disease (n = 4), and Lewy body dementia (n = 1) in the COVID-19 group. The brain tissues from patients who died of COVID-19 with no history of dementia showed a diffuse microangiopathy marked by endocytosis of spike subunit S1 and S2 in primarily CD31+ endothelia with strong co-localization with ACE2, Caspase-3, IL6, TNFα, and Complement component 6 that was not associated with SARS-CoV2 RNA. Microglial activation marked by increased TMEM119 and MCP1 protein expression closely paralleled the endocytosed spike protein. The COVID-19 tissues from people with no pre-existing dementia showed, compared to controls, 5-10× fold increases in expression of neuronal NOS and NMDAR2 as well as a marked decrease in the expression of proteins whose loss is associated with worsening Alzheimer's disease: MFSD2a, SHIP1, BCL6, BCL10, and BACH1. In COVID-19 tissues from people with dementia the widespread spike-induced microencephalitis with the concomitant microglial activation co-existed in the same areas where neurons had hyperphosphorylated tau protein suggesting that the already dysfunctional neurons were additionally stressed by the SARS-CoV2 induced microangiopathy. ACE2+ human brain endothelial cells treated with high dose (but not vaccine equivalent low dose) spike S1 protein demonstrated each of the molecular changes noted in the in vivo COVID-19 and COVID-19/Alzheimer's disease brain tissues. It is concluded that fatal COVID-19 induces a diffuse microencephalitis and microglial activation in the brain due to endocytosis of circulating viral spike protein that amplifies pre-existing dementia in at least two ways: 1) modulates the expression of proteins that may worsen Alzheimer's disease and 2) stresses the already dysfunctional neurons by causing an acute proinflammatory/hypercoagulable/hypoxic microenvironment in areas with abundant hyperphosphorylated tau protein and/or ßA-42.


Assuntos
Doença de Alzheimer , COVID-19 , Idoso , Humanos , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Enzima de Conversão de Angiotensina 2 , COVID-19/complicações , Células Endoteliais/metabolismo , RNA Viral , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Proteínas tau/metabolismo , Sistema Nervoso Central
3.
Front Mol Neurosci ; 15: 788301, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35185466

RESUMO

Aortic aneurism open repair surgery can cause spinal cord (SC) injury with 5-15% of patients developing paraparesis or paraplegia. Using a mouse model of transient aortic cross-clamping (ACC), we have previously found that the expression of proinflammatory microRNA miR-155 increases in motoneurons (MNs) and endothelial cells (ECs) of ischemic SCs, and that global miR-155 deletion decreases the percentage of paraplegia by 37.4% at 48-h post-ACC. Here, we investigated the cell-specific contribution of miR-155 in choline acetyltransferase-positive (ChAT+) neurons (that include all MNs of the SC) and ECs to SC injury after ACC. Mice lacking miR-155 in ChAT+ neurons (MN-miR-155-KO mice) developed 24.6% less paraplegia than control mice at 48-h post-ACC. In contrast, mice lacking miR-155 in ECs (ECs-miR-155-KO mice) experienced the same percentage of paraplegia as control mice, despite presenting smaller central cord edema. Unexpectedly, mice overexpressing miR-155 in ChAT+ neurons were less likely than control mice to develop early paraplegia during the first day post-ACC, however they reached the same percentage of paraplegia at 48-h. In addition, all mice overexpressing miR-155 in ECs (ECs-miR-155-KI mice) were paraplegic at 48-h post-ACC. Altogether, our results suggest that miR-155 activity in ChAT+ neurons protects the SC against ischemic injury during the first day post-ACC before becoming deleterious during the second day, which indicates that early and late paraplegias arise from different molecular malfunctions. These results point to the need to develop specific protective therapeutics aimed at inhibiting both the early and late deleterious events after open repair surgery of aortic aneurisms.

4.
Ann Diagn Pathol ; 57: 151881, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34968863

RESUMO

Hepatic disease is common in severe COVID-19. This study compared the histologic/molecular findings in the liver in fatal COVID-19 (n = 9) and age-matched normal controls (n = 9); three of the fatal COVID-19 livers had pre-existing alcohol use disorder (AUD). Controls showed a high resident population of sinusoidal macrophages that had variable ACE2 expression. Histologic findings in the cases included periportal/lobular inflammation. SARS-CoV2 RNA and nucleocapsid protein were detected in situ in 2/9 COVID-19 livers in low amounts. In 9/9 cases, there was ample in situ SARS-CoV-2 spike protein that co-localized with viral matrix and envelope proteins. The number of cells positive for spike/100× field was significantly greater in the AUD/COVID-19 cases (mean 5.9) versus the non-AUD/COVID-19 cases (mean 0.4, p < 0.001) which was corroborated by Western blots. ACE2+ cells were 10× greater in AUD/COVID-19 livers versus the other COVID-19/control liver samples (p < 0.001). Co-expression experiments showed that the spike protein localized to the ACE2 positive macrophages and, in the AUD cases, hepatic stellate cells that were activated as evidenced by IL6 and TNFα expression. Injection of the S1, but not S2, subunit of spike in mice induced hepatic lobular inflammation in activated macrophages. It is concluded that endocytosed viral spike protein can induce hepatitis in fatal COVID-19. This spike induced hepatitis is more robust in the livers with pre-existing AUD which may relate to why patients with alcohol abuse are at higher risk of severe liver disease with SARS-CoV2 infection.


Assuntos
Alcoolismo/patologia , COVID-19/patologia , Hepatopatias/patologia , Idoso , Alcoolismo/complicações , Animais , COVID-19/complicações , Feminino , Humanos , Hepatopatias/complicações , Masculino , Camundongos , Pessoa de Meia-Idade
5.
Sci Rep ; 11(1): 7834, 2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33837260

RESUMO

Both endovascular repair (EVR) and open repair (OR) surgery of thoraco-abdominal aortic aneurysms cause spinal cord (SC) injury that can lead to paraparesis or paraplegia. It has been assumed that mechanisms responsible for SC damage after EVR are similar to those after OR. This pilot study compared the pathophysiology of SC injury after EVR versus OR using a newly developed EVR dog model. An increasing number of stents similar to those used in patients were inserted in the aorta of three dogs to ensure thoracic or thoracic plus lumbar coverage. The aorta of OR dogs was cross-clamped for 45 min. Behavior assessment demonstrated unique patterns of proprioceptive ataxia and evolving paraparesis in EVR versus irreversible paraplegia in OR. MRI showed posterior signal in lumbar SC after EVR versus central cord edema after OR. Histopathology showed white matter edema in L3-L5 localized to the dorsal column medial lemniscus area associated with loss of myelin basic protein but not neurons after EVR, versus massive neuronal loss in the gray matter in L3-L5 after OR. Metabolome analysis demonstrates a distinctive chemical fingerprint of cellular processes in both interventions. Our results call for the development of new therapeutics tailored to these distinct pathophysiologic findings.


Assuntos
Aneurisma da Aorta Torácica/cirurgia , Implante de Prótese Vascular/efeitos adversos , Prótese Vascular/efeitos adversos , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/métodos , Complicações Pós-Operatórias/etiologia , Traumatismos da Medula Espinal/etiologia , Stents/efeitos adversos , Animais , Comportamento Animal , Angiografia por Tomografia Computadorizada/métodos , Modelos Animais de Doenças , Cães , Imageamento por Ressonância Magnética/métodos , Masculino , Metaboloma , Paraplegia/etiologia , Projetos Piloto , Complicações Pós-Operatórias/diagnóstico por imagem , Medula Espinal/diagnóstico por imagem , Traumatismos da Medula Espinal/diagnóstico por imagem , Resultado do Tratamento
6.
Ann Diagn Pathol ; 51: 151682, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33360731

RESUMO

Neurologic complications of symptomatic COVID-19 are common. Brain tissues from 13 autopsies of people who died of COVID-19 were examined. Cultured endothelial and neuronal cells were incubated with and wild type mice were injected IV with different spike subunits. In situ analyses were used to detect SARS-CoV-2 proteins and the host response. In 13/13 brains from fatal COVID-19, pseudovirions (spike, envelope, and membrane proteins without viral RNA) were present in the endothelia of microvessels ranging from 0 to 14 positive cells/200× field (mean 4.3). The pseudovirions strongly co-localized with caspase-3, ACE2, IL6, TNFα, and C5b-9. The surrounding neurons demonstrated increased NMDAR2 and neuronal NOS plus decreased MFSD2a and SHIP1 proteins. Tail vein injection of the full length S1 spike subunit in mice led to neurologic signs (increased thirst, stressed behavior) not evident in those injected with the S2 subunit. The S1 subunit localized to the endothelia of microvessels in the mice brain and showed co-localization with caspase-3, ACE2, IL6, TNFα, and C5b-9. The surrounding neurons showed increased neuronal NOS and decreased MFSD2a. It is concluded that ACE2+ endothelial damage is a central part of SARS-CoV2 pathology and may be induced by the spike protein alone. Thus, the diagnostic pathologist can use either hematoxylin and eosin stain or immunohistochemistry for caspase 3 and ACE2 to document the endothelial cell damage of COVID-19.


Assuntos
COVID-19/virologia , Células Endoteliais/virologia , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Autopsia/métodos , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Feminino , Humanos , Masculino , Camundongos , Microvasos/metabolismo , Microvasos/virologia , Pessoa de Meia-Idade , Subunidades Proteicas/metabolismo , RNA Viral/genética , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética
7.
Genes Chromosomes Cancer ; 58(4): 208-218, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30382602

RESUMO

MicroRNAs are small noncoding RNAs that modulate gene expression either directly, by impairing the stability and/or translation of transcripts that contain their specific target sequence, or indirectly through the targeting of transcripts that encode transcription factors, factors implicated in signal transduction pathways, or epigenetic regulators. Abnormal expression of micro-RNAs has been found in nearly all types of pathologies, including cancers. MiR-155 has been the first microRNA to be implicated in the regulation of the innate and adaptative immune responses, and its expression is either increased or decreased in a variety of liquid and solid malignancies. In this review, we examine the oncogenic and antitumor potentials of miR-155, with special emphasize on its dose-dependent effects. We describe the impact of miR-155 levels on antitumor activity of lymphocytes and myeloid cells. We discuss miR-155 dose-dependent effects in leukemias and analyze results showing that miR-155 intermediate levels tend to be detrimental, whereas high levels of miR-155 expression usually prove beneficial. We also examine the beneficial effects of high levels of miR-155 expression in solid tumors. We discuss the possible causal involvement of miR-155 in leukemias and dementia in individuals with Down's syndrome. We finally propose that increasing miR-155 levels in immune cells might increase the efficiency of newly developed cancer immunotherapies, due to miR-155 ability to target transcripts encoding immune checkpoints such as cytotoxic T lymphocyte antigen-4 or programmed death-ligand 1.


Assuntos
Carcinogênese/genética , Leucemia/genética , MicroRNAs/genética , Evasão Tumoral/genética , Animais , Carcinogênese/imunologia , Síndrome de Down/genética , Síndrome de Down/imunologia , Humanos , Imunoterapia/métodos , Leucemia/imunologia , Leucemia/terapia , MicroRNAs/metabolismo
9.
Medicines (Basel) ; 5(3)2018 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-29987196

RESUMO

Resveratrol (trans-3,5,4′-trihydroxystilbene, RSV) is a non-flavonoid dietary polyphenol with antioxidant, anti-inflammatory and anti-cancer properties that is primarily found in red berries. While RSV displays many beneficial effects in vitro, its actual effects in vivo or in animal models remain passionately debated. Recent publications suggest that RSV pleiotropic effects could arise from its capability to regulate the expression and activity of microRNAs, short regulators themselves capable of regulating up to several hundreds of target genes. In particular, RSV increases microRNA miR-663 expression in different human cell lines, suggesting that at least some of its multiple beneficial properties are through the modulation of expression of this microRNA. Indeed, the expression of microRNA miR-663 is reduced in certain cancers where miR-663 is considered to act as a tumor suppressor gene, as well as in other pathologies such as cardiovascular disorders. Target of miR-663 include genes involved in tumor initiation and/or progression as well as genes involved in pathologies associated with chronic inflammation. Here, we review the direct and indirect effects of RSV on the expression of miR-663 and its target transcripts, with emphasise on TGFβ1, and their expected health benefits, and argue that elucidating the molecular effects of different classes of natural compounds on the expression of microRNAs should help to identify new therapeutic targets and design new treatments.

10.
Ann Diagn Pathol ; 36: 12-20, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29966831

RESUMO

Spinal cord paralysis is relatively common after surgical repair of thoraco-abdominal aortic aneurysm (TAAA) and its etiology is unknown. The present study was designed to examine the histopathology of the disease and investigate whether miR-155 ablation would reduce spinal cord ischemic damage and delayed hindlimb paralysis induced by aortic cross-clamping (ACC) in our mouse model. The loss of locomotor function in ACC-paralyzed mice correlated with the presence of extensive gray matter damage and central cord edema, with minimal white matter histopathology. qRTPCR and Western blotting showed that the spinal cords of wild-type ACC mice that escaped paralysis showed lower miR-155 expression and higher levels of transcripts encoding Mfsd2a, which is implicated in the maintenance of blood-brain barrier integrity. In situ based testing demonstrated that increased miR-155 detection in neurons was highly correlated with the gray matter damage and the loss of one of its targets, Mfsd2a, could serve as a good biomarker of the endothelial cell damage. In vitro, we demonstrated that miR-155 targeted Mfsd2a in endothelial cells and motoneurons and increased endothelial cell permeability. Finally, miR-155 ablation slowed the progression of central cord edema, and reduced the incidence of paralysis by 40%. In sum, the surgical pathology findings clearly indicated that the epicenter of the ischemic-induced paralysis was the gray matter and that endothelial cell damage correlated to Mfsd2a loss is a good biomarker of the disease. MiR-155 targeting therefore offers new therapeutic opportunity for edema caused by traumatic spinal cord injury and diagnostic pathologists, by using immunohistochemistry, can clarify if this mechanism also is important in other ischemic diseases of the CNS, including stroke.


Assuntos
Isquemia/metabolismo , Proteínas de Membrana Transportadoras/genética , MicroRNAs/genética , Traumatismos da Medula Espinal/genética , Animais , Modelos Animais de Doenças , Imuno-Histoquímica/métodos , Isquemia/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/metabolismo , Doenças do Sistema Nervoso/genética , Neurônios/metabolismo , Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia , Simportadores , Proteínas Supressoras de Tumor/genética
11.
Ann Diagn Pathol ; 34: 103-109, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29661714

RESUMO

This study examined the molecular correlates of Down's dementia. qRTPCR for chromosome 21 microRNAs was correlated with in situ hybridization, immunohistochemistry for microRNA targets, mRNAs located on chromosome 21, and neurofibrillary tangles in human and the Ts65 dn mouse Down's model. qRTPCR for the microRNAs on the triplicated chromosome showed miR-155 dominance in brain tissues (14.3 fold increase, human and 24.2 fold increase, mouse model) that co-expressed with hyperphosphorylated tau protein. miR-155 was not elevated in Alzheimer's disease or neonates with Downs' syndrome. Chromosome 21 genes APP/BA-42, DYRK1a and BACH1 were not correlated to pathologic changes in Down's dementia. Validated CNS targets of miR-155 that were present in controls and Alzheimer's disease but lacking in Down's dementia brains included BACH1, CoREST1, bcl6, BIM, bcl10, cyclin D, and SAPK4. It is concluded that Down's dementia strongly correlated with overexpression of chromosome 21 microRNA 155 with concomitant reduction of multiple CNS-functional targets. This study highlights the need for anatomic pathologists to determine the specific and diverse pathways cells may take to form neurofibrillary tangles in the different dementias.


Assuntos
Doença de Alzheimer/genética , Demência/genética , Síndrome de Down/genética , MicroRNAs/genética , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Síndrome de Down/patologia , Humanos , Imuno-Histoquímica , Camundongos , MicroRNAs/isolamento & purificação , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Regulação para Cima
12.
Curr Opin Pharmacol ; 37: 142-150, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29154194

RESUMO

The initiation and development or inflammatory bowel disease (IBD) and associated colorectal cancers, have been linked to inflammation. MicroRNAs are non-coding regulators of gene expression that have gained great attention due to their capability to regulate the expression of a number of target transcripts. It is now generally admitted that microRNAs are instrumental in gut pathologies, in particular through their targeting of transcripts encoding proteins of the intestinal barrier (IB) and their regulators. Intense research is conducted to identify microRNAs susceptible to be used as biomarkers and to design new therapeutic approaches based upon using synthetic microRNA mimics and inhibitors as well as finding new drugs capable to restore or modify microRNA expression in the context of gut pathologies.


Assuntos
Doenças Inflamatórias Intestinais/genética , Mucosa Intestinal/metabolismo , MicroRNAs/metabolismo , Neoplasias/genética , Animais , Biomarcadores , Humanos , Inflamação/complicações , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/metabolismo
13.
Molecules ; 21(9)2016 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-27657035

RESUMO

Recent years have seen the exploration of a puzzling number of compounds found in human diet that could be of interest for prevention or treatment of various pathologies. Although many of these natural products (NPs) have long been used as remedies, their molecular effects still remain elusive. With the advent of biotechnology revolution, NP studies turned from chemistry and biochemistry toward global analysis of gene expression. Hope is to use genetics to identify groups of patient for whom certain NPs or their derivatives may offer new preventive or therapeutic treatments. Recently, microRNAs have gained the statute of global regulators controlling cell homeostasis by regulating gene expression through genetic and epigenetic regulatory loops. Realization that certain plant polyphenols can modify microRNA expression and thus impact gene expression globally, initiated new, mainly in vitro studies, in particular to determine phytochemicals effects on inflammatory response, whose exacerbation has been linked to several disorders including cancer, auto-immune, metabolic, cardiovascular and neuro-inflammatory diseases. However, very few mechanistic insights have been provided, given the complexity of genetic regulatory networks implicated. In this review, we will concentrate on data showing the potential interest of some plant polyphenols in manipulating the expression of pro- and anti-inflammatory microRNAs in pathological conditions.

14.
Oncotarget ; 6(28): 24599-610, 2015 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-26337206

RESUMO

Quaking (QKI) is a tumor-suppressor gene encoding a conserved RNA-binding protein, whose expression is downregulated in several solid tumors. Here we report that QKI plays an important role in the immune response and suppression of leukemogenesis. We show that the expression of Qki is reduced in lipopolysaccharide (LPS)-challenged macrophages, suggesting that Qki is a key regulator of LPS signaling pathway. Furthermore, LPS-induced downregulation of Qki expression is miR-155-dependent. Qki overexpression impairs LPS-induced phosphorylation of JNK and particularly p38 MAPKs, in addition to increasing the production of anti-inflammatory cytokine IL-10. In contrast, Qki ablation decreases Fas expression and the rate of Caspase3/7 activity, while increasing the levels of IL-1α, IL-1ß and IL-6, and p38 phosphorylation. Similarly, the p38 pathway is also a target of QKI activity in chronic lymphocytic leukemia (CLL)-derived MEC2 cells. Finally, B-CLL patients show lower levels of QKI expression compared with B cells from healthy donor, and Qki is similarily downregulated with the progression of leukemia in Eµ-miR-155 transgenic mice. Altogether, these data implicate QKI in the pathophysiology of inflammation and oncogenesis where miR-155 is involved.


Assuntos
Linfócitos B/metabolismo , Inflamação/metabolismo , Leucemia Linfocítica Crônica de Células B/metabolismo , Macrófagos/metabolismo , MicroRNAs/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Linfócitos B/imunologia , Linfócitos B/patologia , Estudos de Casos e Controles , Citocinas/metabolismo , Humanos , Imunidade Inata , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/patologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Camundongos Transgênicos , MicroRNAs/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação , Células RAW 264.7 , Proteínas de Ligação a RNA/genética , Transdução de Sinais , Fatores de Tempo , Transfecção , Células U937
15.
Ann N Y Acad Sci ; 1348(1): 97-106, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26190093

RESUMO

This review presents recent evidence implicating microRNAs (miRNAs) in the beneficial effects of resveratrol (trihydroxystilbene), a nonflavonoid plant polyphenol, with emphasis on its anti-inflammatory effects. Many diseases and pathologies have been linked, directly or indirectly, to inflammation. These include infections, injuries, atherosclerosis, diabetes mellitus, obesity, cancer, osteoarthritis, age-related macular degeneration, demyelination, and neurodegenerative diseases. Resveratrol can both decrease the secretion of proinflammatory cytokines (e.g., IL-6, IL-8, and TNF-α) and increase the production of anti-inflammatory cytokines; it also decreases the expression of adhesion proteins (e.g., ICAM-1) and leukocyte chemoattractants (e.g., MCP-1). Resveratrol's primary targets appear to be the transcription factors AP-1 and NF-κB, as well as the gene COX2. Although no mechanistic link between any particular miRNA and resveratrol has been identified, resveratrol effects depend at least in part upon the modification of the expression of a variety of miRNAs that can be anti-inflammatory (e.g., miR-663), proinflammatory (e.g., miR-155), tumor suppressing (e.g., miR-663), or oncogenic (e.g., miR-21).


Assuntos
Anti-Inflamatórios/farmacologia , MicroRNAs/fisiologia , Estilbenos/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Ácidos Araquidônicos/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Imunidade Inata , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Interferência de RNA , Resveratrol , Estilbenos/uso terapêutico
16.
J Sci Food Agric ; 93(13): 3155-64, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23674481

RESUMO

Besides synthesizing nutritive substances (proteins, fats and carbohydrates) for energy and growth, plants produce numerous non-energetic so-called secondary metabolites (mainly polyphenols) that allow them to protect themselves against infections and other types of hostile environments. Interestingly, these polyphenols often provide cells with valuable bioactive properties for the maintenance of their functions and homeostasis (signaling, gene regulation, protection against acquired or infectious diseases, etc.) both in humans and animals. Namely, from a nutritional point of view, and based on epidemiological data, it is now well accepted that the regular consumption of green vegetables, fruits and fibers has protective effects against the onset of cancer as well as of inflammatory, neurodegenerative, metabolic and cardiovascular diseases, and consequently increases the overall longevity. In particular, grapevine plants produce large amounts of a wide variety of polyphenols. The most prominent of those-resveratrol-has been shown to impair or delay cardiovascular alterations, cancer, inflammation, aging, etc. Until recently, the molecular bases of the pleiotropic effects of resveratrol remained largely unclear despite numerous studies on a variety of signaling pathways and the transcriptional networks that they control. However, it has been recently proposed that the protective properties of resveratrol may arise from its modulation of small non-coding regulatory RNAs, namely microRNAs. The aim of this review is to present up-to-date data on the control of microRNA expression by dietary phytophenols in different types of human cells, and their impact on cell differentiation, cancer development and the regulation of the inflammatory response.


Assuntos
Fenômenos Fisiológicos Celulares/efeitos dos fármacos , Dieta , Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , Fenóis/administração & dosagem , Plantas/química , Animais , Antioxidantes/administração & dosagem , Doenças Cardiovasculares/prevenção & controle , Diferenciação Celular/efeitos dos fármacos , Fibras na Dieta , Frutas , Homeostase/efeitos dos fármacos , Humanos , Inflamação/prevenção & controle , MicroRNAs/fisiologia , Neoplasias/prevenção & controle , Polifenóis/administração & dosagem , Resveratrol , Transdução de Sinais/efeitos dos fármacos , Estilbenos/administração & dosagem , Verduras
17.
Immunol Rev ; 253(1): 167-84, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23550646

RESUMO

It is now largely admitted that a pro-inflammatory environment may curtail anti-tumor immunity and favor cancer initiation and progression. The discovery that small non-coding regulatory RNAs, namely microRNAs (miRNAs), regulate all aspects of cell proliferation, differentiation, and function has shed a new light on regulatory mechanisms linking inflammation and cancer. Thus, miRNAs such as miR-21, miR-125b, miR-155, miR-196, and miR-210 that are critical for the immune response or hypoxia are often overexpressed in cancers and leukemias. Given the high number of their target transcripts, their deregulation may have a number of deleterious consequences, depending on the cellular context. In this review, we focus on how the factors encoded by transcripts targeted by these five miRNAs, be they transcription factors, tumor-suppressors, or regulators of different signaling pathways, can deregulate the immune response and favor pro-tumor immunity. Furthermore, we expose how the misdirected action of the main regulators of these miRNAs, such as nuclear factor κB (NF-κB), activator protein-1 (AP-1), and signal transduction and activators of transcription (STAT) transcription factors, or AKT and transforming growth factor ß (TGFß) signaling pathways, can contribute to decrease anti-tumor immunity and enhance cell proliferation and oncogenesis. We conclude by briefly discussing about how these discoveries may possibly lead to the development of new miRNA-based cancer therapies.


Assuntos
Transformação Celular Neoplásica , Inflamação/imunologia , MicroRNAs/imunologia , Neoplasias/imunologia , Animais , Terapia Biológica , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Imunidade/genética , Inflamação/genética , Neoplasias/genética , Neoplasias/terapia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/imunologia , Evasão Tumoral
18.
Biochem Pharmacol ; 84(10): 1251-9, 2012 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-22975027

RESUMO

Resveratrol is one of the most widely studied bio-active plant polyphenols. While its effect on endothelial blood vessel cells, cancer cells, inflammatory processes and neurodegenerative events is well documented, little is known about the implication of this phytophenol in differentiating processes, particularly in skeletal muscle cells. Here, we report the effects of resveratrol on mouse skeletal muscle-derived cells (C2C12) in either a nondifferentiated (myoblasts) or differentiated state (myotubes) by evaluating resveratrol uptake, cell proliferation, changes in cell shape, and the expression of genes encoding muscle-specific transcription factors or contractile proteins. Resveratrol: (1) rapidly accumulates within cells through passive and facilitated processes; (2) does not strongly affect cell viability, cell cycle and apoptosis; (3) behaves as a pro-differentiating agent as shown by the lengthening of cells, leading to a myotube phenotype; (4) upregulates muscular pro-differentiation markers and transcription factors (myogenin, Scrp3) starting after 12h of exposure and strongly increases heavy chain myosin content after 18h of exposure to resveratrol; (5) increases the Srf transcription factor's transcript level, a target mRNA of the miRNA-133b, which is itself downregulated by this polyphenol. These results put forward new pro-differentiating regulatory properties of resveratrol on skeletal muscles at least partly via modulation of specific miRNAs.


Assuntos
Fibras Musculares Esqueléticas/efeitos dos fármacos , Mioblastos Esqueléticos/efeitos dos fármacos , Estilbenos/farmacologia , Animais , Diferenciação Celular , Linhagem Celular , Proliferação de Células , Forma Celular/efeitos dos fármacos , Camundongos , MicroRNAs/genética , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/metabolismo , Mioblastos Esqueléticos/citologia , Mioblastos Esqueléticos/metabolismo , Miosinas/metabolismo , Resveratrol , Fatores de Transcrição/metabolismo , Transcrição Gênica
19.
Blood ; 120(13): 2631-8, 2012 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-22723551

RESUMO

MiR-125b-1 maps at 11q24, a chromosomal region close to the epicenter of 11q23 deletions in chronic lymphocytic leukemias (CLLs). Our results establish that both aggressive and indolent CLL patients show reduced expression of miR-125b. Overexpression of miR-125b in CLL-derived cell lines resulted in the repression of many transcripts encoding enzymes implicated in cell metabolism. Metabolomics analyses showed that miR-125b overexpression modulated glucose, glutathione, lipid, and glycerolipid metabolism. Changes on the same metabolic pathways also were observed in CLLs. We furthermore analyzed the expression of some of miR-125b-target transcripts that are potentially involved in the aforementioned metabolic pathways and defined a miR-125b-dependent CLL metabolism-related transcript signature. Thus, miR-125b acts as a master regulator for the adaptation of cell metabolism to a transformed state. MiR-125b and miR-125b-dependent metabolites therefore warrant further investigation as possible novel therapeutic approaches for patients with CLL.


Assuntos
Biomarcadores Tumorais/genética , Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Leucemia Linfocítica Crônica de Células B/genética , MicroRNAs/genética , Linfócitos B/metabolismo , Biomarcadores Tumorais/metabolismo , Western Blotting , Proliferação de Células , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Células Cultivadas , Perfilação da Expressão Gênica , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Metabolômica , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
20.
J Agric Food Chem ; 60(36): 8783-9, 2012 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-22571175

RESUMO

Grapes produce large amounts of polyphenols. Many of them accumulate in the skin, pulp, and seeds and are consequently found in wine. The health benefits of a moderate consumption of wine have been attributed at least in part to grape's polyphenols. Among them, resveratrol (3,5,4'-trihydroxystilbene) is a phytoalexin that stimulates plant cell defenses against infections and also plays protective roles in humans, where it delays cardiovascular alterations and exerts anticancer and anti-inflammatory effects. Despite numerous studies, the molecular mechanisms of resveratrol action are only partially understood. Given its pleiotropic effects, it was previously suggested that resveratrol protective properties may arise from its modulation of the expression of microRNAs. Therefore, this review will focus on the effects of resveratrol on microRNA populations in humans and human cell lines, especially emphasizing the microRNAs that have been implicated in resveratrol effects on inflammation, cancer, metabolism, and muscle differentiation.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Neoplasias/genética , Extratos Vegetais/farmacologia , Estilbenos/farmacologia , Animais , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Resveratrol , Vitis/química
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