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1.
Neurogastroenterol Motil ; : e13808, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32114712

RESUMO

BACKGROUND: Electroacupuncture (EA) is widely used in various gastrointestinal diseases around the world, including POI. Here, we investigated different therapeutic effects of EA using lower limb and abdomen acupoints. METHODS: Intestinal manipulation was performed in 88 mice, and eight mice underwent a sham operation. Forty mice were randomly divided into model group and four EA groups receiving stimulation at ST36 (2, 10, 30, 100 Hz). The most effective frequency was then used in the following experiments. Forty-eight mice were randomly divided into six groups receiving EA treatment at ST37, ST39, ST25, CV4, CV12, and a non-acupuncture point. Gastrointestinal motility and plasma TNF-α, IL-6 were evaluated in all mice. The local immune response and α-smooth muscle actin (α-SMA) expression were assessed by immunofluorescence, ELISA, and HE staining. RESULTS: ST36 stimulated with 10 or 30 Hz EA significantly increased the gastrointestinal motility and attenuated peripheral inflammation; however, ST36 stimulated with 2 or 100 Hz did not induce any effect. The therapeutic effects on motility and inflammation of 10 Hz EA in the ST36 group were similar in the ST36, ST37, ST39, or CV4 groups, but when applied to ST25, CV12 or non-acupoint had no significant differences. EA at ST36, ST37, ST39, or CV4 significantly inhibited local MPO activity, immune cells infiltration, and increased α-SMA. CONCLUSIONS: EA at lower limb and abdomen acupoints with the same stimulation parameters had different therapeutic effects on postoperative dysmotility and inflammation. Furthermore, EA protected SMC to improve gastrointestinal transit by reducing local inflammation in the intestinal musculature in POI.

2.
Nat Commun ; 11(1): 588, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32001709

RESUMO

Alteration of normal ploidy (aneuploidy) can have a number of opposing effects, such as unbalancing protein abundances and inhibiting cell growth but also accelerating genetic diversification and rapid adaptation. The interplay of these detrimental and beneficial effects remains puzzling. Here, to understand how cells develop tolerance to aneuploidy, we subject disomic (i.e. with an extra chromosome copy) strains of yeast to long-term experimental evolution under strong selection, by forcing disomy maintenance and daily population dilution. We characterize mutations, karyotype alterations and gene expression changes, and dissect the associated molecular strategies. Cells with different extra chromosomes accumulated mutations at distinct rates and displayed diverse adaptive events. They tended to evolve towards normal ploidy through chromosomal DNA loss and gene expression changes. We identify genes with recurrent mutations and altered expression in multiple lines, revealing a variant that improves growth under genotoxic stresses. These findings support rapid evolvability of disomic strains that can be used to characterize fitness effects of mutations under different stress conditions.

3.
Nat Genet ; 52(2): 177-186, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32015526

RESUMO

Lung cancer is the world's leading cause of cancer death and shows strong ancestry disparities. By sequencing and assembling a large genomic and transcriptomic dataset of lung adenocarcinoma (LUAD) in individuals of East Asian ancestry (EAS; n = 305), we found that East Asian LUADs had more stable genomes characterized by fewer mutations and fewer copy number alterations than LUADs from individuals of European ancestry. This difference is much stronger in smokers as compared to nonsmokers. Transcriptomic clustering identified a new EAS-specific LUAD subgroup with a less complex genomic profile and upregulated immune-related genes, allowing the possibility of immunotherapy-based approaches. Integrative analysis across clinical and molecular features showed the importance of molecular phenotypes in patient prognostic stratification. EAS LUADs had better prediction accuracy than those of European ancestry, potentially due to their less complex genomic architecture. This study elucidated a comprehensive genomic landscape of EAS LUADs and highlighted important ancestry differences between the two cohorts.

4.
Gastroenterology ; 157(6): 1615-1629.e17, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31446059

RESUMO

BACKGROUND & AIMS: Some oncogenes encode transcription factors, but few drugs have been successfully developed to block their activity specifically in cancer cells. The transcription factor SALL4 is aberrantly expressed in solid tumor and leukemia cells. We developed a screen to identify compounds that reduce the viability of liver cancer cells that express high levels of SALL4, and we investigated their mechanisms. METHODS: We developed a stringent high-throughput screening platform comprising unmodified SNU-387 and SNU-398 liver cancer cell lines and SNU-387 cell lines engineered to express low and high levels of SALL4. We screened 1597 pharmacologically active small molecules and 21,575 natural product extracts from plant, bacteria, and fungal sources for those that selectively reduce the viability of cells with high levels of SALL4 (SALL4hi cells). We compared gene expression patterns of SALL4hi cells vs SALL4-knockdown cells using RNA sequencing and real-time polymerase chain reaction analyses. Xenograft tumors were grown in NOD/SCID gamma mice from SALL4hi SNU-398 or HCC26.1 cells or from SALL4lo patient-derived xenograft (PDX) cells; mice were given injections of identified compounds or sorafenib, and the effects on tumor growth were measured. RESULTS: Our screening identified 1 small molecule (PI-103) and 4 natural compound analogues (oligomycin, efrapeptin, antimycin, and leucinostatin) that selectively reduced viability of SALL4hi cells. We performed validation studies, and 4 of these compounds were found to inhibit oxidative phosphorylation. The adenosine triphosphate (ATP) synthase inhibitor oligomycin reduced the viability of SALL4hi hepatocellular carcinoma and non-small-cell lung cancer cell lines with minimal effects on SALL4lo cells. Oligomycin also reduced the growth of xenograft tumors grown from SALL4hi SNU-398 or HCC26.1 cells to a greater extent than sorafenib, but oligomycin had little effect on tumors grown from SALL4lo PDX cells. Oligomycin was not toxic to mice. Analyses of chromatin immunoprecipitation sequencing data showed that SALL4 binds approximately 50% of mitochondrial genes, including many oxidative phosphorylation genes, to activate their transcription. In comparing SALL4hi and SALL4-knockdown cells, we found SALL4 to increase oxidative phosphorylation, oxygen consumption rate, mitochondrial membrane potential, and use of oxidative phosphorylation-related metabolites to generate ATP. CONCLUSIONS: In a screening for compounds that reduce the viability of cells that express high levels of the transcription factor SALL4, we identified inhibitors of oxidative phosphorylation, which slowed the growth of xenograft tumors from SALL4hi cells in mice. SALL4 activates the transcription of genes that regulate oxidative phosphorylation to increase oxygen consumption, mitochondrial membrane potential, and ATP generation in cancer cells. Inhibitors of oxidative phosphorylation might be used for the treatment of liver tumors with high levels of SALL4.


Assuntos
Antineoplásicos/farmacologia , Ensaios de Triagem em Larga Escala/métodos , Neoplasias Hepáticas/tratamento farmacológico , Fatores de Transcrição/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Fosforilação Oxidativa/efeitos dos fármacos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Acupunct Med ; 37(5): 283-291, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31166115

RESUMO

BACKGROUD: Patients with multiple infarct dementia (MID) have subtle deficits that commonly go unnoticed, and are at risk of developing Alzheimer's disease. Oxidative stress induced by ischaemic injury results in intracellular calcium accumulation and neuronal apoptosis, leading to cognitive impairment by triggering various cellular signal transduction pathways. Several studies have suggested that NF-κB in the presence of p53 has a pro-apoptotic function in various models, but the mechanism is unclear. AIMS: The aim of this study was to investigate whether acupuncture could protect cognitive function against cerebral multi-infarction (CMi) induced oxidative stress by inhibiting the activation of NF-κB and its target gene p53. METHODS: An animal model of CMi was established by injecting homologous blood emboli into the right internal carotid artery of male Wistar rats. After 2 weeks of acupuncture treatment, cognitive function was detected by novel object recognition. Electron spin resonance and Fluo-3 fuorescence imaging were used to test the generation of ROS and intracellular calcium accumulation, respectively. Expression of NF-κB and p53 was examined by Western blot analysis and immunofluorescence. RESULTS: CMi induced spatial learning and memory impairment, overproduction of intracellular hydroxyl radicals, and elevations of Ca2+, which were ameliorated by verum acupuncture treatment. Acupuncture inhibited activation of NF-κB and its downstream target gene p53. CONCLUSION: These findings suggest that acupuncture could protect cognitive function against oxidative stress induced by CMi, which is partially associated with suppression of NF-κB-p53 activation.


Assuntos
Terapia por Acupuntura , Infarto Cerebral/terapia , Disfunção Cognitiva/terapia , NF-kappa B/metabolismo , Estresse Oxidativo , Animais , Cálcio/metabolismo , Infarto Cerebral/genética , Infarto Cerebral/metabolismo , Infarto Cerebral/psicologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/psicologia , Modelos Animais de Doenças , Humanos , Masculino , NF-kappa B/genética , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
6.
Nat Med ; 25(6): 1022, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31114058

RESUMO

In the version of this article originally published, there is an error in Fig. 5a. Originally, 'MAT2A' appeared between 'Methionine' and 'Homocysteine'. 'MAT2A' should have been 'MTR'. The error has been corrected in the PDF and HTML versions of this article.

7.
Nat Med ; 25(5): 825-837, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31061538

RESUMO

Understanding cellular metabolism holds immense potential for developing new classes of therapeutics that target metabolic pathways in cancer. Metabolic pathways are altered in bulk neoplastic cells in comparison to normal tissues. However, carcinoma cells within tumors are heterogeneous, and tumor-initiating cells (TICs) are important therapeutic targets that have remained metabolically uncharacterized. To understand their metabolic alterations, we performed metabolomics and metabolite tracing analyses, which revealed that TICs have highly elevated methionine cycle activity and transmethylation rates that are driven by MAT2A. High methionine cycle activity causes methionine consumption to far outstrip its regeneration, leading to addiction to exogenous methionine. Pharmacological inhibition of the methionine cycle, even transiently, is sufficient to cripple the tumor-initiating capability of these cells. Methionine cycle flux specifically influences the epigenetic state of cancer cells and drives tumor initiation. Methionine cycle enzymes are also enriched in other tumor types, and MAT2A expression impinges upon the sensitivity of certain cancer cells to therapeutic inhibition.


Assuntos
Metionina/metabolismo , Células-Tronco Neoplásicas/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Diferenciação Celular , Linhagem Celular Tumoral , Feminino , Técnicas de Silenciamento de Genes , Glicina Desidrogenase (Descarboxilante)/antagonistas & inibidores , Glicina Desidrogenase (Descarboxilante)/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Redes e Vias Metabólicas , Metabolômica , Metionina Adenosiltransferase/antagonistas & inibidores , Metionina Adenosiltransferase/metabolismo , Camundongos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , S-Adenosilmetionina/metabolismo
8.
Artigo em Inglês | MEDLINE | ID: mdl-30906419

RESUMO

Hypertension is a global health problem. It has been reported that acupuncture at Taichong acupoints (LR3) decreases high blood pressure in spontaneously hypertensive rats. A transcriptome analysis can profile gene expression and its relationship with acupuncture. In this study, rats were treated with 2 weeks of acupuncture followed by regular recording of blood pressure (BP). The mRNA changes in the rostral ventrolateral medulla (RVLM) were evaluated to uncover the genetic mechanisms of acupuncture by using a whole transcript array (Affymetrix Rat Gene 1.0 ST array). BP measurements showed that acupuncture significantly decreased systolic blood pressure (SBP), mean arterial pressure (MAP), and heart rate (HR). In the bioinformatics results, 2371 differentially expressed genes (DEGs) were identified, where 83 DEGs were overlapped among Wistar-Kyoto rats (WKYs), spontaneously hypertensive rats (SHRs), and SHRs + acupuncture rats (SHRs+Acu). Gene ontology (GO) and pathway analysis revealed that 279 GO terms and 20 pathways with significant differences were related to oxidative stress, inflammation, and vascular endothelial function. In addition, coexpressed DEGs networks indicated that Cd4 and Il-33 might mediate the cascade of inflammation and oxidative stress responses, which could serve as a potential target of acupuncture treatment. In conclusion, our study demonstrated that acupuncture is a promising therapy for treating hypertension and could regulate multiple biological processes mainly involving oxidative stress, inflammation, and vascular endothelial function.

9.
Neurobiol Dis ; 124: 1-13, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30391288

RESUMO

Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by the expansion of polyglutamine region in the androgen receptor. To gain insights into mechanisms of SBMA, four wild-type and five SBMA iPSC lines were differentiated to spinal motor neurons (sMNs) with high efficiency. SBMA sMNs showed neurite defects, reduced sMN survival and decreased protein synthesis levels. Microarray analysis revealed a dysregulation in various neuronal-related signalling pathways in SBMA sMNs. Strikingly, FAM135B a novel gene of unknown function, was found drastically downregulated in SBMA sMNs. Knockdown of FAM135B in wild-type sMNs reduced their survival and contributed to neurite defects, similar to SBMA sMNs, suggesting a functional role of FAM135B in SBMA. The degenerative phenotypes and dysregulated genes revealed could be potential therapeutic targets for SBMA.


Assuntos
Atrofia Bulboespinal Ligada ao X/metabolismo , Atrofia Bulboespinal Ligada ao X/patologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Neuritos/metabolismo , Neuritos/patologia , Atrofia Bulboespinal Ligada ao X/genética , Diferenciação Celular , Perfilação da Expressão Gênica , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fenótipo , Transdução de Sinais
10.
Aging Cell ; 17(4): e12740, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29671950

RESUMO

Lifespan varies dramatically among species, but the biological basis is not well understood. Previous studies in model organisms revealed the importance of nutrient sensing, mTOR, NAD/sirtuins, and insulin/IGF1 signaling in lifespan control. By studying life-history traits and transcriptomes of 14 Drosophila species differing more than sixfold in lifespan, we explored expression divergence and identified genes and processes that correlate with longevity. These longevity signatures suggested that longer-lived flies upregulate fatty acid metabolism, downregulate neuronal system development and activin signaling, and alter dynamics of RNA splicing. Interestingly, these gene expression patterns resembled those of flies under dietary restriction and several other lifespan-extending interventions, although on the individual gene level, there was no significant overlap with genes previously reported to have lifespan-extension effects. We experimentally tested the lifespan regulation potential of several candidate genes and found no consistent effects, suggesting that individual genes generally do not explain the observed longevity patterns. Instead, it appears that lifespan regulation across species is modulated by complex relationships at the system level represented by global gene expression.


Assuntos
Drosophila/classificação , Drosophila/genética , Longevidade/genética , Transcriptoma , Animais , Especificidade da Espécie
11.
Genome Biol Evol ; 10(3): 967-975, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29608729

RESUMO

Cetaceans (whales, dolphins, and porpoises) are a group of specialized mammals that evolved from terrestrial ancestors and are fully adapted to aquatic habitats. Taking advantage of the recently sequenced finless porpoise genome, we conducted comparative analyses of the genomes of seven cetaceans and related terrestrial species to provide insight into the molecular bases of adaptation of these aquatic mammals. Changes in gene sequences were identified in main lineages of cetaceans, offering an evolutionary picture of cetacean genomes that reveal new pathways that could be associated with adaptation to aquatic lifestyle. We profiled bone microanatomical structures across 28 mammals, including representatives of cetaceans, pinnipeds, and sirenians. Subsequent phylogenetic comparative analyses revealed genes (including leptin, insulin-like growth factor 1, and collagen type I alpha 2 chain) with the root-to-tip substitution rate significantly correlated with bone compactness, implicating these genes could be involved in bone mass control. Overall, this study described adjustments of the genomes of cetaceans according to lifestyle, phylogeny, and bone mass.


Assuntos
Adaptação Fisiológica/genética , Osso e Ossos , Cetáceos/genética , Animais , Cetáceos/fisiologia
12.
Mol Neurobiol ; 55(10): 7677-7690, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29435917

RESUMO

It is widely accepted that the synaptic dysfunction and synapse loss contribute to the cognitive deficits of vascular dementia (VD) patients. We have previously reported that acupuncture improved cognitive function in rats with VD. However, the mechanisms involved in acupuncture improving cognitive ability remain to be elucidated. The present study aims to investigate the pathways and molecules involved in the neuroprotective effect of acupuncture. We assessed the effects of acupuncture on hippocampal long-term potentiation (LTP), the most prominent cellular model of memory formation. Acupuncture enhanced LTP and norepinephrine (NE) levels in the hippocampus. Inhibition of the ß-adrenergic receptor (AR), but not the α-AR, was able to block the effects of acupuncture on hippocampal LTP. Furthermore, inhibition of ß1-AR, not ß2-AR, abolished the enhanced LTP induced by acupuncture. The expression analysis revealed a significant upregulation of ß1-AR and unchanged ß2-AR with acupuncture, which supported the above findings. Specifically, increased ß1-ARs in the dentate gyrus were expressed on neurons exclusively. Taken together, the present data supports a beneficial role of acupuncture in synaptic plasticity challenged with VD. A likely mechanism is the increase of NE and activation of ß1-AR in the hippocampus.


Assuntos
Terapia por Acupuntura , Demência Vascular/fisiopatologia , Demência Vascular/terapia , Hipocampo/patologia , Hipocampo/fisiopatologia , Potenciação de Longa Duração , Receptores Adrenérgicos beta/metabolismo , Animais , Giro Denteado/metabolismo , Masculino , Norepinefrina/metabolismo , Ratos Wistar , Receptores Adrenérgicos alfa/metabolismo
13.
Neuromodulation ; 21(8): 762-776, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29111577

RESUMO

OBJECTIVE: Acupuncture is widely applied for treatment of various neurological disorders. This manuscript will review the preclinical evidence of acupuncture in mediating neural plasticity, the mechanisms involved. MATERIALS AND METHODS: We searched acupuncture, plasticity, and other potential related words at the following sites: PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), and VIP information data base. The following keywords were used: acupuncture, electroacupuncture, plasticity, neural plasticity, neuroplasticity, neurogenesis, neuroblast, stem cell, progenitor cell, BrdU, synapse, synapse structure, synaptogenesis, axon, axon regeneration, synaptic plasticity, LTP, LTD, neurotrophin, neurotrophic factor, BDNF, GDNF, VEGF, bFGF, EGF, NT-3, NT-4, NT-5, p75NTR, neurotransmitter, acetylcholine, norepinephrine, noradrenaline, dopamine, monamine. We assessed the effects of acupuncture on plasticity under pathological conditions in this review. RESULTS: Relevant references were reviewed and presented to reflect the effects of acupuncture on neural plasticity. The acquired literatures mainly focused on neurogenesis, alterations of synapses, neurotrophins (NTs), and neurotranimitters. Acupuncture methods mentioned in this article include manual acupuncture and electroacupuncture. CONCLUSIONS: The cumulative evidences demonstrated that acupuncture could induce neural plasticity in rodents exposed to cerebral ischemia. Neural plasticity mediated by acupuncture in other neural disorders, such as Alzheimer's disease, Parkinson's disease, and depression, were also investigated and there is evidence of positive role of acupuncture induced plasticity in these disorders as well. Mediation of neural plasticity by acupuncture is likely associated with its modulation on NTs and neurotransmitters. The exact mechanisms underlying acupuncture's effects on neural plasticity remain to be elucidated. Neural plasticity may be the potential bridge between acupuncture and the treatment of various neurological diseases.


Assuntos
Terapia por Acupuntura , Sistema Nervoso Central/fisiologia , Plasticidade Neuronal/fisiologia , Animais , Humanos , Doenças do Sistema Nervoso/fisiopatologia , Doenças do Sistema Nervoso/terapia
14.
CNS Neurosci Ther ; 24(1): 39-46, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29110407

RESUMO

AIMS: Oxidative stress and inflammation have been implicated in the pathogenesis of vascular dementia (VD). Thioredoxin-interacting protein (TXNIP) plays a vital role in oxidative stress and NOD-like receptor protein 3 (NLRP3) inflammasome activation. There is evidence that acupuncture has an antioxidative and neuroprotective effect in VD. In this study, we investigated whether acupuncture can attenuate cognitive impairment via inhibiting TXNIP-associated oxidative stress and inflammation in VD rats. METHODS: Both common carotid arteries were occluded (2-vessel occlusion [2VO]) in rats to model VD. The neuroprotective effect of acupuncture was assessed by the Morris water maze and Nissl staining. Oxidative stress was assessed by detecting levels of reactive oxygen species, DNA oxidation, and antioxidase. Western blot, real-time PCR, and immunofluorescence were used to detect the expression of TXNIP, NLRP3, caspase-1, and IL-1ß. A TXNIP siRNA intraventricular injection was applied to investigate whether acupuncture mimicked the effect of TXNIP inhibitor. RESULTS: Our findings demonstrated that VD rats treated with acupuncture had reduced hippocampal neuronal loss and oxidative stress. The upregulation of TXNIP, NLRP3, caspase-1, and IL-1ß induced by 2VO was also reversed by acupuncture. Furthermore, TXNIP siRNA had a similar effect as acupuncture on cognition, hippocampal neurons, and ROS production in VD rats. CONCLUSION: In conclusion, our study suggests that the neuroprotective effects of acupuncture in VD are mediated through reducing expression of TXNIP-associated oxidative stress and inflammation.


Assuntos
Terapia por Acupuntura/métodos , Proteínas de Transporte/metabolismo , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/terapia , Demência Vascular/complicações , Estresse Oxidativo/fisiologia , Animais , Proteínas de Transporte/genética , Caspase 3/metabolismo , Proteínas de Ciclo Celular , Demência Vascular/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/fisiologia , Hipocampo/metabolismo , Hipocampo/patologia , Inflamassomos/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Aprendizagem em Labirinto/fisiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fosfopiruvato Hidratase/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
15.
Semin Cell Dev Biol ; 70: 190-203, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28800931

RESUMO

Much of the current research on longevity focuses on the aging process within a single species. Several molecular players (e.g. IGF1 and MTOR), pharmacological compounds (e.g. rapamycin and metformin), and dietary approaches (e.g. calorie restriction and methionine restriction) have been shown to be important in regulating and modestly extending lifespan in model organisms. On the other hand, natural lifespan varies much more significantly across species. Within mammals alone, maximum lifespan differs more than 100 fold, but the underlying regulatory mechanisms remain poorly understood. Recent comparative studies are beginning to shed light on the molecular signatures associated with exceptional longevity. These include genome sequencing of microbats, naked mole rat, blind mole rat, bowhead whale and African turquoise killifish, and comparative analyses of gene expression, metabolites, lipids and ions across multiple mammalian species. Together, they point towards several putative strategies for lifespan regulation and cancer resistance, as well as the pathways and metabolites associated with longevity variation. In particular, longevity may be achieved by both lineage-specific adaptations and common mechanisms that apply across the species. Comparing the resulting cross-species molecular signatures with the within-species lifespan extension strategies will improve our understanding of mechanisms of longevity control and provide a starting point for novel and effective interventions.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Genoma , Longevidade/genética , Metaboloma , Transcriptoma , Animais , Baleia Franca/genética , Baleia Franca/crescimento & desenvolvimento , Baleia Franca/metabolismo , Restrição Calórica , Quirópteros/genética , Quirópteros/crescimento & desenvolvimento , Quirópteros/metabolismo , Humanos , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Peixes Listrados/genética , Peixes Listrados/crescimento & desenvolvimento , Peixes Listrados/metabolismo , Longevidade/efeitos dos fármacos , Metformina/farmacologia , Metionina/deficiência , Ratos-Toupeira/genética , Ratos-Toupeira/crescimento & desenvolvimento , Ratos-Toupeira/metabolismo , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
16.
Stroke ; 48(4): 1044-1051, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28289242

RESUMO

BACKGROUND AND PURPOSE: Emerging evidence suggests that acupuncture could improve cognitive impairment in vascular dementia by enhancing synaptic plasticity in the hippocampus. The purpose of this study is to investigate whether dopamine, a key mediator of synaptic plasticity, is involved in this cognitive improvement. METHODS: Vascular dementia model was established by bilateral common carotid arteries occlusion in male Wistar rats. Three days after the operation, animals received acupuncture treatment for 2 weeks, once daily. The D1/D5 receptors antagonist SCH23390 was administered intraperitoneally 15 minutes before each acupuncture treatment. Morris water maze was examined after acupuncture. Long-term potentiation was studied by an electrophysiological technique. Dopamine and metabolites levels were detected by microdialysis and high-performance liquid chromatography from brain tissue. The expression of D1R and D5R was analyzed by immunofluorescence. RESULTS: Acupuncture remarkably reversed cognitive deficits in 2-vessel occlusion model (2VO) rats, and the acupuncture points Zusanli (ST36) and Baihui (GV20) were confirmed to be the most effective combination. Electrophysiological recording data showed that 2VO-induced impairments of long-term potentiation were prevented by acupuncture. In addition, acupuncture promoted the release of dopamine and its major metabolites in the hippocampus of 2VO rats. The immunofluorescence experiment showed that the decrease of D1R and D5R in hippocampal dentate gyrus region of 2VO rats was reversed by acupuncture. Furthermore, we found that the effects of acupuncture against 2VO-induced impairments in cognition and synaptic plasticity were abolished by SCH23390. CONCLUSIONS: Improvement in cognition and hippocampal synaptic plasticity induced by acupuncture was achieved via activation of D1/D5 receptors in 2VO rats.


Assuntos
Terapia por Acupuntura/métodos , Demência Vascular/terapia , Giro Denteado/metabolismo , Giro Denteado/fisiopatologia , Antagonistas de Dopamina/farmacologia , Potenciação de Longa Duração/fisiologia , Transtornos da Memória/terapia , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D5/metabolismo , Animais , Comportamento Animal , Benzazepinas/administração & dosagem , Benzazepinas/farmacologia , Demência Vascular/complicações , Modelos Animais de Doenças , Antagonistas de Dopamina/administração & dosagem , Masculino , Transtornos da Memória/etiologia , Ratos , Ratos Wistar
17.
Elife ; 52016 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-27874830

RESUMO

Mammalian lifespan differs by >100 fold, but the mechanisms associated with such longevity differences are not understood. Here, we conducted a study on primary skin fibroblasts isolated from 16 species of mammals and maintained under identical cell culture conditions. We developed a pipeline for obtaining species-specific ortholog sequences, profiled gene expression by RNA-seq and small molecules by metabolite profiling, and identified genes and metabolites correlating with species longevity. Cells from longer lived species up-regulated genes involved in DNA repair and glucose metabolism, down-regulated proteolysis and protein transport, and showed high levels of amino acids but low levels of lysophosphatidylcholine and lysophosphatidylethanolamine. The amino acid patterns were recapitulated by further analyses of primate and bird fibroblasts. The study suggests that fibroblast profiling captures differences in longevity across mammals at the level of global gene expression and metabolite levels and reveals pathways that define these differences.


Assuntos
Reparo do DNA , Metabolismo Energético , Longevidade , Animais , Aves , Técnicas de Cultura de Células , Células Cultivadas , Fibroblastos/fisiologia , Perfilação da Expressão Gênica , Mamíferos , Metabolômica
18.
Environ Sci Technol ; 50(21): 12040-12047, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27723318

RESUMO

Novel magnetic biochars (MBC) were prepared by one-step pyrolysis of FeCl3-laden biomass and employed for Hg0 removal in simulated combustion flue gas. The sample characterization indicated that highly dispersed Fe3O4 particles could be deposited on the MBC surface. Both enhanced surface area and excellent magnetization property were obtained. With the activation of FeCl3, more oxygen-rich functional groups were formed on the MBC, especially the C═O group. The MBC exhibited far greater Hg0 removal performance compared to the nonmagnetic biochar (NMBC) under N2 + 4% O2 atmosphere in a wide reaction temperature window (120-250 °C). The optimal pyrolysis temperature for the preparation of MBC is 600 °C, and the best FeCl3/biomass impregnation mass ratio is 1.5 g/g. At the optimal temperature (120 °C), the Fe1.5MBC600 was superior in both Hg0 adsorption capacity and adsorption rate to a commercial brominated activated carbon (Br-AC) used for mercury removal in power plants. The mechanism of Hg0 removal was proposed, and there are two types of active adsorption/oxidation sites for Hg0: Fe3O4 and oxygen-rich functional groups. The role of Fe3O4 in Hg0 removal was attributed to the Fe3+(t) coordination and lattice oxygen. The C═O group could act as act as electron acceptors, facilitating the electron transfer for Hg0 oxidation.


Assuntos
Carvão Vegetal , Imãs , Mercúrio , Adsorção , Oxirredução , Centrais Elétricas , Temperatura Ambiente
19.
J Virol ; 90(11): 5329-5342, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27009954

RESUMO

UNLABELLED: Although Kaposi's sarcoma-associated herpesvirus (KSHV) ORF52 (also known as KSHV inhibitor of cGAS [KicGAS]) has been detected in purified virions, the roles of this protein during KSHV replication have not been characterized. Using specific monoclonal antibodies, we revealed that ORF52 displays true late gene expression kinetics and confirmed its cytoplasmic localization in both transfected and KSHV-infected cells. We demonstrated that ORF52 comigrates with other known virion proteins following sucrose gradient centrifugation. We also determined that ORF52 resides inside the viral envelope and remains partially associated with capsid when extracellular virions are treated with various detergents and/or salts. There results indicate that ORF52 is a tegument protein abundantly present in extracellular virions. To characterize the roles of ORF52 in the KSHV life cycle, we engineered a recombinant KSHV ORF52-null mutant virus and found that loss of ORF52 results in reduced virion production and a further defect in infectivity. Upon analysis of the virion composition of ORF52-null viral particles, we observed a decrease in the incorporation of ORF45, as well as other tegument proteins, suggesting that ORF52 is important for the packaging of other virion proteins. In summary, our results indicate that, in addition to its immune evasion function, KSHV ORF52 is required for the optimal production of infectious virions, likely due to its roles in virion assembly as a tegument protein. IMPORTANCE: The tegument proteins of herpesviruses, including Kaposi's sarcoma-associated herpesvirus (KSHV), play key roles in the viral life cycle. Each of the three subfamilies of herpesviruses (alpha, beta, and gamma) encode unique tegument proteins with specialized functions. We recently found that one such gammaherpesvirus-specific protein, ORF52, has an important role in immune evasion during KSHV primary infection, through inhibition of the host cytosolic DNA sensing pathway. In this report, we further characterize ORF52 as a tegument protein with vital roles during KSHV lytic replication. We found that ORF52 is important for the production of infectious viral particles, likely through its role in virus assembly, a critical process for KSHV replication and pathogenesis. More comprehensive investigation of the functions of tegument proteins and their roles in viral replication may reveal novel targets for therapeutic interventions against KSHV-associated diseases.


Assuntos
Herpesvirus Humano 8/química , Herpesvirus Humano 8/fisiologia , Proteínas do Envelope Viral/metabolismo , Vírion/química , Replicação Viral , Animais , Citoplasma/ultraestrutura , Citoplasma/virologia , DNA Viral , Células HeLa , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/imunologia , Humanos , Evasão da Resposta Imune , Camundongos , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/isolamento & purificação , Vírion/genética , Vírion/metabolismo , Montagem de Vírus
20.
NPJ Aging Mech Dis ; 2: 16014, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28721269

RESUMO

Different cell types within the body exhibit substantial variation in the average time they live, ranging from days to the lifetime of the organism. The underlying mechanisms governing the diverse lifespan of different cell types are not well understood. To examine gene expression strategies that support the lifespan of different cell types within the human body, we obtained publicly available RNA-seq data sets and interrogated transcriptomes of 21 somatic cell types and tissues with reported cellular turnover, a bona fide estimate of lifespan, ranging from 2 days (monocytes) to a lifetime (neurons). Exceptionally long-lived neurons presented a gene expression profile of reduced protein metabolism, consistent with neuronal survival and similar to expression patterns induced by longevity interventions such as dietary restriction. Across different cell lineages, we identified a gene expression signature of human cell and tissue turnover. In particular, turnover showed a negative correlation with the energetically costly cell cycle and factors supporting genome stability, concomitant risk factors for aging-associated pathologies. In addition, the expression of p53 was negatively correlated with cellular turnover, suggesting that low p53 activity supports the longevity of post-mitotic cells with inherently low risk of developing cancer. Our results demonstrate the utility of comparative approaches in unveiling gene expression differences among cell lineages with diverse cell turnover within the same organism, providing insights into mechanisms that could regulate cell longevity.

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