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1.
BMC Res Notes ; 14(1): 300, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34353359

RESUMO

OBJECTIVE: The Hedgehog pathway is a fundamental signaling pathway in organogenesis. The expression patterns of the ligand Sonic Hedgehog (Shh) and key pathway components have been studied in many tissues but direct spatial comparisons across tissues with different cell compositions and structural organization are not common and could reveal tissue-specific differences in pathway dynamics. RESULTS: We directly compared the expression characteristics of Shh, and four genes with functional roles in signaling and whose expression levels serve as readouts of pathway activity in multiple tissues of the embryonic mouse head at embryonic day 15.5 by serial in situ hybridization. The four readout genes were the positive feedback regulator Gli1, and three negative feedback regulators, Patched1, Patched2, and Hedgehog Interacting Protein. While the relative abundance of Gli1 was similar across tissues, the relative expression levels and spatial distribution of Shh and the negative feedback regulators differed, suggesting that feedback regulation of hedgehog signaling is context dependent. This comparative analysis offers insight into how consistent pathway activity could be achieved in tissues with different morphologies and characteristics of ligand expression.


Assuntos
Cabeça/embriologia , Proteínas Hedgehog , Transdução de Sinais , Animais , Retroalimentação Fisiológica , Proteínas Hedgehog/genética , Camundongos , Proteína GLI1 em Dedos de Zinco/genética
2.
Nat Commun ; 12(1): 5053, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417459

RESUMO

Previous studies have suggested that PTEN loss is associated with p110ß signaling dependency, leading to the clinical development of p110ß-selective inhibitors. Here we use a panel pre-clinical models to reveal that PI3K isoform dependency is not governed by loss of PTEN and is impacted by feedback inhibition and concurrent PIK3CA/PIK3CB alterations. Furthermore, while pan-PI3K inhibition in PTEN-deficient tumors is efficacious, upregulation of Insulin Like Growth Factor 1 Receptor (IGF1R) promotes resistance. Importantly, we show that this resistance can be overcome through targeting AKT and we find that AKT inhibitors are superior to pan-PI3K inhibition in the context of PTEN loss. However, in the presence of wild-type PTEN and PIK3CA-activating mutations, p110α-dependent signaling is dominant and selectively inhibiting p110α is therapeutically superior to AKT inhibition. These discoveries reveal a more nuanced understanding of PI3K isoform dependency and unveil novel strategies to selectively target PI3K signaling nodes in a context-specific manner.


Assuntos
Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/enzimologia , Transdução de Sinais , Animais , Linhagem Celular Tumoral , Retroalimentação Fisiológica , Humanos , Isoenzimas/metabolismo , Masculino , Camundongos , Modelos Biológicos , Organoides/efeitos dos fármacos , Organoides/metabolismo , PTEN Fosfo-Hidrolase/deficiência , PTEN Fosfo-Hidrolase/metabolismo , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Receptor IGF Tipo 1/metabolismo , Regulação para Cima/efeitos dos fármacos
3.
Nucleic Acids Res ; 49(13): 7537-7553, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34197600

RESUMO

The synaptonemal complex (SC) is a proteinaceous structure that mediates homolog engagement and genetic recombination during meiosis. In budding yeast, Zip-Mer-Msh (ZMM) proteins promote crossover (CO) formation and initiate SC formation. During SC elongation, the SUMOylated SC component Ecm11 and the Ecm11-interacting protein Gmc2 facilitate the polymerization of Zip1, an SC central region component. Through physical recombination, cytological, and genetic analyses, we found that ecm11 and gmc2 mutants exhibit chromosome-specific defects in meiotic recombination. CO frequencies on a short chromosome (chromosome III) were reduced, whereas CO and non-crossover frequencies on a long chromosome (chromosome VII) were elevated. Further, in ecm11 and gmc2 mutants, more double-strand breaks (DSBs) were formed on a long chromosome during late prophase I, implying that the Ecm11-Gmc2 (EG) complex is involved in the homeostatic regulation of DSB formation. The EG complex may participate in joint molecule (JM) processing and/or double-Holliday junction resolution for ZMM-dependent CO-designated recombination. Absence of the EG complex ameliorated the JM-processing defect in zmm mutants, suggesting a role for the EG complex in suppressing ZMM-independent recombination. Our results suggest that the SC central region functions as a compartment for sequestering recombination-associated proteins to regulate meiosis specificity during recombination.


Assuntos
Proteínas de Ciclo Celular/genética , Troca Genética , Quebras de DNA de Cadeia Dupla , Meiose/genética , Proteínas de Saccharomyces cerevisiae/genética , Complexo Sinaptonêmico/metabolismo , Cromossomos Fúngicos , Replicação do DNA , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Retroalimentação Fisiológica , Deleção de Genes , Recombinação Genética , Saccharomyces cerevisiae/genética , Temperatura , Fatores de Transcrição/genética , Ubiquitina-Proteína Ligases/genética
4.
Int J Mol Sci ; 22(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34298972

RESUMO

Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant inherited multiple cancer syndrome of neuroendocrine tissues. Tumors are caused by an inherited germinal heterozygote inactivating mutation of the MEN1 tumor suppressor gene, followed by a somatic loss of heterozygosity (LOH) of the MEN1 gene in target neuroendocrine cells, mainly at parathyroids, pancreas islets, and anterior pituitary. Over 1500 different germline and somatic mutations of the MEN1 gene have been identified, but the syndrome is completely missing a direct genotype-phenotype correlation, thus supporting the hypothesis that exogenous and endogenous factors, other than MEN1 specific mutation, are involved in MEN1 tumorigenesis and definition of individual clinical phenotype. Epigenetic factors, such as microRNAs (miRNAs), are strongly suspected to have a role in MEN1 tumor initiation and development. Recently, a direct autoregulatory network between miR-24, MEN1 mRNA, and menin was demonstrated in parathyroids and endocrine pancreas, showing a miR-24-induced silencing of menin expression that could have a key role in initiation of tumors in MEN1-target neuroendocrine cells. Here, we review the current knowledge on the post-transcriptional regulation of MEN1 and menin expression by miR-24, and its possible direct role in MEN1 syndrome, describing the possibility and the potential approaches to target and silence this miRNA, to permit the correct expression of the wild type menin, and thereby prevent the development of cancers in the target tissues.


Assuntos
Terapia Genética , MicroRNAs/genética , Terapia de Alvo Molecular , Neoplasia Endócrina Múltipla Tipo 1/genética , Regiões 3' não Traduzidas , Animais , Antagomirs/farmacologia , Antagomirs/uso terapêutico , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 9/genética , Dano ao DNA , Retroalimentação Fisiológica , Previsões , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Neoplasia Endócrina Múltipla Tipo 1/metabolismo , Neoplasia Endócrina Múltipla Tipo 1/terapia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Isoformas de Proteínas/genética , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/genética , RNA Neoplásico/antagonistas & inibidores , RNA Neoplásico/genética , Ratos
5.
Nat Commun ; 12(1): 4321, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262040

RESUMO

Symmetry establishment is a critical process in the development of multicellular organs and requires careful coordination of polarity axes while cells actively divide within tissues. Formation of the apical style in the Arabidopsis gynoecium involves a bilateral-to-radial symmetry transition, a stepwise process underpinned by the dynamic distribution of the plant morphogen auxin. Here we show that SPATULA (SPT) and the HECATE (HEC) bHLH proteins mediate the final step in the style radialisation process and synergistically control the expression of adaxial-identity genes, HOMEOBOX ARABIDOPSIS THALIANA 3 (HAT3) and ARABIDOPSIS THALIANA HOMEOBOX 4 (ATHB4). HAT3/ATHB4 module drives radialisation of the apical style by promoting basal-to-apical auxin flow and via a negative feedback mechanism that finetune auxin distribution through repression of SPT expression and cytokinin sensitivity. Thus, this work reveals the molecular basis of axes-coordination and hormonal cross-talk during the sequential steps of symmetry transition in the Arabidopsis style.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/crescimento & desenvolvimento , Proteínas de Homeodomínio/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Transporte Biológico , Citocininas/metabolismo , Retroalimentação Fisiológica , Flores/genética , Flores/crescimento & desenvolvimento , Flores/metabolismo , Regulação da Expressão Gênica de Plantas , Proteínas de Homeodomínio/genética , Ácidos Indolacéticos/metabolismo
6.
Nat Commun ; 12(1): 4415, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285228

RESUMO

Complex dynamical fluctuations, from intracellular noise, brain dynamics or computer traffic display bursting dynamics consistent with a critical state between order and disorder. Living close to the critical point has adaptive advantages and it has been conjectured that evolution could select these critical states. Is this the case of living cells? A system can poise itself close to the critical point by means of the so-called self-organized criticality (SOC). In this paper we present an engineered gene network displaying SOC behaviour. This is achieved by exploiting the saturation of the proteolytic degradation machinery in E. coli cells by means of a negative feedback loop that reduces congestion. Our critical motif is built from a two-gene circuit, where SOC can be successfully implemented. The potential implications for both cellular dynamics and behaviour are discussed.


Assuntos
Engenharia Celular/métodos , Proteínas de Escherichia coli/metabolismo , Escherichia coli/crescimento & desenvolvimento , Regulação Bacteriana da Expressão Gênica , Engenharia Genética , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Retroalimentação Fisiológica , Modelos Genéticos , Proteólise , Análise de Célula Única
7.
Methods Mol Biol ; 2329: 29-38, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34085213

RESUMO

The anaphase promoting complex/cyclosome (APC/C), a large E3 ubiquitin ligase, is a key regulator of mitotic progression. Upon activation in mitosis, the APC/C targets its two essential substrates, securin and cyclin B, for proteasomal destruction. Cyclin B is the activator of cyclin-dependent kinase 1 (Cdk1), the major mitotic kinase, and both cyclin B and securin are safeguards of sister chromatid cohesion. Conversely, the degradation of securin and cyclin B promotes sister chromatid separation and mitotic exit. The negative feedback loop between Cdk1 and APC/C-Cdk1 activating the APC/C and the APC/C inactivating Cdk1-constitutes the core of the biochemical cell cycle oscillator.Since its discovery three decades ago, the mechanisms of APC /C regulation have been intensively studied, and several in vitro assays exist to measure the activity of the APC /C in different activation states. However, most of these assays require the purification of numerous recombinant enzymes involved in the ubiquitylation process (e.g., ubiquitin, the E1 and E2 ubiquitin ligases, and the APC /C) and/or the use of radioactive isotopes. In this chapter, we describe an easy-to-implement method to continuously measure APC /C activity in Xenopus laevis egg extracts using APC /C substrates fused to fluorescent proteins and a fluorescence plate reader. Because the egg extract provides all important enzymes and proteins for the reaction, this method can be used largely without the need for recombinant protein purification. It can also easily be adapted to test the activity of APC /C mutants or investigate other mechanisms of APC /C regulation.


Assuntos
Ciclossomo-Complexo Promotor de Anáfase/metabolismo , Ciclina B/metabolismo , Proteínas Luminescentes/metabolismo , Securina/metabolismo , Xenopus laevis/fisiologia , Animais , Proteínas de Ciclo Celular/metabolismo , Ciclina B/genética , Retroalimentação Fisiológica , Feminino , Proteínas Luminescentes/genética , Mitose , Imagem Óptica/instrumentação , Óvulo/metabolismo , Proteínas Quinases/metabolismo , Proteólise , Proteínas Recombinantes/metabolismo , Securina/genética , Proteínas de Xenopus/metabolismo , Xenopus laevis/metabolismo
8.
Front Immunol ; 12: 616451, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34163463

RESUMO

Gain-of-function mutations of the TLR adaptor and oncoprotein MyD88 drive B cell lymphomagenesis via sustained NF-κB activation. In myeloid cells, both short and sustained TLR activation and NF-κB activation lead to the induction of inhibitory MYD88 splice variants that restrain prolonged NF-κB activation. We therefore sought to investigate whether such a negative feedback loop exists in B cells. Analyzing MYD88 splice variants in normal B cells and different primary B cell malignancies, we observed that MYD88 splice variants in transformed B cells are dominated by the canonical, strongly NF-κB-activating isoform of MYD88 and contain at least three novel, so far uncharacterized signaling-competent splice isoforms. Sustained TLR stimulation in B cells unexpectedly reinforces splicing of NF-κB-promoting, canonical isoforms rather than the 'MyD88s', a negative regulatory isoform reported to be typically induced by TLRs in myeloid cells. This suggests that an essential negative feedback loop restricting TLR signaling in myeloid cells at the level of alternative splicing, is missing in B cells when they undergo proliferation, rendering B cells vulnerable to sustained NF-κB activation and eventual lymphomagenesis. Our results uncover MYD88 alternative splicing as an unappreciated promoter of B cell lymphomagenesis and provide a rationale why oncogenic MYD88 mutations are exclusively found in B cells.


Assuntos
Linfócitos B/fisiologia , Linfoma de Células B/genética , Mutação/genética , Células Mieloides/fisiologia , Fator 88 de Diferenciação Mieloide/genética , NF-kappa B/metabolismo , Isoformas de Proteínas/genética , Processamento Alternativo , Carcinogênese/genética , Células Cultivadas , Retroalimentação Fisiológica , Humanos , Linfoma de Células B/imunologia , Transdução de Sinais , Receptores Toll-Like/metabolismo
9.
eNeuro ; 8(4)2021.
Artigo em Inglês | MEDLINE | ID: mdl-34135001

RESUMO

Gonadotropin-releasing hormone (GnRH) drives pituitary secretion of luteinizing hormone and follicle-stimulating hormone, which in turn regulate gonadal functions including steroidogenesis. The pattern of GnRH release and thus fertility depend on gonadal steroid feedback. Under homeostatic (negative) feedback conditions, removal of the gonads from either females or males increases the amplitude and frequency of GnRH release and alters the long-term firing pattern of these neurons in brain slices. The neurobiological mechanisms intrinsic to GnRH neurons that are altered by homeostatic feedback are not well studied and have not been compared between sexes. During estradiol-positive feedback, which is unique to females, there are correlated changes in voltage-gated potassium currents and neuronal excitability. We thus hypothesized that these same mechanisms would be engaged in homeostatic negative feedback. Voltage-gated potassium channels play a direct role in setting excitability and action potential properties. Whole-cell patch-clamp recordings of GFP-identified GnRH neurons in brain slices from sham-operated and castrated adult female and male mice were made to assess fast and slow inactivating potassium currents as well as action potential properties. Surprisingly, no changes were observed among groups in most potassium current properties, input resistance, or capacitance, and this was reflected in a lack of differences in excitability and specific action potential properties. These results support the concept that, in contrast to positive feedback, steroid-negative feedback regulation of GnRH neurons in both sexes is likely conveyed to GnRH neurons via mechanisms that do not induce major changes in the biophysical properties of these cells.


Assuntos
Retroalimentação Fisiológica , Hormônio Liberador de Gonadotropina , Potássio , Animais , Estradiol , Feminino , Masculino , Camundongos , Neurônios , Ovariectomia
10.
Theranostics ; 11(14): 7110-7125, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093874

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fatal interstitial lung disease characterized by abnormal transition and proliferation of fibroblasts. The uncontrolled transition of fibroblasts, commonly known as myofibroblasts, are the principal source of the enormous extracellular matrix (ECM) depositing in lung parenchyma, leading to gradual failure of gas exchange and mortality of the patients. However, up to now, rare effective therapeutic strategies have been developed to blockade fibroblast-to-myofibroblast transition (FMT) in IPF. Method: We illustrated that the lungs originated from IPF patients and mice with pulmonary fibrosis are characterized by the overexpression of sushi-repeat-containing protein, X-linked 2 (SRPX2). Further functionality studies identified the pivotal role of SRPX2 in FMT. Mechanistically, SRPX2 was involved in a TGFßR1/SMAD3/SRPX2/AP1/SMAD7 positive feedback loop. Specifically, SRPX2 was upregulated by TGF-ß1 in a TGFßR1/SMAD3-dependent manner, after which SRPX2 in turn repressed the expression of AP1, subsequently minimized SMAD7 expression, through which it reduced the formation of inhibitory complex with TGFßR1 and enhanced SMAD signaling pathway to promote FMT and exacerbate pulmonary fibrosis. Notably, intratracheal administration of siRNA-loaded liposomes could effectively suppress the expression of Srpx2 in the lung and remarkably protect mice against BLM-induced pulmonary fibrosis, concomitant with a significant reduction of FMT. Results: Accordingly, these data indicate that Srpx2 plays an essential role in the pathogenesis of pulmonary fibrosis and suggests the strategy aiming at silencing Srpx2 could be a promising therapeutic approach against pulmonary fibrosis in clinical settings.


Assuntos
Proliferação de Células/genética , Fibroblastos/metabolismo , Terapia Genética/métodos , Lipossomos/administração & dosagem , Proteínas de Membrana/metabolismo , Mioblastos/metabolismo , Proteínas de Neoplasias/metabolismo , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/terapia , Idoso , Animais , Movimento Celular/genética , Retroalimentação Fisiológica , Feminino , Fibroblastos/patologia , Inativação Gênica , Humanos , Lipossomos/metabolismo , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mioblastos/patologia , Proteínas de Neoplasias/genética , Fibrose Pulmonar/genética , RNA Interferente Pequeno , RNA-Seq , Proteína Smad3/metabolismo , Proteína Smad7/metabolismo , Fator de Transcrição AP-1/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Regulação para Cima
11.
Methods Mol Biol ; 2324: 149-164, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34165714

RESUMO

Pools of RNA molecules can act as competing endogenous RNAs (ceRNAs) and indirectly alter their expression levels by competitively binding shared microRNAs. This ceRNA cross talk yields an additional posttranscriptional regulatory layer, which plays key roles in both physiological and pathological processes. MicroRNAs can act as decoys by binding multiple RNAs, as well as RNAs can act as ceRNAs by competing for binding multiple microRNAs, leading to many cross talk interactions that could favor significant large-scale effects in spite of the weakness of single interactions. Identifying and studying these extended ceRNA interaction networks could provide a global view of the fine-tuning gene regulation in a wide range of biological processes and tumor progressions. In this chapter, we review current progress of predicting ceRNA cross talk, by summarizing the most up-to-date databases, which collect computationally predicted and/or experimentally validated miRNA-target and ceRNA-ceRNA interactions, as well as the widespread computational methods for discovering and modeling possible evidences of ceRNA-ceRNA interaction networks. These methods can be grouped in two categories: statistics-based methods exploit multivariate analysis to build ceRNA networks, by considering the miRNA expression levels when evaluating miRNA sponging relationships; mathematical methods build deterministic or stochastic models to analyze and predict the behavior of ceRNA cross talk.


Assuntos
Biologia Computacional/métodos , Regulação Neoplásica da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , MicroRNAs/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Sequências Reguladoras de Ácido Ribonucleico/genética , Bases de Dados Factuais , Bases de Dados Genéticas , Retroalimentação Fisiológica , Humanos , MicroRNAs/genética , Modelos Teóricos , Análise Multivariada
12.
Nat Commun ; 12(1): 3419, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103495

RESUMO

Bacteria can be harnessed to synthesise high-value chemicals. A promising strategy for increasing productivity uses inducible control systems to switch metabolism from growth to chemical synthesis once a large population of cell factories are generated. However, use of expensive chemical inducers limits scalability of this approach for biotechnological applications. Switching using cheap nutrients is an appealing alternative, but their tightly regulated uptake and consumption again limits scalability. Here, using mathematical models of fatty acid uptake in E. coli as an exemplary case study, we unravel how the cell's native regulation and program of induction can be engineered to minimise inducer usage. We show that integrating positive feedback loops into the circuitry creates an irreversible metabolic switch, which, requiring only temporary induction, drastically reduces inducer usage. Our proposed switch should be widely applicable, irrespective of the product of interest, and brings closer the realization of scalable and sustainable microbial chemical production.


Assuntos
Escherichia coli/metabolismo , Engenharia Metabólica , Retroalimentação Fisiológica , Homeostase , Ácido Oleico/metabolismo
13.
Nat Commun ; 12(1): 3256, 2021 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-34059671

RESUMO

Macrophages perform diverse functions within tissues during immune responses to pathogens and injury, but molecular mechanisms by which physical properties of the tissue regulate macrophage behavior are less well understood. Here, we examine the role of the mechanically activated cation channel Piezo1 in macrophage polarization and sensing of microenvironmental stiffness. We show that macrophages lacking Piezo1 exhibit reduced inflammation and enhanced wound healing responses. Additionally, macrophages expressing the transgenic Ca2+ reporter, Salsa6f, reveal that Ca2+ influx is dependent on Piezo1, modulated by soluble signals, and enhanced on stiff substrates. Furthermore, stiffness-dependent changes in macrophage function, both in vitro and in response to subcutaneous implantation of biomaterials in vivo, require Piezo1. Finally, we show that positive feedback between Piezo1 and actin drives macrophage activation. Together, our studies reveal that Piezo1 is a mechanosensor of stiffness in macrophages, and that its activity modulates polarization responses.


Assuntos
Materiais Biocompatíveis/efeitos adversos , Reação a Corpo Estranho/imunologia , Canais Iônicos/metabolismo , Macrófagos/imunologia , Cicatrização/imunologia , Actinas/metabolismo , Animais , Células Cultivadas , Microambiente Celular/imunologia , Modelos Animais de Doenças , Retroalimentação Fisiológica , Feminino , Humanos , Canais Iônicos/genética , Ativação de Macrófagos , Macrófagos/metabolismo , Masculino , Mecanotransdução Celular/imunologia , Camundongos , Cultura Primária de Células , Tela Subcutânea/cirurgia
14.
Int J Mol Sci ; 22(11)2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-34071053

RESUMO

Under stressful conditions, the hypothalamic-pituitary-adrenal (HPA) axis acts to promote transitory physiological adaptations that are often resolved after the stressful stimulus is no longer present. In addition to corticosteroids (e.g., cortisol), the neurosteroid allopregnanolone (3α,5α-tetrahydroprogesterone, 3α-hydroxy-5α-pregnan-20-one) participates in negative feedback mechanisms that restore homeostasis. Chronic, repeated exposure to stress impairs the responsivity of the HPA axis and dampens allopregnanolone levels, participating in the etiopathology of psychiatric disorders, such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). MDD and PTSD patients present abnormalities in the HPA axis regulation, such as altered cortisol levels or failure to suppress cortisol release in the dexamethasone suppression test. Herein, we review the neurophysiological role of allopregnanolone both as a potent and positive GABAergic neuromodulator but also in its capacity of inhibiting the HPA axis. The allopregnanolone function in the mechanisms that recapitulate stress-induced pathophysiology, including MDD and PTSD, and its potential as both a treatment target and as a biomarker for these disorders is discussed.


Assuntos
Transtorno Depressivo Maior/fisiopatologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Pregnanolona/fisiologia , Adaptação Fisiológica , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Doença Crônica , Corticosterona/metabolismo , Transtorno Depressivo Maior/tratamento farmacológico , Retroalimentação Fisiológica , Feminino , Agonistas de Receptores de GABA-A/uso terapêutico , Humanos , Masculino , Modelos Biológicos , Pregnanolona/biossíntese , Receptores de GABA-A/fisiologia , Caracteres Sexuais , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Estresse Fisiológico , Estresse Psicológico/fisiopatologia , Estresse Psicológico/psicologia , Ácido gama-Aminobutírico/fisiologia
15.
J Mol Biol ; 433(15): 167073, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34058151

RESUMO

Biogenic polyamines are natural aliphatic polycations formed from amino acids by biochemical pathways that are highly conserved from bacteria to humans. Their cellular concentrations are carefully regulated and dysregulation causes severe cell growth defects. Polyamines have high affinity for nucleic acids and are known to interact with mRNA, tRNA and rRNA to stimulate the translational machinery, but the exact molecular mechanism(s) for this stimulus is still unknown. Here we exploit that Escherichia coli is viable in the absence of polyamines, including the universally conserved putrescine and spermidine. Using global macromolecule labelling approaches we find that ribosome efficiency is reduced by 50-70% in the absence of polyamines and this reduction is caused by slow translation elongation speed. The low efficiency causes rRNA and multiple tRNA species to be overproduced in the absence of polyamines, suggesting an impact on the feedback regulation of stable RNA transcription. Importantly, we find that polyamine deficiency affects both tRNA levels and tRNA modification patterns. Specifically, a large fraction of tRNAhis, tRNAtyr and tRNAasn lack the queuosine modification in the anticodon "wobble" base, which can be reversed by addition of polyamines to the growth medium. In conclusion, we demonstrate that polyamines are needed for modification of specific tRNA, possibly by facilitating the interaction with modification enzymes.


Assuntos
Anticódon/química , Escherichia coli/genética , Poliaminas/química , Escherichia coli/metabolismo , Retroalimentação Fisiológica , Conformação de Ácido Nucleico , Biossíntese de Proteínas , RNA Bacteriano/química , RNA Ribossômico/química , RNA de Transferência/química
16.
Am J Physiol Gastrointest Liver Physiol ; 321(1): G55-G66, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33978477

RESUMO

Regulation of bile acid metabolism is normally discussed as the regulation of bile acid synthesis, which serves to compensate for intestinal loss in order to maintain a constant pool size. After a meal, bile acids start cycling in the enterohepatic circulation. Farnesoid X receptor-dependent ileal and hepatic processes lead to negative feedback inhibition of bile acid synthesis. When the intestinal bile acid flux decreases, the inhibition of synthesis is released. The degree of inhibition of synthesis and the mechanism and degree of activation are still unknown. Moreover, in humans, a biphasic diurnal expression pattern of bile acid synthesis has been documented, indicating maximal synthesis around 3 PM and 9 PM. Quantitative data on the hourly synthesis schedule as compensation for intestinal loss are lacking. In this review, we describe the classical view on bile acid metabolism and present alternative concepts that are based on the overlooked feature that bile acids transit through the enterohepatic circulation very rapidly. A daily profile of the cycling and total bile acid pool sizes and potential controlled and uncontrolled mechanisms for synthesis are predicted. It remains to be elucidated by which mechanism clock genes interact with the Farnesoid X receptor-controlled regulation of bile acid synthesis. This mechanism could become an attractive target to enhance bile acid synthesis at night, when cholesterol synthesis is high, thus lowering serum LDL-cholesterol.


Assuntos
Ácidos e Sais Biliares/metabolismo , Circulação Êntero-Hepática/fisiologia , Intestinos/fisiologia , Fígado/metabolismo , Animais , Retroalimentação Fisiológica/fisiologia , Humanos , Íleo/metabolismo
17.
Nucleic Acids Res ; 49(9): 5393-5406, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-34009384

RESUMO

Computations widely exist in biological systems for functional regulations. Recently, incoherent feedforward loop and integral feedback controller have been implemented into Escherichia coli to achieve a robust adaptation. Here, we demonstrate that an indirect coherent feedforward loop and mutual inhibition designs can experimentally improve the fold change of promoters, by reducing the basal level while keeping the maximum activity high. We applied both designs to six different promoters in E. coli, starting with synthetic inducible promoters as a proof-of-principle. Then, we examined native promoters that are either functionally specific or systemically involved in complex pathways such as oxidative stress and SOS response. Both designs include a cascade having a repressor and a construct of either transcriptional interference or antisense transcription. In all six promoters, an improvement of up to ten times in the fold change activation was observed. Theoretically, our unitless models show that when regulation strength matches promoter basal level, an optimal fold change can be achieved. We expect that this methodology can be applied in various biological systems for biotechnology and therapeutic applications.


Assuntos
Redes Reguladoras de Genes , Genes Sintéticos , Escherichia coli/genética , Retroalimentação Fisiológica , Regulação da Expressão Gênica , Regiões Promotoras Genéticas , Biologia Sintética
18.
J Theor Biol ; 525: 110763, 2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34000285

RESUMO

The retina is a part of the central nervous system that is accessible, well documented, and studied by researchers spanning the clinical, experimental, and theoretical sciences. Here, we mathematically model the subcircuits of the outer plexiform layer of the retina on two spatial scales: that of an individual synapse and that of the scale of the receptive field (hundreds to thousands of synapses). To this end we formulate a continuum spine model (a partial differential equation system) that incorporates the horizontal cell syncytium and its numerous processes (spines) within cone pedicles. With this multiscale modeling approach, detailed biophysical mechanisms at the synaptic level are retained while scaling up to the receptive field level. As an example of its utility, the model is applied to study background-induced flicker enhancement in which the onset of a dim background enhances the center flicker response of horizontal cells. Simulation results, in comparison with flicker enhancement data for square, slit, and disk test regions, suggest that feedback mechanisms that are voltage-axis modulators of cone calcium channels (for example, ephaptic and/or pH feedback) are robust in capturing the temporal dynamics of background-induced flicker enhancement. The value and potential of this continuum spine approach is that it provides a framework for mathematically modeling the input-output properties of the entire receptive field of the outer retina while implementing the latest models for transmission mechanisms at the synaptic level.


Assuntos
Retina , Células Fotorreceptoras Retinianas Cones , Animais , Retroalimentação Fisiológica , Sinapses , Vertebrados
19.
Mol Carcinog ; 60(7): 481-496, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34018249

RESUMO

c-Hepatocyte growth factor receptor (Met) inhibitors have demonstrated clinical benefits in some types of solid tumors. However, the efficacy of c-Met inhibitors in esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we discovered that c-Met inhibitors induced "Signal Transducer and Activator of Transcription (STAT3)-addiction" in ESCC cells, and the feedback activation of STAT3 in ESCC cells limits the tumor response to c-Met inhibition. Mechanistically, c-Met inhibition increased the autocrine of several cytokines, including CCL2, interleukin 8, or leukemia inhibitory factor, and facilitated the interactions between the receptors of these cytokines and Janus Kinase1/2 (JAK1/2) to resultantly activate JAKs/STAT3 signaling. Pharmacological inhibition of c-Met together with cytokines/JAKs/STAT3 axis enhanced cancer cells regression in vitro. Importantly, combined c-Met and STAT3 inhibitors synergistically suppressed tumor growth and promoted the apoptosis of tumor cells without producing systematic toxicity. These findings suggest that inhibition of the STAT3 feedback loop may augment the response to c-Met inhibitors via the STAT3-mediated oncogene addiction in ESCC cells.


Assuntos
Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Ácidos Aminossalicílicos/administração & dosagem , Ácidos Aminossalicílicos/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzenossulfonatos/administração & dosagem , Benzenossulfonatos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/mortalidade , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/mortalidade , Retroalimentação Fisiológica/efeitos dos fármacos , Feminino , Humanos , Masculino , Camundongos Endogâmicos BALB C , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas c-met/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Transdução de Sinais/efeitos dos fármacos , Tirosina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Cancer Sci ; 112(8): 3099-3110, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34050704

RESUMO

With the ability to activate certain signaling pathways, chemokines and their receptors may facilitate tumor progression at key steps, including proliferation, immunomodulation, and metastasis. Nevertheless, their prognostic value and regulatory mechanism warrant thorough studies in liver cancer. Here, by screening the expression profiles of all known chemokines in independent liver cancer cohorts, we found that CCL23 was frequently downregulated at mRNA and protein levels in liver cancer. Decreased CCL23 correlated with shortened patient survival, enrichment of signatures related to cancer stem cell property, and metastatic potential. In addition to serving as a tumor suppressor through recruiting CD8+ T cell infiltration in liver cancer, CCL23 could repress cancer cell proliferation, stemness, and mobility. Mechanistically, the expression of CCL23 was transcriptionally regulated by ESR1. On the other hand, CCL23 could suppress the activation of AKT signaling and thus promote the expression of ESR1, forming a feedback loop in liver cancer cells. Collectively, these findings reveal that loss of CCL23 drives liver cancer progression by coordinating immune evasion and metastasis initiation. Targeting the ESR1/CCL23/CCR1/AKT regulatory axis could be an effective therapeutic strategy.


Assuntos
Quimiocinas CC/genética , Quimiocinas CC/metabolismo , Regulação para Baixo , Receptor alfa de Estrogênio/metabolismo , Neoplasias Hepáticas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Retroalimentação Fisiológica , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Gradação de Tumores , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores CCR1/metabolismo , Análise de Sobrevida
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