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1.
Endocrinology ; 163(1)2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34534278

RESUMO

Cross-talk between peripheral tissues is essential to ensure the coordination of nutrient intake with disposition during the feeding period, thereby preventing metabolic disease. This mini-review considers the interactions between the key peripheral tissues that constitute the metabolic clock, each of which is considered in a separate mini-review in this collation of articles published in Endocrinology in 2020 and 2021, by Martchenko et al (Circadian rhythms and the gastrointestinal tract: relationship to metabolism and gut hormones); Alvarez et al (The microbiome as a circadian coordinator of metabolism); Seshadri and Doucette (Circadian regulation of the pancreatic beta cell); McCommis et al (The importance of keeping time in the liver); Oosterman et al (The circadian clock, shift work, and tissue-specific insulin resistance); and Heyde et al (Contributions of white and brown adipose tissues to the circadian regulation of energy metabolism). The use of positive- and negative-feedback signals, both hormonal and metabolic, between these tissues ensures that peripheral metabolic pathways are synchronized with the timing of food intake, thus optimizing nutrient disposition and preventing metabolic disease. Collectively, these articles highlight the critical role played by the circadian clock in maintaining metabolic homeostasis.


Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano , Comportamento Alimentar , Homeostase , Fígado/fisiologia , Adipócitos/citologia , Animais , Endocrinologia/métodos , Ingestão de Energia , Metabolismo Energético/fisiologia , Retroalimentação Fisiológica , Hepatócitos/citologia , Hepatócitos/metabolismo , Humanos , Intestinos/fisiologia , Ilhotas Pancreáticas/citologia , Mamíferos/fisiologia , Doenças Metabólicas/metabolismo , Microbiota , Modelos Biológicos , Células Musculares/citologia , Músculo Esquelético/fisiologia
2.
Biomolecules ; 11(12)2021 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-34944495

RESUMO

Mutualistic symbiosis refers to the symbiotic relationship between individuals of different species in which both individuals benefit from the association. S100A10, a member of the S100 family of Ca2+-binding proteins, exists as a tight dimer and binds two annexin A2 molecules. This association forms the annexin A2/S100A10 complex known as AIIt, and modifies the distinct functions of both proteins. Annexin A2 is a Ca2+-binding protein that binds F-actin, phospholipid, RNA, and specific polysaccharides such as heparin. S100A10 does not bind Ca2+, but binds tPA, plasminogen, certain plasma membrane ion channels, neurotransmitter receptors, and the structural scaffold protein, AHNAK. S100A10 relies on annexin A2 for its intracellular survival: in the absence of annexin A2, it is rapidly destroyed by ubiquitin-dependent and independent proteasomal degradation. Annexin A2 requires S100A10 to increase its affinity for Ca2+, facilitating its participation in Ca2+-dependent processes such as membrane binding. S100A10 binds tissue plasminogen activator and plasminogen, and promotes plasminogen activation to plasmin, which is a process stimulated by annexin A2. In contrast, annexin A2 acts as a plasmin reductase and facilitates the autoproteolytic destruction of plasmin. This review examines the relationship between annexin A2 and S100A10, and how their mutualistic symbiosis affects the function of both proteins.


Assuntos
Anexina A2/metabolismo , Proteínas S100/metabolismo , Dipeptídeos/metabolismo , Retroalimentação Fisiológica , Fibrinolisina/metabolismo , Humanos , Proteólise , Ubiquitinação
3.
BMC Bioinformatics ; 22(1): 481, 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34607562

RESUMO

BACKGROUND: Feedback loops in gene regulatory networks play pivotal roles in governing functional dynamics of cells. Systems approaches demonstrated characteristic dynamical features, including multistability and oscillation, of positive and negative feedback loops. Recent experiments and theories have implicated highly interconnected feedback loops (high-feedback loops) in additional nonintuitive functions, such as controlling cell differentiation rate and multistep cell lineage progression. However, it remains challenging to identify and visualize high-feedback loops in complex gene regulatory networks due to the myriad of ways in which the loops can be combined. Furthermore, it is unclear whether the high-feedback loop structures with these potential functions are widespread in biological systems. Finally, it remains challenging to understand diverse dynamical features, such as high-order multistability and oscillation, generated by individual networks containing high-feedback loops. To address these problems, we developed HiLoop, a toolkit that enables discovery, visualization, and analysis of several types of high-feedback loops in large biological networks. RESULTS: HiLoop not only extracts high-feedback structures and visualize them in intuitive ways, but also quantifies the enrichment of overrepresented structures. Through random parameterization of mathematical models derived from target networks, HiLoop presents characteristic features of the underlying systems, including complex multistability and oscillations, in a unifying framework. Using HiLoop, we were able to analyze realistic gene regulatory networks containing dozens to hundreds of genes, and to identify many small high-feedback systems. We found more than a 100 human transcription factors involved in high-feedback loops that were not studied previously. In addition, HiLoop enabled the discovery of an enrichment of high feedback in pathways related to epithelial-mesenchymal transition. CONCLUSIONS: HiLoop makes the study of complex networks accessible without significant computational demands. It can serve as a hypothesis generator through identification and modeling of high-feedback subnetworks, or as a quantification method for motif enrichment analysis. As an example of discovery, we found that multistep cell lineage progression may be driven by either specific instances of high-feedback loops with sparse appearances, or generally enriched topologies in gene regulatory networks. We expect HiLoop's usefulness to increase as experimental data of regulatory networks accumulate. Code is freely available for use or extension at https://github.com/BenNordick/HiLoop .


Assuntos
Retroalimentação Fisiológica , Redes Reguladoras de Genes , Retroalimentação , Humanos , Modelos Biológicos , Modelos Teóricos , Fatores de Transcrição
4.
Nat Commun ; 12(1): 5931, 2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34635673

RESUMO

The chromatin remodeler RSF1 enriched at mitotic centromeres is essential for proper chromosome alignment and segregation and underlying mechanisms remain to be disclosed. We here show that PLK1 recruitment by RSF1 at centromeres creates an activating phosphorylation on Thr236 in the activation loop of Aurora B and this is indispensable for the Aurora B activation. In structural modeling the phosphorylated Thr236 enhances the base catalysis by Asp200 nearby, facilitating the Thr232 autophosphorylation. Accordingly, RSF1-PLK1 is central for Aurora B-mediated microtubule destabilization in error correction. However, under full microtubule-kinetochore attachment RSF1-PLK1 positions at kinetochores, halts activating Aurora B and phosphorylates BubR1, regardless of tension. Spatial movement of RSF1-PLK1 to kinetochores is triggered by Aurora B-mediated phosphorylation of centromeric histone H3 on Ser28. We propose a regulatory RSF1-PLK1 axis that spatiotemporally controls on/off switch on Aurora B. This feedback circuit among RSF1-PLK1-Aurora B may coordinate dynamic microtubule-kinetochore attachment in early mitosis when full tension yet to be generated.


Assuntos
Aurora Quinase B/genética , Proteínas de Ciclo Celular/genética , Segregação de Cromossomos , Mitose , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas/genética , Transdução de Sinais/genética , Transativadores/genética , Ácido Aspártico/metabolismo , Aurora Quinase B/metabolismo , Proteínas de Ciclo Celular/metabolismo , Cromatina/química , Cromatina/metabolismo , Retroalimentação Fisiológica , Regulação da Expressão Gênica , Células HeLa , Histonas/genética , Histonas/metabolismo , Humanos , Cinetocoros/metabolismo , Cinetocoros/ultraestrutura , Microtúbulos/metabolismo , Microtúbulos/ultraestrutura , Proteínas Nucleares/deficiência , Fosforilação , Proteínas Proto-Oncogênicas/metabolismo , Serina/metabolismo , Transativadores/deficiência
5.
Int J Mol Sci ; 22(19)2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34638930

RESUMO

No gene has garnered more interest than p53 since its discovery over 40 years ago. In the last two decades, thanks to seminal work from Uri Alon and Ghalit Lahav, p53 has defined a truly synergistic topic in the field of mathematical biology, with a rich body of research connecting mathematic endeavour with experimental design and data. In this review we survey and distill the extensive literature of mathematical models of p53. Specifically, we focus on models which seek to reproduce the oscillatory dynamics of p53 in response to DNA damage. We review the standard modelling approaches used in the field categorising them into three types: time delay models, spatial models and coupled negative-positive feedback models, providing sample model equations and simulation results which show clear oscillatory dynamics. We discuss the interplay between mathematics and biology and show how one informs the other; the deep connections between the two disciplines has helped to develop our understanding of this complex gene and paint a picture of its dynamical response. Although yet more is to be elucidated, we offer the current state-of-the-art understanding of p53 response to DNA damage.


Assuntos
Algoritmos , Dano ao DNA , Modelos Teóricos , Transdução de Sinais/fisiologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Simulação por Computador , Retroalimentação Fisiológica , Humanos , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Transdução de Sinais/genética , Proteína Supressora de Tumor p53/genética
6.
Nutrients ; 13(10)2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34684432

RESUMO

Overweight and obesity in children and adolescents are overwhelming problems in western countries. Adipocytes, far from being only fat deposits, are capable of endocrine functions, and the endocrine activity of adipose tissue, resumable in adipokines production, seems to be a key modulator of central nervous system function, suggesting the existence of an "adipo-cerebral axis." This connection exerts a key role in children growth and puberty development, and it is exemplified by the leptin-kisspeptin interaction. The aim of this review was to describe recent advances in the knowledge of adipose tissue endocrine functions and their relations with nutrition and growth. The peculiarities of major adipokines are briefly summarized in the first paragraph; leptin and its interaction with kisspeptin are focused on in the second paragraph; the third paragraph deals with the regulation of the GH-IGF axis, with a special focus on the model represented by growth hormone deficiency (GHD); finally, old and new nutritional aspects are described in the last paragraph.


Assuntos
Tecido Adiposo/metabolismo , Córtex Cerebral/metabolismo , Retroalimentação Fisiológica , Obesidade Pediátrica/etiologia , Obesidade Pediátrica/metabolismo , Adipócitos/metabolismo , Adipocinas/metabolismo , Animais , Biomarcadores , Criança , Desenvolvimento Infantil , Fenômenos Fisiológicos da Nutrição Infantil , Pré-Escolar , Suscetibilidade a Doenças , Hormônio do Crescimento/metabolismo , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Kisspeptinas/metabolismo , Puberdade/genética , Puberdade/metabolismo , Transdução de Sinais
7.
Nutrients ; 13(10)2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34684436

RESUMO

Metabolic-associated fatty liver disease is a major cause of chronic pathologies, of which maternal obesity is a frequent risk factor. Gut wall and microbiota, visceral fat, and liver form a pre-systemic network for substrates and pro-inflammatory factors entering the body, undergoing accelerated maturation in early-life when the weaning reaction, i.e., a transitory inflammatory condition, affects lifelong health. We aimed to characterize organ metabolism in the above network, in relation to weaning reaction and maternal obesity. Weaning or 6-months-old offspring of high-fat-diet and normal-diet fed dams underwent in vivo imaging of pre-/post-systemic glucose uptake and tissue radiodensity in the liver, visceral fat, and intestine, a liver histology, and microbiota and metabolic pathway analyses. Weaning mice showed the dominance of gut Clostridia and Bacteroidia members, overexpressing pathways of tissue replication and inflammation; adulthood increased proneness to steatohepatitis, and Desulfovibrio and RF39 bacteria, and lipopolysaccharide, bile acid, glycosaminoglycan, and sphingolipid metabolic pathways. In vivo imaging could track organ maturation, liver inflammation, and protective responses. A maternal high-fat diet amplified the weaning reaction, elevating liver glucose uptake, triglyceride levels, and steatohepatitis susceptibility along the lifespan. The visceral network establishes a balance between metabolism and inflammation, with clear imaging biomarkers, and crucial modulation in the weaning time window.


Assuntos
Tecido Adiposo/metabolismo , Dieta Hiperlipídica , Retroalimentação Fisiológica , Trato Gastrointestinal/metabolismo , Fígado/metabolismo , Fenômenos Fisiológicos da Nutrição Materna , Efeitos Tardios da Exposição Pré-Natal , Desmame , Fatores Etários , Animais , Biomarcadores , Suscetibilidade a Doenças , Metabolismo Energético , Feminino , Microbioma Gastrointestinal , Imuno-Histoquímica , Redes e Vias Metabólicas , Camundongos , Especificidade de Órgãos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Gravidez
8.
Am J Physiol Heart Circ Physiol ; 321(5): H893-H904, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34559579

RESUMO

We have previously shown that several components of the RhoA signaling pathway control smooth muscle cell (SMC) phenotype by altering serum response factor (SRF)-dependent gene expression. Because our genome-wide analyses of chromatin structure and transcription factor binding suggested that the actin depolymerizing factor, destrin (DSTN), was regulated in a SMC-selective fashion, the goals of the current study were to identify the transcription mechanisms that control DSTN expression in SMC and to test whether it regulates SMC function. Immunohistochemical analyses revealed strong and at least partially SMC-selective expression of DSTN in many mouse tissues, a result consistent with human data from the genotype-tissue expression (GTEx) consortium. We identified several regulatory regions that control DSTN expression including a SMC-selective enhancer that was activated by myocardin-related transcription factor-A (MRTF-A), recombination signal binding protein for immunoglobulin κ-J region (RBPJ), and the SMAD transcription factors. Indeed, enhancer activity and endogenous DSTN expression were upregulated by RhoA and transforming growth factor-ß (TGF-ß) signaling and downregulated by inhibition of Notch cleavage. We also showed that DSTN expression was decreased in vivo by carotid artery injury and in cultured SMC cells by platelet-derived growth factor-BB (PDGF-BB) treatment. siRNA-mediated depletion of DSTN significantly enhanced MRTF-A nuclear localization and SMC differentiation marker gene expression, decreased SMC migration in scratch wound assays, and decreased SMC proliferation, as measured by cell number and cyclin-E expression. Taken together our data indicate that DSTN is a negative feedback inhibitor of RhoA/SRF-dependent gene expression in SMC that coordinately promotes SMC phenotypic modulation. Interventions that target DSTN expression or activity could serve as potential therapies for atherosclerosis and restenosis.NEW & NOTEWORTHY First, DSTN is selectively expressed in SMC in RhoA/SRF-dependent manner. Second, a SMC-selective enhancer just upstream of DSTN TSS harbors functional SRF, SMAD, and Notch/RBPJ binding elements. Third, DSTN depletion increased SRF-dependent SMC marker gene expression while inhibiting SMC migration and proliferation. Taken together, our data suggest that DSTN is a critical negative feedback inhibitor of SMC differentiation.


Assuntos
Actinas/metabolismo , Lesões das Artérias Carótidas/metabolismo , Diferenciação Celular , Destrina/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Animais , Lesões das Artérias Carótidas/genética , Lesões das Artérias Carótidas/patologia , Movimento Celular , Proliferação de Células , Células Cultivadas , Quimiocina CXCL12/metabolismo , Destrina/genética , Modelos Animais de Doenças , Retroalimentação Fisiológica , Regulação da Expressão Gênica , Humanos , Camundongos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Fenótipo , Regiões Promotoras Genéticas , Ratos , Ratos Wistar , Receptores Notch/metabolismo , Transdução de Sinais , Transcrição Genética , Proteína rhoA de Ligação ao GTP/metabolismo
9.
Nat Commun ; 12(1): 5651, 2021 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-34561433

RESUMO

The design and implementation of synthetic circuits that operate robustly in the cellular context is fundamental for the advancement of synthetic biology. However, their practical implementation presents challenges due to low predictability of synthetic circuit design and time-intensive troubleshooting. Here, we present the Cyberloop, a testing framework to accelerate the design process and implementation of biomolecular controllers. Cellular fluorescence measurements are sent in real-time to a computer simulating candidate stochastic controllers, which in turn compute the control inputs and feed them back to the controlled cells via light stimulation. Applying this framework to yeast cells engineered with optogenetic tools, we examine and characterize different biomolecular controllers, test the impact of non-ideal circuit behaviors such as dilution on their operation, and qualitatively demonstrate improvements in controller function with certain network modifications. From this analysis, we derive conditions for desirable biomolecular controller performance, thereby avoiding pitfalls during its biological implementation.


Assuntos
Regulação da Expressão Gênica/genética , Optogenética/métodos , Análise de Célula Única/métodos , Processos Estocásticos , Biologia Sintética/métodos , Simulação por Computador , Retroalimentação Fisiológica/efeitos da radiação , Regulação da Expressão Gênica/efeitos da radiação , Luz , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/fisiologia , Saccharomyces cerevisiae/efeitos da radiação
10.
Int J Mol Sci ; 22(18)2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34575911

RESUMO

Schizophrenia is a severe neuropsychiatric disorder, and its etiology remains largely unknown. Environmental factors have been reported to play roles in the pathogenesis of schizophrenia, and one of the major environmental factors identified for this disorder is psychosocial stress. Several studies have suggested that stressful life events, as well as the chronic social stress associated with city life, may lead to the development of schizophrenia. The other factor is the gut-brain axis. The composition of the gut microbiome and alterations thereof may affect the brain and may lead to schizophrenia. The main interest of this review article is in overviewing the major recent findings on the effects of stress and the gut-brain axis, as well as their possible bidirectional effects, in the pathogenesis of schizophrenia.


Assuntos
Encéfalo/metabolismo , Suscetibilidade a Doenças , Retroalimentação Fisiológica , Trato Gastrointestinal/metabolismo , Esquizofrenia/etiologia , Esquizofrenia/metabolismo , Estresse Psicológico/complicações , Animais , Encéfalo/fisiopatologia , Microbioma Gastrointestinal , Humanos
11.
Int J Mol Sci ; 22(18)2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34576172

RESUMO

Global data correlate severe vitamin D deficiency with COVID-19-associated coagulopathy, further suggesting the presence of a hypercoagulable state in severe COVID-19 patients, which could promote thrombosis in the lungs and in other organs. The feedback loop between COVID-19-associated coagulopathy and vitamin D also involves platelets (PLTs), since vitamin D deficiency stimulates PLT activation and aggregation and increases fibrinolysis and thrombosis. Vitamin D and PLTs share and play specific roles not only in coagulation and thrombosis but also during inflammation, endothelial dysfunction, and immune response. Additionally, another 'fil rouge' between vitamin D and PLTs is represented by their role in mineral metabolism and bone health, since vitamin D deficiency, low PLT count, and altered PLT-related parameters are linked to abnormal bone remodeling in certain pathological conditions, such as osteoporosis (OP). Hence, it is possible to speculate that severe COVID-19 patients are characterized by the presence of several predisposing factors to bone fragility and OP that may be monitored to avoid potential complications. Here, we hypothesize different pervasive actions of vitamin D and PLT association in COVID-19, also allowing for potential preliminary information on bone health status during COVID-19 infection.


Assuntos
Plaquetas/imunologia , COVID-19/complicações , Osteoporose/imunologia , Trombose/imunologia , Deficiência de Vitamina D/imunologia , Vitamina D/metabolismo , Plaquetas/metabolismo , Remodelação Óssea/imunologia , COVID-19/sangue , COVID-19/diagnóstico , COVID-19/imunologia , Retroalimentação Fisiológica , Humanos , Osteoporose/sangue , Ativação Plaquetária/imunologia , Contagem de Plaquetas , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Trombose/sangue , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/complicações
12.
Int J Mol Sci ; 22(17)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34502135

RESUMO

Estrogen produced by ovarian follicles plays a key role in the central mechanisms controlling reproduction via regulation of gonadotropin-releasing hormone (GnRH) release by its negative and positive feedback actions in female mammals. It has been well accepted that estrogen receptor α (ERα) mediates both estrogen feedback actions, but precise targets had remained as a mystery for decades. Ever since the discovery of kisspeptin neurons as afferent ERα-expressing neurons to govern GnRH neurons, the mechanisms mediating estrogen feedback are gradually being unraveled. The present article overviews the role of kisspeptin neurons in the arcuate nucleus (ARC), which are considered to drive pulsatile GnRH/gonadotropin release and folliculogenesis, in mediating the estrogen negative feedback action, and the role of kisspeptin neurons located in the anteroventral periventricular nucleus-periventricular nucleus (AVPV-PeN), which are thought to drive GnRH/luteinizing hormone (LH) surge and consequent ovulation, in mediating the estrogen positive feedback action. This implication has been confirmed by the studies showing that estrogen-bound ERα down- and up-regulates kisspeptin gene (Kiss1) expression in the ARC and AVPV-PeN kisspeptin neurons, respectively. The article also provides the molecular and epigenetic mechanisms regulating Kiss1 expression in kisspeptin neurons by estrogen. Further, afferent ERα-expressing neurons that may regulate kisspeptin release are discussed.


Assuntos
Encéfalo/metabolismo , Estrogênios/metabolismo , Retroalimentação Fisiológica , Kisspeptinas/metabolismo , Ovulação , Animais , Encéfalo/citologia , Encéfalo/fisiologia , Feminino , Humanos , Neurônios/metabolismo , Neurônios/fisiologia , Receptores de Estrogênio/metabolismo , Transdução de Sinais
13.
Front Immunol ; 12: 672312, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34484176

RESUMO

Eosinophilic asthma (EA) is a common subtype of asthma and often progresses to severe disease. In order to understand its pathogenesis, targeted next-generation gene sequencing was performed on 77 Chinese EA patients and 431 Chinese healthy controls to obtain differential genomic variations. Among the 41 Single Nucleotide Polymorphisms (SNPs) screened for mutation sites in more than 3 patients, filaggrin gene FLG rs192116923 T>G and FLG rs75235053 C>G were newly found to be associated with EA patients with atopic dermatitis (AD) (P <0.001) and severe EA (P=0.032), respectively. Filaggrin has been shown to be mainly expressed in epithelial cells and plays an important role in formation of an effective skin barrier. Bioinformatic analysis indicated FLG rs192116923 T>G may increase the binding of Smad3 to transmit TGF-ß1 signaling, and thereby inhibit filaggrin expression, and FLG rs75235053 C>G may add new splicing sites to reduce filaggrin monomers. It has been known that the level of Th2 cytokine IL-4 is increased in EA patients, and IL-4 increases airway epithelial permeability and enhances inflammatory response through some unclear mechanisms. To figure out whether filaggrin is involved in immune responses in asthma, we have treated human respiratory epithelial cell line BEAS-2B cells with IL-4 and found that the expression levels of filaggrin and E-cadherin decreased significantly in a time and dose-dependent manner, suggesting that IL-4 increased airway epithelial permeability by reducing filaggrin and adhesion molecule. In addition, in our study, IL-4 increased the expression of epithel-derived inflammatory cytokines IL-33 and TSLP which further enhanced the Th2 inflammatory response. To investigate the role of filaggrin in development of EA, knockdown filaggrin with siRNA revealed a decrease in E-cadherin levels, which were further down-regulated by IL-4 stimulation. Knockdown of filaggrin alone did not affect the levels of IL-33 and TSLP, but further exacerbated the decrease of IL-33/TSLP caused by IL-4, suggesting that filaggrin may involve in IL-4R signaling pathway to regulate the level of IL-33/TSLP. In conclusion, in the Th2 cytokine milieu of asthma, FLG deficient mutation in airway epithelial cells may increase the epithelial permeability and the expression of IL-33/TSLP which positively feedback the Th2 inflammation response.


Assuntos
Asma/genética , Asma/imunologia , Proteínas S100/genética , Células Th2/imunologia , Adulto , Citocinas/imunologia , Eosinofilia/genética , Eosinofilia/imunologia , Retroalimentação Fisiológica , Feminino , Humanos , Interleucina-33/imunologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Proteínas S100/imunologia , Proteínas S100/metabolismo
14.
Plant Mol Biol ; 107(3): 147-158, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34562198

RESUMO

KEY MESSAGE: The GAF1 transcription factor is shown to bind to the promoter of the Arabidopsis GA-biosynthetic enzyme GA20ox1 and, in association with DELLA protein, promotes GA20ox1 expression, thereby contributing to its feedback regulation and tissue specificity. Gibberellins (GAs) are phytohormones that promote plant growth and development, including germination, elongation, flowering, and floral development. Homeostasis of endogenous GA levels is controlled by GA feedback regulation. DELLAs are negative regulators of GA signaling that are rapidly degraded in the presence of GAs. DELLAs regulate several target genes, including AtGA20ox2 and AtGA3ox1, encoding the GA-biosynthetic enzymes GA 20-oxidase and GA 3-oxidase, respectively. Previous studies have identified GAI-ASSOCIATED FACTOR 1 (GAF1) as a DELLA interactor, with which DELLAs act as transcriptional coactivators; furthermore, AtGA20ox2, AtGA3ox1, and AtGID1b were identified as target genes of the DELLA-GAF1 complex. Among the five Arabidopsis GA20ox genes, AtGA20ox1 is the most highly expressed gene during vegetative growth; its expression is controlled by GA feedback regulation. Here, we investigated whether AtGA20ox1 is regulated by the DELLA-GAF1 complex. The electrophoretic mobility shift and transactivation assays showed that three GAF1-binding sites exist in the AtGA20ox1 promoter. Using transgenic plants, we further evaluated the contribution of the DELLA-GAF1 complex to GA feedback regulation and tissue-specific expression. Mutations in two GAF1-binding sites obliterated the negative feedback regulation and tissue-specific expression of AtGA20ox1 in transgenic plants. Thus, our results showed that GAF1-binding sites are involved in GA feedback regulation and tissue-specific expression of AtGA20ox1 in Arabidopsis, suggesting that the DELLA-GAF1 complex is involved in both processes.


Assuntos
Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Arabidopsis/fisiologia , Proteínas de Ligação ao Cálcio/metabolismo , Giberelinas/metabolismo , Oxigenases de Função Mista/genética , Arabidopsis/efeitos dos fármacos , Sítios de Ligação , Proteínas de Ligação ao Cálcio/genética , Retroalimentação Fisiológica , Flores/genética , Regulação da Expressão Gênica de Plantas , Giberelinas/farmacologia , Oxigenases de Função Mista/metabolismo , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , Folhas de Planta/genética , Plantas Geneticamente Modificadas , Regiões Promotoras Genéticas
15.
Nat Commun ; 12(1): 5475, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34531380

RESUMO

Acetylcholine release in the hippocampus plays a central role in the formation of new memory representations. An influential but largely untested theory proposes that memory formation requires acetylcholine to enhance responses in CA1 to new sensory information from entorhinal cortex whilst depressing inputs from previously encoded representations in CA3. Here, we show that excitatory inputs from entorhinal cortex and CA3 are depressed equally by synaptic release of acetylcholine in CA1. However, feedforward inhibition from entorhinal cortex exhibits greater depression than CA3 resulting in a selective enhancement of excitatory-inhibitory balance and CA1 activation by entorhinal inputs. Entorhinal and CA3 pathways engage different feedforward interneuron subpopulations and cholinergic modulation of presynaptic function is mediated differentially by muscarinic M3 and M4 receptors, respectively. Thus, our data support a role and mechanisms for acetylcholine to prioritise novel information inputs to CA1 during memory formation.


Assuntos
Acetilcolina/metabolismo , Região CA1 Hipocampal/fisiologia , Córtex Entorrinal/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Retroalimentação Fisiológica/fisiologia , Transmissão Sináptica/fisiologia , Animais , Região CA1 Hipocampal/citologia , Carbacol/farmacologia , Agonistas Colinérgicos/farmacologia , Córtex Entorrinal/citologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Retroalimentação Fisiológica/efeitos dos fármacos , Interneurônios/metabolismo , Interneurônios/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Técnicas de Patch-Clamp , Células Piramidais/metabolismo , Células Piramidais/fisiologia , Receptor Muscarínico M3/genética , Receptor Muscarínico M3/metabolismo , Transmissão Sináptica/efeitos dos fármacos
16.
J Immunol ; 207(8): 2039-2050, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34535574

RESUMO

Thymic epithelial cells (TECs) are critical for the development and generation of functionally competent T cells. Until now, the mechanism that regulates the survival of TECs is poorly understood. In the current study, we found that Tsc1 controls the homeostasis of medullary TECs (mTECs) by inhibiting lysosomal-mediated apoptosis pathway in mice. TEC-specific deletion of Tsc1 predominately decreased the cell number of mTECs and, to a lesser content, affected the development cortical TECs. The defect of mTECs caused by Tsc1 deficiency in mice impaired thymocyte development and peripheral T cell homeostasis. Mechanistically, Tsc1 deficiency did not affect the cell proliferation of mTECs but increased the apoptosis of mTECs significantly. RNA-sequencing analysis showed that pathways involved in lysosomal biogenesis, cell metabolism, and apoptosis were remarkably elevated in Tsc1-deficient mTECs compared with their wild-type counterparts. Tsc1-deficient mTECs exhibited overproduction of reactive oxygen species and malfunction of lysosome, with lysosome membrane permeabilization and the release of cathepsin B and cathepsin L to the cytosol, which then lead to Bid cleaved into active truncated Bid and subsequently intrinsic apoptosis. Finally, we showed that the impaired development of mTECs could be partially reversed by decreasing mTORC1 activity via haploinsufficiency of Raptor Thus, Tsc1 is essential for the homeostasis of mTECs by inhibiting lysosomal-mediated apoptosis through mTORC1-dependent pathways.


Assuntos
Células Epiteliais/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Timo/citologia , Proteína 1 do Complexo Esclerose Tuberosa/metabolismo , Animais , Apoptose , Diferenciação Celular , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Células Epiteliais/citologia , Retroalimentação Fisiológica , Haploinsuficiência , Homeostase , Camundongos , Camundongos Knockout , Espécies Reativas de Oxigênio/metabolismo , Proteína Regulatória Associada a mTOR/genética , Proteína 1 do Complexo Esclerose Tuberosa/genética
17.
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
18.
PLoS Genet ; 17(8): e1009693, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34351909

RESUMO

The ubiquitin-proteasome system plays important roles in various biological processes as it degrades the majority of cellular proteins. Adequate proteasomal degradation of crucial transcription regulators ensures the proper development of neutrophils. The ubiquitin E3 ligase of Growth factor independent 1 (GFI1), a key transcription repressor governing terminal granulopoiesis, remains obscure. Here we report that the deficiency of the ring finger protein Interferon regulatory factor 2 binding protein 2a (Irf2bp2a) leads to an impairment of neutrophils differentiation in zebrafish. Mechanistically, Irf2bp2a functions as a ubiquitin E3 ligase targeting Gfi1aa for proteasomal degradation. Moreover, irf2bp2a gene is repressed by Gfi1aa, thus forming a negative feedback loop between Irf2bp2a and Gfi1aa during neutrophils maturation. Different levels of GFI1 may turn it into a tumor suppressor or an oncogene in malignant myelopoiesis. Therefore, discovery of certain drug targets GFI1 for proteasomal degradation by IRF2BP2 might be an effective anti-cancer strategy.


Assuntos
Proteínas de Ligação a DNA/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/crescimento & desenvolvimento , Animais , Proteínas de Ligação a DNA/metabolismo , Retroalimentação Fisiológica , Feminino , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Células HEK293 , Células HL-60 , Humanos , Leucopoese , Masculino , Proteólise , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética
19.
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
20.
Front Immunol ; 12: 658432, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34367130

RESUMO

The physiological process of male reproduction relies on the orchestration of neuroendocrine, immune, and energy metabolism. Spermatogenesis is controlled by the hypothalamic-pituitary-testicular (HPT) axis, which modulates the production of gonadal steroid hormones in the testes. The immune cells and cytokines in testes provide a protective microenvironment for the development and maturation of germ cells. The metabolic cellular responses and processes in testes provide energy production and biosynthetic precursors to regulate germ cell development and control testicular immunity and inflammation. The metabolism of immune cells is crucial for both inflammatory and anti-inflammatory responses, which supposes to affect the spermatogenesis in testes. In this review, the role of immunometabolism in male reproduction will be highlighted. Obesity, metabolic dysfunction, such as type 2 diabetes mellitus, are well documented to impact male fertility; thus, their impacts on the immune cells distributed in testes will also be discussed. Finally, the potential significance of the medicine targeting the specific metabolic intermediates or immune metabolism checkpoints to improve male reproduction will also be reassessed.


Assuntos
Metabolismo Energético , Imunomodulação , Reprodução/fisiologia , Animais , Gerenciamento Clínico , Suscetibilidade a Doenças , Retroalimentação Fisiológica , Hormônios Esteroides Gonadais/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Humanos , Sistema Hipotálamo-Hipofisário/imunologia , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Infertilidade Masculina/etiologia , Infertilidade Masculina/metabolismo , Infertilidade Masculina/terapia , Masculino , Testículo/imunologia , Testículo/metabolismo
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