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Environmental chemicals, such as plasticizers, have been linked to increased rates of obesity, according to epidemiological studies. Acetyl triethyl citrate (ATEC) is a plasticizer that is commonly utilized in pharmaceutical products and food packaging as a non-phthalate alternative. Due to its direct contact with the human body and high leakage rate from the polymers, assessment of the potential risk of ATEC exposure at environmentally relevant low doses to human health is needed. Male C57BL/6 J mice were fed diets containing ATEC at doses of either 0.1 or 10 µg/kg per day in a period of 12 weeks to mimic the real exposure environment. The findings suggest that in C57BL/6 J mice, ATEC exposure resulted in increased body weight gain, body fat percentage, and benign hepatocytes, as well as adipocyte size. Consistent with in vivo models, ATEC treatment obviously stimulated the increase of intracellular lipid load in both mouse and human hepatocytes. Mechanically, ATEC induced the transcriptional expression of genes involved in de novo lipogenesis and lipid uptake. Using both enzyme inhibitor and small interfering RNA (siRNA) transfection, we found that stearoyl-coenzyme A desaturase 1 (SCD1) played a significant role in ATEC-induced intracellular lipid accumulation. This study for the first time provided initial evidence suggesting the obesogenic and fatty liver-inducing effect of ATEC at low doses near human exposure levels, and ATEC might be a potential environmental obesogen and its effect on human health need to be further evaluated.
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Citratos , Lipogênese , Plastificantes , Masculino , Camundongos , Humanos , Animais , Plastificantes/toxicidade , Camundongos Endogâmicos C57BL , Obesidade/induzido quimicamente , Obesidade/metabolismo , Lipídeos , Fígado , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismoRESUMO
Diisobutyl adipate (DIBA), as a novel non-phthalate plasticizer, is widely used in various products. However, little effort has been made to investigate whether DIBA might have adverse effects on human health. In this study, we integrated an in silico and in vitro strategy to assess the impact of DIBA on cellular homeostasis. Since numerous plasticizers could activate peroxisome proliferator-activated receptor γ (PPARγ) pathway to interrupt metabolism systems, we first utilized molecular docking to analyze interaction between DIBA and PPARγ. Results indicated that DIBA had strong affinity with the ligand-binding domain of PPARγ (PPARγ-LBD) at Histidine 499. Afterwards, we used cellular models to investigate in vitro effects of DIBA. Results demonstrated that DIBA exposure increased intracellular lipid content in murine and human hepatocytes, and altered transcriptional expression of genes related to PPARγ signaling and lipid metabolism pathways. At last, target genes regulated by DIBA were predicted and enriched for Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Protein-protein interaction (PPI) network and transcriptional factors (TFs)-genes network were established accordingly. Target genes were enriched in Phospholipase D signaling pathway, phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) and Epidermal growth factor receptor (EGFR) signaling pathway which were related to lipid metabolism. These findings suggested that DIBA exposure might disturb intracellular lipid metabolism homeostasis via targeting PPARγ. This study also demonstrated that this integrated in silico and in vitro methodology could be utilized as a high throughput, cost-saving and effective tool to assess the potential risk of various environmental chemicals on human health.
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PPAR gama , Plastificantes , Camundongos , Humanos , Animais , Plastificantes/toxicidade , PPAR gama/metabolismo , Metabolismo dos Lipídeos , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/metabolismo , AdipatosRESUMO
The epidemic of Coronavirus Disease 2019 has been a serious threat to public health worldwide. Data from 23 January to 31 March at Jiangsu and Anhui provinces in China were collected. We developed an adjusted model with two novel features: the asymptomatic population and threshold behavior in recovery. Unbiased parameter estimation identified faithful model fitting. Our model predicted that the epidemic for asymptomatic patients (ASP) was similar in both provinces. The latent periods and outbreak sizes are extremely sensitive to strongly controlled interventions such as isolation and quarantine for both asymptomatic and imported cases. We predicted that ASP serve as a more severe factor with faster outbreaks and larger outbreak sizes compared with imported patients. Therefore, we argued that the currently strict interventions should be continuously implemented, and unraveling the asymptomatic pool is critically important before preventive strategy such as vaccines.
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Infecções Assintomáticas/epidemiologia , COVID-19/epidemiologia , Pandemias/estatística & dados numéricos , China/epidemiologia , Surtos de Doenças , Humanos , Modelos Teóricos , Pneumonia Viral/epidemiologia , Saúde Pública/estatística & dados numéricos , Quarentena/métodos , SARS-CoV-2/patogenicidade , Isolamento SocialRESUMO
The Coronavirus Disease 2019 (COVID-19) surges worldwide. However, massive imported patients especially into Heilongjiang Province in China recently have been an alert for local COVID-19 outbreak. We collected data from January 23 to March 25 from Heilongjiang province and trained an ordinary differential equation model to fit the epidemic data. We extended the simulation using this trained model to characterize the effect of an imported 'escaper'. We showed that an imported 'escaper' was responsible for the newly confirmed COVID-19 infections from Apr 9 to Apr 19 in Heilongjiang province. Stochastic simulations further showed that significantly increased local contacts among imported 'escaper', its epidemiologically associated cases and susceptible populations greatly contributed to the local outbreak of COVID-19. Meanwhile, we further found that the reported number of asymptomatic patients was markedly lower than model predictions implying a large asymptomatic pool which was not identified. We further forecasted the effect of implementing strong interventions immediately to impede COVID-19 outbreak for Heilongjiang province. Implementation of stronger interventions to lower mutual contacts could accelerate the complete recovery from coronavirus infections in Heilongjiang province. Collectively, our model has characterized the epidemic of COVID-19 in Heilongjiang province and implied that strongly controlled measured should be taken for infected and asymptomatic patients to minimize total infections.
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Our previous investigations have demonstrated that microinjection of acetylcholine (ACh) or muscarinic ACh receptor activation in the cerebellar cortex induces a systemic blood pressure depressor response. This study aimed to determine the role of muscarinic ACh receptor-2 (M2 receptor) in the cerebellar cortex in cardiovascular function regulation in rats. A nonselective muscarinic receptor agonist (oxotremorine M, OXO; 30 mM), a selective M2 receptor agonist (arecaidine but-2-ynyl ester tosylate, ABET; 3, 10, and 30 mM), 30 mM OXO mixed with a selective M2 receptor antagonist (methoctramine hydrate, MCT; 0.3, 1, and 3 mM), and normal saline (0.9 % NaCl) were separately microinjected (0.5 µl/5 s) into the cerebellar cortex (lobule VI) of anaesthetized rats. We measured the mean arterial pressure (MAP), maximum change in MAP, and reactive time (RT; the duration required for the blood pressure to return to basal levels), heart rate (HR) and the maximum change in HR during the RT in response to drug activation. The results demonstrated that ABET dose-dependently decreased MAP and HR, increased the maximum change in MAP and the maximum change in HR, and prolonged the RT. Furthermore, MCT dose-dependently blocked the OXO-mediated cardiovascular depressor response. This study provides the first evidence that M2 receptors in the cerebellar cortex are involved in cardiovascular regulation, the activation of which evokes significant depressor and bradycardic responses.
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Pressão Sanguínea/efeitos dos fármacos , Córtex Cerebelar/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Agonistas Muscarínicos/farmacologia , Receptor Muscarínico M2/metabolismo , Animais , Relação Dose-Resposta a Droga , Masculino , Microinjeções , Antagonistas Muscarínicos/farmacologia , Ratos Sprague-DawleyRESUMO
Secretin, a gastrointestinal peptide, has been found to be expressed in mouse endometrial stromal cells (mESCs) during early pregnancy. In order to further investigate the function of secretin during embryo implantation, the expression levels of secretin, secretin receptor, cytosolic phospholipase A2 (cPLA2) and membrane prostaglandin E synthase 1 (mPGEs-1) were detected in the mice uterus from day 4 to 8 of pregnancy by real-time PCR, ELISA and in situ hybridization. mESCs isolated and cultured from day 4 of pregnancy were transfected with secretin expression vectors or treated with H89, a PKA inhibitor. Then the expression levels of cPLA2, mPGEs-1 and cAMP responsive element-binding protein (CREB) were detected by real-time PCR and Western blot. The concentration of prostaglandin E2 (PGE2) in the supernatant was determined by ELISA. The result showed that secretin, cPLA2 and mPGEs-1 mRNA expression increased gradually in implantation sites from day 5 to day 7 of pregnancy with the same tendency. The secretin levels in serum were significantly higher on days 6, 7 and 8 of pregnancy than that on day 5 of pregnancy. The concentration of secretin was significantly higher in implantation sites on days 6, 7 than that in non-implantation site on day 5. Transfection of secretin expression vector promoted cPLA2, p-cPLA2 and mPGEs-1 expressions in mESCs, but not PGE2 level in the supernatant. H89 could effectively inhibit the expression of CREB, p-CREB, p-cPLA2 and cPLA2 induced by secretin. The results showed that the increased secretin expression in mESCs during embryo implantation may promote p-cPLA2, cPLA2 and mPGEs-1 expression, and the promotion may be through PKA signaling pathway.
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Células Estromais , Animais , Western Blotting , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Dinoprostona , Feminino , Camundongos , Fosfolipases A2 Citosólicas , Gravidez , Prostaglandina-E Sintases , Reação em Cadeia da Polimerase em Tempo Real , Secretina , ÚteroRESUMO
Accumulating epidemiological evidence underscores the association between pervasive environmental factors and an increased risk of metabolic diseases. Environmental chemicals, recognized disruptors of endocrine and metabolic processes, may contribute to the global prevalence of metabolic disorders, including obesity. Acetyl tributyl citrate (ATHC), categorized as a citric acid ester plasticizer, serves as a substitute for di-(2-ethylhexyl) phthalate (DEHP) in various everyday products. Despite its widespread use and the increasing risk of exposure in humans and animals due to its high leakage rates, information regarding the safety of exposure to environmentally relevant doses of ATHC remains limited. This study aimed to investigate the potential impact of ATHC exposure on metabolic homeostasis. Both in vivo and in vitro exposure models were used to characterize the effects induced by ATHC exposure. C57BL/6 J male mice were subjected to a diet containing ATHC for 12 weeks, and metabolism-related parameters were monitored and analyzed throughout and after the exposure period. Results indicated that sub-chronic dietary exposure to ATHC induced an increase in body fat percentage, elevated serum lipid levels, and increased lipid content in the liver tissue of mice. Furthermore, the effect of ATHC exposure on murine hepatocytes were examined and results indicated that ATHC significantly augmented lipid levels in AML12 hepatocytes, disrupting energy homeostasis and altering the expression of genes associated with fatty acid synthesis, uptake, oxidation, and secretion pathways. Conclusively, both in vivo and in vitro results suggest that exposure to low levels of ATHC may be linked to an elevated risk of obesity and fatty liver in mice. The potential implications of ATHC on human health warrant comprehensive evaluation in future studies.
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Acute respiratory distress syndrome (ARDS) is characterized by lung tissue oedema and inflammatory cell infiltration, with limited therapeutic interventions available. Receptor-interacting protein kinase 1 (RIPK1), a critical regulator of cell death and inflammation implicated in many diseases, is not fully understood in the context of ARDS. In this study, we employed RIP1 kinase-inactivated (Rip1K45A/K45A) mice and two distinct RIPK1 inhibitors to investigate the contributions of RIP1 kinase activity in lipopolysaccharide (LPS)-induced ARDS pathology. Our results indicated that RIPK1 kinase inactivation, achieved through both genetic and chemical approaches, significantly attenuated LPS-induced ARDS pathology, as demonstrated by reduced polymorphonuclear neutrophil percentage (PMN%) in alveolar lavage fluid, expression of inflammatory and fibrosis-related factors in lung tissues, as well as histological examination. Results by tunnel staining and qRT-PCR analysis indicated that RIPK1 kinase activity played a role in regulating cell apoptosis and inflammation induced by LPS administration in lung tissue. In summary, employing both pharmacological and genetic approaches, this study demonstrated that targeted RIPK1 kinase inactivation attenuates the pathological phenotype induced by LPS inhalation in an ARDS mouse model. This study enhances our understanding of the therapeutic potential of RIPK1 kinase modulation in ARDS, providing insights for the pathogenesis of ARDS.
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Lipopolissacarídeos , Inibidores de Proteínas Quinases , Proteína Serina-Treonina Quinases de Interação com Receptores , Síndrome do Desconforto Respiratório , Animais , Humanos , Masculino , Camundongos , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Pulmão/patologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Neutrófilos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Síndrome do Desconforto Respiratório/induzido quimicamente , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/imunologiaRESUMO
Triptolide, a diterpene triepoxide, is one of the major components of most functional extracts of Tripterygium wilfordii Hook f, which is known to have various biological effects, including immunosuppressive, anti-inflammatory and anti-tumor functions. We studied the inhibitory effect of triptolide on endotoxemia (ETM)-induced oxidative stress, which was induced in C57BL/6 mice by lipopolysaccharide (LPS) and D-galactosamine (D-GalN). Pretreatment with triptolide decreased the reactive oxygen species (ROS) levels, mortality rate and liver injury after LPS/D-GalN injection. We utilized comprehensive proteomics to identify alterations in liver protein expression during pretreatment with triptolide or N-acetylcysteine (NAC) after LPS/D-GalN injection, 44 proteins were found to be related to oxidative stress, mitochondria, metabolism and signal transduction, and 23 proteins of them seemed to be significantly up- or down-regulated. Furthermore, both triptolide and NAC inhibited activation of c-jun NH2-terminal kinases (JNK) and mitogen-activated protein kinase p38 (p38), phosphorylation of inhibitor of nuclear factor-kappa B (IκB) and activation of nuclear factor-κB (NF-κB). These results demonstrated that triptolide inhibited the activation of JNK and p38 by decreasing ROS levels, which in turn inhibited the hepatic injury. In addition, we set and validated the phosphorylation model of extracellular signal-regulated kinase (ERK) and proposed that triptolide probably induced ERK phosphorylation through inhibiting its dephosphorylation rates. These results showed that triptolide can effectively reduce the oxidative stress and partially rescue the damage in the liver induced by LPS/D-GalN.
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Antioxidantes/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Diterpenos/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Fenantrenos/uso terapêutico , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Compostos de Epóxi/uso terapêutico , Galactosamina , Lipopolissacarídeos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Proteômica , Espécies Reativas de Oxigênio/metabolismoRESUMO
[This corrects the article DOI: 10.1016/j.isci.2020.100881.].
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Currently, the standard therapeutic approach of AML consists of chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). However, these strategies are usually associated with adverse side effects and high risk of relapse following HSCT. Thus, it is imperative to find an alternative way against AML progression. Here, we showed that treatment with umbilical cord-derived mesenchymal stem cells (UC-MSCs) could efficiently induce apoptosis in both primary AML patient-derived leukemic cells and AML cell lines. Mechanistically, tumor necrosis factor-α-related apoptosis-inducing ligand (TRAIL) in UC-MSCs mediated the proapoptotic effect in AML cells. Besides, indoleamine 2,3-dioxygenase (IDO) secreted by UC-MSCs blocked the cell cycle progression and inhibited the proliferation of AML cells. Importantly, we found that incubation of UC-MSCs with IFN-γ and TNF-α could upregulate the expression of TRAIL and IDO, resulting in an intensive pro-apoptotic efficacy. UC-MSCs pre-treatment could not only relieve the AML burden but also eliminate AML cells in a xenograft AML model. Our findings have shed light on an effective pre-activated approach to aggravating the anti-leukemia effect of MSC. Furthermore, a novel and safe stem cell-based therapy approach for AML treatment.
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Leucemia Mieloide Aguda , Células-Tronco Mesenquimais , Humanos , Interferon gama/metabolismo , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/terapia , Células-Tronco Mesenquimais/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Cordão Umbilical/metabolismoRESUMO
The tea green leaf hopper, Empoasca onukii Matsuda, is a severe pest of tea plants. Volatile emissions from tea shoots infested by the tea green leafhopper may directly repel insect feeding or attract natural enemies. Many studies have been conducted on various aspects of the tritrophic relationship involving tea plants, tea green leafhoppers and natural enemies. However, mathematic models which could explain the dynamic mechanisms of this tritrophic interaction are still lacking. In the current work, we constructed a realistic and stochastic model with temperature-dependent features to characterize the tritrophic interactions in the tea agroecosystem. Model outputs showed that two leafhopper outbreaks occur in a year, with their features being consistent with field observations. Simulations showed that daily average effective accumulated temperature (EAT) might be an important metric for outbreak prediction. We also showed that application of slow-releasing semiochemicals, as either repellents or attractants, may be highly efficacious for pest biocontrol and can significantly increase tea yields. Furthermore, the start date of applying semiochemicals can be optimized to effectively increase tea yields. The current model qualitatively characterizes key features of the tritrophic interactions and provides critical insight into pest control in tea ecosystems.
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The Hippo signaling primarily includes LATS1/2 and YAP1. Recent work has demonstrated a novel negative feedback between YAP1 and LATS1/2. However, how YAP-LATS negative feedback regulates cancer progression remains elusive. We constructed a multi-scale model which integrates angiogenesis, spatiotemporal variation of microenvironmental factors and phenotypic switch of tumor cells. Our simulation replicated the findings that YAP overexpression markedly attenuated cell proliferation owing to elevated negative feedback strength. After disruption of YAP-LATS negative feedback loop, however, YAP overexpression would promote cell proliferation. Consistently, LATS overexpression inhibited cell growth and lowered the proliferation potential. We also employed a putative LATS agonist and identified its dose-dependent tumor suppressive effects. Furthermore, targeted delivery could more effectively inhibit tumor growth. Our model has reconciled experimental findings and implied that reconstruction of functional and/or hyperactivated YAP-LATS negative feedback might be a promising strategy to homeostatic maintenance and tumor suppression.
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Retroalimentação Fisiológica/fisiologia , Via de Sinalização Hippo/fisiologia , Homeostase/fisiologia , Modelos Biológicos , Proteínas Supressoras de Tumor/fisiologia , Proteínas de Sinalização YAP/fisiologia , Animais , Proliferação de Células/fisiologia , Humanos , Neoplasias/patologia , Proteínas Serina-Treonina Quinases/fisiologiaRESUMO
Ischemic stroke presents a leading cause of mortality and morbidity worldwide. Theaflavic acid (TFA) is a theaflavin isolated from black tea that exerts a potentially neuro-protective effect. However, the dynamic properties of TFA-mediated protection remain largely unknown. In the current study, we evaluated the function of TFA in the mitochondria apoptotic pathway using mathematical modeling. We found that TFA-enhanced B-cell lymphoma 2 (Bcl-2) overexpression can theoretically give rise to bistability. The bistability is highly robust against parametric stochasticity while also conferring considerable variability in survival threshold. Stochastic simulations faithfully match the TFA dose response pattern seen in experimental studies. In addition, we identified a dose- and time-dependent synergy between TFA and nimodipine, a clinically used neuro-protective drug. This synergistic effect was enhanced by bistability independent of temporal factors. Precise application of pulsed doses of TFA can also promote survival compared with sustained TFA treatment. These data collectively demonstrate that TFA treatment can give rise to bistability and that synergy between TFA and nimodipine may offer a promising strategy for developing therapeutic neuro-protection against ischemic stroke.
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Benzopiranos/farmacologia , Mitocôndrias , Fármacos Neuroprotetores/farmacologia , Nimodipina/farmacologia , Chá/química , Animais , Apoptose , Sinergismo Farmacológico , Modelos Biológicos , Células PC12 , Proteínas Proto-Oncogênicas c-bcl-2 , RatosRESUMO
Ubiquitination plays a crucial role in retinoic acid-inducible gene I (RIG-I)-induced antiviral responses. However, the precise regulatory mechanisms of RIG-I activity mediated by conjugated and unanchored ubiquitin chains remain to be determined. In this study, we discovered that T55 of RIG-I was required for its binding ability for the unanchored ubiquitin chains. Experimental and mathematical analysis showed that unanchored ubiquitin chains associated with RIG-I were essential for sustained activation of type I interferon (IFN) signaling. Transcriptomics study revealed that the binding of RIG-I with unanchored ubiquitin chains additionally regulated the expression of a subset of metabolic and cell fate decision genes. Moreover, we found that ubiquitin-specific peptidase 21 (USP21) and USP3 deubiquitinate conjugated and unanchored ubiquitin chains on RIG-I respectively. Taken together, characterization of the regulation mode and functions of conjugated ubiquitination and the unconjugated ubiquitin chain-binding of RIG-I may provide means to fine-tune RIG-I-mediated type I IFN signaling.
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Organotin compounds (OTs) act as potent endocrine disruptors that are often found in polluted food and water. UDP-glucuronosyltransferases (UGTs) are responsible for termination of multiple endogenous hormones. This study was conducted to investigate the inhibitory effects of two tri-submitted OTs tributyltin (TBT) and triphenyltin (TPT), against activities of UGTs. It is revealed that TBT and TPT act as two potent inhibitors for multiple UGTs. UGT1A8 and -2B15 were coinhibited by the two OTs. UGT1A1 and -1A10 were inhibited by TPT, whereas UGT 2B4 and -2B7 were inhibited by TBT. Kinetic analyses further indicated that TBT and TPT are two competitive nanomolar inhibitors of UGT2B15, with Ki values of 0.45 and 0.46 µM, respectively. Ki values for the other UGTs are determined to be a few micromolars. In addition, the two OTs displayed effective inhibition against UGT2B15 in catalyzing dihydrotestosterone glucuronidation, with IC50 values both in nano-molar range. TPT can additionally inhibit activities of UGT1A1 and -1A10 in estradiol-3-O-glucuronidation, with IC50 values of a few micro-molars. These results indicated that the two OTs can extensively interfere with glucuronidation of endogenous hormones, which may act as a new potential mechanism resulting in endocrine disrupting actions.
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Disruptores Endócrinos/farmacologia , Glucuronosiltransferase/antagonistas & inibidores , Glucuronosiltransferase/classificação , Compostos Orgânicos de Estanho/farmacologia , Compostos de Trialquitina/farmacologia , Animais , Relação Dose-Resposta a Droga , Glucuronosiltransferase/metabolismo , Humanos , Cinética , Microssomos Hepáticos , Isoformas de ProteínasRESUMO
The tumor suppressor p53 coordinates many attributes of cellular processes via interlocked feedback loops. To understand the biological implications of feedback loops in a p53 system, a two-component model which encompasses essential feedback loops was constructed and further explored. Diverse bifurcation properties, such as bistability and oscillation, emerge by manipulating the feedback strength. The p53-mediated MDM2 induction dictates the bifurcation patterns. We first identified irradiation dichotomy in p53 models and further proposed that bistability and oscillation can behave in a coordinated manner. Further sensitivity analysis revealed that p53 basal production and MDM2-mediated p53 degradation, which are central to cellular control, are most sensitive processes. Also, we identified that the much more significant variations in amplitude of p53 pulses observed in experiments can be derived from overall amplitude parameter sensitivity. The combined approach with bifurcation analysis, stochastic simulation and sampling-based sensitivity analysis not only gives crucial insights into the dynamics of the p53 system, but also creates a fertile ground for understanding the regulatory patterns of other biological networks.
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Modelos Biológicos , Proteína Supressora de Tumor p53/metabolismo , Apoptose , Retroalimentação Fisiológica , Proteínas Proto-Oncogênicas c-mdm2/química , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Processos Estocásticos , IncertezaRESUMO
Although the dynamic features of type I coherent feedforward loop (C1-FFL) has been well studied, how C1-FFL shapes cell-to-cell heterogeneity remains unclear. Here, we found that C1-FFL with OR logic serves as "noise reducer," whereas C1-FFL with AND logic functions as "noise propagator" to fine-tune the heterogeneity of signaling molecule's activation. Within Toll-like receptor 4 (TLR4) signaling pathway, we demonstrated that MyD88 together with TRIF generates a C1-FFL to control TBK1 phosphorylation and reduce its cell-to-cell heterogeneity, whereas noisy TRIF activation induced high heterogeneity of IRF3 activation through another C1-FFL. We further developed a mathematical model with dual C1-FFLs to uncover how MyD88 and TRIF encoded differential dynamics for TBK1 and IRF3 activation. Integration of dual FFLs drives MyD88-TBK1 axis to determine the specificity of IFN-stimulated genes transcription. Collectively, our work elucidates a paradigm that tunable TLR4-mediated type I IFN responses are subtly controlled by dual FFLs.
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BACKGROUND: The tumor suppressor p53 plays pivotal roles in tumorigenesis suppression. Although oscillations of p53 have been extensively studied, the mechanism of p53 pulses and their physiological roles in DNA damage response remain unclear. RESULTS: To address these questions we presented an integrated model in which Ataxia-Telangiectasia Mutated (ATM) activation and p53 oscillation were incorporated with downstream apoptotic events, particularly the interplays between Bcl-2 family proteins. We first reproduced digital oscillation of p53 as the response of normal cells to DNA damage. Subsequent modeling in mutant cells showed that high basal DNA damage is a plausible cause for sustained p53 pulses observed in tumor cells. Further computational analyses indicated that p53-dependent PUMA accumulation and the PUMA-controlled Bax activation switch might play pivotal roles to count p53 pulses and thus decide the cell fate. CONCLUSION: The high levels of basal DNA damage are responsible for generating sustained pulses of p53 in the tumor cells. Meanwhile, the Bax activation switch can count p53 pulses through PUMA accumulation and transfer it into death signal. Our modeling provides a plausible mechanism about how cells generate and orchestrate p53 pulses to tip the balance between survival and death.
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Morte Celular , Dano ao DNA , Modelos Teóricos , Proteína Supressora de Tumor p53/genética , Animais , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular/química , Proteínas de Ligação a DNA/química , Humanos , Proteínas Serina-Treonina Quinases/química , Proteínas Proto-Oncogênicas c-mdm2/química , Proteínas Supressoras de Tumor/química , Proteína X Associada a bcl-2/químicaRESUMO
Functional p53 signaling is essential for appropriate responses to diverse stimuli. P53 dynamics employs the information from the stimulus leading to selective gene expression and cell fate decision. However, the decoding mechanism of p53 dynamics under DNA damage challenge remains poorly understood. Here we mathematically modeled the recently dual-phase p53 dynamics under doxorubicin treatment. We found that p53 could perform sequential pulses followed by a high-amplitude terminal pulse at relatively low doxorubicin treatment, whereas p53 became steadily accumulated when damage level was high. The effective p53 integral above a threshold but not the absolute accumulation of p53 precisely discriminated survival and death. Silencing negative regulators in p53 network might promote the occurrence of terminal pulse. Furthermore, lower binding affinity and degradation rate of p53 target genes could favorably discriminate high and low dose doxorubicin treatment. Grouping by temporal profiles suggested that the p53 dynamics rather than the doxorubicin doses could better discriminate cellular outcomes and confer less variation for effective p53 integral reemphasizing the importance of p53 level regulation. Our model has established a theoretical framework that p53 dynamics can work cooperatively with its binding affinity to target genes leading to cell fate choice, providing new clues of optimized clinical design by manipulating p53 dynamics.