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BACKGROUND: Long non-coding RNAs (LncRNAs) have been implicated as critical regulators of cancer tumorigenesis and progression. However, their functions and molecular mechanisms in colorectal cancer (CRC) still remain to be further elucidated. METHODS: LINC00460 was identified by differential analysis between human CRC and normal tissues and verified by in situ hybridization (ISH) and qRT-PCR. We investigated the biological functions of LINC00460 in CRC by in vitro and in vivo experiments. We predicted the mechanism and downstream functional molecules of LINC00460 by bioinformatics analysis, and confirmed them by dual luciferase reporter gene assay, RNA immunoprecipitation (RIP), RNA pull-down, etc. RESULTS: LINC00460 was found to be significantly overexpressed in CRC and associated with poor prognosis. Overexpression of LINC00460 promoted CRC cell immune escape and remodeled a suppressive tumor immune microenvironment, thereby promoting CRC proliferation and metastasis. Mechanistic studies showed that LINC00460 served as a molecular sponge for miR-186-3p, and then promoted the expressions of MYC, CD47 and PD-L1 to facilitate CRC cell immune escape. We also demonstrated that MYC upregulated LINC00460 expression at the transcriptional level and formed a positive feedback loop. CONCLUSIONS: The LINC00460/miR-186-3p/MYC feedback loop promotes CRC cell immune escape and subsequently facilitates CRC proliferation and metastasis. Our findings provide novel insight into LINC00460 as a CRC immune regulator, and provide a potential therapeutic target for CRC patients.
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Antígeno B7-H1 , Antígeno CD47 , Neoplasias Colorrectales , MicroARNs , ARN Largo no Codificante , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/inmunología , MicroARNs/genética , Antígeno CD47/metabolismo , Antígeno CD47/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Ratones , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Animales , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Escape del Tumor/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Masculino , Femenino , Proliferación Celular , Retroalimentación Fisiológica , Pronóstico , Ratones DesnudosRESUMEN
UBE2M, a NEDD8-conjugating enzyme, is dysregulated in various human cancers and promotes tumor cell proliferation. However, its role in estrogen receptor-positive (ER+) breast cancer remains unknown. We found that UBE2M expression was significantly higher in ER+ breast cancer tissues than in ER-negative (ER-) breast cancer tissues. Higher expression of UBE2M indicated a poorer prognosis in patients with ER+ breast cancer but not in those with ER- breast cancer. Of interest, a positive feedback loop was observed between UBE2M and ERα. Specifically, ERα enhanced the HIF-1α-mediated transcription of UBE2M. In turn, UBE2M maintained ERα expression by inhibiting its ubiquitination and degradation through UBE2M-CUL3/4A-E6AP-ERα axis. Functionally, silencing of UBE2M suppressed the growth of breast cancer cells by inducing cell cycle arrest and apoptosis and improved their sensitivity to fulvestrant both in vitro and in vivo. Altogether, our findings reveal that the UBE2M-ERα feedback loop drives breast cancer progression and fulvestrant resistance, suggesting UBE2M as a viable target for endocrine therapy of ER+ breast cancer.
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Neoplasias de la Mama , Resistencia a Antineoplásicos , Receptor alfa de Estrógeno , Retroalimentación Fisiológica , Enzimas Ubiquitina-Conjugadoras , Humanos , Enzimas Ubiquitina-Conjugadoras/metabolismo , Enzimas Ubiquitina-Conjugadoras/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Resistencia a Antineoplásicos/efectos de los fármacos , Receptor alfa de Estrógeno/metabolismo , Animales , Progresión de la Enfermedad , Ratones Desnudos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ratones , Apoptosis/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Fulvestrant/farmacología , Ubiquitinación , Células MCF-7RESUMEN
Acute graft-versus-host disease (aGVHD) is primarily driven by allogeneic donor T cells associated with an altered composition of the host gut microbiome and its metabolites. The severity of aGVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not solely determined by the host and donor characteristics; however, the underlying mechanisms remain unclear. Using single-cell RNA sequencing, we decoded the immune cell atlas of 12 patients who underwent allo-HSCT: six with aGVHD and six with non-aGVHD. We performed a fecal microbiota (16SrRNA sequencing) analysis to investigate the fecal bacterial composition of 82 patients: 30 with aGVHD and 52 with non-aGVHD. Fecal samples from these patients were analyzed for bile acid metabolism. Through multi-omic analysis, we identified a feedback loop involving "immune cell-gut microbes-bile acid metabolites" contributing to heightened immune responses in patients with aGVHD. The dysbiosis of the gut microbiota and disruption of bile acid metabolism contributed to an exaggerated interleukin-1 mediated immune response. Our findings suggest that resistin and defensins are crucial in mitigating against aGVHD. Therefore, a comprehensive multi-omic atlas incorporating immune cells, gut microbes, and bile acid metabolites was developed in this study and used to propose novel, non-immunosuppressive approaches to prevent aGVHD.
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Ácidos y Sales Biliares , Heces , Microbioma Gastrointestinal , Enfermedad Injerto contra Huésped , Ácidos y Sales Biliares/metabolismo , Humanos , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/microbiología , Microbioma Gastrointestinal/inmunología , Femenino , Masculino , Heces/microbiología , Persona de Mediana Edad , Enfermedad Aguda , Adulto , Retroalimentación Fisiológica , Inmunidad , Metabolómica , Trasplante de Células Madre Hematopoyéticas , MultiómicaRESUMEN
Background: Myocardial inflammation and apoptosis induced by cirrhosis are among the primary mechanisms of cirrhotic cardiomyopathy. CD73, a common extracellular nucleotidase also known as 5'-nucleotidase, is associated with the progression of inflammation and immunity in multiple organs. However, the mechanism by which CD73 contributes to myocardial inflammation and apoptosis in cirrhosis remains unclear. Methods: In this study, a cirrhotic cardiomyopathy model in mice was established by bile duct ligation. Myocardial-specific overexpression of CD73 was achieved by tail vein injection of AAV9 (adeno-associated virus)-cTNT-NT5E-mCherry, and cardiac function in mice was assessed using echocardiography. Myocardial inflammation infiltration and apoptosis were evaluated through pathological observation and ELISA assays. The expression of CD73, A2AR, apoptotic markers, and proteins related to the NF-κB pathway in myocardial tissue were measured. Results: In the myocardial tissue of the cirrhotic cardiomyopathy mouse model, the expression of CD73 and A2AR increased. Overexpression of CD73 in the myocardium via AAV9 injection and stimulation of A2AR with CGS 21680 inhibited myocardial inflammation and cardiomyocyte apoptosis induced by cirrhosis. Additionally, overexpression of CD73 suppressed the activation of the NF-κB pathway by upregulating the expression of the adenosine receptor A2A. Conclusion: Our study reveals that the CD73/A2AR signaling axis mitigates myocardial inflammation and apoptosis induced by cirrhosis through negative feedback regulation of the NF-κB pathway.
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5'-Nucleotidasa , Cardiomiopatías , Cirrosis Hepática , FN-kappa B , Receptor de Adenosina A2A , Transducción de Señal , Animales , 5'-Nucleotidasa/metabolismo , FN-kappa B/metabolismo , Ratones , Receptor de Adenosina A2A/metabolismo , Cardiomiopatías/metabolismo , Cardiomiopatías/etiología , Cardiomiopatías/inmunología , Cirrosis Hepática/inmunología , Cirrosis Hepática/metabolismo , Masculino , Retroalimentación Fisiológica , Apoptosis , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Proteínas Ligadas a GPIRESUMEN
Glioma is the most common primary brain tumor, and targeting glioma stem cells (GSCs) has become a key aspect of glioma treatment. In this study, we discovered a molecular network in which circRNA forms an R-loop structure with its parental gene to regulate the biological behavior of GSCs. Genes with abnormal expression in GSCs were screened using RNA-seq and circRNA microarray analyses. The study results showed that high expression of YTHDC1 in GSCs promoted the transportation of N6-methyladenosine (m6A)-modified circPOLR2B from the nucleus to the cytoplasm. Decreased circPOLR2B levels in the nucleus resulted in fewer R-loop structures formed with its parental gene POLR2B. This reduction in R-loop structures relieved the inhibitory effect on POLR2B transcription and upregulated PBX1 expression through alternative polyadenylation (APA) action, thereby promoting the malignant biological behavior of GSCs. Knockdown of YTHDC1, POLR2B, and PBX1 reduced xenograft tumor volume and prolonged the survival of nude mice. The YTHDC1/circPOLR2B/POLR2B/PBX1 axis plays a regulatory role in the biological behavior of GSCs, offering potential targets and novel strategies for the treatment of glioma.
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Adenosina , Glioma , Ratones Desnudos , Células Madre Neoplásicas , ARN Circular , Humanos , Glioma/genética , Glioma/patología , Glioma/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Animales , ARN Circular/genética , ARN Circular/metabolismo , Ratones , Adenosina/análogos & derivados , Adenosina/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Metilación , Factores de Empalme de ARN/metabolismo , Factores de Empalme de ARN/genética , Retroalimentación Fisiológica , Ratones Endogámicos BALB C , Proteínas del Tejido NerviosoRESUMEN
BACKGROUND: Recent studies have highlighted the significant role of the NF-κB signaling pathway in the initiation and progression of cancer. Furthermore, long noncoding RNAs (lncRNAs) have been identified as pivotal regulators in sustaining the NF-κB signaling pathway's functionality. Despite these findings, the underlying molecular mechanisms through which lncRNAs influence the NF-κB pathway remain largely unexplored. METHODS: Bioinformatic analyses were utilized to investigate the differential expression and prognostic significance of XTP6. The functional roles of XTP6 were further elucidated through both in vitro and in vivo experimental approaches. To estimate the interaction between XTP6 and NDH2, RNA pulldown and RNA Immunoprecipitation (RIP) assays were conducted. The connection between XTP6 and the IκBα promoter was examined using Chromatin Isolation by RNA Purification (ChIRP) assays. Additionally, Chromatin Immunoprecipitation (ChIP) assays were implemented to analyze the binding affinity of c-myc to the XTP6 promoter, providing insights into the regulatory mechanisms at play. RESULTS: XTP6 was remarkedly upregulated in glioblastoma multiforme (GBM) tissues and was connected with adverse prognosis in GBM patients. Our investigations revealed that XTP6 can facilitate the malignant progression of GBM both in vitro and in vivo. Additionally, XTP6 downregulated IκBα expression by recruiting NDH2 to the IκBα promoter, which resulted in elevated levels of H3K27me3, thereby reducing the transcriptional activity of IκBα. Moreover, the progression of GBM was further driven by the c-myc-mediated upregulation of XTP6, establishing a positive feedback loop with IκBα that perpetuated the activation of the NF-κB signaling pathway. Notably, the application of an inhibitor targeting the NF-κB signaling pathway effectively inhibited the continuous activation induced by XTP6, leading to a significant reduction in tumor formation in vivo. CONCLUSION: The results reveal that XTP6 unveils an innovative epigenetic mechanism instrumental in the sustained activation of the NF-κB signaling pathway, suggesting a promising therapeutic target for the treatment of GBM.
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Progresión de la Enfermedad , Glioblastoma , FN-kappa B , Proteínas Proto-Oncogénicas c-myc , ARN Largo no Codificante , Humanos , Glioblastoma/metabolismo , Glioblastoma/patología , Glioblastoma/genética , FN-kappa B/metabolismo , Ratones , Animales , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Transducción de Señal , Pronóstico , Retroalimentación Fisiológica , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genética , Masculino , Proliferación Celular , FemeninoRESUMEN
One of the hallmarks of living organisms is their capacity for self-organization and regeneration, which requires a tight integration of metabolic and genetic networks. We sought to construct a linked metabolic and genetic network in vitro that shows such lifelike behavior outside of a cellular context and generates its own building blocks from nonliving matter. We integrated the metabolism of the crotonyl-CoA/ethyl-malonyl-CoA/hydroxybutyryl-CoA cycle with cell-free protein synthesis using recombinant elements. Our network produces the amino acid glycine from CO2 and incorporates it into target proteins following DNA-encoded instructions. By orchestrating ~50 enzymes we established a basic cell-free operating system in which genetically encoded inputs into a metabolic network are programmed to activate feedback loops allowing for self-integration and (partial) self-regeneration of the complete system.
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Dióxido de Carbono , Sistema Libre de Células , Glicina , Redes y Vías Metabólicas , Biosíntesis de Proteínas , Acilcoenzima A/metabolismo , Dióxido de Carbono/metabolismo , Retroalimentación Fisiológica , Redes Reguladoras de Genes , Glicina/biosíntesis , Glicina/genéticaRESUMEN
Common models of circadian rhythms are typically constructed as compartmental reactions of well-mixed biochemicals, incorporating a negative-feedback loop consisting of several intermediate reaction steps essentially required to produce oscillations. Spatial transport of each reactant is often represented as an extra compartmental reaction step. Contrary to this traditional understanding, in this Letter we demonstrate that a single activation-repression biochemical reaction pair is sufficient to generate sustained oscillations if the sites of both reactions are spatially separated and molecular transport is mediated by diffusion. Our proposed scenario represents the simplest configuration in terms of the participating chemical reactions and offers a conceptual basis for understanding biological oscillations and inspiring in vitro assays aimed at constructing minimal clocks.
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Ritmo Circadiano , Modelos Biológicos , Difusión , Ritmo Circadiano/fisiología , Retroalimentación FisiológicaRESUMEN
Purpose: Due to intrinsic defensive response, ferroptosis-activating targeted therapy fails to achieve satisfactory clinical benefits. Though p62-Keap1-Nrf2 axis is activated to form a negative feedback loop during ferroptosis induction, how p62 is activated remains largely unknown. Methods: MTS assay was applied to measure cell growth. Lipid ROS was detected with C11-BODIPY reagent by flow cytometer. Quantitative real-time PCR (qPCR) and western blotting were performed to determine mRNA and protein level. Immunofluorescence (IF) was performed to examine the distribution of proteins. Fluorescence recovery after photobleaching (FRAP) was adopted to evaluate p62 phase separation. Immunoprecipitation (IP), co-IP and Proximal ligation assay (PLA) were performed to detected protein posttranslational modifications and protein-protein interactions. Tumor xenograft model was employed to inspect in vivo growth of pancreatic cancer cells. Results: Upon ferroptosis induction, Nuclear Factor E2 Related Factor 2 (Nrf2) protein and its downstream genes such as HMOX1 and NQO1 were upregulated. Knockdown of p62 significantly reversed Nrf2 upregulation and Keap1 decrease after ferroptosis induction. Knockdown of either p62 or Nrf2 remarkably sensitized ferroptosis induction. Due to augmented p62 phase separation, formation of p62 bodies were increased to recruit Keap1 after ferroptosis induction. Protein arginine methyltransferase 6 (PRMT6) mediated asymmetric dimethylarginine (ADMA) of p62 to increase its oligomerization, promoting p62 phase separation and p62 body formation. Knockdown of p62 or PRMT6 notably sensitized pancreatic cancer cells to ferroptosis both in vitro and in vivo through suppressing Nrf2 signaling. Conclusion: During ferroptosis induction, PRMT6 mediated p62 ADMA to promote its phase separation, sequestering Keap1 to activate Nrf2 signaling and inhibit ferroptosis. Therefore, targeting PRMT6-mediated p62 ADMA could be a new option to sensitize ferroptosis for cancer treatment.
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Arginina , Ferroptosis , Proteína 1 Asociada A ECH Tipo Kelch , Factor 2 Relacionado con NF-E2 , Proteína-Arginina N-Metiltransferasas , Proteína-Arginina N-Metiltransferasas/metabolismo , Proteína-Arginina N-Metiltransferasas/genética , Humanos , Animales , Arginina/metabolismo , Arginina/análogos & derivados , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Ratones , Línea Celular Tumoral , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/genética , Retroalimentación Fisiológica , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/genética , Proteína Sequestosoma-1/metabolismo , Proteína Sequestosoma-1/genética , Ratones Desnudos , Transducción de Señal , Separación de Fases , Proteínas de Unión al ARNRESUMEN
Heat Shock Factor 1 (HSF1) is best known as the master transcriptional regulator of the heat-shock response (HSR), a conserved adaptive mechanism critical for protein homeostasis (proteostasis). Combining a genome-wide RNAi library with an HSR reporter, we identified Jumonji domain-containing protein 6 (JMJD6) as an essential mediator of HSF1 activity. In follow-up studies, we found that JMJD6 is itself a noncanonical transcriptional target of HSF1 which acts as a critical regulator of proteostasis. In a positive feedback circuit, HSF1 binds and promotes JMJD6 expression, which in turn reduces heat shock protein 70 (HSP70) R469 monomethylation to disrupt HSP70-HSF1 repressive complexes resulting in enhanced HSF1 activation. Thus, JMJD6 is intricately wired into the proteostasis network where it plays a critical role in cellular adaptation to proteotoxic stress.
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Proteínas HSP70 de Choque Térmico , Factores de Transcripción del Choque Térmico , Respuesta al Choque Térmico , Histona Demetilasas con Dominio de Jumonji , Proteostasis , Humanos , Factores de Transcripción del Choque Térmico/metabolismo , Factores de Transcripción del Choque Térmico/genética , Respuesta al Choque Térmico/fisiología , Histona Demetilasas con Dominio de Jumonji/metabolismo , Histona Demetilasas con Dominio de Jumonji/genética , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas HSP70 de Choque Térmico/genética , Proteostasis/fisiología , Retroalimentación Fisiológica , Adaptación Fisiológica , Células HEK293 , Estrés ProteotóxicoRESUMEN
BACKGROUND AND AIMS: To develop a model that describes how the pancreas functions, how the rate of synthesis of digestive enzymes is regulated, and finally what puts the pancreas to rest between meals. METHODS: We applied the principals of control theory to previously published canine data to develop a model for how the canine pancreas functions. Using this model, we then describe the steps needed to apply this model to the human pancreas. RESULTS: This new closed-loop negative feedback model describes what regulates digestive enzyme synthesis. This model is based on basolateral exocytosis of butyrylcholinesterase (BCHE) into the interstitial space. It is this level of BCHE * BCHE activity that controls the rate of canine pancreas digestive enzyme synthesis, and in the absence of stimulation from the vagus nerve, puts the pancreas to rest between meals. CONCLUSIONS: Finding secretagogue-specific inhibitory enzymes in the human pancreas that are analogous to BCHE in the canine, and blocking its associated receptors, may lead to a cure for human pancreatitis.
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Butirilcolinesterasa , Retroalimentación Fisiológica , Páncreas , Páncreas/enzimología , Perros , Humanos , Animales , Butirilcolinesterasa/metabolismo , Modelos Biológicos , Pancreatitis , Nervio Vago/fisiologíaRESUMEN
Antibodies are powerful modulators of ongoing and future B cell responses. While the concept of antibody feedback has been appreciated for over a century, the topic has seen a surge in interest due to the evidence that the broadening of antibody responses to SARS-CoV-2 after a third mRNA vaccination is a consequence of antibody feedback. Moreover, the discovery that slow antigen delivery can lead to more robust humoral immunity has put a spotlight on the capacity for early antibodies to augment B cell responses. Here, we review the mechanisms whereby antibody feedback shapes B cell responses, integrating findings in humans and in mouse models. We consider the major influence of epitope masking and the diverse actions of complement and Fc receptors and provide a framework for conceptualizing the ways antigen-specific antibodies may influence B cell responses to any form of antigen, in conditions as diverse as infectious disease, autoimmunity, and cancer.
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Linfocitos B , COVID-19 , SARS-CoV-2 , Animales , Humanos , Linfocitos B/inmunología , SARS-CoV-2/inmunología , COVID-19/inmunología , Ratones , Anticuerpos Antivirales/inmunología , Inmunidad Humoral/inmunología , Receptores Fc/inmunología , Receptores Fc/metabolismo , Retroalimentación Fisiológica , Formación de Anticuerpos/inmunologíaRESUMEN
Large-scale cell death is commonly observed during organismal development and in human pathologies1-5. These cell death events extend over great distances to eliminate large populations of cells, raising the question of how cell death can be coordinated in space and time. One mechanism that enables long-range signal transmission is trigger waves6, but how this mechanism might be used for death events in cell populations remains unclear. Here we demonstrate that ferroptosis, an iron- and lipid-peroxidation-dependent form of cell death, can propagate across human cells over long distances (≥5 mm) at constant speeds (around 5.5 µm min-1) through trigger waves of reactive oxygen species (ROS). Chemical and genetic perturbations indicate a primary role of ROS feedback loops (Fenton reaction, NADPH oxidase signalling and glutathione synthesis) in controlling the progression of ferroptotic trigger waves. We show that introducing ferroptotic stress through suppression of cystine uptake activates these ROS feedback loops, converting cellular redox systems from being monostable to being bistable and thereby priming cell populations to become bistable media over which ROS propagate. Furthermore, we demonstrate that ferroptosis and its propagation accompany the massive, yet spatially restricted, cell death events during muscle remodelling of the embryonic avian limb, substantiating its use as a tissue-sculpting strategy during embryogenesis. Our findings highlight the role of ferroptosis in coordinating global cell death events, providing a paradigm for investigating large-scale cell death in embryonic development and human pathologies.
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Retroalimentación Fisiológica , Ferroptosis , Especies Reactivas de Oxígeno , Animales , Embrión de Pollo , Humanos , Cistina/metabolismo , Retroalimentación Fisiológica/fisiología , Ferroptosis/fisiología , Glutatión/metabolismo , Hierro/metabolismo , Peroxidación de Lípido , NADPH Oxidasas/metabolismo , Oxidación-Reducción , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Desarrollo Embrionario , Extremidades/embriologíaRESUMEN
Mitochondrial dysfunction is critical in the pathogenesis of asthma. Mitochondrial permeability transition pore (mPTP) regulates the release of mitochondrial damage-associated molecular patterns (mtDAMPs) to maintain mitochondrial homeostasis. Bongkrekic acid (BKA) is a highly selective inhibitor of mPTP opening, participates the progression of various diseases. This research investigated the exact roles of BKA and mPTP in the pathogenesis of asthma and elucidated its underlying mechanisms. In the present study, cytochrome c, one of the mtDAMPs, levels were elevated in asthmatic patients, and associated to airway inflammation and airway obstruction. BKA, the inhibitor of mPTP markedly reversed TDI-induced airway hyperresponsiveness, airway inflammation, and mitochondrial dysfunction. Pretreatment with mitochondrial precipitation, to simulate the release of mtDAMPs, further increased TDI-induced airway inflammation and the expression of RAGE in mice. Administration of the inhibitor of RAGE, FPS-ZM1, alleviated the airway inflammation, the abnormal open of mPTP and mitochondrial dysfunction induced by mtDAMPs and TDI. Furthermore, stimulation with different mtDAMPs activated RAGE signaling in human bronchial epithelial cells. Accordingly, our study indicated that mPTP was important and BKA was efficient in alleviating inflammation in TDI-induced asthma. A positive feedback loop involving mPTP, mtDAMPs and RAGE was present in TDI-induced asthma, indicating that mPTP might serve as a potential therapeutic target for asthma.
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Asma , Modelos Animales de Enfermedad , Poro de Transición de la Permeabilidad Mitocondrial , Asma/tratamiento farmacológico , Asma/metabolismo , Animales , Humanos , Ratones , Poro de Transición de la Permeabilidad Mitocondrial/metabolismo , Masculino , Retroalimentación Fisiológica/efectos de los fármacos , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Femenino , Ratones Endogámicos BALB C , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Ratones Endogámicos C57BL , AdultoRESUMEN
Parkinson's disease (PD) is characterized by decreased dopamine in the basal ganglia that causes excessive tonic inhibition of the thalamus. This excessive inhibition seems to explain inhibitory motor symptoms in PD, but the source of tremor remains unclear. This paper investigates how neural inhibition may change the closed-loop characteristics of the human motor control system to determine how this established pathophysiology could produce tremor. The rate-coding model of neural signals suggests increased inhibition decreases signal amplitude, which could create a mismatch between the closed-loop dynamics and the internal models that overcome proprioceptive feedback delays. This paper aims to identify a candidate model structure with decreased-amplitude-induced tremor in PD that also agrees with previously recorded movements of healthy and cerebellar patients. The optimal feedback control theory of human motor control forms the basis of the model. Key additional elements include gating of undesired movements via the basal ganglia-thalamus-motor cortex circuit and the treatment of the efferent copy of the control input as a measurement in the state estimator. Simulations confirm the model's ability to capture tremor in PD and also demonstrate how disease progression could affect tremor and other motor symptoms, providing insight into the existence of tremor and non-tremor phenotypes. Altogether, the physiological underpinnings of the model structure and the agreement of model predictions with clinical observations provides support for the hypothesis that unstable feedback produces parkinsonian tremor. Consequently, these results also support the associated framework for the neuroanatomy of human motor control.
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Ganglios Basales , Simulación por Computador , Enfermedad de Parkinson , Temblor , Humanos , Temblor/fisiopatología , Temblor/etiología , Ganglios Basales/fisiopatología , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/complicaciones , Modelos Neurológicos , Corteza Motora/fisiopatología , Tálamo/fisiopatología , Algoritmos , Retroalimentación Fisiológica , Cerebelo/fisiopatología , Movimiento/fisiologíaRESUMEN
Establishing a mapping between the emergent biological properties and the repository of network structures has been of great relevance in systems and synthetic biology. Adaptation is one such biological property of paramount importance that promotes regulation in the presence of environmental disturbances. This paper presents a nonlinear systems theory-driven framework to identify the design principles for perfect adaptation with respect to external disturbances of arbitrary magnitude. Based on the prior information about the network, we frame precise mathematical conditions for adaptation using nonlinear systems theory. We first deduce the mathematical conditions for perfect adaptation for constant input disturbances. Subsequently, we translate these conditions to specific necessary structural requirements for adaptation in networks of small size and then extend to argue that there exist only two classes of architectures for a network of any size that can provide local adaptation in the entire state space, namely, incoherent feed-forward (IFF) structure and negative feedback loop with buffer node (NFB). The additional positiveness constraints further narrow the admissible set of network structures. This also aids in establishing the global asymptotic stability for the steady state given a constant input disturbance. The proposed method does not assume any explicit knowledge of the underlying rate kinetics, barring some minimal assumptions. Finally, we also discuss the infeasibility of certain IFF networks in providing adaptation in the presence of downstream connections. Moreover, we propose a generic and novel algorithm based on non-linear systems theory to unravel the design principles for global adaptation. Detailed and extensive simulation studies corroborate the theoretical findings.
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Adaptación Fisiológica , Conceptos Matemáticos , Modelos Biológicos , Dinámicas no Lineales , Biología de Sistemas , Adaptación Fisiológica/fisiología , Simulación por Computador , Retroalimentación Fisiológica , Biología Sintética , Teoría de Sistemas , CinéticaRESUMEN
The actomyosin cortex is an active material that generates force to drive shape changes via cytoskeletal remodeling. Cytokinesis is the essential cell division event during which a cortical actomyosin ring closes to separate two daughter cells. Our active gel theory predicted that actomyosin systems controlled by a biochemical oscillator and experiencing mechanical strain would exhibit complex spatiotemporal behavior. To test whether active materials in vivo exhibit spatiotemporally complex kinetics, we imaged the C. elegans embryo with unprecedented temporal resolution and discovered that sections of the cytokinetic cortex undergo periodic phases of acceleration and deceleration. Contractile oscillations exhibited a range of periodicities, including those much longer periods than the timescale of RhoA pulses, which was shorter in cytokinesis than in any other biological context. Modifying mechanical feedback in vivo or in silico revealed that the period of contractile oscillation is prolonged as a function of the intensity of mechanical feedback. Fast local ring ingression occurs where speed oscillations have long periods, likely due to increased local stresses and, therefore, mechanical feedback. Fast ingression also occurs where material turnover is high, in vivo and in silico. We propose that downstream of initiation by pulsed RhoA activity, mechanical feedback, including but not limited to material advection, extends the timescale of contractility beyond that of biochemical input and, therefore, makes it robust to fluctuations in activation. Circumferential propagation of contractility likely allows for sustained contractility despite cytoskeletal remodeling necessary to recover from compaction. Thus, like biochemical feedback, mechanical feedback affords active materials responsiveness and robustness.
Asunto(s)
Actomiosina , Caenorhabditis elegans , Citocinesis , Citocinesis/fisiología , Animales , Caenorhabditis elegans/fisiología , Actomiosina/metabolismo , Fenómenos Biomecánicos , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Retroalimentación Fisiológica , Proteína de Unión al GTP rhoA/metabolismo , Embrión no Mamífero/fisiologíaRESUMEN
Models of biochemical networks are often large intractable sets of differential equations. To make sense of the complexity, relationships between genes/proteins are presented as connected graphs, the edges of which are drawn to indicate activation or inhibition relationships. These diagrams are useful for drawing qualitative conclusions in many cases by the identifying recurring of topological motifs, for example positive and negative feedback loops. These topological features are usually classified under the presumption that activation and inhibition are inverse relationships. For example, inhibition of an inhibitor is often classified the same as activation of an activator within a motif classification, effectively treating them as equivalent. Whilst in many contexts this may not lead to catastrophic errors, drawing conclusions about the behavior of motifs, pathways or networks from these broad classes of topological feature without adequate mathematical descriptions can lead to obverse outcomes. We investigate the extent to which a biochemical pathway/network will behave quantitatively dissimilar to pathway/ networks with similar typologies formed by swapping inhibitors as the inverse of activators. The purpose of the study is to determine under what circumstances rudimentary qualitative assessment of network structure can provide reliable conclusions as to the quantitative behaviour of the network. Whilst there are others, We focus on two main mathematical qualities which may cause a divergence in the behaviour of two pathways/networks which would otherwise be classified as similar; (i) a modelling feature we label 'bias' and (ii) the precise positioning of activators and inhibitors within simple pathways/motifs.
Asunto(s)
Modelos Biológicos , Redes Reguladoras de Genes , Retroalimentación Fisiológica , Transducción de Señal , Conceptos MatemáticosRESUMEN
The GTPase Cdc42 regulates polarized growth in most eukaryotes. In the bipolar yeast Schizosaccharomyces pombe, Cdc42 activation cycles periodically at sites of polarized growth. These periodic cycles are caused by alternating positive feedback and time-delayed negative feedback loops. At each polarized end, negative feedback is established when active Cdc42 recruits the Pak1 kinase to prevent further Cdc42 activation. It is unclear how Cdc42 activation returns to each end after Pak1-dependent negative feedback. We find that disrupting branched actin-mediated endocytosis disables Cdc42 reactivation at the cell ends. Using experimental and mathematical approaches, we show that endocytosis-dependent Pak1 removal from the cell ends allows the Cdc42 activator Scd1 to return to that end to enable reactivation of Cdc42. Moreover, we show that Pak1 elicits its own removal via activation of endocytosis. These findings provide a deeper insight into the self-organization of Cdc42 regulation and reveal previously unknown feedback with endocytosis in the establishment of cell polarity.
Asunto(s)
Complejo 2-3 Proteico Relacionado con la Actina , Polaridad Celular , Endocitosis , Retroalimentación Fisiológica , Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Proteína de Unión al GTP cdc42 , Quinasas p21 Activadas , Schizosaccharomyces/metabolismo , Schizosaccharomyces/genética , Proteínas de Schizosaccharomyces pombe/metabolismo , Proteínas de Schizosaccharomyces pombe/genética , Quinasas p21 Activadas/metabolismo , Quinasas p21 Activadas/genética , Complejo 2-3 Proteico Relacionado con la Actina/metabolismo , Complejo 2-3 Proteico Relacionado con la Actina/genética , Proteína de Unión al GTP cdc42/metabolismo , Proteína de Unión al GTP cdc42/genética , Actinas/metabolismoRESUMEN
Systemic sclerosis (SSc) is characterized by dermal fibrosis with a female predominance, suggesting a hormonal influence. Patients with SSc have elevated interleukin (IL)-6 levels, and post-menopausal women and older men also have high estradiol (E2) levels. In the skin, IL-6 increases the enzymatic activity of aromatase, thereby amplifying the conversion of testosterone to E2. Therefore, we hypothesized that an interplay between E2 and IL-6 contributes to dermal fibrosis. We used primary dermal fibroblasts from healthy donors and patients with diffuse cutaneous (dc)SSc, and healthy donor skin tissues stimulated with recombinant IL-6 and its soluble receptor (sIL-6R) or E2. Primary human dermal fibroblasts and tissues from healthy donors stimulated with IL-6+sIL-6R produced E2, while E2-stimulated dermal tissues and fibroblasts produced IL-6. Primary dermal fibroblasts from healthy donors treated with IL-6+sIL-6R and the aromatase inhibitor anastrozole (ANA) and dcSSc fibroblasts treated with ANA produced less fibronectin (FN), type III collagen A1 (Col IIIA1), and type V collagen A1 (Col VA1). Finally, dcSSc dermal fibroblasts treated with the estrogen receptor inhibitor fulvestrant also generated less FN, Col IIIA1, and Col VA1. Our data show that IL-6 exerts its pro-fibrotic influence in human skin in part through E2 and establish a positive feedback loop between E2 and IL-6.