RESUMEN
Cancer cells alter their metabolism for the production of precursors of macromolecules. However, the control mechanisms underlying this reprogramming are poorly understood. Here we show that metabolic reprogramming of colorectal cancer is caused chiefly by aberrant MYC expression. Multiomics-based analyses of paired normal and tumor tissues from 275 patients with colorectal cancer revealed that metabolic alterations occur at the adenoma stage of carcinogenesis, in a manner not associated with specific gene mutations involved in colorectal carcinogenesis. MYC expression induced at least 215 metabolic reactions by changing the expression levels of 121 metabolic genes and 39 transporter genes. Further, MYC negatively regulated the expression of genes involved in mitochondrial biogenesis and maintenance but positively regulated genes involved in DNA and histone methylation. Knockdown of MYC in colorectal cancer cells reset the altered metabolism and suppressed cell growth. Moreover, inhibition of MYC target pyrimidine synthesis genes such as CAD, UMPS, and CTPS blocked cell growth, and thus are potential targets for colorectal cancer therapy.
Asunto(s)
Adenoma/metabolismo , Neoplasias Colorrectales/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Adenoma/genética , Animales , Carcinogénesis/genética , Carcinogénesis/metabolismo , Proliferación Celular/fisiología , Neoplasias Colorrectales/genética , Modelos Animales de Enfermedad , Femenino , Genes myc , Humanos , Masculino , Metabolómica/métodos , Ratones , Proteínas Proto-Oncogénicas c-myc/genética , Pirimidinas/biosíntesis , TranscriptomaRESUMEN
Iodothyronine deiodinase 2 (DIO2) converts the prohormone thyroxine (T4) to bioactive T3 in peripheral tissues and thereby regulates local thyroid hormone (TH) levels. Although epidemiologic studies suggest the contribution of TH to the progression of colorectal cancer (CRC), the role of DIO2 in CRC remains elusive. Here we show that Dio2 is highly expressed in intestinal polyps of ApcΔ716 mice, a mouse model of familial adenomatous polyposis and early stage sporadic CRC. Laser capture microdissection and in situ hybridization analysis show almost exclusive expression of Dio2 in the stroma of ApcΔ716 polyps in the proximity of the COX-2-positive areas. Treatment with iopanoic acid, a deiodinase inhibitor, or chemical thyroidectomy suppresses tumor formation in ApcΔ716 mice, accompanied by reduced tumor cell proliferation and angiogenesis. Dio2 expression in ApcΔ716 polyps is strongly suppressed by treatment with the COX-2 inhibitor meloxicam. Analysis of The Cancer Genome Atlas data shows upregulation of DIO2 in CRC clinical samples and a close association of its expression pattern with the stromal component, consistently with almost exclusive expression of DIO2 in the stroma of human CRC as revealed by in situ hybridization. These results indicate essential roles of stromal DIO2 and thyroid hormone signaling in promoting the growth of intestinal tumors.
Asunto(s)
Proliferación Celular/fisiología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Yoduro Peroxidasa/metabolismo , Poliposis Adenomatosa del Colon/tratamiento farmacológico , Poliposis Adenomatosa del Colon/metabolismo , Poliposis Adenomatosa del Colon/patología , Animales , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/farmacología , Modelos Animales de Enfermedad , Humanos , Pólipos Intestinales/tratamiento farmacológico , Pólipos Intestinales/metabolismo , Pólipos Intestinales/patología , Ratones , Ratones Noqueados , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Hormonas Tiroideas/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiología , Yodotironina Deyodinasa Tipo IIRESUMEN
PURPOSE: To evaluate the effects of unilateral intravitreal ranibizumab (IVR) on the ocular circulation of the fellow eyes. METHODS: Fifteen eyes of 15 patients with macular edema (average age 69.6 ± 11.8 years) were studied. Eleven eyes had diabetic macular edema (DME) and four eyes had macular edema associated with a branch retinal vein occlusion. Each eye received 0.5 mg of IVR. The blood circulation on the optic nerve head of the treated and untreated eyes were determined by laser speckle flowgraphy (LSFG, Softcare Co., Ltd) before, 1 day, and 1 week after the IVR. The mean blur rate (MBR) and the relative changes of the MBRs determined as dMBR(%) = 100-(MBR before/MB after) × 100) were evaluated. The central macular thickness (CMT) and the rate of reduction in the thickness (dCMT = 100-(CMT before/CMT after) × 100) were also evaluated. RESULTS: The mean dMBR was significantly higher in the treated eyes than the untreated eyes at 1 day (-16.4 ± 17.0% vs 2.31 ± 19.3%) and at 1 week (-12.0 ± 14.6% vs 4.50 ± 25.9%) after the IVR (P = 0.02, paired t tests). CONCLUSION: These findings indicate that if ranibizumab enters the systemic circulation, the concentration is not high enough to affect the ocular circulation of the fellow eyes.
Asunto(s)
Retinopatía Diabética/tratamiento farmacológico , Edema Macular/tratamiento farmacológico , Microcirculación/efectos de los fármacos , Disco Óptico/irrigación sanguínea , Ranibizumab/administración & dosificación , Vasos Retinianos/fisiopatología , Agudeza Visual , Anciano , Inhibidores de la Angiogénesis/administración & dosificación , Retinopatía Diabética/complicaciones , Retinopatía Diabética/diagnóstico , Femenino , Estudios de Seguimiento , Humanos , Inyecciones Intravítreas , Edema Macular/diagnóstico , Edema Macular/etiología , Masculino , Vasos Retinianos/efectos de los fármacos , Vasos Retinianos/patología , Estudios Retrospectivos , Tomografía de Coherencia ÓpticaRESUMEN
Extracellular signal-regulated kinase is an MAPK that is most closely associated with cell proliferation, and the MEK/ERK signaling pathway is implicated in various human cancers. Although epidermal growth factor receptor, KRAS, and BRAF are considered major targets for colon cancer treatment, the precise roles of the MEK/ERK pathway, one of their major downstream effectors, during colon cancer development remain to be determined. Using Apc(Δ716) mice, a mouse model of familial adenomatous polyposis and early-stage sporadic colon cancer formation, we show that MEK/ERK signaling is activated not only in adenoma epithelial cells, but also in tumor stromal cells including fibroblasts and vascular endothelial cells. Eight-week treatment of Apc(Δ716) mice with trametinib, a small-molecule MEK inhibitor, significantly reduced the number of polyps in the large size class, accompanied by reduced angiogenesis and tumor cell proliferation. Trametinib treatment reduced the COX-2 level in Apc(Δ716) tumors in vivo and in primary culture of intestinal fibroblasts in vitro. Antibody array analysis revealed that trametinib and the COX-2 inhibitor rofecoxib both reduced the level of CCL2, a chemokine known to be essential for the growth of Apc mutant polyps, in intestinal fibroblasts in vitro. Consistently, trametinib treatment reduced the Ccl2 mRNA level in Apc(Δ716) tumors in vivo. These results suggest that MEK/ERK signaling plays key roles in intestinal adenoma formation in Apc(Δ716) mice, at least in part, through COX-2 induction in tumor stromal cells.
Asunto(s)
Antineoplásicos/farmacología , Ciclooxigenasa 2/análisis , Genes APC/fisiología , Pólipos Intestinales/tratamiento farmacológico , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Piridonas/farmacología , Pirimidinonas/farmacología , Animales , Quimiocina CCL2/análisis , Quimiocina CCL2/genética , Modelos Animales de Enfermedad , Femenino , Pólipos Intestinales/enzimología , Masculino , RatonesRESUMEN
Background: In households with older individuals, where a patient is experiencing heart failure (HF), effective cooperation between patients and caregivers is crucial for disease management. However, there is limited evidence regarding the impact of cooperative HF management on the incidence of exacerbation. Therefore, the aim of this 6-month prospective cohort study was to investigate the association between HF management capability and exacerbations. MethodsâandâResults: The study enrolled outpatients (age ≥65 years) with chronic HF from a cardiology clinic and their caregivers. Self-care capabilities among patients and caregivers were evaluated using the Self-Care of Heart Failure Index (SCHFI) and Caregiver Contribution-SCHFI, respectively. Total scores were calculated using the highest score for each item. During the follow-up period, 31 patients experienced worsening HF. The analysis revealed no significant association between the total HF management score and HF exacerbation among all eligible patients. However, in patients with preserved left ventricular ejection fraction (LVEF), high HF management capability of the family unit was associated with a reduced risk of HF exacerbation, even after adjusting for the severity of HF. Conclusions: In older patients with HF and preserved LVEF, effective HF management may contribute to a lower risk of exacerbations.
RESUMEN
Background: The purpose of this study was to investigate the actual conditions of cardiac rehabilitation (CR) for elderly patients with heart failure (HF) in outpatient rehabilitation (OR) facilities using long-term care insurance systems. MethodsâandâResults: This was a cross-sectional web-based questionnaire survey conducted at 1,258 facilities in the Kansai region (6 prefectures) of Japan from October to December 2021. In all, 184 facilities responded to the web-based questionnaire (response rate 14.8%). Of these facilities, 159 (86.4%) accepted patients with HF. Among the patients with HF, 94.3% were aged ≥75 years and 66.7% were classified as New York Heart Association functional class I/II. Facilities treating patients with HF generally provided exercise therapy, patient education, and disease management, which were components of CR. Many facilities not currently treating patients with HF responded positively stating they will accept HF patients in the future. However, a few facilities responded by stating that they are waiting for clearer evidence demonstrating the beneficial effect of OR on patients with HF. Conclusions: The present results show the possibility that outpatient CR can be performed for elderly patients with HF in other than medical insurance.
RESUMEN
Oncometabolites, such as D/L-2-hydroxyglutarate (2HG), have directly been implicated in carcinogenesis; however, the underlying molecular mechanisms remain poorly understood. Here, we showed that the levels of the L-enantiomer of 2HG (L2HG) were specifically increased in colorectal cancer (CRC) tissues and cell lines compared with the D-enantiomer of 2HG (D2HG). In addition, L2HG increased the expression of ATF4 and its target genes by activating the mTOR pathway, which subsequently provided amino acids and improved the survival of CRC cells under serum deprivation. Downregulating the expression of L-2-hydroxyglutarate dehydrogenase (L2HGDH) and oxoglutarate dehydrogenase (OGDH) increased L2HG levels in CRC, thereby activating mTOR-ATF4 signaling. Furthermore, L2HGDH overexpression reduced L2HG-mediated mTOR-ATF4 signaling under hypoxia, whereas L2HGDH knockdown promoted tumor growth and amino acid metabolism in vivo. Together, these results indicate that L2HG ameliorates nutritional stress by activating the mTOR-ATF4 axis and thus could be a potential therapeutic target for CRC.
Asunto(s)
Neoplasias Colorrectales , Serina-Treonina Quinasas TOR , Humanos , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Transducción de Señal , Neoplasias Colorrectales/patología , Aminoácidos , Factor de Transcripción Activador 4/genética , Factor de Transcripción Activador 4/metabolismo , Oxidorreductasas de Alcohol/metabolismoRESUMEN
Cancer cachexia is a complex metabolic disorder accounting for ~20% of cancer-related deaths, yet its metabolic landscape remains unexplored. Here, we report a decrease in B vitamin-related liver enzymes as a hallmark of systemic metabolic changes occurring in cancer cachexia. Metabolomics of multiple mouse models highlights cachexia-associated reductions of niacin, vitamin B6, and a glycine-related subset of one-carbon (C1) metabolites in the liver. Integration of proteomics and metabolomics reveals that liver enzymes related to niacin, vitamin B6, and glycine-related C1 enzymes dependent on B vitamins decrease linearly with their associated metabolites, likely reflecting stoichiometric cofactor-enzyme interactions. The decrease of B vitamin-related enzymes is also found to depend on protein abundance and cofactor subtype. These metabolic/proteomic changes and decreased protein malonylation, another cachexia feature identified by protein post-translational modification analysis, are reflected in blood samples from mouse models and gastric cancer patients with cachexia, underscoring the clinical relevance of our findings.
Asunto(s)
Niacina , Neoplasias Gástricas , Complejo Vitamínico B , Ratones , Animales , Humanos , Caquexia/etiología , Caquexia/metabolismo , Proteómica , Piridoxina , Vitamina B 6 , Hígado/metabolismo , Glicina/metabolismoRESUMEN
The intestinal epithelium is constantly exposed to inducers of reactive oxygen species (ROS), such as commensal microorganisms. Levels of ROS are normally maintained at nontoxic levels, but dysregulation of ROS is involved in intestinal inflammatory diseases. In this article, we report that TGF-ß-activated kinase 1 (TAK1) is a key regulator of ROS in the intestinal epithelium. tak1 gene deletion in the mouse intestinal epithelium caused tissue damage involving enterocyte apoptosis, disruption of tight junctions, and inflammation. Disruption of TNF signaling, which is a major intestinal damage inducer, rescued the inflammatory conditions but not apoptosis or disruption of tight junctions in the TAK1-deficient intestinal epithelium, suggesting that TNF is not a primary inducer of the damage noted in TAK1-deficient intestinal epithelium. We found that TAK1 deficiency resulted in reduced expression of several antioxidant-responsive genes and reduced the protein level of a key antioxidant transcription factor NF-E2-related factor 2, which resulted in accumulation of ROS. Exogenous antioxidant treatment reduced apoptosis and disruption of tight junctions in the TAK1-deficient intestinal epithelium. Thus, TAK1 signaling regulates ROS through transcription factor NF-E2-related factor 2, which is important for intestinal epithelial integrity.
Asunto(s)
Inmunidad Mucosa/fisiología , Mucosa Intestinal/enzimología , Quinasas Quinasa Quinasa PAM/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Animales , Western Blotting , Epitelio/enzimología , Epitelio/inmunología , Expresión Génica , Regulación de la Expresión Génica/inmunología , Inmunohistoquímica , Mucosa Intestinal/inmunología , Quinasas Quinasa Quinasa PAM/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Factor 2 Relacionado con NF-E2/inmunología , Estrés Oxidativo/inmunología , Especies Reactivas de Oxígeno/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
SIGNIFICANCE: This study identifies signaling pathways essential for maintaining the stemness and metastatic potential of colorectal cancer cells and proposes CREB as a therapeutic target in metastatic colorectal cancer.
Asunto(s)
Neoplasias Colorrectales , Células Madre Neoplásicas , Humanos , Línea Celular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Transducción de Señal , Proteína Smad4/genética , Proteína Smad4/metabolismo , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Células Madre Neoplásicas/metabolismo , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/fisiopatologíaRESUMEN
Chronic pain and fatigue have negative effects on the health, ADL, work, and hobbies of the elderly. As the proportion of people 65 years of age and older in the population increases, chronic pain and disability research regarding this group is receiving more consideration. However, little empirical evidence of the association between chronic pain, fatigue, and physical disability between the sexes is available. This study investigated the association between chronic pain, fatigue, and instrumental activities of daily living among community-dwelling elderly people by sex in Japan. Concerning the presence of chronic pain, 61% of males and 78% of females reported chronic pain, indicating that many elderly people living in the community suffer from chronic pain and fatigue on a daily basis. The number of sites of chronic pain was higher in females than in males (p = 0.016), with more chronic pain in the knees (p < 0.001) and upper arms (p = 0.014). Regarding chronic pain, males showed a higher correlation with QuickDASH-DS (rs = 0.433, p = 0.017) and QuickDASH-SM (rs = 0.643, p = 0.018) than females. Furthermore, fatigue also showed a higher correlation with QuickDASH-W (rs = 0.531, p = 0.003) in males than in females. These results indicate that the association between chronic pain, fatigue, and QuickDASH differed between the sexes among community-dwelling elderly people in Japan. A better understanding of the risk factors for elderly chronic pain and fatigue among sexes will facilitate the development of elderly healthcare welfare and policies.
RESUMEN
Although the Wnt/ß-catenin pathway plays a central role in the carcinogenesis and maintenance of colorectal cancer (CRC), attempts to target the pathway itself have not been very successful. MyD88, an adaptor protein of the TLR/IL-1ß signaling, has been implicated in the integrity of the intestines as well as in their tumorigenesis. In this study, we aimed to clarify the mechanisms by which epithelial MyD88 contributes to intestinal tumor formation and to address whether MyD88 can be a therapeutic target of CRC. Conditional knockout of MyD88 in intestinal epithelial cells (IECs) reduced tumor formation in Apc+/Δ716 mice, accompanied by decreased proliferation and enhanced apoptosis of tumor epithelial cells. Mechanistically, the MyD88 loss caused inactivation of the JNK-mTORC1, NF-κB, and Wnt/ß-catenin pathways in tumor cells. Induction of MyD88 knockout in the intestinal tumor-derived organoids, but not in the normal IEC-derived organoids, induced apoptosis and reduced their growth. Treatment with the MyD88 inhibitor ST2825 also suppressed the growth of the intestinal tumor-derived organoids. Knockdown of MYD88 in human CRC cell lines with mutations in APC or CTNNB1 induced apoptosis and reduced their proliferation as well. These results indicate that MyD88 loss is synthetic lethal with mutational activation of the Wnt/ß-catenin signaling in intestinal tumor epithelial cells. Inhibition of MyD88 signaling can thus be a novel therapeutic strategy for familial adenomatous polyposis (FAP) as well as for colorectal cancer harboring mutations in the Wnt/ß-catenin signaling.
Asunto(s)
Mucosa Intestinal/patología , Neoplasias Intestinales/patología , Factor 88 de Diferenciación Mieloide/fisiología , Mutaciones Letales Sintéticas , Proteínas Wnt/genética , beta Catenina/genética , Animales , Apoptosis , Proliferación Celular , Células Cultivadas , Femenino , Mucosa Intestinal/metabolismo , Neoplasias Intestinales/genética , Neoplasias Intestinales/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Recent studies have revealed that TAK1 kinase is an essential intermediate in several innate immune signaling pathways. In this study, we investigated the role of TAK1 signaling in maintaining intestinal homeostasis by generating enterocyte-specific constitutive and inducible gene-deleted TAK1 mice. We found that enterocyte-specific constitutive TAK1-deleted mice spontaneously developed intestinal inflammation as observed by histological analysis and enhanced expression of IL-1beta, MIP-2, and IL-6 around the time of birth, which was accompanied by significant enterocyte apoptosis. When TAK1 was deleted in the intestinal epithelium of 4-wk-old mice using an inducible knockout system, enterocytes underwent apoptosis and intestinal inflammation developed within 2-3 days following the initiation of gene deletion. We found that enterocyte apoptosis and intestinal inflammation were strongly attenuated when enterocyte-specific constitutive TAK1-deleted mice were crossed to TNF receptor 1(-/-) mice. However, these mice later (>14 days) developed ileitis and colitis. Thus, TAK1 signaling in enterocytes is essential for preventing TNF-dependent epithelium apoptosis and the TNF-independent development of ileitis and colitis. We propose that aberration in TAK1 signaling might disrupt intestinal homeostasis and favor the development of inflammatory disease.
Asunto(s)
Apoptosis , Colitis/inmunología , Enterocitos/inmunología , Ileítis/inmunología , Mucosa Intestinal/inmunología , Quinasas Quinasa Quinasa PAM/metabolismo , Animales , Colitis/metabolismo , Enterocitos/citología , Enterocitos/metabolismo , Ileítis/metabolismo , Mucosa Intestinal/metabolismo , Quinasas Quinasa Quinasa PAM/inmunología , Ratones , Ratones Noqueados , Ratones Mutantes , Transducción de Señal , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Kinesin-1 is a heterotetramer composed of kinesin heavy chain (KHC) and kinesin light chain (KLC). The Caenorhabditis elegans genome has a single KHC, encoded by the unc-116 gene, and two KLCs, encoded by the klc-1 and klc-2 genes. We show here that UNC-116/KHC and KLC-2 form a complex orthologous to conventional kinesin-1. KLC-2 also binds UNC-16, the C. elegans JIP3/JSAP1 JNK-signaling scaffold protein, and the UNC-14 RUN domain protein. The localization of UNC-16 and UNC-14 depends on kinesin-1 (UNC-116 and KLC-2). Furthermore, mutations in unc-16, klc-2, unc-116, and unc-14 all alter the localization of cargos containing synaptic vesicle markers. Double mutant analysis is consistent with these four genes functioning in the same pathway. Our data support a model whereby UNC-16 and UNC-14 function together as kinesin-1 cargos and regulators for the transport or localization of synaptic vesicle components.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiología , Proteínas Portadoras/metabolismo , Cinesinas/metabolismo , Vesículas Sinápticas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/química , Proteínas Adaptadoras Transductoras de Señales/genética , Secuencia de Aminoácidos , Animales , Western Blotting , Caenorhabditis elegans/genética , Caenorhabditis elegans/crecimiento & desarrollo , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/genética , Proteínas Portadoras/química , Proteínas Portadoras/genética , Línea Celular , Proteínas del Citoesqueleto , Técnica del Anticuerpo Fluorescente Indirecta , Expresión Génica , Genes de Helminto , Proteínas Fluorescentes Verdes/análisis , Humanos , Modelos Genéticos , Datos de Secuencia Molecular , Mutación , Neuronas/metabolismo , Pruebas de Precipitina , Unión Proteica , Estructura Terciaria de Proteína , Homología de Secuencia de Aminoácido , Transgenes , Técnicas del Sistema de Dos Híbridos , Proteínas de Transporte Vesicular/metabolismoRESUMEN
Increasing evidence implies an extensive and universal interaction between the immune system and the nervous system. Previous studies showed that OCTR-1, a neuronal G-protein-coupled receptor (GPCR) analogous to human norepinephrine receptors, functions in sensory neurons to control the gene expression of both microbial killing pathways and the unfolded protein response (UPR) in Caenorhabditis elegans. Here, we found that OCTR-1-expressing neurons, ASH, are involved in controlling innate immune pathways. In contrast, another group of OCTR-1-expressing neurons, ASI, was shown to promote pathogen avoidance behavior. We also identified neuropeptide NLP-20 and AIA interneurons, which are responsible for the integration of conflicting cues and behaviors, as downstream components of the ASH/ASI neural circuit. These findings provide insights into a neuronal network involved in regulating pathogen defense mechanisms in C. elegans and might have broad implications for the strategies utilized by metazoans to balance the energy-costly immune activation and behavioral response.
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Proteínas de Caenorhabditis elegans/metabolismo , Inmunidad Innata , Neuropéptidos/metabolismo , Pseudomonas aeruginosa/patogenicidad , Células Receptoras Sensoriales/metabolismo , Animales , Conducta Animal , Caenorhabditis elegans/inmunología , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Microscopía Fluorescente , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Mutagénesis , Neuropéptidos/genética , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
AIMS: Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) is the master transcriptional regulator of antioxidant gene expression. On increased oxidative stress, an adaptor for Nrf2 degradation, Kelch-like ECH-associated protein 1 (Keap1), is directly modulated by oxidants in the cytoplasm, which results in stabilization and activation of Nrf2. Nrf2 is also constitutively active, to some extent, in the absence of exogenous oxidative stress. We have previously demonstrated that intestinal epithelium-specific TGF-ß-activated kinase 1 (TAK1) deletion downregulates the level of Nrf2 protein, resulting in an increase of reactive oxygen species (ROS) in a mouse model. We aim at determining the mechanism by which TAK1 modulates the level of Nrf2. RESULTS: We found that TAK1 upregulated serine 351 phosphorylation of an autophagic adaptor protein, p62/Sequestosome-1 (SQSTM1), which facilitates interaction between p62/SQSTM1 and Keap1 and subsequent Keap1 degradation. This, ultimately, causes increased Nrf2. Tak1 deficiency reduced the phosphorylation of p62/SQSTM1, resulting in decreased steady-state levels of Nrf2 along with increased Keap1. We also found that this regulation is independent of the canonical redox-mediated Nrf2 activation mechanism. In Tak1-deficient intestinal epithelium, a synthetic phenolic electrophile, butylated hydroxyanisole still effectively upregulated Nrf2 and reduced ROS. INNOVATION: Our results identify for the first time that TAK1 is a modulator of p62/SQSTM1-dependent Keap1 degradation and maintains the steady state-level of Nrf2. CONCLUSION: TAK1 regulates Nrf2 through modulation of Keap-p62/SQSTM1 interaction. This regulation is important for homeostatic antioxidant protection in the intestinal epithelium. Antioxid. Redox Signal. 25, 953-964.
Asunto(s)
Antioxidantes/metabolismo , Quinasas Quinasa Quinasa PAM/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Proteína Sequestosoma-1/metabolismo , Animales , Línea Celular , Regulación de la Expresión Génica , Humanos , Mucosa Intestinal/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Quinasas Quinasa Quinasa PAM/genética , Ratones , Ratones Noqueados , Modelos Biológicos , Factor 2 Relacionado con NF-E2/genética , Estrés Oxidativo , Unión Proteica , Proteolisis , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Magnetic resonance (MR) findings in cases of total asphyxia, whose lesions are mainly in the brainstem and deep nuclei, have not been clarified. In this study, we investigated MR images in neonates with total asphyxia. MR images of six infants (three males and three females; gestational age, 35-39 weeks; birth weights, 1880-3572 g) with total asphyxia were examined. In all subjects, neonatal cortical MR lesions were limited to the hippocampus with highlighting on T1-weighted imaging (T1-WI). The neonatal MR lesions of the cerebral white matter were limited to the white matter between the insula and putamen in four infants, and were diffusely involved in two infants. The ventral lateral nucleus of the thalamus was hyperintense on T1-WI in all of the subjects. Other nuclei in the thalamus, the globus pallidus and the putamen were involved in neonatal MR images of all subjects. High intensity areas on T2- weighted imaging were observed at the dorsal areas in the midbrain, pons and medulla oblongata in all or most of the subjects at the neonatal period. Also, high intensity areas on T1-WI were observed in the tegmentum of the pons and the midbrain in five cases. Neonates with total asphyxia had lesions mainly in the tegmentem of the brainstem, thalamus, putamen and globus palludus. Some of the infants had extensive lesions of the white matter.
Asunto(s)
Asfixia Neonatal/patología , Encéfalo/patología , Fibras Nerviosas Mielínicas/patología , Femenino , Humanos , Recién Nacido , Imagen por Resonancia Magnética , MasculinoRESUMEN
The unfolded protein response (UPR), which is activated when unfolded or misfolded proteins accumulate in the endoplasmic reticulum, has been implicated in the normal physiology of immune defense and in several human diseases, including diabetes, cancer, neurodegenerative disease, and inflammatory disease. In this study, we found that the nervous system controlled the activity of a noncanonical UPR pathway required for innate immunity in Caenorhabditis elegans. OCTR-1, a putative octopamine G protein-coupled catecholamine receptor (GPCR, G protein-coupled receptor), functioned in sensory neurons designated ASH and ASI to actively suppress innate immune responses by down-regulating the expression of noncanonical UPR genes pqn/abu in nonneuronal tissues. Our findings suggest a molecular mechanism by which the nervous system may sense inflammatory responses and respond by controlling stress-response pathways at the organismal level.
Asunto(s)
Proteínas de Caenorhabditis elegans/fisiología , Caenorhabditis elegans/genética , Caenorhabditis elegans/inmunología , Genes de Helminto , Inmunidad Innata , Pseudomonas aeruginosa/inmunología , Receptores Acoplados a Proteínas G/fisiología , Células Receptoras Sensoriales/fisiología , Respuesta de Proteína Desplegada/genética , Animales , Carga Bacteriana , Caenorhabditis elegans/microbiología , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Regulación hacia Abajo , Retículo Endoplásmico/metabolismo , Mucosa Intestinal/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas Quinasas Activadas por Mitógenos/genética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Mutación , Faringe/metabolismo , Pseudomonas aeruginosa/patogenicidad , Receptores Acoplados a Proteínas G/genética , Transducción de Señal , Estrés Fisiológico , Transcripción Genética , Regulación hacia ArribaAsunto(s)
Proteínas Adaptadoras Transductoras de Señales , Caenorhabditis elegans , Sistema de Señalización de MAP Quinasas/fisiología , Vesículas Sinápticas/metabolismo , Animales , Transporte Biológico , Proteínas de Caenorhabditis elegans/fisiología , Proteínas Portadoras/fisiología , Cinesinas/fisiología , Proteínas Quinasas Activadas por Mitógenos/fisiología , Proteínas Asociadas a Matriz Nuclear/fisiologíaRESUMEN
BACKGROUND: We have previously reported that intestinal epithelium-specific TAK1 deleted mice exhibit severe inflammation and mortality at postnatal day 1 due to TNF-induced epithelial cell death. Although deletion of TNF receptor 1 (TNFR1) can largely rescue those neonatal phenotypes, mice harboring double deletion of TNF receptor 1 (TNFR1) and intestinal epithelium-specific deletion of TAK1 (TNFR1KO/TAK1(IE)KO) still occasionally show increased inflammation. This indicates that TAK1 is important for TNF-independent regulation of intestinal integrity. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we investigated the TNF-independent role of TAK1 in the intestinal epithelium. Because the inflammatory conditions were sporadically developed in the double mutant TNFR1KO/TAK1(IE)KO mice, we hypothesize that epithelial TAK1 signaling is important for preventing stress-induced barrier dysfunction. To test this hypothesis, the TNFR1KO/TAK1(IE)KO mice were subjected to acute colitis by administration of dextran sulfate sodium (DSS). We found that loss of TAK1 significantly augments DSS-induced experimental colitis. DSS induced weight loss, intestinal damages and inflammatory markers in TNFR1KO/TAK1(IE)KO mice at higher levels compared to the TNFR1KO control mice. Apoptosis was strongly induced and epithelial cell proliferation was decreased in the TAK1-deficient intestinal epithelium upon DSS exposure. These suggest that epithelial-derived TAK1 signaling is important for cytoprotection and repair against injury. Finally, we showed that TAK1 is essential for interleukin 1- and bacterial components-induced expression of cytoprotective factors such as interleukin 6 and cycloxygenase 2. CONCLUSIONS: Homeostatic cytokines and microbes-induced intestinal epithelial TAK1 signaling regulates cytoprotective factors and cell proliferation, which is pivotal for protecting the intestinal epithelium against injury.