RESUMEN
Ethylene regulates plant growth, development, and stress adaptation. However, the early signaling events following ethylene perception, particularly in the regulation of ethylene receptor/CTRs (CONSTITUTIVE TRIPLE RESPONSE) complex, remains less understood. Here, utilizing the rapid phospho-shift of rice OsCTR2 in response to ethylene as a sensitive readout for signal activation, we revealed that MHZ3, previously identified as a stabilizer of ETHYLENE INSENSITIVE 2 (OsEIN2), is crucial for maintaining OsCTR2 phosphorylation. Genetically, both functional MHZ3 and ethylene receptors prove essential for OsCTR2 phosphorylation. MHZ3 physically interacts with both subfamily I and II ethylene receptors, e.g., OsERS2 and OsETR2 respectively, stabilizing their association with OsCTR2 and thereby maintaining OsCTR2 activity. Ethylene treatment disrupts the interactions within the protein complex MHZ3/receptors/OsCTR2, reducing OsCTR2 phosphorylation and initiating downstream signaling. Our study unveils the dual role of MHZ3 in fine-tuning ethylene signaling activation, providing insights into the initial stages of the ethylene signaling cascade.
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Etilenos , Regulación de la Expresión Génica de las Plantas , Oryza , Proteínas de Plantas , Receptores de Superficie Celular , Transducción de Señal , Oryza/metabolismo , Oryza/genética , Etilenos/metabolismo , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Fosforilación , Receptores de Superficie Celular/metabolismo , Receptores de Superficie Celular/genética , Plantas Modificadas Genéticamente , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genéticaRESUMEN
The cell wall shapes plant cell morphogenesis and affects the plasticity of organ growth. However, the way in which cell wall establishment is regulated by ethylene remains largely elusive. Here, by analyzing cell wall patterns, cell wall composition and gene expression in rice (Oryza sativa, L.) roots, we found that ethylene induces cell wall thickening and the expression of cell wall synthesis-related genes, including CELLULOSE SYNTHASE-LIKE C1, 2, 7, 9, 10 (OsCSLC1, 2, 7, 9, 10) and CELLULOSE SYNTHASE A3, 4, 7, 9 (OsCESA3, 4, 7, 9). Overexpression and mutant analyses revealed that OsCSLC2 and its homologs function in ethylene-mediated induction of xyloglucan biosynthesis mainly in the cell wall of root epidermal cells. Moreover, OsCESA-catalyzed cellulose deposition in the cell wall was enhanced by ethylene. OsCSLC-mediated xyloglucan biosynthesis likely plays an important role in restricting cell wall extension and cell elongation during the ethylene response in rice roots. Genetically, OsCSLC2 acts downstream of ETHYLENE-INSENSITIVE3-LIKE1 (OsEIL1)-mediated ethylene signaling, and OsCSLC1, 2, 7, 9 are directly activated by OsEIL1. Furthermore, the auxin signaling pathway is synergistically involved in these regulatory processes. These findings link plant hormone signaling with cell wall establishment, broadening our understanding of root growth plasticity in rice and other crops.
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Nonalcoholic fatty liver disease (NAFLD) is one of the common causes of chronic liver disease in the world. The problem of NAFLD had become increasingly prominent. However, its pathogenesis is still indistinct. As we all know, NAFLD begins with the accumulation of triglyceride (TG), leading to fatty degeneration, inflammation and other liver tissues damage. Notably, structure of nucleoporin 85 (NUP85) is related to lipid metabolism and inflammation of liver diseases. In this study, the results of researches indicated that NUP85 played a critical role in NAFLD. Firstly, the expression level of NUP85 in methionine-choline-deficient (MCD)-induced mice increased distinctly, as well as the levels of fat disorder and inflammation. On the contrary, knockdown of NUP85 had the opposite effects. In vitro, AML-12 cells were stimulated with 2 mm free fatty acids (FFA) for 24 h. Results also proved that NUP85 significantly increased in model group, and increased lipid accumulation and inflammation level. Besides, NUP85 protein could interact with C-C motif chemokine receptor 2 (CCR2). Furthermore, when NUP85 protein expressed at an extremely low level, the expression level of CCR2 protein also decreased, accompanied with an inhibition of phosphorylation of phosphoinositol-3 kinase (PI3K)-protein kinase B (AKT) signaling pathway. What is more, trans isomer (ISRIB), a targeted inhibitor of NUP85, could alleviate NAFLD. In summary, our findings suggested that NUP85 functions as an important regulator in NAFLD through modulation of CCR2.
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Enfermedad del Hígado Graso no Alcohólico , Animales , Ratones , Metabolismo de los Lípidos/genética , Proteínas Proto-Oncogénicas c-akt , Fosfatidilinositol 3-Quinasas , Transducción de Señal , Receptores de Quimiocina , InflamaciónRESUMEN
Nicotinic acetylcholine receptors (nAChRs) regulate pain pathways with various outcomes depending on receptor subtypes, neuron types, and locations. But it remains unknown whether α4ß2 nAChRs abundantly expressed in the substantia nigra pars reticulata (SNr) have potential to mitigate hyperalgesia in pain states. We observed that injection of nAChR antagonists into the SNr reduced pain thresholds in naïve mice, whereas injection of nAChR agonists into the SNr relieved hyperalgesia in mice, subjected to capsaicin injection into the lower hind leg, spinal nerve injury, chronic constriction injury, or chronic nicotine exposure. The analgesic effects of nAChR agonists were mimicked by optogenetic stimulation of cholinergic inputs from the pedunculopontine nucleus (PPN) to the SNr, but attenuated upon downregulation of α4 nAChRs on SNr GABAergic neurons and injection of dihydro-ß-erythroidine into the SNr. Chronic nicotine-induced hyperalgesia depended on α4 nAChRs in SNr GABAergic neurons and was associated with the reduction of ACh release in the SNr. Either activation of α4 nAChRs in the SNr or optogenetic stimulation of the PPN-SNr cholinergic projection mitigated chronic nicotine-induced hyperalgesia. Interestingly, mechanical stimulation-induced ACh release was significantly attenuated in mice subjected to either capsaicin injection into the lower hind leg or SNI. These results suggest that α4 nAChRs on GABAergic neurons mediate a cholinergic analgesic circuit in the SNr, and these receptors may be effective therapeutic targets to relieve hyperalgesia in acute and chronic pain, and chronic nicotine exposure.
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Neuronas GABAérgicas , Hiperalgesia , Ratones Endogámicos C57BL , Receptores Nicotínicos , Animales , Receptores Nicotínicos/metabolismo , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/efectos de los fármacos , Neuronas GABAérgicas/fisiología , Masculino , Hiperalgesia/metabolismo , Hiperalgesia/tratamiento farmacológico , Ratones , Porción Reticular de la Sustancia Negra/metabolismo , Porción Reticular de la Sustancia Negra/efectos de los fármacos , Nicotina/farmacología , Analgésicos/farmacología , Agonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/farmacología , Capsaicina/farmacología , Acetilcolina/metabolismo , Optogenética , Umbral del Dolor/efectos de los fármacosRESUMEN
Microglial are major players in neuroinflammation that have recently emerged as potential therapeutic targets for neuropathic pain. Glucose metabolic programming has been linked to differential activation state and function in microglia. Tumor necrosis factor α-induced protein 8-like-2 (TNFAIP8L2) is an important component in regulating the anti-inflammatory response. However, the role of TNFAIP8L2 in microglia differential state during neuropathic pain and its interplay with glucose metabolic reprogramming in microglia has not yet been determined. Thus, we aimed to investigate the role of TNFAIP8L2 in the status of microglia in vitro and in vivo. BV2 microglial cells were treated with lipopolysaccharides plus interferon-gamma (LPS/IFNγ) or interleukin-4 (IL-4) to induce the two different phenotypes of microglia in vitro. In vivo experiments were conducted by chronic constriction injury of the sciatic nerve (CCI). We investigated whether TNFAIP8L2 regulates glucose metabolic programming in BV2 microglial cells. The data in vitro showed that TNFAIP8L2 lowers glycolysis and increases mitochondrial oxidative phosphorylation (OXPHOS) in inflammatory microglia. Blockade of glycolytic pathway abolished TNFAIP8L2-mediated differential activation of microglia. TNFAIP8L2 suppresses inflammatory microglial activation and promotes restorative microglial activation in BV2 microglial cells and in spinal cord microglia after neuropathic pain. Furthermore, TNFAIP8L2 controls differential activation of microglia and glucose metabolic reprogramming through the MAPK/mTOR/HIF-1α signaling axis. This study reveals that TNFAIP8L2 plays a critical role in neuropathic pain, providing important insights into glucose metabolic reprogramming and microglial phenotypic transition, which indicates that TNFAIP8L2 may be used as a potential drug target for the prevention of neuropathic pain.
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Microglía , Neuralgia , Humanos , Microglía/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Reprogramación Metabólica , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Proteínas Portadoras/metabolismo , Fenotipo , Glucosa/farmacología , Glucosa/metabolismo , Lipopolisacáridos/farmacologíaRESUMEN
BACKGROUND: Cognitive behavioral stress management (CBSM) modifies individuals' maladaptive cognition and improves their ability in managing stress. The present study was to inquire about the utility of CBSM in mental health and quality of life in patients with cervical cancer. METHODS: Totally, 172 postoperative cervical cancer patients were randomly classified into CBSM (N=86) and normal care group (N=86) to receive 8-week CBSM and normal care, correspondingly. Self-rating anxiety/depression scale (SAS/SDS), EuroQol-5 dimensions (EQ-5D), EuroQol-visual analogue scale (EQ-VAS), and quality of life questionnaire-core 30 (QLQ-C30) scores were evaluated at discharge (M0), 1st month (M1), M3, and M6 after discharge. RESULTS: SAS scores at M6 (P=0.003), M1 (P=0.042), and M3 (P=0.010), and the proportion of patients with SAS-defined anxiety at M3 (P=0.040) and M6 (P=0.019) were reduced in CBSM group versus normal care group. SDS scores at M3 (P=0.020) and M6 (P=0.016), and the proportion of patients with SDS-defined depression at M6 (P=0.036) was descended in CBSM group versus normal care group. EQ-VAS score at M1 (P=0.044), M3 (P=0.014), and M6 (P=0.002) were increased, while EQ-5D score at M3 (P=0.030) was descended in CBSM group versus normal care group. Meanwhile, QLQ-C30 global health status score at M1 (P=0.046), M3 (P=0.037), and M6 (P=0.007), QLQ-C30 function score at M3 (P=0.033) and M6 (P=0.016) were ascended, but QLQ-C30 symptom score at M3 (P=0.042) was declined in CBSM group versus normal care group. CONCLUSION: CBSM is an effective intervention for decreasing anxiety and depression, and improving quality of life in patients with cervical cancer.
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Calidad de Vida , Neoplasias del Cuello Uterino , Femenino , Humanos , Ansiedad/terapia , Cognición , Depresión/etiología , Depresión/terapia , Depresión/psicología , Calidad de Vida/psicología , Neoplasias del Cuello Uterino/terapiaRESUMEN
ABSTACTA chemical investigation of the endophyte Penicillium sp. Nb 19, isolated from leaves of the traditionally medical plant Baphicacanthus cusia (Nees) Bremek., yielded one new indole diterpenoid, 7-methoxy-13-dehydroxypaxilline (1) together with seven known metabolites (2-8). The obtained structure of compound 1 was elucidated by its spectroscopic data. In addition, the absolute configuration of compound 6 was confirmed by ECD for the first time. Compounds 1-6 were evaluated for antitumor activity against MCF-7, HepG2, and HCCC-9810 cell lines.
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Diterpenos , Penicillium , Niobio/metabolismo , Diterpenos/química , Hongos , Indoles/química , Penicillium/química , Estructura MolecularRESUMEN
Macrophages are heterogeneous and play critical roles in development and disease, but their diversity, function, and specification remain inadequately understood during human development. We generated a single-cell RNA sequencing map of the dynamics of human macrophage specification from PCW 4-26 across 19 tissues. We identified a microglia-like population and a proangiogenic population in 15 macrophage subtypes. Microglia-like cells, molecularly and morphologically similar to microglia in the CNS, are present in the fetal epidermis, testicle, and heart. They are the major immune population in the early epidermis, exhibit a polarized distribution along the dorsal-lateral-ventral axis, and interact with neural crest cells, modulating their differentiation along the melanocyte lineage. Through spatial and differentiation trajectory analysis, we also showed that proangiogenic macrophages are perivascular across fetal organs and likely yolk-sac-derived as microglia. Our study provides a comprehensive map of the heterogeneity and developmental dynamics of human macrophages and unravels their diverse functions during development.
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Macrófagos , Humanos , Diferenciación Celular , Linaje de la Célula , Macrófagos/citología , Microglía , Especificidad de ÓrganosRESUMEN
Ethylene plays essential roles in rice growth, development and stress adaptation. Translational control of ethylene signaling remains unclear in rice. Here, through analysis of an ethylene-response mutant mhz9, we identified a glycine-tyrosine-phenylalanine (GYF) domain protein MHZ9, which positively regulates ethylene signaling at translational level in rice. MHZ9 is localized in RNA processing bodies. The C-terminal domain of MHZ9 interacts with OsEIN2, a central regulator of rice ethylene signaling, and the N-terminal domain directly binds to the OsEBF1/2 mRNAs for translational inhibition, allowing accumulation of transcription factor OsEIL1 to activate the downstream signaling. RNA-IP seq and CLIP-seq analyses reveal that MHZ9 associates with hundreds of RNAs. Ribo-seq analysis indicates that MHZ9 is required for the regulation of ~ 90% of genes translationally affected by ethylene. Our study identifies a translational regulator MHZ9, which mediates translational regulation of genes in response to ethylene, facilitating stress adaptation and trait improvement in rice.
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Oryza , Oryza/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Mutación , Etilenos/metabolismo , ARN/metabolismo , Regulación de la Expresión Génica de las PlantasRESUMEN
Chronic morphine tolerance is a repulsive barrier to the clinical treatment of pain. Whereas the underlying molecular mechanisms of morphine tolerance remain unknown. Here, we proposed that tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) is an essential control point regarding the progression of chronic morphine antinociceptive tolerance. We found that TIPE2 levels in the lumbar spinal cord were significantly downregulated in the morphine tolerance mouse model. Specifically, decreased TIPE2 by morphine tolerance was primarily expressed in spinal neurons, while increased expression of spinal TIPE2 distinctly attenuated the chronic morphine antinociceptive tolerance and tolerance-associated hyperalgesia. We also observed that increased expression of spinal TIPE2 significantly reduced morphine tolerance-induced neuronal ROS production and apoptosis, along with the activation of MAPKs and NF-κB signaling pathways. Moreover, the increased TIPE2 expression inhibited neuronal activation and glial reactivity in the spinal dorsal horn after chronic morphine exposure. Additionally, TIPE2 overexpression in cultured SH-SY5Y cells significantly suppressed ROS production and apoptosis in response to morphine challenge. Therefore, we can conclude that the upregulation of spinal TIPE2 may attenuate the morphine antinociceptive tolerance via TIPE2-dependent downregulation of neuronal ROS, inhibition of neuronal apoptosis, suppression of MAPKs and NF-κB activation. TIPE2 may be a potential strategy for preventing morphine tolerance in the future studies and clinical settings.
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Morfina , Neuroblastoma , Humanos , Ratones , Animales , Morfina/farmacología , Morfina/metabolismo , FN-kappa B/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Neuroblastoma/patología , Asta Dorsal de la Médula Espinal/metabolismo , Médula Espinal/metabolismo , Transducción de Señal , Analgésicos/farmacología , Analgésicos/metabolismo , Apoptosis , Péptidos y Proteínas de Señalización Intracelular/metabolismoRESUMEN
Surgeries may have worse clinical outcomes in pancreatitis. In our institute surgical procedure is barely used surgery to treat pancreatitis nowadays. Chinese guidelines recommended regular exercise for severe pancreatitis. The objectives of the current study were to compare nurse-led resistance training at the institute against usual care provided to patients with acute pancreatitis for favorable clinical outcome measures. For acute pancreatitis, patients (≥18 years, of age) received 6 months of resistance training in the garden of the institute under the supervision of registered nurses (NR cohort, n = 102), or received 6 months of resistance training at their home by themselves according to a training manual (HR cohort, n = 120) or received 6 months of usual care only (UC cohort, n = 120). Fewer numbers patients died in the follow-up period in the NR cohort than those of the HR (8 vs 21, P = .0447) and the UC (8 vs 32, P = .0046) cohorts. The frequency of rehospitalization of patients due to any of the reasons in the follow-up period was fewer for patients of the NR cohort than those of the HR and the UC cohorts (P < .05 for both). Hospitalization of patients due to any of the reasons in the follow-up period was fewer for patients of the HR cohort than those of the UC cohort (P < .05). A 52 median score was the quality of life of patients before the start of the non-treatment intervention(s). After 6 months of non-treatment intervention(s), patients of the NR cohort improved their quality of life as compared to their initial quality of life (P < .001), those of HR cohort (P < .05), and those of UC cohort (P < .001). The quality of life of patients with severe pancreatitis after the surgical procedure was worse. Six months of nurse-assisted resistant training at the institute has significant improvement on the quality of life of patients in the follow-up periods of acute pancreatitis. Resistant training at the institute would improve the quality of life of patients with acute pancreatitis (Level of Evidence: IV; Technical Efficacy Stage: 5).
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Pancreatitis , Entrenamiento de Fuerza , Humanos , Lactante , Calidad de Vida , Enfermedad Aguda , Rol de la Enfermera , Pancreatitis/terapiaRESUMEN
Non-alcoholic fatty liver disease (NAFLD) is a major health problem in Western countries and has become the most common cause of chronic liver disease. Although NAFLD is closely associated with obesity, inflammation, and insulin resistance, its pathogenesis remains unclear. The disease begins with excessive accumulation of triglycerides in the liver, which in turn leads to liver cell damage, steatosis, inflammation, and so on. P38γ is one of the four isoforms of P38 mitogen-activated protein kinases (P38 MAPKs) that contributes to inflammation in different diseases. In this research, we investigated the role of P38γ in NAFLD. In vivo, a NAFLD model was established by feeding C57BL/6J mice with a methionine- and choline-deficient (MCD) diet and adeno-associated virus (AAV9-shRNA-P38γ) was injected into C57BL/6J mice by tail vein for knockdown P38γ. The results indicated that the expression level of P38γ was upregulated in MCD-fed mice. Furthermore, the downregulation of P38γ significantly attenuated liver injury and lipid accumulation in mice. In vitro, mouse hepatocytes AML-12 were treated with free fatty acid (FFA). We found that P38γ was obviously increased in FFA-treated AML-12 cells, whereas knockdown of P38γ significantly suppressed lipid accumulation in FFA-treated AML-12 cells. Furthermore, P38γ regulated the Janus Kinase-Signal transducers and activators of transcription (JAK-STAT) signaling pathway. Inhibition of P38γ can inhibit the JAK-STAT signaling pathway, thereby inhibiting lipid accumulation in FFA-treated AML-12 cells. In conclusion, our results suggest that targeting P38γ contributes to the suppression of lipid accumulation in fatty liver disease.
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Leucemia Mieloide Aguda , Enfermedad del Hígado Graso no Alcohólico , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Metabolismo de los Lípidos , Quinasas Janus/metabolismo , Dieta Alta en Grasa , Ratones Endogámicos C57BL , Hígado/metabolismo , Transducción de Señal , Ácidos Grasos no Esterificados/metabolismo , Inflamación/metabolismo , Metionina/farmacología , Metionina/metabolismo , Leucemia Mieloide Aguda/metabolismoRESUMEN
Rice is an important food crop in the world and the study of its growth and plasticity has a profound influence on sustainable development. Ethylene modulates multiple agronomic traits of rice as well as abiotic and biotic stresses during its lifecycle. It has diverse roles, depending on the organs, developmental stages and environmental conditions. Compared to Arabidopsis (Arabidopsis thaliana), rice ethylene signalling pathway has its own unique features due to its special semiaquatic living environment and distinct plant structure. Ethylene signalling and responses are part of an intricate network in crosstalk with internal and external factors. This review will summarize the current progress in the mechanisms of ethylene-regulated coleoptile growth in rice, with a special focus on ethylene signaling and interaction with other hormones. Insights into these molecular mechanisms may shed light on ethylene biology and should be beneficial for the genetic improvement of rice and other crops.
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Arabidopsis , Oryza , Reguladores del Crecimiento de las Plantas/metabolismo , Plantones/metabolismo , Oryza/genética , Cotiledón/metabolismo , Etilenos/metabolismo , Arabidopsis/metabolismo , Regulación de la Expresión Génica de las PlantasRESUMEN
Common liver tissue damage is mainly due to the accumulation of toxic aldehydes in lipid peroxidation under oxidative stress. Cumulative toxic aldehydes in the liver can be effectively metabolized by acetaldehyde dehydrogenase 2 (ALDH2), thereby alleviating various liver diseases. Notably, gene mutation of ALDH2 leads to impaired ALDH2 enzyme activity, thus aggravating the progress of liver diseases. However, the relationship and specific mechanism between ALDH2 and liver diseases are not clear. Consequently, the review explains the relationship between ALDH2 and liver diseases such as alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), liver fibrosis and hepatocellular carcinoma (HCC). In addition, this review also discusses ALDH2 as a potential therapeutic target for various liver diseases,and focuses on summarizing the regulatory mechanism of ALDH2 in these liver diseases.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Aldehído Deshidrogenasa/genética , Aldehído Deshidrogenasa Mitocondrial/genética , Neoplasias Hepáticas/genética , AldehídosRESUMEN
Ethylene plays essential roles in adaptive growth of rice (Oryza sativa). Understanding of the crosstalk between ethylene and auxin (Aux) is limited in rice. Here, from an analysis of the root-specific ethylene-insensitive rice mutant mao hu zi 10 (mhz10), we identified the tryptophan aminotransferase (TAR) MHZ10/OsTAR2, which catalyzes the key step in indole-3-pyruvic acid-dependent Aux biosynthesis. Genetically, OsTAR2 acts downstream of ethylene signaling in root ethylene responses. ETHYLENE INSENSITIVE3 like1 (OsEIL1) directly activated OsTAR2 expression. Surprisingly, ethylene induction of OsTAR2 expression still required the Aux pathway. We also show that Os indole-3-acetic acid (IAA)1/9 and OsIAA21/31 physically interact with OsEIL1 and show promotive and repressive effects on OsEIL1-activated OsTAR2 promoter activity, respectively. These effects likely depend on their EAR motif-mediated histone acetylation/deacetylation modification. The special promoting activity of OsIAA1/9 on OsEIL1 may require both the EAR motifs and the flanking sequences for recruitment of histone acetyltransferase. The repressors OsIAA21/31 exhibit earlier degradation upon ethylene treatment than the activators OsIAA1/9 in a TIR1/AFB-dependent manner, allowing OsEIL1 activation by activators OsIAA1/9 for OsTAR2 expression and signal amplification. This study reveals a positive feedback regulation of ethylene signaling by Aux biosynthesis and highlights the crosstalk between ethylene and Aux pathways at a previously underappreciated level for root growth regulation in rice.
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Etilenos , Ácidos Indolacéticos , Oryza , Raíces de Plantas , Triptófano-Transaminasa , Etilenos/metabolismo , Regulación de la Expresión Génica de las Plantas , Ácidos Indolacéticos/metabolismo , Oryza/crecimiento & desarrollo , Oryza/metabolismo , Raíces de Plantas/crecimiento & desarrollo , Raíces de Plantas/metabolismo , Triptófano-Transaminasa/genética , Triptófano-Transaminasa/metabolismoRESUMEN
Acetaminophen (APAP) is one of the major causes of drug-induced acute liver injury, and ethanol may aggravate APAP-induced liver injury. The problem of ethanol- and APAP-induced liver injury becomes increasingly prominent, but the mechanism of ethanol- and APAP-induced liver injury remains ambiguous. p38γ is one of the four isoforms of P38 mitogen activated protein kinases, that contributes to inflammation in different diseases. In this study we investigated the role of p38γ in ethanol- and APAP-induced liver injury. Liver injury was induced in male C57BL/6 J mice by giving liquid diet containing 5% ethanol (v/v) for 10 days, followed by gavage of ethanol (25% (v/v), 6 g/kg) once or injecting APAP (200 mg/kg, ip), or combined the both treatments. We showed that ethanol significantly aggravated APAP-induced liver injury in C57BL/6 J mice. Moreover, the expression level of p38γ was up-regulated in the liver of ethanol-, APAP- and ethanol+APAP-treated mice. Knockdown of p38γ markedly attenuated liver injury, inflammation, and steatosis in ethanol+APAP-treated mice. Liver sections of p38γ-knockdown mice displayed lower levels of Oil Red O stained dots and small leaky shapes. AML-12 cells were exposed to APAP (5 mM), ethanol (100 mM) or combined treatments. We showed that P38γ was markedly increased in ethanol+APAP-treated AML-12 cells, whereas knockdown of p38γ significantly inhibited inflammation, lipid accumulation and oxidative stress in ethanol+APAP-treated AML-12 cells. Furthermore, we revealed that p38γ could combine with Dlg1, a member of membrane-associated guanylate kinase family. Deletion of p38γ up-regulated the expression level of Dlg1 in ethanol+APAP-treated AML-12 cells. In summary, our results suggest that p38γ functions as an important regulator in ethanol- and APAP-induced liver injury through modulation of Dlg1.
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Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Enfermedad Hepática Inducida por Sustancias y Drogas , Leucemia Mieloide Aguda , Acetaminofén/efectos adversos , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Etanol/toxicidad , Inflamación/metabolismo , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Hyperglycemia-induced neuroinflammation promotes the progression of diabetic encephalopathy. Hydrogen sulfide (H2S) exerts anti-inflammatory and neuroprotective activities against neurodegenerative diseases. However, the effects of H2S on hyperglycemia-induced neuroinflammation has not been investigated in neurons. Herein, by using HT-22 neuronal cells, we found that high glucose decreased the levels of endogenous H2S and its catalytic enzyme, cystathionine-ß-synthase (CBS). The administration of sodium hydrosulfide (NaHS, a H2S donor) or S-adenosylmethionine (SAMe, an allosteric activator of CBS) restored high glucose-induced downregulation of CBS and H2S levels. Importantly, H2S ameliorated high glucose-induced inflammation in HT-22 cells, evidenced by NaHS or SAMe inhibited the pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α) expression in HT-22 cells exposed to high glucose. Furthermore, NaHS or SAMe restored the SIRT1 level and the phosphorylation of mTOR and NF-κB p65 disturbed by high glucose in HT-22 cells, suggesting H2S reversed high glucose-induced alteration of SIRT1-mTOR/NF-κB signaling pathway. Our results demonstrated that exogenous H2S treatment or enhancing endogenous H2S synthesis prevents the inflammatory processes in the neurons with the exposure of high glucose. Therefore, increasing the H2S level using NaHS or SAMe might shed light on the prophylactic treatment of diabetic encephalopathy.
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Sulfuro de Hidrógeno/metabolismo , FN-kappa B/metabolismo , Neuronas/efectos de los fármacos , Sirtuina 1/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Animales , Línea Celular , Citocinas/genética , Glucosa , Inflamación/metabolismo , Ratones , Neuronas/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Ethylene is a gaseous hormone which plays important roles in both plant growth and development and stress responses. Based on studies in the dicot model plant species Arabidopsis, a linear ethylene signaling pathway has been established, according to which ethylene is perceived by ethylene receptors and transduced through CONSTITUTIVE TRIPLE RESPONSE 1 (CTR1) and ETHYLENE-INSENSITIVE 2 (EIN2) to activate transcriptional reprogramming. In addition to this canonical signaling pathway, an alternative ethylene receptor-mediated phosphor-relay pathway has also been proposed to participate in ethylene signaling. In contrast to Arabidopsis, rice, a monocot, grows in semiaquatic environments and has a distinct plant structure. Several novel regulators and/or mechanisms of the rice ethylene signaling pathway have recently been identified, indicating that the ethylene signaling pathway in rice has its own unique features. In this review, we summarize the latest progress and compare the conserved and divergent aspects of the ethylene signaling pathway between Arabidopsis and rice. The crosstalk between ethylene and other plant hormones is also reviewed. Finally, we discuss how ethylene regulates plant growth, stress responses and agronomic traits. These analyses should help expand our knowledge of the ethylene signaling mechanism and could further be applied for agricultural purposes.
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Arabidopsis/genética , Etilenos/metabolismo , Oryza/genética , Transducción de Señal/genética , Transducción de Señal/fisiologíaRESUMEN
Ethylene plays important roles in plant growth and development, but the regulation of ethylene signaling is largely unclear, especially in crops such as rice (Oryza sativa). Here, by analysis of the ethylene-insensitive mutant mao huzi 11 (mhz11), we identified the GDSL lipase MHZ11, which modulates ethylene signaling in rice roots. MHZ11 localized to the endoplasmic reticulum membrane and has acyl-hydrolyzing activity. This activity affects the homeostasis of sterols in rice roots and is required for root ethylene response. MHZ11 overexpression caused constitutive ethylene response in roots. Genetically, MHZ11 acts with the ethylene receptor ETHYLENE RESPONSE SENSOR2 (OsERS2) upstream of CONSTITUTIVE TRIPLE RESPONSE2 (OsCTR2) and ETHYLENE INSENSITIVE2 (OsEIN2). The mhz11 mutant maintains more OsCTR2 in the phosphorylated form whereas MHZ11 overexpression promotes ethylene-mediated inhibition of OsCTR2 phosphorylation. MHZ11 colocalized with the ethylene receptor OsERS2, and its effect on OsCTR2 phosphorylation requires ethylene perception and initiation of ethylene signaling. The mhz11 mutant overaccumulated sterols and blocking sterol biosynthesis partially rescued the mhz11 ethylene response, likely by reducing receptor-OsCTR2 interaction and OsCTR2 phosphorylation. We propose that MHZ11 reduces sterol levels to impair receptor-OsCTR2 interactions and OsCTR2 phosphorylation for triggering ethylene signaling. Our study reveals a mechanism by which MHZ11 participates in ethylene signaling for regulation of root growth in rice.