RESUMEN
Signaling across cellular membranes, the 826 human G protein-coupled receptors (GPCRs) govern a wide range of vital physiological processes, making GPCRs prominent drug targets. X-ray crystallography provided GPCR molecular architectures, which also revealed the need for additional structural dynamics data to support drug development. Here, nuclear magnetic resonance (NMR) spectroscopy with the wild-type-like A2A adenosine receptor (A2AAR) in solution provides a comprehensive characterization of signaling-related structural dynamics. All six tryptophan indole and eight glycine backbone 15N-1H NMR signals in A2AAR were individually assigned. These NMR probes provided insight into the role of Asp522.50 as an allosteric link between the orthosteric drug binding site and the intracellular signaling surface, revealing strong interactions with the toggle switch Trp 2466.48, and delineated the structural response to variable efficacy of bound drugs across A2AAR. The present data support GPCR signaling based on dynamic interactions between two semi-independent subdomains connected by an allosteric switch at Asp522.50.
Asunto(s)
Regulación Alostérica , Receptor de Adenosina A2A/química , Transducción de Señal , Agonistas del Receptor de Adenosina A2/química , Agonistas del Receptor de Adenosina A2/farmacología , Sitio Alostérico , Animales , Simulación del Acoplamiento Molecular , Pichia , Unión Proteica , Receptor de Adenosina A2A/metabolismo , Células Sf9 , SpodopteraRESUMEN
The κ-opioid receptor (KOP) mediates the actions of opioids with hallucinogenic, dysphoric, and analgesic activities. The design of KOP analgesics devoid of hallucinatory and dysphoric effects has been hindered by an incomplete structural and mechanistic understanding of KOP agonist actions. Here, we provide a crystal structure of human KOP in complex with the potent epoxymorphinan opioid agonist MP1104 and an active-state-stabilizing nanobody. Comparisons between inactive- and active-state opioid receptor structures reveal substantial conformational changes in the binding pocket and intracellular and extracellular regions. Extensive structural analysis and experimental validation illuminate key residues that propagate larger-scale structural rearrangements and transducer binding that, collectively, elucidate the structural determinants of KOP pharmacology, function, and biased signaling. These molecular insights promise to accelerate the structure-guided design of safer and more effective κ-opioid receptor therapeutics.
Asunto(s)
Simulación del Acoplamiento Molecular , Receptores Opioides kappa/química , Analgésicos/química , Analgésicos/farmacología , Animales , Sitios de Unión , Células HEK293 , Humanos , Simulación de Dinámica Molecular , Morfinanos/química , Morfinanos/farmacología , Unión Proteica , Estabilidad Proteica , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/metabolismo , Células Sf9 , SpodopteraRESUMEN
Fanconi anemia (FA) pathway genes are important tumor suppressors whose best-characterized function is repair of damaged nuclear DNA. Here, we describe an essential role for FA genes in two forms of selective autophagy. Genetic deletion of Fancc blocks the autophagic clearance of viruses (virophagy) and increases susceptibility to lethal viral encephalitis. Fanconi anemia complementation group C (FANCC) protein interacts with Parkin, is required in vitro and in vivo for clearance of damaged mitochondria, and decreases mitochondrial reactive oxygen species (ROS) production and inflammasome activation. The mitophagy function of FANCC is genetically distinct from its role in genomic DNA damage repair. Moreover, additional genes in the FA pathway, including FANCA, FANCF, FANCL, FANCD2, BRCA1, and BRCA2, are required for mitophagy. Thus, members of the FA pathway represent a previously undescribed class of selective autophagy genes that function in immunity and organellar homeostasis. These findings have implications for understanding the pathogenesis of FA and cancers associated with mutations in FA genes.
Asunto(s)
Proteína del Grupo de Complementación C de la Anemia de Fanconi/metabolismo , Animales , Autofagia , Embrión de Mamíferos/citología , Proteína del Grupo de Complementación C de la Anemia de Fanconi/genética , Proteínas del Grupo de Complementación de la Anemia de Fanconi/metabolismo , Fibroblastos/metabolismo , Células HeLa , Herpesvirus Humano 1/metabolismo , Humanos , Inflamasomas/metabolismo , Ratones , Mitofagia , Especies Reactivas de Oxígeno/metabolismo , Virus Sindbis/metabolismoRESUMEN
Genes disrupted in schizophrenia may be revealed by de novo mutations in affected persons from otherwise healthy families. Furthermore, during normal brain development, genes are expressed in patterns specific to developmental stage and neuroanatomical structure. We identified de novo mutations in persons with schizophrenia and then mapped the responsible genes onto transcriptome profiles of normal human brain tissues from age 13 weeks gestation to adulthood. In the dorsolateral and ventrolateral prefrontal cortex during fetal development, genes harboring damaging de novo mutations in schizophrenia formed a network significantly enriched for transcriptional coexpression and protein interaction. The 50 genes in the network function in neuronal migration, synaptic transmission, signaling, transcriptional regulation, and transport. These results suggest that disruptions of fetal prefrontal cortical neurogenesis are critical to the pathophysiology of schizophrenia. These results also support the feasibility of integrating genomic and transcriptome analyses to map critical neurodevelopmental processes in time and space in the brain.
Asunto(s)
Redes Reguladoras de Genes , Mutación , Corteza Prefrontal/embriología , Mapas de Interacción de Proteínas , Esquizofrenia/genética , Esquizofrenia/metabolismo , Encéfalo/embriología , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Análisis Mutacional de ADN , Bases de Datos Genéticas , Femenino , Humanos , Masculino , Neurogénesis , Corteza Prefrontal/crecimiento & desarrollo , Corteza Prefrontal/metabolismo , Esquizofrenia/fisiopatología , Transcripción Genética , TranscriptomaRESUMEN
Cardiac disease remains the leading cause of morbidity and mortality worldwide. The ß1-adrenergic receptor (ß1-AR) is a major regulator of cardiac functions and is downregulated in the majority of heart failure cases. A key physiological process is the activation of heterotrimeric G-protein Gs by ß1-ARs, leading to increased heart rate and contractility. Here, we use cryo-electron microscopy and functional studies to investigate the molecular mechanism by which ß1-AR activates Gs. We find that the tilting of α5-helix breaks a hydrogen bond between the sidechain of His373 in the C-terminal α5-helix and the backbone carbonyl of Arg38 in the N-terminal αN-helix of Gαs. Together with the disruption of another interacting network involving Gln59 in the α1-helix, Ala352 in the ß6-α5 loop, and Thr355 in the α5-helix, these conformational changes might lead to the deformation of the GDP-binding pocket. Our data provide molecular insights into the activation of G-proteins by G-protein-coupled receptors.
Asunto(s)
Subunidades alfa de la Proteína de Unión al GTP Gs/química , Subunidades alfa de la Proteína de Unión al GTP Gs/metabolismo , Isoproterenol/metabolismo , Receptores Adrenérgicos beta 1/química , Receptores Adrenérgicos beta 1/metabolismo , Animales , Sitios de Unión , Bovinos , Línea Celular , Guanosina Difosfato/metabolismo , Guanosina Trifosfato/metabolismo , Modelos Moleculares , Unión Proteica , Dominios Proteicos , Estructura Secundaria de ProteínaRESUMEN
Diet-induced obesity can be caused by impaired thermogenesis of beige adipocytes, the brown-like adipocytes in white adipose tissue (WAT). Promoting brown-like features in WAT has been an attractive therapeutic approach for obesity. However, the mechanism underlying beige adipocyte formation is largely unknown. N-α-acetyltransferase 10 protein (Naa10p) catalyzes N-α-acetylation of nascent proteins, and overexpression of human Naa10p is linked to cancer development. Here, we report that both conventional and adipose-specific Naa10p deletions in mice result in increased energy expenditure, thermogenesis, and beige adipocyte differentiation. Mechanistically, Naa10p acetylates the N terminus of Pgc1α, which prevents Pgc1α from interacting with Pparγ to activate key genes, such as Ucp1, involved in beige adipocyte function. Consistently, fat tissues of obese human individuals show higher NAA10 expression. Thus, Naa10p-mediated N-terminal acetylation of Pgc1α downregulates thermogenic gene expression, making inhibition of Naa10p enzymatic activity a potential strategy for treating obesity.
Asunto(s)
Adipocitos Beige/enzimología , Tejido Adiposo Beige/enzimología , Acetiltransferasa A N-Terminal/metabolismo , Acetiltransferasa E N-Terminal/metabolismo , Obesidad/enzimología , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Procesamiento Proteico-Postraduccional , Termogénesis , Acetilación , Tejido Adiposo Beige/fisiopatología , Adiposidad , Adolescente , Adulto , Anciano , Animales , Estudios de Casos y Controles , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Metabolismo Energético , Femenino , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Acetiltransferasa A N-Terminal/deficiencia , Acetiltransferasa A N-Terminal/genética , Acetiltransferasa E N-Terminal/deficiencia , Acetiltransferasa E N-Terminal/genética , Células 3T3 NIH , Obesidad/genética , Obesidad/fisiopatología , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Fenotipo , Transducción de Señal , Adulto JovenRESUMEN
Acetylation of histone and nonhistone proteins is an important posttranslational modification affecting many cellular processes. Here, we report that NuA4 acetylation of Sip2, a regulatory ß subunit of the Snf1 complex (yeast AMP-activated protein kinase), decreases as cells age. Sip2 acetylation, controlled by antagonizing NuA4 acetyltransferase and Rpd3 deacetylase, enhances interaction with Snf1, the catalytic subunit of Snf1 complex. Sip2-Snf1 interaction inhibits Snf1 activity, thus decreasing phosphorylation of a downstream target, Sch9 (homolog of Akt/S6K), and ultimately leading to slower growth but extended replicative life span. Sip2 acetylation mimetics are more resistant to oxidative stress. We further demonstrate that the anti-aging effect of Sip2 acetylation is independent of extrinsic nutrient availability and TORC1 activity. We propose a protein acetylation-phosphorylation cascade that regulates Sch9 activity, controls intrinsic aging, and extends replicative life span in yeast.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/citología , Saccharomyces cerevisiae/fisiología , Transactivadores/metabolismo , Acetilación , Restricción Calórica , División Celular , Histona Acetiltransferasas/metabolismo , Histona Desacetilasas/metabolismo , Proteínas Quinasas/metabolismo , Saccharomyces cerevisiae/enzimología , Factores de Transcripción/metabolismoRESUMEN
Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D)1,2; however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells3. At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes-NKX6-3 and ANK1-in different tissues4-6. Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways.
Asunto(s)
Pueblo Asiatico/genética , Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad , Aldehído Deshidrogenasa Mitocondrial/genética , Alelos , Ancirinas/genética , Índice de Masa Corporal , Estudios de Casos y Controles , Europa (Continente)/etnología , Proteínas del Ojo/genética , Asia Oriental/etnología , Femenino , Estudio de Asociación del Genoma Completo , Proteínas de Homeodominio/genética , Humanos , Masculino , Proteínas del Tejido Nervioso/genética , ARN Mensajero/análisis , Factores de Transcripción/genética , Transcripción Genética , Proteína Homeobox SIX3RESUMEN
Nuclear deubiquitinase BAP1 (BRCA1-associated protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor whose germline loss-of-function variants predispose to cancer. To our knowledge, there are very rare examples of different germline variants in the same gene causing either a neurodevelopmental disorder (NDD) or a tumor predisposition syndrome. Here, we report a series of 11 de novo germline heterozygous missense BAP1 variants associated with a rare syndromic NDD. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired. In matching peripheral blood mononuclear cells, histone H3 K27 acetylation ChIP-seq indicated that these BAP1 variants induced genome-wide chromatin state alterations, with enrichment for regulatory regions surrounding genes of the ubiquitin-proteasome system (UPS). Altogether, these results define a clinical syndrome caused by rare germline missense BAP1 variants that alter chromatin remodeling through abnormal histone ubiquitination and lead to transcriptional dysregulation of developmental genes.
Asunto(s)
Proteína BRCA1/genética , Mutación de Línea Germinal , Mutación con Pérdida de Función , Mutación Missense , Trastornos del Neurodesarrollo/genética , Proteínas Supresoras de Tumor/genética , Ubiquitina Tiolesterasa/genética , Adolescente , Proteína BRCA1/inmunología , Niño , Preescolar , Cromatina/química , Cromatina/inmunología , Ensamble y Desensamble de Cromatina/genética , Ensamble y Desensamble de Cromatina/inmunología , Familia , Femenino , Regulación de la Expresión Génica , Heterocigoto , Histonas/genética , Histonas/inmunología , Factor C1 de la Célula Huésped/genética , Factor C1 de la Célula Huésped/inmunología , Humanos , Lactante , Masculino , Trastornos del Neurodesarrollo/inmunología , Trastornos del Neurodesarrollo/patología , Complejo de la Endopetidasa Proteasomal/genética , Complejo de la Endopetidasa Proteasomal/inmunología , Linfocitos T/inmunología , Linfocitos T/patología , Proteínas Supresoras de Tumor/deficiencia , Proteínas Supresoras de Tumor/inmunología , Ubiquitina/genética , Ubiquitina/inmunología , Ubiquitina Tiolesterasa/deficiencia , Ubiquitina Tiolesterasa/inmunología , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/inmunología , UbiquitinaciónRESUMEN
This study aims to understand the impact of early antiretroviral therapy (ART) on HIV-specific T-cell responses measured after treatment interruption may inform strategies to deliver ART-free immune-mediated viral suppression. HIV-specific T-cell immunity was analysed using gamma interferon enzyme-linked immunospot assays in two studies. SPARTAC included individuals with primary HIV infection randomised to 48 weeks of ART (n = 24) or no immediate therapy (n = 37). The PITCH (n = 7) cohort started antiretroviral therapy in primary infection for at least one year, followed by TI. In SPARTAC, participants treated in PHI for 48 weeks followed by TI for 12 weeks, and those who remained untreated for 60 weeks made similar HIV Gag-directed responses (both magnitude and breadth) at week 60. However, the treated group made a greater proportion of novel HIV Gag-directed responses by Week 60, suggestive of a greater reserve to produce new potentially protective responses. In the more intensively followed PITCH study, 6/7 participants showed dominant Gag and/or Pol-specific responses post-TI compared with pre-TI. Although early ART in PHI was not associated with major differences in HIV-specific immunity following TI compared with untreated participants, the potential to make more new Gag-directed responses warrants further investigation as this may inform strategies to achieve ART-free control.
RESUMEN
BACKGROUND: Polygenic risk scores (PRS) derived from European individuals have reduced portability across global populations, limiting their clinical implementation at worldwide scale. Here, we investigate the performance of a wide range of PRS models across four ancestry groups (Africans, Europeans, East Asians, and South Asians) for 14 conditions of high-medical interest. METHODS: To select the best-performing model per trait, we first compared PRS performances for publicly available scores, and constructed new models using different methods (LDpred2, PRS-CSx and SNPnet). We used 285 K European individuals from the UK Biobank (UKBB) for training and 18 K, including diverse ancestries, for testing. We then evaluated PRS portability for the best models in Europeans and compared their accuracies with respect to the best PRS per ancestry. Finally, we validated the selected PRS models using an independent set of 8,417 individuals from Biobank of the Americas-Genomelink (BbofA-GL); and performed a PRS-Phewas. RESULTS: We confirmed a decay in PRS performances relative to Europeans when the evaluation was conducted using the best-PRS model for Europeans (51.3% for South Asians, 46.6% for East Asians and 39.4% for Africans). We observed an improvement in the PRS performances when specifically selecting ancestry specific PRS models (phenotype variance increase: 1.62 for Africans, 1.40 for South Asians and 0.96 for East Asians). Additionally, when we selected the optimal model conditional on ancestry for CAD, HDL-C and LDL-C, hypertension, hypothyroidism and T2D, PRS performance for studied populations was more comparable to what was observed in Europeans. Finally, we were able to independently validate tested models for Europeans, and conducted a PRS-Phewas, identifying cross-trait interplay between cardiometabolic conditions, and between immune-mediated components. CONCLUSION: Our work comprehensively evaluated PRS accuracy across a wide range of phenotypes, reducing the uncertainty with respect to which PRS model to choose and in which ancestry group. This evaluation has let us identify specific conditions where implementing risk-prioritization strategies could have practical utility across diverse ancestral groups, contributing to democratizing the implementation of PRS.
Asunto(s)
Predisposición Genética a la Enfermedad , Herencia Multifactorial , Humanos , Herencia Multifactorial/genética , Población Blanca/genética , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Pueblo Asiatico/genética , Femenino , Modelos Genéticos , Puntuación de Riesgo GenéticoRESUMEN
In this Article, the top label in Fig. 5d should read 'DISH 3/16' instead of 'DISH 3/17'. This error has been corrected online.
RESUMEN
GABAA receptors containing the α6 subunit are highly expressed in cerebellar granule cells and less abundantly in many other neuronal and peripheral tissues. Here, we for the first time summarize their importance for the functions of the cerebellum and the nervous system. The cerebellum is not only involved in motor control but also in cognitive, emotional, and social behaviors. α6ßγ2 GABAA receptors located at cerebellar Golgi cell/granule cell synapses enhance the precision of inputs required for cerebellar timing of motor activity and are thus involved in cognitive processing and adequate responses to our environment. Extrasynaptic α6ßδ GABAA receptors regulate the amount of information entering the cerebellum by their tonic inhibition of granule cells, and their optimal functioning enhances input filtering or contrast. The complex roles of the cerebellum in multiple brain functions can be compromised by genetic or neurodevelopmental causes that lead to a hypofunction of cerebellar α6-containing GABAA receptors. Animal models mimicking neuropsychiatric phenotypes suggest that compounds selectively activating or positively modulating cerebellar α6-containing GABAA receptors can alleviate essential tremor and motor disturbances in Angelman and Down syndrome as well as impaired prepulse inhibition in neuropsychiatric disorders and reduce migraine and trigeminal-related pain via α6-containing GABAA receptors in trigeminal ganglia. Genetic studies in humans suggest an association of the human GABAA receptor α6 subunit gene with stress-associated disorders. Animal studies support this conclusion. Neuroimaging and post-mortem studies in humans further support an involvement of α6-containing GABAA receptors in various neuropsychiatric disorders, pointing to a broad therapeutic potential of drugs modulating α6-containing GABAA receptors. SIGNIFICANCE STATEMENT: α6-Containing GABAA receptors are abundantly expressed in cerebellar granule cells, but their pathophysiological roles are widely unknown, and they are thus out of the mainstream of GABAA receptor research. Anatomical and electrophysiological evidence indicates that these receptors have a crucial function in neuronal circuits of the cerebellum and the nervous system, and experimental, genetic, post-mortem, and pharmacological studies indicate that selective modulation of these receptors offers therapeutic prospects for a variety of neuropsychiatric disorders and for stress and its consequences.
Asunto(s)
Cerebelo , Receptores de GABA-A , Animales , Cerebelo/metabolismo , Humanos , Neuronas/metabolismo , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Ácido gamma-AminobutíricoRESUMEN
Several life-prolonging therapies for metastatic castration-resistant prostate cancer (mCRPC) are available, including radium-223 dichloride (223Ra), which was approved based on phase 3 data demonstrating improved overall survival (OS) and a favorable safety profile. To date, real-world evidence for 223Ra use in Taiwan is from three studies of <50 patients. This observational study (NCT04232761) enrolled male patients with histologically/cytologically confirmed mCRPC with bone metastases from centers across Taiwan. 223Ra was prescribed as part of routine practice by investigators. Patients with prior 223Ra treatment were excluded. The primary objective was to assess 223Ra safety; secondary objectives evaluated efficacy parameters, including OS. Overall, 224 patients were enrolled. Most patients had an Eastern Cooperative Oncology Group performance status of 0/1 (79.0%) and ≤20 bone metastases (69.2%); no patients had visceral metastases. 223Ra was first- or second-line therapy in 23.2% and 47.7% of patients, respectively. The total proportion of patients who received 5-6 223Ra cycles was 68.8%; this proportion was greater with first-line use (84.3%) than second- (65.7%) or third-/fourth-line use (64.1%). More chemotherapy-naïve patients (61.9%) completed the 6-cycle 223Ra treatment than chemotherapy-exposed patients (56.7%). Any-grade treatment-emergent adverse events (TEAEs) and serious TEAEs occurred in 54.0% and 28.6% of patients, respectively, while 12% experienced 223Ra-related adverse events. Median OS was 15.7 months (95% confidence interval 12.13-19.51); patients receiving 5-6 223Ra injections and earlier 223Ra use had longer OS than those receiving fewer injections and later 223Ra use. 223Ra provides a well-tolerated and effective treatment for Taiwanese patients with mCRPC and bone metastases.
Asunto(s)
Neoplasias Óseas , Neoplasias de la Próstata Resistentes a la Castración , Radio (Elemento) , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/radioterapia , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Radio (Elemento)/uso terapéutico , Radio (Elemento)/efectos adversos , Anciano , Neoplasias Óseas/secundario , Neoplasias Óseas/radioterapia , Estudios Prospectivos , Persona de Mediana Edad , Anciano de 80 o más Años , Taiwán/epidemiología , Resultado del Tratamiento , Radioisótopos/uso terapéutico , Radioisótopos/efectos adversosRESUMEN
An increased neutrophil-to-lymphocyte ratio (NLR) is a poor prognostic biomarker in various types of cancer, because it reflects the inhibition of lymphocytes in the circulation and tumors. In urologic cancers, upper tract urothelial carcinoma (UTUC) is known for its aggressive features and lack of T cell infiltration; however, the association between neutrophils and suppressed T lymphocytes in UTUC is largely unknown. In this study, we examined the relationship between UTUC-derived factors and tumor-associated neutrophils or T lymphocytes. The culture supernatant from UTUC tumor tissue modulated neutrophils to inhibit T cell proliferation. Among the dominant factors secreted by UTUC tumor tissue, apolipoprotein A1 (Apo-A1) exhibited a positive correlation with NLR. Moreover, tumor-infiltrating neutrophils were inversely correlated with tumor-infiltrating T cells. Elevated Apo-A1 levels in UTUC were also inversely associated with the population of tumor-infiltrating T cells. Our findings indicate that elevated Apo-A1 expression in UTUC correlates with tumor-associated neutrophils and T cells. This suggests a potential immunomodulatory effect on neutrophils and T cells within the tumor microenvironment, which may represent therapeutic targets for UTUC treatment.
RESUMEN
Metabolic reprogramming is recognized as a hallmark of cancer, enabling cancer cells to acquire essential biomolecules for cell growth, often characterized by upregulated glycolysis and/or fatty acid synthesis-related genes. The transcription factor forkhead box M1 (FOXM1) has been implicated in various cancers, contributing significantly to their development, including colorectal cancer (CRC), a major global health concern. Despite FOXM1's established role in cancer, its specific involvement in the Warburg effect and fatty acid biosynthesis in CRC remains unclear. We analyzed The Cancer Genome Atlas (TCGA) Colonic Adenocarcinoma and Rectal Adenocarcinoma (COADREAD) datasets to derive the correlation of the expression levels between FOXM1 and multiple genes and the survival prognosis based on FOXM1 expression. Using two human CRC cell lines, HT29 and HCT116, we conducted RNAi or plasmid transfection procedures, followed by a series of assays, including RNA extraction, quantitative real-time polymerase chain reaction, Western blot analysis, cell metabolic assay, glucose uptake assay, Oil Red O staining, cell viability assay, and immunofluorescence analysis. Higher expression levels of FOXM1 correlated with a poorer survival prognosis, and the expression of FOXM1 was positively correlated with glycolysis-related genes SLC2A1 and LDHA, de novo lipogenesis-related genes ACACA and FASN, and MYC. FOXM1 appeared to modulate AKT/mammalian target of rapamycin (mTOR) signaling, the expression of c-Myc, proteins related to glycolysis and fatty acid biosynthesis, and glucose uptake, as well as extracellular acidification rate in HT29 and HCT116 cells. In summary, FOXM1 plays a regulatory role in glycolysis, fatty acid biosynthesis, and cellular energy consumption, thereby influencing CRC cell growth and patient prognosis.NEW & NOTEWORTHY Transcription factor forkhead box M1 (FOXM1) regulates glycolysis, fatty acid biosynthesis, and cellular energy consumption, which, together, controls cell growth and patient prognosis in colorectal cancer (CRC).
Asunto(s)
Neoplasias Colorrectales , Proteína Forkhead Box M1 , Humanos , Proteína Forkhead Box M1/metabolismo , Proteína Forkhead Box M1/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Células HT29 , Células HCT116 , Glucólisis , Regulación Neoplásica de la Expresión Génica , Efecto Warburg en Oncología , Transducción de Señal , Proliferación Celular , Reprogramación Celular/fisiología , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Reprogramación MetabólicaRESUMEN
Menopause-associated mood disorder is characterized by emotional depression, anxiety, and stress, which accompany hypogonadism in women in the menopausal phase. The current treatment for menopause-associated mood disorder provides only symptomatic relief and is associated with many side effects. Supplementation with vitamin E has been shown to be effective in ameliorating anxiety and depression. However, the effects of vitamin E and its underlying mechanism in ameliorating menopause-associated mood disorders remain uncertain. This work evaluated the effects of α-tocopherol and tocotrienol-rich palm oil extract on depressive and anxiety-related phenotypes induced by estrogen deficiency through ovariectomy in mice. Our study revealed that ovariectomized mice exhibited alterations in behavior indicative of depressive- and anxiety-like behaviors. The serum corticosterone level, a glucocorticoid hormone associated with stress, was found to be elevated in ovariectomized mice as compared to the sham group. Oral administration of α-tocopherol (50 and 100 mg/kg) and tocotrienol-rich palm oil extract (100 and 200 mg/kg) for 14 days alleviated these behavioral changes, as observed in open field, social interaction, and tail suspension tests. However, treatment with tocotrienol-rich palm oil extract, but not α-tocopherol, modulated the depressive- and anxiety-like responses in ovariectomized mice subjected to chronic restraint stress. Both treatments suppressed the elevated serum corticosterone level. Our findings suggested that α-tocopherol and tocotrienol-rich palm oil extract alleviated menopause-associated mood disorder, at least in part, by modulating the hypothalamic-pituitary-adrenal (HPA) axis. The findings of this study can provide a new foundation for the treatment of menopause-associated depressive- and anxiety-like phenotypes, for the betterment of psychological wellbeing.
RESUMEN
PURPOSE OF REVIEW: There are numerous sarcoma subtypes and vary widely in terms of epidemiology, clinical characteristics, genetic profiles, and pathophysiology. They also differ widely between ethnic groups. This review focuses on the different incidence rates of sarcomas in different regions and the potential explanations for these disparities. RECENT FINDINGS: In an intercontinental study using national cancer registry databases from France and Taiwan, the French population had a higher risk of liposarcomas, leiomyosarcomas, and synovial sarcomas, whereas the Taiwanese population had a higher incidence of angiosarcomas and malignant peripheral nerve sheath tumors. The anatomical distribution of these sarcomas also varied between these two regions. In France, most angiosarcoma cases occurred in the extremities and trunk, whereas in Taiwan, angiosarcoma cases in the abdomen and pelvis were more common. Another international study showed that in addition to the common known TP53 and NF1 germline mutations, genes involved in centromere and telomere maintenance were also involved in sarcomagenesis. We reviewed factors related to genetics, environmental effects, chemical exposure, and radiation exposure that could explain the differences in sarcoma incidence among different geographical or ethnic regions. SUMMARY: Our understanding of the potential cause of sarcomas with different subtypes is limited. Establishing a comprehensive global database for patients with sarcomas from all ethnic groups is essential to deepen our understanding of the potential risk factors and the pathophysiology of all sarcoma subtypes.
Asunto(s)
Sarcoma , Humanos , Salud Global , Incidencia , Sarcoma/epidemiología , Sarcoma/genética , Sarcoma/patología , Taiwán/epidemiología , Francia/epidemiologíaRESUMEN
To overcome the low efficiency of overall water splitting, highly effective and stable catalysts are in urgent need, especially for the anode oxygen evolution reaction (OER). In this case, nickel selenides appear as good candidates to catalyze OER and other substitutable anodic reactions due to their high electronic conductivity and easily tunable electronic structure to meet the optimized adsorption ability. Herein, an interesting phase transition from the hexagonal phase of NiSe (H-NiSe) to the rhombohedral phase of NiSe (R-NiSe) induced by the doping of cobalt atoms is reported. The five-coordinated R-NiSe is found to grow adjacent to the six-coordinated H-NiSe, resulting in the formation of the H-NiSe/R-NiSe heterostructure. Further characterizations and calculations prove the reduced splitting energy for R-NiSe and thus the less occupancy in the t2g orbits, which can facilitate the electron transfer process. As a result, the Co2 -NiSe/NF shows a satisfying catalytic performance toward OER, hydrogen evolution reaction, and (hybrid) overall water splitting. This work proves that trace amounts of Co doping can induce the phase transition from H-NiSe to R-NiSe. The formation of less-coordinated species can reduce the t2g occupancy and thus enhance the catalytic performance, which might guide rational material design.
RESUMEN
This work pioneers to combine fast self-assembly of polyhedral oligomeric silsesquioxanes (POSS) nanocage-based giant surfactants with high etching contrast and directed self-assembly for reliable long-range lateral order to create well-aligned sub-10 nm line nanopatterns via reactive ion etching (RIE). Polystyrene-block-oligo(dimethylsiloxane) substituted POSS (PS-b-oDMS7POSS) with seven oligo(dimethylsiloxane) at the corners of the POSS nanocage and one polystyrene (PS) tail is designed and synthesized as a giant surfactant with self-assembly behaviors like block copolymer (BCP). In contrast to BCP, oDMS7POSS gives a volume-persistent "nanoatom" particle with higher mobility for fast self-assembly and higher segregation strength with PS for smaller feature size. By taking advantage of directed self-assembly using nano-trench fabricated by electron beam lithography, well-ordered nanostructured monolayer with well-aligned parallel oDMS7POSS cylinders can be formed by confined self-assembly within the nano-trench. With the optimization of the RIE treatment using O2 as an etchant, the high etching contrast from the oDMS7POSS and PS gives the formation of well-defined line nanopatterns with sub-10 nm critical dimension that can serve as a mask for pattern transfer in lithography. These results demonstrate a cost-effective approach for nanopatterning by utilizing a creatively designed giant surfactant with sub-10 nm feature size and excellent etching contrast for modern lithographic applications.