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1.
Cancers (Basel) ; 16(9)2024 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-38730619

RESUMEN

Pediatric T-cell Acute Lymphoblastic Leukemia (T-ALL) relapses are still associated with a dismal outcome, justifying the search for new therapeutic targets and relapse biomarkers. Using single-cell RNA sequencing (scRNAseq) data from three paired samples of pediatric T-ALL at diagnosis and relapse, we first conducted a high-dimensional weighted gene co-expression network analysis (hdWGCNA). This analysis highlighted several gene co-expression networks (GCNs) and identified relapse-associated hub genes, which are considered potential driver genes. Shared relapse-expressed genes were found to be related to antigen presentation (HLA, B2M), cytoskeleton remodeling (TUBB, TUBA1B), translation (ribosomal proteins, EIF1, EEF1B2), immune responses (MIF, EMP3), stress responses (UBC, HSP90AB1/AA1), metabolism (FTH1, NME1/2, ARCL4C), and transcriptional remodeling (NF-κB family genes, FOS-JUN, KLF2, or KLF6). We then utilized sparse partial least squares discriminant analysis to select from a pool of 481 unique leukemic hub genes, which are the genes most discriminant between diagnosis and relapse states (comprising 44, 35, and 31 genes, respectively, for each patient). Applying a Cox regression method to these patient-specific genes, along with transcriptomic and clinical data from the TARGET-ALL AALL0434 cohort, we generated three model gene signatures that efficiently identified relapsed patients within the cohort. Overall, our approach identified new potential relapse-associated genes and proposed three model gene signatures associated with lower survival rates for high-score patients.

2.
Oncogene ; 43(11): 804-820, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38279062

RESUMEN

HJURP is overexpressed in several cancer types and strongly correlates with patient survival. However, the mechanistic basis underlying the association of HJURP with cancer aggressiveness is not well understood. HJURP promotes the loading of the histone H3 variant, CENP-A, at the centromeric chromatin, epigenetically defining the centromeres and supporting proper chromosome segregation. In addition, HJURP is associated with DNA repair but its function in this process is still scarcely explored. Here, we demonstrate that HJURP is recruited to DSBs through a mechanism requiring chromatin PARylation and promotes epigenetic alterations that favor the execution of DNA repair. Incorporation of HJURP at DSBs promotes turnover of H3K9me3 and HP1, facilitating DNA damage signaling and DSB repair. Moreover, HJURP overexpression in glioma cell lines also affected global structure of heterochromatin independently of DNA damage induction, promoting genome-wide reorganization and assisting DNA damage response. HJURP overexpression therefore extensively alters DNA damage signaling and DSB repair, and also increases radioresistance of glioma cells. Importantly, HJURP expression levels in tumors are also associated with poor response of patients to radiation. Thus, our results enlarge the understanding of HJURP involvement in DNA repair and highlight it as a promising target for the development of adjuvant therapies that sensitize tumor cells to irradiation.


Asunto(s)
Cromatina , Glioma , Humanos , Centrómero/metabolismo , Proteína A Centromérica/genética , Proteína A Centromérica/metabolismo , Cromatina/genética , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Reparación del ADN/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Glioma/genética
3.
Int J Infect Dis ; 139: 59-68, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38029834

RESUMEN

OBJECTIVE: The invasion of dengue virus (DENV)-2 Cosmopolitan genotype into the Philippines, where the Asian II genotype previously circulated challenges the principle of dengue serotype-specific immunity. Assessment of antibodies in this population may provide a mechanistic basis for how new genotypes emerge in dengue-endemic areas. METHODS: We evaluated the neutralizing antibody (nAb) and antibody-dependent enhancement (ADE) responses against the two genotypes using archived serum samples collected from 333 patients with confirmed dengue in Metro Manila, Philippines, before, during, and after the introduction of the Cosmopolitan genotype. We quantified nAb titers in baby hamster kidney (BHK-21) cells with or without the Fcγ receptor IIA (FcγRIIA) to detect the capacity of virus-antibody complexes to neutralize or enhance DENV. RESULTS: The nAb potency of the archived serum samples against the two genotypes was greatly affected by the presence of FcγRIIA. We found significant differences in nAb titers between the two genotypes in BHK-21 cells with FcγRIIA (P <0.0001). The archived serum samples were incapable of fully neutralizing the Cosmopolitan genotype, but instead strongly promoted its ADE compared to the Asian II genotype (P <0.0001). CONCLUSION: These results reinforce the role of pre-existing immunity in driving genotype shifts. Our finding that specific genotypes exhibit differing susceptibilities to ADE by cross-reactive antibodies may have implications for dengue vaccine development.


Asunto(s)
Virus del Dengue , Dengue , Animales , Cricetinae , Humanos , Anticuerpos Antivirales , Serogrupo , Filipinas , Estudios Retrospectivos , Anticuerpos Neutralizantes , Genotipo
4.
Front Immunol ; 14: 1130933, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37063913

RESUMEN

The initiation of type 2 immune responses at mucosal barriers is regulated by rapidly secreted cytokines called alarmins. The alarmins IL-33, IL-25 and TSLP are mainly secreted by stromal and epithelial cells in tissues and were linked to chronic inflammatory diseases, such as allergic lung inflammation, or to resistance against worm infections. Receptors for alarmins are expressed by a variety of immune cells, including group 2 innate lymphoid cells (ILC2s), an early source of the type 2 cytokines, such as IL-5 and IL-13, which have been linked to atopic diseases and anti-worm immunity as well. However, the precise contribution of the IL-33 receptor signals for ILC2 activation still needs to be completed due to limitations in targeting genes in ILC2. Using the newly established Nmur1 iCre-eGFP mouse model, we obtained specific conditional genetic ablation of the IL-33 receptor subunit ST2 in ILC2s. ST2-deficient ILC2s were unresponsive to IL-33 but not to stimulation with the alarmin IL-25. As a result of defective ST2 signals, ILC2s produced limited amounts of IL-5 and IL-13 and failed to support eosinophil homeostasis. Further, ST2-deficient ILC2s were unable to expand and promote the recruitment of eosinophils during allergic lung inflammation provoked by papain administration. During infection with Nippostrongylus brasiliensis, ILC2-intrinsic ST2 signals were required to mount an effective type 2 immune response against the parasite leading to higher susceptibility against worm infection in conditional knockout mice. Therefore, this study argues for a non-redundant role of cell-intrinsic ST2 signals triggering proper activation of ILC2 for initiation of type 2 immunity.


Asunto(s)
Proteína 1 Similar al Receptor de Interleucina-1 , Eosinofilia Pulmonar , Infecciones por Strongylida , Animales , Ratones , Alarminas , Citocinas/inmunología , Inmunidad Innata , Proteína 1 Similar al Receptor de Interleucina-1/inmunología , Interleucina-13 , Interleucina-33 , Interleucina-5 , Linfocitos , Eosinofilia Pulmonar/inmunología , Nippostrongylus , Infecciones por Strongylida/inmunología
5.
Nature ; 611(7937): 794-800, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36323785

RESUMEN

Protective immunity relies on the interplay of innate and adaptive immune cells with complementary and redundant functions. Innate lymphoid cells (ILCs) have recently emerged as tissue-resident, innate mirror images of the T cell system, with which they share lineage-specifying transcription factors and effector machinery1. Located at barrier surfaces, ILCs are among the first responders against invading pathogens and thus could potentially determine the outcome of the immune response2. However, so far it has not been possible to dissect the unique contributions of ILCs to protective immunity owing to limitations in specific targeting of ILC subsets. Thus, all of the available data have been generated either in mice lacking the adaptive immune system or with tools that also affect other immune cell subsets. In addition, it has been proposed that ILCs might be dispensable for a proper immune response because other immune cells could compensate for their absence3-7. Here we report the generation of a mouse model based on the neuromedin U receptor 1 (Nmur1) promoter as a driver for simultaneous expression of Cre recombinase and green fluorescent protein, which enables gene targeting in group 2 ILCs (ILC2s) without affecting other innate and adaptive immune cells. Using Cre-mediated gene deletion of Id2 and Gata3 in Nmur1-expressing cells, we generated mice with a selective and specific deficiency in ILC2s. ILC2-deficient mice have decreased eosinophil counts at steady state and are unable to recruit eosinophils to the airways in models of allergic asthma. Further, ILC2-deficient mice do not mount an appropriate immune and epithelial type 2 response, resulting in a profound defect in worm expulsion and a non-protective type 3 immune response. In total, our data establish non-redundant functions for ILC2s in the presence of adaptive immune cells at steady state and during disease and argue for a multilayered organization of the immune system on the basis of a spatiotemporal division of labour.


Asunto(s)
Sistema Inmunológico , Inmunidad Innata , Linfocitos , Animales , Ratones , Asma/genética , Asma/inmunología , Asma/patología , Modelos Animales de Enfermedad , Eosinófilos/patología , Inmunidad Innata/inmunología , Linfocitos/clasificación , Linfocitos/inmunología , Proteínas Fluorescentes Verdes , Sistema Inmunológico/citología , Sistema Inmunológico/inmunología , Sistema Inmunológico/patología
6.
Int J Mol Sci ; 23(18)2022 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-36142200

RESUMEN

Viral infections have always been a serious burden to public health, increasing morbidity and mortality rates worldwide. Zika virus (ZIKV) is a flavivirus transmitted by the Aedes aegypti vector and the causative agent of severe fetal neuropathogenesis and microcephaly. The virus crosses the placenta and reaches the fetal brain, mainly causing the death of neuronal precursor cells (NPCs), glial inflammation, and subsequent tissue damage. Genetic differences, mainly related to the antiviral immune response and cell death pathways greatly influence the susceptibility to infection. These components are modulated by many factors, including microRNAs (miRNAs). MiRNAs are small noncoding RNAs that regulate post-transcriptionally the overall gene expression, including genes for the neurodevelopment and the formation of neural circuits. In this context, we investigated the pathways and target genes of miRNAs modulated in NPCs infected with ZIKV. We observed downregulation of miR-302b, miR-302c and miR-194, whereas miR-30c was upregulated in ZIKV infected human NPCs in vitro. The analysis of a public dataset of ZIKV-infected human NPCs evidenced 262 upregulated and 3 downregulated genes, of which 142 were the target of the aforementioned miRNAs. Further, we confirmed a correlation between miRNA and target genes affecting pathways related to antiviral immune response, cell death and immune cells chemotaxis, all of which could contribute to the establishment of microcephaly and brain lesions. Here, we suggest that miRNAs target gene expression in infected NPCs, directly contributing to the pathogenesis of fetal microcephaly.


Asunto(s)
MicroARNs , Microcefalia , Malformaciones del Sistema Nervioso , Infección por el Virus Zika , Virus Zika , Animales , Antivirales , Muerte Celular/genética , Quimiotaxis , Femenino , Humanos , Inmunidad , MicroARNs/genética , Microcefalia/genética , Mosquitos Vectores , Embarazo , Virus Zika/fisiología
7.
Pharmeur Bio Sci Notes ; 2022: 32-36, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35702978

RESUMEN

The control of somatropin products according to the monographs of the European Pharmacopoeia (Ph. Eur.) requires a system suitability preparation for the test for related proteins by liquid chromatography. A preparation consisting in a mixture of somatropin and desamidosomatropin, such as the Ph. Eur. Somatropin/desamidosomatropin resolution mixture Chemical Reference Substance (CRS), is to be used to ascertain adequate resolution of the chromatographic setup. Due to low stocks, the Biological Standardisation Programme (BSP) of the Council of Europe and the European Union ran a study to establish a new batch of this system suitability CRS. A freeze-dried candidate batch (cCRS2) was produced and tested at the European Directorate for the Quality of Medicines and HealthCare (EDQM, Council of Europe). The resolution between the peaks due to somatropin and desamidosomatropin was 1.7 and the symmetry factor for the somatropin peak was 1.2. The mean percentage area of the desamidosomatropin peak was 14.6 %. These results showed that cCRS2 is suitable for its intended purpose. Based on these data, in May 2020 the Ph. Eur. Commission established the candidate batch as Ph. Eur. Soma-tropin/desamidosomatropin resolution mixture CRS batch 2.


Asunto(s)
Hormona de Crecimiento Humana , Europa (Continente) , Estándares de Referencia
8.
Mult Scler Relat Disord ; 57: 103321, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-35158439

RESUMEN

We report on nine patients (eight cases of MS and one case of NMOSD) who presented a disease relapse in close temporal association with their first AZD1222 vaccination dose against COVID-19. These patients had been stable for a median period of six years, with no evidence of disease activity and no change in their medication. After a median of 13 days (7 to 25 days) from vaccination, they developed a new relapse with increased disability and new lesions on magnetic resonance imaging. Although this association may be rare, it might be an adverse event of AZD1222.


Asunto(s)
COVID-19 , Esclerosis Múltiple , Neuromielitis Óptica , ChAdOx1 nCoV-19 , Humanos , Recurrencia , SARS-CoV-2 , Vacunación
10.
Mol Biol Evol ; 38(6): 2396-2412, 2021 05 19.
Artículo en Inglés | MEDLINE | ID: mdl-33533884

RESUMEN

The cell cycle is a fundamental process that has been extensively studied in bacteria. However, many of its components and their interactions with machineries involved in other cellular processes are poorly understood. Furthermore, most knowledge relies on the study of a few models, but the real diversity of the cell division apparatus and its evolution are largely unknown. Here, we present a massive in-silico analysis of cell division and associated processes in around 1,000 genomes of the Firmicutes, a major bacterial phylum encompassing models (i.e. Bacillus subtilis, Streptococcus pneumoniae, and Staphylococcus aureus), as well as many important pathogens. We analyzed over 160 proteins by using an original approach combining phylogenetic reconciliation, phylogenetic profiles, and gene cluster survey. Our results reveal the presence of substantial differences among clades and pinpoints a number of evolutionary hotspots. In particular, the emergence of Bacilli coincides with an expansion of the gene repertoires involved in cell wall synthesis and remodeling. We also highlight major genomic rearrangements at the emergence of Streptococcaceae. We establish a functional network in Firmicutes that allows identifying new functional links inside one same process such as between FtsW (peptidoglycan polymerase) and a previously undescribed Penicilin-Binding Protein or between different processes, such as replication and cell wall synthesis. Finally, we identify new candidates involved in sporulation and cell wall synthesis. Our results provide a previously undescribed view on the diversity of the bacterial cell cycle, testable hypotheses for further experimental studies, and a methodological framework for the analysis of any other biological system.


Asunto(s)
Evolución Biológica , División Celular/genética , Firmicutes/genética , Familia de Multigenes , Simulación por Computador , Sintenía
11.
Front Pharmacol ; 12: 511078, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-35126097

RESUMEN

An ethnopharmacological metanalysis was conducted with a large database available on antidiabetic activities of plant foods and medicines from the northern boreal forest, which are traditionally used by the indigenous Cree of James Bay, Quebec, Canada. The objective was to determine which bioassays are closely associated with the traditional knowledge of the Cree and which pharmacological metrics and phytochemical signals best define these plants and their groups. Data from 17 plant species, ethnobotanically ranked by syndromic importance value for treatment of 15 diabetic symptoms, was used along with 49 bioassay endpoints reported across numerous pharmacological studies and a metabolomics dataset. Standardized activities were separated into primary, secondary and safety categories and summed to produce a Pharmacological Importance Value (PIV) in each of the three categories for each species. To address the question of which pharmacological metrics and phytochemical signals best define the CEI anti-diabetes plants, multivariate analyses were undertaken to determine groupings of plant families and plant parts. The analysis identified Larix larcina as the highest PIV species in primary assays, Salix planifolia in secondary assays, and Kalmia angustifolia in safety assays, as well as a ranking of other less active species by PIV. Multivariate analysis showed that activity in safety PIV monitored mainly with cytochrome P450 inhibition patterns best reflected patterns of traditional medicine importance in Cree traditional knowledge, whereas potent primary bioactivities were seen in individual plants determined to be most important to the Cree for anti-diabetes purposes. In the secondary anti-diabetes assays, pharmacological variability was better described by plant biology, mostly in terms of the plant part used. Key signal in the metabolomics loadings plots for activity were phenolics especially quercetin derivatives. Traditional Indigenous knowledge in this analysis was shown to be able to guide the identification of plant pharmacological qualities in scientific terms.

12.
J Anim Ecol ; 89(12): 2852-2862, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33111342

RESUMEN

Many species show territoriality, in which territory owners have exclusive or priority use of a region. In humans, tolerance of others within our space also depends greatly on our social relationships with them. This has been hypothesized as one potential driver of the evolution of long-term, inter-group relationships, through enabling shared access of resources and easing disputes over space. However, extremely little is known about the importance of social relationships between neighbouring groups in non-humans for how space is used and shared. Using 16 years of data on the simultaneous movement and interaction patterns of 17 mountain gorilla groups, we investigated how the occurrence of aggressive and affiliative behaviour during inter-group encounters was influenced by both their social and spatial context. We found evidence of territorial defence, with rates of aggression increasing towards the centre of home ranges. Groups which had previously split from each other showed higher levels of affiliation during encounters with each other and experienced lower levels of aggression when within the other's peripheral home range. However, encounters within core areas of the home range consistently elicited higher aggression, regardless of the groups' history. Our findings indicate that not only are the social relationships between groups retained after they split from one another but also that these relationships enable groups to access certain areas with a reduced risk of aggression. This suggests that reduced aggression when accessing areas within neighbours' home ranges may be an advantage for the maintenance of inter-group relationships and a potential driver in the evolution of long-term, post-dispersal relationships and complex multi-level societies.


Asunto(s)
Gorilla gorilla , Territorialidad , Agresión , Animales , Fenómenos de Retorno al Lugar Habitual
13.
Nature ; 586(7830): 509-515, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32967005

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the aetiological agent of coronavirus disease 2019 (COVID-19), an emerging respiratory infection caused by the introduction of a novel coronavirus into humans late in 2019 (first detected in Hubei province, China). As of 18 September 2020, SARS-CoV-2 has spread to 215 countries, has infected more than 30 million people and has caused more than 950,000 deaths. As humans do not have pre-existing immunity to SARS-CoV-2, there is an urgent need to develop therapeutic agents and vaccines to mitigate the current pandemic and to prevent the re-emergence of COVID-19. In February 2020, the World Health Organization (WHO) assembled an international panel to develop animal models for COVID-19 to accelerate the testing of vaccines and therapeutic agents. Here we summarize the findings to date and provides relevant information for preclinical testing of vaccine candidates and therapeutic agents for COVID-19.


Asunto(s)
Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/prevención & control , Modelos Animales de Enfermedad , Pandemias/prevención & control , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/prevención & control , Animales , Betacoronavirus/efectos de los fármacos , Betacoronavirus/inmunología , COVID-19 , Vacunas contra la COVID-19 , Infecciones por Coronavirus/inmunología , Hurones/virología , Humanos , Mesocricetus/virología , Ratones , Neumonía Viral/inmunología , Primates/virología , SARS-CoV-2 , Vacunas Virales/inmunología
14.
Sci Rep ; 10(1): 12139, 2020 07 22.
Artículo en Inglés | MEDLINE | ID: mdl-32699233

RESUMEN

A large number of hepatic functions are regulated by the circadian clock and recent evidence suggests that clock disruption could be a risk factor for liver complications. The circadian transcription factor Krüppel like factor 10 (KLF10) has been involved in liver metabolism as well as cellular inflammatory and death pathways. Here, we show that hepatic steatosis and inflammation display diurnal rhythmicity in mice developing steatohepatitis upon feeding with a methionine and choline deficient diet (MCDD). Core clock gene mRNA oscillations remained mostly unaffected but rhythmic Klf10 expression was abolished in this model. We further show that Klf10 deficient mice display enhanced liver injury and fibrosis priming upon MCDD challenge. Silencing Klf10 also sensitized primary hepatocytes to apoptosis along with increased caspase 3 activation in response to TNFα. This data suggests that MCDD induced steatohepatitis barely affects the core clock mechanism but leads to a reprogramming of circadian gene expression in the liver in analogy to what is observed in other experimental disease paradigms. We further identify KLF10 as a component of this transcriptional reprogramming and a novel hepato-protective factor.


Asunto(s)
Biomarcadores/metabolismo , Ritmo Circadiano/genética , Dieta , Factores de Transcripción de la Respuesta de Crecimiento Precoz/genética , Factores de Transcripción de Tipo Kruppel/genética , Enfermedad del Hígado Graso no Alcohólico/etiología , Animales , Apoptosis , Caspasa 3/metabolismo , Células Cultivadas , Colina/química , Dieta/veterinaria , Modelos Animales de Enfermedad , Factores de Transcripción de la Respuesta de Crecimiento Precoz/deficiencia , Fibrosis , Hepatocitos/citología , Hepatocitos/metabolismo , Factores de Transcripción de Tipo Kruppel/deficiencia , Hígado/lesiones , Hígado/metabolismo , Hígado/patología , Masculino , Metionina/química , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/patología , Factor de Necrosis Tumoral alfa/metabolismo
15.
Cytokine ; 133: 155144, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32559663

RESUMEN

INTRODUCTION: Adipose tissue secretes various bioactive peptides/proteins, immune molecules and inflammatory mediators which are known as adipokines or adipocytokines. Adipokines play important roles in the maintenance of energy homeostasis, appetite, glucose and lipid metabolism, insulin sensitivity, angiogenesis, immunity and inflammation. Enormous number of studies from all over the world proved that adipocytokines are involved in the pathogenesis of diseases affecting nearly all body systems, which raises the question whether we can always blame adipocytokines as the triggering factor of every disease that may hit the body. OBJECTIVE: Our review targeted the role played by adipocytokines in the pathogenesis of different diseases affecting different body systems including diabetes mellitus, kidney diseases, gynecological diseases, rheumatologic disorders, cancers, Alzheimer's, depression, muscle disorders, liver diseases, cardiovascular and lung diseases. METHODOLOGY: We cited more than 33 recent literature reviews that discussed the role played by adipocytokines in the pathogenesis of different diseases affecting different body systems. CONCLUSION: More evidence is being discovered to date about the role played by adipocytokines in more diseases and extra research is needed to explore hidden roles played by adipokine imbalance on disease pathogenesis.


Asunto(s)
Adipoquinas/metabolismo , Tejido Adiposo/metabolismo , Animales , Humanos , Inmunidad/fisiología , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo
16.
J Ethnopharmacol ; 257: 112877, 2020 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-32305639

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Psidium guajava L. (Myrtaceae) leaves are used as an herbal antidiabetic remedy in several parts of the world. On Madagascar, both the bark and leaves are used for treatment of diabetes. MATERIALS AND METHODS: Dilution series of ethanolic extracts of P. guajava leaves and bark were used for determining inhibitory activities against yeast α-glucosidase and porcine α-amylase. Skeletal muscle glucose uptake was measured using 2-deoxy-D-(1-3H)-glucose in murine C2C12 skeletal muscle cells. Hepatic glucose-6-phosphatase activity in rat hepatoma H4IIE cells and triglyceride accumulation in murine 3T3-L1 adipocyte-like cells were assessed using Wako AutoKit Glucose assays and AdipoRed reagent, respectively. Cells were incubated for 18 h with the maximal non-toxic concentrations of the plant extracts determined by the lactate dehydrogenase cytotoxicity assay. RESULTS: Ethanolic extracts of P. guajava leaf and bark inhibited α-glucosidase with IC50 values of 1.0 ± 0.3 and 0.5 ± 0.01 µg/mL, respectively. In the α-amylase inhibition assay, the ethanolic extract of bark of P. guajava showed an IC50 value of 10.6 ± 0.4 µg/mL. None of the extracts were able to reduce glucose-6-phosphatase activity in rat hepatoma H4IIE cells. In contrast, P. guajava leaf extract significantly increased 2-deoxy-D-[1-3H]-glucose uptake in C2C12 muscle cells (161.4 ± 10.1%, p = 0.0015) in comparison to the dimethyl sulfoxide (DMSO) vehicle control, as did the reference compounds metformin (144.0 ± 7.7%, p = 0.0345) and insulin (141.5 ± 13.8%, p = 0.0495). Furthermore, P. guajava leaf and bark extracts, as well as the reference compound rosiglitazone, significantly enhanced triglyceride accumulation in 3T3-L1 cells (252.6 ± 14.2%, p < 0.0001, 211.1 ± 12.7%, p < 0.0001, and 201.1 ± 9.2%, p < 0.0001, respectively) to levels higher than the DMSO vehicle control. Moreover, P. guajava leaf extract significantly enhanced the triglyceride accumulation in 3T3-L1 cells compared to rosiglitazone. CONCLUSION: The results demonstrated that P. guajava leaf and bark extracts can be used as a natural source of α-glucosidase inhibitors. In addition, the bark extract of P. guajava was an effective α-amylase inhibitor. Moreover, P. guajava leaf extract improved glucose uptake in muscle cells, while both leaf and bark extracts enhanced the triglyceride content in adipocytes in culture. P. guajava leaf and bark extracts may thus hypothetically have future applications in the treatment of type 2 diabetes.


Asunto(s)
Adipocitos/efectos de los fármacos , Glucosa/metabolismo , Inhibidores de Glicósido Hidrolasas/farmacología , Hígado/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Psidium , Triglicéridos/metabolismo , alfa-Amilasas/antagonistas & inhibidores , Células 3T3-L1 , Adipocitos/enzimología , Animales , Línea Celular Tumoral , Inhibidores de Glicósido Hidrolasas/aislamiento & purificación , Hígado/enzimología , Ratones , Músculo Esquelético/enzimología , Corteza de la Planta , Hojas de la Planta , Psidium/química , Ratas , alfa-Amilasas/metabolismo
17.
Biochim Biophys Acta Mol Basis Dis ; 1866(5): 165705, 2020 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-32001301

RESUMEN

The proteolytic cleavage of Fibronectin type III domain-containing 5 (FNDC5) generates soluble irisin. Initially described as being mainly produced in muscle during physical exercise, irisin mediates adipose tissue thermogenesis and also regulates carbohydrate and lipid metabolism. The aim of this study was to evaluate the hepatic expression of FNDC5 and its role in hepatocytes in Non-Alcoholic Fatty Liver (NAFL). Here we report that hepatic expression of FNDC5 increased with hepatic steatosis and liver injury without impacting the systemic level of irisin in mouse models of NAFLD (HFD and MCDD) and in obese patients. The increased Fndc5 expression in fatty liver resulted from its upregulation in hepatocytes and non-parenchymal cells in mice. The local production of Fndc5 in hepatocytes was influenced by genotoxic stress and p53-dependent pathways. The down-regulation of FNDC5 in human HepG2 cells and in primary mouse hepatocytes increased the expression of PEPCK, a key enzyme involved in gluconeogenesis associated with a decrease in the expression of master genes involved in the VLDL synthesis (CIDEB and APOB). These alterations in FNDC5-silenced cells resulted to increased steatosis and insulin resistance in response to oleic acid and N-acetyl glucosamine, respectively. The downregulation of Fndc5 also sensitized primary hepatocytes to apoptosis in response to TNFα, which has been associated with decreased hepatoprotective autophagic flux. In conclusion, our human and experimental data strongly suggest that the hepatic expression of FNDC5 increased with hepatic steatosis and its upregulation in hepatocytes could dampen the development of NAFLD by negatively regulating steatogenesis and hepatocyte death.


Asunto(s)
Fibronectinas/metabolismo , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico/patología , Obesidad Mórbida/complicaciones , Adulto , Apoptosis , Cirugía Bariátrica , Biopsia , Dieta Alta en Grasa/efectos adversos , Femenino , Fibronectinas/sangre , Fibronectinas/genética , Perfilación de la Expresión Génica , Células Hep G2 , Hepatocitos/metabolismo , Humanos , Resistencia a la Insulina , Lipogénesis , Hígado/citología , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/etiología , Obesidad Mórbida/sangre , Obesidad Mórbida/patología , Obesidad Mórbida/cirugía , Fosfoenolpiruvato Carboxiquinasa (ATP)/metabolismo , Cultivo Primario de Células , Factores Protectores , Regulación hacia Arriba
18.
Behav Neurosci ; 134(1): 45-58, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31904252

RESUMEN

To further assess orbitofrontal cortex (OFC) contribution to the processing of socioemotional signals, spontaneous scanning patterns and pupil diameter variations were measured while adult rhesus macaques with either bilateral lesions of OFC areas 11 and 13 (Group O-asp) or sham-operations (Group C) freely viewed pictures of neutral and expressive faces of conspecifics, of other nonhuman primates and humans, and of objects with and without facial features. As compared to Group C, Group O-asp displayed (a) increased overall spontaneous visual exploration and increased scanning of primate neutral faces regardless of species and face orientation (upright/inverted), (b) longer gazes at the eyes of faces and of objects with facial features, and (c) intact ability to discriminate emotional from neutral faces, but (d) altered scanning patterns at emotional macaque faces coupled with (e) increased pupil dilation for conspecific faces according to face emotion and orientation (profile/stare). Thus, the primate OFC appears essential in the attention to and processing of faces, especially attention to the eyes and arousal self-regulation. (PsycINFO Database Record (c) 2020 APA, all rights reserved).


Asunto(s)
Reconocimiento Facial/fisiología , Reconocimiento Visual de Modelos/fisiología , Corteza Prefrontal/fisiología , Animales , Nivel de Alerta , Atención/fisiología , Emociones/fisiología , Ojo , Movimientos Oculares , Cara , Expresión Facial , Macaca mulatta , Masculino , Corteza Prefrontal/metabolismo
19.
Resusc Plus ; 3: 100021, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34223304

RESUMEN

OBJECTIVES: We evaluated the feasibility of optimising coronary perfusion pressure (CPP) during cardiopulmonary resuscitation (CPR) with a closed-loop, machine-controlled CPR system (MC-CPR) that sends real-time haemodynamic feedback to a set of machine learning and control algorithms which determine compression/decompression characteristics over time. BACKGROUND: American Heart Association CPR guidelines (AHA-CPR) and standard mechanical devices employ a "one-size-fits-all" approach to CPR that fails to adjust compressions over time or individualise therapy, thus leading to deterioration of CPR effectiveness as duration exceeds 15-20 â€‹min. METHODS: CPR was administered for 30 â€‹min in a validated porcine model of cardiac arrest. Intubated anaesthetised pigs were randomly assigned to receive MC-CPR (6), mechanical CPR conducted according to AHA-CPR (6), or human-controlled CPR (HC-CPR) (10). MC-CPR directly controlled the CPR piston's amplitude of compression and decompression to maximise CPP over time. In HC-CPR a physician controlled the piston amplitudes to maximise CPP without any algorithmic feedback, while AHA-CPR had one compression depth without adaptation. RESULTS: MC-CPR significantly improved CPP throughout the 30-min resuscitation period compared to both AHA-CPR and HC-CPR. CPP and carotid blood flow (CBF) remained stable or improved with MC-CPR but deteriorated with AHA-CPR. HC-CPR showed initial but transient improvement that dissipated over time. CONCLUSION: Machine learning implemented in a closed-loop system successfully controlled CPR for 30 â€‹min in our preclinical model. MC-CPR significantly improved CPP and CBF compared to AHA-CPR and ameliorated the temporal haemodynamic deterioration that occurs with standard approaches.

20.
Front Endocrinol (Lausanne) ; 11: 597648, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33384662

RESUMEN

Non-Alcoholic Steatohepatitis (NASH) is the progressive form of Non-Alcoholic Fatty Liver Disease (NAFLD), the main cause of chronic liver complications. The development of NASH is the consequence of aberrant activation of hepatic conventional immune, parenchymal, and endothelial cells in response to inflammatory mediators from the liver, adipose tissue, and gut. Hepatocytes, Kupffer cells and liver sinusoidal endothelial cells contribute to the significant accumulation of bone-marrow derived-macrophages and neutrophils in the liver, a hallmark of NASH. The aberrant activation of these immune cells elicits harmful inflammation and liver injury, leading to NASH progression. In this review, we highlight the processes triggering the recruitment and/or activation of hepatic innate immune cells, with a focus on macrophages, neutrophils, and innate lymphoid cells as well as the contribution of hepatocytes and endothelial cells in driving liver inflammation/fibrosis. On-going studies and preliminary results from global and specific therapeutic strategies to manage this NASH-related inflammation will also be discussed.


Asunto(s)
Inmunidad Innata/inmunología , Mediadores de Inflamación/metabolismo , Inflamación/complicaciones , Enfermedad del Hígado Graso no Alcohólico/patología , Animales , Humanos , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/terapia
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