RESUMEN
Therapeutic advancements in treatments for cancer, a leading cause of mortality worldwide, have lagged behind the increasing incidence of this disease. There is a growing interest in multifaceted approaches for cancer treatment, such as chemotherapy, targeted therapy, and immunotherapy, but due to their low efficacy and severe side effects, there is a need for the development of new cancer therapies. Recently, the human microbiome, which is comprised of various microorganisms, has emerged as an important research field due to its potential impact on cancer treatment. Among these microorganisms, Bifidobacterium infantis has been shown to significantly improve the efficacy of various anticancer drugs. However, research on the role of B. infantis in cancer treatment remains insufficient. Thus, in this study, we explored the anticancer effect of treatment with B. infantis DS1685 supernatant (BI sup) in colorectal and breast cancer cell lines. Treatment with BI sup induced SMAD4 expression to suppress cell growth in colon and breast cancer cells. Furthermore, a decrease in tumor cohesion was observed through the disruption of the regulation of EMT-related genes by BI sup in 3D spheroid models. Based on these findings, we anticipate that BI sup could play an adjunctive role in cancer therapy, and future cotreatment of BI sup with various anticancer drugs may lead to synergistic effects in cancer treatment.
Asunto(s)
Bifidobacterium longum subspecies infantis , Neoplasias de la Mama , Neoplasias Colorrectales , Proteína Smad4 , Factor de Crecimiento Transformador beta , Humanos , Proteína Smad4/metabolismo , Proteína Smad4/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias Colorrectales/microbiología , Neoplasias Colorrectales/patología , Línea Celular Tumoral , Factor de Crecimiento Transformador beta/metabolismo , Bifidobacterium longum subspecies infantis/metabolismo , Bifidobacterium longum subspecies infantis/genética , Femenino , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Probióticos , Antineoplásicos/farmacologíaRESUMEN
The main cause of death in lung cancer patients is metastasis. Thus, efforts to suppress micrometastasis or distant metastasis in lung cancer, identify therapeutic targets and develop related drugs are ongoing. In this study, we identified SET and MYND domain-containing protein 5 (SMYD5) as a novel metastasis regulator in lung cancer and found that SMYD5 was overexpressed in lung cancer based on both RNA-sequencing analysis results derived from the TCGA portal and immunohistochemical analysis results; knockdown of SMYD5 inhibited cell migration and invasion by changing epithelial-mesenchymal transition markers and MMP9 expression in NCI-H1299 and H1703 cell lines. Additionally, SMYD5 knockdown increased Src homology 2-b3 expression by decreasing the level of H4K20 trimethylation. Furthermore, in an in vitro epithelial-mesenchymal transition system using TGF-ß treatment, SMYD5 knockdown resulted in reduced cell migration and invasion in the highly invasive NCI-H1299 and H1703 cell lines. Based on these findings, we propose that SMYD5 could serve as a potential therapeutic target for lung cancer treatment and that cotreatment with an SMYD5 inhibitor and chemotherapy may enhance the therapeutic effect of lung cancer treatment.
Asunto(s)
Movimiento Celular , Transición Epitelial-Mesenquimal , Neoplasias Pulmonares , Humanos , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Invasividad NeoplásicaRESUMEN
Regulation of myeloid cell activity is critical for successful myelin regeneration (remyelination) in demyelinating diseases, such as multiple sclerosis (MS). Here, we show aromatic alpha-keto acids (AKAs) generated from the amino acid oxidase, interleukin-4 induced 1 (IL4I1), promote efficient remyelination in mouse models of MS. During remyelination, myeloid cells upregulated the expression of IL4I1. Conditionally knocking out IL4I1 in myeloid cells impaired remyelination efficiency. Mice lacking IL4I1 expression exhibited a reduction in the AKAs, phenylpyruvate, indole-3-pyruvate, and 4-hydroxyphenylpyruvate, in remyelinating lesions. Decreased AKA levels were also observed in people with MS, particularly in the progressive phase when remyelination is impaired. Oral administration of AKAs modulated myeloid cell-associated inflammation, promoted oligodendrocyte maturation, and enhanced remyelination in mice with focal demyelinated lesions. Transcriptomic analysis revealed AKA treatment induced a shift in metabolic pathways in myeloid cells and upregulated aryl hydrocarbon receptor activity in lesions. Our results suggest myeloid cell-associated aromatic amino acid metabolism via IL4I1 produces AKAs in demyelinated lesions to enable efficient remyelination. Increasing AKA levels or targeting related pathways may serve as a strategy to facilitate the regeneration of myelin in inflammatory demyelinating conditions.
RESUMEN
PURPOSE: Increased portal venous flow pulsatility is associated with major complications after adult cardiac surgery. Nevertheless, no data are available for pediatric patients with congenital heart disease. We hypothesized that Doppler parameters including portal flow pulsatility could be associated with postoperative outcomes in children undergoing various cardiac surgeries. METHODS: We conducted a prospective observational cohort study in children undergoing congenital cardiac surgery. We obtained postoperative portal, splenic, and hepatic venous Doppler data and perioperative clinical data including major postoperative complications. Portal and splenic venous flow pulsatility were calculated. We evaluated the association between venous Doppler parameters and adverse outcomes. The primary objective was to determine whether postoperative portal flow pulsatility could indicate major complications following congenital heart surgery. RESULTS: In this study, we enrolled 389 children, 74 of whom experienced major postoperative complications. The mean (standard deviation) portal pulsatility (44 [30]% vs 25 [14]%; 95% confidence interval [CI] for mean difference, 12 to 26; P < 0.001] and splenic pulsatility indices (41 [30]% vs 26 [16]%; 95% CI, 7 to 23; P < 0.001) were significantly higher in children with postoperative complications than in those without complications. The portal pulsatility index was able to help identify postoperative complications in biventricular patients and univentricular patients receiving bidirectional cavopulmonary shunt whereas it did not in other univentricular patients. An increased postoperative portal pulsatility index was significantly associated with major complications after pediatric cardiac surgery (odds ratio, 1.40; 95% CI, 1.29 to 1.91; P < 0.001). CONCLUSIONS: Higher portal venous pulsatility is associated with major postoperative complications in children undergoing cardiac surgery. Nevertheless, more data are needed to conclude the efficacy of portal venous pulsatility in patients with univentricular physiology. STUDY REGISTRATION: ClinicalTrials.gov (NCT03990779); registered 19 June 2019.
RéSUMé: OBJECTIF: L'augmentation de la pulsatilité du flux de la veine porte est associée à des complications majeures après une chirurgie cardiaque chez l'adulte. Néanmoins, aucune donnée n'est disponible pour la patientèle pédiatrique atteinte de cardiopathie congénitale. Nous avons émis l'hypothèse que les paramètres Doppler, y compris la pulsatilité du flux de la veine porte, pourraient être associés aux devenirs postopératoires des enfants bénéficiant de diverses chirurgies cardiaques. MéTHODE: Nous avons réalisé une étude de cohorte observationnelle prospective portant sur des enfants bénéficiant d'une chirurgie cardiaque congénitale. Nous avons obtenu des données Doppler des veines porte, spléniques et hépatiques postopératoires ainsi que des données cliniques périopératoires, y compris les complications postopératoires majeures. La pulsatilité du flux des veines porte et spléniques a été calculée. Nous avons évalué l'association entre les paramètres Doppler veineux et les issues indésirables. L'objectif principal était de déterminer si la pulsatilité du flux postopératoire de la veine porte pouvait constituer un indicateur des complications majeures après une chirurgie cardiaque congénitale. RéSULTATS: Dans cette étude, nous avons recruté 389 enfants, dont 74 ont présenté des complications postopératoires majeures. La pulsatilité moyenne de la veine porte (écart type) (44 [30] % vs 25 [14] %; intervalle de confiance [IC] à 95 % pour la différence moyenne, 12 à 26; P < 0,001] et les indices de pulsatilité splénique (41 [30] % vs 26 [16] %; IC 95 %, 7 à 23; P < 0,001) étaient significativement plus élevés chez les enfants présentant des complications postopératoires que chez les enfants sans complications. L'indice de pulsatilité de la veine porte a permis d'identifier les complications postopératoires chez les patient·es biventriculaires et les patient·es univentriculaires recevant une anastomose cavo-pulmonaire bidirectionnelle (procédure de Glenn), alors que ce n'était pas le cas chez les autres patient·es univentriculaires. Une augmentation postopératoire de l'indice de pulsatilité de la veine porte était significativement associée à des complications majeures après une chirurgie cardiaque pédiatrique (rapport de cotes, 1,40; IC 95 %, 1,29 à 1,91; P < 0,001). CONCLUSION: Une pulsatilité plus élevée de la veine porte est associée à des complications postopératoires majeures chez les enfants bénéficiant d'une chirurgie cardiaque. Néanmoins, davantage de données sont nécessaires pour conclure à l'efficacité de la pulsatilité de la veine porte chez les patient·es présentant une physiologie univentriculaire. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT03990779); enregistrée le 19 juin 2019.
Asunto(s)
Cardiopatías Congénitas , Vena Porta , Niño , Humanos , Cardiopatías Congénitas/cirugía , Cardiopatías Congénitas/complicaciones , Vena Porta/diagnóstico por imagen , Complicaciones Posoperatorias/etiología , Estudios Prospectivos , Ultrasonografía DopplerRESUMEN
BACKGROUND: Individualised positive end-expiratory pressure (PEEP) improves respiratory mechanics. However, whether PEEP reduces postoperative pulmonary complications (PPCs) remains unclear. We investigated whether driving pressure-guided PEEP reduces PPCs after laparoscopic/robotic abdominal surgery. METHODS: This single-centre, randomised controlled trial enrolled patients at risk for PPCs undergoing laparoscopic or robotic lower abdominal surgery. The individualised group received driving pressure-guided PEEP, whereas the comparator group received 5 cm H2O fixed PEEP during surgery. Both groups received a tidal volume of 8 ml kg-1 ideal body weight. The primary outcome analysed per protocol was a composite of pulmonary complications (defined by pre-specified clinical and radiological criteria) within 7 postoperative days after surgery. RESULTS: Some 384 patients (median age: 67 yr [inter-quartile range: 61-73]; 66 [18%] female) were randomised. Mean (standard deviation) PEEP in patients randomised to individualised PEEP (n=178) was 13.6 cm H2O (2.1). Individualised PEEP resulted in lower mean driving pressures (14.7 cm H2O [2.6]), compared with 185 patients randomised to standard PEEP (18.4 cm H2O [3.2]; mean difference: -3.7 cm H2O [95% confidence interval (CI): -4.3 to -3.1 cm H2O]; P<0.001). There was no difference in the incidence of pulmonary complications between individualised (25/178 [14.0%]) vs standard PEEP (36/185 [19.5%]; risk ratio [95% CI], 0.72 [0.45-1.15]; P=0.215). Pulmonary complications as a result of desaturation were less frequent in patients randomised to individualised PEEP (8/178 [4.5%], compared with standard PEEP (30/185 [16.2%], risk ratio [95% CI], 0.28 [0.13-0.59]; P=0.001). CONCLUSIONS: Driving pressure-guided PEEP did not decrease the incidence of pulmonary complications within 7 days of laparoscopic or robotic lower abdominal surgery, although uncertainty remains given the lower than anticipated event rate for the primary outcome. CLINICAL TRIAL REGISTRATION: KCT0004888 (http://cris.nih.go.kr, registration date: April 6, 2020).
Asunto(s)
Laparoscopía , Procedimientos Quirúrgicos Robotizados , Humanos , Femenino , Anciano , Masculino , Procedimientos Quirúrgicos Robotizados/efectos adversos , Procedimientos Quirúrgicos Robotizados/métodos , Pulmón , Respiración con Presión Positiva/métodos , Laparoscopía/efectos adversos , Laparoscopía/métodos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/etiología , Volumen de Ventilación PulmonarRESUMEN
This study compared the condylar volume, length, and articular eminence (AE) characteristics of normal individuals to those with unilateral and bilateral juvenile idiopathic osteoarthritis (JOA). The 116 patients were divided into four groups: Control (n = 16), affected condyle of unilateral JOA (Aff-Uni) (n = 36), non-affected condyle of JOA (NonAff-uni) (n = 36), and bilateral JOA (Bilateral) (n = 28). The differences in condyle volume and length and AE were analyzed using ANOVA and Bonferroni post-hoc tests. The results showed that Bilateral had a significantly different condylar volume, especially in the condylar head (p < 0.01), specifically the middle, anterior, and medial parts (p < 0.05). Condylar length also differed among the groups, with differences observed between the control group and the other three groups, as well as between the bilateral group and the other three groups (p < 0.01). AE total volume differed between the control group and Aff-Uni. In the detailed comparison, Aff-Uni and NonAff-Uni were smaller than the control group in the posterior, lateral, and medial sections (p < 0.05). In conclusion, depending on the involvement of unilateral or bilateral JOA, there were differences in condylar volume and AE when compared to the normal control group. Therefore, a prognosis should be evaluated by distinguishing between patients with unilateral and bilateral JOA.
RESUMEN
In degenerative cervical myelopathy (DCM), the low anteroposterior compression ratio of the spinal cord is known to be associated with a neurologic deficit. However, there is little detailed analysis of spinal cord compression. Axial magnetic resonance images of 183 DCM patients at normal C2-C3 and maximal cord compression segments were analyzed. The anterior (A), posterior (P), and anteroposterior length and width (W) of the spinal cord were measured. Correlation analyses between radiographic parameters and each section of Japanese Orthopedic Association (JOA) scores and comparisons of the patients divided by A (below or above 0, 1, or 2 mm) were performed. Between C2-C3 and maximal compression segments, the mean differences of A and P were 2.0 (1.2) and 0.2 (0.8) mm. The mean anteroposterior compression ratios were 0.58 (0.13) at C2-C3 and 0.32 (0.17) at maximal compression. The A and A/W ratio were significantly correlated with four sections and the total JOA scores (p < 0.05), but the P and P/W ratio did not demonstrate any correlations. Patients with A < 1 mm had significantly lower JOA scores than those with A ≥ 1 mm. In patients with DCM, spinal cord compression occurs mainly in the anterior part and the anterior cord length of <1 mm is particularly associated with neurologic deficits.
RESUMEN
AIM: In our pilot study, we found an increase in tyrosine hydroxylase (Th) mRNA expression in the prefrontal cortex of 72-h REM sleep-deprived (SD) rats, a mania model. Additionally, the expression levels of miR-325-3p, miR-326-3p, and miR-330-5p, the predicted target miRNAs on TH, were significantly decreased. Based on these results, in this study, we investigated whether miRNA-325-3p, miR-326-3p, and miR-330-5p modulate TH and manic-like behaviors in SD rats. METHODS: Manic-like behaviors were assessed using the open field test (OFT) and elevated plus-maze (EPM) test. The direct binding activity of miRNAs to the 3'-untranslated region (3'-UTR) of the Th gene was measured in HEK-293 cells using a luciferase reporter system. We also examined mRNA and protein expression of TH after intracerebroventricular (ICV) injection of miR-330-5p agomir to SD rats, along with manic-like behaviors. RESULTS: We observed an upregulation in mRNA and protein expression of TH and downregulation in miRNA-325-3p, miR-326-3p, and miR-330-5p expressions in the prefrontal cortex of SD rats, together with increased manic-like behaviors. The luciferase reporter assay showed that miR-330-5p could repress TH expression through direct binding to its target site in the 3'-UTR of Th, whereas miR-326-3p and miR-330-5p could not. In addition, ICV injection of miR-330-5p agomir alleviated the increase in TH expression in the prefrontal cortex of SD rats and manic-like behaviors. CONCLUSIONS: TH expression regulation through miR-330-5p may be implicated in the pathophysiology of mania in SD rats.
Asunto(s)
MicroARNs , Tirosina 3-Monooxigenasa , Animales , Humanos , Ratas , Regulación hacia Abajo , Células HEK293 , Manía , MicroARNs/metabolismo , Proyectos Piloto , ARN Mensajero , Sueño REM , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
The human papillomavirus (HPV) E6 and E7 oncogenes are expressed at all stages of HPV-mediated carcinogenesis and are essential drivers of cancers caused by high-risk HPV. Some of the activities of HPV E6 and E7, such as their interactions with host cellular tumor suppressors, have been characterized extensively. There is less information about how high-risk HPV E6 and E7 alter cellular responses to cytokines that are present in HPV-infected tissues and are an important component of the tumor microenvironment. We used several models of HPV oncoprotein activity to assess how HPV16 E6 and E7 alter the cellular response to the proinflammatory cytokine IL-1ß. Models of early stage HPV infection and of established HPV-positive head and neck cancers exhibited similar dysregulation of IL-1 pathway genes and suppressed transcriptional responses to IL-1ß treatment. Such overlap in cell responses supports that changes induced by HPV16 E6 and E7 early in infection could persist and contribute to a dysregulated immune environment throughout carcinogenesis. HPV16 E6 and E7 also drove the upregulation of several suppressors of IL-1 cytokine signaling, including SIGIRR, both in primary keratinocytes and in cancer cells. SIGIRR knockout was insufficient to increase IL-1ß-dependent gene expression in the presence of HPV16 E6 and E7, suggesting that multiple suppressors of IL-1 signaling contribute to dampened IL-1 responses in HPV16-positive cells. IMPORTANCE Human papillomavirus (HPV) infection is responsible for nearly 5% of the worldwide cancer burden. HPV-positive tumors develop over years to decades in tissues that are subject to frequent stimulation by proinflammatory cytokines. However, the effects of HPV oncoproteins on the cellular response to cytokine stimulation are not well defined. We analyzed IL-1 cytokine signaling in several models of HPV biology and disease. We found that HPV16 E6 and E7 oncoproteins mediate a broad and potent suppression of cellular responses to IL-1ß in models of both early and late stages of carcinogenesis. Our data provide a resource for future investigation of IL-1 signaling in HPV-positive cells and cancers.
Asunto(s)
Proteínas Oncogénicas Virales , Infecciones por Papillomavirus , Humanos , Papillomavirus Humano 16/fisiología , Proteínas Oncogénicas Virales/metabolismo , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/metabolismo , Papillomaviridae/metabolismo , Carcinogénesis , Microambiente TumoralRESUMEN
HMGB1 is a highly conserved, ubiquitous protein in eukaryotic cells. HMGB1 is normally localized to the nucleus, where it acts as a chromatin associated non-histone binding protein. In contrast, extracellular HMGB1 is an alarmin released by stressed cells to act as a danger associated molecular pattern (DAMP). We have recently determined that progenitor cells from multiple sclerosis patients exhibit a cellular senescent phenotype and release extracellular HMGB1 which directly impaired the maturation of oligodendrocyte progenitor cells (OPCs) to myelinating oligodendrocytes (OLs). Herein, we report that administration of recombinant HMGB1 into the spinal cord at the time of lysolecithin administration resulted in arrest of OPC differentiation in vivo, and a profound impairment of remyelination. To define the receptor by which extracellular HMGB1 mediates its inhibitory influence on OPCs to impair OL differentiation, we tested selective inhibitors against the four primary receptors known to mediate the effects of HMGB1, the toll-like receptors (TLRs)-2, -4, -9 or the receptor for advanced glycation end-products (RAGE). We found that inhibition of neither TLR9 nor RAGE increased OL differentiation in the presence of HMGB1, while inhibition of TLR4 resulted in partial restoration of OL differentiation and inhibiting TLR2 fully restored differentiation of OLs in the presence of HMGB1. Analysis of transcriptomic data (RNAseq) from OPCs identified an overrepresentation of NFκB regulated genes in OPCs when in the presence of HMGB1. We found that application of HMGB1 to OPCs in culture resulted in a rapid and concentration dependent shift in NFκB nuclear translocation which was also attenuated with coincident TLR2 inhibition. These data provide new information on how extracellular HMGB1 directly affects the differentiation potential of OPCs. Recent and past evidence for elevated HMGB1 released from senescent progenitor cells within demyelinated lesions in the MS brain suggests that a greater understanding of how this molecule acts on OPCs may unfetter the endogenous remyelination potential in MS.
RESUMEN
Persistent human papillomavirus (HPV) infection of stratified squamous epithelial cells causes nearly 5% of cancer cases worldwide. HPV-positive oropharyngeal cancers harbor few mutations in the Hippo signaling pathway compared to HPV-negative cancers at the same anatomical site, prompting the hypothesis that an HPV-encoded protein inactivates the Hippo pathway and activates the Hippo effector yes-associated protein (YAP1). The HPV E7 oncoprotein is required for HPV infection and for HPV-mediated oncogenic transformation. We investigated the effects of HPV oncoproteins on YAP1 and found that E7 activates YAP1, promoting YAP1 nuclear localization in basal epithelial cells. YAP1 activation by HPV E7 required that E7 binds and degrades the tumor suppressor protein tyrosine phosphatase non-receptor type 14 (PTPN14). E7 required YAP1 transcriptional activity to extend the lifespan of primary keratinocytes, indicating that YAP1 activation contributes to E7 carcinogenic activity. Maintaining infection in basal cells is critical for HPV persistence, and here we demonstrate that YAP1 activation causes HPV E7 expressing cells to be retained in the basal compartment of stratified epithelia. We propose that YAP1 activation resulting from PTPN14 inactivation is an essential, targetable activity of the HPV E7 oncoprotein relevant to HPV infection and carcinogenesis.
The 'epithelial' cells that cover our bodies are in a constant state of turnover. Every few weeks, the outermost layers die and are replaced by new cells from the layers below. For scientists, this raises a difficult question. Cells infected by human papillomaviruses, often known as HPV, can become cancerous over years or even decades. How do infected cells survive while the healthy cells around them mature and get replaced? One clue could lie in PTPN14, a human protein which many papillomaviruses eliminate using their viral E7 protein; this mechanism could be essential for the virus to replicate and cause cancer. To find out the impact of losing PTPN14, Hatterschide et al. used human epithelial cells to make three-dimensional models of infected tissues. These experiments showed that, when papillomaviruses destroy PTPN14, a human protein called YAP1 turns on in the lowest, most long-lived layer of the tissue. Cells in which YAP1 is activated survive while those that carry the inactive version mature and die. This suggests that papillomaviruses turn on YAP1 to remain in tissues for long periods. Papillomaviruses cause about five percent of all human cancers. Finding ways to stop them from activating YAP1 has the potential to prevent disease. Overall, the research by Hatterschide et al. also sheds light on other epithelial cancers which are not caused by viruses.
Asunto(s)
Alphapapillomavirus , Carcinoma de Células Escamosas , Infecciones por Papillomavirus , Alphapapillomavirus/metabolismo , Carcinoma de Células Escamosas/metabolismo , Humanos , Papillomaviridae , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/metabolismo , Infecciones por Papillomavirus/genética , Proteínas Tirosina Fosfatasas no Receptoras/genética , Proteínas Señalizadoras YAPRESUMEN
IL-13 induces mucus metaplasia, which causes airway obstruction in asthma. Bee venom (BV) and its components have shown anti-inflammatory effects in allergic diseases such as atopic dermatitis and asthma. In this study, we investigated the effect of BV on IL-13-induced mucus metaplasia through activation of the signal transducer and activator of transcription (STAT6), and regulation of SAM-pointed domain containing Ets-like factor (SPDEF) and forkhead box A2 (FOXA2) in the airway epithelia cell line A549. In A549 cells, BV (1.0 µg/mL) inhibited IL-13 (10 ng/mL)-induced AKT phosphorylation, increase in SPDEF protein expression, and decrease in FOXA2 protein expression-but not STAT6 phosphorylation. BV also prevented the IL-13-induced increase in mucin 5AC (MUC5AC) mRNA and protein expression. Moreover, we observed that inhibition of phosphoinositide 3 kinase (PI3K)/AKT using LY294002 (50 µM) could reverse the alterations in FOXA2 and MUC5AC expression -by IL-13 and BV. However, LY294002 did not affect IL-13- and BV-induced changes in SPDEF expression. These findings indicate that BV inhibits MUC5AC production through the regulation of SPDEF and FOXA2. The inhibition of MUC5AC production through FOXA2 is mediated via the suppression of PI3K/AKT activation by BV. BV may be helpful in the prevention of mucus metaplasia in asthma.
Asunto(s)
Antiinflamatorios/farmacología , Venenos de Abeja/farmacología , Células Epiteliales/inmunología , Mucina 5AC/antagonistas & inhibidores , Mucosa Respiratoria/inmunología , Células A549 , Humanos , Metaplasia/metabolismo , Mucina 5AC/metabolismo , Moco/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Proto-Oncogénicas c-ets/metabolismoRESUMEN
High-risk human papillomavirus (HPV) E7 proteins enable oncogenic transformation of HPV-infected cells by inactivating host cellular proteins. High-risk but not low-risk HPV E7 target PTPN14 for proteolytic degradation, suggesting that PTPN14 degradation may be related to their oncogenic activity. HPV infects human keratinocytes but the role of PTPN14 in keratinocytes and the consequences of PTPN14 degradation are unknown. Using an HPV16 E7 variant that can inactivate retinoblastoma tumor suppressor (RB1) but cannot degrade PTPN14, we found that high-risk HPV E7-mediated PTPN14 degradation impairs keratinocyte differentiation. Deletion of PTPN14 from primary human keratinocytes decreased keratinocyte differentiation gene expression. Related to oncogenic transformation, both HPV16 E7-mediated PTPN14 degradation and PTPN14 deletion promoted keratinocyte survival following detachment from a substrate. PTPN14 degradation contributed to high-risk HPV E6/E7-mediated immortalization of primary keratinocytes and HPV+ but not HPV- cancers exhibit a gene-expression signature consistent with PTPN14 inactivation. We find that PTPN14 degradation impairs keratinocyte differentiation and propose that this contributes to high-risk HPV E7-mediated oncogenic activity independent of RB1 inactivation.
Asunto(s)
Diferenciación Celular , Transformación Celular Viral , Papillomavirus Humano 16/metabolismo , Queratinocitos/enzimología , Proteínas E7 de Papillomavirus/metabolismo , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Proteolisis , Línea Celular , Supervivencia Celular , Regulación de la Expresión Génica , Papillomavirus Humano 16/genética , Humanos , Queratinocitos/patología , Queratinocitos/virología , Proteínas E7 de Papillomavirus/genética , Proteínas Tirosina Fosfatasas no Receptoras/genética , Proteínas de Unión a Retinoblastoma/genética , Proteínas de Unión a Retinoblastoma/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
This paper proposes a cooperative medium access control (MAC) protocol for underwater wireless sensor networks (UWSNs) named UCMAC, which fundamentally benefits from cooperative communication. In UCMAC, a source identifies cooperators and provides its destination with a list of the cooperators while also delineating their proximity to the destination. For erroneous reception of data packets, the destination then requests retransmission to the cooperators in a closest-one-first manner. A designated cooperator transmits the buffered data packet it has successfully overheard from the source or other cooperators. A signaling procedure and the various waiting times of the nodes are carefully designed to address the overheads that stem from cooperation. Through computer simulation, this paper evaluates UCMAC in terms of system throughput, latency, single-hop packet delivery ratio (PDR), and energy efficiency. The results show that UCMAC performs better than existing schemes, including MACA-U and CD-MACA.
RESUMEN
Sickle cell disease is caused by a mutant form of hemoglobin that polymerizes under hypoxic conditions, increasing rigidity, fragility, calcium influx-mediated dehydration, and adhesivity of red blood cells. Increased red cell fragility results in hemolysis, which reduces nitric oxide (NO) bioavailability, and induces platelet activation and inflammation leading to adhesion of circulating blood cells. Nitric Oxide inhibits adhesion and platelet activation. Nitrite has emerged as an attractive therapeutic agent that targets delivery of NO activity to areas of hypoxia through bioactivation by deoxygenated red blood cell hemoglobin. In this study, we demonstrate anti-platelet activity of nitrite at doses achievable through dietary interventions with comparison to similar doses with other NO donating agents. Unlike other NO donating agents, nitrite activity is shown to be potentiated in the presence of red blood cells in hypoxic conditions. We also show that nitrite reduces calcium associated loss of phospholipid asymmetry that is associated with increased red cell adhesion, and that red cell deformability is also improved. We show that nitrite inhibits red cell adhesion in a microfluidic flow-channel assay after endothelial cell activation. In further investigations, we show that leukocyte and platelet adhesion is blunted in nitrite-fed wild type mice compared to control after either lipopolysaccharide- or hemolysis-induced inflammation. Moreover, we demonstrate that nitrite treatment results in a reduction in adhesion of circulating blood cells and reduced red blood cell hemolysis in humanized transgenic sickle cell mice subjected to local hypoxia. These data suggest that nitrite is an effective anti-platelet and anti-adhesion agent that is activated by red blood cells, with enhanced potency under physiological hypoxia and in venous blood that may be useful therapeutically.
Asunto(s)
Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/tratamiento farmacológico , Nitritos/administración & dosificación , Inhibidores de Agregación Plaquetaria/administración & dosificación , Animales , Plaquetas/citología , Plaquetas/efectos de los fármacos , Calcio/metabolismo , Modelos Animales de Enfermedad , Células Endoteliales de la Vena Umbilical Humana , Humanos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/efectos de los fármacos , Ratones , Nitritos/farmacología , Adhesividad Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacologíaRESUMEN
In this paper, we propose an underwater wireless sensor network (UWSN) named SOUNET where sensor nodes form and maintain a tree-topological network for data gathering in a self-organized manner. After network topology discovery via packet flooding, the sensor nodes consistently update their parent node to ensure the best connectivity by referring to the timevarying neighbor tables. Such a persistent and self-adaptive method leads to high network connectivity without any centralized control, even when sensor nodes are added or unexpectedly lost. Furthermore, malfunctions that frequently happen in self-organized networks such as node isolation and closed loop are resolved in a simple way. Simulation results show that SOUNET outperforms other conventional schemes in terms of network connectivity, packet delivery ratio (PDR), and energy consumption throughout the network. In addition, we performed an experiment at the Gyeongcheon Lake in Korea using commercial underwater modems to verify that SOUNET works well in a real environment.
RESUMEN
Rice flour-zein composites in a hydrated viscoelastic state were utilized to compensate for the role of wheat gluten in gluten-free sheeted dough. The use of zein above its glass transition temperature was able to form a viscoelastic protein network of non-wheat dough with rice flour. The mixing stability and development time of the rice dough were positively increased with increasing levels of zein. The protein secondary structural analysis by FTIR spectroscopy demonstrated that the rice doughs with high levels of zein showed significant increases in ß-sheet structures whose intensity was almost doubled by the use of 10% zein. The use of zein at more than 5% (w/w) successfully produced gluten-free dough sheets that could be slit into thin and long noodle strands. In addition, the composites were effective in improving the rheological characteristics of gluten-free noodle strands by increasing their maximum force to extension, compared to wheat-based noodles.
Asunto(s)
Harina/análisis , Oryza/química , Triticum/química , Zeína/química , Glútenes/química , Fenómenos Mecánicos , ReologíaRESUMEN
Stimuli-responsive hybrid materials that combine the dynamic nature self-assembled organic nanostructures, unique photophysical properties of inorganic materials, and molecular recognition capability of biopolymers can provide sophisticated nanoarchitectures with unprecedented functions. In this report, infrared (IR)-responsive self-assembled peptide-carbon nanotube (CNT) hybrids that enable the spatiotemporal control of bioactive ligand multivalency and subsequent human neural stem cell (hNSC) differentiation are reported. The switching between the ligand presented and hidden states was controlled via IR-induced photothermal heating of CNTs, followed by the shrinkage of the thermoresponsive dendrimers that exhibited lower critical solution temperature (LCST) behavior. The control of the ligand spacing via molecular coassembly and IR-triggered ligand presentation promoted the sequential events of integrin receptor clustering and the differentiation of hNSCs into electrophysiologically functional neurons. Therefore, the combination of our nanohybrid with biomaterial scaffolds may be able to further improve effectiveness, durability, and functionality of the nanohybrid systems for spatiotemporal control of stem cell differentiation. Moreover, these responsive hybrids with remote-controllable functions can be developed as therapeutics for the treatment of neuronal disorders and as materials for the smart control of cell function.
Asunto(s)
Nanotubos de Carbono , Materiales Biocompatibles , Diferenciación Celular , Humanos , Ligandos , Células-Madre Neurales , Péptidos , Procesos FotoquímicosRESUMEN
The relationships between the ionization profile, sensitivity, and structures of 64 exogenous anabolic steroids (groups I-IV) was investigated under electrospray ionization (ESI) conditions. The target analytes were ionized as [M + H](+) or [M + H-nH2 O](+) in the positive mode, and these ions were used as precursor ions for selected reaction monitoring analysis. The collision energy and Q3 ions were optimized based on the sensitivity and selectivity. The limits of detection (LODs) were 0.05-20 ng/mL for the 64 steroids. The LODs for 38 compounds, 14 compounds and 12 compounds were in the range of 0.05-1, 2-5 and 10-20 ng/mL, respectively. Steroids including the conjugated keto-functional group at C3 showed good proton affinity and stability, and generated the [M + H](+) ion as the most abundant precursor ion. In addition, the LODs of steroids using the [M + H](+) ion as the precursor ion were mostly distributed at low concentrations. In contrast, steroids containing conjugated/unconjugated hydroxyl functional groups at C3 generated [M + H - H2 O](+) or [M + H - 2H2 O](+) ions, and these steroids showed relatively high LODs owing to poor stability and multiple ion formation. An LC-MS/MS method based on the present ionization profile was developed and validated for the determination of 78 steroids (groups I-V) in human urine.
Asunto(s)
Anabolizantes/orina , Cromatografía Liquida/métodos , Espectrometría de Masa por Ionización de Electrospray/métodos , Esteroides/orina , Anabolizantes/química , Humanos , Iones/química , Límite de Detección , Esteroides/química , Espectrometría de Masas en Tándem/métodosRESUMEN
PURPOSE: A new rabies vaccine for animals, including raccoon dogs, in Korea is needed to eradicate rabies infection. In this study, we constructed two recombinant adenoviruses expressing the glycoprotein or nucleoprotein of the rabies virus (RABV). We then investigated the safety and immunogenicity of these strains in raccoon dogs, depending on inoculation route. MATERIALS AND METHODS: Recombinant adenoviruses expressing the glycoprotein (Ad-0910G) or nucleoprotein (Ad-0910N) of rabies were constructed in 293A cells using an adenoviral system. One-year-old raccoon dogs underwent intramuscular (IM) inoculation or oral administration of the recombinant Ad-0910G and Ad-0910N. Clinical symptoms were observed and virus-neutralizing antibodies (VNA) against RABV were measured at 0, 2, 4, and 6 weeks after the immunization. Raccoons were considered positive if VNA titers were ≥ 0.1 IU/mL. RESULTS: Raccoon dogs inoculated with the combined Ad-0910G and Ad-0910N virus via the IM route did not exhibit any clinical sign of rabies during the observation period. All raccoon dogs (n = 7) immunized IM had high VNA titers, ranging from 0.17 to 41.6 IU/mL at 2 weeks after inoculation, but 70% (7/10) of raccoon dogs administered viruses via the oral route responded by 6 weeks after administration against RABV. CONCLUSION: Raccoon dogs inoculated with Ad-0910G and Ad-0910N viruses showed no adverse effects. Immunization with the combined Ad-0910G and Ad-0910N strains may play an important role in inducing VNA against RABV in raccoon dogs.