RESUMO
PURPOSE: Dyadic communication positively affects marital relationships, good relationships help restore body image, and this study explores the relationship between dyadic communication and body image of breast cancer patients. METHODS: Cross-sectional correlation design with convenience sampling was used to recruit participants from two outpatient medical centers. Demographic information, medical records, and two questionnaires, dyadic communicative resilience scale (DCRS) and body image scale (BIS), were administered. Participants comprised women with breast cancer and their partners. Multiple regression analysis was performed to control related factors to understand the association between the DCRS of the women with breast cancer and their partners and the women's body image. Analysis of variance (ANOVA) was performed to analyze between three categories of couple's communication status (consistent and good, consistent and poor, and inconsistent) and body image of women with breast cancer. RESULTS: Data were obtained from 162 women with breast cancer and 90 partners. The study found (1) significant correlation between the women's perception of their communication and body image, (2) humor in partner's perception of their communication was significantly associated with women's body image, and (3) dyadic communication that both patients and partners were consistent and good in the domain of keeping pre-cancer routines and attractiveness was associated with women's body image. CONCLUSION: The correlation between dyadic communication and the body image of women with breast cancer is significant. Improving communication specific on keeping pre-cancer routines and attractiveness between women with breast cancer and their partners could enhance the women's body image.
Assuntos
Imagem Corporal , Neoplasias da Mama , Comunicação , Humanos , Feminino , Neoplasias da Mama/psicologia , Imagem Corporal/psicologia , Estudos Transversais , Pessoa de Meia-Idade , Adulto , Inquéritos e Questionários , Cônjuges/psicologia , Relações Interpessoais , Masculino , Idoso , Análise de Regressão , Análise de Variância , Resiliência PsicológicaRESUMO
The orbital angular momentum (OAM) generation as well as its associated orbital torque is currently a matter of great interest in spin-orbitronics and is receiving increasing attention. In particular, recent theoretical work predicts that the oxidized light metal Cu can serve as an efficient OAM generator through its surface orbital Rashba effect. Here, for the first time, the crucial current-induced magnetic-field-free in-plane magnetization reversal is experimentally demonstrated in CoFeB/CuOx bilayers without any heavy elements. We show that the critical current density can be comparable to that of strong spin-orbit coupling systems with heavy metals (Pt and Ta) and that the magnetization reversal mechanism is governed by coherent rotation in the grains through the second-harmonic and magneto-optical Kerr effect measurements. Our results indicate that light metal oxides can play an equally important role as heavy metals in magnetization reversal, broadening the choice of materials for engineering spintronic devices.
RESUMO
Proinflammatory cytokines such as IL-6 induce endothelial cell (EC) barrier disruption and trigger an inflammatory response in part by activating the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. The protein suppressor of cytokine signaling-3 (SOCS3) is a negative regulator of JAK-STAT, but its role in modulation of lung EC barrier dysfunction caused by bacterial pathogens has not been investigated. Using human lung ECs and EC-specific SOCS3 knockout mice, we tested the hypothesis that SOCS3 confers microtubule (MT)-mediated protection against endothelial dysfunction. SOCS3 knockdown in cultured ECs or EC-specific SOCS3 knockout in mice resulted in exacerbated lung injury characterized by increased permeability and inflammation in response to IL-6 or heat-killed Staphylococcus aureus (HKSA). Ectopic expression of SOCS3 attenuated HKSA-induced EC dysfunction, and this effect required assembled MTs. SOCS3 was enriched in the MT fractions, and treatment with HKSA disrupted SOCS3-MT association. We discovered that-in addition to its known partners gp130 and JAK2-SOCS3 interacts with MT plus-end binding proteins CLIP-170 and CLASP2 via its N-terminal domain. The resulting SOCS3-CLIP-170/CLASP2 complex was essential for maximal SOCS3 anti-inflammatory effects. Both IL-6 and HKSA promoted MT disassembly and disrupted SOCS3 interaction with CLIP-170 and CLASP2. Moreover, knockdown of CLIP-170 or CLASP2 impaired SOCS3-JAK2 interaction and abolished the anti-inflammatory effects of SOCS3. Together, these findings demonstrate for the first time an interaction between SOCS3 and CLIP-170/CLASP2 and reveal that this interaction is essential to the protective effects of SOCS3 in lung endothelium.
Assuntos
Inflamação/genética , Lesão Pulmonar/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas de Neoplasias/genética , Proteína 3 Supressora da Sinalização de Citocinas/genética , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/microbiologia , Lesão Pulmonar Aguda/patologia , Animais , Citoesqueleto/genética , Células Endoteliais , Endotélio Vascular/metabolismo , Endotélio Vascular/microbiologia , Endotélio Vascular/patologia , Humanos , Inflamação/metabolismo , Inflamação/microbiologia , Inflamação/patologia , Junções Intercelulares/genética , Interleucina-6/genética , Lesão Pulmonar/metabolismo , Lesão Pulmonar/microbiologia , Lesão Pulmonar/patologia , Camundongos , Camundongos Knockout , Permeabilidade , Staphylococcus aureus/patogenicidadeRESUMO
Coordinated development of the germline and the somatic compartments within a follicle is an essential prerequisite for creating a functionally normal oocyte. Bi-directional communication between the oocyte and the granulosa cells enables the frequent interchange of metabolites and signals that support the development and functions of both compartments. Mechanistic target of rapamycin (MTOR), a conserved serine/threonine kinase and a widely recognized integrator of signals and pathways key for cellular metabolism, proliferation, and differentiation, is emerging as a major player that regulates many facets of oocyte and follicle development. Here, we summarized our recent observations on the role of oocyte- and granulosa cell-expressed MTOR in the control of the oocyte's and granulosa cell's own development, as well as the development of one another, and provided new data that further strengthen the role of cumulus cell-expressed MTOR in synchronizing oocyte and follicle development. Inhibition of MTOR induced oocyte meiotic resumption in cultured large antral follicles, as well as cumulus expansion and the expression of cumulus expansion-related transcripts in cumulus-oocyte complexes in vitro. In vivo, the activity of MTOR in cumulus cells was diminished remarkably by 4 h after hCG administration. These results thus suggest that activation of MTOR in cumulus cells contributes to the maintenance of oocyte meiotic arrest before the LH surge. Based on the observations made by us here and previously, we propose that MTOR is an essential mediator of the bi-directional communication between the oocyte and granulosa cells that regulates the development and function of both compartments.
Assuntos
Células da Granulosa , Meiose , Oócitos , Serina-Treonina Quinases TOR , Animais , Feminino , Células da Granulosa/metabolismo , Camundongos , Oócitos/metabolismo , Folículo Ovariano/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
Chemokine (C-C motif) ligand 5 (CCL5) and CCR5, one of its receptors have been reported to be highly expressed in white adipose tissue (WAT) and are associated with the progression of inflammation and the development of insulin resistance in obese humans and mice. However, the role of CCL5/CCR5 signaling in obesity-associated dysregulation of energy metabolism remains unclear. Here, we demonstrate that global CCL5/CCR5 double knockout (DKO) mice have higher cold stress-induced energy expenditure and thermogenic function in brown adipose tissue (BAT) than wildtype (WT) mice. DKO mice have higher cold stress-induced energy expenditure and thermogenic function in BAT than WT mice. KEGG pathway analysis indicated that deletion of CCL5/CCR5 further facilitated the cold-induced expression of genes related to oxidative phosphorylation (OxPhos) and lipid metabolic pathways. In primary brown adipocytes of DKO mice, the augmentation of CL-316243-stimulated thermogenic and lipolysis responses was reversed by co-treatment with AMPKα1 and α2 short interfering RNA (siRNA). Overexpression of BAT CCL5/CCR5 genes by local lentivirus injection in WT mice suppressed cold stress-induced lipolytic processes and thermogenic activities. In contrast, knockdown of BAT CCL5/CCR5 signaling further up-regulated AMPK phosphorylation as well as thermogenic and lipolysis responses to chronic adrenergic stimuli and subsequently decreased level of body weight gain. Chronic knockdown of BAT CCL5/CCR5 signaling improved high-fat diet (HFD)-induced insulin resistance in WT mice. It is suggested that obesity-induced augmentation of adipose tissue (AT) CCL5/CCR5 signaling could, at least in part, suppress energy expenditure and adaptive thermogenesis by inhibiting AMPK-mediated lipolysis and oxidative metabolism in thermogenic AT to exacerbate the development of obesity and insulin resistance.
Assuntos
Tecido Adiposo Marrom/metabolismo , Quimiocina CCL5/metabolismo , Resistência à Insulina , Obesidade/metabolismo , Receptores CCR5/metabolismo , Animais , Quimiocina CCL5/genética , Dieta Hiperlipídica , Regulação da Expressão Gênica , Camundongos , Camundongos Knockout , Fosforilação Oxidativa , Receptores CCR5/genética , Transdução de Sinais , TermogêneseRESUMO
BACKGROUND: Previous studies observed that sleep disorders potentially increased the risk of asthma and asthmatic exacerbation. We aimed to examine whether excessive daytime sleepiness (EDS), probable insomnia, objective short sleep duration (OSSD), and obstructive sleep apnea (OSA) affect all-cause mortality (ACM) in individuals with or without asthma. METHODS: We extracted relevant data from the Sleep Heart Health Study established in 1995-1998 with an 11.4-year follow-up. Multivariate Cox regression analysis with a proportional hazards model was used to estimate the associations between ACM and four sleep disorders among asthmatic patients and individuals without asthma. Dose-response analysis and machine learning (random survival forest and CoxBoost) further evaluated the impact of sleep disorders on ACM in asthmatic patients. RESULTS: A total of 4538 individuals with 990 deaths were included in our study, including 357 asthmatic patients with 64 deaths. Three multivariate Cox regression analyses suggested that OSSD (adjusted HR = 2.67, 95% CI: 1.23-5.77) but not probable insomnia, EDS or OSA significantly increased the risk of ACM in asthmatic patients. Three dose-response analyses also indicated that the extension of objective sleep duration was associated with a reduction in ACM in asthmatic patients compared to very OSSD patients. Severe EDS potentially augmented the risk of ACM compared with asthmatics without EDS (adjusted HR = 3.08, 95% CI: 1.11-8.56). Machine learning demonstrated that OSSD of four sleep disorders had the largest relative importance for ACM in asthmatics, followed by EDS, OSA and probable insomnia. CONCLUSIONS: This study observed that OSSD and severe EDS were positively associated with an increase in ACM in asthmatic patients. Periodic screening and effective intervention of sleep disorders are necessary for the management of asthma.
Assuntos
Asma , Distúrbios do Sono por Sonolência Excessiva , Apneia Obstrutiva do Sono , Distúrbios do Início e da Manutenção do Sono , Transtornos do Sono-Vigília , Humanos , Pessoa de Meia-Idade , Idoso , Distúrbios do Sono por Sonolência Excessiva/diagnóstico , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/diagnóstico , Transtornos do Sono-Vigília/diagnóstico , Asma/diagnóstico , Asma/complicaçõesRESUMO
BACKGROUND: Sarcopenia is listed as a treatment trait in behavioral/risk factors for severe asthma, but studies on asthma and sarcopenia are lacking. This study aimed to determine the associations between sarcopenia with asthmatic prevalence, symptoms, lung function and comorbidities. METHODS: Fifteen thousand four hundred four individuals from the China Health and Retirement Longitudinal Study(CHARLS) and 10,263 individuals from the Study on global AGEing and adult health(SAGE) in China were included in this study. Four components of this study were used to assess the bidirectional association in the prevalence between sarcopenia with asthma, and estimate the relationships between sarcopenia with asthmatic symptoms, lung function and comorbidities via generalized additive models. The 10-item Center for Epidemiological Studies-Depression Scale ≥ 12 scores was classified as depression. RESULTS: In the CHARLS and SAGE, the prevalence of sarcopenia in asthmatics was higher than those without asthma. Asthmatics with sarcopenia had a significantly increased prevalence of severe shortness of breath(sarcopenia yes vs. no, adjusted OR = 3.71, 95%CI: 1.43-9.60) and airway obstruction in the SAGE(sarcopenia yes vs. no, adjusted OR = 6.82, 95%CI: 2.54-18.34) and an obvious reduction of PEF in the CHARLS and SAGE(sarcopenia yes vs. no, adjusted RR = 0.86, 95%CI: 0.82-0.91) compared to asthmatics without sarcopenia. The presence of sarcopenia was positively associated with the prevalence of chronic obstructive pulmonary disease(sarcopenia yes vs no, adjusted OR = 5.76, 95%CI:2.01-16.5) and depression(sarcopenia yes vs no, adjusted OR = 1.87, 95%CI:1.11-3.14) in asthmatics. CONCLUSIONS: Our findings indicated that sarcopenia partakes in the development of asthma by affecting lung function and comorbidities and maybe considered a treatable trait of asthma management.
Assuntos
Asma , Sarcopenia , Asma/diagnóstico , Asma/epidemiologia , Comorbidade , Humanos , Estudos Longitudinais , Pulmão , Prevalência , Sarcopenia/diagnóstico , Sarcopenia/epidemiologiaRESUMO
The C-C chemokine motif ligand 5 (CCL5) and its receptors have recently been thought to be substantially involved in the development of obesity-associated adipose tissue inflammation and insulin resistance. However, the respective contributions of tissue-derived and myeloid-derived CCL5 to the etiology of obesity-induced adipose tissue inflammation and insulin resistance, and the involvement of monocytic myeloid-derived suppressor cells (MDSCs), remain unclear. This study used CCL5-knockout mice combined with bone marrow transplantation (BMT) and mice with local injections of shCCL5/shCCR5 or CCL5/CCR5 lentivirus into bilateral epididymal white adipose tissue (eWAT). CCL5 gene deletion significantly ameliorated HFD-induced inflammatory reactions in eWAT and protected against the development of obesity and insulin resistance. In addition, tissue (non-hematopoietic) deletion of CCL5 using the BMT method not only ameliorated adipose tissue inflammation by suppressing pro-inflammatory M-MDSC (CD11b+Ly6G-Ly6Chi) accumulation and skewing local M1 macrophage polarization, but also recruited reparative M-MDSCs (CD11b+Ly6G-Ly6Clow) and M2 macrophages to the eWAT of HFD-induced obese mice, as shown by flow cytometry. Furthermore, modulation of tissue-derived CCL5/CCR5 expression by local injection of shCCL5/shCCR5 or CCL5/CCR5 lentivirus substantially impacted the distribution of pro-inflammatory and reparative M-MDSCs as well as macrophage polarization in bilateral eWAT. These findings suggest that an obesity-induced increase in adipose tissue CCL5-mediated signaling is crucial in the recruitment of tissue M-MDSCs and their trans-differentiation to tissue pro-inflammatory macrophages, resulting in adipose tissue inflammation and insulin resistance.
Assuntos
Tecido Adiposo , Quimiocina CCL5 , Inflamação , Células Supressoras Mieloides , Receptores CCR5 , Animais , Camundongos , Tecido Adiposo/química , Tecido Adiposo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Inflamação/metabolismo , Resistência à Insulina/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Células Supressoras Mieloides/metabolismo , Obesidade/metabolismo , Receptores CCR5/genética , Receptores CCR5/metabolismo , Quimiocina CCL5/metabolismo , Quimiocina CCL5/farmacologiaRESUMO
The mitogen-activated protein kinase (MAPK) pathway is a widely distributed signaling cascade in eukaryotes and is involved in regulating plant growth, development, and stress responses. High temperature, a frequently occurring environmental stressor, causes premature bolting in lettuce with quality decline and yield loss. However, whether MAPKs play roles in thermally induced bolting remains poorly understood. In this study, 17 LsMAPK family members were identified from the lettuce genome. The physical and chemical properties, subcellular localization, chromosome localization, phylogeny, gene structure, family evolution, cis-acting elements, and phosphorylation sites of the LsMAPK gene family were evaluated via in silico analysis. According to phylogenetic relationships, LsMAPKs can be divided into four groups, A, B, C, and D, which is supported by analyses of gene structure and conserved domains. The collinearity analysis showed that there were 5 collinearity pairs among LsMAPKs, 8 with AtMAPKs, and 13 with SlMAPKs. The predicted cis-acting elements and potential phosphorylation sites were closely associated with hormones, stress resistance, growth, and development. Expression analysis showed that most LsMAPKs respond to high temperatures, among which LsMAPK4 is significantly and continuously upregulated upon heat treatments. Under heat stress, the stem length of the LsMAPK4-knockdown lines was significantly shorter than that of the control plants, and the microscope observations demonstrated that the differentiation time of flower buds at the stem apex was delayed accordingly. Therefore, silencing of LsMAPK4 significantly inhibited the high- temperature-accelerated bolting in lettuce, indicating that LsMPAK4 might be a potential regulator of lettuce bolting. This study provides a theoretical basis for a better understanding of the molecular mechanisms underlying the MAPK genes in high-temperature-induced bolting.
Assuntos
Lactuca , Proteínas Quinases Ativadas por Mitógeno , Regulação da Expressão Gênica de Plantas , Hormônios/metabolismo , Lactuca/metabolismo , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Família Multigênica , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , TemperaturaRESUMO
The relative low hole mobility of p-channel building block device challenges the continued miniaturization of modern electronic chips. Metal-semiconductor junction is always an efficient strategy to control the carrier concentration of channel semiconductor, benefiting the carrier mobility regulation of building block device. In this work, complementary metal oxide semiconductor (CMOS)-compatible metals are selected to deposit on the surface of the important p-channel building block of GaSb nanowire field-effect-transistors (NWFETs), demonstrating the efficient strategy of hole mobility enhancement by metal-semiconductor junction. When deposited with lower work function metal of Al, the peak hole mobility of GaSb NWFET can be enhanced to as high as ≈3372 cm2 V-1 s-1 , showing three times than the un-deposited one. The as-studied metal-semiconductor junction is also efficient for the hole mobility enhancement of other p-channel devices, such as GaAs NWFET, GaAs film FET, and WSe2 FET. With the enhanced mobility, the as-constructed CMOS inverter shows good invert characteristics, showing a relatively high gain of ≈18.1. All results may be regarded as important advances to the next-generation electronics.
RESUMO
As one of the omics fields, metabolomics has unique advantages in facilitating the understanding of physiological and pathological activities in biology, physiology, pathology, and food science. In this review, based on developments in analytical chemistry tools, cheminformatics, and bioinformatics methods, we highlight the current applications of metabolomics in food safety, food authenticity and quality, and food traceability. Additionally, the combined use of metabolomics with other omics techniques for "foodomics" is comprehensively described. Finally, the latest developments and advances, practical challenges and limitations, and requirements related to the application of metabolomics are critically discussed, providing new insight into the application of metabolomics in food analysis.
Assuntos
Análise de Alimentos , Metabolômica , Inocuidade dos Alimentos , Tecnologia de Alimentos , Espectrometria de MassasRESUMO
PURPOSE: Several studies have investigated the association between gastroesophageal reflux disease (GERD) and colorectal cancer (CRC) risk, but the presented scientific results are highly debatable. This study examined the longitudinal association between GERD and CRC in an Asian population. METHODS: A retrospective cohort study was performed using the National Health Insurance Research Database of Taiwan. The study cohort comprised 45,828 individuals with newly diagnosed GERD (the GERD cohort) and 229,140 age, sex, and date of enrollment-matched patients without GERD (the comparison cohort) from 2000 to 2006. The primary outcome was the incidence of CRC. To estimate the effect of GERD on the risk of CRC, the Cox proportional hazards model was fitted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: There were 785 newly diagnosed CRC patients in the 45,828 patients with GERD. Relatively, there were 2375 incident CRC cases in 229,140 patients without GERD. The incidence rate of CRC for the GERD cohort (17.60 per 10,000 person-years) was significantly higher than the corresponding incidence rate for the comparison cohort (10.22 per 10,000 person-years). After adjustment for confounders, GERD was associated with a significantly increased risk of CRC (adjusted HR,1.76; 95% CI, 1.62-2.90). Of note, a significant association between GERD and CRC risk was evident in both genders. CONCLUSIONS: In conclusion, this nationwide population-based cohort study supports the hypothesis that GERD was associated with a significantly increased risk of CRC. Our findings warrant still further investigation of the underlying mechanisms related to carcinogenic effect of GERD on colorectal carcinoma.
Assuntos
Neoplasias Colorretais , Refluxo Gastroesofágico , Estudos de Coortes , Neoplasias Colorretais/epidemiologia , Feminino , Refluxo Gastroesofágico/complicações , Refluxo Gastroesofágico/epidemiologia , Humanos , Incidência , Masculino , Estudos Retrospectivos , Fatores de Risco , Taiwan/epidemiologiaRESUMO
BACKGROUND: Rectal cancer patients can conceivably obtain relief from neoadjuvant concurrent chemoradiotherapy (CCRT) for downstaging before resection, but the stratification of risk and clinical outcomes remains challenging. Therefore, identifying effective predictive biomarkers offers clinicians the opportunity to individually tailor early interventions, which would help optimize therapy. METHODS: Using a public rectal cancer transcriptome dataset (GSE35452), we focused on cytoskeletal protein binding (GO: 0008092)-related genes and identified FERM domain containing 3 (FRMD3) as the most significant differentially expressed gene associated with CCRT resistance. We gathered 172 tumor samples from rectal cancer patients treated with neoadjuvant CCRT accompanied by curative resection and estimated the expression level of FRMD3 using immunohistochemistry. RESULTS: The results revealed that high FRMD3 immunoexpression was remarkably associated with advanced pre-CCRT and post-CCRT tumor status (p = 0.004 and p < 0.001), pre-CCRT and post-CCRT lymph node metastasis (both p < 0.001), more perineurial invasion (p = 0.023), and a smaller extent of tumor regression (p = 0.018). High FRMD3 immunoexpression was remarkably correlated with inferior disease-specific survival (DSS) (p = 0.0001), local recurrence-free survival (LRFS) (p = 0.0003), and metastasis-free survival (MeFS) (p = 0.0023) at the univariate level. Furthermore, in multivariate analysis, high FRMD3 immunoexpression remained independently predictive of inferior DSS (p = 0.002), LRFS (p = 0.005), and MeFS (p = 0.015). CONCLUSION: These results suggest that high FRMD3 expression is related to advanced clinicopathological features and inferior therapeutic responses in rectal cancer patients treated with CCRT, validating the promising prognostic value of FRMD3 expression.
RESUMO
Several studies have reported inconsistent results about second primary lung cancer (SPLC) after irradiation for initial primary lung cancer (IPLC). The present study aims to assess the effect of ionising radiation on the risk of SPLC. The study population came from SEER database, and included a population-based cohort of 21,397 individuals diagnosed with IPLC between 2004 and 2009 who survived more than 7 years after the initial diagnosis. The first aim was to estimate the risk of SPLC in different periods and the cumulative risk of SPLC. Subsequently, a generalized additive model with Poisson regression analysis and a proportional sub-distribution hazard model was used to determine whether radiation affected the risk of SPLC. Until Dec 2016, there were 488 individuals who developed SPLC, 5368 individuals who died, and there were 15,541 alive individuals, respectively. The risk of SPLC was found to gradually decline with the extent of follow-up time. Age and histology were the two main risk factors of developing SPLC in Poisson regression and competing risk analyses. In Poisson regression analysis, radiation had no significant effect on the risk of developing SPLC (adjusted OR = 0.80, 95% CI 0.54, 1.19, P = 0.28). When considered competing risk of all-cause death, the risk of SPLC in the radiation group was similar to that in the non-radiation group (adjusted sHR = 0.80, 95% CI 0.56, 1.13, P = 0.21). The risk of SPLC was different during different follow-up time. Irradiation for IPLC seemingly did not affect the risk of developing SPLC.
Assuntos
Neoplasias Pulmonares/tratamento farmacológico , Segunda Neoplasia Primária/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Pulmonares/epidemiologia , Masculino , Pessoa de Meia-Idade , RiscoRESUMO
Macrophage effector function is dynamic in nature and largely dependent on not only the type of immunological challenge but also the tissue-specific environment and developmental origin of a given macrophage population. Recent research has highlighted the importance of glycolytic metabolism in the regulation of effector function as a common feature associated with macrophage activation. Yet, most research has used macrophage cell lines and bone marrow-derived macrophages, which do not account for the diversity of macrophage populations and the role of tissue specificity in macrophage immunometabolism. Tissue-resident alveolar macrophages (TR-AMs) reside in an environment characterized by remarkably low glucose concentrations, making glycolysis-linked immunometabolism an inefficient and unlikely means of immune activation. In this study, we show that TR-AMs rely on oxidative phosphorylation to meet their energy demands and maintain extremely low levels of glycolysis under steady-state conditions. Unlike bone marrow-derived macrophages, TR-AMs did not experience enhanced glycolysis in response to LPS, and glycolytic inhibition had no effect on their proinflammatory cytokine production. Hypoxia-inducible factor 1α stabilization promoted glycolysis in TR-AMs and shifted energy production away from oxidative metabolism at baseline, but it was not sufficient for TR-AMs to mount further increases in glycolysis or enhance immune function in response to LPS. Importantly, we confirmed these findings in an in vivo influenza model in which infiltrating macrophages had significantly higher glycolytic and proinflammatory gene expression than TR-AMs. These findings demonstrate that glycolysis is dispensable for macrophage effector function in TR-AM and highlight the importance of macrophage tissue origin (tissue resident vs. recruited) in immunometabolism.
Assuntos
Glicólise/efeitos dos fármacos , Inflamação/metabolismo , Ativação de Macrófagos/imunologia , Macrófagos Alveolares/efeitos dos fármacos , Animais , Inflamação/genética , Lipopolissacarídeos/farmacologia , Macrófagos Alveolares/metabolismo , Fosforilação Oxidativa/efeitos dos fármacosRESUMO
Idiopathic pulmonary fibrosis is a fatal interstitial lung disease characterized by the TGF-ß (transforming growth factor-ß)-dependent differentiation of lung fibroblasts into myofibroblasts, which leads to excessive deposition of collagen proteins and progressive scarring. We have previously shown that synthesis of collagen by myofibroblasts requires de novo synthesis of glycine, the most abundant amino acid found in collagen protein. TGF-ß upregulates the expression of the enzymes of the de novo serine-glycine synthesis pathway in lung fibroblasts; however, the transcriptional and signaling regulators of this pathway remain incompletely understood. Here, we demonstrate that TGF-ß promotes accumulation of ATF4 (activating transcription factor 4), which is required for increased expression of the serine-glycine synthesis pathway enzymes in response to TGF-ß. We found that induction of the integrated stress response (ISR) contributes to TGF-ß-induced ATF4 activity; however, the primary driver of ATF4 downstream of TGF-ß is activation of mTORC1 (mTOR Complex 1). TGF-ß activates the PI3K-Akt-mTOR pathway, and inhibition of PI3K prevents activation of downstream signaling and induction of ATF4. Using a panel of mTOR inhibitors, we found that ATF4 activation is dependent on mTORC1, independent of mTORC2. Rapamycin, which incompletely and allosterically inhibits mTORC1, had no effect on TGF-ß-mediated induction of ATF4; however, Rapalink-1, which specifically targets the kinase domain of mTORC1, completely inhibited ATF4 induction and metabolic reprogramming downstream of TGF-ß. Our results provide insight into the mechanisms of metabolic reprogramming in myofibroblasts and clarify contradictory published findings on the role of mTOR inhibition in myofibroblast differentiation.
Assuntos
Fator 4 Ativador da Transcrição/metabolismo , Fibroblastos/metabolismo , Pulmão/citologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Colágeno/biossíntese , Fibroblastos/efeitos dos fármacos , Glicina/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Fisiológico , Serina-Treonina Quinases TOR/metabolismoRESUMO
Staphylococcus aureus is a major etiological agent of sepsis and induces endothelial cell (EC) barrier dysfunction and inflammation, two major hallmarks of acute lung injury. However, the molecular mechanisms of bacterial pathogen-induced EC barrier disruption are incompletely understood. Here, we investigated the role of microtubules (MT) in the mechanisms of EC barrier compromise caused by heat-killed S. aureus (HKSA). Using a customized monolayer permeability assay in human pulmonary EC and MT fractionation, we observed that HKSA-induced barrier disruption is accompanied by MT destabilization and increased histone deacetylase-6 (HDAC6) activity resulting from elevated reactive oxygen species (ROS) production. Molecular or pharmacological HDAC6 inhibition rescued barrier function in HKSA-challenged vascular endothelium. The HKSA-induced EC permeability was associated with impaired MT-mediated delivery of cytoplasmic linker-associated protein 2 (CLASP2) to the cell periphery, limiting its interaction with adherens junction proteins. HKSA-induced EC barrier dysfunction was also associated with increased Rho GTPase activity via activation of MT-bound Rho-specific guanine nucleotide exchange factor-H1 (GEF-H1) and was abolished by HDAC6 down-regulation. HKSA activated the NF-κB proinflammatory pathway and increased the expression of intercellular and vascular cell adhesion molecules in EC, an effect that was also HDAC6-dependent and mediated, at least in part, by a GEF-H1/Rho-dependent mechanism. Of note, HDAC6 knockout mice or HDAC6 inhibitor-treated WT mice were partially protected from vascular leakage and inflammation caused by both HKSA or methicillin-resistant S. aureus (MRSA). Our results indicate that S. aureus-induced, ROS-dependent up-regulation of HDAC6 activity destabilizes MT and thereby activates the GEF-H1/Rho pathway, increasing both EC permeability and inflammation.
Assuntos
Células Endoteliais/metabolismo , Microtúbulos/metabolismo , Staphylococcus aureus/fisiologia , Células Endoteliais/microbiologia , Desacetilase 6 de Histona/metabolismo , Temperatura Alta , Humanos , Inflamação/microbiologia , Viabilidade Microbiana , Oxirredução , Permeabilidade , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo , Proteínas rho de Ligação ao GTP/metabolismoRESUMO
BACKGROUND/AIM: A great proportion of patients with rectal cancer initially present with locally advanced disease and can potentially benefit from neoadjuvant concurrent chemoradiotherapy (CCRT) for downstaging before surgery. However, risk and clinical outcome stratification remain a great challenge. We aimed to find the potential biomarker to predict the effect of neoadjuvant CCRT on rectal cancer. METHODS: We identified epiregulin (EREG) as the most significant predictive marker for neoadjuvant CCRT response from the published rectal cancer transcriptome data set GSE35452. We collected 172 biopsy specimens from rectal cancer patients who received neoadjuvant CCRT followed by radical proctectomy, performed EREG immunohistochemistry, and analyzed the H-scores. We further examined the correlations between the expression level of EREG and clinicopathological features, tumor regression grade, and survival, including disease-specific survival (DSS), locoregional recurrence-free survival (LRFS), and metastasis-free survival (MeFS). RESULTS: High EREG expression was significantly related to early pretreatment (pre-Tx) and posttreatment (post-Tx) tumor status (T1, T2, p = 0.047 and p < 0.001), pre-Tx and post-Tx negative nodal status (N0, p < 0.001 and p = 0.004), less vascular and perineurial invasion (p = 0.015 and p = 0.023), and higher tumor regression grade (p < 0.001). In the survival analysis, high EREG expression was significantly associated with better DSS (p < 0.0001), LRFS (p = 0.0004), and MeFS (p < 0.0001). In the multivariate analysis, high EREG expression remained prognostically significant for better DSS (p = 0.003; hazard ratio: 5.599). CONCLUSION: These data suggest that EREG is a potential predictive marker and therapeutic target in rectal cancer patients receiving neoadjuvant CCRT.
Assuntos
Quimiorradioterapia/métodos , Epirregulina/metabolismo , Terapia Neoadjuvante/métodos , Neoplasias Retais/metabolismo , Neoplasias Retais/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Intervalo Livre de Doença , Epirregulina/genética , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Retais/patologia , Transcriptoma , Adulto JovemRESUMO
BACKGROUND: Zoledronic acid (ZA) and strontium-89 have been widely used to treat lung cancer with bone metastases. The authors perform this meta-analysis to better evaluate the clinical outcome of ZA and strontium-89 for non-small cell lung cancer (NSCLC) patients. METHODS: We carried out standard meta-analysis and network meta-analysis based on a comprehensive data retrieval of EMBASE, PubMed, and Cochrane Library databases (up to March 2019). Random and fixed effects models were used where indicated and between-study heterogeneity was assessed. The primary endpoints were overall survival (OS) and skeletal-related events (SREs). The second endpoints were progression-free survival (PFS) and overall response rate (ORR). RESULTS: Seven randomized clinical trials, including 1426 NSCLC patients with seven studies of zoledronic acid and two studies of strontium-89, met the inclusion criteria. Compared with the control group, ZA is associated with a OS benefit (1-year survival rate: RR = 1.76, 95% CI 1.36-2.27; and 24-month survival rate: RR = 2.38, 95% CI 1.35-4.19) and a reduction of SREs (RR = 0.57, 95% CI 0.40-0.84) for the patients with bone metastases. No statistical differences were found in PFS and ORR. Network meta-analysis for the patients with bone metastases showed that ZA + strontium-89 and ZA harbored significantly clinical benefits than strontium-89 and placebo in terms of 1-year survival rate and SREs. Both head-to-head study and network meta-analysis showed that strontium-89 had no statistical impact on OS and SREs compared with placebo. CONCLUSION: Our analysis demonstrates that ZA +strontium-89 can be considered a priority for NSCLC patients with bone metastases, followed by ZA.
Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Radioisótopos de Estrôncio/uso terapêutico , Ácido Zoledrônico/uso terapêutico , Conservadores da Densidade Óssea/farmacologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Radioisótopos de Estrôncio/farmacologia , Análise de Sobrevida , Ácido Zoledrônico/farmacologiaRESUMO
Idiopathic pulmonary fibrosis (IPF) is characterized by the transforming growth factor (TGF)-ß-dependent differentiation of lung fibroblasts into myofibroblasts, leading to excessive deposition of extracellular matrix proteins, which distort lung architecture and function. Metabolic reprogramming in myofibroblasts is emerging as an important mechanism in the pathogenesis of IPF, and recent evidence suggests that glutamine metabolism is required in myofibroblasts, although the exact role of glutamine in myofibroblasts is unclear. In the present study, we demonstrate that glutamine and its conversion to glutamate by glutaminase are required for TGF-ß-induced collagen protein production in lung fibroblasts. We found that metabolism of glutamate to α-ketoglutarate by glutamate dehydrogenase or the glutamate-pyruvate or glutamate-oxaloacetate transaminases is not required for collagen protein production. Instead, we discovered that the glutamate-consuming enzymes phosphoserine aminotransferase 1 (PSAT1) and aldehyde dehydrogenase 18A1 (ALDH18A1)/Δ1-pyrroline-5-carboxylate synthetase (P5CS) are required for collagen protein production by lung fibroblasts. PSAT1 is required for de novo glycine production, whereas ALDH18A1/P5CS is required for de novo proline production. Consistent with this, we found that TGF-ß treatment increased cellular concentrations of glycine and proline in lung fibroblasts. Our results suggest that glutamine metabolism is required to promote amino acid biosynthesis and not to provide intermediates such as α-ketoglutarate for oxidation in mitochondria. In support of this, we found that inhibition of glutaminolysis has no effect on cellular oxygen consumption and that knockdown of oxoglutarate dehydrogenase has no effect on the ability of fibroblasts to produce collagen protein. Our results suggest that amino acid biosynthesis pathways may represent novel therapeutic targets for treatment of fibrotic diseases, including IPF.