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1.
Exp Cell Res ; : 114146, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38936759

RESUMO

A microRNA miR-200c-3p is a regulator of epithelial-mesenchymal transition to control adhesion and migration of epithelial and mesenchymal cells. However, little is known about whether miR-200c-3p affects lymphocyte adhesion and migration mediated by integrins. Using TK-1 (a T lymphoblast cell) as a model of T cell, here we show that repressed expression of miR-200c-3p upregulated α4 integrin-mediated adhesion to and migration across mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Conversely, overexpression of miR-200c-3p downregulated α4 integrin-mediated adhesion and migration. Unlike in epithelial cells, miR-200c-3p did not target talin, an conformation activator of integrin, but, targeted E26-transformation-specific sequence 1 (ETS1), a transcriptional activator of α4 integrin, in T cells. Treatment of the miR-200c-3p-low-expressing TK-1 cells that possessed elevated α4 integrin with ETS1 small interfering RNA (siRNA) resulted in the reversion of the α4 integrin expression, supporting that ETS1 is a target of miR-200c-3p. A potential proinflammatory immune-modulator retinoic acid (RA) treatment of TK-1 cells elicited a significant reduction of miR-200c-3p and simultaneously a marked increase in ETS1 and α4 integrin expression. An anti-inflammatory cytokine TGF-ß1 treatment elevated miR-200c-3p, thereby downregulating ETS1 and α4 integrin expression. These results suggest that miR-200c-3p is an important regulator of α4 integrin expression and functions and may be controlled by RA and TGF-ß1 in an opposite way. Overexpression of miR-200c-3p could be a novel therapeutic option for treatment of gut inflammation through suppressing α4 integrin-mediated T cell migration.

2.
Interact J Med Res ; 12: e50148, 2023 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-37935050

RESUMO

BACKGROUND: Effective communication strategies are becoming increasingly important in intensive care units (ICUs) where patients at high risk are treated. Distributed leadership promotes effective communication among health care professionals (HCPs). Moreover, beyond facilitating patient care, it may improve well-being among HCPs by fostering teamwork. However, the impact of distributed leadership on the communication structure and well-being of HCPs remains unclear. OBJECTIVE: We performed a social network analysis (SNA) to assess the characteristics of each HCP in the network, identify the number of HCP connections, analyze 4 centralities that can measure an HCP's importance, and evaluate the impact of distributed leadership structure on the well-being and communication structure of the medical staff. METHODS: Wearable sensors were used to obtain face-to-face interaction data from the ICU medical staff at Mie University Hospital, Japan. Participants wore a badge on the front of their clothing during working hours to measure the total frequency of face-to-face interactions. We collected data about the well-being of medical staff using the Center for Epidemiological Studies-Depression (CES-D) questionnaire and measured 4 centralities using SNA analysis. A CES-D questionnaire was administered during the study to measure the well-being of the HCPs. RESULTS: Overall, 247 ICU workers participated in this clinical study for 4 weeks yearly in February 2016, 2017, and 2018. The distributed leadership structure was established within the ICU in 2017 and 2018. We compared these results with those of the traditional leadership structure used in 2016. Most face-to-face interactions in the ICU were among nurses or between nurses and other professionals. In 2016, overall, 10 nurses could perform leadership tasks, which significantly increased to 24 in 2017 (P=.046) and 20 in 2018 (P=.046). Considering the increased number of nurses who could perform leadership duties and the collaboration created within the organization, SNA in 2018 showed that the betweenness (P=.001), degree (P<.001), and closeness (P<.001) centralities significantly increased compared with those in 2016. However, the eigenvector centrality significantly decreased in 2018 compared with that in 2016 (P=.01). The CES-D scores in 2018 also significantly decreased compared with those in 2016 (P=.01). The betweenness (r=0.269; P=.02), degree (r=0.262; P=.03), and eigenvector (r=0.261; P=.03) centralities and CES-D scores were positively correlated in 2016, whereas the closeness centrality and CES-D scores were negatively correlated (r=-0.318; P=.01). In 2018, the degree (r=-0.280; P=.01) and eigenvector (r=-0.284; P=.01) centralities were negatively correlated with CES-D scores. CONCLUSIONS: Face-to-face interactions of HCPs in the ICU were measured using wearable sensors, and nurses were found to be centrally located. However, the introduction of distributed leadership created collaboration and informal leadership in the organization, altering the social network structure of HCPs and increasing organizational well-being. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) UMIN000037046; https://center6.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000042211.

3.
J Med Internet Res ; 25: e45834, 2023 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-37606971

RESUMO

BACKGROUND: Shift workers are at high risk of developing sleep disorders such as shift worker sleep disorder or chronic insomnia. Cognitive behavioral therapy (CBT) is the first-line treatment for insomnia, and emerging evidence shows that internet-based CBT is highly effective with additional features such as continuous tracking and personalization. However, there are limited studies on internet-based CBT for shift workers with sleep disorders. OBJECTIVE: This study aimed to evaluate the impact of a 4-week, physician-assisted, internet-delivered CBT program incorporating machine learning-based well-being prediction on the sleep duration of shift workers at high risk of sleep disorders. We evaluated these outcomes using an internet-delivered CBT app and fitness trackers in the intensive care unit. METHODS: A convenience sample of 61 shift workers (mean age 32.9, SD 8.3 years) from the intensive care unit or emergency department participated in the study. Eligible participants were on a 3-shift schedule and had a Pittsburgh Sleep Quality Index score ≥5. The study comprised a 1-week baseline period, followed by a 4-week intervention period. Before the study, the participants completed questionnaires regarding the subjective evaluation of sleep, burnout syndrome, and mental health. Participants were asked to wear a commercial fitness tracker to track their daily activities, heart rate, and sleep for 5 weeks. The internet-delivered CBT program included well-being prediction, activity and sleep chart, and sleep advice. A job-based multitask and multilabel convolutional neural network-based model was used for well-being prediction. Participant-specific sleep advice was provided by sleep physicians based on daily surveys and fitness tracker data. The primary end point of this study was sleep duration. For continuous measurements (sleep duration, steps, etc), the mean baseline and week-4 intervention data were compared. The 2-tailed paired t test or Wilcoxon signed rank test was performed depending on the distribution of the data. RESULTS: In the fourth week of intervention, the mean daily sleep duration for 7 days (6.06, SD 1.30 hours) showed a statistically significant increase compared with the baseline (5.54, SD 1.36 hours; P=.02). Subjective sleep quality, as measured by the Pittsburgh Sleep Quality Index, also showed statistically significant improvement from baseline (9.10) to after the intervention (7.84; P=.001). However, no significant improvement was found in the subjective well-being scores (all P>.05). Feature importance analysis for all 45 variables in the prediction model showed that sleep duration had the highest importance. CONCLUSIONS: The physician-assisted internet-delivered CBT program targeting shift workers with a high risk of sleep disorders showed a statistically significant increase in sleep duration as measured by wearable sensors along with subjective sleep quality. This study shows that sleep improvement programs using an app and wearable sensors are feasible and may play an important role in preventing shift work-related sleep disorders. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/24799.


Assuntos
Terapia Cognitivo-Comportamental , Aplicativos Móveis , Distúrbios do Início e da Manutenção do Sono , Humanos , Adulto , Sono , Duração do Sono , Internet
4.
Curr Issues Mol Biol ; 45(5): 4375-4388, 2023 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-37232747

RESUMO

AIM: Primary malignant bone tumor osteosarcoma can metastasize to the lung. Diminishing lung metastasis would positively affect the prognosis of patients. Our previous studies demonstrated that highly metastatic osteosarcoma cell lines are significantly softer than low-metastasis cell lines. We therefore hypothesized that increasing cell stiffness would suppress metastasis by reducing cell motility. In this study, we tested whether carbenoxolone (CBX) increases the stiffness of LM8 osteosarcoma cells and prevents lung metastasis in vivo. METHODS: We evaluated the actin cytoskeletal structure and polymerization of CBX-treated LM8 cells using actin staining. Cell stiffness was measured using atomic force microscopy. Metastasis-related cell functions were analyzed using cell proliferation, wound healing, invasion, and cell adhesion assays. Furthermore, lung metastasis was examined in LM8-bearing mice administered with CBX. RESULTS: Treatment with CBX significantly increased actin staining intensity and stiffness of LM8 cells compared with vehicle-treated LM8 cells (p < 0.01). In Young's modulus images, compared with the control group, rigid fibrillate structures were observed in the CBX treatment group. CBX suppressed cell migration, invasion, and adhesion but not cell proliferation. The number of LM8 lung metastases were significantly reduced in the CBX administration group compared with the control group (p < 0.01). CONCLUSION: In this study, we demonstrated that CBX increases tumor cell stiffness and significantly reduces lung metastasis. Our study is the first to provide evidence that reducing cell motility by increasing cell stiffness might be effective as a novel anti-metastasis approach in vivo.

5.
Cureus ; 15(2): e35233, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36968897

RESUMO

BACKGROUND: Positive end-expiratory pressure (PEEP), especially continuous high PEEP, is thought to be a risk factor for worsening renal function (WRF) due to impaired venous return and the development of renal interstitial edema. In this study, we investigated whether PEEP is a risk factor for WRF in patients with acute respiratory distress syndrome (ARDS), a representative pathology that requires continuous high PEEP for respiratory management. METHODS: We performed retrospective sub-analyses of the Japanese Association for Acute Medicine, a nationwide prospective observational registry of ARDS (FORECAST ARDS registry) prospective multicenter cohort study. WRF was defined on the basis of a worsening renal Sequential Organ Failure Assessment (SOFA) score. We performed univariate and multivariable analyses to identify possible risk factors for WRF, and propensity score analyses to compare the frequency of WRF according to cutoff values for the difference in PEEP between day 1 and day 4. RESULTS: We analyzed 151 cases. Multivariable analysis showed that the difference in PEEP (odds ratio (OR) 1.123 (95% confidence interval (CI) 1.017-1.240), P = 0.022) and male sex (OR 3.287 (95% CI 1.029-10.502), P = 0.045) were risk factors for WRF. Propensity score analysis showed trends towards an increased risk for WRF in each cutoff value for the difference in PEEP: -5 cmH2O (OR 0.389 (95% CI 0.084-1.799), P = 0.229), 0 cmH2O (OR 2.222 (95% CI 0.755-6.540), P = 0.150), and 5 cmH2O (OR 3.277 (95% CI 0.940-11.425), P = 0.065). CONCLUSIONS: This study revealed that the difference in PEEP between days 1 and 4 was positively associated with WRF. However, a significant cutoff value for the difference in PEEP was not determined.

6.
Cells ; 12(5)2023 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-36899862

RESUMO

Sepsis is a systemic inflammatory disorder that leads to the dysfunction of multiple organs. In the intestine, the deregulation of the epithelial barrier contributes to the development of sepsis by triggering continuous exposure to harmful factors. However, sepsis-induced epigenetic changes in gene-regulation networks within intestinal epithelial cells (IECs) remain unexplored. In this study, we analyzed the expression profile of microRNAs (miRNAs) in IECs isolated from a mouse model of sepsis generated via cecal slurry injection. Among 239 miRNAs, 14 miRNAs were upregulated, and 9 miRNAs were downregulated in the IECs by sepsis. Upregulated miRNAs in IECs from septic mice, particularly miR-149-5p, miR-466q, miR-495, and miR-511-3p, were seen to exhibit complex and global effects on gene regulation networks. Interestingly, miR-511-3p has emerged as a diagnostic marker in this sepsis model due to its increase in blood in addition to IECs. As expected, mRNAs in the IECs were remarkably altered by sepsis; specifically, 2248 mRNAs were decreased, while 612 mRNAs were increased. This quantitative bias may be possibly derived, at least partly, from the direct effects of the sepsis-increased miRNAs on the comprehensive expression of mRNAs. Thus, current in silico data indicate that there are dynamic regulatory responses of miRNAs to sepsis in IECs. In addition, the miRNAs that were increased with sepsis had enriched downstream pathways including Wnt signaling, which is associated with wound healing, and FGF/FGFR signaling, which has been linked to chronic inflammation and fibrosis. These modifications in miRNA networks in IECs may lead to both pro- and anti-inflammatory effects in sepsis. The four miRNAs discovered above were shown to putatively target LOX, PTCH1, COL22A1, FOXO1, or HMGA2, via in silico analysis, which were associated with Wnt or inflammatory pathways and selected for further study. The expressions of these target genes were downregulated in sepsis IECs, possibly through posttranscriptional modifications of these miRNAs. Taken together, our study suggests that IECs display a distinctive miRNA profile which is capable of comprehensively and functionally reshaping the IEC-specific mRNA landscape in a sepsis model.


Assuntos
MicroRNAs , Sepse , Camundongos , Animais , Perfilação da Expressão Gênica , MicroRNAs/genética , Células Epiteliais/metabolismo , Intestinos , Sepse/genética
7.
Mol Oncol ; 17(6): 1148-1166, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36688680

RESUMO

Tetraploidy is a hallmark of cancer cells, and tetraploidy-selective cell growth suppression is a potential strategy for targeted cancer therapy. However, how tetraploid cells differ from normal diploids in their sensitivity to anti-proliferative treatments remains largely unknown. In this study, we found that tetraploid cells are significantly more susceptible to inhibitors of a mitotic kinesin (CENP-E) than are diploids. Treatment with a CENP-E inhibitor preferentially diminished the tetraploid cell population in a diploid-tetraploid co-culture at optimum conditions. Live imaging revealed that a tetraploidy-linked increase in unsolvable chromosome misalignment caused substantially longer mitotic delay in tetraploids than in diploids upon moderate CENP-E inhibition. This time gap of mitotic arrest resulted in cohesion fatigue and subsequent cell death, specifically in tetraploids, leading to tetraploidy-selective cell growth suppression. In contrast, the microtubule-stabilizing compound paclitaxel caused tetraploidy-selective suppression through the aggravation of spindle multipolarization. We also found that treatment with a CENP-E inhibitor had superior generality to paclitaxel in its tetraploidy selectivity across a broader spectrum of cell lines. Our results highlight the unique properties of CENP-E inhibitors in tetraploidy-selective suppression and their potential use in the development of tetraploidy-targeting interventions in cancer.


Assuntos
Proteínas Cromossômicas não Histona , Neoplasias , Tetraploidia , Humanos , Linhagem Celular , Microtúbulos , Mitose , Paclitaxel/farmacologia , Proteínas Cromossômicas não Histona/antagonistas & inibidores
8.
Trauma Case Rep ; 42: 100710, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36247879

RESUMO

Tracheobronchial injury (TBI) associated with penetrating injuries has various clinical symptoms and often requires urgent surgical repair. A tracheal tube and/or placement of a drainage tube combined with multidetector computed tomography (CT) could be used to manage TBI without surgical repair in eligible patients. In this case report, we describe an 86-year-old woman with subcutaneous emphysema and suspected TBI caused by three knife wounds in her neck. After tracheal intubation at a local hospital, she was transferred to our hospital. On admission, she was diagnosed with subcutaneous and mediastinal emphysema due to TBI, as well as bilateral pneumothorax. We adjusted the position of the tracheal tube to a distal location from the TBI, and placed bilateral thoracic drainage tubes by referring to the CT images taken on admission and during the follow-up. The follow-up CT images revealed healing of the TBI. She did not show any worsening of her symptoms and she was successfully extubated on day 10 of her hospital stay. On day 18, she was considered self-reliant and was transferred to her previous hospital. Based on our experience in this case, we believe that ventilation with appropriate sedation, placement of a tracheal tube, and drainage are important conservative therapies for TBI caused by penetrating injuries. CT is also useful for evaluating the status of TBI.

9.
Sci Rep ; 12(1): 16373, 2022 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-36180581

RESUMO

Heatstroke is a life-threatening event that affects people worldwide. Currently, there are no established tools to predict the outcomes of heatstroke. Although the Sequential Organ Failure Assessment (SOFA) score is a promising tool for judging the severity of critically ill patients. Therefore, in this study, we investigated whether the SOFA score could predict the outcome of patients hospitalized with severe heatstroke, including the classical and exertional types, by using data from a Japanese nationwide multicenter observational registry. We performed retrospective subanalyses of the Japanese Association for Acute Medicine heatstroke registry, 2019. Adults with a SOFA score ≥ 1 hospitalized for heatstroke were analyzed. We analyzed data for 225 patients. Univariate and multivariable analyses showed a significant difference in the SOFA score between non-survivors and survivors in classical and exertional heatstroke cases. The area under the receiver operating characteristic curve were 0.863 (classical) and 0.979 (exertional). The sensitivity and specificity of SOFA scores were 50.0% and 97.5% (classical), 66.7% and 97.5% (exertional), respectively, at a cutoff of 12.5, and 35.0% and 98.8% (classical), 33.3% and 100.0% (exertional), respectively, at a cutoff of 13.5. This study revealed that the SOFA score may predict mortality in patients with heatstroke and might be useful for assessing prognosis.


Assuntos
Golpe de Calor , Escores de Disfunção Orgânica , Adulto , Estado Terminal , Golpe de Calor/diagnóstico , Humanos , Unidades de Terapia Intensiva , Prognóstico , Curva ROC , Estudos Retrospectivos
10.
Cancers (Basel) ; 14(13)2022 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-35805039

RESUMO

Breast cancer is the most common cancer in women worldwide, and lung metastasis is one of the most frequent distant metastases. When breast cancer metastasizes to the lung, group 2 innate lymphoid cells (ILC2s) are thought to promote tumor growth via the activation of myeloid-derived suppressor cells (MDSCs), which are known to negatively regulate anticancer immune responses. However, it remains to be elucidated exactly how this ILC2-MDSC interaction is involved in tumor growth during metastases formation. Using a 4T1/LM4 breast cancer mouse model, we found that ILC2s were activated in both the micro- and macrometastatic regions, suggesting sustained activation throughout the metastatic cascades via IL-33/ST2 signaling. Consistent with IL-13 secretion from activated ILC2s, the frequencies of polymorphonuclear (PMN)- and monocytic (M)-MDSCs were also significantly elevated during the progression from micro- to macrometastatic cancer. However, the effects of ILC2-induced MDSC functionality on the microenvironment differed in a metastatic-stage-specific manner. Our findings indicate that ILC2s may induce the immunosuppressive functions of MDSCs during the later stages of metastasis. Concomitantly, ILC2 may instigate extracellular matrix remodeling by PMN-MDSC activation during the early stages of metastasis. These metastatic-stage-specific changes may contribute to metastatic tumor growth in the microenvironment of breast cancer lung metastasis.

11.
Sci Rep ; 11(1): 21597, 2021 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-34732818

RESUMO

The ability of integrins on the cell surface to mediate cell adhesion to the extracellular matrix ligands is regulated by intracellular signaling cascades. During this signaling process, the talin (TLN) recruited to integrin cytoplasmic tails plays the critical role of the major adaptor protein to trigger integrin activation. Thus, intracellular levels of TLN are thought to determine integrin-mediated cellular functions. However, the epigenetic regulation of TLN expression and consequent modulation of integrin activation remain to be elucidated. Bioinformatics analysis led us to consider miR-200c-3p as a TLN1-targeting miRNA. To test this, we have generated miR-200c-3p-overexpressing and miR-200c-3p-underexpressing  cell lines, including HEK293T, HCT116, and LNCaP cells. Overexpression of miR-200c-3p resulted in a remarkable decrease in the expression of TLN1, which was associated with the suppression of integrin-mediated cell adhesion to fibronectin. In contrast, the reduction in endogenous miR-200c-3p levels led to increased expression of TLN1 and enhanced cell adhesion to fibronectin and focal adhesion plaques formation. Moreover, miR-200c-3p was found to target TLN1 by binding to its 3'-untranslated region (UTR). Taken together, our data indicate that miR-200c-3p contributes to the regulation of integrin activation and cell adhesion via the targeting of TLN1.


Assuntos
Regulação da Expressão Gênica , MicroRNAs/metabolismo , Talina/metabolismo , Regiões 3' não Traduzidas , Adesão Celular , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Biologia Computacional , Epigênese Genética , Células HCT116 , Células HEK293 , Humanos , Integrinas/metabolismo , Ligação Proteica
12.
Curr Issues Mol Biol ; 43(3): 1255-1266, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34698103

RESUMO

Osteosarcoma is the most common primary malignant bone tumor. The cause of death due to osteosarcoma is typically a consequence of metastasis to the lung. Controlling metastasis leads to improved prognosis for osteosarcoma patients. The cell stiffness of several tumor types is involved in metastatic potential; however, it is unclear whether the metastatic potential of osteosarcoma depends on cell stiffness. In this study, we analyzed the cell stiffness of the low metastatic Dunn cell line and its highly metastatic LM8 subline, and compared actin organization, cell proliferation, and metastasis. Actin cytoskeleton, polymerization, stiffness, and other cellular properties were analyzed. The organization of the actin cytoskeleton was evaluated by staining F-actin with Alexa Fluor 488 phalloidin. Cell stiffness was measured using Atomic Force Microscopy (AFM). Cell proliferation, migration, invasion, and adhesion were also evaluated. All experiments were performed using mouse osteosarcoma cell lines cultured in the absence and presence of cytochalasin. In LM8 cells, actin polymerization was strongly suppressed and actin levels were significantly lower than in Dunn cells. Stiffness evaluation revealed that LM8 cells were significantly softer than Dunn. Young's modulus images showed more rigid fibrillar structures were present in Dunn cells than in LM8 cells. LM8 cells also exhibited a significantly higher proliferation. The migration and invasion potential were also higher in LM8 cells, whereas the adhesion potential was higher in Dunn cells. The administration of cytochalasin resulted in actin filament fragmentation and decreased actin staining intensity and cell stiffness in both LM8 and Dunn cells. Cells with high metastatic potential exhibited lower actin levels and cell stiffness than cells with low metastatic potential. The metastatic phenotype is highly correlated to actin status and cell stiffness in osteosarcoma cells. These results suggest that evaluation of actin dynamics and cell stiffness is an important quantitative diagnostic parameter for predicting metastatic potential. We believe that these parameters represent new reliable quantitative indicators that can facilitate the development of new drugs against metastasis.


Assuntos
Actinas/química , Movimento Celular , Actinas/genética , Actinas/metabolismo , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Módulo de Elasticidade , Imunofluorescência , Imuno-Histoquímica , Camundongos , Metástase Neoplásica , Osteossarcoma/genética , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Multimerização Proteica , Relação Estrutura-Atividade , Migração Transendotelial e Transepitelial
13.
J Clin Med ; 10(18)2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34575296

RESUMO

Background: A deregulated immune system has been implicated in the pathogenesis of post-cardiac arrest syndrome (PCAS). A soluble form of programmed cell death-1 (PD-1) ligand (sPD-L1) has been found at increased levels in cancer and sustained inflammation, thereby deregulating immune functions. Here, we aim to study the possible involvement of sPD-L1 in PCAS. Methods: Thirty out-of-hospital cardiac arrest (OHCA) patients consecutively admitted to the ER of Mie University Hospital were prospectively enrolled. Plasma concentrations of sPD-L1 were measured by an enzyme-linked immunosorbent assay in blood samples of all 30 OHCA patients obtained during cardiopulmonary resuscitation (CPR). In 13 patients who achieved return-of-spontaneous-circulation (ROSC), sPD-L1 levels were also measured daily in the ICU. Results: The plasma concentrations of sPD-L1 in OHCA were significantly increased; in fact, to levels as high as those observed in sepsis. sPD-L1 levels during CPR correlated with reduced peripheral lymphocyte counts and increased C-reactive protein levels. Of 13 ROSC patients, 7 cases survived in the ICU for more than 4 days. A longitudinal analysis of sPD-L1 levels in the 7 ROSC cases revealed that sPD-L1 levels occurred in parallel with organ failure. Conclusions: This study suggests that ischemia- reperfusion during CPR may aberrantly activate immune and endothelial cells to release sPD-L1 into circulation, which may play a role in the pathogenesis of immune exhaustion and organ failures associated with PCAS.

14.
Exp Cell Res ; 408(1): 112835, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34543658

RESUMO

Endothelial cells adapt their functions as a consequence of sensing extracellular substrate stiffness; these alterations allow them to maintain their vascular structure and function. Substrate stiffness-mediated yes-associated protein 1 (YAP) activation plays an important role in mechano-transduction and pro-angiogenic phenotype of endothelial cells, and Delta-like ligand 4 (Dll4)-Notch1 signaling is closely related to angiogenesis; however, the impact of substrate stiffness-mediated interrelation of these pathways on endothelial cell functions remains elusive. We confirmed that endothelial cells on softer substrates not only elongate cellular aspects but also attenuate YAP activation compared to cells on stiffer substrates. Endothelial cells on softer substrates also upregulate the vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2 mRNA expression that is enhanced by VEGF stimulation. We determined that endothelial cells on softer substrates increased Dll4 expression, but not Notch1 expression, via YAP signaling. Moreover, endothelial cells on soft substrates induced not only VEGFRs upregulation but also suppression of pro-inflammatory interleukin-6 and plasminogen activator inhibitor-1 mRNA expression and the facilitation of anti-coagulant thrombomodulin and pro-coagulant tissue factor mRNA expression. Our results suggest that endothelial cells activate the YAP-Dll4-Notch signaling pathway in response to substrate stiffness and dictate cellular function.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Células Endoteliais/metabolismo , Receptor Notch1/metabolismo , Fatores de Transcrição/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neovascularização Patológica/metabolismo , Neovascularização Fisiológica/fisiologia , Proteínas de Sinalização YAP
15.
J Gastroenterol Hepatol ; 36(11): 3149-3157, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34370890

RESUMO

BACKGROUND AND AIM: Epithelial regeneration, a critical step for the mucosal healing in inflammatory bowel disease, is tightly regulated by stem cells. Therefore, identification of the specific factors that induce stem cell proliferation could contribute to the development of effective strategies for treating inflammatory bowel disease. Recombinant soluble thrombomodulin (rsTM) has previously been shown to promote cell proliferation in skin and corneal wound healing in murine models, but its effects on intestinal epithelial cell proliferation remains unclear. METHODS: Mouse intestinal organoids and dextran sulfate sodium (DSS)-induced colitis mouse model were used to assess the effects of rsTM on proliferation of intestinal epithelial cells. The size and budding morphologies of organoids were studied by confocal microscopy. The gene expression levels were analyzed by quantitative real-time polymerase chain reaction and immunofluorescence analysis. The effects of rsTM on DSS-induced colitis were investigated by evaluating body weight changes, colon length, histological score, and survival rate. RESULTS: The rsTM markedly stimulated the growth of intestinal organoids, thereby increasing the surface areas and budding phenotypes of the organoids. rsTM also significantly upregulated the gene expression of intestinal stem cell-specific and epithelial cell-specific markers in a dose-dependent manner. Furthermore, the treatment with high concentrations of rsTM significantly improved the recovery of body weight, histological outcomes, colon length shortening, and prolonged the survival of mice with colitis. CONCLUSIONS: The rsTM promotes intestinal stem cell proliferation in intestinal organoids and enhances the mucosal healing during recovery phase in DSS-induced colitis.


Assuntos
Proliferação de Células , Colite , Mucosa Intestinal , Trombomodulina , Animais , Proliferação de Células/fisiologia , Colite/induzido quimicamente , Colite/fisiopatologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Células Epiteliais/fisiologia , Mucosa Intestinal/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Organoides/fisiologia , Células-Tronco/fisiologia , Trombomodulina/química , Trombomodulina/metabolismo , Cicatrização
16.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361061

RESUMO

Sepsis is a sustained systemic inflammatory condition involving multiple organ failures caused by dysregulated immune response to infections. Sepsis induces substantial changes in energy demands at the cellular level leading to metabolic reprogramming in immune cells and stromal cells. Although sepsis-associated organ dysfunction and mortality have been partly attributed to the initial acute hyperinflammation and immunosuppression precipitated by a dysfunction in innate and adaptive immune responses, the late mortality due to metabolic dysfunction and immune paralysis currently represent the major problem in clinics. It is becoming increasingly recognized that intertissue and/or intercellular metabolic crosstalk via endocrine factors modulates maintenance of homeostasis, and pathological events in sepsis and other inflammatory diseases. Exosomes have emerged as a novel means of intercellular communication in the regulation of cellular metabolism, owing to their capacity to transfer bioactive payloads such as proteins, lipids, and nucleic acids to their target cells. Recent evidence demonstrates transfer of intact metabolic intermediates from cancer-associated fibroblasts via exosomes to modify metabolic signaling in recipient cells and promote cancer progression. Here, we review the metabolic regulation of endothelial cells and immune cells in sepsis and highlight the role of exosomes as mediators of cellular metabolic signaling in sepsis.


Assuntos
Células Endoteliais/patologia , Exossomos/patologia , Terapia de Imunossupressão , Inflamação/patologia , Doenças Metabólicas/patologia , Sepse/fisiopatologia , Animais , Humanos , Inflamação/imunologia , Doenças Metabólicas/etiologia
17.
Biotechniques ; 71(1): 392-399, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34164992

RESUMO

Wearable sensor technology enables objective data collection of direct human interactions. The authors review sociometric wearable devices (SWD) and their application in healthcare. Human interactions captured by wearable sensors have been shown to correlate with social constructs such as teamwork and productivity in the office. Application of SWD in the field of healthcare requires special considerations: validation studies have shown technological disadvantages in acute medical settings. Application of SWD in healthcare should be considered based on the strengths and weaknesses of the methodology. SWD can also play an important role in investigation of human interaction and epidemic spread. When study designs and methodologies are carefully considered, incorporation of SWD in healthcare research has promising potential for new insights.


Assuntos
Comportamento , Dispositivos Eletrônicos Vestíveis , Local de Trabalho , Atenção à Saúde , Instalações de Saúde , Humanos , Projetos de Pesquisa
18.
Biochim Biophys Acta Mol Basis Dis ; 1867(9): 166168, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-33991620

RESUMO

Cardiovascular diseases including blood vessel disorders represent a major cause of death globally. The essential roles played by local and systemic vascular inflammation in the pathogenesis of cardiovascular diseases have been increasingly recognized. Vascular inflammation triggers the aberrant activation of endothelial cells, which leads to the functional and structural abnormalities in vascular vessels. In addition to humoral mediators such as pro-inflammatory cytokines and prostaglandins, the alteration of physical and mechanical microenvironment - including vascular stiffness and shear stress - modify the gene expression profiles and metabolic profiles of endothelial cells via mechano-transduction pathways, thereby contributing to the pathogenesis of vessel disorders. Notably, connexins and integrins crosstalk each other in response to the mechanical stress, and, thereby, play an important role in regulating the mechano-transduction of endothelial cells. Here, we provide an overview on how the inter-play between connexins and integrins in endothelial cells unfold during the mechano-transduction in vascular inflammation.


Assuntos
Conexinas/metabolismo , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Inflamação/metabolismo , Integrinas/metabolismo , Animais , Humanos
19.
Viruses ; 13(4)2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33918599

RESUMO

The spike glycoprotein attached to the envelope of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to and exploits angiotensin-converting enzyme 2 (ACE2) as an entry receptor to infect pulmonary epithelial cells. A subset of integrins that recognize the arginyl-glycyl-aspartic acid (RGD) sequence in the cognate ligands has been predicted in silico to bind the spike glycoprotein and, thereby, to be exploited for viral infection. Here, we show experimental evidence that the ß1 integrins predominantly expressed on human pulmonary epithelial cell lines and primary mouse alveolar epithelial cells bind to this spike protein. The cellular ß1 integrins support adhesive interactions with the spike protein independently of ACE2, suggesting the possibility that the ß1 integrins may function as an alternative receptor for SARS-CoV-2, which could be targeted for the prevention of viral infections.


Assuntos
Células Epiteliais Alveolares/metabolismo , Integrina beta1/metabolismo , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , COVID-19/virologia , Adesão Celular , Linhagem Celular , Humanos , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Oligopeptídeos , Ligação Proteica , Receptores Virais/metabolismo , Células THP-1 , Internalização do Vírus
20.
Int J Mol Sci ; 22(4)2021 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-33668652

RESUMO

Leukemia is a hematological malignancy that originates from hematopoietic stem cells in the bone marrow. Significant progress has made in understanding its pathogensis and in establishing chemotherapy and hematopoietic stem cell transplantation therapy (HSCT). However, while the successive development of new therapies, such as molecular-targeted therapy and immunotherapy, have resulted in remarkable advances, the fact remains that some patients still cannot be saved, and resistance to treatment and relapse are still problems that need to be solved in leukemia patients. The bone marrow (BM) niche is a microenvironment that includes hematopoietic stem cells and their supporting cells. Leukemia cells interact with bone marrow niches and modulate them, not only inducing molecular and functional changes but also switching to niches favored by leukemia cells. The latter are closely associated with leukemia progression, suppression of normal hematopoiesis, and chemotherapy resistance, which is precisely the area of ongoing study. Exosomes play an important role in cell-to-cell communication, not only with cells in close proximity but also with those more distant due to the nature of exosomal circulation via body fluids. In leukemia, exosomes play important roles in leukemogenesis, disease progression, and organ invasion, and their usefulness in the diagnosis and treatment of leukemia has recently been reported. The interaction between leukemia cell-derived exosomes and the BM microenvironment has received particular attention. Their interaction is believed to play a very important role; in addition to their diagnostic value, exosomes could serve as a marker for monitoring treatment efficacy and as an aid in overcoming drug resistance, among the many problems in leukemia patients that have yet to be overcome. In this paper, we will review bone marrow niches in leukemia, findings on leukemia-derived exosomes, and exosome-induced changes in bone marrow niches.


Assuntos
Medula Óssea/metabolismo , Comunicação Celular , Exossomos/metabolismo , Leucemia/metabolismo , Microambiente Tumoral , Medula Óssea/patologia , Exossomos/patologia , Humanos , Leucemia/patologia
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