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Front Med (Lausanne) ; 8: 713333, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34660625

RESUMO

Extracorporeal membrane oxygenation (ECMO), a life-saving technique for patients with severe respiratory and cardiac diseases, is being increasingly utilized worldwide, particularly during the coronavirus disease 2019(COVID-19) pandemic, and there has been a sharp increase in the implementation of ECMO. However, due to the presence of various complications, the survival rate of patients undergoing ECMO remains low. Among the complications, the neurologic morbidity significantly associated with venoarterial and venovenous ECMO has received increasing attention. Generally, failure to recognize neurologic injury in time is reportedly associated with poor outcomes in patients on ECMO. Currently, multimodal monitoring is increasingly utilized in patients with devastating neurologic injuries and has been advocated as an important approach for early diagnosis. Here, we highlight the prevalence and outcomes, risk factors, current monitoring technologies, prevention, and treatment of neurologic complications in adult patients on ECMO. We believe that an improved understanding of neurologic complications presumably offers promising therapeutic solutions to prevent and treat neurologic morbidity.

4.
Front Med (Lausanne) ; 8: 694754, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34676222

RESUMO

To investigate the characteristics of SARS-CoV-2 pneumonia and evaluate whether CT scans, especially at a certain CT level, could be used to predict the severity of SARS-CoV-2 pneumonia. In total 118 confirmed patients had been enrolled. All data including epidemiological, clinical characteristics, laboratory results, and images were collected and analyzed when they were administrated for the first time. All patients were divided into two groups. There were 106 severe/critical patients and 12 common ones. A total of 38 of the patients were women. The mean age was 50.5 ± 11.5 years. Overall, 80 patients had a history of exposure. The median time from onset of symptoms to administration was 8.0 days. The main symptoms included fever, cough, anorexia, fatigue, myalgia, headaches, and chills. Lymphocytes and platelets decreased and lactate dehydrogenase increased with increased diseased severity (P < 0.05). Calcium and chloride ions were decreased more significantly in severe/critical patients than in common ones (P < 0.05). The main comorbidities were diabetes, chronic cardiovascular disease, and chronic pulmonary disease, which occurred in 47 patients. In all 69 patients had respiratory failure, which is the most common SARS-CoV-2 complication, and liver dysfunction presented in 37 patients. Nine patients received mechanical ventilation therapy. One patient received continuous blood purification and extracorporeal membrane oxygenation (EMCO) treatments. The average stay was 18.1 ± 10.8 days. Four patients died. The median of the radiographic score was four in common, and five in the severe/critical illness, which was a significant difference between the two groups. The radiographic score was in negative correlation with OI (ρ = -0.467, P < 0.01). The OI in severe/critically ill cases decreased significantly as the disease progressed, which was related to the lesion area in the left lung and right lungs (ρ = 0.688, R = 0.733). OI, the lesion area in the left lung and right lungs, lymphocytes, etc. were associated with different degrees of SARS-CoV-2 pneumonia (P < 0.05). The lesion area in both lungs were possible predictive factors for severe/critical cases. Patients with SARS-CoV-2 pneumonia showed obvious clinical manifestations and laboratory result changes. Combining clinical features and the quantity of the lesion area in the fourth level of CT could effectively predict severe/critical SARS-CoV-2 cases.

5.
Front Med (Lausanne) ; 8: 659793, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34712673

RESUMO

Background: Extracorporeal membrane oxygenation (ECMO) might benefit critically ill COVID-19 patients. But the considerations besides indications guiding ECMO initiation under extreme pressure during the COVID-19 epidemic was not clear. We aimed to analyze the clinical characteristics and in-hospital mortality of severe critically ill COVID-19 patients supported with ECMO and without ECMO, exploring potential parameters for guiding the initiation during the COVID-19 epidemic. Methods: Observational cohort study of all the critically ill patients indicated for ECMO support from January 1 to May 1, 2020, in all 62 authorized hospitals in Wuhan, China. Results: Among the 168 patients enrolled, 74 patients actually received ECMO support and 94 not were analyzed. The in-hospital mortality of the ECMO supported patients was significantly lower than non-ECMO ones (71.6 vs. 85.1%, P = 0.033), but the role of ECMO was affected by patients' age (Logistic regression OR 0.62, P = 0.24). As for the ECMO patients, the median age was 58 (47-66) years old and 62.2% (46/74) were male. The 28-day, 60-day, and 90-day mortality of these ECMO supported patients were 32.4, 68.9, and 74.3% respectively. Patients survived to discharge were younger (49 vs. 62 years, P = 0.042), demonstrated higher lymphocyte count (886 vs. 638 cells/uL, P = 0.022), and better CO2 removal (PaCO2 immediately after ECMO initiation 39.7 vs. 46.9 mmHg, P = 0.041). Age was an independent risk factor for in-hospital mortality of the ECMO supported patients, and a cutoff age of 51 years enabled prediction of in-hospital mortality with a sensitivity of 84.3% and specificity of 55%. The surviving ECMO supported patients had longer ICU and hospital stays (26 vs. 18 days, P = 0.018; 49 vs. 29 days, P = 0.001 respectively), and ECMO procedure was widely carried out after the supplement of medical resources after February 15 (67.6%, 50/74). Conclusions: ECMO might be a benefit for severe critically ill COVID-19 patients at the early stage of epidemic, although the in-hospital mortality was still high. To initiate ECMO therapy under tremendous pressure, patients' age, lymphocyte count, and adequacy of medical resources should be fully considered.

6.
Anticancer Res ; 41(10): 4781-4787, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593427

RESUMO

BACKGROUND: Hypoxia can happen during solid tumor growth including osteosarcoma. This study investigated the relationship of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) on osteosarcoma cell growth and apoptosis under hypoxic conditions. MATERIALS AND METHODS: Human osteosarcoma cells were cultured under normal or hypoxic conditions. Inhibitors of HIF-1α and VEGF were applied to the cells separately or in combination to block the respective proteins. Cell proliferation and apoptosis were examined by MTT and TUNEL assays, and real-time PCR and ELISA were performed for mRNA and protein expression. RESULTS: There was a dramatic decrease of cell proliferation and an elevation of apoptosis under hypoxia. Blockage of HIF-1α and VEGFR enhanced the cell growth retardation and promoted apoptotic changes. Moreover, blockage of HIF-1α significantly eliminated the expression of VEGF in the cell culture media, and vice versa. CONCLUSION: HIF-1α and VEGF work closely in regulating osteosarcoma cell growth under hypoxic conditions and blockage of either of them may subsequently influence the presence of the other.


Assuntos
Apoptose , Proliferação de Células , Osteossarcoma/patologia , Hipóxia Tumoral , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Osteossarcoma/metabolismo , Hipóxia Tumoral/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
7.
Bioengineering (Basel) ; 8(10)2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34677205

RESUMO

We have recently identified a population of cells within the peripheral nerves of adult rodent animals (mice and rats) that can respond to Bone Morphogenetic Protein-2 (BMP-2) exposure or physical injury to rapidly proliferate. More importantly, these cells exhibited embryonic differentiation potentials that could be induced into osteoblastic and endothelial cells in vitro. The current study examined human nerve specimens to compare and characterize the cells after BMP-2 stimulation. Fresh pieces of human nerve tissue were minced and treated with either BMP-2 (750 ng/mL) or a PBS vehicle for 12 h at 37 °C, before being digested in 0.2% collagenase and 0.05% trypsin-EDTA. Isolated cells were cultured in a restrictive stem cell medium. Significantly more cells were obtained from the nerve pieces with the BMP-2 treatment in comparison with the PBS vehicle controls. Cell colonies started to form at Day 3. Expressions of the four transcription factors, namely, Klf4, c-Myc, Sox2, and Oct4, were confirmed at both the transcriptional and translational levels. The cells can be maintained in the stem cell culture medium for at least 6 weeks without changing their morphology. When the cells were transferred to a fibroblast growth medium, dispersed spindle-shaped motile cells were noted and became fibroblast activated protein-α (FAP) positive with immunocytochemistry staining. The data suggest that human peripheral nerve tissue also contains a population of cells that can respond to BMP-2 and express Klf4, Sox2, cMyc, and Oct4-the four transcription factors driving cell pluripotency. These cells are able to differentiate into FAP-positive fibroblasts. In summary, in human peripheral nerves also reside a population of quiescent cells with pluripotency potential that may be the same cells as rodent nerve-derived adult stem (NEDAPS) cells. It is proposed that these cells are possibly at the core of a previously unknown natural mechanism for healing an injury.

8.
Br J Pharmacol ; 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34625952

RESUMO

BACKGROUND AND PURPOSE: In chronic kidney disease (CKD), patients inevitably reach end-stage renal disease and require renal transplant. Evidence suggests that CKD is associated with metabolite disorders. However, the molecular pathways targeted by metabolites remain enigmatic. Here, we describe roles of 1-hydroxypyrene in mediating renal fibrosis. EXPERIMENTAL APPROACH: We analysed 5406 urine and serum samples from patients with Stage 1-5 CKD using metabolomics, and 1-hydroxypyrene was identified and validated using longitudinal and drug intervention cohorts as well as 5/6 nephrectomised and adenine-induced rats. KEY RESULTS: We identified correlations between the urine and serum levels of 1-hydroxypyrene and the estimated GFR in patients with CKD onset and progression. Moreover, increased 1-hydroxypyrene levels in serum and kidney tissues correlated with decreased renal function in two rat models. Up-regulated mRNA expression of aryl hydrocarbon receptor and its target genes, including CYP1A1, CYP1A2 and CYP1B1, were observed in patients and rats with progressive CKD. Further we showed up-regulated mRNA expression of aryl hydrocarbon receptor and its three target genes, plus up-regulated nuclear aryl hydrocarbon receptor protein levels in mice and HK-2 cells treated with 1-hydroxypyrene, which caused accumulation of extracellular matrix components. Treatment with aryl hydrocarbon receptor short hairpin RNA or flavonoids inhibited mRNA expression of aryl hydrocarbon receptor and its target genes in 1-hydroxypyrene-induced HK-2 cells and mice. CONCLUSION AND IMPLICATIONS: Metabolite 1-hydroxypyrene was demonstrated to mediate renal fibrosis through activation of the aryl hydrocarbon receptor signalling pathway. Targeting aryl hydrocarbon receptor may be an alternative therapeutic strategy for CKD progression.

9.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 33(8): 903-917, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34590555

RESUMO

Enteral nutrition plays an irreplaceable role in the nutritional treatment of critically ill patients. In order to help clinical medical staff to manage the common complications during the implementations of enteral nutrition for critically ill patients, the consensus writing team carried out literature retrieval, literature quality evaluation, evidence synthesis. Several topics such as diarrhea, aspiration, high gastric residual volume, abdominal distension, etc. were assessed by evidence-based methodology and Delphi method. After two rounds of expert investigations, Expert consensus on prevention and management of enteral nutrition therapy complications for critically ill patients in China (2021 edition) developed, and provided guidance for clinical medical staff.


Assuntos
Estado Terminal , Nutrição Enteral , China , Consenso , Diarreia , Nutrição Enteral/efeitos adversos , Humanos
10.
Ann Transl Med ; 9(15): 1219, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34532356

RESUMO

Background: Shock is a critical illness that seriously threatens the lives of patients. This study explains the epidemiology of shock, mortality of shock, and identify factors that related to hospital death. Methods: This is a multi-centre cross-sectional survey, which included 1,064 tertiary hospitals in 31 provinces, municipalities, and autonomous regions across China mainland. Totally 289,428 patients who diagnosed with shock based on the ICD-10 abstracted from the Hospital Quality Monitoring System (HQMS) in 2018, a national database administrated by National Health Commission of the PRC. Results: Patients diagnosed with shock were screened and classified according to the type of shock. Regression analysis was used to identify factors that related to death. A total of 79,668,156 medical records were included in HQMS in 2018, from which a total of 289,428 records with shock were identified. Hypovolemic shock occurred in 128,436 cases (44.38%), septic shock occurred in 121,543 cases (41.99%), cardiogenic shock occurred in 44,597 cases (15.41), and obstructive shock occurred in 3,168 cases (1.09%). Of these, 8,147 cases (2.81%) had mixed shock, which means had two or more types of shock. For all the shock cases, the top three frequent concomitant diseases recorded were circulatory system diseases (55.22%), digestive system diseases (53.64%), and respiratory system diseases (53.31%). Of the four types of shock, cases with cardiogenic shock had the highest in-hospital mortality (31.6%), followed by those with obstructive shock (25.2%), septic shock (22.9%), and hypovolemic shock (15.5%). Interestingly, the combination of shock and malignant tumors is one of the major factors that related to hospital deaths. Conclusions: Shock is a serious disease with a high fatality rate and huge clinical costs. According to this epidemiological survey of shock in China 2018, we should clarify the factors related to the hospital death in shock cases.

11.
Matern Fetal Med ; 3(1): 24-32, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34522894

RESUMO

Objective: To determine the pregnancy and neonatal outcomes of women who recovered from coronavirus disease 2019 (COVID-19) that developed in early pregnancy. Methods: This case series analyzed five pregnant women (26-33 years) whom recovered from COVID-19 which were developed in early pregnancy (6-27 weeks) and admitted at the Wuhan Union Hospital from January 15, 2020 to April 30, 2020. The clinical manifestation, laboratory examinations, treatment, pregnancy outcomes, maternal and neonatal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) throat swab reverse transcription polymerase chain reaction test results, and SARS-CoV-2 antibody test results in neonates were reviewed. The placental pathology, placental angiotensin-converting enzyme 2 expression were studied by hematoxylin-eosin and immunohistochemistry staining, SARS-CoV-2 presence was examined by QT-PCR. We also followed up the infants at 3-6 months. Results: Three pregnant women were diagnosed with COVID-19 in early pregnancy (Cases 1-3), and two were serum immunoglobulin G positive asymptomatic cases (Cases 4 and 5). Cases 1-3 showed complete recovery after severe COVID-19. Case 3 was infected at 6 weeks of gestation during the first trimester and had induced medical abortion at 12 weeks of gestation. All neonates had no pneumonia, SARS-CoV-2 mRNA reverse transcription polymerase chain reaction and serum immunoglobulin M were negative, and immunoglobulin G were positive. All placental samples were negative for SARS-CoV-2 in the nucleic acid test. Placental pathology showed chronic ischemia changes. ACE-2 expressed in both placenta and decidua. The follow-up showed that the infants were healthy and asymptomatic at 3-6 months. Conclusion: No adverse outcomes was observed in our case series. However, systemic inflammatory responses to SARS-CoV-2 infection may cause placental injury. At the time of delivery after recovery from COVID-19, no SARS-CoV-2 positive results was found in the placenta in this case series.

12.
Bioengineered ; 12(1): 5529-5539, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34506261

RESUMO

The objective of this study was to explore the effect of argon preconditioning on myocardial ischemia reperfusion (MI/R) injury and its mechanism. Cardiomyocytes H2C9 were pre-treated with 50% argon, and a cell model of oxygen-glucose deprivation (OGD) was established. CCK-8 and cytotoxicity detection kits were used to detect cell viability and lactate dehydrogenase (LDH) release. The miR-21 expression was detected using quantitative real-time polymerase chain reaction. Western blot analysis was performed to detect the expression of programmed cell death protein 4 (PDCD4) and homologous phosphatase and tensin homolog (PTEN) proteins. The levels of inflammatory factors (IL-1ß, IL-6, and IL-8) and oxidative stress factors (reactive oxygen species ROS], malondialdehyde [MDA], and superoxide dismutase [SOD]) were measured using an enzyme-linked immunosorbent assay. The effect of argon on cell apoptosis was detected using flow cytometry. Argon increased the proliferation of cardiomyocytes induced by OGD, decreased the release of LDH in cell culture medium, increased miR-21 expression in cells, decreased the expression of miR-21 target proteins PDCD4 and PTEN, decreased the levels of inflammatory factors (interleukin-1ß [IL-1ß], interleukin-6 [IL-6], and interleukin-8 [IL-8]) and oxidative stress factors (ROS and MDA), increased the SOD content, and decreased the cell apoptosis rate. Our results suggest that argon preconditioning inhibited the PDCD4/PTEN pathway via miR-21, thereby inhibiting ROS oxidative stress and preventing MI/R injury.

13.
Oxid Med Cell Longev ; 2021: 5579736, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34484565

RESUMO

Although intervertebral disc degeneration (IDD) can be described as different stages of change through biological methods, this long and complex process cannot be defined in stages by single or simple combination of biological techniques. Under the background of the development of nuclear magnetic resonance (NMR) technology and the emerging metabonomics, we based on animal models and expanded to the study of clinical human degeneration models. The characteristics of different stages of IDD were analyzed by omics. Omics imaging combined with histology, cytology, and proteomics was used for screening of the intervertebral disc (IVD) of research subjects. Furthermore, mass spectrometry nontargeted metabolomics was used to explore profile of metabolites at different stages of the IDD process, to determine differential metabolic pathways and metabolites. NMR spectroscopy was used to qualitatively and quantitatively identify markers of degeneration. NMR was combined with mass spectrometry metabolomics to explore metabolic pathways. Metabolic pathways were determined through protein molecular biology and histocytology of the different groups. Distinguishing advantages of magnetic resonance spectroscopy (MRS) for analysis of metabolites and effective reflection of structural integrity and water molecule metabolism through diffusion tensor imaging (DTI) were further used to verify the macrometabolism profile during degeneration. A corresponding model of in vitro metabolomics and in vivo omics imaging was established. The findings of this study show that a series of metabolic pathways associated with the glycine-serine-threonine (Gly-Ser-Thr) metabolic axis affects carbohydrate patterns and energy utilization efficiency and ultimately delays disc degeneration through antioxidant effects.

15.
Cell Biosci ; 11(1): 167, 2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34446102

RESUMO

BACKGROUND: Annexin A1 (ANXA1) exerts anti-nociceptive effect through ANXA1 receptor formyl peptide receptor 2 (FPR2/ALX (receptor for lipoxin A4), FPR2) at the dorsal root ganglia (DRG) level. However, the mechanisms remain elucidated. By using radiant heat, hot/cold plate, tail flick, von Frey, and Randall-Selitto tests to detect nociception in intact and chemical (capsaicin, menthol, mustard oil, formalin or CFA) injected AnxA1 conditional knockout (AnxA1-/-) mice, applying calcium imaging and patch clamp recordings in cultured DRG neurons to measure neuronal excitability, conducting immunofluorescence and western blotting to detect the protein levels of TRPV1, FPR2 and its downstream molecules, and performing double immunofluorescence and co-immunoprecipitation to investigate the interaction between Calmodulin (CaM) and TRPV1; we aim to uncover the molecular and cellular mechanisms of ANXA1's role in antinociception. RESULTS: AnxA1-/- mice exhibited significant sensitivity to noxious heat (mean ± SD, 6.2 ± 1.0 s vs. 9.9 ± 1.6 s in Hargreaves test; 13.6 ± 1.5 s vs. 19.0 ± 1.9 s in hot plate test; n = 8; P < 0.001), capsaicin (101.0 ± 15.3 vs. 76.2 ± 10.9; n = 8; P < 0.01), formalin (early phase: 169.5 ± 32.8 s vs. 76.0 ± 21.9 s; n = 8; P < 0.05; late phase: 444.6 ± 40.1 s vs. 320.4 ± 33.6 s; n = 8; P < 0.01) and CFA (3.5 ± 0.8 s vs. 5.9 ± 1.4 s; n = 8; P < 0.01). In addition, we found significantly increased capsaicin induced Ca2+ response, TRPV1 currents and neuronal firing in AnxA1 deficient DRG neurons. Furthermore, ANXA1 mimic peptide Ac2-26 robustly increased intracellular Ca2+, inhibited TRPV1 current, activated PLCß and promoted CaM-TRPV1 interaction. And these effects of Ac2-26 could be attenuated by FPR2 antagonist Boc2. CONCLUSIONS: Selective deletion of AnxA1 in DRG neurons enhances TRPV1 sensitivity and deteriorates noxious heat or capsaicin induced nociception, while ANXA1 mimic peptide Ac2-26 desensitizes TRPV1 via FPR2 and the downstream PLCß-Ca2+-CaM signal. This study may provide possible target for developing new analgesic drugs in inflammatory pain.

17.
Org Lett ; 23(16): 6212-6216, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34355911

RESUMO

The reaction of o-benzofulvene with TfOH leads to intramolecular cyclization through novel C-C and C-N bond formation, resulting in the formation of 5H,10'H-spiro[benzo[k]phenanthridine-5,6'-dibenzopentalene]. This protocol provides a new molecular framework with reasonable to excellent yields and tolerates various electron-withdrawing/donating substituents. This method yields diastereoselectivity of up to >20:1. Furthermore, it is free of bases, oxidants, and metals and proceeds under mild reaction conditions, which are favorable for synthetic organic chemistry.

18.
Neurotoxicology ; 86: 10-18, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34216683

RESUMO

Biochanin A (BCA) is a natural organic O-methylated isoflavone with a variety of pharmacological effects, and has been reported to have neuroprotective properties. Here, we explored whether BCA protects neurocytes against isoflurane-induced neurotoxicity and investigated the underlying mechanism. Cell viability was tested by cell counting kit-8 and lactate dehydrogenase release assays. Apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and caspase-3/7 activity assays. Superoxide dismutase (SOD) and catalase (CAT) activities and levels of glutathione (GSH) and malondialdehyde (MDA) were measured to assess oxidative stress. Expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase (NQO1) was determined by western blotting. Treatment with BCA significantly attenuated the reduction of cell viability induced by isoflurane in SH-SY5Y cells. In addition, BCA treatment reversed isoflurane-induced SOD and CAT activity reduction, GSH level decline and MDA level increase. Isoflurane-induced apoptosis was also attenuated by treatment with BCA. The increase in nuclear Nrf2, HO-1 and NQO1 expression induced by isoflurane was amplified by treatment with BCA. These inhibitory effects of BCA on isoflurane-induced oxidative stress, viability reduction and cell apoptosis were attenuated in Nrf2 knockdown SH-SY5Y cells. Our findings indicate that BCA protects SH-SY5Y cells against isoflurane-induced neurotoxicity via inducing the Nrf2/ARE pathway.

19.
Shock ; 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34265832

RESUMO

OBJECTIVES: Mechanical stretch induced alveolar epithelial cell (AEC) apoptosis participates in the onset of ventilator induced lung injury (VILI). In this study, we explored whether death associated protein kinase 1 (DAPK1) mediated cyclic stretch (CS) induced AEC apoptosis and VILI though P53 pathway. MATERIALS AND METHODS: AEC apoptosis was induced by CS using the FX-5000T Flexercell Tension Plus system. C57BL/6 mouse received high tidal volume ventilation to build VILI model. DAPK1 inhibitor, P53 inhibitor or DAPK1 plasmid was used to regulate the expression of DAPK1 and P53, respectively. Flow cytometery was performed to assay cell apoptosis and the changes of mitochondrial membrane potential (MMP); Immunoblotting was adopted to analyse related protein expression; The binding of related proteins was detected by coimmunoprecipitation; AEC apoptosis in vivo was determined by immunohistochemistry assay. RESULTS: CS promoted AEC apoptosis, increased DAPK1 and P53 expression and induced the binding of DAPK1 and P53; inhibition of DAPK1 or P53 reduced CS induced AEC apoptosis, suppressed the expression of Bax, increased Bcl-2 level and stabilized MMP; AEC apoptosis and the level of P53 were both increased after overexpressing of DAPK1. Moreover, DAPK1 plasmid transfection also promoted the expression of Bax and the change of MMP, but decreased the level of Bcl-2. Inhibition of DAPK1 or P53 in vivo alleviated high tidal volume ventilation induced AEC apoptosis and lung injury. CONCLUSIONS: DAPK1 contributes to AEC apoptosis and the onset of VILI though P53 and its intrinsic pro-apoptotic pathway. Inhibition of DAPK1 or P53 alleviates high tidal volume ventilation induced lung injury and AEC apoptosis.

20.
Lab Invest ; 101(9): 1166-1175, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34168289

RESUMO

Epithelial-mesenchymal transition (EMT) plays a crucial role in the development of pulmonary fibrosis. This study aims to investigate the effects of valproic acid (VPA) on EMT in vitro and in vivo. In vitro, EMT was induced by the administration of transforming growth factor-ß1 (TGF-ß1) in a human alveolar epithelial cell line (A549). The dose effects of VPA (0.1-3 mM) on EMT were subsequently evaluated at different timepoints. VPA (1 mM) was applied prior to the administration of TGF-ß1 and the expression of E-cadherin, vimentin, p-Smad2/3 and p-Akt was assessed. In addition, the effects of a TGF-ß type I receptor inhibitor (A8301) and PI3K-Akt inhibitor (LY294002) on EMT were evaluated. In vivo, the effects of VPA on bleomycin-induced lung fibrosis were evaluated by assessing variables such as survival rate, body weight and histopathological changes, whilst the expression of E-cadherin and vimentin in lung tissue was also evaluated. A8301 and LY294002 were used to ascertain the cellular signaling pathways involved in this model. The administration of VPA prior to TGF-ß1 in A549 cells prevented EMT in both a time- and concentration-dependent manner. Pretreatment with VPA downregulated the expression of both p-Smad2/3 and p-Akt. A8301 administration increased the expression of E-cadherin and reduced the expression of vimentin. LY294002 inhibited Akt phosphorylation induced by TGF-ß1 but failed to prevent EMT. Pretreatment with VPA both increased the survival rate and prevented the loss of body weight in mice with pulmonary fibrosis. Interestingly, both VPA and A8301 prevented EMT and facilitated an improvement in lung structure. Overall, pretreatment with VPA attenuated the development of pulmonary fibrosis by inhibiting EMT in mice, which was associated with Smad2/3 deactivation but without Akt cellular signal involvement.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Fibrose Pulmonar/metabolismo , Ácido Valproico/farmacologia , Células A549 , Animais , Humanos , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad Reguladas por Receptor/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
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