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1.
J Biomech ; 127: 110666, 2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34371474

RESUMO

Underwater explosion (UNDEX) can cause severe damage to hull structure, equipment and human. In this paper, the effect of UNDEX load, including shock wave and bubble pulsation, on seated human response was investigated. The incident pressure of non-contact UNDEX was calculated. A lumped parameter interaction model of the ship structure (single-deck and multi-deck) and seated human was created based on the Taylor's theory and its veracity was verified. The results indicated that the pelvis, which is in direct contact with the structure, is the most vulnerable part of seated human when suffered impact. The shock wave and bubble pulsation had equal destructive potential to upper torso, viscera and head. The low pass filtering feature of multi-deck configuration may magnify the human response caused by the upper deck motion. The energy carried by the low and high frequency component was the dominant factors to human injury and the broadband protection to human shock isolation design is essential.

2.
J Plant Physiol ; 264: 153487, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34358944

RESUMO

AtCYP38, a thylakoid lumen localized immunophilin, is found to be essential for photosystem II assembly and maintenance, but how AtCYP38 functions in chloroplast remains unknown. Based on previous functional studies and its crystal structure, we hypothesize that AtCYP38 should function via binding its targets or cofactors in the thylakoid lumen. To identify potential interacting proteins of AtCYP38, we first adopted ATTED-II and STRING web-tools, and found 12 proteins functionally related to AtCYP38. We then screened a yeast two-hybrid library including an Arabidopsis genome wide cDNA with different domain of AtCYP38, and five thylakoid lumen-localized targets were identified. In order to specifically search interacting proteins of AtCYP38 in the thylakoid lumen, we generated a yeast two-hybrid mini library including the thylakoid lumenal proteins and lumenal fractions of thylakoid membrane proteins, and we obtained six thylakoid membrane proteins and nine thylakoid lumenal proteins as interacting proteins of AtCYP38. The interactions between AtCYP38 and several potential targets were further confirmed via pull-down and co-immunoprecipitation assays. Together, a couple of new potential candidate interacting proteins of AtCYP38 were identified, and the results will lay a foundation for unveiling the regulatory mechanisms in photosynthesis by AtCYP38.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Cloroplastos/metabolismo , Ciclofilinas/metabolismo , Proteínas de Arabidopsis/fisiologia , Ciclofilinas/fisiologia , Imunoprecipitação , Complexo de Proteína do Fotossistema II/metabolismo , Domínios e Motivos de Interação entre Proteínas , Técnicas do Sistema de Duplo-Híbrido
3.
Drug Des Devel Ther ; 15: 689-698, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33628014

RESUMO

Purpose: The present study aimed to determine the effectiveness of intravenous dexmedetomidine of different concentrations and to evaluate its maternal and neonatal safety when combined with butorphanol in parturients undergoing cesarean section. Patients and Methods: A total of 114 parturients between 24 and 43 years of age, with singleton pregnancy who underwent elective cesarean section under epidural anesthesia, were randomly allocated to four groups: group C received 0.9% sodium chloride after delivery, followed by butorphanol (3 µg·kg-1·h-1); patients in groups D1, D2, and D3 received 0.5 µg·kg-1·h-1 dexmedetomidine after delivery, followed by butorphanol (3 µg·kg-1·h-1) combined with dexmedetomidine 0.03, 0.05, and 0.08 µg·kg-1·h-1, respectively. The primary outcome was the visual analogue scale (VAS) score at 6 h after delivery when patients were at rest. Secondary outcome measures included VAS after delivery when patients were on movement and uterine cramping, Ramsay sedation scale (RSS), relative infant dose (RID) of dexmedetomidine, satisfaction with analgesia after surgery and symptoms of CNS depression in neonates. Results: There were no significant differences in patient characteristics among the groups (P > 0.05). The VAS at all timepoints after delivery in groups D2 and D3 were significantly lower than in groups C and D1 (P < 0.001). RSS scores were clearly higher in group D3 than in the other three groups at 6 h and 12 h (P < 0.0001). RID in groups D1, D2, and D3 was 0.171%, 0.197%, and 0.370%, respectively. Compared with group D1, RID was higher in group D3 (P = 0.0079). Degree of satisfaction with analgesia was higher in groups D2 and D3 (P < 0.005). Conclusion: Continuous intravenous infusion of 0.05 µg·kg-1·h-1 dexmedetomidine combined with 3 µg·kg-1·h-1 butorphanol could be safely applied in healthy parturients with satisfactory analgesia after cesarean section without changes in sedation.


Assuntos
Analgésicos Opioides/uso terapêutico , Butorfanol/uso terapêutico , Dexmedetomidina/uso terapêutico , Dor Pós-Operatória/tratamento farmacológico , Adulto , Analgesia Controlada pelo Paciente , Analgésicos Opioides/administração & dosagem , Butorfanol/administração & dosagem , Cesárea , Dexmedetomidina/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Injeções Intravenosas , Estrutura Molecular , Dor Pós-Operatória/cirurgia , Gravidez , Relação Estrutura-Atividade , Adulto Jovem
4.
BMC Anesthesiol ; 21(1): 49, 2021 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-33581727

RESUMO

BACKGROUND: Postoperative nausea and vomiting (PONV) is one of the most frequent complications following strabismus surgery. Penehyclidine, an anticholinergic agent, is widely used as premedication. This study investigated the effect of preoperative penehyclidine on PONV in patients undergoing strabismus surgery. METHODS: In this prospective, randomized, double-blind study, patients scheduled for strabismus surgery under general anesthesia were randomly assigned to either penehyclidine (n = 114) or normal saline (n = 104) group. Penehyclidine was administrated immediately after anesthesia induction, and normal saline was substituted as control. PONV was investigated from 0 to 48 h after surgery. Intraoperative oculocardiac reflex (OCR) was also recorded. RESULTS: Compared with normal saline, penehyclidine significantly reduced PONV incidence (30.7% vs. 54.8%, P < 0.01) and mitigated PONV severity as indicated by severity scoring (P < 0.01). Compared with normal saline, penehyclidine also significantly reduced OCR incidence (57.9% vs. 77.9%, P < 0.01) and mitigated OCR severity, as indicated by the requirement for atropine rescue (77.3% vs. 90.1%, P < 0.05) and the maximum decrease of heart rate during OCR (23.1 ± 9.4 bpm vs. 27.3 ± 12.4 bpm, P < 0.05). The recovery course did not differ between groups. CONCLUSIONS: Penehyclidine administrated after anesthesia induction significantly reduced the incidence of PONV and alleviated intraoperative OCR in patients undergoing strabismus surgery. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT04054479 ). Retrospectively registered August 13, 2019.

5.
Anticancer Drugs ; 32(1): 66-73, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32932277

RESUMO

A growing number of evidence has revealed that aberrantly expressed long noncoding RNAs (lncRNAs) are involved in the development of a variety of malignancies, including colorectal cancer (CRC). However, the clinical relevance of most lncRNAs and their potential biological functions in CRC remains poorly understood. The aim of this study was to identify the key lncRNAs related to patient prognosis as well as their biological function and underlying mechanism in CRC. Therefore, five independent datasets containing CRC and normal tissue RNA sequencing, microarray data and the corresponding clinical data from The Cancer Genome Atlas and Gene Expression Omnibus were screened. Hundreds of significantly differentially expressed lncRNAs in CRC were determined, and Kaplan-Meier analyses revealed that some of these lncRNAs were related to the overall survival and progression-free survival of patients with CRC, such as RP11-108K3.2, FOXD3-AS1, H19 and AP001469.9. Among these dysregulated lncRNAs, LINC02163 and FEZF1-AS1 were significantly upregulated in CRC tissues, suggesting that they may have oncogenic roles in CRC. Furthermore, loss of function assays revealed that downregulation of LINC02163 and FEZF1-AS1 impaired CRC cell proliferation. In addition, RNA Immunoprecipitation and Chromatin Immunoprecipitation assays determined that FEZF1-AS1 regulates CRC cell growth via interacting with LSD1 and repressing KLF2 expression. Collectively, hundreds of dysregulated lncRNAs and their associated biological roles identified in this study may provide potentially useful biomarkers and therapeutic targets for CRC.

6.
Int J Clin Pract ; 74(12): e13642, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32741071

RESUMO

BACKGROUND: Fentanyl-induced cough (FIC) usually occurs after the intravenous administration of fentanyl during general anaesthesia induction. It is a transient condition depending on the fentanyl administration dose and injection speed. Oxycodone can also prevent FIC because it has been proven to treat coughing. This study aimed to evaluate the efficacy of different oxycodone doses to prevent FIC during general anaesthesia induction. METHODS: In a double-blind randomised controlled trial, 210 adult patients who were undergoing elective surgery, classified as American Society of Anaesthesiologists physical status I-II, and aged 20-65 years were randomly assigned into five equally sized groups: Sham group, Group Ⅰ, Group II, Group III and Group IV. Groups Ⅰ-IV were each intravenously injected with oxycodone 0.025, 0.05, 0.075 and 0.100 mg/kg, while an equal volume of normal saline was given instead of oxycodone in the Sham group. Five minutes later, fentanyl 3 µg/kg was intravenously injected within 5 seconds, then, 2 minutes later the other drugs were administered for general anaesthesia induction. The occurrence and severity of coughing were observed within 2 minutes of the fentanyl injection. Vital signs and intensities of coughing were recorded and analysed. RESULTS: Coughing incidences were each 57.1, 50, 42.8, 33.3 and 21.4% in the Sham group and Groups Ⅰ-IV. Significant differences were found in the incidences of coughing between the Sham group and Groups III-IV. No significant differences in FIC incidences have been detected between the Sham group and Groups Ⅰ-II. However, no significant difference in FIC incidence existed between Group III and Group IV. Cough severities in Groups III and IV were significantly lower than in Groups Ⅰ and II (P < .05). No significant differences existed in the hypotension or severe bradycardia incidences during anaesthesia induction among the five groups (P > .05). CONCLUSION: Oxycodone 0.075 mg/kg provided more effective FIC prevention during general anaesthesia induction.


Assuntos
Oxicodona , Preparações Farmacêuticas , Adulto , Idoso , Anestesia Geral/efeitos adversos , Tosse/induzido quimicamente , Tosse/prevenção & controle , Fentanila/efeitos adversos , Humanos , Pessoa de Meia-Idade , Oxicodona/efeitos adversos , Adulto Jovem
7.
Clin Oral Investig ; 24(12): 4335-4342, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32748071

RESUMO

OBJECTIVE: In this study, we aimed to assess the feasibility of fiberoptic intubation (FOI), using a new, self-designed, "tongue root holder" device, in combination with the jaw thrust maneuver. METHODS: Three hundred patients undergoing elective surgery requiring orotracheal intubation were enrolled. Patients presented at least one or more risk factors for difficult airway. The patients were randomly allocated at a 1:1 ratio to one of two groups: group L, FOI with tongue root holder, or group C, standard FOI. Orotracheal FOI was performed after commencement of anesthesia. The jaw thrust maneuver was applied in both groups to facilitate advancement of the fiberoptic bronchoscope. The primary endpoint was the feasibility of FOI. The secondary endpoints were number of attempts, time to intubation, and airway clearance at the soft palate and epiglottis levels. RESULTS: The FOI was achieved in all 150 patients in group L, significantly higher than that in group C (100% vs 95.3%; P = 0.015). Less attempts of intubation were made in group L (P = 0.039). Mean time to successful intubation on the first attempt was shorter in group L (P < 0.001). The mean times to view the vocal cord and carina were also shorter in group L (P = 0.011 and P < 0.001, respectively). Airway clearance was better in group L at both the soft palate and the glottis levels (P = 0.010 and P = 0.038, respectively). CONCLUSIONS: This study shows that FOI is feasible with the newly introduced, self-designed, "tongue root holder" device, when combined with the jaw thrust maneuver in patients with risk factors for difficult airway. The device also provides better airway clearance, less intubation attempts, and shorter time to intubation at first attempt. CLINICAL RELEVANCE: Fiberoptic bronchoscope has been the gold standard for routine management of difficult airway. A technique to open the airway is introduced to reduce the incidence rate of upper airway obstruction.


Assuntos
Tecnologia de Fibra Óptica , Intubação Intratraqueal , Humanos , Palato Mole , Fatores de Risco , Língua
8.
Theranostics ; 10(19): 8573-8590, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32754264

RESUMO

Background: Metastasis accounts for 90% of cancer-associated mortality in patients with renal cell carcinoma (RCC). However, the clinical management of RCC metastasis is challenging. Lactate export is known to play an important role in cancer cell migration. This study investigated the role of heat shock protein A12A (HSPA12A) in RCC migration. Methods: HSPA12A expression was examined in 82 pairs of matched RCC tumors and corresponding normal kidney tissues from patients by immunoblotting and immunofluorescence analyses. The proliferation of RCC cells was analyzed using MTT and EdU incorporation assays. The migration of RCC cells was evaluated by wound healing and Transwell migration assays. Extracellular acidification was examined using Seahorse technology. Protein stability was determined following treatment with protein synthesis inhibitor cycloheximide and proteasome inhibitor MG132. Mass spectrometry, immunoprecipitation, and immunoblotting were employed to examine protein-protein interactions. Results: RCC tumors from patients showed downregulation of HSPA12A, which was associated with advanced tumor node metastasis stage. Intriguingly, overexpression of HSPA12A in RCC cells inhibited migration, whereas HSPA12A knockdown had the opposite effect. Lactate export, glycolysis rate, and CD147 protein abundance were also inhibited by HSPA12A overexpression but promoted by HSPA12A knockdown. An interaction of HSPA12A with HRD1 ubiquitin E3 ligase was detected in RCC cells. Further studies demonstrated that CD147 ubiquitination and proteasomal degradation were promoted by HSPA12A overexpression whereas inhibited by HSPA12A knockdown. Notably, the HSPA12A overexpression-induced inhibition of lactate export and migration were abolished by CD147 overexpression. Conclusion: Human RCC shows downregulation of HSPA12A. Overexpression of HSPA12A in RCC cells unstabilizes CD147 through increasing its ubiquitin-proteasome degradation, thereby inhibits lactate export and glycolysis, and ultimately suppresses RCC cell migration. Our results demonstrate that overexpression of HSPA12A might represent a viable strategy for managing RCC metastasis.


Assuntos
Basigina/metabolismo , Carcinoma de Células Renais/patologia , Regulação para Baixo , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Neoplasias Renais/patologia , Ácido Láctico/metabolismo , Transporte Biológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Glicólise , Células Hep G2 , Humanos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Prognóstico , Estabilidade Proteica , Análise de Sobrevida
9.
Cell Death Differ ; 27(9): 2651-2667, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32332915

RESUMO

Liver dysfunction is strongly associated with poor survival of sepsis patients. Cytosolic lipopolysaccharide (LPS) sensing by Caspase-4/5/11 for pyroptosis activation is a major driver of the development of sepsis. Studies in macrophages and endothelial cells have demonstrated that LPS is inactivated by acyloxyacyl hydrolase (AOAH) and leading to desensitizing Caspase-4/5/11 to LPS. However, little is known about the cytosolic LPS-induced pyroptosis in hepatocytes during sepsis. Heat shock protein 12A (HSPA12A) is a novel member of the HSP70 family. Here, we report that LPS increased HSPA12A nuclear translocation in hepatocytes, while knockout of HSPA12A (Hspa12a-/-) in mice promoted LPS-induced acute liver injury. We also noticed that the LPS-induced Caspase-11 activation and its cleavage of gasdermin D (GSDMD) to produce the membrane pore-forming GSDMDNterm (markers of pyroptosis) were greater in livers of Hspa12a-/- mice compared with its wild type controls. Loss- and gain-of-function studies showed that HSPA12A deficiency promoted, whereas HSPA12A overexpression inhibited, cytosolic LPS accumulation, Caspase-11 activation and GSDMDNterm generation in primary hepatocytes following LPS incubation. Notably, LPS-induced AOAH expression was suppressed by HSPA12A deficiency, whereas AOAH overexpression reversed the HSPA12A deficiency-induced promotion of LPS-evoked and Caspase-11-mediated pyroptosis of hepatocytes. In-depth molecular analysis showed that HSPA12A interacted directly with peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and increased its nuclear translocation, thereby inducing AOAH expression for cytosolic LPS inactivation, which ultimately leading to inhibition of the Caspase-11 mediated pyroptosis of hepatocytes. Taken together, these findings revealed HSPA12A as a novel player against LPS-induced liver injury by inhibiting cytosolic LPS-induced hepatocyte pyroptosis via PGC-1α-mediated AOAH expression. Therefore, targeting hepatocyte HSPA12A represents a viable strategy for the management of liver injury in sepsis patients.

10.
J Cell Sci ; 133(8)2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32184267

RESUMO

Folding of proteins entering the mammalian secretory pathway requires the insertion of the correct disulfides. Disulfide formation involves both an oxidative pathway for their insertion and a reductive pathway to remove incorrectly formed disulfides. Reduction of these disulfides is crucial for correct folding and degradation of misfolded proteins. Previously, we showed that the reductive pathway is driven by NADPH generated in the cytosol. Here, by reconstituting the pathway using purified proteins and ER microsomal membranes, we demonstrate that the thioredoxin reductase system provides the minimal cytosolic components required for reducing proteins within the ER lumen. In particular, saturation of the pathway and its protease sensitivity demonstrates the requirement for a membrane protein to shuttle electrons from the cytosol to the ER. These results provide compelling evidence for the crucial role of the cytosol in regulating ER redox homeostasis, ensuring correct protein folding and facilitating the degradation of misfolded ER proteins.


Assuntos
Proteínas de Membrana , Tiorredoxina Dissulfeto Redutase , Animais , Citosol , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Oxirredução , Dobramento de Proteína , Tiorredoxina Dissulfeto Redutase/genética , Tiorredoxina Dissulfeto Redutase/metabolismo
11.
Int J Biol Sci ; 16(6): 935-946, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32140063

RESUMO

Lymphoma is a malignant disease of the hematopoietic system that typically affects B cells. The up-regulation of miR-148b is associated with radiosensitization in B-cell lymphoma (BCL). This study aimed to explore the role of miR-148b in regulating the radiosensitivity of BCL cells and to investigate the underlying mechanism. miR-148b directly targeted Bcl-w, decreased the cell viability and colony formation, while promoted apoptosis, in irradiated BCL cells. These changes were accompanied by decreased mitochondrial membrane potential, release of cytochrome C, increased levels of the cleaved caspase 9 and caspase 3, and increased expression of other proteins related to the mitochondrial apoptosis pathway. These effects of miR-148b were effectively inhibited by Bcl-w. In addition, miR-148b inhibited the growth of tumors in nude mice implanted with xenografts of irradiated Raji cells. In patients with BCL, levels of miR-148b were downregulated, while levels of Bcl-w were upregulated; a significant negative correlation between levels of miR-148b and Bcl-w was confirmed. Taken together, these experiments showed that miR-148b promoted radiation-induced apoptosis in BCL cells by targeting anti-apoptotic Bcl-w. miR-148b might be used as a marker to predict the radiosensitivity of BCL.


Assuntos
MicroRNAs/metabolismo , Adulto , Idoso , Animais , Apoptose/genética , Apoptose/fisiologia , Western Blotting , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Lentivirus/genética , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Linfoma de Células B , Masculino , Potencial da Membrana Mitocondrial/genética , Potencial da Membrana Mitocondrial/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Pessoa de Meia-Idade , Fases de Leitura Aberta/genética , Reação em Cadeia da Polimerase em Tempo Real
12.
FEBS J ; 287(24): 5464-5477, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32128976

RESUMO

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. Proliferating cell nuclear antigen (PCNA) plays a pivotal role in cancer development and progression. However, the long-term dismal prognosis of HCC mandates more investigation to identify novel regulators in HCC pathogenesis. Heat-shock protein A12A (HSPA12A) encodes a novel member of the HSP70 family. Here, we report that HCC cells showed increased HSPA12A expression, and overexpression of HSPA12A promoted HCC growth and angiogenesis in mice. Gain- and loss-of-functional studies demonstrated that the proliferation of HCC HepG2 cells, as well as ß-catenin expression and nuclear translocation, was promoted by HSPA12A overexpression, but in turn suppressed by HSPA12A knockdown. HSPA12A did not impact PCNA expression; however, mass spectrometry and co-immunoprecipitation immunoblotting analysis revealed that HSPA12A directly binds to PCNA and promotes its trimerization, which is an essential functional conformation of PCNA for carcinogenesis. Importantly, PCNA inhibition by PCNA-I1 reversed the HSPA12A-mediated HepG2 cell differentiation. These findings indicate that HSPA12A is a novel regulator of HCC cell proliferation and tumor growth through binding to PCNA for its trimerization. HSPA12A inhibition might represent a viable strategy for the management of HCC in humans.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células , Proteínas de Choque Térmico HSP70/metabolismo , Neoplasias Hepáticas/patologia , Neovascularização Patológica/patologia , Antígeno Nuclear de Célula em Proliferação/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas de Choque Térmico HSP70/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Nus , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Fosforilação , Antígeno Nuclear de Célula em Proliferação/genética , Ligação Proteica , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Cell Stress Chaperones ; 25(3): 455-466, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32219685

RESUMO

Endothelial cells play essential roles in angiogenesis. Heat shock protein A12B (HSPA12B), a novel member of the multigene Hsp70 family, expresses specifically in endothelial cells. Alpha-lipoic acid (LA) has been used for the treatment of human diabetic complications for more than 20 years. However, little is known whether LA impacts endothelial proliferation and migration. To address these questions, primary human umbilical vein endothelial cells (HUVECs) were isolated and treated with LA. We found that LA reduced viable HUVECs but not caused LDH leakage and nuclear condensation, suggesting an inhibitory effect of LA on HUVEC proliferation. We also noticed that LA impeded wound closure of HUVEC monolayers. The expressions of C-Myc, VEGF, and eNOS and phosphorylation of focal adhesion kinase were reduced by LA. Moreover, LA decreased the expression of heat shock protein A12B (HSPA12B). Notably, overexpression of HSPA12B in endothelial cells prevented the LA-induced loss of VEGF. More importantly, HSPA12B overexpression attenuated the LA-induced inhibition of endothelial proliferation and migration. Collectively, the results demonstrated that LA inhibited proliferative and migratory abilities in human vascular endothelial cells through the downregulation of the HSPA12B/VEGF signaling axis. The data suggest that besides the treatment in diabetic complications, LA might represent a viable therapeutic potential for human diseases that involve high angiogenic activities such as cancers.


Assuntos
Proteínas de Choque Térmico HSP70/metabolismo , Ácido Tióctico/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Regulação para Baixo , Quinase 1 de Adesão Focal/metabolismo , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico/metabolismo , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Óxido Nítrico Sintase Tipo III/metabolismo , Transdução de Sinais/efeitos dos fármacos
14.
FEBS Open Bio ; 10(4): 607-618, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32090494

RESUMO

Lung cancer is the leading cause of cancer-related death, and there remains a need for novel therapies for this malignancy. Here, we examined the effects of alpha-lipoic acid (LA), a drug used for treating human diabetic complications, on lung cancer growth. We report that LA limited lung cancer growth in xenograft mice and reduced lung cancer A549 cell viability. We observed autophagy activation in human lung cancers, and report that LA inactivated autophagy in A549 cells. In addition, LA activated mammalian target of rapamycin (mTOR)/p70S6K signaling. Inhibition of mTOR with rapamycin reversed LA-induced inactivation of autophagy and abolished LA-induced suppression of A549 cell viability. Altogether, the data suggest that LA exerts an anti-lung cancer effect through mTOR-mediated inhibition of autophagy, and thus LA may have therapeutic potential for lung cancer management.

15.
J Biol Chem ; 295(8): 2438-2448, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-31953323

RESUMO

How and when disulfide bonds form in proteins relative to the stage of their folding is a fundamental question in cell biology. Two models describe this relationship: the folded precursor model, in which a nascent structure forms before disulfides do, and the quasi-stochastic model, where disulfides form prior to folding. Here we investigated oxidative folding of three structurally diverse substrates, ß2-microglobulin, prolactin, and the disintegrin domain of ADAM metallopeptidase domain 10 (ADAM10), to understand how these mechanisms apply in a cellular context. We used a eukaryotic cell-free translation system in which we could identify disulfide isomers in stalled translation intermediates to characterize the timing of disulfide formation relative to translocation into the endoplasmic reticulum and the presence of non-native disulfides. Our results indicate that in a domain lacking secondary structure, disulfides form before conformational folding through a process prone to nonnative disulfide formation, whereas in proteins with defined secondary structure, native disulfide formation occurs after partial folding. These findings reveal that the nascent protein structure promotes correct disulfide formation during cotranslational folding.


Assuntos
Proteína ADAM10/química , Proteína ADAM10/metabolismo , Secretases da Proteína Precursora do Amiloide/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Dissulfetos/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Prolactina/química , Prolactina/metabolismo , Dobramento de Proteína , Microglobulina beta-2/química , Microglobulina beta-2/metabolismo , Animais , Bovinos , Cisteína/metabolismo , Retículo Endoplasmático/metabolismo , Humanos , Modelos Moleculares , Domínios Proteicos , Estrutura Secundária de Proteína , Ribossomos/metabolismo , Processos Estocásticos , Fatores de Tempo
16.
Phys Chem Chem Phys ; 22(4): 2449-2456, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31939946

RESUMO

First-principles calculations based on density functional theory were carried out to explore the geometric structure, light absorption, charge separation, over-potential and stability of Bi2O4 (101)/BiVO4 (010) heterojunction. The results show that the formed heterojunction can improve visible light utilization and promote transfer of photo-generated holes from BiVO4 to Bi2O4. Furthermore, the Bi5+ site in the Bi2O4(101) surface is energetically more favorable as the photoanode for the oxygen evolution reaction (OER) than the Bi3+ sites in Bi2O4(101) and BiVO4(010). At the same time, it is also found that the Bi5+ in Bi2O4(101) are more stable than the Bi3+ due to the lower surface energy and stronger bond energy with neighbors. Therefore, forming the Bi2O4/BiVO4 heterojunction can effectively improve the activity and stability of BiVO4 for water splitting reactions.

17.
ACS Appl Mater Interfaces ; 11(39): 35914-35923, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31495172

RESUMO

The ON/OFF ratio and long-term stability are two important issues for flexible organic-inorganic hybrid perovskite (OHP) resistive random access memory (RRAM) for practical applications. In this work, polyvinylammonium (PVAm) is applied to partially replace methylamine ions (MA+) to fabricate the stable and flexible polymeric OHP RRAM devices, wherein PVAm acts as nucleation sites and the template for crystalline growth of MAPbI3 to tune the microscopic perovskite structure. Simultaneously, the multiple perovskite grain interfaces are strengthened through the long-carbochain polymeric backbone, hence producing a continuous and compact perovskite film. As a result, the PVAm-modified OHP RRAM device shows remarkable enhancement of the ON/OFF ratio, long-term stability, and flexibility compared with the unmodified OHP device. Specifically, the polymeric OHP device exhibits fast and stable nonvolatile resistive switching (RS) characteristics with an ON/OFF ratio of ∼105 and a set voltage of -0.45 V under ambient conditions. Also, the distinct multilevel RS behavior can be realized in this device by controlling the compliance current in the SET process. Additionally, the unsealed polymeric OHP device manifests the striking long-term stability, which can still maintain the stable memory performance after 1 year exposure to the humid and thermal ambient environment. Furthermore, the flexible polymeric OHP device was also fabricated and affords the excellent bending endurance behavior by showing a reproducible RS property over 100-cycle bending experiments. This work provides a new perovskite-based material design strategy of polymeric OHP for stable and flexible RRAM devices with the high ON/OFF ratio.

18.
Front Chem ; 7: 444, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31263695

RESUMO

Ni5P4 has received considerable attention recently as a potentially viable substitute for Pt as the cathode material for catalytic water splitting. The current investigation focuses on theoretical understandings of the characteristics of active sites toward water splitting using first-principle calculations. The results indicate that the activity of bridge NiNi sites is highly related on the bond number with neighbors. If the total bond number of NiNi is higher than 14, the sites will exhibit excellent HER performance. For the top P sites, the activity is greatly affected by the position of coplanar atoms besides the bond number. Data of bond length with neighbors can be used to predict the activity of P sites as reviewed by machine learning. Partial density of state (PDOS) analysis of different P sites illustrates that the activity of P sites should form the appropriate bond to localize some 3p orbits of the P atoms. Bond number and position of neighbors are two key parameters for the prediction of the HER activity. Based on the current work, most of the low-energy surfaces of Ni5P4 are active, indicating a good potential of this materials for hydrogen evolution reactions.

19.
Clin Endosc ; 52(4): 365-368, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30862154

RESUMO

Air embolism is a rare complication of upper endoscopy and potentially causes life-threatening events. A 67-year-old man with a history of surgery of cardiac carcinoma and pancreatic neuroendocrine tumor underwent painless upper endoscopy because of tarry stools. During the procedure, air embolism developed, which caused decreased pulse oxygen saturation and delayed sedation recovery. He recovered with some weakness of the left upper limb in the intensive care unit without hyperbaric oxygen therapy. The etiology, clinical manifestations, and treatments of air embolism are discussed based on the literature reports. Although air embolism is uncommon in endoscopic examinations, the patients' outcomes could be improved if clinicians are alert to this potential complication, and promptly start proper diagnostic and therapeutic measures.

20.
BMC Cancer ; 19(1): 209, 2019 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-30849960

RESUMO

BACKGROUND: MicroRNA-148b (miR-148b) has been detected in various types of tumors, and is generally viewed as a tumor suppressor. Our previous study found the decreased expression of miR-148b in human non small cell lung cancer (NSCLC) specimens and cell lines. However, the underlying mechanisms of miR-148b in regulating tumor progression remain unclear. METHODS: Firstly animal experiments were performed to verify whether miR-148b could inhibit the tumor growth. Then, the underlying mechanisms were studied by transfecting recombinant plasmids containing a miR-148b mimic or a negative control (NC) mimic (shRNA control) into NSCLC cell lines PC14/B and A549 cells. Tumor cells transfected with unpackaged lentiviral vectors was used as blank control. Cell proliferation capabilities were measured by using CCK-8 kit and colony formation assay. Cell cycle arrest was compared to clarify the mechanism underlying the tumor cell proliferation. Annexin V-FITC Apoptosis Detection kit was applied to investigate the effect of miR-148b on cell apoptosis. Furthermore, western blot analysis were performed to study the targeting pathway. RESULTS: We found that over-expression of miR148b could significantly inhibit tumor growth, while knocking down miR148b could obviously promote tumor growth. Further experiment showed that miR-148b inhibited tumor cell proliferation. Besides, over-expression of miR148b decreased the G2/M phase population of the cell cycle by preventing NSCLC cells from entering the mitotic phase and enhanced tumor cell apoptosis. Further western blot analysis indicated that miR148b could inhibit mitogen-activated protein kinase/Jun N-terminal kinase (MAPK/JNK) signaling by decreasing the expression of phosphorylated (p) JNK. CONCLUSIONS: These results demonstrate that miR-148b could inhibit the tumor growth and act as tumor suppressor by inhibiting the proliferation and inducing apoptosis of NSCLC cells by blocking the MAPK/JNK pathway.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Sistema de Sinalização das MAP Quinases , MicroRNAs/genética , Animais , Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Feminino , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Fosforilação , Interferência de RNA
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