Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 62
Filtrar
1.
Proc Natl Acad Sci U S A ; 121(19): e2315729121, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38687789

RESUMO

Genetic elements are foundational in synthetic biology serving as vital building blocks. They enable programming host cells for efficient production of valuable chemicals and recombinant proteins. The unfolded protein response (UPR) is a stress pathway in which the transcription factor Hac1 interacts with the upstream unfolded protein response element (UPRE) of the promoter to restore endoplasmic reticulum (ER) homeostasis. Here, we created a UPRE2 mutant (UPRE2m) library. Several rounds of screening identified many elements with enhanced responsiveness and a wider dynamic range. The most active element m84 displayed a response activity 3.72 times higher than the native UPRE2. These potent elements are versatile and compatible with various promoters. Overexpression of HAC1 enhanced stress signal transduction, expanding the signal output range of UPRE2m. Through molecular modeling and site-directed mutagenesis, we pinpointed the DNA-binding residue Lys60 in Hac1(Hac1-K60). We also confirmed that UPRE2m exhibited a higher binding affinity to Hac1. This shed light on the mechanism underlying the Hac1-UPRE2m interaction. Importantly, applying UPRE2m for target gene regulation effectively increased both recombinant protein production and natural product synthesis. These genetic elements provide valuable tools for dynamically regulating gene expression in yeast cell factories.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica , Regulação Fúngica da Expressão Gênica , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Resposta a Proteínas não Dobradas , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Resposta a Proteínas não Dobradas/genética , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Regiões Promotoras Genéticas , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Retículo Endoplasmático/metabolismo , Transdução de Sinais/genética
2.
Phys Chem Chem Phys ; 26(15): 11722-11730, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38563575

RESUMO

Ferrovalley materials hold great promise for implementation of logic and memory devices in valleytronics. However, there have so far been limited ferrovalley materials exhibiting significant valley polarization and high Curie temperature (TC). Using first-principles calculations, we predict that the TiTeBr monolayer is a promising ferrovalley candidate. It exhibits intrinsic ferromagnetism with TC as high as 220 K. It is indicated that an out-of-plane alignment of magnetization demonstrates a valley polarization up to 113 meV in the topmost valence band, as further verified by perturbation theory considering both the spin polarization and spin-orbit coupling. Under an in-plane electric field, the valley-dependent Berry curvature results in the anomalous valley Hall effect (AVHE). Moreover, under a suitable in-plane biaxial strain, the TiTeBr monolayer transforms into a Chern insulator with a nonzero Chern number, yet retains its ferrovalley characters and thus the emergent quantum anomalous valley Hall effect (QAVHE). Our study indicates that the TiTeBr monolayer is a promising ferrovalley material, and it provides a platform for investigating the valley-dependent Hall effect.

3.
J Transl Med ; 21(1): 726, 2023 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-37845765

RESUMO

OBJECTIVES: Gastrointestinal stromal tumors (GISTs) carrying different KIT exon 11 (KIT-11) mutations exhibit varying prognoses and responses to Imatinib. Herein, we aimed to determine whether computed tomography (CT) radiomics can accurately stratify KIT-11 mutation genotypes to benefit Imatinib therapy and GISTs monitoring. METHODS: Overall, 1143 GISTs from 3 independent centers were separated into a training cohort (TC) or validation cohort (VC). In addition, the KIT-11 mutation genotype was classified into 4 categories: no KIT-11 mutation (K11-NM), point mutations or duplications (K11-PM/D), KIT-11 557/558 deletions (K11-557/558D), and KIT-11 deletion without codons 557/558 involvement (K11-D). Subsequently, radiomic signatures (RS) were generated based on the arterial phase of contrast CT, which were then developed as KIT-11 mutation predictors using 1408 quantitative image features and LASSO regression analysis, with further evaluation of its predictive capability. RESULTS: The TC AUCs for K11-NM, K11-PM/D, K11-557/558D, and K11-D ranged from 0.848 (95% CI 0.812-0.884), 0.759 (95% CI 0.722-0.797), 0.956 (95% CI 0.938-0.974), and 0.876 (95% CI 0.844-0.908), whereas the VC AUCs ranged from 0.723 (95% CI 0.660-0.786), 0.688 (95% CI 0.643-0.732), 0.870 (95% CI 0.824-0.918), and 0.830 (95% CI 0.780-0.878). Macro-weighted AUCs for the KIT-11 mutant genotype ranged from 0.838 (95% CI 0.820-0.855) in the TC to 0.758 (95% CI 0.758-0.784) in VC. TC had an overall accuracy of 0.694 (95%CI 0.660-0.729) for RS-based predictions of the KIT-11 mutant genotype, whereas VC had an accuracy of 0.637 (95%CI 0.595-0.679). CONCLUSIONS: CT radiomics signature exhibited good predictive performance in estimating the KIT-11 mutation genotype, especially in prediction of K11-557/558D genotype. RS-based classification of K11-NM, K11-557/558D, and K11-D patients may be an indication for choice of Imatinib therapy.


Assuntos
Tumores do Estroma Gastrointestinal , Humanos , Tumores do Estroma Gastrointestinal/diagnóstico por imagem , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Genótipo , Mesilato de Imatinib , Mutação/genética , Proteínas Proto-Oncogênicas c-kit/genética , Receptores Proteína Tirosina Quinases , Estudos Retrospectivos
4.
Surg Endosc ; 36(6): 3798-3804, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-34462869

RESUMO

BACKGROUND: Whether to preserve the uterine round ligament during laparoscopic inguinal hernia repair in women is controversial. In this study, we aimed to compare outcomes of uterine round ligament preservation versus transection during such surgery and to explore the impact and long-term outcomes of transecting the round ligament. METHODS: The study cohort comprised 419 women who had undergone laparoscopic inguinal hernia repair in Beijing Chaoyang Hospital and Qilu Hospital from January 2013 to January 2020; 393 (93.8%) of whom were successfully followed up. Patient characteristics and technical details of the operative procedure were collected and analyzed retrospectively. Early and late postoperative follow-up data, complications, especially symptoms related to retroflexed uterus, and fertility outcomes, were collected by a single follow-up nurse who was blinded to the operative procedure. RESULTS: There were 218 women (239 sides) in the uterine round ligament preservation group and 175 (182 sides) in the transection group. The patients in the preservation group were younger (45.9 vs. 53.6 years, p = 0.000), and had lower American Society of Anesthesiologists scores (p = 0.000). The median follow-up times in the preservation and transection groups were 41.8 ± 24.2 and 42.7 ± 24.6 months, respectively (p = 0.692). Compared with the transection group, the preservation group had longer operative times for repair of both primary and recurrent hernias. Intraoperative bleeding, length of hospital stay, development of seromas, recurrence rate, incidence of postoperative pain at the first and third postoperative months, and time of last outpatient visit were similar in the two groups. There were more premenopausal patients in the preservation group; however, we found no evidence that transection of the round ligament affected subsequent pregnancy or childbirth. Moreover, we identified no differences in dyspareunia, dysmenorrhea, chronic pelvic pain, or uterine prolapse. CONCLUSION: Transection of the round ligament during laparoscopic inguinal hernia repair in women does not increase the incidence of dyspareunia, dysmenorrhea, chronic pelvic pain, or uterine prolapse, whereas it has the advantage of reducing the operation time.


Assuntos
Dispareunia , Hérnia Inguinal , Laparoscopia , Ligamentos Redondos , Prolapso Uterino , Dismenorreia/cirurgia , Feminino , Seguimentos , Hérnia Inguinal/cirurgia , Herniorrafia/métodos , Humanos , Laparoscopia/efeitos adversos , Laparoscopia/métodos , Masculino , Dor Pélvica/cirurgia , Gravidez , Estudos Retrospectivos , Ligamentos Redondos/cirurgia , Prolapso Uterino/cirurgia
5.
Angew Chem Int Ed Engl ; 61(38): e202206446, 2022 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-35866449

RESUMO

A facile benzylic alkylation of indenes and other arenes was developed from readily available primary and secondary alcohols using our newly investigated CCC pincer IrIII catalyst (SNIr-H). Excellent regioselectivity and yield (89 %) of the C3-alkylated indenes were obtained. Additionally, the challenging sp2 C-alkylation was readily accomplished. This method could be utilized for the synthesis of the analogs of a histamine H1 receptor antagonist and the functional material template molecule, indeno[2,1-a]indene. A hemilabile IrIII -dihydride intermediate was proposed based on control experiments and previous density functional theory (DFT) calculations for the borrowing hydrogen mechanism and is key to the success of this IrIII catalyst in the reduction of unactivated multi-substituted olefin intermediates.

6.
Am J Physiol Endocrinol Metab ; 321(3): E392-E409, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34370593

RESUMO

The improvement of cognitive function following bariatric surgery has been highlighted, yet its underlying mechanisms remain elusive. Finding the improved brain glucose uptake of patients after Roux-en-Y gastric bypass (RYGB), duodenum-jejunum bypass (DJB), and sham surgery (Sham) were performed on obese and diabetic Wistar rats, and intracerebroventricular (ICV) injection of glucagon-like peptide-1 (GLP-1) analog liraglutide (Lira), antagonist exendin-(9-39) (Exe-9), and the viral-mediated GLP-1 receptor (Glp-1r) knockdown (KD) were applied on both groups to elucidate the role of GLP-1 in mediating cognitive function and brain glucose uptake assessed with the Morris water maze (MWM) and positron emission tomography (PET). Insulin and GLP-1 in serum and cerebral spinal fluid (CSF) were measured, and the expression of glucose uptake-related proteins including glucose transporter 1 (GLUT-1), GLUT-4, phospho-Akt substrate of 160kDa (pAS160), AS160, Rab10, Myosin-Va as well as the c-fos marker in the brain were examined. Along with augmented glucose homeostasis following DJB, central GLP-1 was correlated with the improved cognitive function and ameliorated brain glucose uptake, which was further confirmed by the enhancive role of Lira on both groups whereas the Exe-9 and Glp-1r KD were opposite. Known to activate insulin-signaling pathways, central GLP-1 contributes to improved cognitive function and brain glucose uptake after DJB.NEW & NOTEWORTHY The improvement of cognitive function following bariatric surgery has been highlighted while its mechanisms remain elusive. The brain glucose uptake of patients was improved after RYGB, and the DJB and sham surgery performed on obese and diabetic Wistar rats revealed that the elevated central GLP-1 contributes to the dramatic improvement of cognitive function, brain glucose uptake, transport, glucose sensing, and neuronal activation.


Assuntos
Cognição , Diabetes Mellitus Experimental/metabolismo , Derivação Gástrica , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Obesidade/metabolismo , Animais , Encéfalo/metabolismo , Duodeno/cirurgia , Glucose , Jejuno/cirurgia , Obesidade/cirurgia , Ratos Wistar
7.
Biosci Biotechnol Biochem ; 85(12): 2392-2403, 2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34747973

RESUMO

Endothelial barrier integrity requires recycling of VE-cadherin to adherens junctions. Both p18 and Rab11a play significant roles in VE-cadherin recycling. However, the underlying mechanism and the role of p18 in activating Rab11a have yet to be elucidated. Performing in vitro and in vivo experiments, we showed that p18 protein bound to VE-cadherin before Rab11a through its VE-cadherin-binding domain (aa 1-39). Transendothelial resistance showed that overexpression of p18 promoted the circulation of VE-cadherin to adherens junctions and the recovery of the endothelial barrier. Silencing of p18 caused endothelial barrier dysfunction and prevented Rab11a-positive recycling endosome accumulation in the perinuclear recycling compartments. Furthermore, p18 knockdown in pulmonary microvessels markedly increased vascular leakage in mice challenged with lipopolysaccharide and cecal ligation puncture. This study showed that p18 regulated the pulmonary endothelial barrier function in vitro and in vivo by regulating the binding of Rab11a to VE-cadherin and the activation of Rab11a.


Assuntos
Antígenos CD , Caderinas
8.
Int J Obes (Lond) ; 44(12): 2394-2404, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32719432

RESUMO

BACKGROUND: Bariatric surgeries have been shown to be effective in reversing damaged pulmonary function in individuals suffering from obesity and type 2 diabetes mellitus, whereas its underlying mechanisms remain largely unknown. METHODS: Sleeve gastrectomy (SG) was performed on obese and diabetic Wistar rats, and their pulmonary function and lung tissues were compared to sham-operated (SH) obese and diabetic rats, and age-matched healthy controls (C) to explore the improvements in microstructures and expression of surfactant protein (SP)-A and -C at postoperative 4th, 8th, and 12th week. RESULT: Apart from the profound metabolic changes and improvement in pulmonary function, lung volume was restored along with an improved diffusion capacity noted by thinned capillary basement membrane and decreased harmonic mean length of diffusion barrier in SG rats. The digital slices of light microscope showed the general changes brought on by the SG, including normalized basic structures, ameliorated inflammatory status, as well as reduced lipid deposition, where the hydroxyproline (HYP), triglyceride (TG) assays, and electron microscope further suggested that the improvement in alveolar structures lies in reduced collagen fibers, lipids and septal tissues, increased capillary blood, and normalized alveolar type 2 (AT2) cells. Besides, disrupted SP-A and SP-C expression were also normalized after SG. CONCLUSION: The improvement of lung function after SG is related to the ameliorated alveolar structures, and surface protein expression induced by weight loss and improved glucose metabolism.


Assuntos
Diabetes Mellitus Experimental/cirurgia , Gastrectomia , Obesidade/cirurgia , Alvéolos Pulmonares/anatomia & histologia , Surfactantes Pulmonares/química , Animais , Pulmão , Alvéolos Pulmonares/patologia , Alvéolos Pulmonares/ultraestrutura , Ratos , Ratos Wistar , Redução de Peso
9.
Surg Endosc ; 33(4): 1147-1154, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30327912

RESUMO

BACKGROUND: Seroma is the most common early minor complication of inguinal hernia repair. Seromas generally resolve spontaneously within a few weeks, but can sometimes cause other complications. The optimal ways to repair inguinal hernia and handle the hernial sac are still debatable. Large scale, prospective, randomized, controlled studies focusing on the correlation between transection of the hernial sac and seroma formation are scarce. METHODS: A total of 159 adult male patients with primary indirect inguinal hernia who underwent laparoscopic transabdominal preperitoneal repair were recruited. The patients were randomized to undergo either complete dissection or transection of the hernial sacs. Patients were followed up at postoperative 7 days, 1 and 3 months, looking specifically for seroma. Seroma was diagnosed via physical examination, and a prestructured form was used to evaluate patient recovery and define the type of seroma present at each follow-up visit. RESULTS: There were 83 patients in the completely dissected group and 76 in the transected group. The overall incidence of postoperative seroma was 12.6% (n = 20). The χ2 test demonstrated that significantly more patients developed seroma in the transected group than in the completely dissected group (18.4% vs. 7.2%, p = 0.034); there were also significant differences between the two groups in the incidences of seroma at postoperative 7 days (18.4% vs. 6.0%, p = 0.016) and 1 month (14.5% vs. 4.8%, p = 0.037). Seroma formation was correlated with age, body mass index, use of anticoagulants, hernia type, hernia size, sac size, and operative time. There were no significant differences between the two groups in the degree of postoperative pain and time taken for the resumption of outdoor activities. CONCLUSIONS: When using the laparoscopic transabdominal preperitoneal technique for indirect inguinal hernia repair, the risk of postoperative seroma formation is greater after transection compared with complete dissection of the hernial sac.


Assuntos
Hérnia Inguinal/cirurgia , Laparoscopia/efeitos adversos , Laparoscopia/métodos , Seroma/etiologia , Adulto , Fatores Etários , Idoso , Anticoagulantes/uso terapêutico , Índice de Massa Corporal , Seguimentos , Hérnia Inguinal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Dor Pós-Operatória/etiologia , Exame Físico , Complicações Pós-Operatórias , Estudos Prospectivos , Seroma/diagnóstico
10.
J Am Chem Soc ; 140(32): 10099-10103, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30067344

RESUMO

A novel chiral spirocyclic amide (SPA)-derived triazolium organocatalyst has been designed and demonstrated to effect asymmetric homo- and heterodialkylations of various bisoxindoles, enabling enantioselective construction of vicinal all-carbon quaternary stereocenters. These reactions feature excellent enantio- and diastereoselectivities (up to 99% ee and >20:1 dr) as well as good to high yields (up to 89% over two steps). As an application of this methodology, the first asymmetric total synthesis of (-)-chimonanthidine has been achieved.

11.
Nanotechnology ; 29(10): 105402, 2018 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-29381478

RESUMO

Solar-driven photoelectrochemical (PEC) water splitting has attracted a great deal of attention recently. Silicon (Si) is an ideal light absorber for solar energy conversion. However, the poor stability and inefficient surface catalysis of Si photocathodes for the hydrogen evolution reaction (HER) have remained key challenges. Alternatively, MoS2 has been reported to exhibit excellent catalysis performance if sufficient active sites for the HER are available. Here, ultrathin MoS2 nanoflakes are directly synthesized to coat arrays of Ag-core Si-shell nanospheres (Ag@Si NSs) by using chemical vapor deposition. Due to the high surface area ratio and large curvature of these NSs, the as-grown MoS2 nanoflakes can accommodate more active sites. In addition, the high-quality coating of MoS2 nanoflakes on the Ag@Si NSs protects the photocathode from damage during the PEC reaction. An photocurrent density of 33.3 mA cm-2 at a voltage of -0.4 V is obtained versus the reversible hydrogen electrode. The as-prepared nanostructure as a hydrogen photocathode is evidenced to have high stability over 12 h PEC performance. This work opens up opportunities for composite photocathodes with high activity and stability using cheap and stable co-catalysts.

12.
Arterioscler Thromb Vasc Biol ; 36(2): 339-49, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26663395

RESUMO

OBJECTIVE: Vascular endothelial (VE)-cadherin is the predominant component of endothelial adherens junctions essential for cell-cell adhesion and formation of the vascular barrier. Endocytic recycling is an important mechanism for maintaining the expression of cell surface membrane proteins. However, little is known about the molecular mechanism of VE-cadherin recycling and its role in maintenance of vascular integrity. APPROACH AND RESULTS: Using calcium-switch assay, confocal imaging, cell surface biotinylation, and flow cytometry, we showed that VE-cadherin recycling required Ras-related proteins in brain (Rab)11a and Rab11 family-interacting protein 2. Yeast 2-hybrid assay and coimmunoprecipitation demonstrated that direct interaction of VE-cadherin with family-interacting protein 2 (at aa 453-484) formed a ternary complex with Rab11a in human endothelial cells. Silencing of Rab11a or Rab11 family-interacting protein 2 in endothelial cells prevented VE-cadherin recycling and VE-cadherin expression at endothelial plasma membrane. Furthermore, inactivation of Rab11a signaling blocked junctional reannealing after vascular inflammation. Selective knockdown of Rab11a in pulmonary microvessels markedly increased vascular leakage in mice challenged with lipopolysaccharide or polymicrobial sepsis. CONCLUSIONS: Rab11a/Rab11 family-interacting protein 2-mediated VE-cadherin recycling is required for formation of adherens junctions and restoration of VE barrier integrity and hence a potential target for clinical intervention in inflammatory disease.


Assuntos
Antígenos CD/metabolismo , Caderinas/metabolismo , Permeabilidade Capilar , Endocitose , Células Endoteliais/enzimologia , Pulmão/irrigação sanguínea , Edema Pulmonar/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo , Junções Aderentes/metabolismo , Junções Aderentes/patologia , Animais , Antígenos CD/genética , Caderinas/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Modelos Animais de Doenças , Células Endoteliais/patologia , Endotoxemia/metabolismo , Endotoxemia/microbiologia , Células HEK293 , Humanos , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Ligação Proteica , Estabilidade Proteica , Transporte Proteico , Edema Pulmonar/microbiologia , Edema Pulmonar/patologia , Interferência de RNA , Sepse/metabolismo , Sepse/microbiologia , Transdução de Sinais , Fatores de Tempo , Transfecção , Proteínas rab de Ligação ao GTP/genética
13.
J Immunol ; 193(4): 1931-41, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-25015829

RESUMO

Activation of TLR signaling through recognition of pathogen-associated molecular patterns is essential for the innate immune response against bacterial and viral infections. We have shown that p120-catenin (p120) suppresses TLR4-mediated NF-кB signaling in LPS-challenged endothelial cells. In this article, we report that p120 differentially regulates LPS/TLR4 signaling in mouse bone marrow-derived macrophages. We observed that p120 inhibited MyD88-dependent NF-κB activation and release of TNF-α and IL-6, but enhanced TIR domain-containing adapter-inducing IFN-ß-dependent IFN regulatory factor 3 activation and release of IFN-ß upon LPS exposure. p120 silencing diminished LPS-induced TLR4 internalization, whereas genetic and pharmacological inhibition of RhoA GTPase rescued the decrease in endocytosis of TLR4 and TLR4-MyD88 signaling, and reversed the increase in TLR4-TIR domain-containing adapter-inducing IFN-ß signaling induced by p120 depletion. Furthermore, we demonstrated that altered p120 expression in macrophages regulates the inflammatory phenotype of LPS-induced acute lung injury. These results indicate that p120 functions as a differential regulator of TLR4 signaling pathways by facilitating TLR4 endocytic trafficking in macrophages, and support a novel role for p120 in influencing the macrophages in the lung inflammatory response to endotoxin.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/imunologia , Cateninas/genética , Macrófagos Alveolares/imunologia , Receptor 4 Toll-Like/imunologia , Proteína rhoA de Ligação ao GTP/antagonistas & inibidores , Lesão Pulmonar Aguda/imunologia , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Cateninas/biossíntese , Células Cultivadas , Endocitose/imunologia , Fator Regulador 3 de Interferon/imunologia , Interferon beta/imunologia , Interferon beta/metabolismo , Interleucina-6/metabolismo , Contagem de Leucócitos , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 88 de Diferenciação Mieloide/imunologia , NF-kappa B/imunologia , Neutrófilos/imunologia , Transporte Proteico/imunologia , Interferência de RNA , Transdução de Sinais/imunologia , Receptor 2 Toll-Like/imunologia , Receptor 3 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismo , delta Catenina
14.
J Immunol ; 190(7): 3590-9, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23436933

RESUMO

Mechanical ventilation of lungs is capable of activating the innate immune system and inducing sterile inflammatory response. The proinflammatory cytokine IL-1ß is among the definitive markers for accurately identifying ventilator-induced lung inflammation. However, mechanisms of IL-1ß release during mechanical ventilation are unknown. In this study, we show that cyclic stretch activates the nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasomes and induces the release of IL-1ß in mouse alveolar macrophages via caspase-1- and TLR4-dependent mechanisms. We also observed that NADPH oxidase subunit gp91(phox) was dispensable for stretch-induced cytokine production, whereas mitochondrial generation of reactive oxygen species was required for stretch-induced NLRP3 inflammasome activation and IL-1ß release. Further, mechanical ventilation activated the NLRP3 inflammasomes in mouse alveolar macrophages and increased the production of IL-1ß in vivo. IL-1ß neutralization significantly reduced mechanical ventilation-induced inflammatory lung injury. These findings suggest that the alveolar macrophage NLRP3 inflammasome may sense lung alveolar stretch to induce the release of IL-1ß and hence may contribute to the mechanism of lung inflammatory injury during mechanical ventilation.


Assuntos
Proteínas de Transporte/metabolismo , Inflamassomos/metabolismo , Macrófagos Alveolares/metabolismo , Pneumonia/etiologia , Animais , Caspase 1/metabolismo , Modelos Animais de Doenças , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Macrófagos Alveolares/imunologia , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Pneumonia/imunologia , Pneumonia/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Ácido Úrico/metabolismo , Lesão Pulmonar Induzida por Ventilação Mecânica/imunologia , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismo
15.
J Immunol ; 191(12): 6191-9, 2013 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24244013

RESUMO

Activation of TLR4 by the endotoxin LPS is a critical event in the pathogenesis of Gram-negative sepsis. Caveolin-1, the signaling protein associated with caveolae, is implicated in regulating the lung inflammatory response to LPS; however, the mechanism is not understood. In this study, we investigated the role of caveolin-1 in regulating TLR4 signaling in endothelial cells. We observed that LPS interaction with CD14 in endothelial cells induced Src-dependent caveolin-1 phosphorylation at Tyr(14). Using a TLR4-MD2-CD14-transfected HEK-293 cell line and caveolin-1-deficient (cav-1(-/-)) mouse lung microvascular endothelial cells, we demonstrated that caveolin-1 phosphorylation at Tyr(14) following LPS exposure induced caveolin-1 and TLR4 interaction and, thereby, TLR4 activation of MyD88, leading to NF-κB activation and generation of proinflammatory cytokines. Exogenous expression of phosphorylation-deficient Y14F caveolin-1 mutant in cav-1(-/-) mouse pulmonary vasculature rendered the mice resistant to LPS compared with reintroduction of wild-type caveolin-1. Thus, caveolin-1 Y14 phosphorylation was required for the interaction with TLR4 and activation of TLR4-MyD88 signaling and sepsis-induced lung inflammation. Inhibiting caveolin-1 Tyr(14) phosphorylation and resultant inactivation of TLR4 signaling in pulmonary vascular endothelial cells represent a novel strategy for preventing sepsis-induced lung inflammation and injury.


Assuntos
Caveolina 1/metabolismo , Células Endoteliais/metabolismo , Fosfotirosina/fisiologia , Receptor 4 Toll-Like/fisiologia , Substituição de Aminoácidos , Animais , Caveolina 1/química , Caveolina 1/genética , Células Cultivadas , Endotélio Vascular/citologia , Endotoxemia/patologia , Humanos , Proteínas I-kappa B/metabolismo , Inflamação , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Interleucina-6/biossíntese , Interleucina-6/genética , Lipopolissacarídeos/toxicidade , Pulmão/irrigação sanguínea , Pulmão/patologia , Camundongos , Microvasos/citologia , Mutação de Sentido Incorreto , Fator 88 de Diferenciação Mieloide/fisiologia , Inibidor de NF-kappaB alfa , Fosforilação , Fosfotirosina/biossíntese , Mutação Puntual , Processamento de Proteína Pós-Traducional , Proteínas Recombinantes de Fusão/metabolismo , Transfecção , Fator de Necrose Tumoral alfa/genética , Quinases da Família src/metabolismo
16.
J Agric Food Chem ; 72(1): 516-528, 2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-38130104

RESUMO

Pterostilbene, a derivative of resveratrol, is of increasing interest due to its increased bioavailability and potential health benefits. Sustainable production of pterostilbene is important, especially given the challenges of traditional plant extraction and chemical synthesis methods. While engineered microbial cell factories provide a potential alternative for pterostilbene production, most approaches necessitate feeding intermediate compounds. To address these limitations, we adopted a modular coculture engineering strategy, dividing the pterostilbene biosynthetic pathway between two engineered E. coli strains. Using a combination of gene knockout, atmospheric and room-temperature plasma mutagenesis, and error-prone PCR-based whole genome shuffling to engineer strains for the coculture system, we achieved a pterostilbene production titer of 134.84 ± 9.28 mg/L from glucose using a 1:3 inoculation ratio and 0.1% dimethyl sulfoxide supplementation. This represents the highest reported de novo production titer. Our results underscore the potential of coculture systems and metabolic balance in microbial biosynthesis.


Assuntos
Escherichia coli , Glucose , Escherichia coli/genética , Escherichia coli/metabolismo , Glucose/metabolismo , Técnicas de Cocultura , Embaralhamento de DNA , Vias Biossintéticas , Engenharia Metabólica/métodos
17.
J Phys Condens Matter ; 36(23)2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38408425

RESUMO

Hexagonal manganites, as a functional ferroelectric (FE) material, receive considerable attention due to their improper ferroelectricity and topological vortex structures. This family exhibits three low-symmetry states accompanied by distinct vortex domain structures. In addition to the FEP63cmand anti-FE (AFE)P-3c1 states accompanied by dual six-fold vortex structures, there is another FEP3c1 state accompanied by a twelve-fold vortex structure. The responses of FE materials to external stimuli, such as external electric fields, are the core ingredients in the physics of FEs and are significant for technological applications. Under external electric fields, the responses of FE materials are determined by special FE domain structures. The electric properties of the FEP63cmand AFEP-3c1 states are very different. However, the electric properties of the FEP3c1 state, which only stabilizes in Ga-substituted In(Mn, Ga)O3, are unclear. The present work studies the electric properties of the FEP3c1 state. The electric-field-driven transition of the FEP3c1 state is found to follow two sequences, i.e. (1) twelve-foldP3c1 → nine-foldP3c1 +P63cm→ three-foldP63cm, and (2) twelve-foldP3c1 → six-foldP3c1 → three-foldP63cm. The variation of average polarization withEfor the FEP3c1 state with the second transition sequence manifests as an unusual triple-hysteresis loop, different from the usual single-hysteresis loop of FE materials. The results are related to the coexistence of the FE and non-FE domain walls in the FEP3c1 state. Furthermore, it is found that the FEP3c1 state at substitution concentration 0.39 exhibits the highest dielectric response. The results advance our understanding of topological vortex structures in hexagonal manganites.

18.
J Agric Food Chem ; 72(9): 4880-4887, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38386432

RESUMO

Dihydroquercetin (DHQ), known for its varied physiological benefits, is widely used in the food, chemical, and pharmaceutical industries. However, the efficiency of the DHQ synthesis is significantly limited by the substantial accumulation of intermediates during DHQ biosynthesis. In this study, DHQ production was achieved by integrating genes from various organisms into the yeast chromosome for the expression of flavanone-3-hydroxylase (F3H), flavonoid-3'-hydroxylase, and cytochrome P450 reductase. A computer-aided protein design approach led to the development of optimal F3H mutant P221A, resulting in a 1.67-fold increase in DHQ yield from naringenin (NAR) compared with the control. Subsequently, by analysis of the enzyme reaction and optimization of the culture medium composition, 637.29 ± 20.35 mg/L DHQ was synthesized from 800 mg/L NAR. This corresponds to a remarkable conversion rate of 71.26%, one of the highest reported values for DHQ synthesis from NAR to date.


Assuntos
Flavanonas , Quercetina/análogos & derivados , Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Flavanonas/metabolismo , Quercetina/química
19.
ACS Appl Mater Interfaces ; 16(10): 12773-12780, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38437709

RESUMO

Tin halide perovskites are rising as promising candidates for next-generation optoelectronic materials due to their good optoelectronic properties and relatively low toxicity. However, the high defect density and the easy oxidation of Sn2+ have limited their optoelectronic performance. Herein, we report the treatment of the FASnI3 (formamidinium tin, FA) perovskite film by a bifunctional cesium fluoride (CsF) additive, which improves the film quality and significantly enhances the photoelectric performance. The responsivity of the perovskite-based photodetector (PD) with an optimal CsF concentration of 15% is over 60 times larger than that of the PD without CsF. It indicates that both the Cs substitution and the fluoride anion additive from CsF inhibit the oxidation of Sn2+, optimize the crystal growth, and passivate the defects, demonstrating the dual roles of the CsF additive in improving the photoelectric performance. This work offers valuable insights into the additive selection for developing high-quality tin-based perovskite films and devices.

20.
J Colloid Interface Sci ; 652(Pt B): 1117-1125, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-37657212

RESUMO

Tailoring surface composition and coordinative environment of catalysts in a nano-meter region often influence their chemical performance. It is reported that CoP exhibits a low dissociation ability of H-OH, originating from the poor desorption of intermediate species. Herein, we provide a feasible method to construct P-Fe2O3-CoP nanosheets through a gas-phase phosphorization process. P doping induces the formation of interfacial structure between Fe2O3 and CoP and the generation of defective structures. The resulting P-Fe2O3-CoP nanosheets afford high freshwater/seawater oxidation activity (250/270 mV@10 mA/cm2) in 1 mol/L (M) KOH, which is even lower than commercial RuO2. Compared with CoP||CoP, P-Fe2O3||P-Fe2O3, and Co3O4||Co3O4, the assembled P-Fe2O3-CoP||P-Fe2O3-CoP exhibits the superior water/seawater electrolysis performance with 1.61/1.65 V@10 mA/cm2. The synergistic effect of P doping, defective structure, and heterojunction leads to high water oxidation efficiency and water splitting efficiency.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA