RESUMO
OBJECTIVES: Despite advances in the maintenance of arteriovenous fistulas (AVFs), the patency rates remain suboptimal. Most AVFs fail due to outflow vein stenosis; however, the underlying mechanism of AVF stenosis remains unclear. The present study aimed to identify key factors associated with AVF outflow stenosis. METHODS: We obtained gene expression profiling data for the outflow vein of AVF from three Gene Expression Omnibus database datasets (GSE39488, GSE97377, and GSE116268) and analyzed the common differentially expressed genes (DEGs). We evaluated a common DEG in an aortocaval mouse model and the stenotic outflow veins of AVFs collected from patients. Furthermore, we isolated vascular smooth muscle cells (VSMCs) from the inferior vena cava (IVC) of wild-type (WT) and osteopontin (Opn)-knockout (KO) mice and assessed the proliferation of VSMCs following stimulation with platelet-derived growth factors (PDGFs). RESULTS: OPN was the only common upregulated DEG among all datasets. OPN was expressed in the medial layer of the outflow vein of AVF in aortocaval mouse models and co-stained with the VSMC marker (α-smooth muscle actin). OPN expression was markedly increased in the VSMCs of stenotic outflow veins of AVF collected from patients undergoing hemodialysis compared to presurgical veins acquired during AVF formation surgery. PDGF-induced VSMC proliferation was significantly increased in the VSMCs isolated from the IVC of WT mice but not in those isolated from the IVC of Opn-KO mice. CONCLUSIONS: OPN may be a key gene involved in VSMC proliferation in the AVF outflow veins and a therapeutic target to improve the AVF patency rate.
Assuntos
Fístula Arteriovenosa , Derivação Arteriovenosa Cirúrgica , Camundongos , Animais , Músculo Liso Vascular/metabolismo , Derivação Arteriovenosa Cirúrgica/efeitos adversos , Osteopontina/genética , Osteopontina/metabolismo , Constrição Patológica/metabolismo , Fator de Crescimento Derivado de Plaquetas , Proliferação de Células , Fístula Arteriovenosa/metabolismoRESUMO
BACKGROUND: Dexmedetomidine, one of the sedatives, has an analgesic effect. We aimed to investigate postoperative analgesia with dexmedetomidine as adjuvants for procedural sedation using perfusion index (PI). METHODS: In this prospective, randomized, case-control, observational study, 72 adult patients, 19-70 years, who were scheduled for chemoport insertion under monitored anesthesia care were performed. According to the group assignment, remifentanil or dexmedetomidine was simultaneously infused with propofol. The primary outcome was PI 30 min after admission to the post anesthesia care unit (PACU). And, pain severity using numerical rating scale (NRS) score and the relationship between NRS score and PI were investigated. RESULTS: During PACU staying, PI values were significantly different between the two groups PI values at 30 min after admission to the PACU were 1.3 (0.9-2.0) in the remifentanil group and 4.5 (2.9-6.8) in the dexmedetomidine group (median difference, 3; 95% CI, 2.1 to 4.2; P < 0.001). The NRS scores at 30 min after admission to the PACU were significantly lower in the dexmedetomidine group (P = 0.002). However, there was a weak positive correlation between NRS score and PI in the PACU (correlation coefficient, 0.188; P = 0.01). CONCLUSION: We could not find a significant correlation between PI and NRS score for postoperative pain control. Using PI as a single indicator of pain is insufficient. TRIAL REGISTRATION: Clinical Trial Registry of Korea, https://cris.nih.go.kr : KCT0003501, the date of registration: 13/02/2019.
Assuntos
Anestesia , Dexmedetomidina , Propofol , Adulto , Humanos , Remifentanil , Estudos Prospectivos , Índice de Perfusão , Estudos de Casos e ControlesRESUMO
Profilin-1 (PFN1) regulates actin polymerization and cytoskeletal growth. Despite the essential roles of PFN1 in cell integration, its subcellular function in keratinocyte has not been elucidated yet. Here we characterize the specific regulation of PFN1 in DNA damage response and repair machinery. PFN1 depletion accelerated DNA damage-mediated apoptosis exhibiting PTEN loss of function instigated by increased phosphorylated inactivation followed by high levels of AKT activation. PFN1 changed its predominant cytoplasmic localization to the nucleus upon DNA damage and subsequently restored the cytoplasmic compartment during the recovery time. Even though γH2AX was recruited at the sites of DNA double strand breaks in response to DNA damage, PFN1-deficient cells failed to recruit DNA repair factors, whereas control cells exhibited significant increases of these genes. Additionally, PFN1 depletion resulted in disruption of PTEN-AKT cascade upon DNA damage and CHK1-mediated cell cycle arrest was not recovered even after the recovery time exhibiting γH2AX accumulation. This might suggest PFN1 roles in regulating DNA damage response and repair machinery to protect cells from DNA damage. Future studies addressing the crosstalk and regulation of PTEN-related DNA damage sensing and repair pathway choice by PFN1 may further aid to identify new mechanistic insights for various DNA repair disorders.
Assuntos
Distúrbios no Reparo do DNA/genética , Reparo do DNA/genética , Histonas/genética , Profilinas/genética , Actinas/genética , Apoptose/genética , Pontos de Checagem do Ciclo Celular/genética , Quinase 1 do Ponto de Checagem/genética , Citoplasma/genética , Citoesqueleto/genética , Dano ao DNA/genética , Distúrbios no Reparo do DNA/patologia , Humanos , Queratinócitos/metabolismo , Queratinócitos/patologia , Fosforilação/genéticaRESUMO
Pneumonia due to Gram-negative bacteria is associated with high mortality. Acinetobacter baumannii is a Gram-negative bacterium that is associated with hospital-acquired and ventilator-associated pneumonia. Bacteria have been described to release outer membrane vesicles (OMVs) that are capable of mediating systemic inflammation. The mechanism by which A. baumannii OMVs mediate inflammation is not fully defined. We sought to investigate the roles that Toll-like receptors (TLRs) play in A. baumannii OMV-mediated pulmonary inflammation. We isolated OMVs from A. baumannii cultures and intranasally introduced the OMVs into mice. Intranasal introduction of A. baumannii OMVs mediated pulmonary inflammation, which is associated with neutrophil recruitment and weight loss. In addition, A. baumannii OMVs increased the release of several chemokines and cytokines in the mouse lungs. The proinflammatory responses were partially inhibited in TLR2- and TLR4-deficient mice compared to those of wild-type mice. This study highlights the important roles of TLRs in A. baumannii OMV-induced pulmonary inflammation in vivo.
Assuntos
Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/fisiologia , Pneumonia/microbiologia , Vesículas Secretórias/fisiologia , Receptor 2 Toll-Like/fisiologia , Receptor 4 Toll-Like/fisiologia , Infecções por Acinetobacter/metabolismo , Animais , Proteínas da Membrana Bacteriana Externa , Quimiocinas/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , CamundongosRESUMO
TopBP1 was initially identified as a topoisomerase II-ß-binding protein and it plays roles in DNA replication and repair. We found that TopBP1 is expressed at high levels in lymphoid tissues and is essential for early lymphocyte development. Specific abrogation of TopBP1 expression resulted in transitional blocks during early lymphocyte development. These defects were, in major part, due to aberrant V(D)J rearrangements in pro-B cells, double-negative and double-positive thymocytes. We also show that TopBP1 was located at sites of V(D)J rearrangement. In TopBP1-deficient cells, γ-H2AX foci were found to be increased. In addition, greater amount of γ-H2AX product was precipitated from the regions where TopBP1 was localized than from controls, indicating that TopBP1 deficiency results in inefficient DNA double-strand break repair. The developmental defects were rescued by introducing functional TCR αß transgenes. Our data demonstrate a novel role for TopBP1 as a crucial factor in V(D)J rearrangement during the development of B, T and iNKT cells.
Assuntos
Proteínas de Transporte/genética , Reparo do DNA , DNA/genética , Linfócitos/fisiologia , Recombinação V(D)J/imunologia , Animais , Proteínas de Transporte/imunologia , Proteínas de Transporte/metabolismo , Imunoprecipitação da Cromatina , Quebras de DNA de Cadeia Dupla , Dano ao DNA , Expressão Gênica , Histonas/genética , Histonas/metabolismo , Linfócitos/imunologia , Camundongos , Camundongos Knockout , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/fisiologia , Células Precursoras de Linfócitos B/imunologia , Células Precursoras de Linfócitos B/fisiologia , Deleção de Sequência , Organismos Livres de Patógenos Específicos , Transgenes , Recombinação V(D)J/genéticaRESUMO
The julolidine based interfacial modifier (IM-J) for cathode buffer layer following the "donor-acceptor" design concept with julolidine substituent as an electron donating moiety was incoporated to improve the surface properties of ZnO. Simple treatment of metal oxide type cathode buffer materials with organic interfacial modifier induces the enhanced photovoltaic performance and could effectively overcome several interfacial problems in inverted organic photovoltaic cells (I-OPVs). We studied on the coverage of IM-J on ZnO surface with variation of solution concentrations to reduce charge recombination and macroscopic phase separation. At the optimum condition, ZnO/IM-J (0.05 w/v%), IM-J significantly decreased the surface tension (46.1 mN/m) and improved surface morphology (RMS roughness: 0.61 nm). As a result, compared to the unmodified ZnO based device, the ZnO/IM-J based I-OPVs showed significantly improved power conversion efficiency (PCE) from 7.41 to 8.07% due to the increased photocurrent density (Jsc) and fill factor (FF). It is concluded that IM-J is one of the promising candidates for controlling electronic property of ZnO buffer layer in inverted organic photovoltaic cells. Also, our interfacial modified system can be utilized in other optoelectronic devices.
RESUMO
Botulinum toxin type A (BoNT/A) has been used therapeutically for various conditions including dystonia, cerebral palsy, wrinkle, hyperhidrosis and pain control. The substantia gelatinosa (SG) neurons of the trigeminal subnucleus caudalis (Vc) receive orofacial nociceptive information from primary afferents and transmit the information to higher brain center. Although many studies have shown the analgesic effects of BoNT/A, the effects of BoNT/A at the central nervous system and the action mechanism are not well understood. Therefore, the effects of BoNT/A on the spontaneous postsynaptic currents (sPSCs) in the SG neurons were investigated. In whole cell voltage clamp mode, the frequency of sPSCs was increased in 18 (37.5%) neurons, decreased in 5 (10.4%) neurons and not affected in 25 (52.1%) of 48 neurons tested by BoNT/A (3 nM). Similar proportions of frequency variation of sPSCs were observed in 1 and 10 nM BoNT/A and no significant differences were observed in the relative mean frequencies of sPSCs among 1-10 nM BoNT/A. BoNT/A-induced frequency increase of sPSCs was not affected by pretreated tetrodotoxin (0.5 µM). In addition, the frequency of sIPSCs in the presence of CNQX (10 µM) and AP5 (20 µM) was increased in 10 (53%) neurons, decreased in 1 (5%) neuron and not affected in 8 (42%) of 19 neurons tested by BoNT/A (3 nM). These results demonstrate that BoNT/A increases the frequency of sIPSCs on SG neurons of the Vc at least partly and can provide an evidence for rapid action of BoNT/A at the central nervous system.
RESUMO
Hyaluronic acid (HA) has an immediate volumizing effect, due to its strong water-binding potential, and stimulates fibroblasts, causing collagen synthesis, with short- and long-term effects on wrinkle improvement. We investigated the efficacy and safety of HA microneedle patches for crow's feet wrinkles. Using a randomized spilt-face design, we compared microneedle patches with a topical application containing the same active ingredients. We enrolled 34 Korean female subjects with mild to moderate crow's feet wrinkles. The wrinkle on each side of the subject's face was randomly assigned to a HA microneedle patch or HA essence application twice a week for 8 weeks. Efficacy was evaluated at weeks 2, 4, and 8. Skin wrinkles were measured as average roughness using replica and PRIMOS. Skin elasticity was assessed using a cutometer. Two independent blinded dermatologists evaluated the changes after treatment using the global visual wrinkle assessment score. Subjects assessed wrinkles using the subject global assessment score. Skin wrinkles were significantly reduced and skin elasticity significantly increased in both groups, although improvement was greater in the patch group at week 8 after treatment. In the primary and cumulative skin irritation tests, the HA microneedle patch did not induce any skin irritation. The HA microneedle patch is more effective than the HA essence for wrinkle improvement and is a safe and convenient without skin irritation.
Assuntos
Técnicas Cosméticas/instrumentação , Preenchedores Dérmicos/administração & dosagem , Ácido Hialurônico/administração & dosagem , Miniaturização , Agulhas , Rejuvenescimento , Envelhecimento da Pele , Adulto , Técnicas Cosméticas/efeitos adversos , Preenchedores Dérmicos/efeitos adversos , Desenho de Equipamento , Estética , Feminino , Humanos , Ácido Hialurônico/efeitos adversos , Injeções Intradérmicas , Pessoa de Meia-Idade , Satisfação do Paciente , República da Coreia , Fatores de Tempo , Resultado do TratamentoRESUMO
Small molecular donor, DTDCTB achieved a high power conversion efficiency (PCE) value of 6.6 ± 0.2% in vacuum-deposited planar mixed heterojunction (PMHJ) structure. However, the same material just recorded PCE of 0.34% in solution processed small molecule based bulk heterjunction (BHJ) organic photovoltaic cells. For the improvement of organic photovoltaic cells (OPVs), In this study, we designed and synthesized several D-A-A (donor-acceptor-acceptor) type molecular electron donating materials. Ditolylaminothienyl moiety as an electron donating group connected to 1,2,5-benzothiadiazole as a conjugated electron accepting unit, simultaneously with an electron accepting terminal group such as cyano alkyl acetate and N-alkyl rhodanine. The thermal, photophysical, and electrochemical properties of prepared small molecules were investigated by DSC, UV/Vis spectroscopy and Cyclic Voltametry, respectively. As a result, 0.89% of PCE can be obtained from OPV using a mixture of DTATBTER and PCBM as an active layer with a Voc of 0.87 V, a Jsc of 3.20 mA/cm2, and a fill factor of 31.9%.
Assuntos
Fontes de Energia Elétrica , Espectroscopia de Prótons por Ressonância Magnética , Espectrofotometria UltravioletaRESUMO
Organic photovoltaic Cells (OPVs) have been considered to be a next-generation energy source to overcome exhaustion of resources. Currently, OPVs are developed based on two types of donor material with polymer and small molecule. Polymeric donor materials have shown better power conversion efficiency (PCE) than small molecular donor materials, since it's easy to control the morphology of photoactive film. However, the difficulty in synthetic reproducibility and purification of polymeric donor were main drawback to overcome. And then, recently small molecule donor materials have been overcome bad morphology of OPVs film by using appropriate alkyl substituents and relatively long conjugation system. In this study, we designed and synthesized D-A-D-A-D type small molecular donor materials containing alternatively linked benzodithiophene (BDT) and diketopyrrolopyrrole (DPP) units. Also, we studied on the effect of photovoltaic performance of prepared small molecular D-A-D-A-D type donor with variation of thiophene links and with/without hexyl substituent. Our small molecular donors showed HOMO energy levels from -5.26 to -5.34 eV and optical bandgaps from 1.70 to 1.87 eV by CV (cyclic voltammetry) and UV/Vis spectroscopy, respectively. Finally, 3.4% of PCE can be obtained using a mixture of BDT(DPP)2-T2 and PCBM as an active layer with a Voc of 0.78 V, a Jsc of 9.72 mA/cm2, and a fill factor of 0.44 under 100 mW/cm2 AM 1.5G simulated light. We will discuss the performance of D-A-D-A-D type small molecular donor based OPVs with variation of both terminal substituents.
Assuntos
Cetonas/química , Pirróis/química , Tiofenos/química , Microscopia de Força Atômica , Espectroscopia de Prótons por Ressonância MagnéticaRESUMO
Complex organisms may coordinate molecular responses to hypoxia by specialized avenues of communication across multiple tissues, but these mechanisms are poorly understood. Plasma-based, extracellular microRNAs have been described, yet their regulation and biological functions in hypoxia remain enigmatic. We found a unique pattern of release of the hypoxia-inducible microRNA-210 (miR-210) from hypoxic and reoxygenated cells. This microRNA is also elevated in human plasma in physiologic and pathologic conditions of altered oxygen demand and delivery. Released miR-210 can be delivered to recipient cells, and the suppression of its direct target ISCU and mitochondrial metabolism is primarily evident in hypoxia. To regulate these hypoxia-specific actions, prolyl-hydroxylation of Argonaute 2 acts as a molecular switch that reciprocally modulates miR-210 release and intracellular activity in source cells as well as regulates intracellular activity in recipient cells after miR-210 delivery. Therefore, Argonaute 2-dependent control of released miR-210 represents a unique communication system that integrates the hypoxic response across anatomically distinct cells, preventing unnecessary activity of delivered miR-210 in normoxia while still preparing recipient tissues for incipient hypoxic stress and accelerating adaptation.
RESUMO
During the process of B cell development, transcription factors, such as E2A and Ebf1, have been known to play key roles. Although transcription factors and chromatin regulators work in concert to direct the expression of B lineage-specific genes, little is known about the involvement of regulators for chromatin structure during B lymphopoiesis. In this article, we show that deletion of Srg3/mBaf155, a scaffold subunit of the SWI/SNF-like BAF complex, in the hematopoietic lineage caused defects at both the common lymphoid progenitor stage and the transition from pre-pro-B to early pro-B cells due to failures in the expression of B lineage-specific genes, such as Ebf1 and Il7ra, and their downstream target genes. Moreover, mice that were deficient in the expression of Brg1, a subunit of the complex with ATPase activity, also showed defects in early B cell development. We also found that the expression of Ebf1 and Il7ra is directly regulated by the SWI/SNF-like BAF complex. Thus, our results suggest that the SWI/SNF-like BAF complex facilitates early B cell development by regulating the expression of B lineage-specific genes.
Assuntos
Diferenciação Celular/imunologia , Cromatina/imunologia , Proteínas Cromossômicas não Histona/imunologia , Células Precursoras de Linfócitos B/imunologia , Fatores de Transcrição/imunologia , Proteínas E2 de Adenovirus/genética , Proteínas E2 de Adenovirus/imunologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Diferenciação Celular/genética , Linhagem da Célula/imunologia , Cromatina/genética , Proteínas Cromossômicas não Histona/deficiência , Proteínas Cromossômicas não Histona/genética , DNA Helicases/deficiência , DNA Helicases/genética , DNA Helicases/imunologia , Regulação da Expressão Gênica , Camundongos , Camundongos Knockout , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Proteínas Nucleares/imunologia , Poli I-C/farmacologia , Células Precursoras de Linfócitos B/citologia , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/imunologia , Transdução de Sinais , Transativadores/genética , Transativadores/imunologia , Fatores de Transcrição/deficiência , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: Liver transplantation (LT) increases the heart and vessel workload in patients with cirrhotic cardiomyopathy. While the interaction of the left ventricle (LV) with the arterial system (ventriculoarterial coupling, VAC) is a key determinant of cardiovascular performance, little is known about changes in VAC after LT. Therefore, we evaluated the relationship between VAC after LT and cardiovascular outcomes. METHODS: 344 consecutive patients underwent echocardiographic assessments before and within 30 days after LT. Non-invasive arterial elastance (Ea), LV end-systolic elastance (Ees), and LV end-diastolic elastance (Eed) were calculated. The postoperative outcomes included the development of major adverse cardiovascular events (MACE) and the length of stay in the intensive care unit and hospital. RESULTS: A total of 240 patients were included in the analyses. After LT, Ea increased by 16% (P < 0.001), and Ees and contractility index of systolic velocity (S') increased by 18% (P < 0.001) and 7% (P < 0.001), respectively. The Eed increased by 6% (P < 0.001). The VAC remained unchanged (0.56 to 0.56, P = 0.912). Of these patients, 29 had MACE, and those with MACE had significantly higher postoperative VAC. Additionally, a higher postoperative VAC was an independent risk factor for a longer postoperative hospital stay (P = 0.038). CONCLUSIONS: These data suggest that ventriculoarterial decoupling is associated with poor postoperative outcomes after LT.
Assuntos
Transplante de Fígado , Humanos , Ventrículos do Coração/diagnóstico por imagem , EcocardiografiaRESUMO
This work highlights the novel approach of incorporating potassium iodide (KI) doping during the synthesis of In0.53P0.47 core quantum dots (QDs) to significantly reduce the concentration of vacancies (i.e., In vacancies; VIn-) within the bulk of the core QD and inhibit the formation of InPOx at the core QD-Zn0.6Se0.4 shell interfaces. The photoluminescence quantum yield (PLQY) of ~97% and full width at half maximum (FWHM) of ~40 nm were achieved for In0.53P0.47/Zn0.6Se0.4/Zn0.6Se0.1S0.3/Zn0.5S0.5 core/multi-shell QDs emitting red light, which is essential for a quantum-dot organic light-emitting diode (QD-OLED) without red, green, and blue crosstalk. KI doping eliminated VIn- in the core QD bulk by forming K+-VIn- substitutes and effectively inhibited the formation of InPO4(H2O)2 at the core QD-Zn0.6Se0.4 shell interface through the passivation of phosphorus (P)-dangling bonds by P-I bonds. The elimination of vacancies in the core QD bulk was evidenced by the decreased relative intensity of non-radiative unpaired electrons, measured by electron spin resonance (ESR). Additionally, the inhibition of InPO4(H2O)2 formation at the core QD and shell interface was confirmed by the absence of the {210} X-ray diffraction (XRD) peak intensity for the core/multi-shell QDs. By finely tuning the doping concentration, the optimal level was achieved, ensuring maximum K-VIn- substitution, minimal K+ and I- interstitials, and maximum P-dangling bond passivation. This resulted in the smallest core QD diameter distribution and maximized optical properties. Consequently, the maximum PLQY (~97%) and minimum FWHM (~40 nm) were observed at 3% KI doping. Furthermore, the color gamut of a QD-OLED display using R-, G-, and B-QD functional color filters (i.e., ~131.1%@NTSC and ~98.2@Rec.2020) provided a nearly perfect color representation, where red-light-emitting KI-doped QDs were applied.
RESUMO
BACKGROUND: Hypoxia induces an inflammatory response in the lung manifested by alternative activation of macrophages with elevation of proinflammatory mediators that are critical for the later development of hypoxic pulmonary hypertension. Mesenchymal stromal cell transplantation inhibits lung inflammation, vascular remodeling, and right heart failure and reverses hypoxic pulmonary hypertension in experimental models of disease. In this study, we aimed to investigate the paracrine mechanisms by which mesenchymal stromal cells are protective in hypoxic pulmonary hypertension. METHODS AND RESULTS: We fractionated mouse mesenchymal stromal cell-conditioned media to identify the biologically active component affecting in vivo hypoxic signaling and determined that exosomes, secreted membrane microvesicles, suppressed the hypoxic pulmonary influx of macrophages and the induction of proinflammatory and proproliferative mediators, including monocyte chemoattractant protein-1 and hypoxia-inducible mitogenic factor, in the murine model of hypoxic pulmonary hypertension. Intravenous delivery of mesenchymal stromal cell-derived exosomes (MEX) inhibited vascular remodeling and hypoxic pulmonary hypertension, whereas MEX-depleted media or fibroblast-derived exosomes had no effect. MEX suppressed the hypoxic activation of signal transducer and activator of transcription 3 (STAT3) and the upregulation of the miR-17 superfamily of microRNA clusters, whereas it increased lung levels of miR-204, a key microRNA, the expression of which is decreased in human pulmonary hypertension. MEX produced by human umbilical cord mesenchymal stromal cells inhibited STAT3 signaling in isolated human pulmonary artery endothelial cells, demonstrating a direct effect of MEX on hypoxic vascular cells. CONCLUSION: This study indicates that MEX exert a pleiotropic protective effect on the lung and inhibit pulmonary hypertension through suppression of hyperproliferative pathways, including STAT3-mediated signaling induced by hypoxia.
Assuntos
Exossomos/fisiologia , Hipertensão Pulmonar/patologia , Hipóxia/patologia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Animais , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Modelos Animais de Doenças , Exossomos/metabolismo , Fibroblastos/citologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/prevenção & controle , Humanos , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/terapia , Hipóxia/fisiopatologia , Hipóxia/terapia , Células-Tronco Mesenquimais/metabolismo , Camundongos , MicroRNAs/genética , Comunicação Parácrina/fisiologia , Pneumonia/patologia , Pneumonia/fisiopatologia , Pneumonia/terapia , Fator de Transcrição STAT3/metabolismo , Geleia de Wharton/citologiaRESUMO
BACKGROUND: Postpartum hemorrhage (PPH) is a leading cause of maternal morbidity and mortality. Twin pregnancy and cesarean delivery are well-known risk factors for PPH. However, few studies have investigated PPH risk factors in mothers who have undergone cesarean delivery for twin pregnancies. Therefore, this study investigated the risk factors associated with severe PPH after cesarean delivery for twin pregnancies. METHODS: We searched and reviewed the Korean Health Insurance Review and Assessment Service's claims data from July 2008 to June 2021 using the code corresponding to cesarean delivery for twin pregnancy. Severe PPH was defined as hemorrhage requiring red blood cell (RBC) transfusion during the peripartum period. The risk factors associated with severe PPH were identified among the procedure and diagnosis code variables and analyzed using univariate and multivariate logistic regressions. RESULTS: We analyzed 31,074 cesarean deliveries for twin pregnancies, and 4,892 patients who underwent cesarean deliveries for twin pregnancies and received RBC transfusions for severe PPH were included. According to the multivariate analysis, placental disorders (odds ratio, 4.50; 95% confidence interval, 4.09- 4.95; P < 0.001), general anesthesia (2.33, 2.18-2.49; P < 0.001), preeclampsia (2.20, 1.99-2.43; P < 0.001), hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome (2.12, 1.22-3.68; P = 0.008), induction failure (1.37, 1.07-1.76; P = 0.014), and hypertension (1.31, 1.18-1.44; P < 0.001) predicted severe PPH. CONCLUSIONS: Placental disorders, hypertensive disorders such as preeclampsia and HELLP syndrome, and induction failure increased the risk of severe PPH after cesarean delivery for twin pregnancy.
RESUMO
Recently, the development of non-fullerene acceptors (NFAs) for near-infrared (NIR) organic photodetectors (OPDs) has attracted great interest due to their excellent NIR light absorption properties. Herein, we developed NFAs by substituting an electron-donating moiety (branched alkoxy thiophene (BAT)) asymmetrically (YOR1) and symmetrically (YOR2) for the Y6 framework. YOR1 exhibited nanoscale phase separation in a film blended with PTB7-Th. Moreover, substituting the BAT unit effectively extended the absorption wavelengths of YOR1 over 1000 nm by efficient intramolecular charge transfer and extension of the conjugation length. Consequently, YOR1-OPD exhibited significantly reduced dark current and improved responsivity by simultaneously satisfying optimal nanomorphology and significant suppression of charge recombination, resulting in 1.98 × 1013 and 3.38 × 1012 Jones specific detectivity at 950 and 1000 nm, respectively. Moreover, we successfully demonstrated the application of YOR1-OPD in highly sensitive photoplethysmography sensors using NIR light. This study suggests a strategic approach for boosting the overall performance of NIR OPDs targeting a 1000 nm light signal using an all-in-one (optimal morphology, suppressed dark current, and extended NIR absorption wavelength) NFA.
RESUMO
Despite the capability of extracellular vesicles (EVs) derived from Gram-negative and Gram-positive bacteria to induce potent anti-tumour responses, large-scale production of bacterial EVs remains as a hurdle for their development as novel cancer immunotherapeutic agents. Here, we developed manufacturing processes for mass production of Escherichia coli EVs, namely, outer membrane vesicles (OMVs). By combining metal precipitation and size-exclusion chromatography, we isolated 357 mg in total protein amount of E. coli OMVs, which was equivalent to 3.93 × 1015 particles (1.10 × 1010 particles/µg in total protein amounts of OMVs) from 160 L of the conditioned medium. We show that these mass-produced E. coli OMVs led to complete remission of two mouse syngeneic tumour models. Further analysis of tumour microenvironment in neoantigen-expressing tumour models revealed that E. coli OMV treatment causes increased infiltration and activation of CD8+ T cells, especially those of cancer antigen-specific CD8+ T cells with high expression of TCF-1 and PD-1. Furthermore, E. coli OMVs showed synergistic anti-tumour activity with anti-PD-1 antibody immunotherapy, inducing substantial tumour growth inhibition and infiltration of activated cancer antigen-specific stem-like CD8+ T cells into the tumour microenvironment. These data highlight the potent anti-tumour activities of mass-produced E. coli OMVs as a novel candidate for developing next-generation cancer immunotherapeutic agents.
Assuntos
Vesículas Extracelulares , Neoplasias , Animais , Camundongos , Escherichia coli/metabolismo , Vesículas Extracelulares/química , Membrana Externa Bacteriana/metabolismo , Linfócitos T CD8-Positivos , Imunoterapia , Neoplasias/terapia , Neoplasias/metabolismoRESUMO
BACKGROUND: Lung inflammation precedes the development of hypoxia-induced pulmonary hypertension (HPH); however, its role in the pathogenesis of HPH is poorly understood. We sought to characterize the hypoxic inflammatory response and to elucidate its role in the development of HPH. We also aimed to investigate the mechanisms by which heme oxygenase-1, an anti-inflammatory enzyme, is protective in HPH. METHODS AND RESULTS: We generated bitransgenic mice that overexpress human heme oxygenase-1 under doxycycline control in an inducible, lung-specific manner. Hypoxic exposure of mice in the absence of doxycycline resulted in early transient accumulation of monocytes/macrophages in the bronchoalveolar lavage. Alveolar macrophages acquired an alternatively activated phenotype (M2) in response to hypoxia, characterized by the expression of found in inflammatory zone-1, arginase-1, and chitinase-3-like-3. A brief 2-day pulse of doxycycline delayed, but did not prevent, the peak of hypoxic inflammation, and could not protect against HPH. In contrast, a 7-day doxycycline treatment sustained high heme oxygenase-1 levels during the entire period of hypoxic inflammation, inhibited macrophage accumulation and activation, induced macrophage interleukin-10 expression, and prevented the development of HPH. Supernatants from hypoxic M2 macrophages promoted the proliferation of pulmonary artery smooth muscle cells, whereas treatment with carbon monoxide, a heme oxygenase-1 enzymatic product, abrogated this effect. CONCLUSIONS: Early recruitment and alternative activation of macrophages in hypoxic lungs are critical for the later development of HPH. Heme oxygenase-1 may confer protection from HPH by effectively modifying the macrophage activation state in hypoxia.
Assuntos
Heme Oxigenase-1/imunologia , Hipertensão Pulmonar/imunologia , Hipóxia/imunologia , Ativação de Macrófagos/imunologia , Macrófagos Alveolares/imunologia , Animais , Dióxido de Carbono/metabolismo , Divisão Celular/imunologia , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Hipertensão Pulmonar/patologia , Hipóxia/patologia , Interleucina-10/metabolismo , Macrófagos Alveolares/patologia , Camundongos , Camundongos Transgênicos , Monócitos/imunologia , Monócitos/patologia , Músculo Liso Vascular/imunologia , Músculo Liso Vascular/patologia , Pneumonia/imunologia , Pneumonia/patologia , Artéria Pulmonar/imunologia , Artéria Pulmonar/patologia , Ativação Transcricional/imunologiaRESUMO
Pulmonary arterial hypertension (PAH) remains a serious disease, and although current treatments may prolong and improve quality of life, search for novel and effective therapies is warranted. Using genetically modified mouse lines, we tested the ability of bone marrow-derived stromal cells (mesenchymal stem cells [MSCs]) to treat chronic hypoxia-induced PAH. Recipient mice were exposed for 5 weeks to normobaric hypoxia (8%-10% O(2)), MSC preparations were delivered through jugular vein injection and their effect on PAH was assessed after two additional weeks in hypoxia. Donor MSCs derived from wild-type (WT) mice or heme oxygenase-1 (HO-1) null mice (Hmox1(KO)) conferred partial protection from PAH when transplanted into WT or Hmox1(KO) recipients, whereas treatment with MSCs isolated from transgenic mice harboring a human HO-1 transgene under the control of surfactant protein C promoter (SH01 line) reversed established disease in WT recipients. SH01-MSC treatment of Hmox1(KO) animals, which develop right ventricular (RV) infarction under prolonged hypoxia, resulted in normal RV systolic pressure, significant reduction of RV hypertrophy and prevention of RV infarction. Donor MSCs isolated from a bitransgenic mouse line with doxycycline-inducible, lung-specific expression of HO-1 exhibited similar therapeutic efficacy only on doxycycline treatment of the recipients. In vitro experiments indicate that potential mechanisms of MSC action include modulation of hypoxia-induced lung inflammation and inhibition of smooth muscle cell proliferation. Cumulatively, our results demonstrate that MSCs ameliorate chronic hypoxia-induced PAH and their efficacy is highly augmented by lung-specific HO-1 expression in the transplanted cells, suggesting an interplay between HO-1-dependent and HO-1-independent protective pathways.