Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 55
Filtrar
2.
Phys Chem Chem Phys ; 24(36): 21638-21644, 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36063076

RESUMO

Although considered as promising candidates for lithium-ion secondary batteries, spinel LiMn2O4 cathodes suffer from significant capacity decay owing to the Jahn-Teller effect, dissolution of Mn and lattice oxygen loss during the charge/discharge process, preventing their wider use. In this work, we realize that F-doping at small concentrations could improve the battery voltage and reduce the capacity decay using an atomistic model. For voltage, F-doping improves the voltage to about 4.4 eV under large delithiation. For capacity decay, it retards capacity decay owing to the reduced lattice oxygen loss. The larger Gibbs free energy of oxygen release after F-doping indicates harder lattice oxygen loss. In addition, although F-doping makes the average valence of Mn lower, the existence of Mn4+ during delithiation exerts a positive effect by reducing the Jahn-Teller effect. However, since the Mn3+ ions in the spinel structure could induce Jahn-Teller distortion, the effect of F-doping on Jahn-Teller distortion is determined by the competition between Mn4+ and Mn3+. The atomistic mechanism of F-doping in the performance of LiMn2O4 offers new insight in developing spinel lithium manganese oxide cathode materials with superior performance.

3.
Cell Commun Signal ; 20(1): 144, 2022 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-36114543

RESUMO

BACKGROUND: Notch signaling is highly conserved and critically involved in cell differentiation, immunity, and survival. Activation of the Notch pathway modulates immune cell functions during the inflammatory response. However, it remains unknown whether and how the macrophage Notch1 may control the innate immune signaling TAK1, and RIPK3-mediated hepatocyte necroptosis in liver ischemia and reperfusion injury (IRI). This study investigated the molecular mechanisms of macrophage Notch1 in modulating TAK1-mediated innate immune responses and RIPK3 functions in liver IRI. METHODS: Myeloid-specific Notch1 knockout (Notch1M-KO) and floxed Notch1 (Notch1FL/FL) mice (n = 6/group) were subjected to 90 min partial liver warm ischemia followed by 6 h of reperfusion. In a parallel in vitro study, bone marrow-derived macrophages (BMMs) were isolated from these conditional knockout mice and transfected with CRISPR/Cas9-mediated ß-catenin knockout (KO) vector followed by LPS (100 ng/ml) stimulation. RESULTS: IR stress-induced Notch1 activation evidenced by increased nuclear Notch intracellular domain (NICD) expression in liver macrophages. Myeloid Notch1 deficiency exacerbated IR-induced liver damage, with increased serum ALT levels, macrophage/neutrophil accumulation, and proinflammatory cytokines/chemokines production compared to the Notch1FL/FL controls. Unlike in the Notch1FL/FL controls, Notch1M-KO enhanced TRAF6, TAK1, NF-κB, RIPK3, and MLKL but reduced ß-catenin activation in ischemic livers. However, adoptive transfer of lentivirus ß-catenin-modified macrophages markedly improved liver function with reduced TRAF6, p-TAK1, RIPK3 and p-MLKL in IR-challenged livers. Moreover, disruption of RIPK3 in Notch1M-KO mice with an in vivo mannose-mediated RIPK3 siRNA delivery system diminished IR-triggered hepatocyte death. In vitro studies showed that macrophage NICD and ß-catenin co-localized in the nucleus, whereby ß-catenin interacted with NICD in response to LPS stimulation. Disruption of ß-catenin with a CRISPR/Cas9-mediated ß-catenin KO in Notch1FL/FL macrophage augmented TRAF6 activation leading to enhanced TAK1 function. While CRISPR/Cas9-mediated TRAF6 KO in Notch1M-KO macrophage inhibited RIPK3-mediated hepatocyte necroptosis after co-culture with primary hepatocytes. CONCLUSIONS: Macrophage Notch1 controls TAK1-mediated innate immune responses and RIPK3-mediated hepatocyte necroptosis through activation of ß-catenin. ß-catenin is required for the macrophage Notch1-mediated immune regulation in liver IRI. Our findings demonstrate that the macrophage Notch1-ß-catenin axis is a crucial regulatory mechanism in IR-triggered liver inflammation and provide novel therapeutic potential in organ IRI and transplant recipients. Video abstract.


Assuntos
Necroptose , Traumatismo por Reperfusão , Animais , Citocinas/metabolismo , Hepatócitos/metabolismo , Isquemia/metabolismo , Lipopolissacarídeos , Fígado/metabolismo , Macrófagos/metabolismo , Manose/metabolismo , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , RNA Interferente Pequeno/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores , Traumatismo por Reperfusão/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , beta Catenina/metabolismo
4.
JHEP Rep ; 4(9): 100532, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36035360

RESUMO

Background & Aims: The stimulator of interferon genes (STING)/TANK-binding kinase 1 (TBK1) pathway is vital in mediating innate immune and inflammatory responses during oxidative/endoplasmic reticulum (ER) stress. However, it remains unknown whether macrophage thioredoxin-interacting protein (TXNIP) may regulate TBK1 function and cell death pathways during oxidative/ER stress. Methods: A mouse model of hepatic ischaemia/reperfusion injury (IRI), the primary hepatocytes, and bone marrow-derived macrophages were used in the myeloid-specific TXNIP knockout (TXNIPM-KO) and TXNIP-proficient (TXNIPFL/FL) mice. Results: The TXNIPM-KO mice were resistant to ischaemia/reperfusion (IR) stress-induced liver damage with reduced serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators compared with the TXNIPFL/FL controls. IR stress increased TXNIP, p-STING, and p-TBK1 expression in ischaemic livers. However, TXNIPM-KO inhibited STING, TBK1, interferon regulatory factor 3 (IRF3), and NF-κB activation with interferon-ß (IFN-ß) expression. Interestingly, TXNIPM-KO augmented nuclear factor (erythroid-derived 2)-like 2 (NRF2) activity, increased antioxidant gene expression, and reduced macrophage reactive oxygen species (ROS) production and hepatic apoptosis/necroptosis in IR-stressed livers. Mechanistically, macrophage TXNIP deficiency promoted cylindromatosis (CYLD), which colocalised and interacted with NADPH oxidase 4 (NOX4) to enhance NRF2 activity by deubiquitinating NOX4. Disruption of macrophage NRF2 or its target gene 2',5' oligoadenylate synthetase-like 1 (OASL1) enhanced Ras GTPase-activating protein-binding protein 1 (G3BP1) and TBK1-mediated inflammatory response. Notably, macrophage OASL1 deficiency induced hepatocyte apoptotic peptidase activating factor 1 (APAF1), cytochrome c, and caspase-9 activation, leading to increased caspase-3-initiated apoptosis and receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated necroptosis. Conclusions: Macrophage TXNIP deficiency enhances CYLD activity and activates the NRF2-OASL1 signalling, controlling IR stress-induced liver injury. The target gene OASL1 regulated by NRF2 is crucial for modulating STING-mediated TBK1 activation and Apaf1/cytochrome c/caspase-9-triggered apoptotic/necroptotic cell death pathway. Our findings underscore a novel role of macrophage TXNIP-mediated CYLD-NRF2-OASL1 axis in stress-induced liver inflammation and cell death, implying the potential therapeutic targets in liver inflammatory diseases. Lay summary: Liver inflammation and injury induced by ischaemia and reperfusion (the absence of blood flow to the liver tissue followed by the resupply of blood) is a significant cause of hepatic dysfunction and failure following liver transplantation, resection, and haemorrhagic shock. Herein, we uncover an underlying mechanism that contributes to liver inflammation and cell death in this setting and could be a therapeutic target in stress-induced liver inflammatory injury.

5.
Nanomaterials (Basel) ; 12(16)2022 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-36014741

RESUMO

Hollow nanoboxes structure have raised great attention as microwave absorption materials on account of their ultralow density and large specific area. By introducing an adjustable interior cavity structure, the dielectric loss and microwave absorption performance were affected by the tunable complex permittivity and impedance matching was improved. In our study, hollow CoS2 nanoboxes with designable interspaces were successfully fabricated based on the surfactant-assisted solution method and followed by an in situ ion-exchange process. The structure, elemental compositions and morphology of the products were characterized by XRD, XPS, EDX, SEM and TEM, respectively. In addition, microwave absorption performance and the intrinsic mechanism are investigated in-depth. The paraffin-based composites with 20 wt.% filling contents exhibited superior microwave absorption capacities in view of both maximum reflection loss value (RLmax, -54.48 dB) and effective absorption bandwidth (EAB, below -10 dB, 6.0 GHz), which can be ascribed to unique hollow structure and good impedance matching. With these considerations in mind, this study provides a reference for the construction of high-performance microwave absorbers with unique hollow structure.

6.
Stem Cell Res Ther ; 13(1): 292, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35841118

RESUMO

BACKGROUND: Improved understanding of the stemness regulation mechanism in intrahepatic cholangiocarcinoma (ICC) could identify targets and guidance for adjuvant transarterial chemoembolization (TACE). METHODS: TCGA database was excavated to identify the ICC stemness-associated genes. The pro-stemness effect of target genes was further analyzed by sphere formation assay, qRT-PCR, western blot, flow cytometric analysis, IHC, CCK8 assay and metabolomic analysis. Based on multivariate analysis, a nomogram for ICC patients with adjuvant TACE was established and our result was further confirmed by a validation cohort. Finally, the effect of dietary methionine intervention on chemotherapy was estimated by in vivo experiment and clinical data. RESULTS: In this study, we identified four ICC stemness-associated genes (SDHAF2, MRPS34, MRPL11, and COX8A) that are significantly upregulated in ICC tissues and negatively associated with clinical outcome. Functional studies indicated that these 4-key-genes are associated with self-renewal ability of ICC and transgenic expression of these 4-key-genes could enhance chemoresistance of cholangiocarcinoma cells. Mechanistically, the 4-key-genes-mediated pro-stemness requires the activation of methionine cycle, and their promotion on ICC stemness characteristic is dependent on MAT2A. Importantly, we established a novel nomogram to evaluate the effectiveness of TACE for ICC patients. Further dietary methionine intervene studies indicated that patients with adjuvant TACE might benefit from dietary methionine restriction if they have a relatively high nomogram score (≥ 135). CONCLUSIONS: Our results show that four ICC stemness-associated genes could serve as novel biomarkers in predicting ICC patient's response to adjuvant TACE and their pro-stemness ability may be attributed to the activation of the methionine cycle.


Assuntos
Neoplasias dos Ductos Biliares , Carcinoma Hepatocelular , Quimioembolização Terapêutica , Colangiocarcinoma , Neoplasias Hepáticas , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/terapia , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Autorrenovação Celular , Quimioembolização Terapêutica/métodos , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/terapia , Humanos , Neoplasias Hepáticas/patologia , Metionina/genética , Metionina Adenosiltransferase/genética
7.
Brain Behav ; 12(7): e2620, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35605060

RESUMO

BACKGROUND: It has been well documented that social isolation stress (SIS) can induce posttraumatic stress disorder (PTSD)-like behavior in rodents, however, the underlying mechanism is remained misunderstood. In the current study, we aimed to elucidate the role of NO/NMDAR pathway in PTSD-like behavior through modulating of astrocyte activity and improvement of oxidative stress. METHODS: Male NMRI mice were used to evaluate the memory function by using Morris water maze (MWM) and fear memory extinction by using freezing response. We used MK-801 (NMDAR-antagonist), L-NNA (NOS-inhibitor), NMDA (NMDAR-agonist), and L-arginine (NO-agent) to find a proper treatment. Also, immunohistochemistry, RT-PCR, and oxidative stress assays were used to evaluate the levels of astrocytes and oxidative stress. We used five mice in each experimental task. RESULTS: Our results revealed that SIS could induce learning and memory dysfunction as well as impairment of fear memory extinction in MWM and freezing response tests, respectively. Also, we observed that combined treatment including blockage of NOS (by L-NNA, 0.5 mg/kg) and NMDAR (by MK-801, 0.001 mg/kg) at subeffective doses could result in improvement of both memory and fear memory. In addition, we observed that SIS significantly increases the GFAP expression and astrocyte activity, which results in significant imbalance in oxidative stress. Coadministration of MK-801 and L-NNA at subeffective doses not only decreases the expression of GFAP, but also regulates the oxidative stress imbalance CONCLUSION: Based on these results, it could be hypothesized that blockage of NO/NMDAR pathway might be a novel treatment for PTSD-like behavior in animals by inhibiting the astrocyte and regulating oxidative stress level.


Assuntos
Transtornos de Estresse Pós-Traumáticos , Animais , Astrócitos/metabolismo , Modelos Animais de Doenças , Maleato de Dizocilpina/farmacologia , Maleato de Dizocilpina/uso terapêutico , Masculino , Camundongos , Estresse Oxidativo , Receptores de N-Metil-D-Aspartato/metabolismo , Isolamento Social , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/metabolismo
8.
Chaos ; 32(1): 013130, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35105115

RESUMO

A visibility graph transforms time series into graphs, facilitating signal processing by advanced graph data mining algorithms. In this paper, based on the classic limited penetrable visibility graph method, we propose a novel mapping method named circular limited penetrable visibility graph, which replaces the linear visibility line in limited penetrable visibility graph with nonlinear visibility arc for pursuing more flexible and reasonable mapping of time series. Tests on degree distribution and some common network features of the generated graphs from typical time series demonstrate that our circular limited penetrable visibility graph can effectively capture the important features of time series and show higher robust classification performance than the traditional limited penetrable visibility graph in the presence of noise. The experiments on real-world time-series datasets of radio and electroencephalogram signals also suggest that the structural features provided by a circular limited penetrable visibility graph, rather than a limited penetrable visibility graph, are more useful for time-series classification, leading to higher accuracy. This classification performance can be further enhanced through structural feature expansion by adopting subgraph networks. All of these results demonstrate the effectiveness of our circular limited penetrable visibility graph model.

9.
Phys Chem Chem Phys ; 23(39): 22423-22429, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34585691

RESUMO

The indirect bandgap of two-dimensional GaN hinders its application in the optical field. Hydrogenation can convert the bandgap type of the GaN monolayer from an indirect to a direct one and also tune the bandgap size. The thermal transport, an important property in the application of two-dimensional materials, is also influenced by hydrogenation. By performing first-principles calculations and solving the phonon Boltzmann equation, we investigate the effect of hydrogenation on the thermal conductivity of the GaN monolayer. The results show that hydrogenation will slightly increase the thermal conductivity of the GaN monolayer from 70.62 Wm-1 K-1 to 76.23 Wm-1 K-1 at 300 K. The little effect of hydrogenation on thermal conductivity is mainly dominated by two competing factors: (1) the reduction of ZA mode lifetime due to the breaking of reflection symmetry after hydrogenation and (2) the increased contribution from TA and LA modes due to the reduction of anharmonic scattering caused by the enlarged phonon bandgap after hydrogenation. The results are compared with other two-dimensional materials with hexagonal monolayer structures.

10.
Nephrology (Carlton) ; 26(11): 872-878, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34482582

RESUMO

PURPOSE: Persistent acute kidney injury (AKI) has been shown to be closely associated with poor prognosis in critical patients. Recent studies have shown that procalcitonin (PCT) is valuable for the early prediction of AKI in critically patients. Our aim was to determine whether PCT and its kinetic changes could predict the occurrence of persistent AKI in critical patients. METHODS: This is a prospective observational study. The definition of AKI was based on the Kidney Disease: Improving Global Outcomes criteria. Persistent AKI was defined as renal function that does not return to baseline serum creatinine levels within 48 h. Blood samples were obtained at the onset of AKI and two subsequent days of hospital stay. 24-h PCT change (ΔPCT-24 h) was defined as 24 h PCT minus baseline PCT (day 0). RESULTS: A total of 91 critical patients with AKI were included in this study. The persistent AKI group had a stepwise increase in PCT concentration. ΔPCT-24 h was higher in the persistent AKI group (p < .01). Logistic regression analysis showed that ΔPCT-24 h (p = .04) was independent predictors of persistent AKI. The receiver operating characteristic curves showed that area under the curve of ΔPCT-24 h was 0.84 (p < .01), and the cut-off value for PCT to predict persistent AKI was 0.56 ng/ml. CONCLUSION: Our study showed that the observation of kinetic changes in PCT is more significant for the early prediction of persistent AKI than the index of PCT at a single time point. ΔPCT-24 h is a good predictor of persistent AKI in critical patients.


Assuntos
Injúria Renal Aguda/sangue , Pró-Calcitonina/sangue , Injúria Renal Aguda/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estado Terminal , Feminino , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos
11.
Exp Ther Med ; 22(5): 1250, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34539846

RESUMO

The clinical characteristics and risk factors of patients with coronavirus disease 2019 (COVID-19) with re-positive or false-negative test results have so far remained to be determined. The present study provides a cross-sectional observational study on 134 hospitalized patients selected from Huoshenshan Hospital (Wuhan, China) using cluster sampling. A total of 68 patients had reduced red blood cell (RBC) counts, 55 a decrease in the hemoglobin concentration (HBC) and 73 a decline in hematocrit (HCT). The false-negative rate of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) RNA detection in pharyngeal swab specimens was 18.7%. The absolute lymphocyte count (ALC), RBC, HBC and HCT levels in false-negative patients were significantly higher than those in patients who tested positive for viral nucleic acids. Multivariate logistic regression analysis indicated that RBC [odds ratio (OR)=0.43, 95% CI: 0.18-0.99], HBC (OR=0.97, 95% CI: 0.94-0.99) and ALC (OR=0.43, 95% CI: 0.20-0.91) were the factors influencing the negative testing results for viral nucleic acid. The rate of re-positive patients was 16.4%. The white blood cell, RBC, HBC and HCT values in re-positive patients were lower than those in non-re-positive patients. The median (interquartile range) values for RBC, HBC and HCT of male re-positive patients were 3.95 (3.37, 4.2) x1012/l, 123 (103, 133) g/l and 36.6 (31.1, 39.2)%, respectively, while the RBC, HBC and HCT of female re-positive patients were 3.54 (3.13, 3.74) x1012/l, 115 (102, 118) g/l and 34.2 (28.5, 34.9)%, respectively. It was determined that RBC, HBC and HCT values had moderate accuracy in predicting SARS-CoV-2 recurrence in patients with COVID-19 using receiver operating curve analysis. The present study suggested that RBC may have an important role in the pathogenesis of COVID-19.

12.
Clin Chim Acta ; 523: 38-44, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34480953

RESUMO

BACKGROUND AND AIMS: The early prediction of the development of acute kidney injury (AKI) in critically ill patients with sepsis would facilitate early effective intervention. Recently, interest has focused on the biomarkers for AKI-linked iron metabolism. This study aimed to assess the early predictive values of hepcidin, neutrophil gelatinase-associated lipocalin (NGAL), and their combination for secondary AKI in patients with sepsis. MATERIALS AND METHODS: A prospective cohort study was performed in septic patients. Serum and urine hepcidin, and urine NGAL were analyzed at admission. The primary outcome measure was occurrence of sepsis-induced AKI based on 2011 Kidney Disease: Improving Global Outcomes (KDIGO) criteria during the first week of ICU stay. RESULTS: Of the 90 patients analyzed finally in the study, 44 (48.9%) patients developed AKI. Patients with AKI occurrence were more likely than those without AKI to have higher serum hepcidin and urine NGAL levels at admission (P < 0.01). Higher concentrations of these biomarkers were each independent predictor of the development of AKI in critically septic patients within the first week of their ICU stay. Serum hepcidin and urine NGAL (AUROC 0.787, 95% CI 0.688 to 0.8660 and AUROC 0.729, 95% CI 0.625 to 0.818, respectively) were comparable predictive indicators of AKI occurrence (P = 0.43 for DeLong's test). Combining both biomarkers increased the AUROC to 0.828(95% CI 0.733 to 0.899), and this performance was statistically significantly better than urine NGAL alone (P = 0.03 for DeLong's test). CONCLUSION: Serum hepcidin measured at admission predicts the development of AKI similarly to urine NGAL. However, serum hepcidin adds significant accuracy to this prediction in combination with urine NGAL alone and has a good predictive value in patients with sepsis. Larger studies are needed to validate and explain these findings.


Assuntos
Injúria Renal Aguda , Sepse , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/etiologia , Biomarcadores , Hepcidinas , Humanos , Lipocalina-2 , Estudos Prospectivos , Sepse/complicações , Sepse/diagnóstico
13.
J Gastroenterol Hepatol ; 36(12): 3469-3476, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34432321

RESUMO

BACKGROUND AND AIMS: Epidemiological studies have shown direct associations between type 2 diabetes and the risk of cancers. Accumulating evidence indicates that metformin is profoundly implicated in preventing tumor development. However, the exact mechanism underlying the antitumor effects of metformin in hepatocellular carcinoma (HCC) is still not clear. METHODS: In this study, we investigated the effects of metformin on a mouse HCC model and interleukin-22 (IL-22)-associated carcinogenesis in vitro. RESULTS: We found that metformin significantly suppressed the incidence and tumor burden of HCC in the diethyl-nitrosamine-induced HCC mouse model. As expected, the expression of IL-22, an important factor involved in HCC progression, was markedly reduced by metformin. Treatment of HCC cells with metformin inhibited IL-22 induced cell proliferation, migration, and invasion, and promoted cell apoptosis. Furthermore, ectopic expression of IL-22 makes HCC more aggressive, whereas metformin largely compromised it in vitro and in vivo. Mechanistically, the whole transcriptome analysis and functional analysis revealed that Hippo signaling pathway was involved in the antitumor ability of metformin. Consistent with this, metformin directly inhibited LATS1/2 and activated Mst1/2, phosphorylated YAP1 in vitro. After blocking the Hippo pathway by XMU-MP-1, the inhibitor of MST1/2, the inhibitory effects by metformin were dramatically attenuated as shown by in vitro study. CONCLUSIONS: Collectively, our findings illuminate a new regulatory mechanism, metformin activates Hippo signaling pathway to regulate IL-22 mediated HCC progression and provide new insights into its tumor-suppressive roles.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Metformina , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/etiologia , Modelos Animais de Doenças , Interleucinas/efeitos adversos , Interleucinas/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/etiologia , Metformina/farmacologia , Camundongos
14.
Front Pharmacol ; 12: 518406, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33994999

RESUMO

Marsdeniae tenacissimae Caulis is a traditional Chinese medicine, named Tongguanteng (TGT), that is often used for the adjuvant treatment of cancer. In our previous study, we reported that an ethyl acetate extract of TGT had inhibitory effects against adenocarcinoma A549 cells growth. To identify the components of TGT with anti-tumor activity and to elucidate their underlying mechanisms of action, we developed a technique for isolating compounds, which was then followed by cytotoxicity screening, network pharmacology analysis, and cellular and molecular experiments. We isolated a total of 19 compounds from a TGT ethyl acetate extract. Two novel steroidal saponins were assessed using an ultra-performance liquid chromatography-photodiode array coupled with quadrupole time-of-flight mass (UPLC-ESI-Q/TOF-MS). Then, we screened these constituents for anti-cancer activity against non-small cell lung cancer (NSCLC) in vitro and obtained six target compounds. Furthermore, a compound-target-pathway network of these six bioactive ingredients was constructed to elucidate the potential pathways that controlled anticancer effects. Approximately 205 putative targets that were associated with TGT, as well as 270 putative targets that were related to NSCLC, were obtained from online databases and target prediction software. Protein-protein interaction networks for drugs as well as disease putative targets were generated, and 18 candidate targets were detected based on topological features. In addition, pathway enrichment analysis was performed to identify related pathways, including PI3K/AKT, VEGF, and EGFR tyrosine kinase inhibitor resistance, which are all related to metabolic processes and intrinsic apoptotic pathways involving reactive oxygen species (ROS). Then, various cellular experiments were conducted to validate drug-target mechanisms that had been predicted using network pharmacology analysis. The experimental results showed the four C21 steroidal saponins could upregulate Bax and downregulate Bcl-2 expression, thereby changing the mitochondrial membrane potential, producing ROS, and releasing cytochrome C, which finally activated caspase-3, caspase-9, and caspase-8, all of which induced apoptosis in A549 cells. In addition, these components also downregulated the expression of MMP-2 and MMP-9 proteins, further weakening their degradation of extracellular matrix components and type IV collagen, and inhibiting the migration and invasion of A549 cells. Our study elucidated the chemical composition and underlying anti-tumor mechanism of TGT, which may be utilized in the treatment of lung cancer.

15.
Front Immunol ; 12: 682736, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995425

RESUMO

Liver diseases represent a major global health burden accounting for approximately 2 million deaths per year worldwide. The liver functions as a primary immune organ that is largely enriched with various innate immune cells, including macrophages, dendritic cells, neutrophils, NK cells, and NKT cells. Activation of these cells orchestrates the innate immune response and initiates liver inflammation in response to the danger signal from pathogens or injured cells and tissues. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a crucial signaling cascade of the innate immune system activated by cytosol DNA. Recognizing DNA as an immune-stimulatory molecule is an evolutionarily preserved mechanism in initiating rapid innate immune responses against microbial pathogens. The cGAS is a cytosolic DNA sensor eliciting robust immunity via the production of cyclic GMP-AMPs that bind and activate STING. Although the cGAS-STING pathway has been previously considered to have essential roles in innate immunity and host defense, recent advances have extended the role of the cGAS-STING pathway to liver diseases. Emerging evidence indicates that overactivation of cGAS-STING may contribute to the development of liver disorders, implying that the cGAS-STING pathway is a promising therapeutic target. Here, we review and discuss the role of the cGAS-STING DNA-sensing signaling pathway in a variety of liver diseases, including viral hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), primary hepatocellular cancer (HCC), and hepatic ischemia-reperfusion injury (IRI), with highlights on currently available therapeutic options.


Assuntos
Suscetibilidade a Doenças , Hepatopatias/etiologia , Hepatopatias/metabolismo , Proteínas de Membrana/metabolismo , Nucleotidiltransferases/metabolismo , Transdução de Sinais , Animais , Transformação Celular Neoplásica , Humanos , Imunidade Inata , Hepatopatias/diagnóstico , Proteínas de Membrana/genética , Nucleotídeos Cíclicos/biossíntese , Nucleotidiltransferases/genética , Ligação Proteica , Transporte Proteico , Fatores de Risco
16.
Clin Nephrol ; 95(6): 303-311, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33835014

RESUMO

PURPOSE: Acute kidney injury (AKI) is a common complication of sepsis and has high mortality. The 2017 Acute Disease Quality Initiative (AQDI) workgroup proposed new definitions for AKI - transient AKI and persistent AKI; however, very little is known about the effect of transient and persistent septic AKI on short-term mortality among critically ill patients with sepsis. The purpose of this study was to assess the impact of persistent AKI on mortality and to evaluate whether serum hepcidin can predict the occurrence of persistent AKI in critically ill patients with sepsis. MATERIALS AND METHODS: This prospective observational study was performed in a general hospital mixed surgical-medical ICU in Pudong, China. Consecutive adults with sepsis admitted to the ICU with absence of chronic kidney disease, renal transplant, and AKI were included. AKI was defined according to the KDIGO criteria and classified as transient (< 48-hour duration) or persistent (48-hour duration). Blood samples were obtained within 6 hours from when AKI was diagnosed. RESULTS: A total of 90 patients with sepsis or septic shock were included in the analysis. 44 (48.89%) patients developed AKI during ICU stay: 20 (45.45%) had transient and 24 (54.55%) had persistent AKI. Persistent AKI has a higher mortality than transient AKI (66.7 vs. 30.0%, p = 0.002). Persistent AKI and sequential organ failure assessment (SOFA) scores were an independent predictor of 60-day mortality. Patients with persistent AKI had higher concentrations of serum creatinine (SCr) and hepcidin than transient AKI patients when AKI was diagnosed. Logistic regression indicated that serum hepcidin was an independent predictor of persistent AKI in septic patients, with a fairly predictive value (AUC 0.71, 95% CI: 0.47 - 0.87; p = 0.02). CONCLUSION: Persistent AKI was associated with increased 60-day mortality compared with transient AKI in septic patients. The serum hepcidin levels measured when AKI was diagnosed have a fair predictive value to predict the occurrence of persistent AKI in septic patients.


Assuntos
Injúria Renal Aguda/etiologia , Hepcidinas/sangue , Sepse/mortalidade , Injúria Renal Aguda/sangue , Idoso , Idoso de 80 Anos ou mais , Estado Terminal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sepse/sangue , Sepse/complicações
17.
Phys Chem Chem Phys ; 23(9): 5431-5437, 2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33646234

RESUMO

Two-dimensional (2D) gallium nitride (GaN) has attracted a lot of attention due to its promising applications in photoelectric nano-devices. Most previous research studies have focused on polar c-plane 2D structures. Here, by employing first principles calculations, we systematically investigate the structural and electronic properties of non-polar m-plane GaN with different numbers of atomic layers. The results show a layer-dependent structure transition and electronic band variation for m-plane GaN. It is found that the monolayer keeps a planar hexagonal structure due to sp2 hybridization, whereas the multilayers are formed by stacking of buckled hexagonal monolayers with unsaturated coordination number at the surface sublayer and bulk-like inner layers. These discrepancies in the structure further induce an indirect to direct transition of the band gap type when the layer number reaches twelve. By carefully examining the relationship between the structure and electronic bandgap, we find that the indirect bandgap comes from the unsaturated surface with a planar like structure. On surface modification, saturation of the surface dangling bonds results in an indirect to direct band gap transition.

18.
Hepatology ; 74(3): 1560-1577, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33765345

RESUMO

BACKGROUND AND AIMS: The cluster of differentiation 47 (CD47)-signal regulatory protein alpha (SIRPα) signaling pathway plays important roles in immune homeostasis and tissue inflammatory response. Activation of the Hedgehog/smoothened (SMO)/GLI family zinc finger 1 (Gli1) pathway regulates cell growth, differentiation, and immune function. However, it remains unknown whether and how the CD47-SIRPα interaction may regulate Hedgehog/SMO/Gli1 signaling in mesenchymal stem cell (MSC)-mediated immune regulation during sterile inflammatory liver injury. APPROACH AND RESULTS: In a mouse model of ischemia/reperfusion (IR)-induced sterile inflammatory liver injury, we found that adoptive transfer of MSCs increased CD47 expression and ameliorated liver IR injury. However, deletion of CD47 in MSCs exacerbated IR-induced liver damage, with increased serum ALT levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators. MSC treatment augmented SIRPα, Hedgehog/SMO/Gli1, and Notch1 intracellular domain (NICD), whereas CD47-deficient MSC treatment reduced these gene expressions in IR-stressed livers. Moreover, disruption of myeloid SMO or Notch1 increased IR-triggered liver inflammation with diminished Gli1 and NICD, but enhanced NIMA related kinase 7 (NEK7) and NLR family pyrin domain containing 3 (NLRP3) activation in MSC-transferred mice. Using a MSC/macrophage co-culture system, we found that MSC CD47 and macrophage SIRPα expression were increased after LPS stimulation. The CD47-SIRPα interaction increased macrophage Gli1 and NICD nuclear translocation, whereby NICD interacted with Gli1 and regulated its target gene Dvl2 (dishevelled segment polarity protein 2), which in turn inhibited NEK7/NLRP3 activity. CONCLUSIONS: The CD47-SIRPα signaling activates the Hedgehog/SMO/Gli1 pathway, which controls NEK7/NLRP3 activity through a direct interaction between Gli1 and NICD. NICD is a coactivator of Gli1, and the target gene Dvl2 regulated by the NICD-Gli1 complex is crucial for the modulation of NLRP3-driven inflammatory response in MSC-mediated immune regulation. Our findings provide potential therapeutic targets in MSC-mediated immunotherapy of sterile inflammatory liver injury.


Assuntos
Antígeno CD47/imunologia , Proteínas Hedgehog/imunologia , Inflamação/imunologia , Fígado/imunologia , Células-Tronco Mesenquimais/imunologia , Receptores Imunológicos/imunologia , Traumatismo por Reperfusão/imunologia , Receptor Smoothened/imunologia , Proteína GLI1 em Dedos de Zinco/imunologia , Alanina Transaminase/sangue , Animais , Proteínas Desgrenhadas/imunologia , Inflamação/metabolismo , Inflamação/patologia , Fígado/metabolismo , Fígado/patologia , Macrófagos/imunologia , Transplante de Células-Tronco Mesenquimais , Camundongos , Quinases Relacionadas a NIMA/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Receptor Notch1/imunologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais
19.
Nat Commun ; 12(1): 1721, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33741925

RESUMO

The stacking sequence of hexagonal close-packed and related crystals typically results in steps on vicinal {0001} surfaces that have alternating A and B structures with different growth kinetics. However, because it is difficult to experimentally identify which step has the A or B structure, it has not been possible to determine which has faster adatom attachment kinetics. Here we show that in situ microbeam surface X-ray scattering can determine whether A or B steps have faster kinetics under specific growth conditions. We demonstrate this for organo-metallic vapor phase epitaxy of (0001) GaN. X-ray measurements performed during growth find that the average width of terraces above A steps increases with growth rate, indicating that attachment rate constants are higher for A steps, in contrast to most predictions. Our results have direct implications for understanding the atomic-scale mechanisms of GaN growth and can be applied to a wide variety of related crystals.

20.
Cell Mol Gastroenterol Hepatol ; 12(2): 567-584, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33766785

RESUMO

BACKGROUND & AIMS: DJ-1 is universally expressed in various tissues and organs and is involved in the physiological processes in various liver diseases. However, the role of DJ-1 in liver ischemia-reperfusion (I/R) injury is largely unknown. METHODS: In this study, we first examined the DJ-1 expression changes in the liver tissues of mice and clinical donor after hepatic I/R by both quantitative polymerase chain reaction and Western blotting assays. Then we investigated the role of DJ-1 in I/R injury by using a murine liver I/R model. RESULTS: We demonstrated that DJ-1 down-regulation in both human and mouse liver tissues in response to I/R injury and Dj-1 deficiency in hepatocytes but not in myeloid cells could significantly ameliorate I/R induced liver injury and inflammatory responses. This hepatoprotective effect was dependent on enhanced autophagy in Dj-1 knockout mice, because inhibition of autophagy by 3-methyladenine and chloroquine could reverse the protective effect on hepatic I/R injury in Dj-1 knockout mice. CONCLUSIONS: Dj-1 deficiency in hepatocytes significantly enhanced mitochondrial accumulation and protein stability of PARKIN, which in turn promotes the onset of mitophagy resulting in elevated clearance of damaged mitochondria during I/R injury.


Assuntos
Hepatócitos/metabolismo , Fígado/metabolismo , Fígado/patologia , Mitofagia , Proteína Desglicase DJ-1/deficiência , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Animais , Autofagia , Regulação para Baixo , Inflamação/patologia , Masculino , Camundongos Knockout , Mitocôndrias/metabolismo , Células Mieloides/metabolismo , Substâncias Protetoras/metabolismo , Proteína Desglicase DJ-1/metabolismo , Estabilidade Proteica , Transporte Proteico , Ubiquitina-Proteína Ligases/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...