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1.
Sensors (Basel) ; 19(18)2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31487810

RESUMO

Monitoring of tool wear in machining process has found its importance to predict tool life, reduce equipment downtime, and tool costs. Traditional visual methods require expert experience and human resources to obtain accurate tool wear information. With the development of charge-coupled device (CCD) image sensor and the deep learning algorithms, it has become possible to use the convolutional neural network (CNN) model to automatically identify the wear types of high-temperature alloy tools in the face milling process. In this paper, the CNN model is developed based on our image dataset. The convolutional automatic encoder (CAE) is used to pre-train the network model, and the model parameters are fine-tuned by back propagation (BP) algorithm combined with stochastic gradient descent (SGD) algorithm. The established ToolWearnet network model has the function of identifying the tool wear types. The experimental results show that the average recognition precision rate of the model can reach 96.20%. At the same time, the automatic detection algorithm of tool wear value is improved by combining the identified tool wear types. In order to verify the feasibility of the method, an experimental system is built on the machine tool. By matching the frame rate of the industrial camera and the machine tool spindle speed, the wear image information of all the inserts can be obtained in the machining gap. The automatic detection method of tool wear value is compared with the result of manual detection by high precision digital optical microscope, the mean absolute percentage error is 4.76%, which effectively verifies the effectiveness and practicality of the method.

2.
Mol Cell ; 75(4): 823-834.e5, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31302001

RESUMO

Sirt3, as a major mitochondrial nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, is required for mitochondrial metabolic adaption to various stresses. However, how to regulate Sirt3 activity responding to metabolic stress remains largely unknown. Here, we report Sirt3 as a SUMOylated protein in mitochondria. SUMOylation suppresses Sirt3 catalytic activity. SUMOylation-deficient Sirt3 shows elevated deacetylation on mitochondrial proteins and increased fatty acid oxidation. During fasting, SUMO-specific protease SENP1 is accumulated in mitochondria and quickly de-SUMOylates and activates Sirt3. SENP1 deficiency results in hyper-SUMOylation of Sirt3 and hyper-acetylation of mitochondrial proteins, which reduces mitochondrial metabolic adaption responding to fasting. Furthermore, we find that fasting induces SENP1 translocation into mitochondria to activate Sirt3. The studies on mice show that Sirt3 SUMOylation mutation reduces fat mass and antagonizes high-fat diet (HFD)-induced obesity via increasing oxidative phosphorylation and energy expenditure. Our results reveal that SENP1-Sirt3 signaling modulates Sirt3 activation and mitochondrial metabolism during metabolic stress.

3.
Cancer Res ; 79(15): 3891-3902, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31186231

RESUMO

Myeloid-derived suppressor cells (MDSC) can suppress immunity and promote tumorigenesis, and their abundance is associated with poor prognosis. In this study, we show that SUMO1/sentrin-specific peptidase 1 (SENP1) regulates the development and function of MDSC. SENP1 deficiency in myeloid cells promoted MDSC expansion in bone marrow, spleen, and other organs. Senp1-/- MDSC showed stronger immunosuppressive activity than Senp1+/+ MDSC; we observed no defects in the differentiation of myeloid precursor cell in Senp1-/- mice. Mechanistically, SENP1-mediated regulation of MDSC was dependent on STAT3 signaling. We identified CD45 as a specific STAT3 phosphatase in MDSC. CD45 was SUMOylated in MDSC and SENP1 could deconjugate SUMOylated CD45. In Senp1-/- MDSC, CD45 was highly SUMOylated, which reduced its phosphatase activity toward STAT3, leading to STAT3-mediated MDSC development and function. These results reveal a suppressive function of SENP1 in modulating MDSC expansion and function via CD45-STAT3 signaling axis. SIGNIFICANCE: These findings show that increased SUMOylation of CD45 via loss of SENP1 suppresses CD45-mediated dephosphorylation of STAT3, which promotes MDSC development and function, leading to tumorigenesis.

4.
J Biol Chem ; 294(33): 12339-12348, 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31209108

RESUMO

Hedgehog (Hh) signaling is crucial for establishing complex cellular patterns in embryonic tissues and maintaining homeostasis in adult organs. In Drosophila, Interference hedgehog (Ihog) or its close paralogue Brother of Ihog (Boi) forms a receptor complex with Patched to mediate intracellular Hh signaling. Ihog proteins (Ihog and Boi) also contribute to cell segregation in wing imaginal discs through an unknown mechanism independent of their role in transducing the Hh signal. Here, we report a molecular mechanism by which the Ihog proteins mediate cell-cell interactions. We found that Ihog proteins are enriched at the site of cell-cell contacts and engage in trans-homophilic interactions in a calcium-independent manner. The region that we identified as mediating the trans-Ihog-Ihog interaction overlaps with the Ihog-Hh interface on the first fibronectin repeat of the extracellular domain of Ihog. We further demonstrate that Hh interferes with Ihog-mediated homophilic interactions by competing for Ihog binding. These results, thus, not only reveal a mechanism for Ihog-mediated cell-cell interactions but also suggest a direct Hh-mediated regulation of both intracellular signaling and cell adhesion through Ihog.

5.
J Mol Cell Biol ; 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31169879

RESUMO

Impairment of glucose uptake and storage by skeletal muscle is a prime risk factor for the development of metabolic diseases. Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a highly abundant RNA binding protein that has been implicated in diverse cellular functions. The aim of this study was to investigate the function of hnRNP A1 on muscle tissue insulin sensitivity and systemic glucose homeostasis. Our results showed that conditional deletion of hnRNP A1 in muscle gave rise to a severe insulin resistance phenotype in mice fed a high-fat diet. Conditional knockout mice fed a high-fat diet showed exacerbated obesity, insulin resistance, and hepatic steatosis. In vitro interference of hnRNP A1 in C2C12 myotubes impaired insulin signal transduction and inhibited glucose uptake, whereas hnRNP A1 over-expression in C2C12 myotubes protected against insulin resistance induced by supra-physiological concentrations of insulin. The expression and stability of glycogen synthase (gys1) mRNA were also decreased in the absence of hnRNP A1. Mechanistically, hnRNP A1 interacted with gys1 and stabilized its mRNA, thereby promoting glycogen synthesis and maintaining the insulin sensitivity in muscle tissue. Taken together, our findings are the first to show that reduced expression of hnRNP A1 in skeletal muscle affects that tissue's metabolic properties and systemic insulin sensitivity by inhibiting glycogen synthesis.

6.
Nanoscale ; 11(13): 6228-6234, 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30874699

RESUMO

The strong interaction between transition metal (TM) atoms and semiconductor surface atoms may diminish the magnetic moments of the TM atoms and prevent them from being used as single atom spin-based devices. A carbon cage that can encapsulate TM atoms and isolate them from interacting with surface atoms is considered to protect the magnetic moments of the TM atoms. We have studied the magnetic moments of Fe, Co, and Ni atoms adsorbed inside the corner hole of Si(111)-(7 × 7) by using first-principles calculations based on the density functional theory. The results show that when Co and Ni atoms are directly adsorbed inside the corner hole, the magnetic moments are 1.353µB and 0, respectively. However when a C60 cage is used to encapsulate the atoms, the magnetic moments increase to 1.849µB and 0.884µB, respectively. The results show a clear protecting effect of a carbon cage. For Fe with and without C60, the magnetic moments are 2.909µB and 2.825µB, respectively. The presence of a C60 cage can also maintain their magnetic moments. Further analysis shows that the TM atoms possess magnetic moments when the conduction electrons are localized around them. All the results can be well understood in the framework of the Anderson impurity model. Our results demonstrate that a carbon cage may effectively protect the magnetic moments of TM atoms. This provides a new strategy for developing single atom spin-based devices on semiconductors.

7.
J Food Sci ; 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30461022

RESUMO

The effects of partial enzymatic hydrolysis of soymilk on the characteristics of transglutaminase (TG)-crosslinked tofu gel were studied. SDS-PAGE showed that the molecular weight of the partially hydrolyzed soybean protein was reduced to that of a digested peptide (less than 43.0 kDa) when papain was added at more than 50 µL/100 mL soymilk. The content of free sulfhydryls, ß-sheets, and random coils in papain-treated soymilk increased. When TG was added to soy milk after papain treatment and tofu gel was formed, its storage modulus increased from 957.44 to 1241.39 Pa. The gel strength, water-holding capacity, and nonfreezing water content of the tofu gel were greater than those without enzyme treatment. Scanning electron microscopy revealed that limited papain hydrolysis stimulated TG-catalyzed cross-linking of soymilk to form a dense gel network structure, whereas an extended enzymatic hydrolysis of soymilk did not promote crosslinking by TG. PRACTICAL APPLICATION: This work investigated the effect of partial hydrolysis on TG cross-linked tofu gel. Partial hydrolysis of soybean protein with papain can promote TG cross-linking reaction, thus form a dense network structure, increase gel strength, and water-holding capacity. Therefore, it can be used to produce a good gel product with higher gel strength, springiness, water-holding capacity, and a more dense microstructure.

8.
Br J Pharmacol ; 2018 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-30338847

RESUMO

BACKGROUND AND PURPOSE: Sepsis is a serious clinical condition with a high mortality rate. Anti inflammatory agents have been found to be beneficial for the treatment of sepsis. Here, we have evaluated the anti-inflammatory activity of seselin in models of sepsis and investigated the underlying molecular mechanism(s). EXPERIMENTAL APPROACH: In vivo therapeutic effects of seselin was evaluated in two models of sepsis, caecal ligation and puncture or injection of LPS, in C57BL/6 mice. In vitro, anti-inflammatory activity of seselin was assessed with macrophages stimulated with LPS and IFN-γ. Anti inflammatory actions were analysed with immunohistochemical methods, ELISA and Western blotting. Flow cytometry was used to assess markers of macrophage phenotype (pro- or anti-inflammatory). Other methods used included co-immunoprecipitation, cellular thermal shift assay and molecular docking. KEY RESULTS: In vivo, seselin clearly ameliorated sepsis induced by caecal ligation and puncture. In lung tissue from septic mice and in cultured macrophages, seselin down-regulated levels of proinflammatory factors and activity of STAT1 and p65, the master signal pathway molecules for polarization of macrophages into the proinflammatory phenotype. Importantly, adoptive transfer of bone marrow-derived macrophages, pretreated with seselin, lowered systemic proinflammatory factors in mice challenged with LPS. The underlying mechanism was that seselin targeted Jak2 to block interaction with IFNγ receptors and downstream STAT1. CONCLUSIONS AND IMPLICATIONS: Seselin exhibited anti-inflammatory activity through its action on Jak2. These results indicated a possible application of seselin to the treatment of inflammatory disease via blocking the development of the proinflammatory phenotype of macrophages.

9.
Toxicol Appl Pharmacol ; 360: 249-256, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30290167

RESUMO

BCR-ABL kinase mutations, accounting for clinical resistance to tyrosine kinase inhibitor (TKI) such as imatinib, frequently occur in acquired resistance or in advanced phases of chronic myeloid leukemia (CML). Emerging evidence implicates a critical role for non-mutational drug resistance mechanisms underlying the survival of residual cancer 'persister' cells. Here, we utilized non-mutational imatinib-resistant K562/G cells to reveal SHP-2 as a resistance modulator of imatinib treatment response during the early phase. SHP-2 phosphorylation was significantly higher in K562/G cells than in sensitive K562 cells. In K562 cells, both short-term and long-term exposure to imatinib induced SHP-2 phosphorylation. Consistently, gain- and loss-of-function mutants in SHP-2 proved its regulation of imatinib resistance. SHP-2 inhibitor and imatinib exhibited a strong antitumor synergy in in vitro and in vivo K562/G models. Mechanistically, dual SHP-2 and BCR-ABL inhibition blocked RAF/MEK/ERK and PI3K/AKT/mTOR pathways, respectively, leading to dramatic apoptotic death of K562/G cells. In conclusion, our results highlight that SHP-2 could be exploited as a biomarker and therapeutic target during the early phase of imatinib resistance development in CML.

10.
Nat Commun ; 9(1): 3157, 2018 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-30089837

RESUMO

Regulatory T (Treg) cells are essential for maintaining immune homeostasis and tolerance, but the mechanisms regulating the stability and function of Treg cells have not been fully elucidated. Here we show SUMO-specific protease 3 (SENP3) is a pivotal regulator of Treg cells that functions by controlling the SUMOylation and nuclear localization of BACH2. Treg cell-specific deletion of Senp3 results in T cell activation, autoimmune symptoms and enhanced antitumor T cell responses. SENP3-mediated BACH2 deSUMOylation prevents the nuclear export of BACH2, thereby repressing the genes associated with CD4+ T effector cell differentiation and stabilizing Treg cell-specific gene signatures. Notably, SENP3 accumulation triggered by reactive oxygen species (ROS) is involved in Treg cell-mediated tumor immunosuppression. Our results not only establish the role of SENP3 in the maintenance of Treg cell stability and function via BACH2 deSUMOylation but also clarify the function of SENP3 in the regulation of ROS-induced immune tolerance.

11.
Front Pharmacol ; 9: 761, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30061832

RESUMO

Adenosine monophosphate-activated protein kinase (AMPK), a crucial molecule in energy metabolism, is reported to play a potential role in gut epithelial differentiation and barrier function recently; however, its performance and mechanisms in the pathological process of inflammatory bowel diseases remain unidentified. In this study, we have found that the phosphorylation of AMPK in colonic tissues is negatively correlated with severity of disease during the initiation and development of experimental colitis induced by dextran sulfate sodium. Activation of AMPK by metformin significantly controls the progression of colitis, which is associated with the maintenance of tight junction in colonic epithelium in mice. Moreover, our in vitro data in colonic epithelial Caco2 cells shows that metformin promotes expression and assembly of tight junctions via an AMPK-dependent way. Overall, our results suggested that activating AMPK by a clinically safe drug metformin could be a beneficial choice for colitis treatment.

12.
Science ; 360(6390): 778-783, 2018 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-29773748

RESUMO

Thermoelectric technology enables the harvest of waste heat and its direct conversion into electricity. The conversion efficiency is determined by the materials figure of merit ZT Here we show a maximum ZT of ~2.8 ± 0.5 at 773 kelvin in n-type tin selenide (SnSe) crystals out of plane. The thermal conductivity in layered SnSe crystals is the lowest in the out-of-plane direction [two-dimensional (2D) phonon transport]. We doped SnSe with bromine to make n-type SnSe crystals with the overlapping interlayer charge density (3D charge transport). A continuous phase transition increases the symmetry and diverges two converged conduction bands. These two factors improve carrier mobility, while preserving a large Seebeck coefficient. Our findings can be applied in 2D layered materials and provide a new strategy to enhance out-of-plane electrical transport properties without degrading thermal properties.

13.
Appl Microbiol Biotechnol ; 102(13): 5533-5543, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29691630

RESUMO

Microbial transglutaminase (MTG) from Streptomyces mobaraensis has been widely used for crosslinking proteins in order to acquire products with improved properties. To improve the yield and enable a facile and efficient purification process, recombinant vectors, harboring various heterologous signal peptide-encoding fragments fused to the mtg gene, were constructed in Escherichia coli and then expressed in Bacillus subtilis. Signal peptides of both WapA and AmyQ (SP wapA and SP amyQ ) were able to direct the secretion of pre-pro-MTG into the medium. A constitutive promoter (P hpaII ) was used for the expression of SP wapA -mtg, while an inducible promoter (P lac ) was used for SP amyQ -mtg. After purification from the supernatant of the culture by immobilized metal affinity chromatography and proteolysis by trypsin, 63.0 ± 0.6 mg/L mature MTG was released, demonstrated to have 29.6 ± 0.9 U/mg enzymatic activity and shown to crosslink soy protein properly. This is the first report on secretion of S. mobaraensis MTG from B. subtilis, with similar enzymatic activities and yields to that produced from Escherichia coli, but enabling a much easier purification process.


Assuntos
Bacillus subtilis/genética , Proteínas Recombinantes/metabolismo , Transglutaminases/metabolismo , Bacillus subtilis/metabolismo , Sinais Direcionadores de Proteínas/genética , Streptomyces/enzimologia
14.
Appl Biochem Biotechnol ; 186(1): 217-232, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29552715

RESUMO

The acetic acid bacterium Acetobacter pasteurianus plays an important role in acetic acid fermentation, which involves oxidation of ethanol to acetic acid through the ethanol respiratory chain under specific conditions. In order to obtain more suitable bacteria for the acetic acid industry, A. pasteurianus JST-S screened in this laboratory was compared with A. pasteurianus CICC 20001, a current industrial strain in China, to determine optimal fermentation parameters under different environmental stresses. The maximum total acid content of A. pasteurianus JST-S was 57.14 ± 1.09 g/L, whereas that of A. pasteurianus CICC 20001 reached 48.24 ± 1.15 g/L in a 15-L stir stank. Metabolic flux analysis was also performed to compare the reaction byproducts. Our findings revealed the potential value of the strain in improvement of industrial vinegar fermentation.


Assuntos
Ácido Acético/metabolismo , Acetobacter/metabolismo , Fermentação , Acetobacter/enzimologia , Acetobacter/crescimento & desenvolvimento , Álcool Desidrogenase/metabolismo , Aldeído Desidrogenase/metabolismo , China , Transporte de Elétrons , Etanol/metabolismo , Glucose/metabolismo , Especificidade da Espécie , Estresse Fisiológico
15.
Biochem Pharmacol ; 153: 269-281, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29410374

RESUMO

Methotrexate (MTX) is widely used for rheumatoid arthritis (RA) treatment with frequently serious adverse effects. Therefore, combination of low-dose MTX with other drugs is often used in clinic. In this study, we investigated the improvement of astilbin and low-dose MTX combination on collagen-induced arthritis in DBA/1J mice. Results showed that the clinic score, incidence rate, paw swelling, pathological changes of joints and rheumatoid factors were more alleviated in combination therapy than MTX or astilbin alone group. Elevated antibodies (IgG, IgG1, IgG2a, IgM and anti-collagen IgG) and pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α, IFN-γ and IL-17A) in serum were significantly inhibited, while anti-inflammatory cytokine, IL-10, was enhanced by combination therapy. Further studies indicated that combination therapy significantly decreased Th1 and Th17 cell differentiation and increased Treg cell differentiation. Mechanisms analysis demonstrated combination therapy greatly inhibited Con A-activated MAPK and inflammatory transcriptional signals. Moreover, MTX activated adenosine release and astilbin specifically up-regulated A2A adenosine receptor (A2AAR) expression simultaneously, which most probably contributed to the synergistic efficacy of combination therapy. ZM241385, a specific antagonist of A2AAR, greatly blocked the effects of combination therapy on T cell functions and downstream pathways. All these findings suggest that astilbin is a valuable candidate for low-dose MTX combined therapy in RA via increasing A2AAR/adenosine system and decreasing ERK/NFκB/STATs signals.

16.
Brain Behav Immun ; 68: 111-122, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29017971

RESUMO

Postoperative pain is a common form of acute pain that, if not managed effectively, can become chronic pain. Evidence has shown that glia, especially microglia, mediate neuroinflammation, which plays a vital role in pain sensitization. Moreover, toll-like receptor 4 (TLR4), the tumor necrosis factor receptor (TNF-R), the interleukin-1 receptor (IL-1R), and the interleukin-6 receptor (IL-6R) have been considered key components in central pain sensitization and neuroinflammation. Therefore, we hypothesized that activation of the body's endogenous "immune brakes" will inhibit these receptors and achieve inflammation tolerance as well as relieve postoperative pain. After searching for potential candidates to serve as this immune brake, we identified and focused on the suppressor of cytokine signaling 3 (SOCS3) gene. To regulate SOCS3 expression, we used paeoniflorin to induce heat shock protein 70 (HSP70)/TLR4 signaling. We found that paeoniflorin significantly induced SOCS3 expression both in vitro and in vivo and promoted the efflux of HSP70 from the cytoplasm to the extracellular environment. Furthermore, paeoniflorin markedly attenuated incision-induced mechanical allodynia, and this effect was abolished by small interfering RNAs targeting SOCS3. These findings demonstrated an effective and safe strategy to alleviate postoperative pain.

17.
Appl Biochem Biotechnol ; 184(2): 553-569, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28791562

RESUMO

The use of microorganism fermentation for production of fumaric acid (FA), which is widely used in food, medicine, and other fields, can provide technical support for the FA industry. In this study, we aimed to increase the titer of FA production by using an improved Rhizopus oryzae WHT5, which was domesticated to obtain a furfural-resistant strain in corncob hydrolytes. The metabolic pathways and metabolic network of this strain were investigated, and the related enzymes and metabolic flux were analyzed. Metabolic pathway analysis showed that the R. oryzae WHT5 strain produced FA mainly through two pathways. One occurred in the cytoplasm and the other was a mitochondrial pathway. The key parameters of the fermentation process were analyzed. The FA titer was 49.05 g/L from corncob hydrolytes using R. oryzae WHT5 in a 7-L bioreactor. The use of a furfural-resistant strain developed through domestication effectively increased the titer of FA. This capacity of the microorganisms to produce high amounts of FA by bioconverting corncob hydrolyte can be further applied for industrial production of FA.


Assuntos
Reatores Biológicos , Fumaratos/metabolismo , Rhizopus/crescimento & desenvolvimento , Zea mays/química , Hidrólise
18.
J Phys Chem B ; 122(2): 601-611, 2018 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-28862462

RESUMO

The growth of polycyclic aromatic hydrocarbon (PAH) molecular coronene film on various substrates and the subsequent doping of potassium under ultrahigh vacuum (UHV) conditions have been systematically investigated by low-temperature scanning tunneling microscopy and spectroscopy (STM/STS). The crystalline structures and molecular orientations of coronene thin films are both thickness-dependent and substrate-sensitive due to the competition between molecule-substrate interaction and intermolecular interaction. In mono- or bilayer films, coronene molecules are flat-lying on the surface with hexagonal lattice, whereas in multilayer films, the topmost molecules are in a standing-up but tilted configuration with rectangular lattice. In particular, a 2 × 1 superstructure with respect to that of bulk coronene is formed on thick KCl film. Furthermore, we have studied the potassium doped coronene monolayer and multilayer on Ag(100) and KCl/Ag(100) surface. For K-doped coronene monolayer, at certain doping ratio x = 3, the lowest unoccupied molecular orbital (LUMO) of coronene film moves to the Fermi level, and a splitting of the LUMO state is observed. Increased potassium doping would result in a filled LUMO state below the Fermi level. By contrast, no well-ordered structures are obtained in the K-doped coronene multilayers which are vulnerable to rather moderate annealing processes owing to their relatively weak bonding with the supporting substrates, implying a big challenge of growth of PAH thick films in vacuum. The differences in the crystal structures of coronene thin films compared with that in bulk crystals might shed insight on the controversies in the experimental results on the electronic properties of alkali-metal-doped PAHs.

19.
Cancer Cell ; 32(6): 824-839.e8, 2017 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-29153842

RESUMO

Despite expression of oncogenic KRAS, premalignant pancreatic intraepithelial neoplasia 1 (PanIN1) lesions rarely become fully malignant pancreatic ductal adenocarcinoma (PDAC). The molecular mechanisms through which established risk factors, such as chronic pancreatitis, acinar cell damage, and/or defective autophagy increase the likelihood of PDAC development are poorly understood. We show that accumulation of the autophagy substrate p62/SQSTM1 in stressed KrasG12D acinar cells is associated with PDAC development and maintenance of malignancy in human cells and mice. p62 accumulation promotes neoplastic progression by controlling the NRF2-mediated induction of MDM2, which acts through p53-dependent and -independent mechanisms to abrogate checkpoints that prevent conversion of differentiated acinar cells to proliferative ductal progenitors. MDM2 targeting may be useful for preventing PDAC development in high-risk individuals.


Assuntos
Adenocarcinoma in Situ/patologia , Carcinoma Ductal Pancreático/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Células Acinares/metabolismo , Células Acinares/patologia , Adenocarcinoma in Situ/metabolismo , Animais , Carcinoma Ductal Pancreático/metabolismo , Progressão da Doença , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Pancreáticas/metabolismo , Transdução de Sinais/fisiologia
20.
Biomed Res Int ; 2017: 4734127, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29119107

RESUMO

Santamarine (STM), a sesquiterpene lactone component of Magnolia grandiflora and Ambrosia confertiflora, has been shown to possess antimicrobial, antifungal, antibacterial, anti-inflammatory, and anticancer activities. However, no study has yet been conducted to investigate the molecular mechanism of STM-mediated anticancer activity. In the present study, we found that STM inhibits growth and induces apoptosis in A549 lung adenocarcinoma cells through induction of oxidative stress. STM induces oxidative stress by promoting reactive oxygen species (ROS) generation, depleting intracellular glutathione (GSH), and inhibiting thioredoxin reductase (TrxR) activity in a dose-dependent manner. Further mechanistic study demonstrated that STM induces apoptosis by modulation of Bax/Bcl-2 expressions, disruption of mitochondrial membrane potential, activation of caspase-3, and cleavage of PARP in a dose-dependent manner. Moreover, STM inhibited the constitutive and inducible translocation of NF-κBp65 into the nucleus. IKK-16 (I-κB kinase inhibitor) augmented the STM-induced apoptosis, indicating that STM induces apoptosis in A549 cells at least in part through NF-κB inhibition. Finally, STM-induced apoptosis and expressions of apoptosis regulators were effectively inhibited by thiol antioxidant N-acetyl-L-cysteine (NAC), indicating that STM exerts its anticancer effects mainly through oxidative stress. To the best of our knowledge, this is the first report providing evidence of anticancer activity and molecular mechanism of STM.


Assuntos
Adenocarcinoma/metabolismo , Apoptose/efeitos dos fármacos , Neoplasias Pulmonares/metabolismo , Mitocôndrias/metabolismo , NF-kappa B/metabolismo , Proteínas de Neoplasias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Sesquiterpenos/farmacologia , Células A549 , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Mitocôndrias/patologia , Espécies Reativas de Oxigênio/metabolismo
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